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Sample records for releasing hormone receptor

  1. Estradiol potentiation of gonadotropin-releasing hormone responsiveness in the anterior pituitary is mediated by an increase in gonadotropin-releasing hormone receptors

    International Nuclear Information System (INIS)

    Menon, M.; Peegel, H.; Katta, V.

    1985-01-01

    In order to investigate the mechanism by which 17 beta-estradiol potentiates the action of gonadotropin-releasing hormone on the anterior pituitary in vitro, cultured pituitary cells from immature female rats were used as the model system. Cultures exposed to estradiol at concentrations ranging from 10(-10) to 10(-6) mol/L exhibited a significant augmentation of luteinizing hormone release in response to a 4-hour gonadotropin-releasing hormone (10 mumol/L) challenge at a dose of 10(-9) mol/L compared to that of control cultures. The estradiol augmentation of luteinizing hormone release was also dependent on the duration of estradiol exposure. When these cultures were incubated with tritium-labeled L-leucine, an increase in incorporation of radiolabeled amino acid into total proteins greater than that in controls was observed. A parallel stimulatory effect of estradiol on iodine 125-labeled D-Ala6 gonadotropin-releasing hormone binding was observed. Cultures incubated with estradiol at different concentrations and various lengths of time showed a significant increase in gonadotropin-releasing hormone binding capacity and this increase was abrogated by cycloheximide. Analysis of the binding data showed that the increase in gonadotropin-releasing hormone binding activity was due to a change in the number of gonadotropin-releasing hormone binding sites rather than a change in the affinity. These results suggest that (1) estradiol treatment increases the number of pituitary receptors for gonadotropin-releasing hormone, (2) the augmentary effect of estradiol on luteinizing hormone release at the pituitary level might be mediated, at least in part, by the increase in the number of binding sites of gonadotropin-releasing hormone, and (3) new protein synthesis may be involved in estradiol-mediated gonadotropin-releasing hormone receptor induction

  2. Diseases associated with growth hormone-releasing hormone receptor (GHRHR) mutations.

    Science.gov (United States)

    Martari, Marco; Salvatori, Roberto

    2009-01-01

    The growth hormone (GH)-releasing hormone (GHRH) receptor (GHRHR) belongs to the G protein-coupled receptors family. It is expressed almost exclusively in the anterior pituitary, where it is necessary for somatotroph cells proliferation and for GH synthesis and secretion. Mutations in the human GHRHR gene (GHRHR) can impair ligand binding and signal transduction, and have been estimated to cause about 10% of autosomal recessive familial isolated growth hormone deficiency (IGHD). Mutations reported to date include five splice donor site mutations, two microdeletions, two nonsense mutations, seven missense mutations, and one mutation in the promoter. These mutations have an autosomal recessive mode of inheritance, and heterozygous individuals do not show signs of IGHD, although the presence of an intermediate phenotype has been hypothesized. Conversely, patients with biallelic mutations have low serum insulin-like growth factor-1 and GH levels (with absent or reduced GH response to exogenous stimuli), resulting--if not treated--in proportionate dwarfism. This chapter reviews the biology of the GHRHR, the mutations that affect its gene and their effects in homozygous and heterozygous individuals. Copyright © 2009 Elsevier Inc. All rights reserved.

  3. Internalization and recycling of receptor-bound gonadotropin-releasing hormone agonist in pituitary gonadotropes

    International Nuclear Information System (INIS)

    Schvartz, I.; Hazum, E.

    1987-01-01

    The fate of cell surface gonadotropin-releasing hormone (GnRH) receptors on pituitary cells was studied utilizing lysosomotropic agents and monensin. Labeling of pituitary cells with a photoreactive GnRH derivative, [azidobenzoyl-D-Lys6]GnRH, revealed a specific band of Mr = 60,000. When photoaffinity-labeled cells were exposed to trypsin immediately after completion of the binding, the radioactivity incorporated into the Mr = 60,000 band decreased, with a concomitant appearance of a proteolytic fragment (Mr = 45,000). This fragment reflects cell surface receptors. Following GnRH binding, the hormone-receptor complexes underwent internalization, partial degradation, and recycling. The process of hormone-receptor complex degradation was substantially prevented by lysosomotropic agents, such as chloroquine and methylamine, or the proton ionophore, monensin. Chloroquine and monensin, however, did not affect receptor recycling, since the tryptic fragment of Mr = 45,000 was evident after treatment with these agents. This suggests that recycling of GnRH receptors in gonadotropes occurs whether or not the internal environment is acidic. Based on these findings, we propose a model describing the intracellular pathway of GnRH receptors

  4. Expression and role of gonadotropin-releasing hormone 2 and its receptor in mammals

    Science.gov (United States)

    Gonadotropin-releasing hormone (GnRH1) and its receptor (GnRHR1) drive mammalian reproduction via regulation of the gonadotropins. Yet, a second form of GnRH (GnRH2) and its receptor (GnRHR2) also exist in some mammals. GnRH2 has been completely conserved throughout 500 million years of evolution, s...

  5. Growth hormone (GH)-releasing activity of chicken GH-releasing hormone (GHRH) in chickens.

    Science.gov (United States)

    Harvey, S; Gineste, C; Gaylinn, B D

    2014-08-01

    Two peptides with sequence similarities to growth hormone releasing hormone (GHRH) have been identified by analysis of the chicken genome. One of these peptides, chicken (c) GHRH-LP (like peptide) was previously found to poorly bind to chicken pituitary membranes or to cloned and expressed chicken GHRH receptors and had little, if any, growth hormone (GH)-releasing activity in vivo or in vitro. In contrast, a second more recently discovered peptide, cGHRH, does bind to cloned and expressed cGHRH receptors and increases cAMP activity in transfected cells. The possibility that this peptide may have in vivo GH-releasing activity was therefore assessed. The intravenous (i.v.) administration of cGHRH to immature chickens, at doses of 3-100 μg/kg, significantly increased circulating GH concentrations within 10 min of injection and the plasma GH levels remained elevated for at least 30 min after the injection of maximally effective doses. The plasma GH responses to cGHRH were comparable with those induced by human (h) or porcine (p) GHRH preparations and to that induced by thyrotropin releasing hormone (TRH). In marked contrast, the i.v. injection of cGHRH-LP had no significant effect on circulating GH concentrations in immature chicks. GH release was also increased from slaughterhouse chicken pituitary glands perifused for 5 min with cGHRH at doses of 0.1 μg/ml or 1.0 μg/ml, comparable with GH responses to hGHRH1-44. In contrast, the perifusion of chicken pituitary glands with cGHRH-LP had no significant effect on GH release. In summary, these results demonstrate that cGHRH has GH-releasing activity in chickens and support the possibility that it is the endogenous ligand of the cGHRH receptor. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a.

    Science.gov (United States)

    Casanueva, Felipe F; Camiña, Jesus P; Carreira, Marcos C; Pazos, Yolanda; Varga, Jozsef L; Schally, Andrew V

    2008-12-23

    Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)NH(2) (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wild-type HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of (125)I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control.

  7. Synthesis and in vitro anti-cancer evaluation of luteinizing hormone-releasing hormone-conjugated peptide.

    Science.gov (United States)

    Deng, Xin; Qiu, Qianqian; Ma, Ke; Huang, Wenlong; Qian, Hai

    2015-11-01

    Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hormone released from the hypothalamus and shows high affinity binding to the LHRH receptors. It is reported that several cancer cells also express LHRH receptors such as breast, ovarian, prostatic, bladder and others. In this study, we linked B1, an anti-cancer peptide, to LHRH and its analogs to improve the activity against cancer cells with LHRH receptor. Biological evaluation revealed that TB1, the peptide contains triptorelin sequence, present favorable anti-cancer activity as well as plasma stability. Further investigations disclosed that TB1 trigger apoptosis by activating the mitochondria-cytochrome c-caspase apoptotic pathway, it also exhibited the anti-migratory effect on cancer cells.

  8. The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene.

    Science.gov (United States)

    Baumann, G; Maheshwari, H

    1997-11-01

    We report the discovery of a cluster of severe familial dwarfism in two villages in the Province of Sindh in Pakistan. Dwarfism is proportionate and occurs in members of a kindred with a high degree of consanguinity. Only the last generation is affected, with the oldest dwarf being 28 years old. The mode of inheritance is autosomal recessive. Phenotype analysis and endocrine testing revealed isolated growth hormone deficiency (GHD) as the reason for growth failure. Linkage analysis for the loci of several candidate genes yielded a high lod score for the growth hormone-releasing hormone receptor (GHRH-R) locus on chromosome 7. Amplification and sequencing of the GHRH-R gene in affected subjects demonstrated an amber nonsense mutation (GAG-->TAG; Glu50-->Stop) in exon 3. The mutation, in its homozygous form, segregated 100% with the dwarf phenotype. It predicts a truncation of the GHRH-R in its extracellular domain, which is likely to result in a severely disabled or non-existent receptor protein. Subjects who are heterozygous for the mutation show mild biochemical abnormalities in the growth hormone-releasing hormone (GHRH)--growth hormone--insulin-like growth factor axis, but have only minimal or no growth retardation. The occurrence of an offspring of two dwarfed parents indicates that the GHRH-R is not necessary for fertility in either sex. We conclude that Sindh dwarfism is caused by an inactivating mutation in the GHRH-R gene, resulting in the inability to transmit a GHRH signal and consequent severe isolated GHD.

  9. Molecular Cloning, Genomic Organization and Developmental Regulation of a Novel Receptor from Drosophila melanogaster Structurally Related to Gonadotropin-Releasing Hormone Receptors from Vertebrates

    DEFF Research Database (Denmark)

    Hauser, Frank; Søndergaard, Leif; Grimmelikhuijzen, Cornelis J.P.

    1998-01-01

    After screening the data base of the BerkeleyDrosophilaGenome Project with a sequence coding for the transmembrane region of a G protein-coupled receptor, we found thatDrosophilamight contain a gene coding for a receptor that is structurally related to the Gonadotropin-Releasing Hormone (GnRH) re...

  10. Mathematical modeling of gonadotropin-releasing hormone signaling.

    Science.gov (United States)

    Pratap, Amitesh; Garner, Kathryn L; Voliotis, Margaritis; Tsaneva-Atanasova, Krasimira; McArdle, Craig A

    2017-07-05

    Gonadotropin-releasing hormone (GnRH) acts via G-protein coupled receptors on pituitary gonadotropes to control reproduction. These are G q -coupled receptors that mediate acute effects of GnRH on the exocytotic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the chronic regulation of their synthesis. GnRH is secreted in short pulses and GnRH effects on its target cells are dependent upon the dynamics of these pulses. Here we overview GnRH receptors and their signaling network, placing emphasis on pulsatile signaling, and how mechanistic mathematical models and an information theoretic approach have helped further this field. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Structural and functional divergence of growth hormone-releasing hormone receptors in early sarcopterygians: lungfish and Xenopus.

    Directory of Open Access Journals (Sweden)

    Janice K V Tam

    Full Text Available The evolutionary trajectories of growth hormone-releasing hormone (GHRH receptor remain enigmatic since the discovery of physiologically functional GHRH-GHRH receptor (GHRHR in non-mammalian vertebrates in 2007. Interestingly, subsequent studies have described the identification of a GHRHR(2 in chicken in addition to the GHRHR and the closely related paralogous receptor, PACAP-related peptide (PRP receptor (PRPR. In this article, we provide information, for the first time, on the GHRHR in sarcopterygian fish and amphibians by the cloning and characterization of GHRHRs from lungfish (P. dolloi and X. laevis. Sequence alignment and phylogenetic analyses demonstrated structural resemblance of lungfish GHRHR to their mammalian orthologs, while the X. laevis GHRHR showed the highest homology to GHRHR(2 in zebrafish and chicken. Functionally, lungfish GHRHR displayed high affinity towards GHRH in triggering intracellular cAMP and calcium accumulation, while X. laevis GHRHR(2 was able to react with both endogenous GHRH and PRP. Tissue distribution analyses showed that both lungfish GHRHR and X. laevis GHRHR(2 had the highest expression in brain, and interestingly, X. laevis(GHRHR2 also had high abundance in the reproductive organs. These findings, together with previous reports, suggest that early in the Sarcopterygii lineage, GHRHR and PRPR have already established diverged and specific affinities towards their cognate ligands. GHRHR(2, which has only been found in xenopus, zebrafish and chicken hitherto, accommodates both GHRH and PRP.

  12. A regulator of G Protein signaling, RGS3, inhibits gonadotropin-releasing hormone (GnRH-stimulated luteinizing hormone (LH secretion

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    Musgrove Lois C

    2001-11-01

    Full Text Available Abstract Background Luteinizing hormone secreted by the anterior pituitary gland regulates gonadal function. Luteinizing hormone secretion is regulated both by alterations in gonadotrope responsiveness to hypothalamic gonadotropin releasing hormone and by alterations in gonadotropin releasing hormone secretion. The mechanisms that determine gonadotrope responsiveness are unknown but may involve regulators of G protein signaling (RGSs. These proteins act by antagonizing or abbreviating interaction of Gα proteins with effectors such as phospholipase Cβ. Previously, we reported that gonadotropin releasing hormone-stimulated second messenger inositol trisphosphate production was inhibited when RGS3 and gonadotropin releasing hormone receptor cDNAs were co-transfected into the COS cell line. Here, we present evidence for RGS3 inhibition of gonadotropin releasing hormone-induced luteinizing hormone secretion from cultured rat pituitary cells. Results A truncated version of RGS3 (RGS3T = RGS3 314–519 inhibited gonadotropin releasing hormone-stimulated inositol trisphosphate production more potently than did RSG3 in gonadotropin releasing hormone receptor-bearing COS cells. An RSG3/glutathione-S-transferase fusion protein bound more 35S-Gqα than any other member of the G protein family tested. Adenoviral-mediated RGS3 gene transfer in pituitary gonadotropes inhibited gonadotropin releasing hormone-stimulated luteinizing hormone secretion in a dose-related fashion. Adeno-RGS3 also inhibited gonadotropin releasing hormone stimulated 3H-inositol phosphate accumulation, consistent with a molecular site of action at the Gqα protein. Conclusions RGS3 inhibits gonadotropin releasing hormone-stimulated second messenger production (inositol trisphosphate as well as luteinizing hormone secretion from rat pituitary gonadotropes apparently by binding and suppressing the transduction properties of Gqα protein function. A version of RGS3 that is amino

  13. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

    International Nuclear Information System (INIS)

    Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V.

    1989-01-01

    Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides

  14. New trends in combined use of gonadotropin-releasing hormone antagonists with gonadotropins or pulsatile gonadotropin-releasing hormone in ovulation induction and assisted reproductive technologies.

    Science.gov (United States)

    Gordon, K; Danforth, D R; Williams, R F; Hodgen, G D

    1992-10-01

    The use of gonadotropin-releasing hormone agonists as adjunctive therapy with gonadotropins for ovulation induction in in vitro fertilization and other assisted reproductive technologies has become common clinical practice. With the recent advent of potent gonadotropin-releasing hormone antagonists free from the marked histamine-release effects that stymied earlier compounds, an attractive alternative method may be available. We have established the feasibility of combining gonadotropin-releasing hormone antagonist-induced inhibition of endogenous gonadotropins with exogenous gonadotropin therapy for ovulation induction in a nonhuman primate model. Here, the principal benefits to be gained from using the gonadotropin-releasing hormone antagonist rather than the gonadotropin-releasing hormone agonist are the immediate inhibition of pituitary gonadotropin secretion without the "flare effect," which brings greater safety and convenience for patients and the medical team and saves time and money. We have also recently demonstrated the feasibility of combining gonadotropin-releasing hormone antagonist with pulsatile gonadotropin-releasing hormone therapy for the controlled restoration of gonadotropin secretion and gonadal steroidogenesis culminating in apparently normal (singleton) ovulatory cycles. This is feasible only with gonadotropin-releasing hormone antagonists because, unlike gonadotropin-releasing hormone agonists, they achieve control of the pituitary-ovarian axis without down regulation of the gonadotropin-releasing hormone receptor system. This capacity to override gonadotropin-releasing hormone antagonist-induced suppression of pituitary-ovarian function may allow new treatment modalities to be employed for women who suffer from chronic hyperandrogenemia with polycystic ovarian disease.

  15. A radioreceptor assay of luteinizing hormone-releasing hormone receptor and characterization of LHRH binding to pituitary receptors in Shao duck

    International Nuclear Information System (INIS)

    Yang Peixin; Wu Meiwen; Chen Ziyuan

    2000-01-01

    The properties of Shao duck pituitary luteinizing hormone-releasing hormone (LHRH) receptors were analyzed in pituitary membrane preparation and isolated pituitary cells prepared by enzymatic dispersion with collagenase and trypsin, by using a super-agonist analog of (D-Lys 6 ) LHRH. High binding of 125 I-(D-Lys 6 ) LHRH to 10 6 cultured cells of Shao duck was observed after a 90 minute incubation at 4 degree C, while binding was significantly reduced after a 24h incubation. Binding of the radioligand was a function of tissue concentration of Shao duck pituitary membrane preparation, with a positive correlation over the range of 1-2 pituitary per-tube. Specific binding for 125 I-(D-Lys 6 ) LHRH increased with the increase in the amount of 125 I-(D-Lys 6 ) LHRH. The Scatchard analysis of data revealed a linear relationship between the amount of specific binding and the ratio of specific binding to free 1 '2 5 I(D-Lys 6 )LHRH, indicating a single class of high affinity sites. Equilibrium dissociation constant (Kd) was 0.34 nM in pituitary membrane preparation and 0.43 nM in isolated pituitary cells. Both Kd values were near and the maximum binding capacity (B max ) was great in isolated cells, suggesting no significant loss of the LHRH receptor population caused by the enzymatic procedure employed for cell dispersion in the present study. Addition of 9D-Lys 6 ) LHRH displaced bound 125 I-(D-Lys 6 ) LHRH. These results demonstrated the presence and provided characterization of LHRH receptors in Shao duck pituitary

  16. Effect of thyrotrophin releasing hormone on opiate receptors of the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Balashov, A.M.; Shchurin, M.R.

    1987-01-01

    It has recently been shown that the hypothalamic thyrotropin releasing hormone (TRH) has the properties of a morphine antagonist, blocking its inhibitory action on respiration and, to a lesser degree, its analgesic action. This suggests that the antagonistic effects of TRH are mediated through its interaction with opiate receptors. The aim of this paper is to study this hypothesis experimentally. Tritium-labelled enkephalins in conjunction with scintillation spectroscopy were used to assess the receptor binding behavior. The results indicate the existence of interconnections between the opiate systems and TRH. Although it is too early to reach definite conclusions on the mechanisms of this mutual influence and its physiological significance it can be tentatively suggested that TRH abolishes the pharmacological effects of morphine by modulating the functional state of opiate reception.

  17. Autoradiographic localization of thyrotropin releasing hormone (TRH) receptors in the central nervous system

    International Nuclear Information System (INIS)

    Manaker, S.

    1985-01-01

    Quantitative autoradiography was used to examine the distribution of thyrotropin-releasing hormone (TRH) receptors in the rat and human central nervous system (CNS). The binding of [ 3 H]-3-methyl-histidine 2 -TRH ([ 3 H]-MeTRH) to TRH receptors was saturable, of a high affinity (K/sub d/ = 5 nM), and specific for TRH analogs. Studies with neurotoxins ibotenic acid and 6-hydroxydopamine (6-OHDA) suggest that TRH receptors within the amygdala are predominantly located on cell bodies, and not nerve terminals. Finally, an examination was made of the concentrations of TRH receptors in spinal cords of patients with amyotrophic lateral sclerosis (ALS), a degenerative disease of the motor neurons located in Lamina IX. Large decreases in TRH receptors were noted in ALS spinal cords, when compared to non-neurological controls, probably reflecting the loss of motor neurons. In addition, decreases in the TRH receptor concentration of Lamina II were observed. This finding may reflect the sensitivity of neurons throughout the CNS to the pathophysiologic mechanisms of neuronal degeneration which cause ALS

  18. Effects of corticotropin-releasing hormone and its antagonist on the gene expression of gonadotrophin-releasing hormone (GnRH) and GnRH receptor in the hypothalamus and anterior pituitary gland of follicular phase ewes.

    Science.gov (United States)

    Ciechanowska, Magdalena; Łapot, Magdalena; Malewski, Tadeusz; Mateusiak, Krystyna; Misztal, Tomasz; Przekop, Franciszek

    2011-01-01

    There is no information in the literature regarding the effect of corticotropin-releasing hormone (CRH) on genes encoding gonadotrophin-releasing hormone (GnRH) and the GnRH receptor (GnRHR) in the hypothalamus or on GnRHR gene expression in the pituitary gland in vivo. Thus, the aim of the present study was to investigate, in follicular phase ewes, the effects of prolonged, intermittent infusion of small doses of CRH or its antagonist (α-helical CRH 9-41; CRH-A) into the third cerebral ventricle on GnRH mRNA and GnRHR mRNA levels in the hypothalamo-pituitary unit and on LH secretion. Stimulation or inhibition of CRH receptors significantly decreased or increased GnRH gene expression in the hypothalamus, respectively, and led to different responses in GnRHR gene expression in discrete hypothalamic areas. For example, CRH increased GnRHR gene expression in the preoptic area, but decreased it in the hypothalamus/stalk median eminence and in the anterior pituitary gland. In addition, CRH decreased LH secretion. Blockade of CRH receptors had the opposite effect on GnRHR gene expression. The results suggest that activation of CRH receptors in the hypothalamus of follicular phase ewes can modulate the biosynthesis and release of GnRH through complex changes in the expression of GnRH and GnRHR genes in the hypothalamo-anterior pituitary unit. © CSIRO 2011 Open Access

  19. Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris)

    OpenAIRE

    Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

    2006-01-01

    GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homo-logue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnR...

  20. CHARACTERIZATION OF THE RECEPTOR FOR GONADOTROPIN-RELEASING HORMONE IN THE PITUITARY OF THE AFRICAN CATFISH, CLARIAS-GARIEPINUS

    NARCIS (Netherlands)

    de Leeuw, R.; Conn, P. M.; van't Veer, C.; Goos, H. J.; van Oordt, P. G.

    1988-01-01

    Receptors for gonadotropin-releasing hormone (GnRH) were characterized using a radioligand prepared from a superactive analog of salmon GnRH (sGnRH), D-Arg(6)-Pro(9)-sGnRH-NEt (sGnRHa). Binding of(125)I-sGnRHa to catfish pituitary membrane fractions reached equilibrium after 2 h incubation at 4°C.

  1. Colocalization of corticotropin-releasing hormone and oestrogen receptor-alpha in the paraventricular nucleus of the hypothalamus in mood disorders

    NARCIS (Netherlands)

    Bao, Ai-Min; Hestiantoro, Andon; van Someren, Eus J. W.; Swaab, Dick F.; Zhou, Jiang-Ning

    2005-01-01

    Oestrogens may modulate the activity of the hypothalamic-pituitary-adrenal (HPA) axis. The present study was to investigate whether the activity of the HPA axis in mood disorders might be directly modulated by oestrogens via oestrogen receptors (ORs) in the corticotropin-releasing hormone (CRH)

  2. Growth Hormone-Releasing Hormone in Diabetes

    Directory of Open Access Journals (Sweden)

    Leonid Evsey Fridlyand

    2016-10-01

    Full Text Available Growth hormone-releasing hormone (GHRH is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR has been demonstrated in different peripheral tissues and cell types including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment. This review considers the role of GHRHR in the beta-cell and addresses the unique engineered GHRH agonists and antagonists for treatment of Type 2 diabetes mellitus. We discuss the similarity of signaling pathways activated by GHRHR in pituitary somatotrophs and in pancreatic beta-cells and possible ways as to how the GHRHR pathway can interact with glucose and other secretagogues to stimulate insulin secretion. We also consider the hypothesis that novel GHRHR agonists can improve glucose metabolism in Type 2 diabetes by preserving the function and survival of pancreatic beta-cells. Wound healing and cardioprotective action with new GHRH agonists suggesting that they may prove useful in ameliorating certain diabetic complications. These findings highlight the future potential therapeutic effectiveness of modulators of GHRHR activity for the development of new therapeutic approaches in diabetes and its complications.

  3. Chromosomal localization of the gonadotropin-releasing hormone receptor gene to human chromosome 4q13. 1-q21. 1 and mouse chromosome 5

    Energy Technology Data Exchange (ETDEWEB)

    Kaiser, U.B.; Dushkin, H.; Beier, D.R.; Chin, W.W. (Harvard Medical School, Boston, MA (United States)); Altherr, M.R. (Los Alamos National Lab., NM (United States))

    1994-04-01

    The gonadotropin-releasing hormone receptor (GRHR) is a G-protein-coupled receptor on the cell surface of pituitary gonadotropes, where it serves to transduce signals from the extracellular ligand, the hypothalamic factor gonadotropin-releasing hormone, and to modulate the synthesis and secretion of luteinizing hormone and follicle-stimulating hormone. The authors have localized the GRHR gene to the q13.1-q21.1 region of the human chromosome 4 using mapping panels of human/rodent somatic cell hybrids containing different human chromosomes or different regions of human chromosome 4. Furthermore, using linkage analysis of single-strand conformational polymorphisms, the murine GRHR gene was localized to mouse chromosome 5, linked to the endogenous retroviral marker Pmv-11. This is consistent with the evolutionary conservation of homology between these two regions, as has been previously suggested from comparative mapping of several other loci. The localization of the GRHR gene may be useful in the study of disorders of reproduction. 22 refs., 2 figs.

  4. Changes in gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor gene expression after an increase in carbon monoxide concentration in the cavernous sinus of male wild boar and pig crossbread.

    Science.gov (United States)

    Romerowicz-Misielak, M; Tabecka-Lonczynska, A; Koziol, K; Gilun, P; Stefanczyk-Krzymowska, S; Och, W; Koziorowski, M

    2016-06-01

    Previous studies indicate that there are at least a few regulatory systems involved in photoperiodic synchronisation of reproductive activity, which starts with the retina and ends at the gonadotropin-releasing hormone (GnRH) pulse generator. Recently we have shown indicated that the amount of carbon monoxide (CO) released from the eye into the ophthalmic venous blood depends on the intensity of sunlight. The aim of this study was to test whether changes in the concentration of carbon monoxide in the ophthalmic venous blood may modulate reproductive activity, as measured by changes in GnRH and GnRH receptor gene expression. The animal model used was mature male swine crossbred from wild boars and domestic sows (n = 48). We conducted in vivo experiments to determine the effect of increased CO concentrations in the cavernous sinus of the mammalian perihypophyseal vascular complex on gene expression of GnRH and GnRH receptors as well as serum luteinizing hormone (LH) levels. The experiments were performed during long photoperiod days near the summer solstice (second half of June) and short photoperiod days near the winter solstice (second half of December). These crossbred swine demonstrated a seasonally-dependent marked variation in GnRH and GnRH receptor gene expression and systemic LH levels in response to changes in CO concentration in ophthalmic venous blood. These results seem to confirm the hypothesis of humoral phototransduction as a mechanism for some of bright light's effects in animal chronobiology and the effect of CO on GnRH and GnRH receptor gene expression.

  5. In vitro effect of Δ9-tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E2

    International Nuclear Information System (INIS)

    Rettori, V.; Aguila, M.C.; McCann, S.M.; Gimeno, M.F.; Franchi, A.M.

    1990-01-01

    Previous in vivo studies have shown that Δ 9 -tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E 2 (PGE 2 ) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE 2 suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE 2 synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release

  6. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

    Science.gov (United States)

    Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

    1989-08-01

    Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. For instance, SB-40, a PtCl2-containing metallopeptide in which platinum is coordinated to an N epsilon-(DL-2,3-diaminopropionyl)-D-lysine residue [D-Lys(DL-A2pr] at position 6, showed 50 times higher LH-releasing potency than the native hormone. SB-95, [Ac-D-Nal(2)1,D-Phe(pCl)2, D-Pal(3)2, Arg5,D-Lys[DL-A2pr(Sal2Cu)]6,D-Ala10]LH-RH, where Nal(2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and copper(II) is coordinated to the salicylideneimino moieties resulting from condensation of salicylaldehyde with D-Lys(DL-A2pr)6, caused 100% inhibition of ovulation at a dose of 3 micrograms in rats. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer cell lines in vitro (this will be the subject of a separate paper on cytotoxicity evaluation). Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

  7. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.

    Science.gov (United States)

    Stavreva, Diana A; Wiench, Malgorzata; John, Sam; Conway-Campbell, Becky L; McKenna, Mervyn A; Pooley, John R; Johnson, Thomas A; Voss, Ty C; Lightman, Stafford L; Hager, Gordon L

    2009-09-01

    Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.

  8. Simultaneous measurement of hormone release and secretagogue binding by individual pituitary cells

    International Nuclear Information System (INIS)

    Smith, P.F.; Neill, J.D.

    1987-01-01

    The quantitative relationship between receptor binding and hormone secretion at the single-cell level was investigated in the present study by combining a reverse hemolytic plaque assay for measurement of luteinizing hormone (LH) secretion from individual pituitary cells with an autoradiographic assay of 125 I-labeled gonadontropin-releasing hormone (GnRH) agonist binding to the same cells. In the plaque assay, LH secretion induces complement-mediated lysis of the LH-antibody-coated erythrocytes around the gonadotropes, resulting in areas of lysis (plaques). LH release from individual gonadotropes was quantified by comparing radioimmunoassayable LH release to hemolytic area in similarly treated cohort groups of cells; plaque area was linearly related to the amount of LH secreted. Receptor autoradiography was performed using 125 I-labeled GnRH-A (a superagonist analog of GnRH) both as the ligand and as the stimulant for LH release in the plaque assay. The grains appeared to represent specific and high-affinity receptors for GnRH because (i) no pituitary cells other than gonadotropes bound the labeled ligand and (ii) grain development was progressively inhibited by coincubation with increasing doses of unlabeled GnRH-A. The authors conclude that GnRH receptor number for any individual gonadotrope is a weak determinant of the amount of LH it can secrete; nevertheless, full occupancy of all its GnRH receptors is required for any gonadotrope to reach its full LH-secretory capacity. Apparently the levels of other factors comprising the steps along the secretory pathway determine the secretory capacity of an individual cell

  9. In vitro effect of. Delta. sup 9 -tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E sub 2

    Energy Technology Data Exchange (ETDEWEB)

    Rettori, V.; Aguila, M.C.; McCann, S.M. (Univ. of Texas Southwestern Medical Center at Dallas (United States)); Gimeno, M.F.; Franchi, A.M. (Centro de Estudios Farmacologicos y de Principios Naturales, Buenos Aires (Argentina))

    1990-12-01

    Previous in vivo studies have shown that {Delta}{sup 9}-tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E{sub 2} (PGE{sub 2}) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE{sub 2} suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE{sub 2} synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release.

  10. Luteinizing hormone-releasing hormone inactivation by purified pituitary plasma membranes: effects of receptor-binding studies.

    Science.gov (United States)

    Clayton, R N; Shakespear, R A; Duncan, J A; Marshall, J C

    1979-05-01

    Inactivation of LHRH by purified bovine pituitary plasma membranes was studied in vitro. After incubation of [125I]iodo-LHRH with plasma membranes, the amount of tracer bound to the pellet was measured, and the integrity of the unbound tracer in the supernatant was assessed. Reduction in ability to bind to anti-LHRH serum and to rebind to plasma membranes together with altered electrophoretic mobility on polyacrylamide gels showed that the unbound [125I]iodo-LHRH was inactivated. LHRH inactivation occurred rapidly and was dependent upon membrane concentration and incubation temperature. These results indicate that hormone inactivation must be taken into account in the interpretation of LHRH-receptor interactions. During 37 C incubations, the apparent absence of specific LHRH binding can be explained by inactivation of tracer hormone. Significant LHRH inactivation also occurred at 0 C, which in part explains the insensitivity of LHRH receptor assays. Assessment of LHRH inactivation by different particulate subcellular fractions of pituitary tissue showed that the inactivating enzyme was associated with the plasma membranes; other organelles did not alter LHRH. The enzyme appeared to be an integral part of the plasma membrane structure, since enzymic activity could not be removed by washing without reducing specific LHRH binding. Additionally, reduction of LHRH inactivation by the inhibitors Bacitracin and Trasylol and by magnesium was also accompanied by reduced LHRH binding. Previous studies have shown that the majority of LHRH binding to pituitary plasma membranes is to the low affinity site (approximately 10(-6) M), but the significance of this binding has been uncertain. Our findings indicate that low affinity binding probably represents binding of LHRH to the inactivating enzyme. The LHRH analog, D-Ser6(TBu), des Gly10, ethylamide, has greater biological activity than LHRH and is not inactivated to a significant extent by pituitary plasma membranes. The

  11. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, H.N.; Das, S.

    1986-03-01

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with /sup 3/H-(3MeHis/sup 2/)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of /sup 3/H-MeTRH to membranes prepared from brain without the cerebellum was determined. /sup 3/H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of /sup 3/H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of /sup 3/H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors.

  12. Adipokinetic hormones and their G protein-coupled receptors emerged in Lophotrochozoa

    DEFF Research Database (Denmark)

    Li, Shizhong; Hauser, Frank; Skadborg, Signe K.

    2016-01-01

    the neuropeptide systems used by proto- or deuterostomes. An exception, however, are members of the gonadotropin-releasing hormone (GnRH) receptor superfamily, which occur in both evolutionary lineages, where GnRHs are the ligands in Deuterostomia and GnRH-like peptides, adipokinetic hormone (AKH), corazonin...

  13. Radioiodinated nondegradable gonadotropin-releasing hormone analogs: new probes for the investigation of pituitary gonadotropin-releasing hormone receptors.

    Science.gov (United States)

    Clayton, R N; Shakespear, R A; Duncan, J A; Marshall, J C; Munson, P J; Rodbard, D

    1979-12-01

    Studies of pituitary plasma membrane gonadotropin-releasing hormone (GnRH) receptors using [125I]-iodo-GnRH suffer major disadvantages. Only a small (less than 25%) proportion of specific tracer binding is to high affinity sites, with more than 70% bound to low affinity sites (Ka = 1 x 10(6) M-1). [125I]Iodo-GnRH is also inactivated during incubation with pituitary plasma membrane preparations. Two superactive analongs of GnRH, substituted in positions 6 and 10, were used as the labeled ligand to overcome these problems. Both analogs bound to the same high affinity sites as GnRH on bovine pituitary plasma membranes, though the affinity of the analogs was higher than that of the natural decapeptide (Ka = 2.0 x 10(9), 6.0 x 10(9), and 3.0 x 10(8) M-1 for [D-Ser(TBu)6]des-Gly10-GnRH ethylamide, [D-Ala6]des-Gly10-GnRH ethylamide, and GnRH, respectively. The labeled analogs bound to a single class of high affinity sites with less than 15% of the specific binding being to low affinity sites (Ka approximately equal to 1 x 10(6) M-1). The labeled analogs were not inactivated during incubation with the pituitary membrane preparations. Using the analogs as tracer, a single class of high affinity sites (K1 = 4.0 x 10(9) M-1) was also demonstrated on crude 10,800 x g rat pituitary membrane preparations. Use of these analogs as both the labeled and unlabeled ligand offers substantial advantages over GnRH for investigation of GnRH receptors, allowing accurate determination of changes in their numbers and affinities under various physiological conditions.

  14. Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice.

    Science.gov (United States)

    Phumsatitpong, Chayarndorn; Moenter, Suzanne M

    2018-01-01

    Gonadotropin-releasing hormone (GnRH) neurons are the final central regulators of reproduction, integrating various inputs that modulate fertility. Stress typically inhibits reproduction but can be stimulatory; stress effects can also be modulated by steroid milieu. Corticotropin-releasing hormone (CRH) released during the stress response may suppress reproduction independent of downstream glucocorticoids. We hypothesized CRH suppresses fertility by decreasing GnRH neuron firing activity. To test this, mice were ovariectomized (OVX) and either implanted with an estradiol capsule (OVX+E) or not treated further to examine the influence of estradiol on GnRH neuron response to CRH. Targeted extracellular recordings were used to record firing activity from green fluorescent protein-identified GnRH neurons in brain slices before and during CRH treatment; recordings were done in the afternoon when estradiol has a positive feedback effect to increase GnRH neuron firing. In OVX mice, CRH did not affect the firing rate of GnRH neurons. In contrast, CRH exhibited dose-dependent stimulatory (30 nM) or inhibitory (100 nM) effects on GnRH neuron firing activity in OVX+E mice; both effects were reversible. The dose-dependent effects of CRH appear to result from activation of different receptor populations; a CRH receptor type-1 agonist increased firing activity in GnRH neurons, whereas a CRH receptor type-2 agonist decreased firing activity. CRH and specific agonists also differentially regulated short-term burst frequency and burst properties, including burst duration, spikes/burst, and/or intraburst interval. These results indicate that CRH alters GnRH neuron activity and that estradiol is required for CRH to exert both stimulatory and inhibitory effects on GnRH neurons. Copyright © 2018 Endocrine Society.

  15. Growth inhibition of tumor cells in vitro by using monoclonal antibodies against gonadotropin-releasing hormone receptor.

    Science.gov (United States)

    Lee, Gregory; Ge, Bixia

    2010-07-01

    As the continuation of a previous study, synthetic peptides corresponding to the extracellular domains of human gonadotropin-releasing hormone (GnRH) receptor were used to generate additional monoclonal antibodies which were further characterized biochemically and immunologically. Among those identified to recognize GnRH receptor, monoclonal antibodies designated as GHR-103, GHR-106 and GHR-114 were found to exhibit high affinity (Kd L37), when cancer cells were incubated with GnRH or GHR-106. The widespread expressions of GnRH receptor in almost all of the studied human cancer cell lines were also demonstrated by RT-PCR and Western blot assay, as well as indirect immunofluorescence assay with either of these monoclonal antibodies as the primary antibody. In view of the longer half life of antibodies as compared to that of GnRH or its analogs, anti-GnRH receptor monoclonal antibodies in humanized forms could function as GnRH analogs and serve as an ideal candidate of anti-cancer drugs for therapeutic treatments of various cancers in humans as well as for fertility regulations.

  16. Some theoretical aspects of hormone receptor determination

    International Nuclear Information System (INIS)

    Sluiter, W.J.

    1981-01-01

    Suitable antisera for determination of hormone receptors are not available for the majority of hormone receptors. Therefore, the determination of hormone receptors is mostly performed in terms of binding capacity for the appropriate hormone, using radioactive hormone labels. Some theoretical aspects of such a receptor determination are discussed including the length of incubation (total or unoccupied receptor concentration), single point or multiple point (Scatchard) analysis (regarding the influence of other specific binders), the correction procedure for non-specific binding and the influence of the circulating hormone level. (Auth.)

  17. alpha-difluoromethylornithine modifies gonadotropin-releasing hormone release and follicle-stimulating hormone secretion in the immature female rat.

    Science.gov (United States)

    Thyssen, S M; Becú-Villalobos, D; Lacau-Mengido, I M; Libertun, C

    1997-06-01

    Polyamines play an essential role in tissue growth and differentiation, in body weight increment, in brain organization, and in the molecular mechanisms of hormonal action, intracellular signaling, and cell-to-cell communication. In a previous study, inhibition of their synthesis by alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, during development in female rats, was followed by prolonged high follicle-stimulating hormone (FSH) serum level and a delayed puberty onset. Those changes were relatively independent of body mass and did not impair posterior fertility. The present work studies the mechanisms and site of action of polyamine participation in FSH secretion during development. DFMO was injected in female rats between Days 1 and 9 on alternate days. At 10 days of age, hypothalami from control and DFMO rats were perifused in vitro, and basal and potassium-induced gonadotropin-releasing hormone (GnRH) release were measured. The response to membrane depolarization was altered in DFMO hypothalami. Increased GnRH release in response to a low K+ concentration was evidenced. Adenohypophyses of the same treated prepubertal rats were perifused in vitro and the response to GnRH pulses was checked. In DFMO-treated rats, higher FSH release was observed, with no changes in LH or PRL secretion. Finally, pituitary GnRH receptor number in adenohypophyseal membranes from treated and control groups was quantified. A significant reduction in specific binding was evident in hypophyses from DFMO-treated rats when compared with binding in the control group. In summary, DFMO treatment in a critical developmental period in the female rat impacts the immature GnRH neuronal network and immature gonadotropes. A delay in maturation is evidenced by a higher sensitivity to secretagogs in both pituitary glands and hypothalamic explants. These events could explain the prolonged high FSH serum levels and delayed puberty onset seen in

  18. Growth hormone-releasing peptides.

    Science.gov (United States)

    Ghigo, E; Arvat, E; Muccioli, G; Camanni, F

    1997-05-01

    Growth hormone-releasing peptides (GHRPs) are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. They have no structural homology with GHRH and act via specific receptors present either at the pituitary or the hypothalamic level both in animals and in humans. The GHRP receptor has recently been cloned and, interestingly, it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. The mechanisms underlying the GHRP effect are still unclear. At present, several data favor the hypothesis that GHRPs could act by counteracting somatostatinergic activity both at the pituitary and the hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. GHRP-6 was the first hexapeptide to be extensively studied in humans. More recently, a heptapeptide, GHRP-1, and two other hexapeptides, GHRP-2 and Hexarelin, have been synthesized and are now available for human studies. Moreover, non-peptidyl GHRP mimetics have been developed which act via GHRP receptors and their effects have been clearly demonstrated in animals and in humans in vivo. Among non-peptidyl GHRPs, MK-0677 seems the most interesting molecule. The GH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration: in fact, prolonged administration of GHRPs increases IGF-1 levels both in animals and in humans. The GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations. It increases from birth to puberty, persists at a similar level in adulthood and

  19. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

    OpenAIRE

    Sagami, Y; Shimada, Y; Tayama, J; Nomura, T; Satake, M; Endo, Y; Shoji, T; Karahashi, K; Hongo, M; Fukudo, S

    2004-01-01

    Background and aims: Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of α-helical CRH (αhCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patient...

  20. Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

    Directory of Open Access Journals (Sweden)

    Ivo Heitland

    Full Text Available The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886 and the serotonin transporter (5HTTLPR. These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886 showed no acquisition of fear conditioned responses (FPS to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele and 5HTTLPR (short allele was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

  1. Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

    Science.gov (United States)

    Janáky, T; Juhász, A; Bajusz, S; Csernus, V; Srkalovic, G; Bokser, L; Milovanovic, S; Redding, T W; Rékási, Z; Nagy, A

    1992-02-01

    In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines

  2. Exaggerated gonadotropin response to luteinizing hormone-releasing hormone in amenorrheic runners.

    Science.gov (United States)

    Yahiro, J; Glass, A R; Fears, W B; Ferguson, E W; Vigersky, R A

    1987-03-01

    Most studies of exercise-induced amenorrhea have compared amenorrheic athletes (usually runners) with sedentary control subjects. Such comparisons will identify hormonal changes that develop as a result of exercise training but cannot determine which of these changes play a role in causing amenorrhea. To obviate this problem, we assessed reproductive hormone status in a group of five amenorrheic runners and compared them to a group of six eumenorrheic runners matched for body fatness, training intensity, and exercise performance. Compared to the eumenorrheic runners, the amenorrheic runners had lower serum estradiol concentrations, similar basal serum luteinizing hormone and follicle-stimulating hormone concentrations, and exaggerated responses of serum gonadotropins after administration of luteinizing hormone-releasing hormone (100 micrograms intravenous bolus). Serum prolactin levels, both basally and after thyrotropin-releasing hormone administration (500 micrograms intravenous bolus) or treadmill exercise, was similar in the two groups, as were serum thyroid function tests (including thyrotropin response to thyrotropin-releasing hormone). Changes in serum cortisol levels after short-term treadmill exercise were similar in both groups, and serum testosterone levels increased after exercise only in the eumenorrheic group. In neither group did such exercise change serum luteinizing hormone, follicle-stimulating hormone, or thyrotropin levels. We concluded that exercise-induced amenorrhea is not solely related to the development of increased prolactin output after exercise training. The exaggerated gonadotropin response to luteinizing hormone-releasing hormone seen in amenorrheic runners in comparison with matched eumenorrheic runners is consistent with a hypothalamic etiology for the menstrual dysfunction, analogous to that previously described in "stress-induced" or "psychogenic" amenorrhea.

  3. Spinal cord thyrotropin releasing hormone receptors of morphine tolerant-dependent and abstinent rats

    Energy Technology Data Exchange (ETDEWEB)

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. (Univ. of Illinois, Chicago (USA))

    1990-07-01

    The effect of chronic administration of morphine and its withdrawal on the binding of 3H-(3-MeHis2)thyrotropin releasing hormone (3H-MeTRH) to membranes of the spinal cord of the rat was determined. Male Sprague-Dawley rats were implanted with either 6 placebo or 6 morphine pellets (each containing 75-mg morphine base) during a 7-day period. Two sets of animals were used. In one, the pellets were left intact at the time of sacrificing (tolerant-dependent) and in the other, the pellets were removed 16 hours prior to sacrificing (abstinent rats). In placebo-pellet-implanted rats, 3H-MeTRH bound to the spinal cord membranes at a single high affinity binding site with a Bmax of 21.3 +/- 1.6 fmol/mg protein, and an apparent dissociation constant Kd of 4.7 +/- 0.8 nM. In morphine tolerant-dependent or abstinent rats, the binding constants of 3H-MeTRH to spinal cord membranes were unaffected. Previous studies from this laboratory indicate that TRH can inhibit morphine tolerance-dependence and abstinence processes without modifying brain TRH receptors. Together with the present results, it appears that the inhibitory effect of TRH on morphine tolerance-dependence and abstinence is probably not mediated via central TRH receptors but may be due to its interaction with other neurotransmitter systems.

  4. Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties.

    Science.gov (United States)

    Janáky, T; Juhász, A; Rékási, Z; Serfözö, P; Pinski, J; Bokser, L; Srkalovic, G; Milovanovic, S; Redding, T W; Halmos, G

    1992-11-01

    Five hexapeptide and heptapeptide analogs of luteinizing hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhance target selectivity of the antineoplastic agents linked to them. Native LH-RH-(3-9) and LH-RH-(4-9) containing D-lysine and D-ornithine at position 6 were amidated with ethylamine and acylated on the N terminus. The receptor-binding affinity of one hexapeptide carrier AJ-41 (Ac-Ser-Tyr-D-Lys-Leu-Arg-Pro-NH-Et) to human breast cancer cell membranes was similar to that of [D-Trp6]LH-RH. Alkylating nitrogen mustards (melphalan, Ac-melphalan), anthraquinone derivatives including anticancer antibiotic doxorubicin, antimetabolite (methotrexate), and cisplatin-like platinum complex were linked to these peptides through their omega-amino group at position 6. The hybrid molecules showed no LH-RH agonistic activity in vitro and in vivo but had nontypical antagonistic effects on pituitary cells in vitro at the doses tested. These analogs showed a wide range of receptor-binding affinities to rat pituitaries and cell membranes of human breast cancer and rat Dunning prostate cancer. Several of these conjugates exerted some cytotoxic effects on MCF-7 breast cancer cell line.

  5. Intracellular postsynaptic cannabinoid receptors link thyrotropin-releasing hormone receptors to TRPC-like channels in thalamic paraventricular nucleus neurons.

    Science.gov (United States)

    Zhang, L; Kolaj, M; Renaud, L P

    2015-12-17

    In rat thalamic paraventricular nucleus of thalamus (PVT) neurons, activation of thyrotropin-releasing hormone (TRH) receptors enhances excitability via concurrent decrease in G protein-coupled inwardly-rectifying potassium (GIRK)-like and activation of transient receptor potential cation (TRPC)4/5-like cationic conductances. An exploration of intracellular signaling pathways revealed the TRH-induced current to be insensitive to phosphatidylinositol-specific phospholipase C (PI-PLC) inhibitors, but reduced by D609, an inhibitor of phosphatidylcholine-specific PLC (PC-PLC). A corresponding change in the I-V relationship implied suppression of the cationic component of the TRH-induced current. Diacylglycerol (DAG) is a product of the hydrolysis of PC. Studies focused on the isolated cationic component of the TRH-induced response revealed a reduction by RHC80267, an inhibitor of DAG lipase, the enzyme involved in the hydrolysis of DAG to the endocannabinoid 2-arachidonoylglycerol (2-AG). Further investigation revealed enhancement of the cationic component in the presence of either JZL184 or WWL70, inhibitors of enzymes involved in the hydrolysis of 2-AG. A decrease in the TRH-induced response was noted in the presence of rimonabant or SR144528, membrane permeable CB1 and CB2 receptor antagonists, respectively. A decrease in the TRH-induced current by intracellular, but not by bath application of the membrane impermeable peptide hemopressin, selective for CB1 receptors, suggests a postsynaptic intracellular localization of these receptors. The TRH-induced current was increased in the presence of arachidonyl-2'-chloroethylamide (ACEA) or JWH133, CB1 and CB2 receptor agonists, respectively. The PI3-kinase inhibitor LY294002, known to inhibit TRPC translocation, decreased the response to TRH. In addition, a TRH-induced enhancement of the low-threshold spike was prevented by both rimonabant, and SR144528. TRH had no influence on excitatory or inhibitory miniature

  6. Effects of hyperthyroidism and hypothyroidism on rat growth hormone release induced by thyrotropin-releasing hormone.

    Science.gov (United States)

    Chihara, K; Kato, Y; Ohgo, S; Iwasaki, Y; Maeda, K

    1976-06-01

    The effect of synthetic thyrotropin-releasing hormone (TRH) on the release of growth hormone (GH) and thyroid-stimulating hormone (TSH) was investigated in euthyroid, hypothyroid, and hyperthyroid rats under urethane anesthesia. In euthyroid control rats, intravenous injection of TRH (200 ng/100 g BW) resulted in a significant increase in both plasma GH and TSH. In rats made hypothyroid by treatment with propylthiouracil or by thyroidectomy, basal GH and TSH levels were significantly elevated with exaggerated responses to TRH. In contrast, plasma GH and TSH responses to TRH were both significantly inhibited in rats made hyperthyroid by L-thyroxine (T4) treatment. These results suggest that altered thyroid status influences GH release as well as TSH secretion induced by TRH in rats.

  7. Different serotonin receptor types participate in 5-hydroxytryptophan-induced gonadotropins and prolactin release in the female infantile rat.

    Science.gov (United States)

    Lacau-Mengido, I M; Libertun, C; Becú-Villalobos, D

    1996-05-01

    Serotonin (5-HT) receptors can be classified into at least three, possibly up to seven, classes of receptors. They comprise the 5-HT1, 5-HT2, and 5-HT3 classes, the "uncloned' 5-HT4 receptor and the recombinant receptors 5-ht5, 5-ht6 and 5-ht7. We investigated the role of different serotonin receptor types in a neuroendocrine response to the activation of the serotonergic system. Female immature rats were chosen as an experimental model as it has been shown that during the 3rd week of life, and not at later developmental stages, 5-hydroxytryptophan (5-HTP, a serotonin precursor) induces gonadotropin release in females and not in males. Besides, at this age, serotonin releases prolactin in both sexes. 5-HTP (50 mg/kg) released prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as expected. Ketanserin (5-HT2A antagonist) and methysergide (5-HT2C antagonist) blocked 5-HTP-induced prolactin release, but did not block the LH or FSH responses. Ondansetron (5-HT3 receptor antagonist) did not modify prolactin response to 5-HTP, whereas it blocked 5-HTP-induced LH and FSH release. Propranolol (5-HT1 and beta-adrenergic antagonist) blocked prolactin, LH and FSH release induced by 5-HTP. The 5-HT2C agonist 1-(3-chlorophenyl)piperazine dihydrochloride released prolactin, without modifying LH or FSH release. Methyl-quipazine and phenylbiguanide (5-HT3 agonists) increased both LH and FSH levels, without altering prolactin secretion. The present experiments indicate that serotonin acting at the 5-HT3 receptor mediates LH and FSH release in infantile female rats, whereas 5-HT2C or 2A receptor types participate in the release of prolactin at this age. 5-HT1 receptor type may be involved in the release of the three hormones, though a beta-adrenergic component of the response cannot be discarded.

  8. Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris)

    Science.gov (United States)

    Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

    2005-01-01

    GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homo-logue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnRHR and the chordate GnRHR genes. The oct-GnRHR expressed in Xenopus (South African clawed frog) oocytes was responsive to oct-GnRH, but not to any other HPLC fractions of the Octopus brain extract. These results show that oct-GnRHR is an authentic receptor for oct-GnRH. Southern blotting of reverse-transcription PCR products revealed that the oct-GnRHR mRNA was widely distributed in the central and peripheral nervous systems and in several peripheral tissues. In situ hybridiz-ation showed that oct-GnRHR mRNA was expressed in some regions involved in autonomic functions, feeding, memory and movement. Oct-GnRH was shown to induce steroidogenesis of testosterone, progesterone and 17β-oestradiol in Octopus ovary and testis, where oct-GnRHR was abundantly expressed. These results suggest that oct-GnRH, like its vertebrate counterparts, acts as a multifunctional neurotransmitter, neuromodulator and hormone-like factor, both in Octopus central nervous system and peripheral tissues, and that both structure and functions of the GnRH family are, at least partially, evolutionarily conserved between octopuses and chordates. PMID:16367741

  9. Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris).

    Science.gov (United States)

    Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

    2006-04-01

    GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homologue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnRHR and the chordate GnRHR genes. The oct-GnRHR expressed in Xenopus (South African clawed frog) oocytes was responsive to oct-GnRH, but not to any other HPLC fractions of the Octopus brain extract. These results show that oct-GnRHR is an authentic receptor for oct-GnRH. Southern blotting of reverse-transcription PCR products revealed that the oct-GnRHR mRNA was widely distributed in the central and peripheral nervous systems and in several peripheral tissues. In situ hybridization showed that oct-GnRHR mRNA was expressed in some regions involved in autonomic functions, feeding, memory and movement. Oct-GnRH was shown to induce steroidogenesis of testosterone, progesterone and 17beta-oestradiol in Octopus ovary and testis, where oct-GnRHR was abundantly expressed. These results suggest that oct-GnRH, like its vertebrate counterparts, acts as a multifunctional neurotransmitter, neuromodulator and hormone-like factor, both in Octopus central nervous system and peripheral tissues, and that both structure and functions of the GnRH family are, at least partially, evolutionarily conserved between octopuses and chordates.

  10. Chitosan-based DNA delivery vector targeted to gonadotropin-releasing hormone (GnRH) receptor.

    Science.gov (United States)

    Boonthum, Chatwalee; Namdee, Katawut; Boonrungsiman, Suwimon; Chatdarong, Kaywalee; Saengkrit, Nattika; Sajomsang, Warayuth; Ponglowhapan, Suppawiwat; Yata, Teerapong

    2017-02-10

    The main purpose of this study was to investigate the application of modified chitosan as a potential vector for gene delivery to gonadotropin-releasing hormone receptor (GnRHR)-expressing cells. Such design of gene carrier could be useful in particular for gene therapy for cancers related to the reproductive system, gene disorders of sexual development, and contraception and fertility control. In this study, a decapeptide GnRH was successfully conjugated to chitosan (CS) as confirmed by proton nuclear magnetic resonance spectroscopy ( 1 H NMR) and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The synthesized GnRH-conjugated chitosan (GnRH-CS) was able to condense DNA to form positively charged nanoparticles and specifically deliver plasmid DNA to targeted cells in both two-dimensional (2D) and three-dimensional (3D) cell cultures systems. Importantly, GnRH-CS exhibited higher transfection activity compared to unmodified CS. In conclusion, GnRH-conjugated chitosan can be a promising carrier for targeted DNA delivery to GnRHR-expressing cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Degarelix: A Novel Gonadotropin-Releasing Hormone (GnRH) Receptor Blocker-Results from a 1-yr, Multicentre, Randomised, Phase 2 Dosage-Finding Study in the Treatment of Prostate Cancer

    NARCIS (Netherlands)

    van Poppel, Hendrik; Tombal, Bertrand; de la Rosette, Jean J.; Persson, Bo-Eric; Jensen, Jens-Kristian; Kold Olesen, Tine

    2008-01-01

    Background: Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer. Objective: To determine the efficacy and safety of initial doses of 200 mg or

  12. Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

    Directory of Open Access Journals (Sweden)

    Syed Nuruddin

    Full Text Available Research on Alzheimer's disease (AD has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh and its receptor (Gnrhr were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate. The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP mutations (tgArcSwe. At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental

  13. Hormonal regulation of AMPA receptor trafficking and memory formation

    Directory of Open Access Journals (Sweden)

    Harmen J Krugers

    2009-10-01

    Full Text Available Humans and rodents retain memories for stressful events very well. The facilitated retention of these memories is normally very useful. However, in susceptible individuals a variety of pathological conditions may develop in which memories related to stressful events remain inappropriately present, such as in post-traumatic stress disorder. The memory enhancing effects of stress are mediated by hormones, such as norepinephrine and glucocorticoids which are released during stressful experiences. Here we review recently identified molecular mechanisms that underlie the effects of stress hormones on synaptic efficacy and learning and memory. We discuss AMPA receptors as major target for stress hormones and describe a model in which norepinephrine and glucocorticoids are able to strengthen and prolong different phases of stressful memories.

  14. Gonadotropin-Releasing Hormone Stimulate Aldosterone Production in a Subset of Aldosterone-Producing Adenoma

    Science.gov (United States)

    Kishimoto, Rui; Oki, Kenji; Yoneda, Masayasu; Gomez-Sanchez, Celso E.; Ohno, Haruya; Kobuke, Kazuhiro; Itcho, Kiyotaka; Kohno, Nobuoki

    2016-01-01

    Abstract We aimed to detect novel genes associated with G protein-coupled receptors (GPCRs) in aldosterone-producing adenoma (APA) and elucidate the mechanisms underlying aldosterone production. Microarray analysis targeting GPCR-associated genes was conducted using APA without known mutations (APA-WT) samples (n = 3) and APA with the KCNJ5 mutation (APA-KCNJ5; n = 3). Since gonadotropin-releasing hormone receptor (GNRHR) was the highest expression in APA-WT by microarray analysis, we investigated the effect of gonadotropin-releasing hormone (GnRH) stimulation on aldosterone production. The quantitative polymerase chain reaction assay results revealed higher GNRHR expression levels in APA-WT samples those in APA-KCNJ5 samples (P APA-WT samples, and there was a significant and positive correlation between GNRHR and LHCGR expression in all APA samples (r = 0.476, P APA-WT (n = 9), which showed higher GNRHR and LHCGR levels, had significantly higher GnRH-stimulated aldosterone response than those with APA-KCNJ5 (n = 13) (P APA-WT, and the molecular analysis including the receptor expression associated with clinical findings of GnRH stimulation. PMID:27196470

  15. Sex Hormone Receptor Repertoire in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Gerald M. Higa

    2013-01-01

    Full Text Available Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy, the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

  16. Expression and Role of Gonadotropin-Releasing Hormone 2 and Its Receptor in Mammals

    Directory of Open Access Journals (Sweden)

    Amy T. Desaulniers

    2017-12-01

    Full Text Available Gonadotropin-releasing hormone 1 (GnRH1 and its receptor (GnRHR1 drive mammalian reproduction via regulation of the gonadotropins. Yet, a second form of GnRH (GnRH2 and its receptor (GnRHR2 also exist in mammals. GnRH2 has been completely conserved throughout 500 million years of evolution, signifying high selection pressure and a critical biological role. However, the GnRH2 gene is absent (e.g., rat or inactivated (e.g., cow and sheep in some species but retained in others (e.g., human, horse, and pig. Likewise, many species (e.g., human, chimpanzee, cow, and sheep retain the GnRHR2 gene but lack the appropriate coding sequence to produce a full-length protein due to gene coding errors; although production of GnRHR2 in humans remains controversial. Certain mammals lack the GnRHR2 gene (e.g., mouse or most exons entirely (e.g., rat. In contrast, old world monkeys, musk shrews, and pigs maintain the coding sequence required to produce a functional GnRHR2. Like GnRHR1, GnRHR2 is a 7-transmembrane, G protein-coupled receptor that interacts with Gαq/11 to mediate cell signaling. However, GnRHR2 retains a cytoplasmic tail and is only 40% homologous to GnRHR1. A role for GnRH2 and its receptor in mammals has been elusive, likely because common laboratory models lack both the ligand and receptor. Uniquely, both GnRH2 and GnRHR2 are ubiquitously expressed; transcript levels are abundant in peripheral tissues and scarcely found in regions of the brain associated with gonadotropin secretion, suggesting a divergent role from GnRH1/GnRHR1. Indeed, GnRH2 and its receptor are not physiological modulators of gonadotropin secretion in mammals. Instead, GnRH2 and GnRHR2 coordinate the interaction between nutritional status and sexual behavior in the female brain. Within peripheral tissues, GnRH2 and its receptor are novel regulators of reproductive organs. GnRH2 and GnRHR2 directly stimulate steroidogenesis within the porcine testis. In the female, GnRH2 and

  17. Hmrbase: a database of hormones and their receptors

    Science.gov (United States)

    Rashid, Mamoon; Singla, Deepak; Sharma, Arun; Kumar, Manish; Raghava, Gajendra PS

    2009-01-01

    Background Hormones are signaling molecules that play vital roles in various life processes, like growth and differentiation, physiology, and reproduction. These molecules are mostly secreted by endocrine glands, and transported to target organs through the bloodstream. Deficient, or excessive, levels of hormones are associated with several diseases such as cancer, osteoporosis, diabetes etc. Thus, it is important to collect and compile information about hormones and their receptors. Description This manuscript describes a database called Hmrbase which has been developed for managing information about hormones and their receptors. It is a highly curated database for which information has been collected from the literature and the public databases. The current version of Hmrbase contains comprehensive information about ~2000 hormones, e.g., about their function, source organism, receptors, mature sequences, structures etc. Hmrbase also contains information about ~3000 hormone receptors, in terms of amino acid sequences, subcellular localizations, ligands, and post-translational modifications etc. One of the major features of this database is that it provides data about ~4100 hormone-receptor pairs. A number of online tools have been integrated into the database, to provide the facilities like keyword search, structure-based search, mapping of a given peptide(s) on the hormone/receptor sequence, sequence similarity search. This database also provides a number of external links to other resources/databases in order to help in the retrieving of further related information. Conclusion Owing to the high impact of endocrine research in the biomedical sciences, the Hmrbase could become a leading data portal for researchers. The salient features of Hmrbase are hormone-receptor pair-related information, mapping of peptide stretches on the protein sequences of hormones and receptors, Pfam domain annotations, categorical browsing options, online data submission, Drug

  18. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles

    DEFF Research Database (Denmark)

    Arce, Joan-Carles; La Marca, Antonio; Mirner Klein, Bjarke

    2013-01-01

    To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol....

  19. Asp330 and Tyr331 in the C-terminal cysteine-rich region of the luteinizing hormone receptor are key residues in hormone-induced receptor activation

    NARCIS (Netherlands)

    M.W.P. Bruysters (Martijn); M. Verhoef-Post (Miriam); A.P.N. Themmen (Axel)

    2008-01-01

    textabstractThe luteinizing hormone (LH) receptor plays an essential role in male and female gonadal function. Together with the follicle-stimulating hormone (FSH) and thyroid stimulating hormone (TSH) receptors, the LH receptor forms the family of glycoprotein hormone receptors. All glycoprotein

  20. Corticotropin-releasing hormone and pituitary-adrenal hormones in pregnancies complicated by chronic hypertension.

    Science.gov (United States)

    Warren, W B; Gurewitsch, E D; Goland, R S

    1995-02-01

    We hypothesized that maternal plasma corticotropin-releasing hormone levels are elevated in chronic hypertension and that elevations modulate maternal and fetal pituitary-adrenal function. Venous blood samples and 24-hour urine specimens were obtained in normal and hypertensive pregnancies at 21 to 40 weeks of gestation. Corticotropin-releasing hormone, corticotropin, cortisol, dehydroepiandrosterone sulfate, and total estriol levels were measured by radioimmunoassay. Mean hormone levels were compared by unpaired t test or two-way analysis of variance. Plasma corticotropin-releasing hormone levels were elevated early in hypertensive pregnancies but did not increase after 36 weeks. Levels of pituitary and adrenal hormones were not different in normal and hypertensive women. However, maternal plasma estriol levels were lower in hypertensive pregnancies compared with normal pregnancies. Fetal 16-hydroxy dehydroepiandrosterone sulfate, the major precursor to placental estriol production, has been reported to be lower than normal in hypertensive pregnancies, possibly explaining the decreased plasma estriol levels reported here. Early stimulation of placental corticotropin-releasing hormone production or secretion may be related to accelerated maturation of placental endocrine function in pregnancies complicated by chronic hypertension.

  1. Review: Regulatory mechanisms of gonadotropin-inhibitory hormone (GnIH synthesis and release in photoperiodic animals

    Directory of Open Access Journals (Sweden)

    Kazuyoshi eTsutsui

    2013-04-01

    Full Text Available Gonadotropin-inhibitory hormone (GnIH is a novel hypothalamic neuropeptide that was discovered in quail as an inhibitory factor for gonadotropin release. GnIH inhibits gonadotropin synthesis and release in birds through actions on gonadotropin-releasing hormone (GnRH neurons and gonadotropes, mediated via the GnIH receptor (GnIH-R, GPR147. Subsequently, GnIH was identified in mammals and other vertebrates. As in birds, mammalian GnIH inhibits gonadotropin secretion, indicating a conserved role for this neuropeptide in the control of the hypothalamic-pituitary-gonadal (HPG axis across species. Identification of the regulatory mechanisms governing GnIH expression and release is important in understanding the physiological role of the GnIH system. A nocturnal hormone, melatonin, appears to act directly on GnIH neurons through its receptor to induce expression and release of GnIH in quail, a photoperiodic bird. Recently, a similar, but opposite, action of melatonin on the inhibition of expression of mammalian GnIH was shown in hamsters and sheep, photoperiodic mammals. These results in photoperiodic animals demonstrate that GnIH expression is photoperiodically modulated via a melatonin-dependent process. Recent findings indicate that GnIH may be a mediator of stress-induced reproductive disruption in birds and mammals, pointing to a broad role for this neuropeptide in assessing physiological state and modifying reproductive effort accordingly. This paper summarizes the advances made in our knowledge regarding the regulation of GnIH synthesis and release in photoperiodic birds and mammals. This paper also discusses the neuroendocrine integration of environmental signals, such as photoperiods and stress, and internal signals, such as GnIH, melatonin and glucocorticoids, to control avian and mammalian reproduction.

  2. Octopus gonadotrophin-releasing hormone: a multifunctional peptide in the endocrine and nervous systems of the cephalopod.

    Science.gov (United States)

    Minakata, H; Shigeno, S; Kano, N; Haraguchi, S; Osugi, T; Tsutsui, K

    2009-03-01

    The optic gland, which is analogous to the anterior pituitary in the context of gonadal maturation, is found on the upper posterior edge of the optic tract of the octopus Octopus vulgaris. In mature octopus, the optic glands enlarge and secrete a gonadotrophic hormone. A peptide with structural features similar to that of vertebrate gonadotrophin-releasing hormone (GnRH) was isolated from the brain of octopus and was named oct-GnRH. Oct-GnRH showed luteinising hormone-releasing activity in the anterior pituitary cells of the Japanese quail Coturnix coturnix. Oct-GnRH immunoreactive signals were observed in the glandular cells of the mature optic gland. Oct-GnRH stimulated the synthesis and release of sex steroids from the ovary and testis, and elicited contractions of the oviduct. Oct-GnRH receptor was expressed in the gonads and accessory organs, such as the oviduct and oviducal gland. These results suggest that oct-GnRH induces the gonadal maturation and oviposition by regulating sex steroidogenesis and a series of egg-laying behaviours via the oct-GnRH receptor. The distribution and expression of oct-GnRH in the central and peripheral nervous systems suggest that oct-GnRH acts as a multifunctional modulatory factor in feeding, memory processing, sensory, movement and autonomic functions.

  3. Interleukin 1α inhibits prostaglandin E2 release to suppress pulsatile release of luteinizing hormone but not follicle-stimulating hormone

    International Nuclear Information System (INIS)

    Rettori, V.; McCann, S.M.; Gimeno, M.F.; Karara, A.; Gonzalez, M.C.

    1991-01-01

    Interleukin 1α (IL-1α), a powerful endogenous pyrogen released from monocytes and macrophages by bacterial endotoxin, stimulates corticotropin, prolactin, and somatotropin release and inhibits thyrotropin release by hypothalamic action. The authors injected recombinant human IL-1α into the third cerebral ventricle, to study its effect on the pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in conscious, freely moving, ovariectomized rats. Intraventricular injection of 0.25 pmol of IL-1α caused an almost immediate reduction of plasma LH concentration. To determine the mechanism of the suppression of LH release, mediobasal hypothalamic fragments were incubated in vitro with IL-1α (10 pM) and the release of LH-releasing hormone (LHRH) and prostaglandin E 2 into the medium was measured by RIA in the presence or absence of nonrepinephrine. 1α reduced basal LHRH release and blocked LHRH release induced by nonrepinephrine. In conclusion, IL-1α suppresses LH but not FSH release by an almost complete cessation of pulsatile release of LH in the castrated rat. The mechanism of this effect appears to be by inhibition of prostaglandin E 2 -mediated release of LHRH

  4. Thyroid Hormone Receptor Mutations in Cancer and Resistance to Thyroid Hormone: Perspective and Prognosis

    Directory of Open Access Journals (Sweden)

    Meghan D. Rosen

    2011-01-01

    Full Text Available Thyroid hormone, operating through its receptors, plays crucial roles in the control of normal human physiology and development; deviations from the norm can give rise to disease. Clinical endocrinologists often must confront and correct the consequences of inappropriately high or low thyroid hormone synthesis. Although more rare, disruptions in thyroid hormone endocrinology due to aberrations in the receptor also have severe medical consequences. This review will focus on the afflictions that are caused by, or are closely associated with, mutated thyroid hormone receptors. These include Resistance to Thyroid Hormone Syndrome, erythroleukemia, hepatocellular carcinoma, renal clear cell carcinoma, and thyroid cancer. We will describe current views on the molecular bases of these diseases, and what distinguishes the neoplastic from the non-neoplastic. We will also touch on studies that implicate alterations in receptor expression, and thyroid hormone levels, in certain oncogenic processes.

  5. Hypothalamic regulation of thyroid-stimulating hormone and prolactin release : the role of thyrotrophin-releasing hormone

    NARCIS (Netherlands)

    G.A.C. van Haasteren (Goedele)

    1995-01-01

    textabstractThyrotrophin-releasing-hormone (TRH), a tripeptide, is produced by hypothalamic neurons and transported along their axons to the median eminence (ME). From there it is released at nerve terminals into hypophyseal portal blood. It is then transported to the anterior pituitary gland where

  6. Ghrelin: much more than a hunger hormone

    Science.gov (United States)

    Ghrelin is a multifaceted gut hormone that activates its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin's hallmark functions are its stimulatory effects on growth hormone release, food intake and fat deposition. Ghrelin is famously known as the 'hunger hormone'. However, ample recen...

  7. Enhanced Anti-Tumoral Activity of Methotrexate-Human Serum Albumin Conjugated Nanoparticles by Targeting with Luteinizing Hormone-Releasing Hormone (LHRH) Peptide

    Science.gov (United States)

    Taheri, Azade; Dinarvand, Rassoul; Atyabi, Fatemeh; Ahadi, Fatemeh; Nouri, Farank Salman; Ghahremani, Mohammad Hossein; Ostad, Seyed Nasser; Borougeni, Atefeh Taheri; Mansoori, Pooria

    2011-01-01

    Active targeting could increase the efficacy of anticancer drugs. Methotrexate-human serum albumin (MTX-HSA) conjugates, functionalized by luteinizing hormone-releasing hormone (LHRH) as targeting moieties, with the aim of specifically targeting the cancer cells, were prepared. Owing to the high expression of LHRH receptors in many cancer cells as compared to normal cells, LHRH was used as the targeting ligand in this study. LHRH was conjugated to MTX-HSA nanoparticles via a cross-linker. Three types of LHRH targeted nanoparticles with a mean particle size between 120–138 nm were prepared. The cytotoxicity of LHRH targeted and non-targeted nanoparticles were determined on the LHRH positive and negative cell lines. The internalization of the targeted and non-targeted nanoparticles in LHRH receptor positive and negative cells was investigated using flow cytometry analysis and fluorescence microscopy. The cytotoxicity of the LHRH targeted nanoparticles on the LHRH receptor positive cells were significantly more than non-targeted nanoparticles. LHRH targeted nanoparticles were also internalized by LHRH receptor positive cells significantly more than non-targeted nanoparticles. There were no significant differences between the uptake of targeted and non-targeted nanoparticles to the LHRH receptor negative cells. The active targeting procedure using LHRH targeted MTX-HSA nanoparticles could increase the anti-tumoral activity of MTX. PMID:21845098

  8. Nonpeptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders.

    Science.gov (United States)

    Contoreggi, Carlo; Rice, Kenner C; Chrousos, George

    2004-01-01

    Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are also found in 'somatic' disorders. Some rare forms of Cushing's disease and related pituitary/adrenal disorders are obvious applications for CRHR1 antagonists. In addition, however, these antagonists may also be effective in treating more common somatic diseases. Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists. Hormonal, autonomic, and immune aberrations are also present in chronic inflammatory, autoimmune, and allergic diseases, with considerable evidence linking CRH with the observed abnormalities. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. Patients with irritable bowel syndrome and other gastrointestinal disorders frequently develop altered pain perception and affective symptoms. CRH acts peripherally to modulate bowel activity both directly through the autonomic system and centrally by processing viscerosensory and visceromotor neural signals. This review presents clinical and preclinical evidence for the role of CRH in the pathophysiology of these disorders and for potential diagnostic and therapeutic applications of CRHR1 antagonists. Recognition of a dysfunctional stress system in these and other diseases will alter the understanding and treatment of

  9. Cerebrospinal fluid levels of corticotropin-releasing hormone in women with functional hypothalamic amenorrhea.

    Science.gov (United States)

    Berga, S L; Loucks-Daniels, T L; Adler, L J; Chrousos, G P; Cameron, J L; Matthews, K A; Marcus, M D

    2000-04-01

    Women with functional hypothalamic amenorrhea are anovulatory because of reduced gonadotropin-releasing hormone drive. Several studies have documented hypercortisolemia, which suggests that functional hypothalamic amenorrhea is stress-induced. Further, with recovery (resumption of ovulation), cortisol decreased and gonadotropin-releasing hormone drive increased. Corticotropin-releasing hormone can increase cortisol and decrease gonadotropin-releasing hormone. To determine its role in functional hypothalamic amenorrhea, we measured corticotropin-releasing hormone in cerebrospinal fluid along with arginine vasopressin, another potent adrenocorticotropic hormone secretagog, and beta-endorphin, which is released by corticotropin-releasing hormone and can inhibit gonadotropin-releasing hormone. Corticotropin-releasing hormone, vasopressin, and beta-endorphin levels were measured in cerebrospinal fluid from 14 women with eumenorrhea and 15 women with functional hypothalamic amenorrhea. Levels of corticotropin-releasing hormone in cerebrospinal fluid and of vasopressin were comparable and beta-endorphin levels were lower in women with functional hypothalamic amenorrhea. In women with established functional hypothalamic amenorrhea, increased cortisol and reduced gonadotropin-releasing hormone are not sustained by elevated cerebrospinal-fluid corticotropin-releasing hormone, vasopressin, or beta-endorphin. These data do not exclude a role for these factors in the initiation of functional hypothalamic amenorrhea.

  10. Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model

    Directory of Open Access Journals (Sweden)

    Seok Joo Park

    2014-09-01

    Full Text Available BackgroundIt has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH/insulin-like growth factor-1 (IGF-1.MethodsIn this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice.ResultsThe GH-releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt/phospho-glycogen synthase kinase3β (p-GSK3β, phospho-extracellular signal-related kinase (p-ERK, and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho-c-jun N-terminal kinase (p-JNK, Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist.ConclusionThe results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation.

  11. Hormonal control of spermatogenesis: expression of FSJH receptor and androgen receptor genes

    NARCIS (Netherlands)

    L.J. Blok (Leen)

    1992-01-01

    textabstractFSH and testosterone are the main hormonal regulators of spermatogenesis. The actions of androgens and FSH are mediated by their respective receptors. Receptor gene expression (mRNA and protein). is an important determinant of hormone action. Biochemical aspects of the regulation of

  12. Radioimmunological and clinical studies with luteinizing hormone releasing hormone (LRH)

    International Nuclear Information System (INIS)

    Dahlen, H.G.

    1986-01-01

    Radioimmunoassay for Luteinizing Hormone Releasing Hormone (LRH) has been established, tested and applied. Optimal conditions for the performance with regards to incubation time, incubation temperature, concentration of antiserum and radiolabelled LRH have been established. The specificity of the LRH immunoassay was investigated. Problems with direct measurement of LRH in plasmas of radioimmunoassay are encountered. The LRH distribution in various tissues of the rat are investigated. By means of a system for continuous monitoring of LH and FSH in women the lowest effective dose of LRH causing a significant release of LH and FSH could be established. (Auth.)

  13. The expression of gonadotropin releasing hormone receptor gene in ovaries and uterus cells of Iraqi and Damascus goat breed

    Directory of Open Access Journals (Sweden)

    Alaa kamil Abdulla

    2017-07-01

    Full Text Available Iraqi goats have a major economic role in production of meat, milk and leather as well as it considered a financial source for owners as reproduce twice a year, yet the Damascus goats have great importance than Iraqi goats owing to the number of twin births. The gonadotropin releasing hormone (GnRH and its receptors have great importance in the reproduction and eugenics. To make a comparison between the Iraqi and Damascus goats in terms of this receptor gene expression in the ovaries and uterus tissue cells, the study was performed, in which used the (∆Ct Using a Reference Gene method by quintitive -real time PCR technique. Results were found a significant difference (p<0.05, as the gene expression of (GnRH-R higher in the ovaries and uterus tissue cells in Damascus goats compared with the Iraqi goats. In conclusion; the multiple pregnancies of twins in Damascus goats may be due to an increase gene expression of (GnRH-R in the ovaries and uterus tissue

  14. The interrelationships of thyroid and growth hormones: effect of growth hormone releasing hormone in hypo- and hyperthyroid male rats.

    Science.gov (United States)

    Root, A W; Shulman, D; Root, J; Diamond, F

    1986-01-01

    Growth hormone (GH) and the thyroid hormones interact in the hypothalamus, pituitary and peripheral tissues. Thyroid hormone exerts a permissive effect upon the anabolic and metabolic effects of GH, and increases pituitary synthesis of this protein hormone. GH depresses the secretion of thyrotropin and the thyroid hormones and increases the peripheral conversion of thyroxine to triiodothyronine. In the adult male rat experimental hypothyroidism produced by ingestion of propylthiouracil depresses the GH secretory response to GH-releasing hormone in vivo and in vitro, reflecting the lowered pituitary stores of GH in the hypothyroid state. Short term administration of large amounts of thyroxine with induction of the hyperthyroid state does not affect the in vivo GH secretory response to GH-releasing hormone in this animal.

  15. The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

    Directory of Open Access Journals (Sweden)

    Arpad eDobolyi

    2012-10-01

    Full Text Available The G-protein coupled parathyroid hormone 2 receptor (PTH2R is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand,tuberoinfundibular peptide of 39 residues (TIP39, is synthesized in only 2 brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control

  16. Thyroid Stimulating Hormone Receptor

    Directory of Open Access Journals (Sweden)

    Murat Tuncel

    2017-02-01

    Full Text Available Thyroid stimulating hormone receptor (TSHR plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases.

  17. Pituitary mammosomatotroph adenomas develop in old mice transgenic for growth hormone-releasing hormone

    DEFF Research Database (Denmark)

    Asa, S L; Kovacs, K; Stefaneanu, L

    1990-01-01

    It has been shown that mice transgenic for human growth hormone-releasing hormone (GRH) develop hyperplasia of pituitary somatotrophs and mammosomatotrophs, cells capable of producing both growth hormone and prolactin, by 8 months of age. We now report for the first time that old GRH-transgenic...

  18. Algorithmic complexity of growth hormone release in humans

    Energy Technology Data Exchange (ETDEWEB)

    Prank, K.; Wagner, M.; Brabant, G. [Medical School Hannover (Germany)

    1996-12-31

    Most hormones are secreted in an pulsatile rather than in a constant manner. This temporal pattern of pulsatile hormone release plays an important role in the regulation of cellular function and structure. In healthy humans growth hormone (GH) secretion is characterized by distinct pulses whereas patients bearing a GH producing tumor accompanied with excessive secretion (acromegaly) exhibit a highly irregular pattern of GH release. It has been hypothesized that this highly disorderly pattern of GH release in acromegaly arises from random events in the GH-producing tumor under decreased normal control of GH secretion. Using a context-free grammar complexity measure (algorithmic complexity) in conjunction with random surrogate data sets we demonstrate that the temporal pattern of GH release in acromegaly is not significantly different from a variety of stochastic processes. In contrast, normal subjects clearly exhibit deterministic structure in their temporal patterns of GH secretion. Our results support the hypothesis that GH release in acromegaly is due to random events in the GH-producing tumorous cells which might become independent from hypothalamic regulation. 17 refs., 1 fig., 2 tabs.

  19. Hormone receptor expression in male breast cancers | Akosa ...

    African Journals Online (AJOL)

    Male breast cancers are rare but have been found in higher proportions in Black Africans. Prognostic factors for breast cancers include tumour size, grade and stage, and hormone receptor status. The hormone receptor status is an invaluable guide in the use of adjuvant endocrine therapy, but none of the reports available ...

  20. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

    Directory of Open Access Journals (Sweden)

    Hiroki Ide

    2015-01-01

    Full Text Available There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.

  1. Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart.

    Science.gov (United States)

    Granata, Riccarda; Trovato, Letizia; Gallo, Maria Pia; Destefanis, Silvia; Settanni, Fabio; Scarlatti, Francesca; Brero, Alessia; Ramella, Roberta; Volante, Marco; Isgaard, Jorgen; Levi, Renzo; Papotti, Mauro; Alloatti, Giuseppe; Ghigo, Ezio

    2009-07-15

    The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and release in the pituitary. GHRH also exerts proliferative effects in extrapituitary cells, whereas GHRH antagonists have been shown to suppress cancer cell proliferation. We investigated GHRH effects on cardiac myocyte cell survival and the underlying signalling mechanisms. Reverse transcriptase-polymerase chain reaction analysis showed GHRH receptor (GHRH-R) mRNA in adult rat ventricular myocytes (ARVMs) and in rat heart H9c2 cells. In ARVMs, GHRH prevented cell death and caspase-3 activation induced by serum starvation and by the beta-adrenergic receptor agonist isoproterenol. The GHRH-R antagonist JV-1-36 abolished GHRH survival action under both experimental conditions. GHRH-induced cardiac cell protection required extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide-3 kinase (PI3K)/Akt activation and adenylyl cyclase/cAMP/protein kinase A signalling. Isoproterenol strongly upregulated the mRNA and protein of the pro-apoptotic inducible cAMP early repressor, whereas GHRH completely blocked this effect. Similar to ARVMs, in H9c2 cardiac cells, GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signalling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischaemia-reperfusion (I/R) injury. These effects involved PI3K/Akt signalling and were inhibited by JV-1-36. Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signalling mechanisms and protects against I/R injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.

  2. Efficacy of chemotherapy after hormone therapy for hormone receptor-positive metastatic breast cancer.

    Science.gov (United States)

    Mori, Ryutaro; Nagao, Yasuko

    2014-01-01

    According to the guidelines for metastatic breast cancer, hormone therapy for hormone receptor-positive metastatic breast cancer without life-threatening metastasis should be received prior to chemotherapy. Previous trials have investigated the sensitivity of chemotherapy for preoperative breast cancer based on the efficacy of neoadjuvant hormone therapy. In this retrospective study, we investigated the efficacy of chemotherapy for metastatic breast cancer in hormone therapy-effective and hormone therapy-ineffective cases. Patients who received chemotherapy after hormone therapy for metastatic breast cancer between 2006 and 2013 at our institution were investigated. A total of 32 patients received chemotherapy after hormone therapy for metastatic breast cancer. The median patient age was 59 years, and most of the primary tumors exhibited a T2 status. A total of 26 patients had an N(+) status, while 7 patients had human epidermal growth factor receptor 2-positive tumors. A total of 13 patients received clinical benefits from hormone therapy, with a rate of clinical benefit of subsequent chemotherapy of 30.8%, which was not significantly different from that observed in the hormone therapy-ineffective patients (52.6%). A total of 13 patients were able to continue the hormone therapy for more than 1 year, with a rate of clinical benefit of chemotherapy of 38.5%, which was not significantly different from that observed in the short-term hormone therapy patients (47.4%). The luminal A patients were able to continue hormone therapy for a significantly longer period than the non-luminal A patients (median survival time: 17.8 months vs 6.35 months, p = 0.0085). However, there were no significant differences in the response to or duration of chemotherapy. The efficacy of chemotherapy for metastatic breast cancer cannot be predicted based on the efficacy of prior hormone therapy or tumor subtype, and clinicians should administer chemotherapy in all cases of

  3. Identification of an estrogenic hormone receptor in Caenorhabditis elegans

    International Nuclear Information System (INIS)

    Mimoto, Ai; Fujii, Madoka; Usami, Makoto; Shimamura, Maki; Hirabayashi, Naoko; Kaneko, Takako; Sasagawa, Noboru; Ishiura, Shoichi

    2007-01-01

    Changes in both behavior and gene expression occur in Caenorhabditis elegans following exposure to sex hormones such as estrogen and progesterone, and to bisphenol A (BPA), an estrogenic endocrine-disrupting compound. However, only one steroid hormone receptor has been identified. Of the 284 known nuclear hormone receptors (NHRs) in C. elegans, we selected nhr-14, nhr-69, and nhr-121 for analysis as potential estrogenic hormone receptors, because they share sequence similarity with the human estrogen receptor. First, the genes were cloned and expressed in Escherichia coli, and then the affinity of each protein for estrogen was determined using a surface plasmon resonance (SPR) biosensor. All three NHRs bound estrogen in a dose-dependent fashion. To evaluate the specificity of the binding, we performed a solution competition assay using an SPR biosensor. According to our results, only NHR-14 was able to interact with estrogen. Therefore, we next examined whether nhr-14 regulates estrogen signaling in vivo. To investigate whether these interactions actually control the response of C. elegans to hormones, we investigated the expression of vitellogenin, an estrogen responsive gene, in an nhr-14 mutant. Semi-quantitative RT-PCR showed that vitellogenin expression was significantly reduced in the mutant. This suggests that NHR-14 is a C. elegans estrogenic hormone receptor and that it controls gene expression in response to estrogen

  4. Revisiting available knowledge on teleostean thyroid hormone receptors.

    Science.gov (United States)

    Lazcano, Iván; Orozco, Aurea

    2018-03-21

    Teleosts are the most numerous class of living vertebrates. They exhibit great diversity in terms of morphology, developmental strategies, ecology and adaptation. In spite of this diversity, teleosts conserve similarities at molecular, cellular and endocrine levels. In the context of thyroidal systems, and as in the rest of vertebrates, thyroid hormones in fish regulate development, growth and metabolism by actively entering the nucleus and interacting with thyroid hormone receptors, the final sensors of this endocrine signal, to regulate gene expression. In general terms, vertebrates express the functional thyroid hormone receptors alpha and beta, encoded by two distinct genes (thra and thrb, respectively). However, different species of teleosts express thyroid hormone receptor isoforms with particular structural characteristics that confer singular functional traits to these receptors. For example, teleosts contain two thra genes and in some species also two thrb; some of the expressed isoforms can bind alternative ligands. Also, some identified isoforms contain deletions or large insertions that have not been described in other vertebrates and that have not yet been functionally characterized. As in amphibians, the regulation of some of these teleost isoforms coincides with the climax of metamorphosis and/or life transitions during development and growth. In this review, we aimed to gain further insights into thyroid signaling from a comparative perspective by proposing a systematic nomenclature for teleost thyroid hormone receptor isoforms and summarize their particular functional features when the information was available. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. The interaction of corticotropin-releasing hormone receptor gene and early life stress on emotional empathy.

    Science.gov (United States)

    Grimm, Simone; Wirth, Katharina; Fan, Yan; Weigand, Anne; Gärtner, Matti; Feeser, Melanie; Dziobek, Isabel; Bajbouj, Malek; Aust, Sabine

    2017-06-30

    Early life stress (ELS) is associated with increased vulnerability for depression, changes to the corticotropin-releasing hormone (CRH) system and structural and functional changes in hippocampus. Single nucleotide polymorphisms in the CRH receptor 1 (CRHR1) gene interact with ELS to predict depression, cognitive functions and hippocampal activity. Social cognition has been related to hippocampal function and might be crucial for maintaining mental health. However, the interaction of CRHR1 gene variation and ELS on social cognition has not been investigated yet. We assessed social cognition in 502 healthy subjects to test effects of ELS and the CRHR1 gene. Participants were genotyped for rs110402 and rs242924. ELS was assessed by Childhood Trauma Questionnaire, social cognition was measured via Multifaceted Empathy Test and Empathy Quotient. Severity of ELS was associated with decreased emotional, but not cognitive empathy. Subjects with the common homozygous GG GG genotype showed decreased implicit emotional empathy after ELS exposure regardless of its severity. The results reveal that specific CRHR1 polymorphisms moderate the effect of ELS on emotional empathy. Exposure to ELS in combination with a vulnerable genotype results in impaired emotional empathy in adulthood, which might represent an early marker of increased vulnerability after ELS. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Application of hormone receptor assay for clinical chemistry

    International Nuclear Information System (INIS)

    Sato, Seiya

    1978-01-01

    A conception of hormone receptors was explained to understand radioreceptor assay (RRA), and various problems in the operation of this method were described mainly. The principle of RRA is the same as that of RIA and CPBA, and measured values by RRA resembled to those by bioassay more closely than those by RIA. However, the sensitivity of RRA was inferior to that of RIA. It was important in using this method especially for measurement of peptide hormone not to deactivate biological the base by radioactivation. As the significance of this method in clinical chemistry, it was mentioned that this method was one kind of experiment to observe the biological activity of hormones, and that properties analysis of receptors, studies on action mechanism, the structure and function of hormone, the pathological analysis of endocrine abnormalities, and the development of drugs and treatment methods for receptors may become possible by this method. The other usefulness of this method was also mentioned. (Kanao, N.)

  7. Application of hormone receptor assay for clinical chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Sato, S [Kitasato Univ. Hospital, Sagamihara, Kanagawa (Japan)

    1978-06-01

    A conception of hormone receptors was explained to understand radioreceptor assay (RRA), and various problems in the operation of this method were described mainly. The principle of RRA is the same as that of RIA and CPBA, and measured values by RRA resembled to those by bioassay more closely than those by RIA. However, the sensitivity of RRA was inferior to that of RIA. It was important in using this method especially for measurement of peptide hormone not to deactivate biological the base by radioactivation. As the significance of this method in clinical chemistry, it was mentioned that this method was one kind of experiment to observe the biological activity of hormones, and that properties analysis of receptors, studies on action mechanism, the structure and function of hormone, the pathological analysis of endocrine abnormalities, and the development of drugs and treatment methods for receptors may become possible by this method. The other usefulness of this method was also mentioned.

  8. Function of gonadotropin-releasing hormone in olfaction.

    Science.gov (United States)

    Wirsig-Wiechmann, C R

    2001-06-01

    Gonadotropin-releasing hormone (GnRH) is present within neurons of the nervus terminalis, the zeroeth cranial nerve. In all vertebrate species, except in sharks where it is a separate nerve, the nervus terminalis consists of a chain of neurons embedded within olfactory or vomeronasal nerves in the nasal cavity. The function of the GnRH component of the nervus terminalis is thought to be neuromodulatory. Our research on GnRH effects on olfaction confirms this hypothesis. The processes of GnRH neural cell bodies located within chemosensory nerves project centrally into the ventral forebrain and peripherally into the lamina propria of the nasal chemosensory mucosa. GnRH receptors are expressed by chemosensory neurons as shown by RT-PCR/Southern blotting and GnRH agonist binding studies. Patch-clamp studies have shown that GnRH alters the responses of isolated chemosensory neurons to natural or electrophysiological stimulation through the modulation of voltage-gated and receptor-gated channels. Behavioral experiments demonstrate that interfering with the nasal GnRH system leads to deficits in mating behavior. These studies suggest that the function of the intranasal GnRH system is to modify olfactory information, perhaps at reproductively auspicious times. We speculate that the purpose of this altered olfactory sense is to make pheromones more detectable and salient.

  9. Gonadotropin-Releasing Hormone Regulates Expression of the DNA Damage Repair Gene, Fanconi anemia A, in Pituitary Gonadotroph Cells1

    OpenAIRE

    Larder, Rachel; Chang, Lynda; Clinton, Michael; Brown, Pamela

    2004-01-01

    Gonadal function is critically dependant on regulated secretion of the gonadotropin hormones from anterior pituitary gonadotroph cells. Gonadotropin biosynthesis and release is triggered by the binding of hypothalamic GnRH to GnRH receptor expressed on the gonadotroph cell surface. The repertoire of regulatory molecules involved in this process are still being defined. We used the mouse LβT2 gonadotroph cell line, which expresses both gonadotropin hormones, as a model to investigate GnRH regu...

  10. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor β

    International Nuclear Information System (INIS)

    Sakurai, A.; Takeda, K.; Ain, K.; Ceccarelli, P.; Nakai, A.; Seino, S.; Bell, G.I.; Refetoff, S.; DeGroot, L.J.

    1989-01-01

    The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. The authors have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine → cytosine replacement in the codon for amino acid 340 resulted in a glycine → arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor β gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor β gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule

  11. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling.

    Science.gov (United States)

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook; Baek, Songjoon; Sung, Myong-Hee; Zhao, Li; Park, Jeong Won; Nielsen, Ronni; Walker, Robert L; Zhu, Yuelin J; Meltzer, Paul S; Hager, Gordon L; Cheng, Sheue-yann

    2015-04-28

    A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand.

  12. The role of releasing hormones in the diagnosis of hypopituitarism ...

    African Journals Online (AJOL)

    Luteinising hormone-releasing factor and thyrotrophinreleasing factor were used in conjunction with the insulin tolerance test in 9 patients with known or suspected panhypopituitarism. It appears that growth hormone and luteinising hormone fail early in panhypopituitarism. Cortisol and thyroid-stimulating hormone ...

  13. Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome.

    Directory of Open Access Journals (Sweden)

    Hazuki Komuro

    Full Text Available Corticotropin-releasing hormone (CRH plays an important role in the pathophysiology of irritable bowel syndrome (IBS and regulates the stress response through two CRH receptors (R1 and R2. Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436 and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220 were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale.We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017 and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS, and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710 and two SNPs (rs2284217 and rs2284220 in strong linkage disequilibrium (D' > 0.90. We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion.Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH

  14. Corticotropin-releasing hormone: Mediator of vertebrate life stage transitions?

    Science.gov (United States)

    Watanabe, Yugo; Grommen, Sylvia V H; De Groef, Bert

    2016-03-01

    Hormones, particularly thyroid hormones and corticosteroids, play critical roles in vertebrate life stage transitions such as amphibian metamorphosis, hatching in precocial birds, and smoltification in salmonids. Since they synergistically regulate several metabolic and developmental processes that accompany vertebrate life stage transitions, the existence of extensive cross-communication between the adrenal/interrenal and thyroidal axes is not surprising. Synergies of corticosteroids and thyroid hormones are based on effects at the level of tissue hormone sensitivity and gene regulation. In addition, in representative nonmammalian vertebrates, corticotropin-releasing hormone (CRH) stimulates hypophyseal thyrotropin secretion, and thus functions as a common regulator of both the adrenal/interrenal and thyroidal axes to release corticosteroids and thyroid hormones. The dual function of CRH has been speculated to control or affect the timing of vertebrate life history transitions across taxa. After a brief overview of recent insights in the molecular mechanisms behind the synergic actions of thyroid hormones and corticosteroids during life stage transitions, this review examines the evidence for a possible role of CRH in controlling vertebrate life stage transitions. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Preliminary studies of plasma growth hormone releasing activity during medical therapy of acromegaly

    International Nuclear Information System (INIS)

    Hagen, T.C.; Lawrence, A.M.; Kirsteins, L.

    1978-01-01

    The in vitro growth hormone releasing activity of plasma obtained from six acromegalic subjects was measured before and during therapy. In five subjects, plasmas were obtained before and during successful medical therapy with medroxyprogesterone acetate (MPA). The sixth subject was sampled before and after transphenoidal Sr 90 -induced hypopituitarism. All subjects had a decrement in fasting growth hormone levels with respective therapies (29-88%). The in vitro growth hormone released from Rhesus monkey anterior pituitaries was assessed after incubating one lateral half in control plasma (pre-therapy) and the contralateral pituitary half in plasma obtained during or after therapy. Studies with plasmas obtained from the five patients successfully treated with MPA showed a decrease in growth hormone releasing activity during therapy in all (18-57%). Plasma obtained after Sr 90 pituitary ablation in the sixth subject had 35% more growth hormone releasing activity than obtained before therapy. These results suggest that active acromegalics who respond to MPA with significantly lowered growth hormone levels may actually achieve this response because of a decrease in growth hormone releasing factor measured peripherally. The opposite response in one acromegalic subject, following Sr 90 pituitary ablation and hypopituitarism, suggests that growth hormone releasing factor secretion may increase when growth hormone levels are lowered by ablative therapy. (orig.) [de

  16. Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

    Science.gov (United States)

    Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

    1989-08-01

    The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.

  17. Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6

    International Nuclear Information System (INIS)

    Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V.

    1989-01-01

    The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel 6 ]LH-RH (SB-05) and [Ac-D-Nal(2) 1 ,D-Phe(pCl) 2 ,D-Pal(3) 3 ,Arg 5 ,D-Mel 6 ,D-Ala 10 ]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel 6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells

  18. Endocrine therapy use among elderly hormone receptor-pos...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators or aromatase...

  19. Social information changes stress hormone receptor expression in the songbird brain.

    Science.gov (United States)

    Cornelius, Jamie M; Perreau, Gillian; Bishop, Valerie R; Krause, Jesse S; Smith, Rachael; Hahn, Thomas P; Meddle, Simone L

    2018-01-01

    Social information is used by many vertebrate taxa to inform decision-making, including resource-mediated movements, yet the mechanisms whereby social information is integrated physiologically to affect such decisions remain unknown. Social information is known to influence the physiological response to food reduction in captive songbirds. Red crossbills (Loxia curvirostra) that were food reduced for several days showed significant elevations in circulating corticosterone (a "stress" hormone often responsive to food limitation) only if their neighbors were similarly food restricted. Physiological responses to glucocorticoid hormones are enacted through two receptors that may be expressed differentially in target tissues. Therefore, we investigated the influence of social information on the expression of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA in captive red crossbill brains. Although the role of MR and GR in the response to social information may be highly complex, we specifically predicted social information from food-restricted individuals would reduce MR and GR expression in two brain regions known to regulate hypothalamic-pituitary-adrenal (HPA) activity - given that reduced receptor expression may lessen the efficacy of negative feedback and release inhibitory tone on the HPA. Our results support these predictions - offering one potential mechanism whereby social cues could increase or sustain HPA-activity during stress. The data further suggest different mechanisms by which metabolic stress versus social information influence HPA activity and behavioral outcomes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein

    DEFF Research Database (Denmark)

    Muñoz, A; Zenke, M; Gehring, U

    1988-01-01

    mutations present in the carboxy-terminal half of P75gag-v-erbA co-operate in abolishing hormone binding, and that the ligand-binding domain resides in a position analogous to that of steroid receptors. Furthermore, a point mutation that is located between the putative DNA and ligand-binding domains of P75......To identify and characterize the hormone-binding domain of the thyroid hormone receptor, we analyzed the ligand-binding capacities of proteins representing chimeras between the normal receptor and P75gag-v-erbA, the retrovirus-encoded form deficient in binding ligand. Our results show that several......gag-v-erbA and that renders it biologically inactive fails to affect hormone binding by the c-erbA protein. These results suggest that the mutation changed the ability of P75gag-v-erbA to affect transcription since it also had no effect on DNA binding. Our data also suggest that hormone...

  1. Steroidal Hormone Receptor Expression in Male Breast Cancer

    Directory of Open Access Journals (Sweden)

    Fatemeh Homaei-Shandiz

    2014-01-01

    Full Text Available Introduction: The etiology of male breast cancer is unclear, but hormonal levels may play a role in development of this disease. It seems that the risk of male breast cancer related to increased lifelong exposure to estrogen or reduced androgen. The aim of this study was to investigate the expression of the steroid hormone receptors including estrogen receptor (ER and progesterone receptor (PR in Iranian cases with male breast cancer. Methods: This is a prospective review of 18 cases of male breast cancer in in Omid Hospital, Mashhad, North East of Iran, between October 2001 and October 2006. ER and PR were measured by immunohistochemistry. Clinicopathologic features and family history were obtained by interview. Data were analyzed with SPSS 13 using descriptive statistics.  Results: The median age was 63.2 year. All the cases were infiltrating ductal carcinoma. A high rate of expression of ER (88.8% and PR (66.6% was found in the studied cases. Conclusion: Cancers of the male breast are significantly more likely than cancers of the female breast to express hormonal receptors.

  2. [Common physicochemical characteristics of endogenous hormones-- liberins and statins].

    Science.gov (United States)

    Zamiatnin, A A; Voronina, O L

    1998-01-01

    The common chemical features of oligopeptide releasing-hormones and release inhibiting hormones were investigated with the aid of computer methods. 339 regulatory molecules of such type have been extracted out of data from computer bank EROP-Moscow. They contain from 2 to 47 amino acid residues and their sequences include short sites, which play apparently a decisive role in realization of interactions with the receptors. The analysis of chemical radicals shows that all liberins and statins contain positively charged group and cyclic radical of some amino acids or hydrophobic group. Results of this study indicate that the most chemical radicals of hormones are open for the interaction with potential receptors of target-cells. The mechanism of hormone ligand and receptors binding and conceivable role of amino acid and neurotransmitter radicals in hormonal properties of liberins and statins is discussed.

  3. Hyperinsulinemia is associated with increased soluble insulin receptors release from hepatocytes

    Directory of Open Access Journals (Sweden)

    Marcia eHiriart

    2014-06-01

    Full Text Available It has been generally assumed that insulin circulates freely in blood. However it can also interact with plasma proteins. Insulin receptors are located in the membrane of target cells and consist of an alpha and beta subunits with a tyrosine kinase cytoplasmic domain. The ectodomain, called soluble insulin receptor (SIR has been found elevated in patients with diabetes mellitus. We explored if insulin binds to SIRs in circulation under physiological conditions and hypothesize that this SIR may be released by hepatocytes in response to high insulin concentrations. The presence of SIR in rat and human plasmas and the culture medium of hepatocytes was explored using Western blot analysis. A purification protocol was performed to isolated SIR using affinity, gel filtration and ion exchange chromatographies. A modified reverse hemolytic plaque assay was used to measure SIR release from cultured hepatocytes. Incubation with 1 nmol l-1 insulin induces the release of the insulin receptor ectodomains from normal rat hepatocytes. This effect can be partially prevented by blocking protease activity. Furthermore, plasma levels of SIR were higher in a model of metabolic syndrome, where rats are hyperinsulinemic. We also found increased SIR levels in hyperinsulinemic humans. SIR may be an important regulator of the amount of free insulin in circulation. In hyperinsulinemia the amount of this soluble receptor increases, this could lead to higher amounts of insulin bound to this receptor, rather than free insulin, which is the biologically active form of the hormone. This observation could enlighten the mechanisms of insulin resistance.

  4. Structure and proteolysis of the growth hormone receptor on rat hepatocytes

    International Nuclear Information System (INIS)

    Yamada, K.; Lipson, K.E.; Donner, D.B.

    1987-01-01

    125 I-Labeled human growth hormone is isolated in high molecular weight (M/sub r/) (300,000, 220,000, and 130,000) and low molecular weight complexes on rat hepatocytes after affinity labeling. The time-dependent formation of low molecular weight complexes occurred at the expense of the higher molecular weight species and was inhibited by low temperature or inhibitors of serine proteinases. Exposure to reducing conditions induced loss of M/sub r/ 300,000 and 220,000 species and augmented the amount of M/sub r/ 130,000 complexes. The molecular weight of growth hormone (22,000) suggests that binding had occurred with species of M/sub r/ 280,000, 200,000, and 100,000. Two-dimensional gel electrophoresis demonstrated that the 100,000-dalton receptor subunit is contained in both the 280,000- and 200-000-dalton species. Reduction of interchain disulfide bonds in the growth hormone receptor did not alter its elution from gel filtration columns, but intact, high molecular weight receptor constituents were separated from lower molecular weight degradation products. Digestion of affinity-labeled growth hormone-receptor complexes with neuraminidase increased the mobility of receptor constituents on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These observations show that the growth hormone receptor is degraded by hepatic serine proteinases to low molecular weight degradation products which can be separated from intact receptor by gel filtration. Intact hormone-receptor complexes are aggregates of 100,000-dalton sialoglycoprotein subunits held together by interchain disulfide bonds and by noncovalent forces

  5. Isotocin Regulates Growth Hormone but Not Prolactin Release From the Pituitary of Ricefield Eels

    Directory of Open Access Journals (Sweden)

    Wei Yang

    2018-04-01

    Full Text Available The neurohypophyseal hormone oxytocin (Oxt has been shown to stimulate prolactin (Prl synthesis and release from the adenohypophysis in rats. However, little is known about the functional roles of Oxt-like neuropeptides in the adenohypophysis of non-mammalian vertebrates. In this study, cDNAs encoding ricefield eel oxytocin-like receptors (Oxtlr, namely isotocin (Ist receptor 1 (Istr1 and 2 (Istr2, were isolated and specific antisera were generated, respectively. RT-PCR and Western blot analysis detected the presence of both Istr1 and Istr2 in the brain and pituitary, but differential expression in some peripheral tissues, including the liver and kidney, where only Istr1 was detected. In the pituitary, immunoreactive Istr1 and Istr2 were differentially distributed, with the former mainly in adenohypophyseal cell layers adjacent to the neurohypophysis, whereas the latter in peripheral areas of the adenohypophysis. Double immunofluorescent images showed that immunostaining of Istr1, but not Istr2 was localized to growth hormone (Gh cells, but neither of them was expressed in Prl cells. Ist inhibited Gh release in primary pituitary cells of ricefield eels and increased Gh contents in the pituitary gland of ricefield eels at 6 h after in vivo administration. Ist inhibition of Gh release is probably mediated by cAMP, PKC/DAG, and IP3/Ca2+ pathways. In contrast, Ist did not affect either prl gene expression or Prl contents in primary pituitary cells. Results of this study demonstrated that Ist may not be involved in the regulation of Prl, but inhibit Gh release via Istr1 rather than Istr2 in ricefield eels, and provided evidence for the direct regulation of Gh cells by oxytocin-like neuropeptides in the pituitary of non-mammalian vertebrates.

  6. Isotocin Regulates Growth Hormone but Not Prolactin Release From the Pituitary of Ricefield Eels

    Science.gov (United States)

    Yang, Wei; Zhang, Ning; Shi, Boyang; Zhang, Shen; Zhang, Lihong; Zhang, Weimin

    2018-01-01

    The neurohypophyseal hormone oxytocin (Oxt) has been shown to stimulate prolactin (Prl) synthesis and release from the adenohypophysis in rats. However, little is known about the functional roles of Oxt-like neuropeptides in the adenohypophysis of non-mammalian vertebrates. In this study, cDNAs encoding ricefield eel oxytocin-like receptors (Oxtlr), namely isotocin (Ist) receptor 1 (Istr1) and 2 (Istr2), were isolated and specific antisera were generated, respectively. RT-PCR and Western blot analysis detected the presence of both Istr1 and Istr2 in the brain and pituitary, but differential expression in some peripheral tissues, including the liver and kidney, where only Istr1 was detected. In the pituitary, immunoreactive Istr1 and Istr2 were differentially distributed, with the former mainly in adenohypophyseal cell layers adjacent to the neurohypophysis, whereas the latter in peripheral areas of the adenohypophysis. Double immunofluorescent images showed that immunostaining of Istr1, but not Istr2 was localized to growth hormone (Gh) cells, but neither of them was expressed in Prl cells. Ist inhibited Gh release in primary pituitary cells of ricefield eels and increased Gh contents in the pituitary gland of ricefield eels at 6 h after in vivo administration. Ist inhibition of Gh release is probably mediated by cAMP, PKC/DAG, and IP3/Ca2+ pathways. In contrast, Ist did not affect either prl gene expression or Prl contents in primary pituitary cells. Results of this study demonstrated that Ist may not be involved in the regulation of Prl, but inhibit Gh release via Istr1 rather than Istr2 in ricefield eels, and provided evidence for the direct regulation of Gh cells by oxytocin-like neuropeptides in the pituitary of non-mammalian vertebrates.

  7. Thyrotropin-releasing hormone (TRH) receptors. Localization by light microscopic autoradiography in rat brain using [3H][3-Me-His2]TRH as the radioligand

    International Nuclear Information System (INIS)

    Mantyh, P.W.; Hunt, S.P.

    1985-01-01

    Thyrotropin releasing hormone (TRH) is a putative neurotransmitter in both the central and peripheral nervous system. In the present report, we have used autoradiography coupled with densitometric analysis of tritium-sensitive film to investigate the distribution of [ 3 H][3-Me-His2]TRH [( 3 H]MeTRH)-binding sizes in the rat brain. Previous pharmacological reports have established that many of these [ 3 H]MeTRH-binding sites have a structure-activity profile consistent with being a physiological TRH receptor. A high level of TRH receptors were observed in the accessory olfactory bulb, lateral nucleus of the amygdala, dentate gyrus, and entorhinal cortex. Moderate levels of TRH receptors were observed in the rhinal cortex, hypothalamus, superior colliculus, several brainstem motor nuclei, and lamina I of the spinal trigeminal nucleus pars candalis, while low concentrations of receptors are present in the cerebral cortex, striatum and ventral horn of the spinal cord. Very low levels of receptors were observed in the globus pallidus and in most nuclei of the dorsal thalamus. Comparisons of the distribution of TRH receptors to TRH-immunoreactive content indicates that, while in some areas of the brain there is a rough correlation between levels of TRH peptide and its receptor, in most brain areas there is little obvious correlation between the two. While such a discrepancy has been observed for other peptides and their receptors, the extensive distribution of TRH receptors in the central nervous system does provide an explanation for the variety of behavioral effects observed when TRH is infused into the central nervous system

  8. Association of glucocorticoid and type 1 corticotropin-releasing hormone receptors gene variants and risk for depression during pregnancy and post-partum.

    Science.gov (United States)

    Engineer, Neelam; Darwin, Lucy; Nishigandh, Deole; Ngianga-Bakwin, Kandala; Smith, Steve C; Grammatopoulos, Dimitris K

    2013-09-01

    Women with postnatal depression (PND) appear to have abnormal hypothalamic pituitary adrenal (HPA) axis responses to stress, which might involve a genetic variability component. We investigated association of genetic variants in the glucocorticoid receptor (GR, NR3C1) and corticotropin releasing hormone receptor 1 (CRHR1) genes with increased risk for PND. Two hundred pregnant women were recruited prospectively and PND risk was assessed by the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy and again 2-8 weeks post-natally (CW-GAPND study). The BclI and ER22/23EK single nucleotide polymorphisms (SNPs) of the GR and the haplotype-tagged rs1876828, rs242939 and rs242941 SNPs of the CRHR1 associated with genetic risk to depressive disorders were genotyped. A cut-off score of 10 was used to detect increased risk of PND. Association analysis was carried out in 140 patients that completed the study protocol. The BclI and rs242939 SNPs were over-represented in women with postnatal EPDS score ≥10 with significant allele association (p = 0.011 and depression during pregnancy and postpartum. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Overnight Levels of Luteinizing Hormone, Follicle-Stimulating Hormone and Growth Hormone before and during Gonadotropin-Releasing Hormone Analogue Treatment in Short Boys Born Small for Gestational Age

    NARCIS (Netherlands)

    van der Kaay, Danielle C. M.; de Jong, Frank H.; Rose, Susan R.; Odink, Roelof J. H.; Bakker-van Waarde, Willie M.; Sulkers, Eric J.; Hokken-Koelega, Anita C. S.

    2009-01-01

    Aims: To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone

  10. Biosynthesis of gonadotropin-releasing hormone (GnRH) and GnRH receptor (GnRHR) in hypothalamic-pituitary unit of anoestrous and cyclic ewes.

    Science.gov (United States)

    Ciechanowska, M O; Łapot, M; Mateusiak, K; Paruszewska, E; Malewski, T; Przekop, F

    2017-02-01

    This study was performed to explain how the molecular processes governing the biosynthesis of gonadotropin-releasing hormone (GnRH) and GnRH receptor (GnRHR) in the hypothalamic-pituitary unit are reflected by luteinizing hormone (LH) secretion in sheep during anoestrous period and during luteal and follicular phases of the oestrous cycle. Using an enzyme-linked immunosorbent assay (ELISA), we analyzed the levels of GnRH and GnRHR in preoptic area (POA), anterior (AH) and ventromedial hypothalamus (VM), stalk-median eminence (SME), and GnRHR in the anterior pituitary gland (AP). Radioimmunoassay has also been used to define changes in plasma LH concentrations. The study provides evidence that the levels of GnRH in the whole hypothalamus of anoestrous ewes were lower than that in sheep during the follicular phase of the oestrous cycle (POA: p pituitary unit, as well as LH level, in the blood in anoestrous ewes were significantly lower than those detected in animals of both cyclic groups. Our data suggest that decrease in LH secretion during the long photoperiod in sheep may be due to low translational activity of genes encoding both GnRH and GnRHR.

  11. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects

    Directory of Open Access Journals (Sweden)

    Farhad Dehkhoda

    2018-02-01

    Full Text Available The growth hormone receptor (GHR, although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK–signal transducer and activator of transcription (STAT signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK–STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2. This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling.

  12. Radioreceptor assays: plasma membrane receptors and assays for polypeptide and glycoprotein hormones

    International Nuclear Information System (INIS)

    Schulster, D.

    1977-01-01

    Receptors for peptide, protein and glycoprotein hormones, and the catecholamines are located on the plasma membranes of their target cells. Preparations of the receptors may be used as specific, high-affinity binding agents for these hormones in assay methodology akin to that for radioimmunoassay. A particular advantage of the radioreceptor assay is that it has a specificity directed towards the biologically active region of the hormone, rather than to some immunologically active region that may have little (or no) involvement in the expression of hormonal activity. Methods for hormone receptor preparation vary greatly, and range from the use of intact cells (as the source of hormone receptor) to the use of purified or solubilized membrane receptors. Receptors isolated from plasma membranes have proved to be of variable stability, and may be damaged during preparation and/or storage. Moreover, since they are present in relatively low concentration in the cell, their preparation in sufficient quantity for use in a radioreceptor assay may present technical problems. In general, there is good correlation between radioreceptor assays and in-vitro bioassays; differences between results from radioreceptor assays and radioimmunoassays are similar to those noted between in-vitro bioassays and radioimmunoassays. The sensitivity of the method is such that normal plasma concentrations of various hormones have been assayed by this technique. (author)

  13. Fanconi Anemia a Is a Nucleocytoplasmic Shuttling Molecule Required for Gonadotropin-Releasing Hormone (GnRH) Transduction of the GnRH Receptor

    OpenAIRE

    Larder, Rachel; Karali, Dimitra; Nelson, Nancy; Brown, Pamela

    2006-01-01

    GnRH binds its cognate G protein-coupled GnRH receptor (GnRHR) located on pituitary gonadotropes and drives expression of gonadotropin hormones. There are two gonadotropin hormones, comprised of a common α- and hormone-specific β-subunit, which are required for gonadal function. Recently we identified that Fanconi anemia a (Fanca), a DNA damage repair gene, is differentially expressed within the LβT2 gonadotrope cell line in response to stimulation with GnRH. FANCA is mutated in more than 60%...

  14. The Arabidopsis NPR1 Protein Is a Receptor for the Plant Defense Hormone Salicylic Acid

    Directory of Open Access Journals (Sweden)

    Yue Wu

    2012-06-01

    Full Text Available Salicylic acid (SA is an essential hormone in plant immunity, but its receptor has remained elusive for decades. The transcriptional coregulator NPR1 is central to the activation of SA-dependent defense genes, and we previously found that Cys521 and Cys529 of Arabidopsis NPR1's transactivation domain are critical for coactivator function. Here, we demonstrate that NPR1 directly binds SA, but not inactive structural analogs, with an affinity similar to that of other hormone-receptor interactions and consistent with in vivo Arabidopsis SA concentrations. Binding of SA occurs through Cys521/529 via the transition metal copper. Mechanistically, our results suggest that binding of SA causes a conformational change in NPR1 that is accompanied by the release of the C-terminal transactivation domain from the N-terminal autoinhibitory BTB/POZ domain. While NPR1 is already known as a link between the SA signaling molecule and defense-gene activation, we now show that NPR1 is the receptor for SA.

  15. Antiproliferative effect of growth hormone-releasing hormone (GHRH antagonist on ovarian cancer cells through the EGFR-Akt pathway

    Directory of Open Access Journals (Sweden)

    Varga Jozsef

    2010-05-01

    Full Text Available Abstract Background Antagonists of growth hormone-releasing hormone (GHRH are being developed for the treatment of various human cancers. Methods MTT assay was used to test the proliferation of SKOV3 and CaOV3. The splice variant expression of GHRH receptors was examined by RT-PCR. The expression of protein in signal pathway was examined by Western blotting. siRNA was used to block the effect of EGFR. Results In this study, we investigated the effects of a new GHRH antagonist JMR-132, in ovarian cancer cell lines SKOV3 and CaOV3 expressing splice variant (SV1 of GHRH receptors. MTT assay showed that JMR-132 had strong antiproliferative effects on SKOV3 and CaOV3 cells in both a time-dependent and dose-dependent fashion. JMR-132 also induced the activation and increased cleaved caspase3 in a time- and dose-dependent manner in both cell lines. In addition, JMR-132 treatments decreased significantly the epidermal growth factor receptor (EGFR level and the phosphorylation of Akt (p-Akt, suggesting that JMR-132 inhibits the EGFR-Akt pathway in ovarian cancer cells. More importantly, treatment of SKOV3 and CaOV3 cells with 100 nM JMR-132 attenuated proliferation and the antiapoptotic effect induced by EGF in both cell lines. After the knockdown of the expression of EGFR by siRNA, the antiproliferative effect of JMR-132 was abolished in SKOV3 and CaOV3 cells. Conclusions The present study demonstrates that the inhibitory effect of the GHRH antagonist JMR-132 on proliferation is due, in part, to an interference with the EGFR-Akt pathway in ovarian cancer cells.

  16. Thyroid hormone and retinoic acid nuclear receptors: specific ligand-activated transcription factors

    International Nuclear Information System (INIS)

    Brtko, J.

    1998-01-01

    Transcriptional regulation by both the thyroid hormone and the vitamin A-derived 'retinoid hormones' is a critical component in controlling many aspects of higher vertebrate development and metabolism. Their functions are mediated by nuclear receptors, which comprise a large super-family of ligand-inducible transcription factors. Both the thyroid hormone and the retinoids are involved in a complex arrangement of physiological and development responses in many tissues of higher vertebrates. The functions of 3,5,3'-triiodothyronine (T 3 ), the thyromimetically active metabolite of thyroxine as well as all-trans retinoic acid, the biologically active vitamin A metabolite are mediated by nuclear receptor proteins that are members of the steroid/thyroid/retinoid hormone receptor family. The functions of all members of the receptor super family are discussed. (authors)

  17. Development of New Gonadotropin-Releasing Hormone-Modified Dendrimer Platforms with Direct Antiproliferative and Gonadotropin Releasing Activity.

    Science.gov (United States)

    Varamini, Pegah; Rafiee, Amirreza; Giddam, Ashwini Kumar; Mansfeld, Friederike M; Steyn, Frederik; Toth, Istvan

    2017-10-26

    Gonadotropin-releasing hormone (GnRH) agonists (e.g., triptorelin) are used for androgen suppression therapy. They possess improved stability as compared to the natural GnRH, yet they suffer from a poor pharmacokinetic profile. To address this, we used a GnRH peptide-modified dendrimer platform with and without lipidation strategy. Dendrimers were synthesized on a polylysine core and bore either native GnRH (1, 2, and 5) or lipid-modified GnRH (3 and 4). Compound 3, which bore a lipidic moiety in a branched tetramer structure, showed approximately 10-fold higher permeability and metabolic stability and 39 times higher antitumor activity against hormone-resistant prostate cancer cells (DU145) relative to triptorelin. In gonadotropin-release experiments, dendrimer 3 was shown to be the most potent construct. Dendrimer 3 showed similar luteinizing hormone (LH)-release activity to triptorelin in mice. Our findings indicate that dendrimer 3 is a promising analog with higher potency for the treatment of hormone-resistant prostate cancer than the currently available GnRH agonists.

  18. Effects of an Antagonistic Analog of Growth Hormone-Releasing Hormone on Endometriosis in a Mouse Model and In Vitro.

    Science.gov (United States)

    Köster, Frank; Jin, Li; Shen, Yuanming; Schally, Andrew V; Cai, Ren-Zhi; Block, Norman L; Hornung, Daniela; Marschner, Gabriele; Rody, Achim; Engel, Jörg B; Finas, Dominique

    2017-11-01

    Endometriosis is a benign gynecologic disorder causing dysmenorrhea, pelvic pain, and subfertility. Receptors for the growth hormone-releasing hormone (GHRH) were found in endometriotic tissues. Antagonists of GHRH have been used to inhibit the growth of endometriotic endometrial stromal cells. In this study, the GHRH receptor splice variant (SV) 1 was detected in human endometrial tissue samples by Western blots and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The highest messenger RNA (mRNA) and protein levels of SV1 were found in eutopic endometrium from patients with endometriosis compared to ectopic endometriotic tissues and endometrium from normal patients. The highest expression for GHRH mRNA was found by qRT-PCR in ectopic endometriosis lesions. In an in vivo mouse model with human endometrial explants from patients with endometriosis, 10 μg MIA-602 per day resulted in significantly smaller human endometrial xenotransplants after 4 weeks compared to mice treated with vehicle. The endometrial tissues expressed SV1 before and after xenotransplantation. The proliferation of endometrial stromal cells as well as the endometriosis cell lines 12-Z and 49-Z was decreased by exposure to 1 μM MIA-602 after 72 hours. The protein levels of epithelial growth factor receptors in 12-Z and 49-Z cell lines were reduced 48 and 72 hours after the administration of 1 μM MIA-602. MIA-602 decreased the activation of the MAP-kinases ERK-1/2. Our study demonstrates the presence of SV1 receptor as a target for treatment with GHRH antagonist in endometriosis. Endometrial tissues respond to MIA-602 with inhibition of proliferation in vitro and in vivo. The use of MIA-602 could be an effective supplement to the treatment strategies in endometriosis.

  19. Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1 Clustering with MAGUKs Is Mediated via Its C-Terminal PDZ Binding Motif.

    Directory of Open Access Journals (Sweden)

    Julia Bender

    Full Text Available The corticotropin-releasing hormone receptor type 1 (CRHR1 plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail of the receptor as bait. We identified several members of the membrane-associated guanylate kinase (MAGUK family: postsynaptic density protein 95 (PSD95, synapse-associated protein 97 (SAP97, SAP102 and membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2. CRHR1 is co-expressed with the identified MAGUKs and with the additionally investigated PSD93 in neurons of the adult mouse brain and in primary hippocampal neurons, supporting the probability of a physiological interaction in vivo. The C-terminal PDZ (PSD-95, discs large, zona occludens 1 binding motif of CRHR1 is essential for its physical interaction with MAGUKs, as revealed by the CRHR1-STAVA mutant, which harbors a functionally impaired PDZ binding motif. The imitation of a phosphorylation at Thr413 within the PDZ binding motif also disrupted the interaction with MAGUKs. In contrast, distinct PDZ domains within the identified MAGUKs are involved in the interactions. Expression of CRHR1 in primary neurons demonstrated its localization throughout the neuronal plasma membrane, including the excitatory post synapse, where the receptor co-localized with PSD95 and SAP97. The co-expression of CRHR1 and respective interacting MAGUKs in HEK293 cells resulted in a clustered subcellular co-localization which required an intact PDZ binding motif. In conclusion, our study characterized the PDZ binding motif-mediated interaction of CRHR1 with multiple MAGUKs, which directly affects receptor function.

  20. Effects of long-term treatment with growth hormone-releasing peptide-2 in the GHRH knockout mouse.

    Science.gov (United States)

    Alba, Maria; Fintini, Danilo; Bowers, Cyril Y; Parlow, A F; Salvatori, Roberto

    2005-11-01

    Growth hormone (GH) secretagogues (GHS) stimulate GH secretion in vivo in humans and in animals. They act on the ghrelin receptor, expressed in both the hypothalamus and the pituitary. It is unknown whether GHSs act predominantly by increasing the release of hypothalamic GH-releasing hormone (GHRH) or by acting directly on the somatotroph cells. We studied whether a potent GHS could stimulate growth in the absence of endogenous GHRH. To this end, we used GHRH knockout (GHRH-KO) mice. These animals have proportionate dwarfism due to severe GH deficiency (GHD) and pituitary hypoplasia due to reduced somatotroph cell mass. We treated male GHRH-KO mice for 6 wk (from week 1 to week 7 of age) with GH-releasing peptide-2 (GHRP-2, 10 microg s.c. twice a day). Chronic treatment with GHRP-2 failed to stimulate somatotroph cell proliferation and GH secretion and to promote longitudinal growth. GHRP-2-treated mice showed an increase in total body weight compared with placebo-treated animals, due to worsening of the body composition alterations typical of GHD animals. These data demonstrate that GHRP-2 failed to reverse the severe GHD caused by lack of GHRH.

  1. Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

    Science.gov (United States)

    Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

    2015-11-01

    In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Facial morphometry of Ecuadorian patients with growth hormone receptor deficiency/Laron syndrome.

    Science.gov (United States)

    Schaefer, G B; Rosenbloom, A L; Guevara-Aguirre, J; Campbell, E A; Ullrich, F; Patil, K; Frias, J L

    1994-01-01

    Facial morphometry using computerised image analysis was performed on patients with growth hormone receptor deficiency (Laron syndrome) from an inbred population of southern Ecuador. Morphometrics were compared for 49 patients, 70 unaffected relatives, and 14 unrelated persons. Patients with growth hormone receptor deficiency showed significant decreases in measures of vertical facial growth as compared to unaffected relatives and unrelated persons with short stature from other causes. This report validates and quantifies the clinical impression of foreshortened facies in growth hormone receptor deficiency. Images PMID:7815422

  3. Effects of growth hormone treatment on the pituitary expression of GHRH receptor mRNA in uremic rats.

    Science.gov (United States)

    Ferrando, Susana; Rodríguez, Julián; Santos, Fernando; Weruaga, Ana; Fernández, Marta; Carbajo, Eduardo; García, Enrique

    2002-09-01

    A decreased ability of pituitary cells to secrete growth hormone (GH) in response to growth hormone releasing hormone (GHRH) stimulation has been shown in young uremic rats. The aim of the current study was to examine the effect of uremia and GH treatment on pituitary GHRH receptor expression. Pituitary GHRH receptor mRNA levels were analyzed by RNase protection assay in young female rats made uremic by subtotal nephrectomy, either untreated (UREM) or treated with 10 IU/kg/day of GH (UREM-GH), and normal renal function animals fed ad libitum (SAL) or pair-fed with the UREM group (SPF). Rats were sacrificed 14 days after the second stage nephrectomy. Renal failure was confirmed by concentrations (X +/- SEM) of serum urea nitrogen (mmol/L) and creatinine (micromol/L) in UREM (20 +/- 1 and 89.4 +/- 4.5) and UREM-GH (16 +/- 1 and 91.4 +/- 6.9) that were much higher (P growth retarded as shown by a daily longitudinal tibia growth rate below (P growth rate acceleration (213 +/- 6 microm/day). GHRH receptor mRNA levels were no different among the SAL (0.43 +/- 0.03), SPF (0.43 +/- 0.08) and UREM (0.44 +/- 0.04) groups, whereas UREM-GH rats had significantly higher values (0.72 +/- 0.07). The status of pituitary GHRH receptor is not modified by nutritional deficit or by severe uremia causing growth retardation. By contrast, the growth promoting effect of GH administration is associated with stimulated GHRH receptor gene expression.

  4. EP3 receptors inhibit antidiuretic-hormone-dependent sodium transport across frog skin epithelium

    DEFF Research Database (Denmark)

    Rytved, Klaus A.; Nielsen, Robert

    1999-01-01

    Antidiuretic hormone; tight epithelium; prostaglandin receptors; sulprostone; misoprostol; cAMP; cellular Ca2+......Antidiuretic hormone; tight epithelium; prostaglandin receptors; sulprostone; misoprostol; cAMP; cellular Ca2+...

  5. Hormone action. Part I. Peptide hormones

    International Nuclear Information System (INIS)

    Birnbaumer, L.; O'Malley, B.W.

    1985-01-01

    The major sections of this book on the hormonal action of peptide hormones cover receptor assays, identification of receptor proteins, methods for identification of internalized hormones and hormone receptors, preparation of hormonally responsive cells and cell hybrids, purification of membrane receptors and related techniques, assays of hormonal effects and related functions, and antibodies in hormone action

  6. Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro

    DEFF Research Database (Denmark)

    Billestrup, Nils; Swanson, L W; Vale, W

    1986-01-01

    The mitogenic effect of the hypothalamic peptides growth hormone-releasing factor (GRF) and somatostatin on cultured growth hormone (GH)-producing cells (somatotrophs) was studied. Using autoradiographic detection of [3H]thymidine uptake and immunocytochemical identification of GH-producing cells...

  7. The growth hormone (GH) response to GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2), GH-releasing hormone, and thyrotropin-releasing hormone in acromegaly.

    Science.gov (United States)

    Alster, D K; Bowers, C Y; Jaffe, C A; Ho, P J; Barkan, A L

    1993-09-01

    In patients with acromegaly, GH-producing pituitary tumors release GH in response to specific stimuli such as GH-releasing hormone (GHRH) and are also responsive to a variety of nonspecific stimuli, such as TRH or GnRH, and may exhibit paradoxical responses to glucose and dopamine. In healthy humans, the synthetic peptide GH-releasing peptide (GHRP) (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) releases GH by a putative mechanism of action that is independent of GHRH. How these tumors respond to GHRP is not well characterized. We studied the GH responses to GHRH, GHRP, and TRH stimulation in 11 patients with active acromegaly. The peak GH responses to GHRP and GHRH were not correlated (r = 0.57; P = 0.066). In contrast, the peak GH responses to GHRP and TRH were highly correlated (r = 0.95; P < 0.001). In conclusion, in patients with acromegaly, the GH response to GHRP is qualitatively normal and does not appear to depend on GHRH.

  8. Thyroid hormone receptor binds to a site in the rat growth hormone promoter required for induction by thyroid hormone

    International Nuclear Information System (INIS)

    Koenig, R.J.; Brent, G.A.; Warne, R.L.; Larsen, P.R.; Moore, D.D.

    1987-01-01

    Transcription of the rat growth hormone (rGH) gene in pituitary cells is increased by addition of thyroid hormone (T3). This induction is dependent on the presence of specific sequences just upstream of the rGH promoter. The authors have partially purified T3 receptor from rat liver and examined its interaction with these rGH sequences. They show here that T3 receptor binds specifically to a site just upstream of the basal rGH promoter. This binding site includes two copies of a 7-base-pair direct repeat, the centers of which are separated by 10 base pairs. Deletions that specifically remove the T3 receptor binding site drastically reduce response to T3 in transient transfection experiments. These results demonstrate that T3 receptor can recognize specific DNA sequences and suggest that it can act directly as a positive transcriptional regulatory factor

  9. Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects.

    Science.gov (United States)

    Bajusz, S; Kovacs, M; Gazdag, M; Bokser, L; Karashima, T; Csernus, V J; Janaky, T; Guoth, J; Schally, A V

    1988-03-01

    To eliminate the undesirable edematogenic effect of the luteinizing hormone-releasing hormone (LH-RH) antagonists containing basic D amino acids at position 6, exemplified by [Ac-D-Phe(pCl)1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH [Phe(pCl) indicates 4-chlorophenylalanine], analogs with D-ureidoalkyl amino acids such as D-citrulline (D-Cit) or D-homocitrulline (D-Hci) at position 6 were synthesized and tested in several systems in vitro and in vivo. HPLC analysis revealed that the overall hydrophobicity of the D-Cit/D-Hci6 analogs was similar to that of the basic D-Arg6 antagonists. In vitro, most of the analogs completely inhibited LH-RH-mediated luteinizing hormone release in perfused rat pituitary cell systems at an antagonist to LH-RH molar ratio of 5:1. In vivo, the most active peptides, [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Trp3,D-Cit6,D-Ala10]LH-RH [Nal(2) indicates 3-(2-naphthyl)alanine] and its D-Hci6 analog, caused 100% inhibition of ovulation in cycling rats in doses of 3 micrograms and suppressed the luteinizing hormone level in ovariectomized female rats for 47 hr when administered at doses of 25 micrograms. Characteristically, these peptides did not exert any edematogenic effects even at 1.5 mg/kg. These properties of the D-Cit/D-Hci6 antagonists may make them useful clinically.

  10. Steroid hormone receptors: long- and short-term integrators of the internal milieu and the external environment.

    Science.gov (United States)

    Blaustein, J D

    2012-07-01

    Many of the influences of estrogens and progestins on the brain and behavior are mediated by estrogen receptors and progestin receptors, acting as transcriptional regulators. The homologous and heterologous regulation of the concentrations of these receptors by cognate hormones is well established. However, although they were discovered and characterized based on their binding to cognate hormone and their role in transcriptional regulation, steroid hormone receptors have a more complex role and serve many more functions than originally suspected. First, besides being regulated by steroid hormones, the intracellular concentrations of brain steroid hormone receptors are regulated by neurotransmitters, a pathway by which stimuli from the environment, including from conspecific animals, can modulate the concentration of particular steroid hormone receptors in subsets of cells. Further, besides being activated by cognate steroid hormones, the receptors can be activated by a variety of neurotransmitters and phosphorylation pathways, providing a route through which environmental stimulation can activate steroid-receptor-dependent functions in specific cells. In addition, the transcription factor, estrogen receptor-α, produced from the estrogen receptor-α gene, can be modified to be targeted to membranes, where it can signal via kinase pathways. Finally, developmental experiences, such as particular stressors during the pubertal period, can permanently remodel the brain's response to ovarian hormones, most likely by long-term changes in regulation of the receptors mediating those responses. In addition to their function in responding to cognate ligand, it is now more appropriate to think of steroid hormone receptors as integrators of a wide variety of signaling pathways. © Georg Thieme Verlag KG Stuttgart · New York.

  11. The lower expression of gonadotropin-releasing hormone receptor associated with poor prognosis in gastric cancer

    Science.gov (United States)

    Lu, Mingzhu; Zhu, Jing; Ling, Yang; Shi, Wenping; Zhang, Changsong; Wu, Haorong

    2015-01-01

    Aims: Expression of gonadotropin-releasing hormone receptor (GnRHR) has been demonstrated in a number of malignancies. The aim is to investigate the expression of GnRHR and prognosis in gastric cancer. Methods and materials: GnRHR mRNA was examined in tumor and non-tumor tissues from 48 gastric cancer patients by Real-time PCR. The GnRHR protein expression was performed by immunohistochemical analysis. Results: The expression of GnRHR mRNA was higher (mean ± SD, -10.06 ± 1.28) in gastric tumor tissues than matched non-tumor tissues (mean ± SD, -12.43 ± 1.33). GnRHR mRNA expression was associated with lymph node metastasis, distant metastasis, and TNM stage. We found the decreased expression of GnRHR mRNA were significantly correlated with poor overall survival (P = 0.003). Immunocytochemical staining of GnRHR in tumor tissues showed mainly weak staining (43.48%, 10/23) and moderate staining (21.74%, 5/23) in high GnRHR mRNA patients, and mainly negative staining in low GnRHR mRNA patients. And the staining of GnRHR was not detection in tumor tissues for more than half of gastric patients (52.08%, 25/48). These results implied that the loss of GnRHR protein could be a main event in gastric cancer. Conclusion: The GnRHR expression is very low in gastric cancer, and the loss of GnRHR expression could be a poor prognostic factor, which implied that GnRHR could play an important role in the development of gastric cancer. PMID:26550267

  12. Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor.

    Science.gov (United States)

    Troppmann, Britta; Kleinau, Gunnar; Krause, Gerd; Gromoll, Jörg

    2013-01-01

    BACKGROUND In recent years it became evident that several types of the luteinizing hormone/choriogonadotrophin receptor (LHCGR) exist. In addition to the classical receptor type known in rodents, an LHCGR type containing an additional exon is present in primates and humans. This specific exon 6A introduces a hitherto unknown regulatory pathway of the LHCGR at the transcriptional level which can lead to the expression of an alternative protein covering the extracellular part only. Furthermore, an LHCGR type lacking exon 10 at the mRNA and protein levels has been described in the New World primate lineage, giving rise to an additional receptor type in which amino acids of the extracellular hinge region connecting the leucine-rich repeat domain and transmembrane domain are missing. METHODS Topic-related information was retrieved by systematic searches using Medline/PubMed. Structural homology models were retrieved from a glycoprotein hormone receptors web application and from recent publications. RESULTS In a novel approach, we combine functional aspects with three-dimensional properties of the LHCGR and the different receptor types to deduce causative relationships between these two parameters. On this basis, the physiological impact and patho-physiological consequences of the different LHCGR types are inferred. CONCLUSIONS The complex system of different LHCGR types and two corresponding hormones (LH and CG) represents a major challenge for future studies on selective hormone binding, signal transduction and receptor regulation. The presence of these naturally occurring LHCGR types requires re-examining of our present view on receptor function, experimental set-ups and data interpretation, but also offers new clinical approaches to interfere with LH/CG action in humans.

  13. 64 kDa protein is a candidate for a thyrotropin-releasing hormone receptor in prolactin-producing rat pituitary tumor cells (GH4C1 cells)

    International Nuclear Information System (INIS)

    Wright, M.; Hogset, A.; Alestrom, P.; Gautvik, K.M.

    1988-01-01

    A thyrotropin-releasing hormone (TRH) binding protein of 64 kDa has been identified by covalently crosslinking [ 3 H]TRH to GH4C1 cells by ultraviolet illumination. The crosslinkage of [ 3 H]TRH is UV-dose dependent and is inhibited by an excess of unlabeled TRH. A 64 kDa protein is also detected on immunoblots using an antiserum raised against GH4C1 cell surface epitopes. In a closely related cell line (GH12C1) which does not bind [ 3 H]TRH, the 64 kDa protein cannot be demonstrated by [ 3 H]TRH crosslinking nor by immunoblotting. These findings indicate that the 64 kDa protein is a candidate for a TRH-receptor protein in GH4C1 cells

  14. Decapeptides as effective agonists from L-amino acids biologically equivalent to the luteinizing hormone-releasing hormone

    International Nuclear Information System (INIS)

    Folkers, K.; Bowers, C.Y.; Tang, P.L.; Kubota, M.

    1986-01-01

    Apparently, no agonist has been found that is comparable in potency to the luteinizing hormone-releasing hormone (LHRH) for release of LH and follicle-stimulating hormone (FSH) without substitutions with unnatural or D forms of natural amino acids. Of 139 known agonist analogs of LHRH, two were active in the range of 65%. The four LHRHs known to occur in nature involve a total of six amino acids (Tyr, His, Leu, Trp, Arg, Gln) in positions 5, 7, and 8. There are 16 possible peptides with these six amino acids in positions 5, 7, and 8, of which 4 are the known LHRHs, and 2 more were synthesized. The authors have synthesized the 10 new peptides and assayed 11 in vivo and in vitro, and they found not only 1 but a total of 5 that have activity equivalent to or greater than that of LHRH for the release of LH and/or FSH under at least one assay condition. These five are as follows: [His 5 ,Trp 7 ,Gln 8 ]LHRH; [His 5 ,Trp 7 ,Leu 8 ]LHRH; [His 5 ,Trp 7 ]LHRH; [Trp 7 ]LHRH; [His 5 ]LHRH. These structures are a basis for the design of antagonists without Arg 8 toward avoiding histamine release. Complete inhibition of LH and FSH release in vivo may be induced by joint use of Arg 8 and Gln 8 or Leu 8 antagonists. These potent agonists, related to LHRH, may be therapeutically useful in disorders of reproduction, the central nervous system, and for the control of hormone-dependent carcinomas. Radioreceptor assays and radioimmunoassays were utilized

  15. Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency

    International Nuclear Information System (INIS)

    Lustig, R.H.; Schriock, E.A.; Kaplan, S.L.; Grumbach, M.M.

    1985-01-01

    Five male children who received cranial irradiation for extrahypothalamic intracranial neoplasms or leukemia and subsequently developed severe growth hormone (GH) deficiency were challenged with synthetic growth hormone-releasing factor (GRF-44), in an attempt to distinguish hypothalamic from pituitary dysfunction as a cause of their GH deficiency, and to assess the readily releasable GH reserve in the pituitary. In response to a pulse of GRF-44 (5 micrograms/kg intravenously), mean peak GH levels rose to values higher than those evoked by the pharmacologic agents L-dopa or arginine (6.4 +/- 1.3 ng/mL v 1.5 +/- 0.4 ng/mL, P less than .05). The peak GH value occurred at a mean of 26.0 minutes after administration of GRF-44. These responses were similar to those obtained in children with severe GH deficiency due to other etiologies (peak GH 6.3 +/- 1.7 ng/mL, mean 28.0 minutes). In addition, there was a trend toward an inverse relationship between peak GH response to GRF-44 and the postirradiation interval. Prolactin and somatomedin-C levels did not change significantly after the administration of a single dose of GRF-44. The results of this study support the hypothesis that cranial irradiation in children can lead to hypothalamic GRF deficiency secondary to radiation injury of hypothalamic GRF-secreting neurons. This study also lends support to the potential therapeutic usefulness of GRF-44 or an analog for GH deficiency secondary to cranial irradiation

  16. A role for central nervous growth hormone-releasing hormone signaling in the consolidation of declarative memories.

    Directory of Open Access Journals (Sweden)

    Manfred Hallschmid

    Full Text Available Contributions of somatotropic hormonal activity to memory functions in humans, which are suggested by clinical observations, have not been systematically examined. With previous experiments precluding a direct effect of systemic growth hormone (GH on acute memory formation, we assessed the role of central nervous somatotropic signaling in declarative memory consolidation. We examined the effect of intranasally administered growth hormone releasing-hormone (GHRH; 600 µg that has direct access to the brain and suppresses endogenous GHRH via an ultra-short negative feedback loop. Twelve healthy young men learned word-pair associates at 2030 h and were administered GHRH and placebo, respectively, at 2100 h. Retrieval was tested after 11 hours of wakefulness. Compared to placebo, intranasal GHRH blunted GH release within 3 hours after substance administration and reduced the number of correctly recalled word-pairs by ∼12% (both P<0.05. The impairment of declarative memory consolidation was directly correlated to diminished GH concentrations (P<0.05. Procedural memory consolidation as examined by the parallel assessment of finger sequence tapping performance was not affected by GHRH administration. Our findings indicate that intranasal GHRH, by counteracting endogenous GHRH release, impairs hippocampal memory processing. They provide first evidence for a critical contribution of central nervous somatotropic activity to hippocampus-dependent memory consolidation.

  17. Pentadecapeptide BPC 157 Enhances the Growth Hormone Receptor Expression in Tendon Fibroblasts

    Directory of Open Access Journals (Sweden)

    Chung-Hsun Chang

    2014-11-01

    Full Text Available BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.

  18. Hormone receptor densities in relation to 10B neutron capture therapy

    International Nuclear Information System (INIS)

    Hechter, O.; Schwartz, I.L.

    1982-01-01

    This presentation is a theoretical discussion of the possibility that appropriate steroid-carborane derivatives might be used to selectively deliver boron-10 ( 10 B) to tumor cells with sex-hormone receptors in sufficient concentration for effective neutron capture theory (NCT) of hormone-dependent mammary and prostatic cancer. The results indicate the concentrations of androgen receptors (AR) and progesterone receptors (PR) in malignant prostatic cells or of estrogen receptors (ER) in malignant mammary cells are two low to achieve nuclear 10 B concentrations of 1 + g per g of tumor by using a steroid ligand coupled to a single carborane cage

  19. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Minqian Shen

    2015-01-01

    Full Text Available The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

  20. Nonreproductive role of gonadotropin-releasing hormone in the control of ascidian metamorphosis.

    Science.gov (United States)

    Kamiya, Chisato; Ohta, Naoyuki; Ogura, Yosuke; Yoshida, Keita; Horie, Takeo; Kusakabe, Takehiro G; Satake, Honoo; Sasakura, Yasunori

    2014-12-01

    Gonadotropin-releasing hormones (GnRHs) are neuropeptides that play central roles in the reproduction of vertebrates. In the ascidian Ciona intestinalis, GnRHs and their receptors are expressed in the nervous systems at the larval stage, when animals are not yet capable of reproduction, suggesting that the hormones have non-reproductive roles. We showed that GnRHs in Ciona are involved in the animal's metamorphosis by regulating tail absorption and adult organ growth. Absorption of the larval tail and growth of the adult organs are two major events in the metamorphosis of ascidians. When larvae were treated with GnRHs, they completed tail absorption more frequently than control larvae. cAMP was suggested to be a second messenger for the induction of tail absorption by GnRHs. tGnRH-3 and tGnRH-5 (the "t" indicates "tunicate") inhibited the growth of adult organs by arresting cell cycle progression in parallel with the promotion of tail absorption. This study provides new insights into the molecular mechanisms of ascidian metamorphosis conducted by non-reproductive GnRHs. © 2014 Wiley Periodicals, Inc.

  1. Endocrinology and the brain: corticotropin-releasing hormone signaling.

    Science.gov (United States)

    Inda, Carolina; Armando, Natalia G; Dos Santos Claro, Paula A; Silberstein, Susana

    2017-08-01

    Corticotropin-releasing hormone (CRH) is a key player of basal and stress-activated responses in the hypothalamic-pituitary-adrenal axis (HPA) and in extrahypothalamic circuits, where it functions as a neuromodulator to orchestrate humoral and behavioral adaptive responses to stress. This review describes molecular components and cellular mechanisms involved in CRH signaling downstream of its G protein-coupled receptors (GPCRs) CRHR1 and CRHR2 and summarizes recent findings that challenge the classical view of GPCR signaling and impact on our understanding of CRHRs function. Special emphasis is placed on recent studies of CRH signaling that revealed new mechanistic aspects of cAMP generation and ERK1/2 activation in physiologically relevant contexts of the neurohormone action. In addition, we present an overview of the pathophysiological role of the CRH system, which highlights the need for a precise definition of CRHRs signaling at molecular level to identify novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders. © 2017 The authors.

  2. Developmental programming: Impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus

    International Nuclear Information System (INIS)

    Mahoney, Megan M.; Padmanabhan, Vasantha

    2010-01-01

    Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine-disrupting chemicals (EDCs) with estrogenic and antiandrogenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude, and MXC has profound effects on on LH surge timing in sheep. The neural mechanisms involved in the differential disruption of the LH surge by these two EDCs remain to be elucidated. We tested the hypothesis that the differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2, mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC, or BPA (5 mg/kg/day) from day 30 to 90 of gestation (term 147 d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F 2α , just before the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast, ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female.

  3. Developmental programming: impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus.

    Science.gov (United States)

    Mahoney, Megan M; Padmanabhan, Vasantha

    2010-09-01

    Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine-disrupting chemicals (EDCs) with estrogenic and antiandrogenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude, and MXC has profound effects on on LH surge timing in sheep. The neural mechanisms involved in the differential disruption of the LH surge by these two EDCs remain to be elucidated. We tested the hypothesis that the differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2, mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC, or BPA (5mg/kg/day) from day 30 to 90 of gestation (term 147d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F(2alpha), just before the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast, ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female. 2010 Elsevier Inc. All rights reserved.

  4. Effects of growth hormone deficiency and recombinant growth hormone therapy on postprandial gallbladder motility and cholecystokinin release.

    NARCIS (Netherlands)

    Moschetta, A.; Twickler, M.; Rehfeld, J.F.; Ooteghem, N.A. van; Castro Cabezas, M.; Portincasa, P.; Berge-Henegouwen, G.P. van; Erpecum, K.J. van

    2004-01-01

    In addition to cholecystokinin, other hormones have been suggested to be involved in regulation of postprandial gallbladder contraction. We aimed to evaluate effects of growth hormone (GH) on gallbladder contractility and cholecystokinin release. Gallbladder and gastric emptying (by ultrasound) and

  5. Evolutionary aspects of growth hormones and prolactins and their receptors

    International Nuclear Information System (INIS)

    Tarpey, J.F.

    1986-01-01

    The interactions of GH's, PRL's and PL's with receptors for GH and PRL were examined from a comparative and evolutionary viewpoint. The binding of 125 I-bGH to membrane preparations from liver of representatives of the major classes of non-mammalian vertebrates was also studied. Only hepatic membranes from sturgeon and Gillichthys had significant bGH binding and were further characterized and compared with male rabbit liver membranes in terms of time, temperature, pH, and membrane concentration to optimize binding conditions. The binding of several members of the GH, PRL, PL family of hormones to GH receptors from liver of sturgeon, Gillichthys, rabbit, mouse and rat was investigated. in terms of hormonal specificity, the mammalian receptors and the sturgeon binding sites were similar, while Gillichthys receptors had a different pattern of hormonal specificity. The binding of 125 I-oPRL to renal membranes of the turtle, Pseudemys scripta elegans, was characterized and compared to PRL binding sites of kidney membranes of the bullfrog, Rana catesbeiana, and the tiger salamander, Ambystoma tigrinum

  6. A mutation in the receptor Methoprene-tolerant alters juvenile hormone response in insects and crustaceans.

    Science.gov (United States)

    Miyakawa, Hitoshi; Toyota, Kenji; Hirakawa, Ikumi; Ogino, Yukiko; Miyagawa, Shinichi; Oda, Shigeto; Tatarazako, Norihisa; Miura, Toru; Colbourne, John K; Iguchi, Taisen

    2013-01-01

    Juvenile hormone is an essential regulator of major developmental and life history events in arthropods. Most of the insects use juvenile hormone III as the innate juvenile hormone ligand. By contrast, crustaceans use methyl farnesoate. Despite this difference that is tied to their deep evolutionary divergence, the process of this ligand transition is unknown. Here we show that a single amino-acid substitution in the receptor Methoprene-tolerant has an important role during evolution of the arthropod juvenile hormone pathway. Microcrustacea Daphnia pulex and D. magna share a juvenile hormone signal transduction pathway with insects, involving Methoprene-tolerant and steroid receptor coactivator proteins that form a heterodimer in response to various juvenoids. Juvenile hormone-binding pockets of the orthologous genes differ by only two amino acids, yet a single substitution within Daphnia Met enhances the receptor's responsiveness to juvenile hormone III. These results indicate that this mutation within an ancestral insect lineage contributed to the evolution of a juvenile hormone III receptor system.

  7. Biosynthesis and the conjugation of magnetite nanoparticles with luteinizing hormone releasing hormone (LHRH)

    Energy Technology Data Exchange (ETDEWEB)

    Obayemi, J.D. [Department of Materials Science and Engineering, African University of Science and Technology (AUST) Abuja, Federal Capital Territory (Nigeria); Department of Materials Science and Engineering, Kwara State University, Malete, Kwara State (Nigeria); Dozie-Nwachukwu, S. [Department of Materials Science and Engineering, African University of Science and Technology (AUST) Abuja, Federal Capital Territory (Nigeria); Sheda Science and Technology Complex (SHESTCO) Abuja, Federal Capital Territory (Nigeria); Danyuo, Y. [Department of Materials Science and Engineering, African University of Science and Technology (AUST) Abuja, Federal Capital Territory (Nigeria); Department of Electronics and Electricals Engineering, Nigerian Turkish Nile University, Abuja (Nigeria); Odusanya, O.S. [Department of Materials Science and Engineering, African University of Science and Technology (AUST) Abuja, Federal Capital Territory (Nigeria); Sheda Science and Technology Complex (SHESTCO) Abuja, Federal Capital Territory (Nigeria); Anuku, N. [Department of Chemistry, Bronx Community College, New York, NY 10453 (United States); Princeton Institute of Science and Technology of Materials (PRISM), Princeton, NJ 08544 (United States); Malatesta, K. [Princeton Institute of Science and Technology of Materials (PRISM), Princeton, NJ 08544 (United States); Department of Mechanical and Aerospace Engineering, Princeton University, NJ 08544 (United States); Soboyejo, W.O., E-mail: soboyejo@princeton.edu [Department of Materials Science and Engineering, African University of Science and Technology (AUST) Abuja, Federal Capital Territory (Nigeria); Princeton Institute of Science and Technology of Materials (PRISM), Princeton, NJ 08544 (United States); Department of Mechanical and Aerospace Engineering, Princeton University, NJ 08544 (United States)

    2015-01-01

    This paper presents the results of an experimental study of the biosynthesis of magnetite nanoparticles (BMNPs) with particle sizes between 10 nm and 60 nm. The biocompatible magnetic nanoparticles are produced from Magnetospirillum magneticum (M.M.) bacteria that respond to magnetic fields. M.M. bacteria were cultured and used to synthesize magnetite nanoparticles. This was done in an enriched magnetic spirillum growth medium (EMSGM) at different pH levels. The nanoparticle concentrations were characterized with UV–Visible (UV–Vis) spectroscopy, while the particle shapes were elucidated via transmission electron microscopy (TEM). The structure of the particles was studied using X-ray diffraction (XRD), while the hydrodynamic radii, particle size distributions and polydispersity of the nanoparticles were characterized using dynamic light scattering (DLS). Carbodiimide reduction was also used to functionalize the BMNPs with a molecular recognition unit (luteinizing hormone releasing hormone, LHRH) that attaches specifically to receptors that are over-expressed on the surfaces of most breast cancer cell types. The resulting nanoparticles were examined using Fourier Transform Infrared (FTIR) spectroscopy and quantitative image analysis. The implications of the results are then discussed for the potential development of magnetic nanoparticles for the specific targeting and treatment of breast cancer. - Highlights: • Biosynthesis of MNPs with clinically relevant sizes between 10 and 60 nm. • New insights into the effects of pH and processing time on nanoparticle shapes and sizes. • Successful conjugation of biosynthesized magnetite nanoparticles to LHRH ligands. • Conjugated BMNPs that are monodispersed with potential biomedical relevance. • Magnetic properties of biosynthesized MNPs suggest potential for MRI enhancement.

  8. Biosynthesis and the conjugation of magnetite nanoparticles with luteinizing hormone releasing hormone (LHRH)

    International Nuclear Information System (INIS)

    Obayemi, J.D.; Dozie-Nwachukwu, S.; Danyuo, Y.; Odusanya, O.S.; Anuku, N.; Malatesta, K.; Soboyejo, W.O.

    2015-01-01

    This paper presents the results of an experimental study of the biosynthesis of magnetite nanoparticles (BMNPs) with particle sizes between 10 nm and 60 nm. The biocompatible magnetic nanoparticles are produced from Magnetospirillum magneticum (M.M.) bacteria that respond to magnetic fields. M.M. bacteria were cultured and used to synthesize magnetite nanoparticles. This was done in an enriched magnetic spirillum growth medium (EMSGM) at different pH levels. The nanoparticle concentrations were characterized with UV–Visible (UV–Vis) spectroscopy, while the particle shapes were elucidated via transmission electron microscopy (TEM). The structure of the particles was studied using X-ray diffraction (XRD), while the hydrodynamic radii, particle size distributions and polydispersity of the nanoparticles were characterized using dynamic light scattering (DLS). Carbodiimide reduction was also used to functionalize the BMNPs with a molecular recognition unit (luteinizing hormone releasing hormone, LHRH) that attaches specifically to receptors that are over-expressed on the surfaces of most breast cancer cell types. The resulting nanoparticles were examined using Fourier Transform Infrared (FTIR) spectroscopy and quantitative image analysis. The implications of the results are then discussed for the potential development of magnetic nanoparticles for the specific targeting and treatment of breast cancer. - Highlights: • Biosynthesis of MNPs with clinically relevant sizes between 10 and 60 nm. • New insights into the effects of pH and processing time on nanoparticle shapes and sizes. • Successful conjugation of biosynthesized magnetite nanoparticles to LHRH ligands. • Conjugated BMNPs that are monodispersed with potential biomedical relevance. • Magnetic properties of biosynthesized MNPs suggest potential for MRI enhancement

  9. Active immunization against gonadotropin-releasing hormone : an effective tool to block the fertility axis in mammals

    NARCIS (Netherlands)

    Turkstra, Jouwert Anne

    2005-01-01

    Gonadotropin releasing hormone (GnRH) plays a pivotal role in fertility and reproduction in mammals. It induces the release of luteinising hormone (LH) en follicle stimulating hormone (FSH) from the pituitary. These hormones are responsible for gonadal steroid production and indirectly for

  10. Growth hormone secretagogue receptor (GHS-R1a) knockout mice exhibit improved spatial memory and deficits in contextual memory.

    Science.gov (United States)

    Albarran-Zeckler, Rosie G; Brantley, Alicia Faruzzi; Smith, Roy G

    2012-06-15

    Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation of growth hormone release, it is also reported to have beneficial effects on learning and memory formation in mice. Nevertheless, controversy exists about whether endogenous ghrelin acts on its receptors in extra-hypothalamic areas of the brain. The ghrelin receptor (GHS-R1a) is co-expressed in neurons that express dopamine receptor type-1 (DRD1a) and type-2 (DRD2), and we have shown that a subset of GHS-R1a, which are not occupied by the agonist (apo-GHSR1a), heterodimerize with these two receptors to regulate dopamine signaling in vitro and in vivo. To determine the consequences of ghsr ablation on brain function, congenic ghsr -/- mice on the C57BL6/J background were subjected to a battery of behavioral tests. We show that the ghsr -/- mice exhibit normal balance, movement, coordination, and pain sensation, outperform ghsr +/+ mice in the Morris water maze, but show deficits in contextual fear conditioning. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Melatonin improves memory acquisition under stress independent of stress hormone release

    OpenAIRE

    Rimmele, U; Spillmann, M; Bärtschi, C; Wolf, O T; Weber, C S; Ehlert, Ulrike; Wirtz, P H

    2009-01-01

    RATIONALE: Animal studies suggest that the pineal hormone melatonin influences basal stress hormone levels and dampens hormone reactivity to stress. OBJECTIVES: We investigated whether melatonin also has a suppressive effect on stress-induced catecholamine and cortisol release in humans. As stress hormones affect memory processing, we further examined a possible accompanying modulation of memory function. MATERIALS AND METHODS: Fifty healthy young men received a single oral dose of either 3...

  12. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling

    DEFF Research Database (Denmark)

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook

    2015-01-01

    A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co...

  13. Effects of Asn318 and Asp87Asn318 mutations on signal transduction by the gonadotropin-releasing hormone receptor and receptor regulation.

    Science.gov (United States)

    Awara, W M; Guo, C H; Conn, P M

    1996-02-01

    GnRH receptor (GnRH-R) contains Asn87 and Asp318 instead of the more frequently observed Asp87 and Asn318 found in other G protein-coupled receptors. In the present study, site-directed mutagenesis was used to introduce Asn318 and Asp87Asn318 into GnRH-R. The effect on coupling and regulation of GnRH-R was studied by stable expression of wild and mutant mouse GnRH-R in the lactotropic GH3 cells; these normally release PRL in response to TRH stimulation. The responses to Buserelin (a metabolically stable GnRH analog) in three different cell lines, M1, N8, and ND1 (expressing wild-type, Asn318 mutant, and Asp87Asn318 mutant mouse GnRH-R, respectively) were compared with that observed in the previously characterized GGH3-1' cells, which stably express rat GnRH-R. The Asn318 and Asp87Asn318 mutations had no measurable effect on ligand binding, but abolished the initial down-regulation of receptor that was observed in M1 and GGH3-1' cells, suggesting that the normal location of Asn87 and Asp318 in GnRH-R is involved in the regulation of GnRH-R. In N8 and ND1 cells, Buserelin-stimulated inositol phosphate (IP) production was attenuated, but the release of both cAMP and PRL was stimulated in a dose- and time-dependent manner. These mutations apparently impaired the coupling between GnRH-R and G proteins involved in IP production, but not those involved in cAMP release. In M1 cells, Buserelin stimulation produced a significant increase in IP production, but neither cAMP nor PRL release was significantly stimulated. These findings are consistent with the previous suggestion that GnRH-stimulated PRL release is mediated by a cAMP second messenger system in transfected GGH3 cells.

  14. Prolonged inhibition of luteinizing hormone and testosterone levels in male rats with the luteinizing hormone-releasing hormone antagonist SB-75.

    Science.gov (United States)

    Bokser, L; Bajusz, S; Groot, K; Schally, A V

    1990-09-01

    Inhibitory effects of the potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1,4-chloro-D-phenylalanine2,3- (3-pyridyl)-D- alanine3,D-citrulline6,D-alanine10]luteinizing hormone-releasing hormone (SB-75) free of edematogenic effects were investigated in male rats. In a study to determine the effect on luteinizing hormone levels in castrated male rats, SB-75 was injected s.c. in doses of 0.625, 1.25, 2.5, 5.0, and 10 micrograms. Blood samples were taken at different intervals for 48 hr. All doses of SB-75 significantly decreased luteinizing hormone levels for greater than 6 hr (P less than 0.01); this inhibition lasted for greater than 24 hr (P less than 0.01) with a dose of 5.0 micrograms and greater than 48 hr with 10 micrograms (P less than 0.05). Serum testosterone levels were also measured in intact male rats injected with SB-75 in doses of 25, 50, and 100 micrograms. All doses produced a dramatic fall in testosterone to castration levels 6 hr after injection (P less than 0.01); this inhibition of serum testosterone was maintained for greater than 72 hr, but only the 100-micrograms dose could keep testosterone in the castration range for greater than 24 hr (P less than 0.01). In another study using a specific RIA, we obtained the pharmacokinetic release pattern of SB-75 from two sustained delivery formulations of SB-75 pamoate microgranules and examined their effect on serum testosterone. After a single i.m. injection of 20 mg of one batch of microgranules, a large peak corresponding to SB-75 at 45.8 ng/ml was observed, corresponding to the "burst" effect. Levels of the analog decreased to 19.6 ng/ml on day 2, gradually reached a concentration of 4.7 ng/ml on day 7, and kept declining thereafter. Testosterone levels were reduced on day 1 (P less than 0.01) and were maintained at low values for greater than 7 days (P less than 0.05). In rats injected with 10 mg of SB-75 pamoate microgranules of the second batch, SB-75 serum

  15. Acute gonadotropin-releasing hormone agonist treatment enhances extinction memory in male rats.

    Science.gov (United States)

    Maeng, L Y; Taha, M B; Cover, K K; Glynn, S S; Murillo, M; Lebron-Milad, K; Milad, M R

    2017-08-01

    Leuprolide acetate (LEU), also known as Lupron, is commonly used to treat prostate cancer in men. As a gonadotropin-releasing hormone (GnRH) receptor agonist, it initially stimulates the release of gonadal hormones, testosterone (T) and estradiol. This surge eventually suppresses these hormones, preventing the further growth and spread of cancer cells. Individuals receiving this treatment often report anxiety and cognitive changes, but LEU's effects on the neural mechanisms that are involved in anxiety during the trajectory of treatment are not well known. In this study, we examined the acute effects of LEU on fear extinction, hypothesizing that increased T levels following a single administration of LEU will facilitate extinction recall by altering neuronal activity within the fear extinction circuitry. Two groups of naïve adult male rats underwent a 3-day fear conditioning, extinction, and recall experiment. The delayed group (n=15) received a single injection of vehicle or LEU (1.2mg/kg) 3weeks before behavioral testing. The acute group (n=25) received an injection one day after fear conditioning, 30min prior to extinction training. Following recall, the brains for all animals were collected for c-fos immunohistochemistry. Blood samples were also collected and assayed for T levels. Acute administration of LEU increased serum T levels during extinction training and enhanced extinction recall 24h later. This enhanced extinction memory was correlated with increased c-fos activity within the infralimbic cortex and amygdala, which was not observed in the delayed group. These results suggest that the elevation in T induced by acute administration of LEU can influence extinction memory consolidation, perhaps through modification of neuronal activity within the infralimbic cortex and amygdala. This may be an important consideration in clinical applications of LEU and its effects on anxiety and cognition. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Effects of ionizing radiation and pretreatment with [D-Leu6,des-Gly10] luteinizing hormone-releasing hormone ethylamide on developing rat ovarian follicles

    International Nuclear Information System (INIS)

    Jarrell, J.; YoungLai, E.V.; McMahon, A.; Barr, R.; O'Connell, G.; Belbeck, L.

    1987-01-01

    To assess the effects of a gonadotropin-releasing hormone agonist, [D-Leu6,des-Gly10] luteinizing hormone-releasing hormone ethylamide, in ameliorating the damage caused by ionizing radiation, gonadotropin-releasing hormone agonist was administered to rats from day 22 to 37 of age in doses of 0.1, 0.4, and 1.0 microgram/day or vehicle and the rats were sacrificed on day 44 of age. There were no effects on estradiol, progesterone, luteinizing, or follicle-stimulating hormone, nor an effect on ovarian follicle numbers or development. In separate experiments, rats treated with gonadotropin-releasing hormone agonist in doses of 0.04, 0.1, 0.4, or 1.0 microgram/day were either irradiated or sham irradiated on day 30 and all groups sacrificed on day 44 of age. Irradiation produced a reduction in ovarian weight and an increase in ovarian follicular atresia. Pretreatment with the agonist prevented the reduction in ovarian weight and numbers of primordial and preantral follicles but not healthy or atretic antral follicles. Such putative radioprotection should be tested on actual reproductive performance

  17. Gastrointestinal hormone research - with a Scandinavian annotation

    DEFF Research Database (Denmark)

    Rehfeld, Jens F

    2015-01-01

    Gastrointestinal hormones are peptides released from neuroendocrine cells in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gut, which makes it the largest hormone-producing organ in the body. Modern biology makes it feasible to conceive the hormones...... as a blood-borne hormone, a neurotransmitter, a local growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein-coupled receptors that are expressed in the cell membranes also outside the digestive tract. Thus, gut hormones not only regulate digestive functions...

  18. A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear.

    Science.gov (United States)

    Meyer, R M; Burgos-Robles, A; Liu, E; Correia, S S; Goosens, K A

    2014-12-01

    Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is no clear relationship between the levels of these hormones and stress-associated mental illnesses such as posttraumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin-releasing factor (CRF) or corticosterone. Repeated intraamygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was enhanced by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear-enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and

  19. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome.

    Science.gov (United States)

    Moore, Aleisha M; Prescott, Mel; Marshall, Christopher J; Yip, Siew Hoong; Campbell, Rebecca E

    2015-01-13

    Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is associated with an increase in luteinizing hormone (LH) pulse frequency, implicating abnormal steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons. This study investigated whether modifications in the synaptically connected neuronal network of GnRH neurons could account for this pathology. The PCOS phenotype was induced in mice following prenatal androgen (PNA) exposure. Serial blood sampling confirmed that PNA elicits increased LH pulse frequency and impaired progesterone negative feedback in adult females, mimicking the neuroendocrine abnormalities of the clinical syndrome. Imaging of GnRH neurons revealed greater dendritic spine density that correlated with increased putative GABAergic but not glutamatergic inputs in PNA mice. Mapping of steroid hormone receptor expression revealed that PNA mice had 59% fewer progesterone receptor-expressing cells in the arcuate nucleus of the hypothalamus (ARN). To address whether increased GABA innervation to GnRH neurons originates in the ARN, a viral-mediated Cre-lox approach was taken to trace the projections of ARN GABA neurons in vivo. Remarkably, projections from ARN GABAergic neurons heavily contacted and even bundled with GnRH neuron dendrites, and the density of fibers apposing GnRH neurons was even greater in PNA mice (56%). Additionally, this ARN GABA population showed significantly less colocalization with progesterone receptor in PNA animals compared with controls. Together, these data describe a robust GABAergic circuit originating in the ARN that is enhanced in a model of PCOS and may underpin the neuroendocrine pathophysiology of the syndrome.

  20. Effects of LHRH and ANG II on prolactin stimulation are mediated by hypophysial AT1 receptor subtype.

    Science.gov (United States)

    Becú-Villalobos, D; Lacau-Mengido, I M; Thyssen, S M; Díaz-Torga, G S; Libertun, C

    1994-02-01

    We have used the nonpeptide angiotensin II (ANG II) receptor antagonists losartan (receptor subtype AT1) and PD-123319 (AT2) to determine the participation of ANG II receptor subtypes in luteinizing hormone-releasing hormone (LHRH)-induced prolactin release in a perifusion study using intact pituitaries in vitro. LHRH (1.85 x 10(-7) M) released prolactin consistently, whereas losartan (10(-5) M) abolished prolactin response without modifying basal prolactin or luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release. PD-123319 (10(-5) M) had no effect on basal or LHRH-induced prolactin, LH, or FSH release. We also determined that the effect of ANG II on prolactin release was mediated by the same receptor subtype. In adenohypophysial cells dispersed in vitro ANG II (10(-8) M) released prolactin. Losartan (10(-7) and 10(-6) M), but not PD-123319, inhibited this effect. We conclude that in intact hypophyses of 15-day-old female rats the effect of LHRH on prolactin release is readily demonstrated. LHRH-induced prolactin release appears to be mediated by ANG II acting in a paracrine manner on AT1 receptors located on lactotrophs.

  1. Prolactin, thyrotropin, and growth hormone release during stress associated with parachute jumping.

    Science.gov (United States)

    Noel, G L; Dimond, R C; Earll, J M; Frantz, A G

    1976-05-01

    Prolactin, growth hormone, and thyrotropin (TSH) release during the stress of parachute jumping has been evaluated in 14 male subjects. Subjects were studied at several times before and immediately after their first military parachute jump. All three hormones had risen significantly 1 to 14 min after the jump, compared to mean levels measured immediately beforehand. Earlier studies of physical exercise by ourselves and others would suggest that emotional stress played a role in producing changes of this magnitude. We conclude that prolactin, TSH, and growth hormone are released in physiologically significant amounts in association with the stress of parachute jumping.

  2. Extended hormone binding site of the human thyroid stimulating hormone receptor: distinctive acidic residues in the hinge region are involved in bovine thyroid stimulating hormone binding and receptor activation.

    Science.gov (United States)

    Mueller, Sandra; Kleinau, Gunnar; Jaeschke, Holger; Paschke, Ralf; Krause, Gerd

    2008-06-27

    The human thyroid stimulating hormone receptor (hTSHR) belongs to the glycoprotein hormone receptors that bind the hormones at their large extracellular domain. The extracellular hinge region of the TSHR connects the N-terminal leucine-rich repeat domain with the membrane-spanning serpentine domain. From previous studies we reasoned that apart from hormone binding at the leucine-rich repeat domain, additional multiple hormone contacts might exist at the hinge region of the TSHR by complementary charge-charge recognition. Here we investigated highly conserved charged residues in the hinge region of the TSHR by site-directed mutagenesis to identify amino acids interacting with bovine TSH (bTSH). Indeed, the residues Glu-297, Glu-303, and Asp-382 in the TSHR hinge region are essential for bTSH binding and partially for signal transduction. Side chain substitutions showed that the negative charge of Glu-297 and Asp-382 is necessary for recognition of bTSH by the hTSHR. Multiple combinations of alanine mutants of the identified positions revealed an increased negative effect on hormone binding. An assembled model suggests that the deciphered acidic residues form negatively charged patches at the hinge region resulting in an extended binding mode for bTSH on the hTSHR. Our data indicate that certain positively charged residues of bTSH might be involved in interaction with the identified negatively charged amino acids of the hTSHR hinge region. We demonstrate that the hinge region represents an extracellular intermediate connector for both hormone binding and signal transduction of the hTSHR.

  3. Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism.

    Science.gov (United States)

    Amselem, S; Sobrier, M L; Duquesnoy, P; Rappaport, R; Postel-Vinay, M C; Gourmelen, M; Dallapiccola, B; Goossens, M

    1991-01-01

    In addition to its classical effects on growth, growth hormone (GH) has been shown to have a number of other actions, all of which are initiated by an interaction with specific high affinity receptors present in a variety of tissues. Purification of a rabbit liver protein via its ability to bind GH has allowed the isolation of a cDNA encoding a putative human growth hormone receptor that belongs to a new class of transmembrane receptors. We have previously shown that this putative growth hormone receptor gene is genetically linked to Laron dwarfism, a rare autosomal recessive syndrome caused by target resistance to GH. Nevertheless, the inability to express the corresponding full-length coding sequence and the lack of a test for growth-promoting function have hampered a direct confirmation of its role in growth. We have now identified three nonsense mutations within this growth hormone receptor gene, lying at positions corresponding to the amino terminal extremity and causing a truncation of the molecule, thereby deleting a large portion of both the GH binding domain and the full transmembrane and intracellular domains. Three independent patients with Laron dwarfism born of consanguineous parents were homozygous for these defects. Two defects were identical and consisted of a CG to TG transition. Not only do these results confirm the growth-promoting activity of this receptor but they also suggest that CpG doublets may represent hot spots for mutations in the growth hormone receptor gene that are responsible for hereditary dwarfism. Images PMID:1999489

  4. Mapping the human corticotropin releasing hormone binding protein gene (CRHBP) to the long arm of chromosome 5 (5q11.2-q13.3)

    Energy Technology Data Exchange (ETDEWEB)

    Vamvakopoulos, N.C. [Univ. of Thessaly School of Medicine, Larisa (Greece); Sioutopoulou, T.O. [Univ. of Athens Medical School (Greece); Durkin, S.A. [American Type Culture Collection, Rockville, MD (United States)

    1995-01-01

    Unexpected stimulation or stress activates the heat shock protein (hsp) system at the cellular level and the hypothalamic-pituitary-adrenal (HPA) axis at the level of the whole organism. At the molecular level, these two systems communicate through the functional interaction between hsp90 and glucocorticoid receptor (GR). The corticotropin releasing hormone (CRH) system regulates the mammalian stress response by coordinating the activity of the HPA axis. It consists of the 41-amino-acid-long principal hypothalamic secretagogue for pituitary adrenocorticotropic hormone (ACTH), CRH, its receptor (CRHR), and its binding protein (CRHBP). Because of its central role in the coordination of stress response and whole body homeostasis, the CRH system has been implicated in the pathogenesis of neuroendocrine and psychiatric disease. 19 refs., 1 fig.

  5. Variations in steroid hormone receptor content throughout age and menopausal periods, and menstrual cycle in breast cancer patients

    International Nuclear Information System (INIS)

    Nikolic-Vukosavljevic, D.; Vasiljevic, N.; Brankovic-Magic, M.; Polic, D.

    1996-01-01

    Variations in steroid hormone receptor contents throughout age and menopausal periods define three breast carcinoma groups: younger pre-menopausal carcinomas (aged up to 45), middle-aged carcinomas (aged up to 45), middle-aged carcinomas (pre-, peri-, and postmenopausal aged 45-59) and older postmenopausal carcinomas (aged over 59). Age-related steroid hormone receptor contents within pre-menopausal and postmenopausal carcinoma groups are characterized by the important increase of both receptor contents, while menopausal-related steroid hormone receptor contents within middle-aged carcinoma group (aged 45-59) are characterized by the important decrease of progesterone receptor content and estrogen receptor functionality. No variations in steroid hormone receptor contents throughout menstrual cycle within the follicular and the luteal phases were obtained. The important cycle within the follicular and the luteal phases were obtained. The important decrease of estrogen receptor content in the mid-cycle phase versus the peri-menstrual phase was found. Variations in steroid hormone receptor contents throughout age and menopausal periods, as well as throughout menstrual cycle could nod be associated with variations in the blood steroid hormone concentrations. However, important association between steroid hormone receptor contents and the blood steroid hormone concentrations was found within the luteal phase carcinoma group and within older postmenopausal carcinoma group. It is interesting that within carcinoma group with the highest concentration of progesterone, progesterone receptor content increases with an increase of the ration of estradiol and progesterone blood concentrations, while within carcinoma group with the lowest steroid hormone concentration and the highest content of estrogen receptor content, estrogen receptor content decreases with an increase of either the blood estradiol concentration or the ratio of the blood estradiol and progesterone blood

  6. Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists.

    Science.gov (United States)

    Yanofsky, Stephen D; Shen, Emily S; Holden, Frank; Whitehorn, Erik; Aguilar, Barbara; Tate, Emily; Holmes, Christopher P; Scheuerman, Randall; MacLean, Derek; Wu, May M; Frail, Donald E; López, Francisco J; Winneker, Richard; Arey, Brian J; Barrett, Ronald W

    2006-05-12

    The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC50's = 20 microm) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC50 = 2 nm) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC50 = 980 nm) and estradiol production from primary rat ovarian granulosa cells (EC50 = 10.5 nm). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy.

  7. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome.

    Science.gov (United States)

    Sagami, Y; Shimada, Y; Tayama, J; Nomura, T; Satake, M; Endo, Y; Shoji, T; Karahashi, K; Hongo, M; Fukudo, S

    2004-07-01

    Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients. Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied. The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline. Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of alphahCRH (10 micro g/kg). ES induced significantly higher motility indices of the colon in IBS patients compared with controls. This response was significantly suppressed in IBS patients but not in controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by alphahCRH. Peripheral administration of alphahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.

  8. Up-regulation of corticotropin releasing hormone is associated with ...

    African Journals Online (AJOL)

    Purpose: To determine the expression of corticotropin-releasing hormone (CRH) in psoriasis and ... Methods: Psoriasis and normal skin biopsy samples were obtained from three psoriatic and ... established in literature that stress signals such.

  9. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells

    DEFF Research Database (Denmark)

    Billestrup, N; Møldrup, A; Serup, P

    1990-01-01

    The stimulation of insulin biosynthesis in the pancreatic insulinoma cell line RIN5-AH by growth hormone (GH) is initiated by GH binding to specific receptors. To determine whether the recently cloned rat hepatic GH receptor is able to mediate the insulinotropic effect of GH, we have transfected ...

  10. Dietary modification of metabolic pathways via nuclear hormone receptors.

    Science.gov (United States)

    Caiozzi, Gianella; Wong, Brian S; Ricketts, Marie-Louise

    2012-10-01

    Nuclear hormone receptors (NHRs), as ligand-dependent transcription factors, have emerged as important mediators in the control of whole body metabolism. Because of the promiscuous nature of several members of this superfamily that have been found to bind ligand with lower affinity than the classical steroid NHRs, they consequently display a broader ligand selectivity. This promiscuous nature has facilitated various bioactive dietary components being able to act as agonist ligands for certain members of the NHR superfamily. By binding to these NHRs, bioactive dietary components are able to mediate changes in various metabolic pathways, including, glucose, cholesterol and triglyceride homeostasis among others. This review will provide a general overview of the nuclear hormone receptors that have been shown to be activated by dietary components. The physiological consequences of such receptor activation by these dietary components will then be discussed in more detail. Copyright © 2012 John Wiley & Sons, Ltd.

  11. (−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

    Science.gov (United States)

    2015-01-01

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

  12. Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data

    DEFF Research Database (Denmark)

    Hauser, Frank; Williamson, Michael; Cazzamali, Giuseppe

    2006-01-01

    insect genome, that of the fruitfly Drosophila melanogaster, was sequenced in 2000, and about 200 GPCRs have been annnotated in this model insect. About 50 of these receptors were predicted to have neuropeptides or protein hormones as their ligands. Since 2000, the cDNAs of most of these candidate...... receptors have been cloned and for many receptors the endogenous ligand has been identified. In this review, we will give an update about the current knowledge of all Drosophila neuropeptide and protein hormone receptors, and discuss their phylogenetic relationships. Udgivelsesdato: 2006-Feb...

  13. Status of sex steroid hormone receptors in large bowel cancer

    NARCIS (Netherlands)

    Meggouh, F.; Lointier, P.; Pezet, D.; Saez, S.

    1991-01-01

    To determine the potential role of sex steroid hormones in the development of colorectal tumors in humans, specific androgen (AR), estrogen (ER), and progesterone (PGR) receptors were investigated in normal mucosa (NM) and in tumor (T) paired biopsy specimens from 94 patients. Androgen receptors

  14. Omnigen-AF reduces basal plasma cortisol, AWA cortisol release to adrencocorticotropic hormone or corticotrophin releasing hormone & vasopressin in lactating dairy cows under thermoneutral or acute heat stress conditions.

    Science.gov (United States)

    Differences in the adrenal cortisol response of OmniGen-AF (OG) supplemented dairy cows to a corticotrophin releasing hormone (CRH) and vasopressin (VP) or an adrenocorticotropic hormone (ACTH) challenge when housed at different temperature-humidity indices (THI) were studied. Holstein cows (n=12; 1...

  15. Continuous-release formulation for environmental doses to moving receptors

    International Nuclear Information System (INIS)

    Piepho, M.G.

    1981-01-01

    Atmospheric dispersion models frequently assume a puff release or several puff releases, each of which are described separately. A dispersion model should better describe a continuous release as more puffs are assumed, but the computational cost and bookkeeping difficulty increases with additional puffs. A new formulism is derived in this work which replaces the puff approximation. With the new continuous release formulation, radioactive dose calculations to moving receptors are more accurately calculated without any great additional computation. There are several advantages of a continuous release formulation. With this formulation, a dose rate to a moving receptor is calculated as a function of time. The dose-rate will increase (decrease) as the bulk of the release gets closer (farther) to (from) the receptor which is at position x(t), y(t). The receptor may follow any x, y trajectory as a function of time, and the dose rate will be calculated along the path

  16. Expansion of microsatellite in the thyroid hormone receptor-alpha1 gene linked to increased receptor expression and less aggressive thyroid cancer

    DEFF Research Database (Denmark)

    Onda, Masamitsu; Li, Daisy; Suzuki, Shinichi

    2002-01-01

    PURPOSE: The purpose of this study was to determine whether the length of the THRA1 microsatellite, which resides in a noncoding portion of the thyroid hormone receptor-alpha1 gene, affects receptor expression and is linked to clinicopathological parameters in thyroid cancer. EXPERIMENTAL DESIGN......: In 30 cases of surgically resected sporadic thyroid cancer, the length of the THRA1 microsatellite was determined by DNA sequence analysis, and expression of thyroid hormone receptor-alpha1 was assessed immunohistochemically in thin sections cut from tumor blocks. The length of THRA1 and expression...... of thyroid hormone receptor-alpha1 were also assessed in seven cancer cell lines. Regression analysis was used to gauge the correlation between the size of THRA1 and receptor expression. Multivariate analysis was used to test for links to the clinical parameters of gender, age, histology, stage, nodal...

  17. Use of hormone receptors in scintigraphy of the ovaries

    International Nuclear Information System (INIS)

    Kairento, A.L.; Karonen, S.L.; Adlercreutz, H.

    1981-01-01

    Based on the mechanism of hormone receptors, luteinizing hormone (LH) labelled with 123-iodine was used as tracer in scintigraphy of rabbit ovaries. The ovaries were visualized in static pictures 6-15 min after injection except in the case where the rabbit was pre-injected with 10 μg of cold LH. 3.1% of the injected activity was found in the ovaries 14 h after injection. (orig.) [de

  18. Tripeptide amide L-pyroglutamyl-histidyl-L-prolineamide (L-PHP-thyrotropin-releasing hormone, TRH) promotes insulin-producing cell proliferation.

    Science.gov (United States)

    Luo, LuGuang; Luo, John Z Q; Jackson, Ivor

    2013-02-01

    A very small tripeptide amide L-pyroglutamyl-L-histidyl-L-prolineamide (L-PHP, Thyrotropin-Releasing Hormone, TRH), was first identified in the brain hypothalamus area. Further studies found that L-PHP was expressed in pancreas. The biological role of pancreatic L-PHP is still not clear. Growing evidence indicates that L-PHP expression in the pancreas may play a pivotal role for pancreatic development in the early prenatal period. However, the role of L-PHP in adult pancreas still needs to be explored. L-PHP activation of pancreatic β cell Ca2+ flow and stimulation of β-cell insulin synthesis and release suggest that L-PHP involved in glucose metabolism may directly act on the β cell separate from any effects via the central nervous system (CNS). Knockout L-PHP animal models have shown that loss of L-PHP expression causes hyperglycemia, which cannot be reversed by administration of thyroid hormone, suggesting that the absence of L-PHP itself is the cause. L-PHP receptor type-1 has been identified in pancreas which provides a possibility for L-PHP autocrine and paracrine regulation in pancreatic function. During pancreatic damage in adult pancreas, L-PHP may protect beta cell from apoptosis and initiate its regeneration through signal pathways of growth hormone in β cells. L-PHP has recently been discovered to affect a broad array of gene expression in the pancreas including growth factor genes. Signal pathways linked between L-PHP and EGF receptor phosphorylation suggest that L-PHP may be an important factor for adult β-cell regeneration, which could involve adult stem cell differentiation. These effects suggest that L-PHP may benefit pancreatic β cells and diabetic therapy in clinic.

  19. Pituitary adenomas in mice transgenic for growth hormone-releasing hormone

    DEFF Research Database (Denmark)

    Asa, S L; Kovacs, K; Stefaneanu, L

    1992-01-01

    It has been shown that mice transgenic for human GH-releasing hormone (GRH) develop hyperplasia of pituitary somatotrophs, lactotrophs, and mammosomatotrophs, cells capable of producing both GH and PRL, by 8 months of age. We now report that GRH transgenic mice 10-24 months of age develop pituitary...... adenomas, which we characterized by histology, immunohistochemistry, in situ hybridization, and electron microscopy. Of 13 animals examined, all developed GH-immunoreactive neoplasms that had diffuse positivity for GH mRNA by in situ hybridization. Eleven also contained PRL immunoreactivity; in situ...

  20. Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry

    NARCIS (Netherlands)

    van der Sluis, Tim M.; Bui, Hong N.; Meuleman, Eric J. H.; Heijboer, Annemieke C.; Hartman, Jeroen F.; van Adrichem, Nick; Boevé, Egbert; de Ronde, Willem; van Moorselaar, R. Jeroen A.; Vis, André N.

    2012-01-01

    Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level

  1. Hormonal receptors and vascular endothelial growth factor in juvenile nasopharyngeal angiofibroma: immunohistochemical and tissue microarray analysis.

    Science.gov (United States)

    Liu, Zhuofu; Wang, Jingjing; Wang, Huan; Wang, Dehui; Hu, Li; Liu, Quan; Sun, Xicai

    2015-01-01

    This work demonstrated that juvenile nasopharyngeal angiofibromas (JNAs) express high levels of hormone receptors and vascular endothelial growth factor (VEGF) compared with normal nasal mucosa. The interaction between hormone receptors and VEGF may be involved in the initiation and growth of JNA. JNA is a rare benign tumor that occurs almost exclusively in male adolescents. Although generally regarded as a hormone-dependent tumor, this has not been proven in previous studies. The aim of this study was to investigate the role of hormone receptors in JNA and the relationship with clinical characteristics. Standard immunohistochemical microarray analysis was performed on 70 JNA samples and 10 turbinate tissue samples. Specific antibodies for androgen receptor (AR), estrogen receptor-α (ER-α), estrogen receptor-β (ER-β), progesterone receptor (PR), and VEGF were examined, and the relationships of receptor expression with age, tumor stage, and bleeding were evaluated. RESULTS showed that JNA expressed ER-α (92.9%), ER-β (91.4%), AR (65.7%), PR (12.8%), and VEGF (95.7%) at different levels. High level of VEGF was linked to elevated ER-α and ER-β. There was no significant relationship between hormonal receptors and age at diagnosis, tumor stage or bleeding. However, overexpression of ER-α was found to be an indicator of poor prognosis (p = 0.031).

  2. Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.

    Science.gov (United States)

    Nakata, Daisuke; Masaki, Tsuneo; Tanaka, Akira; Yoshimatsu, Mie; Akinaga, Yumiko; Asada, Mari; Sasada, Reiko; Takeyama, Michiyasu; Miwa, Kazuhiro; Watanabe, Tatsuya; Kusaka, Masami

    2014-01-15

    TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor. The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic-pituitary-gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA).

    Science.gov (United States)

    Nakamura, Yasuhiro; Hattangady, Namita G; Ye, Ping; Satoh, Fumitoshi; Morimoto, Ryo; Ito-Saito, Takako; Sugawara, Akira; Ohba, Koji; Takahashi, Kazuhiro; Rainey, William E; Sasano, Hironobu

    2014-03-25

    Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA). However, the details of its expression and functional role in adrenals are still not clear. In this study, quantitative RT-PCR analysis revealed the mean level of GnRHR mRNA was significantly higher in APAs than in human normal adrenal (NA) (P=0.004). GnRHR protein expression was detected in human NA and neoplastic adrenal tissues. In H295R cells transfected with GnRHR, treatment with GnRH resulted in a concentration-dependent increase in CYP11B2 reporter activity. Chronic activation of GnRHR with GnRH (100nM), in a cell line with doxycycline-inducible GnRHR (H295R-TR/GnRHR), increased CYP11B2 expression and aldosterone production. These agonistic effects were inhibited by blockers for the calcium signaling pathway, KN93 and calmidazolium. These results suggest GnRH, through heterotopic expression of its receptor, may be a potential regulator of CYP11B2 expression levels in some cases of APA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Expression profile and prognostic role of sex hormone receptors in gastric cancer

    International Nuclear Information System (INIS)

    Gan, Lu; He, Jian; Zhang, Xia; Zhang, Yong-Jie; Yu, Guan-Zhen; Chen, Ying; Pan, Jun; Wang, Jie-Jun; Wang, Xi

    2012-01-01

    Increasing interest has been devoted to the expression and possible role of sex hormone receptors in gastric cancer, but most of these findings are controversial. In the present study, the expression profile of sex hormone receptors in gastric cancer and their clinicopathological and prognostic value were determined in a large Chinese cohort. The mRNA and protein expression of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), progesterone receptor (PR), and androgen receptor (AR) in primary gastric tumors and corresponding adjacent normal tissues from 60 and 866 Chinese gastric cancer patients was detected by real-time quantitative PCR and immunohistochemistry method, respectively. The expression profile of the four receptors was compared and their associations with clinicopathological characteristics were assessed by using Chi-square test. The prognostic value of the four receptors in gastric cancer was evaluated by using univariate and multivariate Cox regression analysis. The presence of ERα, ERβ, PR, and AR in both gastric tumors and normal tissues was confirmed but their expression levels were extremely low except for the predominance of ERβ. The four receptors were expressed independently and showed a decreased expression pattern in gastric tumors compared to adjacent normal tissues. The positive expression of the four receptors all correlated with high tumor grade and intestinal type, and ERα and AR were also associated with early TNM stage and thereby a favorable outcome. However, ERα and AR were not independent prognostic factors for gastric cancer when multivariate survival analysis was performed. Our findings indicate that the sex hormone receptors may be partly involved in gastric carcinogenesis but their clinicopathological and prognostic significance in gastric cancer appears to be limited

  5. Radioimmunoassay of thyrotropin releasing hormone in plasma and urine

    International Nuclear Information System (INIS)

    Saito, Shiro; Musa, Kimitaka; Yamamoto, Suzuyo; Oshima, Ichiyo; Funato, Toyohiko

    1975-01-01

    A sensitive and specific radioimmunoassay has been developed capable of measuring thyrotropin releasing hormone (TRH) in extracted human plasma and urine. All of three TRH analogues tested had little cross-reactivity to antibody. Luteinizing hormone releasing hormone, lysine vasopressin, rat growth hormone and bovine albumin were without effect, but rat hypothalamic extract produced a displacement curve which was parallel to that obtained with the synthetic TRH. Sensitivity of the radioimmunoassay was 4 pg per tube with intraassay coefficient of variation of 6.2-9.7%. Synthetic TRH could be quantitatively extracted by methanol when added to human plasma in concentration of 25, 50 and 100 pg/ml. TRH immunoreactivity was rapidly reduced in plasma at 20 0 C than at 0 0 C, but addition of peptidase inhibitors, FOY-007 and BAL, prevented the inactivation of TRH for 3 hr at 0 0 C. The TRH in urine was more stable at 0 0 C than 20 0 C, and recovered 75+-4.6% at 24 hr after being added. The plasma levels of TRH were 19 pg/ml or less in normal adults and no sex difference was observed. The rate of disappearance of TRH administered i.v. from the blood could be represented as half-times of 4-12 min. Between 5.3-12.3% of the injected dose was excreted into urine within 1 hr as an immunoreactive TRH. These results indicate the usefulness of TRH radioimmunoassay for clinical investigation. (auth.)

  6. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone.

    Science.gov (United States)

    Dos Santos, Christine; Essioux, Laurent; Teinturier, Cécile; Tauber, Maïté; Goffin, Vincent; Bougnères, Pierre

    2004-07-01

    Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies largely across individuals. The genetic factors responsible for this variation are entirely unknown. In two cohorts of short children treated with growth hormone, we found that an isoform of the growth hormone receptor gene that lacks exon 3 (d3-GHR) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (P < 0.0001). In transfection experiments, the transduction of growth hormone signaling through d3-GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (P < 0.0001). One-half of Europeans are hetero- or homozygous with respect to the allele encoding the d3-GHR isoform, which is dominant over the full-length isoform. These observations suggest that the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics.

  7. Corticotropin-releasing hormone and mast cells in the regulation of mucosal barrier function in the human colon.

    Science.gov (United States)

    Wallon, Conny; Söderholm, Johan D

    2009-05-01

    Corticotropin-releasing hormone (CRH) is an important neuro-endocrine mediator of the stress response. Local effects of CRH in the intestinal mucosa have become evident in recent years. We showed that CRH activates CRH receptor subtypes R1 and R2 on subepithelial mast cells, thereby inducing increased transcellular uptake of protein antigens in human colonic biopsies in Ussing chambers. Ongoing studies also implicate local cholinergic signaling in regulation of macromolecular permeability in the human colon. Since increased uptake of antigenic molecules is associated with mucosal inflammation, our findings may have implications for understanding stress-related intestinal disorders.

  8. Different growth hormone (GH) response to GH-releasing peptide and GH-releasing hormone in hyperthyroidism.

    Science.gov (United States)

    Ramos-Dias, J C; Pimentel-Filho, F; Reis, A F; Lengyel, A M

    1996-04-01

    Altered GH responses to several pharmacological stimuli, including GHRH, have been found in hyperthyroidism. The mechanisms underlying these disturbances have not been fully elucidated. GH-releasing peptide-6 (GHRP-6) is a synthetic hexapeptide that specifically stimulates GH release both in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably acts by inhibiting the effects of somatostatin on GH release. The aim of this study was to evaluate the effects of GHRP-6 on GH secretion in patients with hyperthyroidism (n = 9) and in control subjects (n = 9). Each subject received GHRP-6 (1 microg/kg, iv), GHRH (100 microg, iv), and GHRP-6 plus GHRH on 3 separate days. GH peak values (mean +/- SE; micrograms per L) were significantly lower in hyperthyroid patients compared to those in control subjects after GHRH alone (9.0 +/- 1.3 vs. 27.0 +/- 5.2) and GHRP-6 plus GHRH (22.5 +/- 3.5 vs. 83.7 +/- 15.2); a lack of the normal synergistic effect of the association of both peptides was observed in thyrotoxicosis. However, a similar GH response was seen in both groups after isolated GHRP-6 injection (31.9 +/- 5.7 vs. 23.2 +/- 3.9). In summary, we have shown that hyperthyroid patients have a normal GH response to GHRP-6 together with a blunted GH responsiveness to GHRH. Our data suggest that thyroid hormones modulate GH release induced by these two peptides in a differential way.

  9. Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue.

    Science.gov (United States)

    Miao, Yifei; Wu, Wanfu; Dai, Yubing; Maneix, Laure; Huang, Bo; Warner, Margaret; Gustafsson, Jan-Åke

    2015-11-10

    The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.

  10. Endurance exercise modulates levodopa induced growth hormone release in patients with Parkinson's disease.

    Science.gov (United States)

    Müller, Thomas; Welnic, Jacub; Woitalla, Dirk; Muhlack, Siegfried

    2007-07-11

    Acute levodopa (LD) application and exercise release human growth hormone (GH). An earlier trial showed, that combined stimulus of exercise and LD administration is the best provocative test for GH response in healthy participants. Objective was to show this combined effect of LD application and exercise on GH response and to investigate the impact on LD metabolism in 20 previously treated patients with Parkinson's disease (PD). We measured GH- and LD plasma concentrations following soluble 200 mg LD/50 mg benserazide administration during endurance exercise and rest on two separate consecutive days. GH concentrations significantly increased on both days, but GH release was significantly delayed during rest. LD metabolism was not altered due to exercise in a clinical relevant manner. Exercise induced a significant faster LD stimulated GH release in comparison with the rest condition. We did not find the supposed increase of LD induced GH release by endurance exercise. We assume, that only a limited amount of GH is available for GH release in the anterior pituitary following an acute 200 mg LD administration. GH disposal also depends on growth hormone releasing hormone (GHRH), which is secreted into hypothalamic portal capillaries. During the exercise condition, the resulting higher blood pressure supports blood flow and thus GHRH transport towards the GH producing cells in the pituitary. This might additionally have caused the significant faster GH release during exercise.

  11. Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors.

    Science.gov (United States)

    Clegg, Deborah; Hevener, Andrea L; Moreau, Kerrie L; Morselli, Eugenia; Criollo, Alfredo; Van Pelt, Rachael E; Vieira-Potter, Victoria J

    2017-05-01

    With increased life expectancy, women will spend over three decades of life postmenopause. The menopausal transition increases susceptibility to metabolic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Thus, it is more important than ever to develop effective hormonal treatment strategies to protect aging women. Understanding the role of estrogens, and their biological actions mediated by estrogen receptors (ERs), in the regulation of cardiometabolic health is of paramount importance to discover novel targeted therapeutics. In this brief review, we provide a detailed overview of the literature, from basic science findings to human clinical trial evidence, supporting a protective role of estrogens and their receptors, specifically ERα, in maintenance of cardiometabolic health. In so doing, we provide a concise mechanistic discussion of some of the major tissue-specific roles of estrogens signaling through ERα. Taken together, evidence suggests that targeted, perhaps receptor-specific, hormonal therapies can and should be used to optimize the health of women as they transition through menopause, while reducing the undesired complications that have limited the efficacy and use of traditional hormone replacement interventions. Copyright © 2017 Endocrine Society.

  12. Novel growth hormone receptor gene mutation in a patient with Laron syndrome.

    Science.gov (United States)

    Arman, Ahmet; Yüksel, Bilgin; Coker, Ajda; Sarioz, Ozlem; Temiz, Fatih; Topaloglu, Ali Kemal

    2010-04-01

    Growth Hormone (GH) is a 22 kDa protein that has effects on growth and glucose and fat metabolisms. These effects are initiated by binding of growth hormone (GH) to growth hormone receptors (GHR) expressed in target cells. Mutations or deletions in the growth hormone receptor cause an autosomal disorder called Laron-type dwarfism (LS) characterized by high circulating levels of serum GH and low levels of insulin like growth factor-1 (IGF-1). We analyzed the GHR gene for genetic defect in seven patients identified as Laron type dwarfism. We identified two missense mutations (S40L and W104R), and four polymorphisms (S473S, L526I, G168G and exon 3 deletion). We are reporting a mutation (W104R) at exon 5 of GHR gene that is not previously reported, and it is a novel mutation.

  13. Action of luteinizing hormone-releasing hormone in rat ovarian cells: Hormone production and signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jian.

    1989-01-01

    The present study was conducted to investigate the hypothesis that the breakdown of membrane phosphoinositides may participate in the actions of luteinizing hormone-releasing hormone (LHRH) on hormone production in rat granulosa cells. In cells prelabeled with ({sup 3}H)inositol or ({sup 3}H)arachidonic acid (AA), treatment with LHRH increased the formation of radiolabeled inositol 1,4,5-trisphosphate (IP{sub 3}) and diacylglycerol (DG), and the release of radiolabeled AA. Since IP{sub 3} induces intracellular Ca{sup 2+} mobilization, changes in the cytosolic free calcium ion concentrations ((Ca{sup 2+})i) induced by LHRH were studied in individual cells using fura-2 microspectrofluorimetry. Alterations in (Ca{sup 2+})i induced by LHRH were rapid and transient, and could be completely blocked by a LHRH antagonist. Sustained perifusion of LHRH resulted in a desensitization of the (Ca{sup 2+})i response to LHRH. LHRH treatment accelerated (Ca{sup 2+})i depletion in the cells perifused with Ca{sup 2+} free medium, indicating the involvement of intracellular Ca{sup 2+} pool(s) in (Ca{sup 2+})i changes. The actions of LHRH on the regulation of progesterone (P{sub 4}) and prostaglandin E{sub 2} (PGE{sub 2}) production were also examined. LHRH increased basal P{sub 4} production and attenuated FSH induced P{sub 4} production. Both basal and FSH stimulated PGE{sub 2} formation were increased by LHRH. Since LHRH also increased the formation of DG that stimulates the activity of protein kinase C, an activator of protein kinase C (12-0-tetradecanolyphorbol-13-acetate: TPA) was used with the Ca{sup 2+} ionophore A23187 and melittin (an activator of phospholipase A{sub 2}) to examine the roles of protein kinase C, Ca{sup 2+} and free AA, respectively, in LHRH action.

  14. Potent agonists of growth hormone-releasing hormone. Part I.

    Science.gov (United States)

    Zarandi, M; Serfozo, P; Zsigo, J; Bokser, L; Janaky, T; Olsen, D B; Bajusz, S; Schally, A V

    1992-03-01

    Analogs of the 29 amino acid sequence of growth hormone-releasing hormone (GH-RH) with agmatine (Agm) in position 29 have been synthesized by the solid phase method, purified, and tested in vitro and in vivo. The majority of the analogs contained desaminotyrosine (Dat) in position 1, but a few of them had Tyr1, or N-MeTyr1. Some peptides contained one or more additional L- or D-amino acid substitutions in positions 2, 12, 15, 21, 27, and/or 28. Compared to the natural sequence of GH-RH(1-29)NH2, [Dat1,Ala15]GH-RH(1-28)Agm (MZ-3-191) and [D-Ala2,Ala15]GH-RH(1-28)Agm (MZ-3-201) were 8.2 and 7.1 times more potent in vitro, respectively. These two peptides contained Met27. Their Nle27 analogs, [Dat1,Ala15,Nle27]GH-RH(1-28)Agm(MZ-2-51), prepared previously (9), and [D-Ala2,Ala15,Nle28]GH-RH(1-28)Agm(MZ-3-195) showed relative in vitro potencies of 10.5 and 2.4, respectively. These data indicate that replacement of Met27 by Nle27 enhanced the GH-releasing activity of the analog when the molecule contained Dat1-Ala2 residues at the N-terminus, but peptides containing Tyr1-D-Ala2 in addition to Nle27 showed decreased potencies. Replacement of Ser28 with Asp in multi-substituted analogs of GH-RH(1-28)Agm resulted in a decrease in in vitro potencies compared to the parent compound. Thus, the Ser28-containing MZ-2-51, and [Dat1,Ala15,D-Lys21,Nle27]GH-RH(1-28)Agm, its Asp28 homolog (MZ-3-149), possessed relative activities of 10.5 and 5.6, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Prolactin receptor, growth hormone receptor, and putative somatolactin receptor in Mozambique tilapia: tissue specific expression and differential regulation by salinity and fasting.

    Science.gov (United States)

    Pierce, A L; Fox, B K; Davis, L K; Visitacion, N; Kitahashi, T; Hirano, T; Grau, E G

    2007-01-01

    In fish, pituitary growth hormone family peptide hormones (growth hormone, GH; prolactin, PRL; somatolactin, SL) regulate essential physiological functions including osmoregulation, growth, and metabolism. Teleost GH family hormones have both differential and overlapping effects, which are mediated by plasma membrane receptors. A PRL receptor (PRLR) and two putative GH receptors (GHR1 and GHR2) have been identified in several teleost species. Recent phylogenetic analyses and binding studies suggest that GHR1 is a receptor for SL. However, no studies have compared the tissue distribution and physiological regulation of all three receptors. We sequenced GHR2 from the liver of the Mozambique tilapia (Oreochromis mossambicus), developed quantitative real-time PCR assays for the three receptors, and assessed their tissue distribution and regulation by salinity and fasting. PRLR was highly expressed in the gill, kidney, and intestine, consistent with the osmoregulatory functions of PRL. PRLR expression was very low in the liver. GHR2 was most highly expressed in the muscle, followed by heart, testis, and liver, consistent with this being a GH receptor with functions in growth and metabolism. GHR1 was most highly expressed in fat, liver, and muscle, suggesting a metabolic function. GHR1 expression was also high in skin, consistent with a function of SL in chromatophore regulation. These findings support the hypothesis that GHR1 is a receptor for SL. In a comparison of freshwater (FW)- and seawater (SW)-adapted tilapia, plasma PRL was strongly elevated in FW, whereas plasma GH was slightly elevated in SW. PRLR expression was reduced in the gill in SW, consistent with PRL's function in freshwater adaptation. GHR2 was elevated in the kidney in FW, and correlated negatively with plasma GH, whereas GHR1 was elevated in the gill in SW. Plasma IGF-I, but not GH, was reduced by 4 weeks of fasting. Transcript levels of GHR1 and GHR2 were elevated by fasting in the muscle. However

  16. MEL-18 loss mediates estrogen receptor-α downregulation and hormone independence.

    Science.gov (United States)

    Lee, Jeong-Yeon; Won, Hee-Young; Park, Ji-Hye; Kim, Hye-Yeon; Choi, Hee-Joo; Shin, Dong-Hui; Kang, Ju-Hee; Woo, Jong-Kyu; Oh, Seung-Hyun; Son, Taekwon; Choi, Jin-Woo; Kim, Sehwan; Kim, Hyung-Yong; Yi, Kijong; Jang, Ki-Seok; Oh, Young-Ha; Kong, Gu

    2015-05-01

    The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.

  17. The diversity of abnormal hormone receptors in adrenal Cushing's syndrome allows novel pharmacological therapies

    Directory of Open Access Journals (Sweden)

    Lacroix A.

    2000-01-01

    Full Text Available Recent studies from several groups have indicated that abnormal or ectopic expression and function of adrenal receptors for various hormones may regulate cortisol production in ACTH-independent hypercortisolism. Gastric inhibitory polypeptide (GIP-dependent Cushing's syndrome has been described in patients with either unilateral adenoma or bilateral macronodular adrenal hyperplasia; this syndrome results from the large adrenal overexpression of the GIP receptor without any activating mutation. We have conducted a systematic in vivo evaluation of patients with adrenal Cushing's syndrome in order to identify the presence of abnormal hormone receptors. In macronodular adrenal hyperplasia, we have identified, in addition to GIP-dependent Cushing's syndrome, other patients in whom cortisol production was regulated abnormally by vasopressin, ß-adrenergic receptor agonists, hCG/LH, or serotonin 5HT-4 receptor agonists. In patients with unilateral adrenal adenoma, the abnormal expression or function of GIP or vasopressin receptor has been found, but the presence of ectopic or abnormal hormone receptors appears to be less prevalent than in macronodular adrenal hyperplasia. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists for the abnormal receptors.

  18. Pulsatile luteinising hormone releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome

    NARCIS (Netherlands)

    Bayram, N.; van Wely, M.; Vandekerckhove, P.; Lilford, R.; van der Veen, F.

    2000-01-01

    BACKGROUND: In normal menstrual cycles, gonadotrophin releasing hormone (GnRH) secretion is pulsatile, with intervals of 60-120 minutes in the follicular phase. Treatment with pulsatile GnRH infusion by the intra-venous or subcutaneous route using a portable pump has been used successfully in

  19. Negative feedback governs gonadotrope frequency-decoding of gonadotropin releasing hormone pulse-frequency.

    Directory of Open Access Journals (Sweden)

    Stefan Lim

    Full Text Available The synthesis of the gonadotropin subunits is directed by pulsatile gonadotropin-releasing hormone (GnRH from the hypothalamus, with the frequency of GnRH pulses governing the differential expression of the common alpha-subunit, luteinizing hormone beta-subunit (LHbeta and follicle-stimulating hormone beta-subunit (FSHbeta. Three mitogen-activated protein kinases, (MAPKs, ERK1/2, JNK and p38, contribute uniquely and combinatorially to the expression of each of these subunit genes. In this study, using both experimental and computational methods, we found that dual specificity phosphatase regulation of the activity of the three MAPKs through negative feedback is required, and forms the basis for decoding the frequency of pulsatile GnRH. A fourth MAPK, ERK5, was shown also to be activated by GnRH. ERK5 was found to stimulate FSHbeta promoter activity and to increase FSHbeta mRNA levels, as well as enhancing its preference for low GnRH pulse frequencies. The latter is achieved through boosting the ultrasensitive behavior of FSHbeta gene expression by increasing the number of MAPK dependencies, and through modulating the feedforward effects of JNK activation on the GnRH receptor (GnRH-R. Our findings contribute to understanding the role of changing GnRH pulse-frequency in controlling transcription of the pituitary gonadotropins, which comprises a crucial aspect in regulating reproduction. Pulsatile stimuli and oscillating signals are integral to many biological processes, and elucidation of the mechanisms through which the pulsatility is decoded explains how the same stimulant can lead to various outcomes in a single cell.

  20. Desensitization of parathyroid hormone receptors on cultured bone cells

    International Nuclear Information System (INIS)

    Pun, K.K.; Ho, P.W.; Nissenson, R.A.; Arnaud, C.D.

    1990-01-01

    Administration of excessive amounts of parathyroid hormone (PTH) in the treatment of osteoporosis can reverse the beneficial effects of a low-dose, intermittent regime. To investigate the direct actions and the possible cellular mechanisms of PTH in inducing desensitization of PTH receptors, we studied the effects of desensitization on rat osteoblastic UMR-106 cells. When the osteoblasts were preincubated with bPTH-(1-34), complete refractoriness to a subsequent challenge with the hormone developed within 1 h and at hormone concentrations as low as 5 nM. When osteoblasts thus desensitized were incubated in hormone-free medium, recovery of the cAMP responses began within 2 h and reached maximum after 16 h. Cycloheximide did not affect the process of desensitization. [Nle8,Nle18,Tyr34]bPTH-(3-34)amide significantly impaired the desensitization process by PTH-(1-34) but did not have stimulatory effect on cAMP responses. No significant heterologous desensitization was obvious after preincubation with isoprenaline (50 microM), prostaglandin E1 (50 microM), or prostaglandin E2 (50 microM) for 2 h. Binding experiments with [125I]PLP-(1-36)amide after desensitization revealed that there was an approximate twofold decrease in receptor affinities as analyzed by Scatchard analysis, showing that the decrease in affinity was prominent in the process of desensitization. When the cells were treated with monensin during desensitization, PTH challenge after desensitization produced significantly lower cyclic AMP responses. Recovery after desensitization occurred over a period of 16 h. Inclusion of monensin, but not cycloheximide, impaired the recovery. The results show that homologous desensitization of rat osteoblasts to PTH is brought about by the occupancy of receptors by PTH-(1-34) but not by cAMP generation itself

  1. The Hypercoagulable state in Hyperthyroidism is mediated via the Thyroid Hormone β Receptor pathway

    NARCIS (Netherlands)

    Elbers, Laura P. B.; Moran, Carla; Gerdes, Victor E. A.; van Zaane, Bregje; Meijers, Joost C. M.; Endert, Erik; Lyons, Greta; Chatterjee, V. Krishna; Bisschop, Peter H.; Fliers, Eric

    2016-01-01

    Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor β (TRβ) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in

  2. Up-regulation of corticotropin releasing hormone is associated with ...

    African Journals Online (AJOL)

    Purpose: To determine the expression of corticotropin-releasing hormone (CRH) in psoriasis and normal skin biopsy samples, and to correlate the expression of CRH with the expression of CRHBP and inflammatory cytokines IL-8 and IL-33. Methods: Psoriasis and normal skin biopsy samples were obtained from three ...

  3. Research resource: novel structural insights bridge gaps in glycoprotein hormone receptor analyses.

    Science.gov (United States)

    Kreuchwig, Annika; Kleinau, Gunnar; Krause, Gerd

    2013-08-01

    The first version of a glycoprotein hormone receptor (GPHR) information resource was designed to link functional with structural GPHR information, in order to support sequence-structure-function analysis of the LH, FSH, and TSH receptors (http://ssfa-gphr.de). However, structural information on a binding- and signaling-sensitive extracellular fragment (∼100 residues), the hinge region, had been lacking. A new FSHR crystal structure of the hormone-bound extracellular domain has recently been solved. The structure comprises the leucine-rich repeat domain and most parts of the hinge region. We have not only integrated the new FSHR/FSH structure and the derived homology models of TSHR/TSH, LHCGR/CG, and LHCGR/LH into our web-based information resource, but have additionally provided novel tools to analyze the advanced structural features, with the common characteristics and distinctions between GPHRs, in a more precise manner. The hinge region with its second hormone-binding site allows us to assign functional data to the new structural features between hormone and receptor, such as binding details of a sulfated tyrosine (conserved throughout the GPHRs) extending into a pocket of the hormone. We have also implemented a protein interface analysis tool that enables the identification and visualization of extracellular contact points between interaction partners. This provides a starting point for comparing the binding patterns of GPHRs. Together with the mutagenesis data stored in the database, this will help to decipher the essential residues for ligand recognition and the molecular mechanisms of signal transduction, extending from the extracellular hormone-binding site toward the intracellular G protein-binding sites.

  4. Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone alpha 1-receptor protein

    NARCIS (Netherlands)

    van Beeren, H. C.; Bakker, O.; Wiersinga, W. M.

    1995-01-01

    Desethylamiodarone (DEA), the major metabolite of the potent antiarrythmic drug amiodarone, is a non-competitive inhibitor of the binding of thyroid hormone (T3) to the beta 1-thyroid hormone receptor (T3R). In the present study, we investigated whether DEA acts in a similar way with respect to the

  5. Analysis of the hormone-binding domain of steroid receptors using chimeras generated by homologous recombination

    International Nuclear Information System (INIS)

    Martinez, Elisabeth D.; Pattabiraman, Nagarajan; Danielsen, Mark

    2005-01-01

    The glucocorticoid receptor and the mineralocorticoid receptor are members of the steroid receptor family that exhibit ligand cross-reactivity. Specificity of steroid receptor action is investigated in the present work by the construction and characterization of chimeras between the glucocorticoid receptor and the mineralocorticoid receptor. We used an innovative approach to make novel steroid receptor proteins in vivo that in general, contrary to our expectations, show increased ligand specificity compared to the parental receptors. We describe a receptor that is specific for the potent synthetic glucocorticoid triamcinolone acetonide and does not bind aldosterone. A further set of chimeras has an increased ability to discriminate between ligands, responding potently to mineralocorticoids and only very weakly to synthetic glucocorticoids. A chimera with the fusion site in the hinge highlights the importance of the region between the DNA-binding and the hormone-binding domains since, unlike both the glucocorticoid and mineralocorticoid receptors, it only responds to mineralocorticoids. One chimera has reduced specificity in that it acts as a general corticoid receptor, responding to glucocorticoids and mineralocorticoids with similar potency and efficacy. Our data suggest that regions of the glucocorticoid and mineralocorticoid receptor hormone-binding domains are functionally non-reciprocal. We present transcriptional, hormone-binding, and structure-modeling evidence that suggests that receptor-specific interactions within and across domains mediate aspects of specificity in transcriptional responses to steroids

  6. Noise stress changes mRNA expressions of corticotropin-releasing hormone, its receptors in amygdala, and anxiety-related behaviors

    Directory of Open Access Journals (Sweden)

    Evren Eraslan

    2015-01-01

    Full Text Available Noise is a psychological, environmental stressor that activates limbic sites in the brain. Limbic sites such as the amygdala and the amygdaloid corticotropin-releasing hormone (CRH system play an important role in integrating stress response. We investigated the association between noise exposures, CRH-related molecules in the amygdala, and behavioral alterations. In total 54 Sprague-Dawley rats were divided into the following three groups: Control (CON, acute noise exposure (ANE, and chronic noise exposure (CNE. The ANE group was exposed to 100 dB white noise only once in 4 h and the CNE group was exposed to the same for 4 h per day for 30 days. Expression profiles of CRH and its receptors CRH-R1 and CRH-R2 were analyzed by quantitative real-time polymerase chain reaction (qPCR. The same stress procedure was applied to the ANE and CNE groups for behavior testing. The anxiety responses of the animals after acute and chronic stress exposure were measured in the defensive withdrawal test. CNE upregulated CRH and CRH-R1 mRNA levels but downregulated CRH-R2 mRNA levels. ANE led to a decrease in both CRH-R1 and CRH-R2 expression. In the defensive withdrawal test, while the ANE increased, CNE reduced anxiety-like behaviors. The present study shows that the exposure of rats to white noise (100 dB leads to behavioral alterations and molecule-specific changes in the CRH system. Behavioral alterations can be related to these molecular changes in the amygdala.

  7. Noise stress changes mRNA expressions of corticotropin-releasing hormone, its receptors in amygdala, and anxiety-related behaviors.

    Science.gov (United States)

    Eraslan, Evren; Akyazi, Ibrahim; Erg L-Ekiz, Elif; Matur, Erdal

    2015-01-01

    Noise is a psychological, environmental stressor that activates limbic sites in the brain. Limbic sites such as the amygdala and the amygdaloid corticotropin-releasing hormone (CRH) system play an important role in integrating stress response. We investigated the association between noise exposures, CRH-related molecules in the amygdala, and behavioral alterations. In total 54 Sprague-Dawley rats were divided into the following three groups: Control (CON), acute noise exposure (ANE), and chronic noise exposure (CNE). The ANE group was exposed to 100 dB white noise only once in 4 h and the CNE group was exposed to the same for 4 h per day for 30 days. Expression profiles of CRH and its receptors CRH-R1 and CRH-R2 were analyzed by quantitative real-time polymerase chain reaction (qPCR). The same stress procedure was applied to the ANE and CNE groups for behavior testing. The anxiety responses of the animals after acute and chronic stress exposure were measured in the defensive withdrawal test. CNE upregulated CRH and CRH-R1 mRNA levels but downregulated CRH-R2 mRNA levels. ANE led to a decrease in both CRH-R1 and CRH-R2 expression. In the defensive withdrawal test, while the ANE increased, CNE reduced anxiety-like behaviors. The present study shows that the exposure of rats to white noise (100 dB) leads to behavioral alterations and molecule-specific changes in the CRH system. Behavioral alterations can be related to these molecular changes in the amygdala.

  8. BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus.

    Science.gov (United States)

    Jeanneteau, Freddy D; Lambert, W Marcus; Ismaili, Naima; Bath, Kevin G; Lee, Francis S; Garabedian, Michael J; Chao, Moses V

    2012-01-24

    Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH.

  9. Pituitary response to thyrotropin releasing hormone in children with overweight and obesity.

    Science.gov (United States)

    Rijks, Jesse; Penders, Bas; Dorenbos, Elke; Straetemans, Saartje; Gerver, Willem-Jan; Vreugdenhil, Anita

    2016-08-03

    Thyroid stimulating hormone (TSH) concentrations in the high normal range are common in children with overweight and obesity, and associated with increased cardiovascular disease risk. Prior studies aiming at unravelling the mechanisms underlying these high TSH concentrations mainly focused on factors promoting thyrotropin releasing hormone (TRH) production as a cause for high TSH concentrations. However, it is unknown whether TSH release of the pituitary in response to TRH is affected in children with overweight and obesity. Here we describe TSH release of the pituitary in response to exogenous TRH in 73 euthyroid children (39% males) with overweight or (morbid) obesity. Baseline TSH concentrations (0.9-5.5 mU/L) were not associated with BMI z score, whereas these concentrations were positively associated with TSH concentrations 20 minutes after TRH administration (r(2) = 0.484, p obesity. The clinical significance and the intermediate factors contributing to pituitary TSH release need to be elucidated in future studies.

  10. Bone Mass in Young Adulthood Following Gonadotropin-Releasing Hormone Analog Treatment and Cross-Sex Hormone Treatment in Adolescents With Gender Dysphoria

    NARCIS (Netherlands)

    Klink, D.T.; Caris, M.G.; Heijboer, A.C.; van Trotsenburg, M.; Rotteveel, J.

    2015-01-01

    Context: Sex steroids are important for bone mass accrual. Adolescents with gender dysphoria (GD) treated with gonadotropin-releasing hormone analog (GnRHa) therapy are temporarily sex-steroid deprived until the addition of cross-sex hormones (CSH). The effect of this treatment on bone mineral

  11. Steroid hormone and epidermal growth factor receptors in meningiomas.

    Science.gov (United States)

    Horsfall, D J; Goldsmith, K G; Ricciardelli, C; Skinner, J M; Tilley, W D; Marshall, V R

    1989-11-01

    A prospective study of steroid hormone and epidermal growth factor receptor expression in 57 meningiomas is presented. Scatchard analysis of radioligand binding identified 20% of meningiomas as expressing classical oestrogen receptors (ER) at levels below that normally accepted for positivity, the remainder being negative. ER could not be visualized in any meningioma using immunocytochemistry. Alternatively, 74% of meningiomas demonstrated the presence of progesterone receptors (PR) by Scatchard analysis, the specificity of which could not be attributed to glucocorticoid or androgen receptors. Confirmation of classical PR presence was determined by immunocytochemical staining. The presence of epidermal growth factor receptor (EGFR) was demonstrated in 100% of meningiomas using immunocytochemical staining. These data are reviewed in the context of previously reported results and are discussed in relation to the potential for medical therapy as an adjunct to surgery.

  12. Evidence for association of the cloned liver growth hormone receptor with a tyrosine kinase

    DEFF Research Database (Denmark)

    Wang, X; Uhler, M D; Billestrup, N

    1992-01-01

    The ability of the cloned liver growth hormone (GH) receptor, when expressed in mammalian cell lines, to copurify with tyrosine kinase activity and be tyrosyl phosphorylated was examined. 125I-human growth hormone-GH receptor complexes isolated from COS-7 cells transiently expressing high levels...... of tyrosine kinase activity with cloned liver GH receptor. The level of phosphorylation of the GH receptor was very low, as compared with the endogenous GH receptor in 3T3-F442A cells, suggesting that tyrosine kinase activity is not intrinsic to the cloned GH receptor but rather resides with a kinase present...... in a variety of cell types. The finding that the level of phosphorylation of GH receptor appears to vary with cell type is consistent with the cloned liver GH receptor being a substrate for an associated tyrosine kinase and with the amount of such a GH receptor-associated tyrosine kinase being cell type-specific....

  13. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors

    DEFF Research Database (Denmark)

    Brighton, Cheryl A.; Rievaj, Juraj; Kuhre, Rune E.

    2015-01-01

    Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium......-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L...... to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms....

  14. Polymorphism of growth hormone receptor (GHR gene in Holstein Friesian dairy cattle

    Directory of Open Access Journals (Sweden)

    Restu Misrianti

    2011-12-01

    Full Text Available Growth hormone gene have a critical role in the regulation of lactation, mammary gland development and growth process through its interaction with a specific receptor. Growth hormone (GH is an anabolic hormone which is synthesized and secreted by somatotrop cell in pituitary anterior lobe, and interacts with a specific receptor on the surface of the target cells. Growth hormone receptor (GHR has been suggested as candidate gene for traits related to milk production in Bovidae. The purpose of this study was to identify genetic polymorphism of the Growth Hormone Receptor (GHR genes in Holstein Friesian (HF cattle. Total of 353 blood samples were collected from five populations belonging to Cikole Dairy Cattle Breeding Station (BPPT-SP Cikole (88 samples, Pasir Kemis (95 samples, Cilumber (98 samples, Cipelang Livestock Embryo Center (BET Cipelang (40 samples, Singosari National Artificial Insemination Centre (BBIB Singosari (32 samples and 17 frozen semen samples from Lembang Artificial Insemination Center (BIB Lembang. Genomic DNAs were extracted by a standard phenol-chloroform protocol and amplified by a polymerase chain reaction (PCR techniques then PCR products were genotyped by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP methods. There were two allele dan three genotypes were found namely: allele A and G, Genotype AA, AG and GG repectively. Allele A frequency (0.70-0.82 relatively higher than allele G frequency (0.18-0.30. Chi square test show that on group of BET Cipelang, BIB Lembang and BBIB Singosari population were not significantly different (0.00-0.93, while on group of BET Cipelang, BIB Lembang dan BBIB Singosari population were significantly different (6.02-11.13. Degree of observed heterozygosity (Ho ranged from 0.13-0.42 and expected heterozygosity (He ranged from 0.29-0.42.

  15. Do unliganded thyroid hormone receptors have physiological functions?

    Science.gov (United States)

    Chassande, O

    2003-08-01

    Thyroid hormone (TH) is required for the development of vertebrates and exerts numerous homeostatic functions in adults. TH acts through nuclear receptors which control the transcription of target genes. Unliganded and liganded thyroid hormone receptors (TRs) have been shown to exert opposite effects on the transcription of target genes in vitro. However, the occurance of an aporeceptor activity in vivo and its potential physiological significance has not been clearly addressed. Several data generated using experimental hypothyroidism and thyrotoxicosis in wild type and TR knockout mice support the notion that apoTRs have an intrinsic activity in several tIssues. ApoTRs, and in particular TRalpha1, are predominant during the early stages of vertebrate development and must be turned into holoTRs for post-natal development to proceed normally. However, the absence of striking alterations of embryonic and fetal development in mice devoid of TRs indicates that apoTRs do not play a fundamental role. During development, as well as in adults, apoTRs rather appears as a system which increases the range of transcriptional responses to moderate variations of T3.

  16. Alterations in the corticotropin-releasing hormone (CRH) neurocircuitry: Insights into post stroke functional impairments.

    Science.gov (United States)

    Barra de la Tremblaye, P; Plamondon, H

    2016-07-01

    Although it is well accepted that changes in the regulation of the hypothalamic-pituitary adrenal (HPA) axis may increase susceptibility to affective disorders in the general population, this link has been less examined in stroke patients. Yet, the bidirectional association between depression and cardiovascular disease is strong, and stress increases vulnerability to stroke. Corticotropin-releasing hormone (CRH) is the central stress hormone of the HPA axis pathway and acts by binding to CRH receptors (CRHR) 1 and 2, which are located in several stress-related brain regions. Evidence from clinical and animal studies suggests a role for CRH in the neurobiological basis of depression and ischemic brain injury. Given its importance in the regulation of the neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation to stress, CRH is likely associated in the pathophysiology of post stroke emotional impairments. The goals of this review article are to examine the clinical and experimental data describing (1) that CRH regulates the molecular signaling brain circuit underlying anxiety- and depression-like behaviors, (2) the influence of CRH and other stress markers in the pathophysiology of post stroke emotional and cognitive impairments, and (3) context and site specific interactions of CRH and BDNF as a basis for the development of novel therapeutic targets. This review addresses how the production and release of the neuropeptide CRH within the various regions of the mesocorticolimbic system influences emotional and cognitive behaviors with a look into its role in psychiatric disorders post stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. The use of gonadotrophin-releasing hormone antagonists in polycystic ovarian disease.

    Science.gov (United States)

    Lubin, V; Charbonnel, B; Bouchard, P

    1998-12-01

    Polycystic ovarian disease (PCOD) is characterized by anovulation, eventually high luteinizing hormone (LH) levels, with increased LH pulse frequency, and hyperandrogenism. As the aetiology of the disease is still unknown, gonadotrophin-releasing hormone (GnRH) antagonists, competitive inhibitors of GnRH for its receptor, are interesting tools in order to study and treat the role of increased LH levels and pulse frequency in this disease. Their administration provokes a rapid decrease in bioactive and immunoactive LH followed by a slower decrease in follicle-stimulating hormone (FSH). In patients with PCOD, the suppression of gonadotrophin secretion eradicates the symptoms of the disease as long as the treatment lasts. Several authors have suggested that increased plasma LH levels have deleterious effects on the fertility of women with PCOD. Indeed, fewer spontaneous pregnancies with more miscarriages are observed when plasma LH levels are high. Assisted reproduction techniques such as in vitro fertilization (IVF) have provided other clues to the role of the LH secretory pattern in women with PCOD. The number of oocytes retrieved, the fertilization rate and the cleavage rate are lower in PCOD patients undergoing IVF and this is inversely correlated with FSH:LH ratio. These abnormalities are corrected when endogenous secretion of LH is suppressed. On the other hand, implantation and pregnancy rates after IVF are similar to those observed in control women. New GnRH antagonists are devoid of side effects and suppress LH secretion within a few hours without a flare-up effect. This action lasts for 10-100 hours. When GnRH antagonists are associated with i.v. pulsatile GnRH, this combination both suppresses the effect of endogenous GnRH and because of the competition for GnRH receptors restores a normal frequency of LH secretion. We have studied two women with PCOD, administering first 10 mg s.c. every 72 hours for 7 days of the GnRH antagonist Nal-Glu, then adding on

  18. Growth hormone receptor deficiency (Laron syndrome) in black ...

    African Journals Online (AJOL)

    Non-Caucasians with growth honnone receptor (GHR) deficiency/Lamn syndrome among the .... 4,3 cm (-2,4 SOS for bone age 8,5 years at age 12); the girl's height at age 7 years was 77,5 cm (-8,0 SOS, height ... of serum incubated with '25I-labelled human growth hormone and expressed as relative specific binding ...

  19. Study of change of sex hormone receptors in diabetic impotent patients

    International Nuclear Information System (INIS)

    Zhang Yong; Chen Weizhen; Zhang Zikang; Hu Xiaoke

    2002-01-01

    To study the relationship between diabetic impotence and sex hormones as well as sex hormone receptors. 32 diabetic impotent patients, 32 diabetic patients with normal sex function, 32 impotent patients without diabetes, and 40 healthy men were enrolled. The plasma sex hormone levels were examined by radioimmunoassay, and sex hormone receptors in white blood cells by radioreceptor assay. Compared with healthy men and impotent patients without diabetes, PRL levels in both diabetic impotent patients and diabetic patients with normal sex function increased markedly, T and AR levels decreased, and the ratio of E 2 /T and ER/AR increased. Compared with diabetic patients with normal sex function, while there was no significant difference in PRL, T and E 2 /T ratio, the AR level of diabetic impotent patients further decreased, and the ER/AR ratio further increased. Negative correlation was found between age and AR as well as T. The decline of AR and the increase of ER/AR ratio might be one main cause of diabetic impotence. And the decline of T and AR might be an important cause of the increase of diabetic impotence incidence with age

  20. Synthesis and release of luteinizing hormone in vitro: manipulations of Ca2+ environment

    International Nuclear Information System (INIS)

    Liu, T.C.; Jackson, G.L.

    1985-01-01

    The authors determined if luteinizing hormone (LH) synthesis is Ca2+ dependent and coupled to LH release. They monitored LH synthesis when LH release was stimulated either by specific [gonadotropin-releasing hormone (GnRH)] or nonspecific stimuli (50 mM K+ and 2 or 20 microM Ca2+ ionophore A23187) and inhibited by Ca2+-reduced medium. LH synthesis was estimated by measuring incorporation of [ 3 H]glucosamine (glycosylation) and [ 14 C]alanine (translation) into total (cell and medium) immunoprecipitable LH by cultured rat anterior pituitary cells. Both GnRH (1 nM) and 50 mM K+ significantly stimulated LH release and glycosylation, but had no effect on LH translation. A23187 also stimulated LH release, but significantly depressed glycosylation of LH and total protein and [ 14 C]alanine uptake. Deletion of Ca2+ from the medium depressed both GnRH-induced LH release and glycosylation. Addition of 0.1 mM EGTA to Ca2+-free medium not only inhibited GnRH-induced release and glycosylation of LH but also uptake of precursors and glycosylation and translation of total protein. Thus, glycosylation and release of LH are Ca2+ dependent. Whether parallel changes in LH release and glycosylation reflect a cause and effect relationship remains to be determined

  1. Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation

    DEFF Research Database (Denmark)

    Behncken, S N; Billestrup, Nils; Brown, R

    2000-01-01

    Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the gro......Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers...

  2. A mathematical model for LH release in response to continuous and pulsatile exposure of gonadotrophs to GnRH

    Directory of Open Access Journals (Sweden)

    Reed Michael C

    2004-09-01

    Full Text Available Abstract In a previous study, a model was developed to investigate the release of luteinizing hormone (LH from pituitary cells in response to a short pulse of gonadotropin-releasing hormone (GnRH. The model included: binding of GnRH to its receptor (R, dimerization and internalization of the hormone receptor complex, interaction with a G protein, production of inositol 1,4,5-trisphosphate (IP3, release of calcium from the endoplasmic reticulum (ER, entrance of calcium into the cytosol via voltage gated membrane channels, pumping of calcium out of the cytosol via membrane and ER pumps, and release of LH. The extended model, presented in this paper, also includes the following physiologically important phenomena: desensitization of calcium channels; internalization of the dimerized receptors and recycling of some of the internalized receptors; an increase in Gq concentration near the plasma membrane in response to receptor dimerization; and basal rates of synthesis and degradation of the receptors. With suitable choices of the parameters, good agreement with a variety of experimental data of the LH release pattern in response to pulses of various durations, repetition rates, and concentrations of GnRH were obtained. The mathematical model allows us to assess the effects of internalization and desensitization on the shapes and time courses of LH response curves.

  3. A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.

    Science.gov (United States)

    Cervetto, Chiara; Venturini, Arianna; Passalacqua, Mario; Guidolin, Diego; Genedani, Susanna; Fuxe, Kjell; Borroto-Esquela, Dasiel O; Cortelli, Pietro; Woods, Amina; Maura, Guido; Marcoli, Manuela; Agnati, Luigi F

    2017-01-01

    Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. © 2016 International Society for Neurochemistry.

  4. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

    Science.gov (United States)

    Khalil, Raouf A

    2013-12-15

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Negative regulation of parathyroid hormone-related protein expression by steroid hormones

    International Nuclear Information System (INIS)

    Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko; Chikamori, Minoru; Iizuka, Masayoshi; Okazaki, Tomoki

    2011-01-01

    Highlights: → Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. → Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. → Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor α, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.

  6. Intrauterine Zn Deficiency Favors Thyrotropin-Releasing Hormone-Increasing Effects on Thyrotropin Serum Levels and Induces Subclinical Hypothyroidism in Weaned Rats

    Directory of Open Access Journals (Sweden)

    Viridiana Alcántara-Alonso

    2017-10-01

    Full Text Available Individuals who consume a diet deficient in zinc (Zn-deficient develop alterations in hypothalamic-pituitary-thyroid axis function, i.e., a low metabolic rate and cold insensitivity. Although those disturbances are related to primary hypothyroidism, intrauterine or postnatal Zn-deficient adults have an increased thyrotropin (TSH concentration, but unchanged thyroid hormone (TH levels and decreased body weight. This does not support the view that the hypothyroidism develops due to a low Zn intake. In addition, intrauterine or postnatal Zn-deficiency in weaned and adult rats reduces the activity of pyroglutamyl aminopeptidase II (PPII in the medial-basal hypothalamus (MBH. PPII is an enzyme that degrades thyrotropin-releasing hormone (TRH. This hypothalamic peptide stimulates its receptor in adenohypophysis, thereby increasing TSH release. We analyzed whether earlier low TH is responsible for the high TSH levels reported in adults, or if TRH release is enhanced by Zn deficiency at weaning. Dams were fed a 2 ppm Zn-deficient diet in the period from one week prior to gestation and up to three weeks after delivery. We found a high release of hypothalamic TRH, which along with reduced MBH PPII activity, increased TSH levels in Zn-deficient pups independently of changes in TH concentration. We found that primary hypothyroidism did not develop in intrauterine Zn-deficient weaned rats and we confirmed that metal deficiency enhances TSH levels since early-life, favoring subclinical hypothyroidism development which remains into adulthood.

  7. Kisspeptin stimulates growth hormone release by utilizing Neuropeptide Y pathways and is dependent on the presence of ghrelin

    Science.gov (United States)

    Although kisspeptin is the primary stimulator of gonadotropin releasing hormone secretion and therefore the hypothalamic-pituitary gonadal axis, new findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Central delivery of kisspep...

  8. Leptin Regulation of Gonadotrope Gonadotropin-Releasing Hormone Receptors As a Metabolic Checkpoint and Gateway to Reproductive Competence

    Directory of Open Access Journals (Sweden)

    Angela K. Odle

    2018-01-01

    Full Text Available The adipokine leptin signals the body’s nutritional status to the brain, and particularly, the hypothalamus. However, leptin receptors (LEPRs can be found all throughout the body and brain, including the pituitary. It is known that leptin is permissive for reproduction, and mice that cannot produce leptin (Lep/Lep are infertile. Many studies have pinpointed leptin’s regulation of reproduction to the hypothalamus. However, LEPRs exist at all levels of the hypothalamic–pituitary–gonadal axis. We have previously shown that deleting the signaling portion of the LEPR specifically in gonadotropes impairs fertility in female mice. Our recent studies have targeted this regulation to the control of gonadotropin releasing hormone receptor (GnRHR expression. The hypotheses presented here are twofold: (1 cyclic regulation of pituitary GnRHR levels sets up a target metabolic checkpoint for control of the reproductive axis and (2 multiple checkpoints are required for the metabolic signaling that regulates the reproductive axis. Here, we emphasize and explore the relationship between the hypothalamus and the pituitary with regard to the regulation of GnRHR. The original data we present strengthen these hypotheses and build on our previous studies. We show that we can cause infertility in 70% of female mice by deleting all isoforms of LEPR specifically in gonadotropes. Our findings implicate activin subunit (InhBa mRNA as a potential leptin target in gonadotropes. We further show gonadotrope-specific upregulation of GnRHR protein (but not mRNA levels following leptin stimulation. In order to try and understand this post-transcriptional regulation, we tested candidate miRNAs (identified with in silico analysis that may be binding the Gnrhr mRNA. We show significant upregulation of one of these miRNAs in our gonadotrope-Lepr-null females. The evidence provided here, combined with our previous work, lay the foundation for metabolically regulated post

  9. Involvement of hormones in olfactory imprinting and homing in chum salmon.

    Science.gov (United States)

    Ueda, Hiroshi; Nakamura, Shingo; Nakamura, Taro; Inada, Kaoru; Okubo, Takashi; Furukawa, Naohiro; Murakami, Reiichi; Tsuchida, Shigeo; Zohar, Yonathan; Konno, Kotaro; Watanabe, Masahiko

    2016-02-16

    The olfactory hypothesis for salmon imprinting and homing to their natal stream is well known, but the endocrine hormonal control mechanisms of olfactory memory formation in juveniles and retrieval in adults remain unclear. In brains of hatchery-reared underyearling juvenile chum salmon (Oncorhynchus keta), thyrotropin-releasing hormone gene expression increased immediately after release from a hatchery into the natal stream, and the expression of the essential NR1 subunit of the N-methyl-D-aspartate receptor increased during downstream migration. Gene expression of salmon gonadotropin-releasing hormone (sGnRH) and NR1 increased in the adult chum salmon brain during homing from the Bering Sea to the natal hatchery. Thyroid hormone treatment in juveniles enhanced NR1 gene activation, and GnRHa treatment in adults improved stream odour discrimination. Olfactory memory formation during juvenile downstream migration and retrieval during adult homing migration of chum salmon might be controlled by endocrine hormones and could be clarified using NR1 as a molecular marker.

  10. The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Casadesus, Gemma; Garrett, Matthew R; Webber, Kate M; Hartzler, Anthony W; Atwood, Craig S; Perry, George; Bowen, Richard L; Smith, Mark A

    2006-01-01

    Estrogen and other sex hormones have received a great deal of attention for their speculative role in Alzheimer's disease (AD), but at present a direct connection between estrogen and the pathogenesis of AD remains elusive and somewhat contradictory. For example, on one hand there is a large body of evidence suggesting that estrogen is neuroprotective and improves cognition, and that hormone replacement therapy (HRT) at the onset of menopause reduces the risk of developing AD decades later. However, on the other hand, studies such as the Women's Health Initiative demonstrate that HRT initiated in elderly women increases the risk of dementia. While estrogen continues to be investigated, the disparity of findings involving HRT has led many researchers to examine other hormones of the hypothalamic-pituitary-gonadal axis such as luteinising hormone (LH) and follicle-stimulating hormone. In this review, we propose that LH, rather than estrogen, is the paramount player in the pathogenesis of AD. Notably, both men and women experience a 3- to 4-fold increase in LH with aging, and LH receptors are found throughout the brain following a regional pattern remarkably similar to those neuron populations affected in AD. With respect to disease, serum LH level is increased in women with AD relative to non-diseased controls, and levels of LH in the brain are also elevated in AD. Mechanistically, we propose that elevated levels of LH may be a fundamental instigator responsible for the aberrant reactivation of the cell cycle that is seen in AD. Based on these aforementioned aspects, clinical trials underway with leuprolide acetate, a gonadotropin-releasing hormone agonist that ablates serum LH levels, hold great promise as a ready means of treatment in individuals afflicted with AD.

  11. Rapid, portable detection of endocrine disrupting chemicals through ligand-nuclear hormone receptor interactions.

    Science.gov (United States)

    Hunt, J Porter; Schinn, Song-Min; Jones, Matthew D; Bundy, Bradley C

    2017-12-04

    Endocrine disrupting chemicals (EDC) are structurally diverse compounds that can interact with nuclear hormone receptors, posing significant risk to human and ecological health. Unfortunately, many conventional biosensors have been too structure-specific, labor-intensive or laboratory-oriented to detect broad ranges of EDC effectively. Recently, several technological advances are providing more rapid, portable, and affordable detection of endocrine-disrupting activity through ligand-nuclear hormone receptor interactions. Here, we overview these recent advances applied to EDC biosensors - including cell lyophilization, cell immobilization, cell-free systems, smartphone-based signal detection, and improved competitive binding assays.

  12. Pancreatic hormones are expressed on the surfaces of human and rat islet cells through exocytotic sites

    DEFF Research Database (Denmark)

    Larsson, L I; Hutton, J C; Madsen, O D

    1989-01-01

    . Electron microscopy reveals the labeling to occur at sites of exocytotic granule release, involving the surfaces of extruded granule cores. The surfaces of islet cells were labeled both by polyclonal and monoclonal antibodies, excluding that receptor-interacting, anti-idiotypic hormone antibodies were...... for these results. It is concluded that the staining reflects interactions between the appropriate antibodies and exocytotic sites of hormone release....

  13. Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Skovbjerg Arildsen, Nicolai; Malander, Susanne

    2015-01-01

    BACKGROUND AND AIMS: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival...... in epithelial ovarian cancer. METHODS: Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer...... in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer....

  14. Childhood lead toxicity and impaired release of thyrotropin-stimulating hormone

    International Nuclear Information System (INIS)

    Huseman, C.A.; Moriarty, C.M.; Angle, C.R.

    1987-01-01

    Decreased stature of children is epidemiologically associated with increased blood lead independent of multiple socioeconomic and nutritional variables. Since endocrine dysfunction occurs in adult lead workers, they studied two girls, 2 years of age, before and after calcium disodium edetate chelation for blood leads (PbB) of 19-72 μg/dl. The height of both children had crossed from the 50th to below the 10th percentile during the course of chronic lead toxicity. Basal free T 4 , T 4 , T 3 , cortisol, somatomedin C, and sex steroids were normal. A decrease in the growth hormone response and elevation of basal prolcatin and gonadotropins were noted in one. Both children demonstrated blunted thyrotropin-stimulating hormone (TSH) responses to thyrotropin-releasing hormone (TRH) in six of seven challenges. This prompted in vitro studies of cultured cells from rat pituitarities. After incubation of pituitary cells with 0.1-10 μM Pb 2+ for 2 hr, followed by the addition of TRH, there was a dose-dependent inhibition of TSH release Lead did not interfere with the assay of TSH. To investigate the interaction of lead and calcium, 45 Ca 2+ kinetic analyses were done on rat pituitary slices after 1 hr incubation with 1.0 μM lead. The impaired late efflux was consistent with a decrease in the size and exchangeability of the tightly bound pool of intracellular microsomal or mitochondrial calcium. The rat pituitary cell model provides a model for the decreased TSH release of lead poisoning, supports the biological plausibility of a neuroendocrine effect on growth, and suggests that interference with calcium-mediated intracellular responses is a basic mechanism of lead toxicity

  15. Regulation of gonadotropin-releasing hormone neurons by glucose

    Science.gov (United States)

    Roland, Alison V.; Moenter, Suzanne M.

    2011-01-01

    Reproduction is influenced by energy balance, but the physiological pathways mediating their relationship have not been fully elucidated. As the central regulators of fertility, gonadotropin-releasing hormone (GnRH) neurons integrate numerous physiological signals, including metabolic cues. Circulating glucose levels regulate GnRH release and may in part mediate the effects of negative energy balance on fertility. Existing evidence suggests that neural pathways originating in the hindbrain, as well as in the hypothalamic feeding nuclei, transmit information concerning glucose availability to GnRH neurons. Here we review recent evidence suggesting that GnRH neurons may directly sense changes in glucose availability by a mechanism involving adenosine monophosphate-activated protein kinase (AMPK). These findings expand our understanding of how metabolic signaling in the brain regulates reproduction. PMID:21855365

  16. Aspects of dopamine and acetylcholine release induced by glutamate receptors

    International Nuclear Information System (INIS)

    Paes, Paulo Cesar de Arruda

    2002-01-01

    The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

  17. Cholecystokinin receptors: disparity between phosphoinositide breakdown and amylase releasing activity of CCK analogues in pancreas

    International Nuclear Information System (INIS)

    Lin, C.W.; Grant, D.; Bianchi, B.; Miller, T.; Witte, D.; Shue, Y.K.; Nadzan, A.

    1986-01-01

    Cholecystokinin (CCK) peptides are a family of hormones which also occur in brain. In pancreas CCK stimulates the release of amylase, a process that is dependent on the mobilization of intracellular Ca 2+ . Recent evidence suggests that inositol 1,4,5-trisphosphate, the breakdown product of phosphatidylinositol 4,5-bisphosphate, is responsible for the rise in intracellular Ca 2+ . Their laboratory has developed assays to study synthetic CCK analogues using radioligand binding, PI breakdown and amylase release. They have shown that there are good correlations among these three assay systems for the carboxy terminal fragments of CCK 8 . Recently, they have discovered synthetic analogues of CCK 4 that are full agonists in amylase release but are ineffective in causing PI breakdown. In particular, A-61576, Boc-5-amino-2-indolemethylene-pent-2-ene-1-oyl-Leu-Asp-Phe-NH 2 , is a full agonist in the amylase releasing assay, but is devoid of PI stimulating activity. A-61576 completely reverses the stimulation of PI response induced by CCK 8 , indicative of an antagonist. Since a mechanism other than the PI breakdown is responsible for amylase release by A-61576, they suggest that separate receptors are responsible for PI breakdown and amylase release

  18. Corticotropin-releasing hormone induces depression-like changes of sleep electroencephalogram in healthy women.

    Science.gov (United States)

    Schüssler, P; Kluge, M; Gamringer, W; Wetter, T C; Yassouridis, A; Uhr, M; Rupprecht, R; Steiger, A

    2016-12-01

    We reported previously that repetitive intravenous injections of corticotropin-releasing hormone (CRH) around sleep onset prompt depression-like changes in certain sleep and endocrine activity parameters (e.g. decrease of slow-wave sleep during the second half of the night, blunted growth hormone peak, elevated cortisol concentration during the first half of the night). Furthermore a sexual dimorphism of the sleep-endocrine effects of the hormones growth hormone-releasing hormone and ghrelin was observed. In the present placebo-controlled study we investigated the effect of pulsatile administration of 4×50μg CRH on sleep electroencephalogram (EEG) and nocturnal cortisol and GH concentration in young healthy women. After CRH compared to placebo, intermittent wakefulness increased during the total night and the sleep efficiency index decreased. During the first third of the night, REM sleep and stage 2 sleep increased and sleep stage 3 decreased. Cortisol concentration was elevated throughout the night and during the first and second third of the night. GH secretion remained unchanged. Our data suggest that after CRH some sleep and endocrine activity parameters show also depression-like changes in healthy women. These changes are more distinct in women than in men. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors

    Directory of Open Access Journals (Sweden)

    Thomas L. Shaak

    2013-01-01

    Full Text Available DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects.

  20. Fanconi anemia A is a nucleocytoplasmic shuttling molecule required for gonadotropin-releasing hormone (GnRH) transduction of the GnRH receptor.

    Science.gov (United States)

    Larder, Rachel; Karali, Dimitra; Nelson, Nancy; Brown, Pamela

    2006-12-01

    GnRH binds its cognate G protein-coupled GnRH receptor (GnRHR) located on pituitary gonadotropes and drives expression of gonadotropin hormones. There are two gonadotropin hormones, comprised of a common alpha- and hormone-specific beta-subunit, which are required for gonadal function. Recently we identified that Fanconi anemia a (Fanca), a DNA damage repair gene, is differentially expressed within the LbetaT2 gonadotrope cell line in response to stimulation with GnRH. FANCA is mutated in more than 60% of cases of Fanconi anemia (FA), a rare genetically heterogeneous autosomal recessive disorder characterized by bone marrow failure, endocrine tissue cancer susceptibility, and infertility. Here we show that induction of FANCA protein is mediated by the GnRHR and that the protein constitutively adopts a nucleocytoplasmic intracellular distribution pattern. Using inhibitors to block nuclear import and export and a GnRHR antagonist, we demonstrated that GnRH induces nuclear accumulation of FANCA and green fluorescent protein (GFP)-FANCA before exporting back to the cytoplasm using the nuclear export receptor CRM1. Using FANCA point mutations that locate GFP-FANCA to the cytoplasm (H1110P) or functionally uncouple GFP-FANCA (Q1128E) from the wild-type nucleocytoplasmic distribution pattern, we demonstrated that wild-type FANCA was required for GnRH-induced activation of gonadotrope cell markers. Cotransfection of H1110P and Q1128E blocked GnRH activation of the alphaGsu and GnRHR but not the beta-subunit gene promoters. We conclude that nucleocytoplasmic shuttling of FANCA is required for GnRH transduction of the alphaGSU and GnRHR gene promoters and propose that FANCA functions as a GnRH-induced signal transducer.

  1. Consensus statement on the use of gonadotropin-releasing hormone analogs in children

    DEFF Research Database (Denmark)

    Carel, Jean-Claude; Eugster, Erica A; Rogol, Alan

    2009-01-01

    , an equal male/female ratio, and a balanced spectrum of professional seniority and expertise. EVIDENCE: Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence......OBJECTIVE: Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society...... for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents. PARTICIPANTS: When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe...

  2. Radioactive probes for adrenocorticotropic hormone receptors

    International Nuclear Information System (INIS)

    Hofmann, K.; Romovacek, H.; Stehle, C.J.; Finn, F.M.; Bothner-By, A.A.; Mishra, P.K.

    1986-01-01

    Our attempts to develop adrenocorticotropic hormone (ACTH) analogues that can be employed for ACTH receptor identification and isolation began with the synthesis of ACTH fragments containing N epsilon-(dethiobiotinyl)lysine (dethiobiocytin) amide in position 25 to be used for affinity chromatographic purification of hormone-receptor complexes on Sepharose-immobilized avidin resins. Because labeling ACTH or ACTH fragments by conventional iodination techniques destroys biological activity due to oxidation of Met4 and incorporation of iodine into Tyr2, we have prepared [Phe2,Nle4]ACTH1-24, [Phe2,Nle4,biocytin25]ACTH1-25 amide, and [Phe2,Nle4,dethiobiocytin25]ACTH1-25 amide by conventional synthetic techniques. The HPLC profiles and amino acid analyses of the final products indicate that the materials are of a high degree of purity. The amount of tertiary butylation of the Trp residue in the peptides was assessed by NMR and was found to be less than 0.5%. All three peptides are equipotent with the standard ACTH1-24 as concerns their ability to stimulate steroidogenesis and cAMP formation in bovine adrenal cortical cells. Iodination of [Phe2,Nle4]ACTH1-24, with iodogen as the oxidizing agent, has been accomplished without any detectable loss of biological activity. The mono- and diiodo derivatives of [Phe2,Nle4]ACTH1-24 have been prepared, separated by HPLC, and assayed for biological activity. Both peptides have the full capacity to stimulate steroidogenesis and cAMP production in bovine adrenal cortical cells

  3. Effect of priming injections of luteinizing hormone-releasing hormone on spermiation and ovulation in Gϋnther's Toadlet, Pseudophryne guentheri

    Directory of Open Access Journals (Sweden)

    Silla Aimee J

    2011-05-01

    Full Text Available Abstract Background In the majority of vertebrates, gametogenesis and gamete-release depend on the pulsatile secretion of luteinizing hormone-releasing hormone (LHRH from the hypothalamus. Studies attempting to artificially stimulate ovulation and spermiation may benefit from mimicking the naturally episodic secretion of LHRH by administering priming injections of a synthetic analogue (LHRHa. This study investigated the impact of low-dose priming injections of LHRHa on gamete-release in the Australian toadlet Pseudophryne guentheri. Methods Toadlets were administered a single dose of two micrograms per. gram LHRHa without a priming injection (no priming, or preceded by one (one priming or two (two priming injections of 0.4 micrograms per. gram LHRHa. Spermiation responses were evaluated at 3, 7 and 12 hrs post hormone administration (PA, and sperm number and viability were quantified using fluorescent microscopy. Oocyte yields were evaluated by stripping females at 10-11 hrs PA. A sub-sample of twenty eggs per female was then fertilised (with sperm obtained from testis macerates and fertilisation success determined. Results No priming induced the release of the highest number of spermatozoa, with a step-wise decrease in the number of spermatozoa released in the one and two priming treatments respectively. Peak sperm-release occurred at 12 hrs PA for all priming treatments and there was no significant difference in sperm viability. Females in the control treatment failed to release oocytes, while those administered an ovulatory dose without priming exhibited a poor ovulatory response. The remaining two priming treatments (one and two priming successfully induced 100% of females to expel an entire clutch. Oocytes obtained from the no, or two priming treatments all failed to fertilise, however oocytes obtained from the one priming treatment displayed an average fertilisation success of 97%. Conclusion Spermiation was most effectively induced in

  4. Addition of sucralose enhances the release of satiety hormones in combination with pea protein.

    Science.gov (United States)

    Geraedts, Maartje C P; Troost, Freddy J; Saris, Wim H M

    2012-03-01

    Exposing the intestine to proteins or tastants, particularly sweet, affects satiety hormone release. There are indications that each sweetener has different effects on this release, and that combining sweeteners with other nutrients might exert synergistic effects on hormone release. STC-1 cells were incubated with acesulfame-K, aspartame, saccharine, sucralose, sucrose, pea, and pea with each sweetener. After a 2-h incubation period, cholecystokinin(CCK) and glucagon-like peptide 1 (GLP-1) concentrations were measured. Using Ussing chamber technology, the mucosal side of human duodenal biopsies was exposed to sucrose, sucralose, pea, and pea with each sweetener. CCK and GLP-1 levels were measured in basolateral secretions. In STC-1 cells, exposure to aspartame, sucralose, sucrose, pea, and pea with sucralose increased CCK levels, whereas GLP-1 levels increased after addition of all test products. Addition of sucrose and sucralose to human duodenal biopsies did not affect CCK and GLP-1 release; addition of pea stimulated CCK and GLP-1 secretion. Combining pea with sucrose and sucralose induced even higher levels of CCK and GLP-1. Synchronous addition of pea and sucralose to enteroendocrine cells induced higher levels of CCK and GLP-1 than addition of each compound alone. This study shows that combinations of dietary compounds synergize to enhance satiety hormone release. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors

    KAUST Repository

    Melcher, Karsten

    2009-12-03

    Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved ?-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling. © 2009 Macmillan Publishers Limited. All rights reserved.

  6. A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors

    KAUST Repository

    Melcher, Karsten; Ng, Ley-Moy; Zhou, X. Edward; Soon, Fen-Fen; Xu, Yong; Suino-Powell, Kelly M.; Park, Sang-Youl; Weiner, Joshua J.; Fujii, Hiroaki; Chinnusamy, Viswanathan; Kovach, Amanda; Li, Jun; Wang, Yonghong; Li, Jiayang; Peterson, Francis C.; Jensen, Davin R.; Yong, Eu-Leong; Volkman, Brian F.; Cutler, Sean R.; Zhu, Jian-Kang; Xu, H. Eric

    2009-01-01

    Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved ?-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling. © 2009 Macmillan Publishers Limited. All rights reserved.

  7. Evidence that shock-induced immune suppression is mediated by adrenal hormones and peripheral beta-adrenergic receptors.

    Science.gov (United States)

    Cunnick, J E; Lysle, D T; Kucinski, B J; Rabin, B S

    1990-07-01

    Our previous work has demonstrated that presentations of mild foot-shock to Lewis rats induces a suppression of splenic and peripheral blood lymphocyte responses to nonspecific T-cell mitogens. The present study demonstrated that adrenalectomy prevented the shock-induced suppression of the mitogenic response of peripheral blood T-cells but did not attenuate the suppression of splenic T-cells. Conversely, the beta-adrenergic receptor antagonists, propranolol and nadolol, attenuated the shock-induced suppression of splenic T-cells in a dose-dependent manner but did not attenuate suppression of the blood mitogen response. These data indicate that distinct mechanisms mediate the shock-induced suppression of T-cell responsiveness to mitogens in the spleen and the peripheral blood. The results indicate that the peripheral release of catecholamines is responsible for splenic immune suppression and that adrenal hormones, which do not interact with beta-adrenergic receptors, are responsible for shock-induced suppression of blood mitogenic responses.

  8. Sex Hormone Receptor Expression in the Human Vocal Fold Subunits.

    Science.gov (United States)

    Kirgezen, Tolga; Sunter, Ahmet Volkan; Yigit, Ozgur; Huq, Gulben Erdem

    2017-07-01

    The study aimed to evaluate the existence of sex hormone receptors in the subunits of vocal fold. This is a cadaver study. The androgen, estrogen, and progesterone receptors were examined in the epithelium (EP), superficial layer of the lamina propria (SLP), vocal ligament (VL), and macula flava (MF) of the vocal folds from 42 human cadavers (21 male, 21 female) by immunohistochemical methods. Their staining ratios were scored and statistically compared. The androgen receptor score was significantly higher for the MF than for the EP and SLP (P vocal fold, mostly in the MF and VLs. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

  9. Protein alterations induced by long-term agonist treatment of HEK293 cells expressing thyrotropin-releasing hormone receptor and G11alpha protein

    Czech Academy of Sciences Publication Activity Database

    Drastichová, Z.; Bouřová, Lenka; Hejnová, L.; Jedelský, P.; Svoboda, Petr; Novotný, J.

    2010-01-01

    Roč. 109, č. 1 (2010), s. 255-264 ISSN 0730-2312 R&D Projects: GA MŠk(CZ) LC554; GA ČR(CZ) GA309/06/0121; GA ČR(CZ) GD305/08/H037 Institutional research plan: CEZ:AV0Z50110509 Keywords : Thyrotropin-releasing hormone * Gq/11 protein * proteomics Subject RIV: ED - Physiology Impact factor: 3.122, year: 2010

  10. Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Yardley DA

    2016-05-01

    Full Text Available Denise A Yardley1,2 1Sarah Cannon Research Institute, Nashville, TN, USA; 2Tennessee Oncology, Nashville, TN, USA Abstract: There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly impact morbidity and mortality. Effective management and minimization of bone-related complications in postmenopausal women with hormone receptor-positive breast cancer remain essential. This review discusses the current understanding of molecular and biological mechanisms involved in bone turnover and metastases, increased risk for bone-related complications from breast cancer and breast cancer therapy, and current and emerging treatment strategies for managing bone metastases and bone turnover in postmenopausal women with hormone receptor-positive breast cancer. Keywords: breast cancer, bone metastases, hormone receptor-positive, bone-related complications, interventions, management and management strategies, estrogen receptor-positive

  11. Expression of Lymphocyte-derived Growth Hormone (GH) and GH-releasing Hormone Receptors in Aging Rats

    OpenAIRE

    Weigent, Douglas A.

    2013-01-01

    In the present study, we show that higher levels of lymphocyte GH are expressed in spleen cells from aging animals compared to young animals. Further, leukocytes from primary and secondary immune tissues and splenic T and B cells from aging rats all express higher levels of GHRH receptors compared to younger animals. Bone marrow and splenic T cells express the highest levels of GHRH receptor in aging animals. Spleen cells from aging animals showed no significant change in proliferation or GH ...

  12. Hypothalamic amenorrhea with normal body weight: ACTH, allopregnanolone and cortisol responses to corticotropin-releasing hormone test.

    Science.gov (United States)

    Meczekalski, B; Tonetti, A; Monteleone, P; Bernardi, F; Luisi, S; Stomati, M; Luisi, M; Petraglia, F; Genazzani, A R

    2000-03-01

    Hypothalamic amenorrhea (HA) is a functional disorder caused by disturbances in gonadotropin-releasing hormone (GnRH) pulsatility. The mechanism by which stress alters GnRH release is not well known. Recently, the role of corticotropin-releasing hormone (CRH) and neurosteroids in the pathophysiology of HA has been considered. The aim of the present study was to explore further the role of the hypothalamic-pituitary-adrenal axis in HA. We included 8 patients (aged 23.16+/-1.72 years) suffering from hypothalamic stress-related amenorrhea with normal body weight and 8 age-matched healthy controls in the follicular phase of the menstrual cycle. We measured basal serum levels of FSH, LH, and estradiol and evaluated ACTH, allopregnanolone and cortisol responses to CRH test in both HA patients and healthy women. Serum basal levels of FSH, LH, and estradiol as well as basal levels of allopregnanolone were significantly lower in HA patients than in controls (P<0.001) while basal ACTH and cortisol levels were significantly higher in amenorrheic patients with respect to controls (P<0.001). The response (area under the curve) of ACTH, allopregnanolone and cortisol to CRH was significantly lower in amenorrheic women compared with controls (P<0.001, P<0.05, P<0.05 respectively). In conclusion, women with HA, despite the high ACTH and cortisol levels and, therefore, hypothalamus-pituitary-adrenal axis hyperactivity, are characterized by low allopregnanolone basal levels, deriving from an impairment of both adrenal and ovarian synthesis. The blunted ACTH, allopregnanolone and cortisol responses to CRH indicate that, in hypothalamic amenorrhea, there is a reduced sensitivity and expression of CRH receptor. These results open new perspectives on the role of neurosteroids in the pathogenesis of hypothalamic amenorrhea.

  13. Hormonal induction of gamete release, and in-vitro fertilisation, in the critically endangered Southern Corroboree Frog, Pseudophryne corroboree

    Directory of Open Access Journals (Sweden)

    Silla Aimee J

    2010-11-01

    Full Text Available Abstract Background Conservation Breeding Programs (CBP's are playing an important role in the protection of critically endangered anuran amphibians, but for many species recruitment is not successful enough to maintain captive populations, or provide individuals for release. In response, there has been an increasing focus on the use of Assisted Reproductive Technologies (ART, including the administration of reproductive hormones to induce gamete release followed by in vitro fertilisation. The objective of this study was to test the efficacy of two exogenous hormones to induce gamete release, for the purpose of conducting in vitro fertilisation (IVF, in one of Australia's most critically endangered frog species, Pseudophryne corroboree. Methods Male frogs were administered a single dose of either human chorionic gonadotropin (hCG or luteinizing hormone-releasing hormone (LHRHa, while female frogs received both a priming and ovulatory dose of LHRHa. Spermiation responses were evaluated at 3, 7, 12, 24, 36, 48, 60 and 72 h post hormone administration (PA, and sperm number and viability were quantified using fluorescent microscopy. Ovulation responses were evaluated by stripping females every 12 h PA for 5 days. Once gametes were obtained, IVF was attempted by combining spermic urine with oocytes in a dilute solution of simplified amphibian ringer (SAR. Results Administration of both hCG and LHRHa induced approximately 80% of males to release sperm over 72 h. Peak sperm release occurred at 12 h PA for hCG treated males and 36 h PA for LHRHa treated males. On average, LHRHa treated males released a significantly higher total number of live sperm, and a higher concentration of sperm, over a longer period. In female frogs, administration of LHRHa induced approximately 30% of individuals to release eggs. On average, eggs were released between 24 and 48 h PA, with a peak in egg release at 36 h PA. IVF resulted in a moderate percentage (54.72% of eggs

  14. The effect of ovarian steroid feedback upon radioimmunoreactive luteinizing hormone releasing hormone in the hypothalamus

    International Nuclear Information System (INIS)

    Yanaihara, Takumi; Arai, Kiyoshi; Kanazawa, Motomi; Okinaga, Shoichi; Yanaihara, Noboru

    1975-01-01

    A radioimmunoassay (RIA) method for luteinizing hormone (LH) releasing hormone (RH) utilizing rabbit antiserum against synthetic (Glu 1 )-LH-RH coupled with human serum albumin at the N-terminus, is described. This assay system for LH-RH also cross-reacted with several LH-RH analogues or fragments, but not with pituitary trophic hormones. The assay was performed on the hypothalamic extracts of adult ovariectomized rats and female immature rats which had been treated with estradiol. The FSH and LH levels in the pituitary gland and serum of the same animals were determined by RIA. The radioimmunoreactive LH-RH content of the stalk median eminence markedly increased seven days after ovariectomy. The serum levels and the pituitary contents of FSH and LH of the same rats were also significantly augmented. In immature rats, the hypothalamic content of LH-RH, as measured by RIA, was significantly increased one hour after the injection of estradiol. The FSH and LH levels in the pituitary showed a significant rise after 7 hours. (auth.)

  15. Towards more physiological manipulations of hormones in field studies: comparing the release dynamics of three kinds of testosterone implants, silastic tubing, time-release pellets and beeswax.

    Science.gov (United States)

    Quispe, Rene; Trappschuh, Monika; Gahr, Manfred; Goymann, Wolfgang

    2015-02-01

    Hormone manipulations are of increasing interest in the areas of physiological ecology and evolution, because hormones are mediators of complex phenotypic changes. Often, however, hormone manipulations in field settings follow the approaches that have been used in classical endocrinology, potentially using supra-physiological doses. To answer ecological and evolutionary questions, it may be important to manipulate hormones within their physiological range. We compare the release dynamics of three kinds of implants, silastic tubing, time-release pellets, and beeswax pellets, each containing 3mg of testosterone. These implants were placed into female Japanese quail, and plasma levels of testosterone measured over a period of 30 days. Testosterone in silastic tubing led to supraphysiological levels. Also, testosterone concentrations were highly variable between individuals. Time-release pellets led to levels of testosterone that were slightly supraphysiological during the first days. Over the period of 30 days, however, testosterone concentrations were more consistent. Beeswax implants led to a physiological increase in testosterone and a relatively constant release. The study demonstrated that hormone implants in 10mm silastic tubing led to a supraphysiological peak in female quail. Thus, the use of similar-sized or even larger silastic implants in males or in other smaller vertebrates needs careful assessment. Time-release pellets and beeswax implants provide a more controlled release and degrade within the body. Thus, it is not necessary to recapture the animal to remove the implant. We propose beeswax implants as an appropriate procedure to manipulate testosterone levels within the physiological range. Hence, such implants may be an effective alternative for field studies. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Prostate-specific antigen and hormone receptor expression in male and female breast carcinoma

    Directory of Open Access Journals (Sweden)

    Cohen Cynthia

    2010-09-01

    Full Text Available Abstract Background Prostate carcinoma is among the most common solid tumors to secondarily involve the male breast. Prostate specific antigen (PSA and prostate-specific acid phosphatase (PSAP are expressed in benign and malignant prostatic tissue, and immunohistochemical staining for these markers is often used to confirm the prostatic origin of metastatic carcinoma. PSA expression has been reported in male and female breast carcinoma and in gynecomastia, raising concerns about the utility of PSA for differentiating prostate carcinoma metastasis to the male breast from primary breast carcinoma. This study examined the frequency of PSA, PSAP, and hormone receptor expression in male breast carcinoma (MBC, female breast carcinoma (FBC, and gynecomastia. Methods Immunohistochemical staining for PSA, PSAP, AR, ER, and PR was performed on tissue microarrays representing six cases of gynecomastia, thirty MBC, and fifty-six FBC. Results PSA was positive in two of fifty-six FBC (3.7%, focally positive in one of thirty MBC (3.3%, and negative in the five examined cases of gynecomastia. PSAP expression was absent in MBC, FBC, and gynecomastia. Hormone receptor expression was similar in males and females (AR 74.1% in MBC vs. 67.9% in FBC, p = 0.62; ER 85.2% vs. 68.5%, p = 0.18; and PR 51.9% vs. 48.2%, p = 0.82. Conclusions PSA and PSAP are useful markers to distinguish primary breast carcinoma from prostate carcinoma metastatic to the male breast. Although PSA expression appeared to correlate with hormone receptor expression, the incidence of PSA expression in our population was too low to draw significant conclusions about an association between PSA expression and hormone receptor status in breast lesions.

  17. Model of the complex of Parathyroid hormone-2 receptor and Tuberoinfundibular peptide of 39 residues

    Directory of Open Access Journals (Sweden)

    Persson Bengt

    2010-10-01

    Full Text Available Abstract Background We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R and its ligand the tuberoinfundibular peptide of 39 residues (TIP39 by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH and parathyroid hormone related protein (PTHrP are compared with the complex to examine their interactions. Findings In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation. Conclusions A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

  18. Hormonally-mediated Epigenetic Changes to Steroid Receptors in the Developing Brain: Implications for Sexual Differentiation

    Science.gov (United States)

    Nugent, Bridget M.; Schwarz, Jaclyn M.; McCarthy, Margaret M.

    2010-01-01

    The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principle organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigenetic changes, such as DNA methylation, allow environmental influences to alter long-term gene expression patterns and therefore may be a potential mediator of estradiol-induced organization of the neonatal brain. Here we review data that demonstrate sex and estradiol-induced differences in DNA methylation on the estrogen receptor α (ERα), estrogen receptor β (ERβ), and progesterone receptor (PR) promoters in sexually dimorphic brain regions across development. Contrary to the overarching view of DNA methylation as a permanent modification directly tied to gene expression, these data demonstrate that methylation patterns on steroid hormone receptors change across the life span and do not necessarily predict expression. Although further exploration into the mechanism and significance of estradiol-induced alterations in DNA methylation patterns in the neonatal brain is necessary, these results provide preliminary evidence that epigenetic alterations can occur in response to early hormone exposure and may mediate estradiol-induced organization of sex differences in the neonatal brain. PMID:20800064

  19. Diagnostic challenges and management of a patient with acromegaly due to ectopic growth hormone-releasing hormone secretion from a bronchial carcinoid tumour

    Directory of Open Access Journals (Sweden)

    Nikolaos Kyriakakis

    2017-01-01

    Full Text Available A male patient presented at the age of 30 with classic clinical features of acromegaly and was found to have elevated growth hormone levels, not suppressing during an oral glucose tolerance test. His acromegaly was originally considered to be of pituitary origin, based on a CT scan, which was interpreted as showing a pituitary macroadenoma. Despite two trans-sphenoidal surgeries, cranial radiotherapy and periods of treatment with bromocriptine and octreotide, his acromegaly remained active clinically and biochemically. A lung mass was discovered incidentally on a chest X-ray performed as part of a routine pre-assessment for spinal surgery 5 years following the initial presentation. This was confirmed to be a bronchial carcinoid tumour, which was strongly positive for growth hormone-releasing hormone (GHRH and somatostatin receptor type 2 by immunohistochemistry. The re-examination of the pituitary specimens asserted the diagnosis of pituitary GH hyperplasia. Complete resolution of the patient’s acromegaly was achieved following right lower and middle lobectomy. Seventeen years following the successful resection of the bronchial carcinoid tumour the patient remains under annual endocrine follow-up for monitoring of the hypopituitarism he developed after the original interventions to his pituitary gland, while there has been no evidence of active acromegaly or recurrence of the carcinoid tumour. Ectopic acromegaly is extremely rare, accounting for <1% of all cases of acromegaly. Our case highlights the diagnostic challenges differentiating between ectopic acromegaly and acromegaly of pituitary origin and emphasises the importance of avoiding unnecessary pituitary surgery and radiotherapy. The role of laboratory investigations, imaging and histology as diagnostic tools is discussed.

  20. Hsp70 cochaperones HspBP1 and BAG-1M differentially regulate steroid hormone receptor function.

    Directory of Open Access Journals (Sweden)

    Regina T Knapp

    Full Text Available Hsp70 binding protein 1 (HspBP1 and Bcl2-associated athanogene 1 (BAG-1, the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70 chaperones, catalyze the release of ADP from Hsp70 while inducing different conformational changes of the ATPase domain of Hsp70. An appropriate exchange rate of ADP/ATP is crucial for chaperone-dependent protein folding processes. Among Hsp70 client proteins are steroid receptors such as the glucocorticoid receptor (GR, the mineralocorticoid receptor (MR, and the androgen receptor (AR. BAG-1 diversely affects steroid receptor activity, while to date the influence of HspBP1 on steroid receptor function is mostly unknown. Here, we compared the influence of HspBP1 and BAG-1M on Hsp70-mediated steroid receptor folding complexes and steroid receptor activity. Coimmunoprecipitation studies indicated preferential binding of Hsp40 and the steroid receptors to BAG-1M as compared to HspBP1. Furthermore, Hsp70 binding to the ligand-binding domain of GR was reduced in the presence of HspBP1 but not in the presence of BAG-1M as shown by pull-down assays. Reporter gene experiments revealed an inhibitory effect on GR, MR, and AR at a wide range of HspBP1 protein levels and at hormone concentrations at or approaching saturation. BAG-1M exhibited a transition from stimulatory effects at low BAG-1M levels to inhibitory effects at higher BAG-1M levels. Overall, BAG-1M and HspBP1 had differential impacts on the dynamic composition of steroid receptor folding complexes and on receptor function with important implications for steroid receptor physiology.

  1. Peroxisome-proliferator-activated receptor-γ agonists inhibit the release of proinflammatory cytokines from RSV-infected epithelial cells

    International Nuclear Information System (INIS)

    Arnold, Ralf; Koenig, Wolfgang

    2006-01-01

    The epithelial cells of the airways are the target cells for respiratory syncytial virus (RSV) infection and the site of the majority of the inflammation associated with the disease. Recently, peroxisome-proliferator-activated receptor γ (PPARγ), a member of the nuclear hormone receptor superfamily, has been shown to possess anti-inflammatory properties. Therefore, we investigated the role of PPARγ agonists (15d-PGJ 2 , ciglitazone and troglitazone) on the synthesis of RSV-induced cytokine release from RSV-infected human lung epithelial cells (A549). We observed that all PPARγ ligands inhibited dose-dependently the release of TNF-α, GM-CSF, IL-1α, IL-6 and the chemokines CXCL8 (IL-8) and CCL5 (RANTES) from RSV-infected A549 cells. Concomitantly, the PPARγ ligands diminished the cellular amount of mRNA encoding for IL-6, CXCL8 and CCL5 and the RSV-induced binding activity of the transcription factors NF-κB (p65/p50) and AP-1 (c-fos), respectively. Our data presented herein suggest a potential application of PPARγ ligands in the anti-inflammatory treatment of RSV infection

  2. Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway.

    Science.gov (United States)

    Li, Shiwei; Li, Qi; Kong, Yuanyuan; Wu, Shuang; Cui, Qingpo; Zhang, Mingming; Zhang, Shaobing O

    2017-08-15

    Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12-dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans This finding suggests the existence of a conserved CYP4V2-POR-nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.

  3. Thyrotropin-luteinizing hormone/chorionic gonadotropin receptor extracellular domain chimeras as probes for thyrotropin receptor function

    International Nuclear Information System (INIS)

    Nagayama, Yuji; Wadsworth, H.L.; Chazenbalk, G.D.; Russo, D.; Seto, Pui; Rapoport, B.

    1991-01-01

    To define the sites in the extracellular domain of the human thyrotropin (TSH) receptor that are involved in TSH binding and signal transduction the authors constructed chimeric thyrotropin-luteinizing hormone/chorionic gonadotropin (TSH-LH/CG) receptors. The extracellular domain of the human TSH receptor was divided into five regions that were replaced, either singly or in various combinations, with homologous regions of the rat LH/CG receptor. The chimeric receptors were stably expressed in Chinese hamster ovary cells. The data obtained suggest that the carboxyl region of the extracellular domain (amino acid residues 261-418) and particularly the middle region (residues 171-260) play a role in signal transduction. The possibility is also raised of an interaction between the amino and carboxyl regions of the extracellular domain in the process of signal transduction. In summary, these studies suggest that the middle region and carboxyl half of the extracellular domain of the TSH receptor are involved in signal transduction and that the TSH-binding region is likely to span the entire extracellular domain, with multiple discontinuous contact sites

  4. Nervus terminalis, olfactory nerve, and optic nerve representation of luteinizing hormone-releasing hormone in primates.

    Science.gov (United States)

    Witkin, J W

    1987-01-01

    The luteinizing hormone-releasing hormone (LHRH) system was examined immunocytochemically in olfactory bulbs of adult monkeys, including two New World species (squirrel monkey, Saimiri sciureus and owl monkey, Aotus trivirgatus) and one Old World species (cynomolgus macaque, Macaca fasciculata), and in the brain and nasal region of a fetal rhesus macaque Macaca mulatta. LHRH neurons and fibers were found sparsely distributed in the olfactory bulbs in all adult monkeys. There was more LHRH in the accessory olfactory bulb (which is absent in Old World monkeys). In the fetal macaque there was a rich distribution of LHRH neurons and fibers along the pathway of the nervus terminalis, anterior and ventral to the olfactory bulb, and in the nasal septum, with fibers branching into the olfactory epithelium. In addition, there were LHRH neurons and fibers in the optic nerve.

  5. Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

    Science.gov (United States)

    Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neur...

  6. Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules.

    Science.gov (United States)

    Mackenzie, Louise S

    2018-01-01

    Thyroid hormone receptors (TRs) are nuclear receptors which control transcription, and thereby have effects in all cells within the body. TRs are an important regulator in many basic physiological processes including development, growth, metabolism, and cardiac function. The hyperthyroid condition results from an over production of thyroid hormones resulting in a continual stimulation of thyroid receptors which is detrimental for the patient. Therapies for hyperthyroidism are available, but there is a need for new small molecules that act as TR antagonists to treat hyperthyroidism. Many compounds exhibit TR antagonism and are considered detrimental to health. Some drugs in the clinic (most importantly, amiodarone) and environmental pollution exhibit TR antagonist properties and thus have the potential to induce hypothyroidism in some people. This chapter provides an overview of novel small molecules that have been specifically designed or screened for their TR antagonist activity as novel treatments for hyperthyroidism. While novel compounds have been identified, to date none have been developed sufficiently to enter clinical trials. Furthermore, a discussion on other sources of TR antagonists is discussed in terms of side effects of current drugs in the clinic as well as environmental pollution. © 2018 Elsevier Inc. All rights reserved.

  7. How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis.

    Science.gov (United States)

    Brunson, K L; Eghbal-Ahmadi, M; Baram, T Z

    2001-11-01

    West syndrome (WS) is associated with diverse etiological factors. This fact has suggested that there must be a 'final common pathway' for these etiologies, which operates on the immature brain to result in WS only at the maturational state present during infancy. Any theory for the pathogenesis of WS has to account for the unique features of this disorder. For example, how can a single entity have so many etiologies? Why does WS arise only in infancy, even when a known insult had occurred prenatally, and why does it disappear? Why is WS associated with lasting cognitive dysfunction? And, importantly, why do these seizures--unlike most others--respond to treatment by a hormone, ACTH? The established hormonal role of ACTH in human physiology is to function in the neuroendocrine cascade of the responses to all stressful stimuli, including insults to the brain. As part of this function, ACTH is known to suppress the production of corticotropin releasing hormone (CRH), a peptide that is produced in response to diverse insults and stressors.The many etiologies of WS all lead to activation of the stress response, including increased production and secretion of the stress-neurohormone CRH. CRH has been shown, in infant animal models, to cause severe seizures and death of neurons in areas involved with learning and memory. These effects of CRH are restricted to the infancy period because the receptors for CRH, which mediate its action on neurons, are most abundant during this developmental period. ACTH administration is known to inhibit production and release of CRH via a negative feedback mechanism. Therefore, the efficacy of ACTH for WS may depend on its ability to decrease the levels of the seizure-promoting stress-neurohormone CRH.This CRH-excess theory for the pathophysiology of WS is consistent not only with the profile of ACTH effects, but also with the many different 'causes' of WS, with the abnormal ACTH levels in the cerebrospinal fluid of affected infants and

  8. Salmonella Typhi sense host neuroendocrine stress hormones and release the toxin haemolysin E

    Science.gov (United States)

    Karavolos, Michail H; Bulmer, David M; Spencer, Hannah; Rampioni, Giordano; Schmalen, Ira; Baker, Stephen; Pickard, Derek; Gray, Joe; Fookes, Maria; Winzer, Klaus; Ivens, Alasdair; Dougan, Gordon; Williams, Paul; Khan, C M Anjam

    2011-01-01

    Salmonella enterica serovar Typhi (S. typhi) causes typhoid fever. We show that exposure of S. typhi to neuroendocrine stress hormones results in haemolysis, which is associated with the release of haemolysin E in membrane vesicles. This effect is attributed to increased expression of the small RNA micA and RNA chaperone Hfq, with concomitant downregulation of outer membrane protein A. Deletion of micA or the two-component signal-transduction system, CpxAR, abolishes the phenotype. The hormone response is inhibited by the β-blocker propranolol. We provide mechanistic insights into the basis of neuroendocrine hormone-mediated haemolysis by S. typhi, increasing our understanding of inter-kingdom signalling. PMID:21331094

  9. Gonadotropin-releasing hormone regulates expression of the DNA damage repair gene, Fanconi anemia A, in pituitary gonadotroph cells.

    Science.gov (United States)

    Larder, Rachel; Chang, Lynda; Clinton, Michael; Brown, Pamela

    2004-09-01

    Gonadal function is critically dependant on regulated secretion of the gonadotropin hormones from anterior pituitary gonadotroph cells. Gonadotropin biosynthesis and release is triggered by the binding of hypothalamic GnRH to GnRH receptor expressed on the gonadotroph cell surface. The repertoire of regulatory molecules involved in this process are still being defined. We used the mouse L beta T2 gonadotroph cell line, which expresses both gonadotropin hormones, as a model to investigate GnRH regulation of gene expression and differential display reverse transcription-polymerase chain reaction (RT-PCR) to identify and isolate hormonally induced changes. This approach identified Fanconi anemia a (Fanca), a gene implicated in DNA damage repair, as a differentially expressed transcript. Mutations in Fanca account for the majority of cases of Fanconi anemia (FA), a recessively inherited disease identified by congenital defects, bone marrow failure, infertility, and cancer susceptibility. We confirmed expression and hormonal regulation of Fanca mRNA by quantitative RT-PCR, which showed that GnRH induced a rapid, transient increase in Fanca mRNA. Fanca protein was also acutely upregulated after GnRH treatment of L beta T2 cells. In addition, Fanca gene expression was confined to mature pituitary gonadotrophs and adult mouse pituitary and was not expressed in the immature alpha T3-1 gonadotroph cell line. Thus, this study extends the expression profile of Fanca into a highly specialized endocrine cell and demonstrates hormonal regulation of expression of the Fanca locus. We suggest that this regulatory mechanism may have a crucial role in the GnRH-response mechanism of mature gonadotrophs and perhaps the etiology of FA.

  10. Interaction between body mass index and hormone-receptor status as a prognostic factor in lymph-node-positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Il Yong Chung

    Full Text Available The aim of this study was to determine the relationship between the body mass index (BMI at a breast cancer diagnosis and various factors including the hormone-receptor, menopause, and lymph-node status, and identify if there is a specific patient subgroup for which the BMI has an effect on the breast cancer prognosis. We retrospectively analyzed the data of 8,742 patients with non-metastatic invasive breast cancer from the research database of Asan Medical Center. The overall survival (OS and breast-cancer-specific survival (BCSS outcomes were compared among BMI groups using the Kaplan-Meier method and Cox proportional-hazards regression models with an interaction term. There was a significant interaction between BMI and hormone-receptor status for the OS (P = 0.029, and BCSS (P = 0.013 in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer showed a poorer OS (adjusted hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 0.92 to 2.48 and significantly poorer BCSS (HR = 1.80, 95% CI = 1.08 to 2.99. In contrast, a high BMI in hormone-receptor-negative breast cancer revealed a better OS (HR = 0.44, 95% CI = 0.16 to 1.19 and BCSS (HR = 0.53, 95% CI = 0.19 to 1.44. Being underweight (BMI < 18.50 kg/m2 with hormone-receptor-negative breast cancer was associated with a significantly worse OS (HR = 1.98, 95% CI = 1.00-3.95 and BCSS (HR = 2.24, 95% CI = 1.12-4.47. There was no significant interaction found between the BMI and hormone-receptor status in the lymph-node-negative setting, and BMI did not interact with the menopause status in any subgroup. In conclusion, BMI interacts with the hormone-receptor status in a lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer.

  11. PERCEPTION OF THE MOLTING HORMONE 20-HYDROXECDYSONE BY HOMARUS AMERICANUS: LOCALIZATION OF STEROID RECEPTORS AND EFFECT ON BEHAVIOR

    Science.gov (United States)

    There is growing evidence that hormones, when released from an animal into the environment, act as chemical signals to other organisms. There is also evidence to suggest that hormones are released by lobsters during sexual and agonistic encounters to signal conspecifics. The go...

  12. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta

    International Nuclear Information System (INIS)

    Robinson, B.G.; Emanuel, R.L.; Frim, D.M.; Majzoub, J.A.

    1988-01-01

    Primary cultures of purified human cytotrophoblasts have been used to examine the expression of the corticotropin-releasing hormone (CRH) gene in placenta. The authors report here that glucocorticoids stimulate placental CRH synthesis and secretion in primary cultures of human placenta. This stimulation is in contrast to the glucocorticoid suppression of CRH expression in hypothalamus. The positive regulation of CRH by glucocorticoids suggests that the rise in CRH preceding parturition could result from the previously described rise in fetal glucocorticoids. Furthermore, this increase in placental CRH could stimulate, via adrenocorticotropic hormone, a further rise in fetal glucocorticoids, completing a positive feedback loop that would be terminated by delivery

  13. Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients.

    Science.gov (United States)

    Kalikiri, Mahesh Kumar; Mamidala, Madhu Poornima; Rao, Ananth N; Rajesh, Vidya

    2017-12-01

    Autism spectrum disorder (ASD) is a neuro developmental disorder, reported to be on a rise in the past two decades. Thyroid hormone-T3 plays an important role in early embryonic and central nervous system development. T3 mediates its function by binding to thyroid hormone receptors, TRα and TRβ. Alterations in T3 levels and thyroid receptor mutations have been earlier implicated in neuropsychiatric disorders and have been linked to environmental toxins. Limited reports from earlier studies have shown the effectiveness of T3 treatment with promising results in children with ASD and that the thyroid hormone levels in these children was also normal. This necessitates the need to explore the genetic variations in the components of the thyroid hormone pathway in ASD children. To achieve this objective, we performed genetic analysis of ligand binding domain of THRA and THRB receptor genes in 30 ASD subjects and in age matched controls from India. Our study for the first time reports novel single nucleotide polymorphisms in the THRA and THRB receptor genes of ASD individuals. Autism Res 2017, 10: 1919-1928. ©2017 International Society for Autism Research, Wiley Periodicals, Inc. Thyroid hormone (T3) and thyroid receptors (TRα and TRβ) are the major components of the thyroid hormone pathway. The link between thyroid pathway and neuronal development is proven in clinical medicine. Since the thyroid hormone levels in Autistic children are normal, variations in their receptors needs to be explored. To achieve this objective, changes in THRA and THRB receptor genes was studied in 30 ASD and normal children from India. The impact of some of these mutations on receptor function was also studied. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  14. Participation of the endoplasmic reticulum protein chaperone thio-oxidoreductase in gonadotropin-releasing hormone receptor expression at the plasma membrane

    Directory of Open Access Journals (Sweden)

    W. Lucca-Junior

    2009-02-01

    Full Text Available Chaperone members of the protein disulfide isomerase family can catalyze the thiol-disulfide exchange reaction with pairs of cysteines. There are 14 protein disulfide isomerase family members, but the ability to catalyze a thiol disulfide exchange reaction has not been demonstrated for all of them. Human endoplasmic reticulum protein chaperone thio-oxidoreductase (ERp18 shows partial oxidative activity as a protein disulfide isomerase. The aim of the present study was to evaluate the participation of ERp18 in gonadotropin-releasing hormone receptor (GnRHR expression at the plasma membrane. Cos-7 cells were cultured, plated, and transfected with 25 ng (unless indicated wild-type human GnRHR (hGnRHR or mutant GnRHR (Cys14Ala and Cys200Ala and pcDNA3.1 without insert (empty vector or ERp18 cDNA (75 ng/well, pre-loaded for 18 h with 1 µCi myo-[2-3H(N]-inositol in 0.25 mL DMEM and treated for 2 h with buserelin. We observed a decrease in maximal inositol phosphate (IP production in response to buserelin in the cells co-transfected with hGnRHR, and a decrease from 20 to 75 ng of ERp18 compared with cells co-transfected with hGnRHR and empty vector. The decrease in maximal IP was proportional to the amount of ERp18 DNA over the range examined. Mutants (Cys14Ala and Cys200Ala that could not form the Cys14-Cys200 bridge essential for plasma membrane routing of the hGnRHR did not modify maximal IP production when they were co-transfected with ERp18. These results suggest that ERp18 has a reduction role on disulfide bonds in wild-type hGnRHR folding.

  15. Vegetable and fruit consumption and the risk of hormone receptor-defined breast cancer in the EPIC cohort.

    Science.gov (United States)

    Emaus, Marleen J; Peeters, Petra H M; Bakker, Marije F; Overvad, Kim; Tjønneland, Anne; Olsen, Anja; Romieu, Isabelle; Ferrari, Pietro; Dossus, Laure; Boutron-Ruault, Marie Christine; Baglietto, Laura; Fortner, Renée T; Kaaks, Rudolf; Boeing, Heiner; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Masala, Giovanna; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Polidoro, Silvia; Skeie, Guri; Lund, Eiliv; Weiderpass, Elisabete; Quirós, J Ramón; Travier, Noémie; Sánchez, María-José; Chirlaque, Maria-Dolores; Ardanaz, Eva; Dorronsoro, Miren; Winkvist, Anna; Wennberg, Maria; Bueno-de-Mesquita, H Bas; Khaw, Kay-Tee; Travis, Ruth C; Key, Timothy J; Aune, Dagfinn; Gunter, Marc; Riboli, Elio; van Gils, Carla H

    2016-01-01

    The recent literature indicates that a high vegetable intake and not a high fruit intake could be associated with decreased steroid hormone receptor-negative breast cancer risk. This study aimed to investigate the association between vegetable and fruit intake and steroid hormone receptor-defined breast cancer risk. A total of 335,054 female participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were included in this study (mean ± SD age: 50.8 ± 9.8 y). Vegetable and fruit intake was measured by country-specific questionnaires filled out at recruitment between 1992 and 2000 with the use of standardized procedures. Cox proportional hazards models were stratified by age at recruitment and study center and were adjusted for breast cancer risk factors. After a median follow-up of 11.5 y (IQR: 10.1-12.3 y), 10,197 incident invasive breast cancers were diagnosed [3479 estrogen and progesterone receptor positive (ER+PR+); 1021 ER and PR negative (ER-PR-)]. Compared with the lowest quintile, the highest quintile of vegetable intake was associated with a lower risk of overall breast cancer (HRquintile 5-quintile 1: 0.87; 95% CI: 0.80, 0.94). Although the inverse association was most apparent for ER-PR- breast cancer (ER-PR-: HRquintile 5-quintile 1: 0.74; 95% CI: 0.57, 0.96; P-trend = 0.03; ER+PR+: HRquintile 5-quintile 1: 0.91; 95% CI: 0.79, 1.05; P-trend = 0.14), the test for heterogeneity by hormone receptor status was not significant (P-heterogeneity = 0.09). Fruit intake was not significantly associated with total and hormone receptor-defined breast cancer risk. This study supports evidence that a high vegetable intake is associated with lower (mainly hormone receptor-negative) breast cancer risk. © 2016 American Society for Nutrition.

  16. Involvement of spinal serotonin receptors in the regulation of intraspinal acetylcholine release.

    Science.gov (United States)

    Kommalage, Mahinda; Höglund, A Urban

    2005-02-21

    Stimulation of spinal serotonin (5-HT) receptors results in analgesia and release of acetylcholine. We investigated the involvement of 5-HT1, 5-HT2, and 5-HT3 receptor subtypes in the regulation of spinal acetylcholine release. A spinal microdialysis probe was placed dorsally at about the C5 level in anaesthetized rats. The selective serotonin reuptake inhibitor citalopram was found to increase acetylcholine release when infused via the microdialysis probe. Several doses of the 5-HT receptor agonists 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT, 5-HT1A), 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (CP93129, 5-HT1B), alpha-methyl-5-hydroxytryptamine maleate (m5-HT, 5-HT2), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 5-HT2C), and 1-(m-chlorophenyl)-biguanide (5-HT3) were subsequently infused via the microdialysis probe. Only 8-OH-DPAT, CP93129, and m5-HT increased acetylcholine release dose dependently. The 5-HT1A receptor selective antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride and the 5-HT2A receptor selective antagonist ketanserin tartrate inhibited the 8-OH-DPAT and the m5-HT induced acetylcholine release. The results suggest that 5-HT1A and the 5-HT2A receptors are involved in the regulation of acetylcholine release in the spinal cord.

  17. Corticotrophin-Releasing Hormone Type 1 Receptor Gene (CRHR1 Variants Predict Posttraumatic Stress Disorder Onset and Course in Pediatric Injury Patients

    Directory of Open Access Journals (Sweden)

    Ananda B. Amstadter

    2011-01-01

    Full Text Available Posttraumatic stress disorder (PTSD is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1, have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n = 103 who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.

  18. Corticotrophin-releasing hormone type 1 receptor gene (CRHR1) variants predict posttraumatic stress disorder onset and course in pediatric injury patients.

    Science.gov (United States)

    Amstadter, Ananda B; Nugent, Nicole R; Yang, Bao-Zhu; Miller, Alisa; Siburian, Richie; Moorjani, Priya; Haddad, Stephen; Basu, Aditi; Fagerness, Jesen; Saxe, Glenn; Smoller, Jordan W; Koenen, Karestan C

    2011-01-01

    Posttraumatic stress disorder (PTSD) is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1), have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs) in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n=103) who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.

  19. Shaping policy: the Canadian Cancer Society and the Hormone Receptor Testing Inquiry.

    Science.gov (United States)

    Mathews, M; Newbury, J; Housser, E M

    2011-08-01

    In 2007, the Government of Newfoundland and Labrador established the Commission of Inquiry on Hormone Receptor Testing to examine problems with estrogen and progesterone hormone receptor tests conducted in the province between 1997 and 2005. Using the Inquiry as a case study, we examine the knowledge transfer activities used by the Canadian Cancer Society - Newfoundland and Labrador Division (CCS-NL) to shape policy and improve cancer control in the province. CCS-NL established a panel to advise its legal counsel and asked academic researchers to prepare papers to submit to the Commission. CCS-NL also interviewed patients to better inform its legal arguments, used its province-wide networks to raise awareness of the Inquiry, and provided a toll-free number that people could call. It also provided basic information, resources, and contact information for people who were affected by the flawed hormone receptor tests. The effectiveness of CCS-NL's activities is reflected by the inclusion of its key messages in the Commission's recommendations, and the investment in cancer care following the Inquiry. The success of the CCS-NL knowledge transfer efforts stemmed from its reputation as an advocate for cancer patients and its long-standing relationship with researchers, especially at the local level. The case illustrates real-world application of knowledge transfer practices in the development of public policy, and describes how community-based non-government organizations can identify and draw attention to important issues that otherwise might not have been addressed.

  20. Selective thyroid hormone receptor modulators

    Directory of Open Access Journals (Sweden)

    Girish Raparti

    2013-01-01

    Full Text Available Thyroid hormone (TH is known to have many beneficial effects on vital organs, but its extrapolation to be used therapeutically has been restricted by the fact that it does have concurrent adverse effects. Recent finding of various thyroid hormone receptors (TR isoforms and their differential pattern of tissue distribution has regained interest in possible use of TH analogues in therapeutics. These findings were followed by search of compounds with isoform-specific or tissue-specific action on TR. Studying the structure-activity relationship of TR led to the development of compounds like GC1 and KB141, which preferentially act on the β1 isoform of TR. More recently, eprotirome was developed and has been studied in humans. It has shown to be effective in dyslipidemia by the lipid-lowering action of TH in the liver and also in obesity. Another compound, 3,5-diiodothyropropionic acid (DITPA, binds to both α- and β-type TRs with relatively low affinity and has been shown to be effective in heart failure (HF. In postinfarction models of HF and in a pilot clinical study, DITPA increased cardiac performance without affecting the heart rate. TR antagonists like NH3 can be used in thyrotoxicosis and cardiac arrhythmias. However, further larger clinical trials on some of these promising compounds and development of newer compounds with increased selectivity is required to achieve higher precision of action and avoid adverse effects seen with TH.

  1. Contribution to the study of TRH (thyrotropin-releasing hormone) conformation using circular dichroism. Physico-chemical studies, radioactive labelling and biological applications

    International Nuclear Information System (INIS)

    Pradelles, Philippe.

    1977-01-01

    In an attempt to reach a better understanding at the molecular level of phenomena connected with the action of TRF the conformation and radioactive labelling of this hormone were investigated. The specific detection of a hormone at its action site is only possible if labelled substances of very high specific activity are used. TRF was tritium labelled by three methods: direct catalytic exchange; catalytic dehalogenation of mono- and di-iodo TRF; catalytic denitrogenation of mono-azo-TRF. Whatever the method used the tritiated TRF has a very high specific activity and keeps all its biological properties. Biological activity measurements carried out on labelled TRF, in vivo in rats and in vitro on a TRF-sensitive prolactine cell clone, are described. TRF tritiated by the above methods is shown to have the same biological activity as standard TRF. Some results are given concerning the application of labelled TRF to research on the hormone action mechanism. The tritiated TRF distribution kinetics were examined in vivo and in vitro. The kinetics of hormone fixation on the antehypophysary tissue match those of in vivo release of the plasma thyreotropic hormone, confirming the relationships between the hormone fixation on its target tissue and its biological effect. Finally an outline is given of work on the interaction of tritiated TRF with prolactine cell receptors and on the penetration of intact tritiated TRF into these cells. In addition the radioimmunological analysis of TRF was developed by the use of 125 I-mono-iodo-TRF at high specific activity (above 2000 Ci/mmole) [fr

  2. Breast cancer with Her-22 hormone receptor-positive neu: primary systemic treatment, sentinel node biopsy and hormone

    International Nuclear Information System (INIS)

    Lopez C, Nayara; Sanchez M, Jose Ignacio; De Santiago G, Javier

    2013-01-01

    Neoadjuvant chemotherapy is an interesting option in the therapy of some breast cancer cases. Cases in which the timing for sentinel lymph node biopsy is controversial. Co-expression of estrogen receptors and Her2/neu (cc-erbB-2) in breast cancer may imply hormone resistance, especially to tamoxifen. We present a clinic case with co-expression of estrogen receptors and Her2/neu that was treated with neoadjuvant chemotherapy and previous sentinel lymph node biopsy followed by breast tumorectomy with axillar lympha- denectomy, radiotherapy and hormonotherapy with letrozol, geserelina and trastuzumab. A good treatment response as found

  3. Acute effects of clonidine and growth-hormone-releasing hormone on growth hormone secretion in patients with hyperthyroidism.

    Science.gov (United States)

    Giustina, A; Buffoli, M G; Bussi, A R; Wehrenberg, W B

    1991-01-01

    Patients with hyperthyroidism have reduced growth hormone (GH) responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of clonidine on GH secretion has been suggested to depend on an enhancement of hypothalamic GH-releasing hormone (GHRH) release. The aim of our study was to evaluate the effects of clonidine and GHRH on GH secretion in patients with hyperthyroidism. Eight hyperthyroid females with recent diagnosis of Graves' disease (age range 20-55 years, body mass index range 19.2-26.2 kg/m2) and 6 healthy female volunteers (age range 22-35 years, body mass index range 19-25 kg/m2) underwent two experimental trials at no less than 7-day intervals: (a) an intravenous infusion of clonidine 150 micrograms in 10 ml of saline, or (b) a bolus intravenous injection of human GHRH (1-29)NH2, 100 micrograms in 1 ml of saline. Hyperthyroid patients showed blunted GH peaks after clonidine (7.1 +/- 1.7 micrograms/l) as compared to normal subjects receiving clonidine (28.5 +/- 4.9 micrograms/l, p less than 0.05). GH peaks after GHRH were also significantly lower in hyperthyroid subjects (8.0 +/- 1.7 micrograms/l) as compared to normal subjects receiving GHRH (27.5 +/- 4.4 micrograms/l, p less than 0.05). No significant differences in the GH values either after clonidine or GHRH were observed in the two groups of subjects examined. Our data demonstrate that the GH responses to clonidine as well as to GHRH in patients with hyperthyroidism are inhibited in a similar fashion with respect to normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Expression of the growth hormone receptor gene in insulin producing cells

    DEFF Research Database (Denmark)

    Møldrup, Annette; Billestrup, N; Nielsen, Jens Høiriis

    1990-01-01

    Growth hormone (GH) plays a dual role in glucose homeostasis. On the one hand, it exerts an insulin antagonistic effect on the peripheral tissue, on the other hand, it stimulates insulin biosynthesis and beta-cell proliferation. The expression of GH-receptors on the rat insulinoma cell line RIN-5...

  5. Cytoplasmic sequences of the growth hormone receptor necessary for signal transduction

    DEFF Research Database (Denmark)

    Goujon, L; Allevato, G; Simonin, G

    1994-01-01

    To study structure-function relationships of the growth hormone (GH) receptor (GHR), two functional systems have been developed. CHO cells were transiently cotransfected with the cDNA encoding the full-length rat GHR and with a construct consisting of the 5' flanking region of one of two GH...

  6. Neurokinin B and serum albumin limit copper binding to mammalian gonadotropin releasing hormone.

    Science.gov (United States)

    Gul, Ahmad Samir; Tran, Kevin K; Jones, Christopher E

    2018-02-26

    Gonadotropin releasing hormone (GnRH) triggers secretion of luteinizing hormone and follicle stimulating hormone from gonadotropic cells in the anterior pituitary gland. GnRH is able to bind copper, and both in vitro and in vivo studies have suggested that the copper-GnRH complex is more potent at triggering gonadotropin release than GnRH alone. However, it remains unclear whether copper-GnRH is the active species in vivo. To explore this we have estimated the GnRH-copper affinity and have examined whether GnRH remains copper-bound in the presence of serum albumin and the neuropeptide neurokinin B, both copper-binding proteins that GnRH will encounter in vivo. We show that GnRH has a copper dissociation constant of ∼0.9 × 10 -9  M, however serum albumin and neurokinin B can extract metal from the copper-GnRH complex. It is therefore unlikely that a copper-GnRH complex will survive transit through the pituitary portal circulation and that any effect of copper must occur outside the bloodstream in the absence of neurokinin B. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Nuclear Import and Export of the Thyroid Hormone Receptor.

    Science.gov (United States)

    Zhang, Jibo; Roggero, Vincent R; Allison, Lizabeth A

    2018-01-01

    The thyroid hormone receptors, TRα1 and TRβ1, are members of the nuclear receptor superfamily that forms one of the most abundant classes of transcription factors in multicellular organisms. Although primarily localized to the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. The fine balance between nuclear import and export of TRs has emerged as a critical control point for modulating thyroid hormone-responsive gene expression. Mutagenesis studies have defined two nuclear localization signal (NLS) motifs that direct nuclear import of TRα1: NLS-1 in the hinge domain and NLS-2 in the N-terminal A/B domain. Three nuclear export signal (NES) motifs reside in the ligand-binding domain. A combined approach of shRNA-mediated knockdown and coimmunoprecipitation assays revealed that nuclear entry of TRα1 is facilitated by importin 7, likely through interactions with NLS-2, and importin β1 and the adapter importin α1 interacting with both NLS-1 and NLS-2. Interestingly, TRβ1 lacks NLS-2 and nuclear import depends solely on the importin α1/β1 heterodimer. Heterokaryon and fluorescence recovery after photobleaching shuttling assays identified multiple exportins that play a role in nuclear export of TRα1, including CRM1 (exportin 1), and exportins 4, 5, and 7. Even single amino acid changes in TRs dramatically alter their intracellular distribution patterns. We conclude that mutations within NLS and NES motifs affect nuclear shuttling activity, and propose that TR mislocalization contributes to the development of some types of cancer and Resistance to Thyroid Hormone syndrome. © 2018 Elsevier Inc. All rights reserved.

  8. Molecular characterization of thyroid hormone receptors from the leopard gecko, and their differential expression in the skin.

    Science.gov (United States)

    Kanaho, Yoh-Ichiro; Endo, Daisuke; Park, Min Kyun

    2006-06-01

    Thyroid hormones (THs) play crucial roles in various developmental and physiological processes in vertebrates, including squamate reptiles. The effect of THs on shedding frequency is interesting in Squamata, since the effects on lizards are quite the reverse of those in snakes: injection of thyroxine increases shedding frequency in lizards, but decreases it in snakes. However, the mechanism underlying this differential effect remains unclear. To facilitate the investigation of the molecular mechanism of the physiological functions of THs in Squamata, their two specific receptor (TRalpha and beta) cDNAs, which are members of the nuclear hormone receptor superfamily, were cloned from a lizard, the leopard gecko, Eublepharis macularius. This is the first molecular cloning of thyroid hormone receptors (TRs) from reptiles. The deduced amino acid sequences showed high identity with those of other species, especially in the C and E/F domains, which are characteristic domains in nuclear hormone receptors. Expression analysis revealed that TRs were widely expressed in many tissues and organs, as in other animals. To analyze their role in the skin, temporal expression analysis was performed by RT-PCR, revealing that the two TRs had opposing expression patterns: TRalpha was expressed more strongly after than before skin shedding, whereas TRbeta was expressed more strongly before than after skin shedding. This provides good evidence that THs play important roles in the skin, and that the roles of their two receptor isoforms are distinct from each other.

  9. Down-regulation of parathyroid hormone (PTH) receptors in cultured bone cells is associated with agonist-specific intracellular processing of PTH-receptor complexes.

    Science.gov (United States)

    Teitelbaum, A P; Silve, C M; Nyiredy, K O; Arnaud, C D

    1986-02-01

    Exposure of cultured embryonic chicken bone cells to the PTH agonists bovine (b) PTH-(1-34) and [8Nle, 18Nle, 34Tyr]bPTH-(1-34)amide [bPTH-(1-34)A] reduces the subsequent cAMP response to the hormone and decreases the specific binding of 125I-labeled PTH to these cultures. To determine whether PTH receptor down-regulation in cultured bone cells is mediated by cellular internalization of PTH-receptor complexes, we measured the uptake of [125I]bPTH-(1-34) into an acid-resistant compartment. Uptake of radioactivity into this compartment was inhibited by incubating cells at 4 C with phenylarsineoxide and unlabeled bPTH-(1-34). Tracer uptake into the acid-resistant compartment at any time was directly proportional to total cell binding at 22 C. Thus, it is likely that PTH-receptor complexes are internalized by bone cells. This mechanism may explain the loss of cell surface receptors after PTH pretreatment. To determine whether internalized PTH-receptor complexes are reinserted into the plasma membrane, we measured PTH binding and PTH stimulation of cAMP production after cells were exposed to monensin, a known inhibitor of receptor recycling. Monensin (25 microM) had no effect on PTH receptor number or affinity and did not alter PTH-stimulated cAMP accumulation. However, monensin (25 microM) incubated with cells pretreated with various concentrations of bPTH-(1-34) for 1 h potentiated the effect of the hormone to reduce subsequent [125I]bPTH-(1-34) binding and PTH-stimulated cAMP accumulation by more than 2 orders of magnitude. Chloroquine also potentiated PTH-induced down-regulation of PTH receptors. By contrast, neither agent influenced PTH binding or PTH-stimulated cAMP production in cells pretreated with the antagonist bPTH-(3-34)A. Thus, monensin potentiated PTH receptor loss only in cells pretreated with PTH agonists, indicating that antagonist-occupied receptors may be processed differently from agonist-occupied receptors in bone cells. The data further suggest

  10. Gonadotropin-Releasing Hormone Regulates Expression of the DNA Damage Repair Gene, Fanconi anemia A, in Pituitary Gonadotroph Cells1

    Science.gov (United States)

    Larder, Rachel; Chang, Lynda; Clinton, Michael; Brown, Pamela

    2007-01-01

    Gonadal function is critically dependant on regulated secretion of the gonadotropin hormones from anterior pituitary gonadotroph cells. Gonadotropin biosynthesis and release is triggered by the binding of hypothalamic GnRH to GnRH receptor expressed on the gonadotroph cell surface. The repertoire of regulatory molecules involved in this process are still being defined. We used the mouse LβT2 gonadotroph cell line, which expresses both gonadotropin hormones, as a model to investigate GnRH regulation of gene expression and differential display reverse transcription-polymerase chain reaction (RT-PCR) to identify and isolate hormonally induced changes. This approach identified Fanconi anemia a (Fanca), a gene implicated in DNA damage repair, as a differentially expressed transcript. Mutations in Fanca account for the majority of cases of Fanconi anemia (FA), a recessively inherited disease identified by congenital defects, bone marrow failure, infertility, and cancer susceptibility. We confirmed expression and hormonal regulation of Fanca mRNA by quantitative RT-PCR, which showed that GnRH induced a rapid, transient increase in Fanca mRNA. Fanca protein was also acutely upregulated after GnRH treatment of LβT2 cells. In addition, Fanca gene expression was confined to mature pituitary gonadotrophs and adult mouse pituitary and was not expressed in the immature αT3-1 gonadotroph cell line. Thus, this study extends the expression profile of Fanca into a highly specialized endocrine cell and demonstrates hormonal regulation of expression of the Fanca locus. We suggest that this regulatory mechanism may have a crucial role in the GnRH-response mechanism of mature gonadotrophs and perhaps the etiology of FA. PMID:15128600

  11. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea.

    Science.gov (United States)

    Jayasena, C N; Nijher, G M K; Abbara, A; Murphy, K G; Lim, A; Patel, D; Mehta, A; Todd, C; Donaldson, M; Trew, G H; Ghatei, M A; Bloom, S R; Dhillo, W S

    2010-12-01

    Kisspeptin is a novel therapeutic target for infertility. A single kisspeptin-54 (KP-54) injection acutely stimulates the release of reproductive hormones in women with hypothalamic amenorrhea (HA), a commonly occurring condition characterized by absence of menstruation; however, twice-daily administration of KP-54 results in tachyphylaxis. We determined the time course of desensitization to twice-daily KP-54 injections, compared the effects of twice-daily and twice-weekly administration regimens of KP-54, and studied the effects of long-term twice-weekly administration of KP-54 on the release of reproductive hormones in women with HA. When KP-54 was administered twice daily, responsiveness to luteinizing hormone (LH) diminished gradually, whereas responsiveness to follicle-stimulating hormone (FSH) was nearly abolished by day 2. Twice-weekly KP-54 administration resulted in only partial desensitization, in contrast to the complete tolerance achieved with twice-daily administration. Women with HA who were treated with twice-weekly KP-54 injections had significantly elevated levels of reproductive hormones after 8 weeks as compared with treatment with saline. No adverse effects were observed. This study provides novel pharmacological data on the effects of KP-54 on the release of reproductive hormones in women with HA.

  12. Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor.

    Science.gov (United States)

    Thompson, P D; Hsieh, J C; Whitfield, G K; Haussler, C A; Jurutka, P W; Galligan, M A; Tillman, J B; Spindler, S R; Haussler, M R

    1999-12-01

    The vitamin D receptor (VDR) is a transcription factor believed to function as a heterodimer with the retinoid X receptor (RXR). However, it was reported [Schräder et al., 1994] that, on putative vitamin D response elements (VDREs) within the rat 9k and mouse 28k calcium binding protein genes (rCaBP 9k and mCaBP 28k), VDR and thyroid hormone receptor (TR) form heterodimers that transactivate in response to both 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and triiodothyronine (T(3)). We, therefore, examined associations of these receptors on the putative rCaBP 9k and mCaBP 28k VDREs, as well as on established VDREs from the rat osteocalcin (rOC) and mouse osteopontin (mOP) genes, plus the thyroid hormone response element (TRE) from the rat myosin heavy chain (rMHC) gene. In gel mobility shift assays, we found no evidence for VDR-TR heterodimer interaction with any tested element. Further, employing these hormone response elements linked to reporter genes in transfected cells, VDR and TR mediated responses to their cognate ligands only from the rOC/mOP and rMHC elements, respectively, while the CaBP elements were unresponsive to any combination of ligand(s). Utilizing the rOC and mOP VDREs, two distinct repressive actions of TR on VDR-mediated signaling were demonstrated: a T(3)-independent action, presumably via direct TR-RXR competition for DNA binding, and a T(3)-dependent repression, likely by diversion of limiting RXR from VDR-RXR toward the formation of TR-RXR heterodimers. The relative importance of these two mechanisms differed in a response element-specific manner. These results may provide a partial explanation for the observed association between hyperthyroidism and bone demineralization/osteoporosis. Copyright 1999 Wiley-Liss, Inc.

  13. Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion.

    Science.gov (United States)

    Khatib, Nazli; Gaidhane, Shilpa; Gaidhane, Abhay M; Khatib, Mahanaaz; Simkhada, Padam; Gode, Dilip; Zahiruddin, Quazi Syed

    2014-08-01

    Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of GH. It is a first hormone linking gastrointestinal-pituitary axis. This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS-GHS receptor signalling system in the regulation of GH secretion. Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH.

  14. Visualization of Oxytocin Release that Mediates Paired Pulse Facilitation in Hypothalamic Pathways to Brainstem Autonomic Neurons

    Science.gov (United States)

    Piñol, Ramón A.; Jameson, Heather; Popratiloff, Anastas; Lee, Norman H.; Mendelowitz, David

    2014-01-01

    Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2) expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV). We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs), neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection. PMID:25379676

  15. Effects of thyrotropin-releasing hormone on regional cerebral blood flow in man

    DEFF Research Database (Denmark)

    Oturai, P S; Friberg, L; Sam, I

    1992-01-01

    emission computerized tomograph and inhalation of 133Xe. Thyrotropin-releasing hormone caused a significant mean increase of 3.7% (range -8.8-22.7) in blood flow in a region consistent with the left thalamus compared to placebo (3.2% decrease). In 25 other regions no significant change was detected...

  16. Flow cytometric measurement of DNA level and steroid hormone receptor assay in breast cancer

    International Nuclear Information System (INIS)

    Zubrikhina, G.N.; Kuz'mina, Eh.V.; Bassalyk, L.S.; Murav'eva, N.I.

    1989-01-01

    DNA level measured by flow cytometry and estrogen and progesteron receptors assayed in tissue samples obtained from 85 malignant and 16 benign lesions of the breast. All the benign tumors revealed 2c DNA content and most of them were receptor-negative, while 74.1% of breast carcinomas displayed aneuploidy. Three patients (3.5%) had two lines of aneuploid cells. Many aneuploid tumors were receptor-negative. Preoperative radiation treatmet (14-20 Gy) did not significantly influence the level of steroid hormone receptors in tumors. Estrogen receptor level was higher in menopausal patients than in premenopausal ones

  17. G protein-coupled receptor mutations and human genetic disease.

    Science.gov (United States)

    Thompson, Miles D; Hendy, Geoffrey N; Percy, Maire E; Bichet, Daniel G; Cole, David E C

    2014-01-01

    Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common

  18. The effect of short-term cortisol changes on growth hormone responses to the pyridostigmine-growth-hormone-releasing-hormone test in healthy adults and patients with suspected growth hormone deficiency

    DEFF Research Database (Denmark)

    Andersen, M; Støving, R K; Hangaard, J

    1998-01-01

    BACKGROUND AND AIMS: The interaction between cortisol and growth hormone (GH)-levels may significantly influence GH-responses to a stimulation test. In order to systematically analyse the interaction in a paired design, it is necessary to use a test, which has been proven safe and reliable...... such as the pyridostigmine-growth-hormone-releasing-hormone (PD-GHRH) test. Three groups of subjects with a different GH-secretory capacity were included. STUDY A: Eight healthy adults were tested seven times, once with placebo throughout the examination and six times with the PD-GHRH test following no glucocorticoid......-responses to a PD-GHRH test were reduced in all individuals during acute stress-appropriate cortisol levels and the percentage reduction in GH-levels was independent of the GH-secretory capacity. Clinically, we found that peak GH-responses were not significantly affected by a short break in conventional HC therapy...

  19. Luteinizing hormone-releasing hormone analogue (Buserelin) treatment for central precocious puberty: a multi-centre trial.

    Science.gov (United States)

    Werther, G A; Warne, G L; Ennis, G; Gold, H; Silink, M; Cowell, C T; Quigley, C; Howard, N; Antony, G; Byrne, G C

    1990-02-01

    A multi-centre open trial of Buserelin, a luteinizing hormone-releasing hormone (LHRH) analogue, was conducted in 13 children with central precocious puberty. Eleven children (eight girls and three boys), aged 3.4-10.2 years at commencement, completed the required 12 month period of treatment. Initially all patients received the drug by intranasal spray in a dose of 1200 micrograms/day, but by the end of the 12 month period two were having daily subcutaneous injections and three were receiving an increased dose intranasally. The first month of treatment was associated in one boy with increased aggression and masturbation, and in the girls with an increase in the prevalence of vaginal bleeding. Thereafter, however, both behavioural abnormalities and menstruation were suppressed. Median bone age increased significantly during the study, but without any significant change in the ratio of height age to bone age. The median predicted adult height for the group therefore did not alter significantly over the twelve months of the study. Buserelin treatment caused a reduction in the peak luteinizing hormone and follicle-stimulating hormone (FSH) responses to LHRH, mostly to prepubertal levels, and also suppressed basal FSH. In the first weeks of treatment, the girls' serum oestradiol levels rose significantly and then fell to prepubertal or early pubertal levels. A similar pattern was seen for serum testosterone levels. Serum somatomedin-C levels, however, showed little fluctuation over the course of the study. Buserelin treatment was safe and well accepted, and offers the promise of improved linear growth potential in precocious puberty.

  20. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

  1. THYROID HORMONE RECEPTOR BETA GENE MUTATION (P453A) IN A TURKISH FAMILY PRODUCING RESISTANCE TO THYROID HORMONE

    Science.gov (United States)

    Bayraktaroglu, Taner; Noel, Janet; Mukaddes, Nahit Motavalli; Refetoff, Samuel

    2018-01-01

    Two members of a Turkish family, a mother and son, had thyroid function tests suggestive of resistance to thyroid hormone (RTH). The clinical presentation was, however, different. The mother (proposita) had palpitation, weakness, tiredness, nervousness, dry mouth and was misdiagnosed as having multinodular toxic goiter which was treated with antithyroid drugs and partial thyroidectomy. Her younger son had attention deficit hyperactivity disorder and primary encopresis, but normal intellectual quotient. Both had elevated serum iodothyronine levels with nonsuppressed thyrotropin. A mutation in one allele of the thyroid hormone receptor beta gene (P453A) was identified, providing a genetic confirmation for the diagnosis of RTH. PMID:18561095

  2. Hepatic receptors for homologous growth hormone in the eel

    International Nuclear Information System (INIS)

    Hirano, T.

    1991-01-01

    The specific binding of 125I-labeled eel growth hormone (eGH) to liver membranes of the eel was examined. The specific binding to the 10,000g pellet was greater than that to the 600g pellet. The specific binding was linear up to about 100 mg fresh tissue, and was saturable with increasing amounts of membrane. The specific binding was pH-, temperature-, and time-dependent, with the optimum pH at 7.4, and greater specific binding was obtained at 15 and 25 degrees than at 35 degrees. Scatchard analysis of liver binding gave an association constant of 1.1 x 10(9) M-1 and a capacity of 105 fmol/mg protein. The receptor preparation was highly specific for GHs. Natural and recombinant eel GHs as well as recombinant salmon GH competed equally with 125I-eGH for the receptor sites of the 10,000g liver membrane. Ovine GH was more potent in displacing the labeled eGH than the homologous eel hormone. Tilapia GH and ovine prolactin (PRL) were needed in greater amounts (40 times) than eGH to displace the labeled eGH. Salmon and tilapia PRLs were still less potent (500 times) than eGH. There was no displacement with eel PRL. No significant change in the specific binding was seen 1 week after hypophysectomy, whereas injection of eGH into the hypophysectomized eel caused a significant reduction after 24 hr. The binding to the membrane fractions from gills, kidney, muscle, intestine, and brain was low and exclusively nonspecific, indicating the presence of specific GH receptors predominantly in the liver

  3. Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

    DEFF Research Database (Denmark)

    Fernández Pérez, Leandro; Flores-Morales, Amilcar; Guerra, Borja

    2016-01-01

    Growth hormone (GH) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic devel...

  4. UV filters induce transcriptional changes of different hormonal receptors in Chironomus riparius embryos and larvae.

    Science.gov (United States)

    Ozáez, Irene; Aquilino, Mónica; Morcillo, Gloria; Martínez-Guitarte, José-Luis

    2016-07-01

    Organic ultraviolet (UV) filters are emerging contaminants that are ubiquitous in fresh and marine aquatic systems due to their extensive use in cosmetics, plastics, paints, textiles, and many other industrial products. The estrogenic effects of organic UV filters have been long demonstrated in vertebrates, and other hormonal activities may be altered, according to more recent reports. The impact of UV filters on the endocrine system of invertebrates is largely unknown. We have previously reported that some UV filters may affect ecdysone-related genes in the aquatic insect Chironomus riparius, an ecotoxicologically important model organism. To further analyze other possible effects on endocrine pathways, we first characterized four pivotal genes related with hormonal pathways in insects; thereafter, these genes were assessed for alterations in transcriptional activity after exposure to 4-methylbenzylidene camphor (4MBC) or benzophenone-3 (BP-3), two extensively used sunscreens. We found that both chemicals disturbed the expression of all four genes analyzed: hormonal receptor 38 (HR38), methoprene-tolerant (Met), membrane-associate progesterone receptor (MAPR) and insulin-like receptor (INSR), measured by changes in mRNA levels by real-time PCR. An upregulatory effect at the genomic level was detected in different developmental stages. Interestingly, embryos appeared to be more sensitive to the action of the UV filters than larvae. Our results suggest that the risk of disruption through different endocrine routes is not negligible, considering the significant effects of UV filters on key hormonal receptor and regulatory genes. Further effort is needed to develop environmental risk assessment studies on these pollutants, particularly for aquatic invertebrate model organisms. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Receptors of Hypothalamic-Pituitary-Ovarian-Axis Hormone in Uterine Myomas

    Directory of Open Access Journals (Sweden)

    Danuta Plewka

    2014-01-01

    Full Text Available In this study the expression of GnRH, FSH, LH, ER-α, ER-β, and PR receptors was examined in uterine myomas of women in reproductive and perimenopausal age. In cases of GnRH and tropic hormones a membranous and cytoplasmic immunohistochemical reaction was detected, in cases of ER-α and PR the reaction was located in cell nucleus, and in the case of ER-β it manifested also a cytoplasmic location. In some of the examined cases the expression was detected in endometrium, myocytes, and endothelium of blood vessels, in uterine glands and myoma cells. In myometrium the level of GnRH and LH receptors increases with age, whereas the level of progesterone and both estrogen receptors decreases. In myomas of women in reproductive age, independently of their size, expression of GnRH, FSH, and LH receptors was more pronounced than in myometrium. In women of perimenopausal age, independently of myoma size, expression of LH and estrogen α receptors was higher while expression of GnRH receptors was lower than in myometrium. FSH receptor expression was not observed. Expression of estrogen receptor β was not affected by age of the woman or size of myoma. Analysis of obtained results indicates on existing in small myomas local feedback axis between GnRH-LH-progesterone.

  6. Machine learning approaches to decipher hormone and HER2 receptor status phenotypes in breast cancer.

    Science.gov (United States)

    Adabor, Emmanuel S; Acquaah-Mensah, George K

    2017-10-16

    Breast cancer prognosis and administration of therapies are aided by knowledge of hormonal and HER2 receptor status. Breast cancer lacking estrogen receptors, progesterone receptors and HER2 receptors are difficult to treat. Regarding large data repositories such as The Cancer Genome Atlas, available wet-lab methods for establishing the presence of these receptors do not always conclusively cover all available samples. To this end, we introduce median-supplement methods to identify hormonal and HER2 receptor status phenotypes of breast cancer patients using gene expression profiles. In these approaches, supplementary instances based on median patient gene expression are introduced to balance a training set from which we build simple models to identify the receptor expression status of patients. In addition, for the purpose of benchmarking, we examine major machine learning approaches that are also applicable to the problem of finding receptor status in breast cancer. We show that our methods are robust and have high sensitivity with extremely low false-positive rates compared with the well-established methods. A successful application of these methods will permit the simultaneous study of large collections of samples of breast cancer patients as well as save time and cost while standardizing interpretation of outcomes of such studies. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Corticotropine-releasing hormone and/or corticosterone differentially affect behavior of rat

    Czech Academy of Sciences Publication Activity Database

    Valeš, Karel; Řezáčová, Lenka; Stuchlík, Aleš

    2008-01-01

    Roč. 11, Suppl.1 (2008), s. 118-118 ISSN 1461-1457. [CINP Congress /26./. 13.07.2008-17.07.2008, Munich] R&D Projects: GA MŠk(CZ) 1M0517; GA MZd NR9180; GA ČR(CZ) GA309/07/0341 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * corticotropine-releasing hormone * corticosterone * behavior Subject RIV: FH - Neurology

  8. Molecular cloning and functional characterization of the diapause hormone receptor in the corn earworm Helicoverpa zea

    Science.gov (United States)

    The diapause hormone (DH) in the heliothine moth has shown its activity in termination of pupal diapause, while the orthology in the silkworm is known to induce embryonic diapause. In the current study, we cloned the diapause hormone receptor from the corn earworm Helicoverpa zea (HzDHr) and tested ...

  9. Role of calcium in gonadotropin releasing hormone-induced luteinizing hormone secretion from the bovine pituitary

    International Nuclear Information System (INIS)

    Kile, J.P.

    1986-01-01

    The hypothesis was tested that GnRH acts to release LH by increasing calcium uptake by gonadotroph which in turn stimulates calcium-calmodulin activity and results in LH release from bovine pituitary cells as it does in the rat. Pituitary glands of calves (4-10 months of age) were enzymatically dispersed (0.2% collagenase) and grown for 5 days to confluency in multiwell plates (3 x 10 5 /well). Cells treated with GnRH Ca ++ ionophore A23187, and ouabain all produced significant releases of LH release in a pronounced all or none fashion, while thorough washing of the cells with 0.5 mM EGTA in Ca ++ -free media prevented the action of GnRH. GnRH caused a rapid efflux of 45 Ca ++ . Both GnRH-stimulated 45 Ca efflux and LH release could be partially blocked by verapamil GnRH-induced LH release could also be blocked by nifedipine and tetrodotoxin, although these agents did not affect 45 Ca efflux. The calmodulin antagonists calmidazolium and W7 were found to block GnRH induced LH release, as well as LH release induced by theophylline, KC PGE 2 and estradiol. These data indicated that: (1) calcium is required for GnRH action, but extracellular Ca ++ does not regulate LH release; (2) GnRH elevates intracellular Ca ++ by opening both voltage sensitive and receptor mediated Ca ++ channels; (3) activation of calmodulin is one mechanism involved in GnRH-induced LH release

  10. Modulation of Sleep Homeostasis by Corticotropin Releasing Hormone in REM Sleep-Deprived Rats

    Directory of Open Access Journals (Sweden)

    Ricardo Borges Machado

    2010-01-01

    Full Text Available Studies have shown that sleep recovery following different protocols of forced waking varies according to the level of stress inherent to each method. Sleep deprivation activates the hypothalamic-pituitary-adrenal axis and increased corticotropin-releasing hormone (CRH impairs sleep. The purpose of the present study was to evaluate how manipulations of the CRH system during the sleep deprivation period interferes with subsequent sleep rebound. Throughout 96 hours of sleep deprivation, separate groups of rats were treated i.c.v. with vehicle, CRH or with alphahelical CRH9−41, a CRH receptor blocker, twice/day, at 07:00 h and 19:00 h. Both treatments impaired sleep homeostasis, especially in regards to length of rapid eye movement sleep (REM and theta/delta ratio and induced a later decrease in NREM and REM sleep and increased waking bouts. These changes suggest that activation of the CRH system impact negatively on the homeostatic sleep response to prolonged forced waking. These results indicate that indeed, activation of the HPA axis—at least at the hypothalamic level—is capable to reduce the sleep rebound induced by sleep deprivation.

  11. Expression of Sex Steroid Hormone Receptors in Vagal Motor Neurons Innervating the Trachea and Esophagus in Mouse

    International Nuclear Information System (INIS)

    Mukudai, Shigeyuki; Ichi Matsuda, Ken; Bando, Hideki; Takanami, Keiko; Nishio, Takeshi; Sugiyama, Yoichiro; Hisa, Yasuo; Kawata, Mitsuhiro

    2016-01-01

    The medullary vagal motor nuclei, the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV), innervate the respiratory and gastrointestinal tracts. We conducted immunohistochemical analysis of expression of the androgen receptor (AR) and estrogen receptor α (ERα), in relation to innervation of the trachea and esophagus via vagal motor nuclei in mice. AR and ERα were expressed in the rostral NA and in part of the DMV. Tracing experiments using cholera toxin B subunit demonstrated that neurons of vagal motor nuclei that innervate the trachea and esophagus express AR and ERα. There was no difference in expression of sex steroid hormone receptors between trachea- and esophagus-innervating neurons. These results suggest that sex steroid hormones may act on vagal motor nuclei via their receptors, thereby regulating functions of the trachea and esophagus

  12. Gender and the use of hormonal contraception in women are not associated with cerebral cortical 5-HT 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, V G; Erritzoe, D; Madsen, J

    2009-01-01

    to frontolimbic 5-HT(2A) receptor binding and to be more pronounced in women, again, the effect of gender was not significant (P=0.42, n=127). Also, the use of hormonal contraception (n=14) within the group of pre-menopausal women (total n=29) was not associated with cortical 5-HT(2A) receptor binding (P=0.......31). In conclusion, neither gender, nor the use of hormonal contraception in premenopausal women was associated with cortical 5-HT(2A) receptor binding....... binding it is not clear if gender or use of hormonal contraception exhibits associations with 5-HT(2A) receptor binding. We found no significant effect of gender on cortical 5-HT(2A) receptor binding (P=0.15, n=132). When adjusting for the personality trait neuroticism, known to be positively correlated...

  13. Receptors for luteinizing hormone-releasing hormone (LHRH) in Dunning R3327 prostate cancers and rat anterior pituitaries after treatment with a sustained delivery system of LHRH antagonist SB-75.

    Science.gov (United States)

    Srkalovic, G; Bokser, L; Radulovic, S; Korkut, E; Schally, A V

    1990-12-01

    Membrane receptors for LHRH were evaluated in Dunning R3327 prostate cancers and rat anterior pituitaries. The receptors were characterized both in untreated animals and after in vivo treatment with microcapsules of the agonist D-Trp6-LHRH and a sustained delivery system releasing different doses (23.8, 47.6, 71.4 micrograms/day) of LHRH antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit6, D-Ala10]-LHRH (SB-75). The therapy, which lasted 8 weeks, strongly inhibited tumor growth. A group of normal Sprague-Dawley male rats was also treated for 6 weeks with microcapsules of SB-75 releasing 25 micrograms/day. In the Dunning tumors from the control group, ligand [125I, D-Trp6]-LHRH was bound to two classes of binding sites [dissociation constant, class a (Kda) = 1.01 +/- 0.30 x 10(-9) M; Kdb = 1.71 +/- 0.41 x 10(-6) M; maximal binding capacity of receptors, class a (Bmaxa) = 48.66 +/- 22.13 fmol/mg of protein; Bmaxb = 92.10 +/- 29.40 pmol/mg of protein] in both kinetic and equilibrium studies. Treatment with D-Trp6-LHRH produced down-regulation of membrane receptors for LHRH in Dunning tumors. Microcapsules of SB-75 resulted in dose-dependent up-regulation of binding sites for LHRH in Dunning tumors. Analysis of the binding data showed that interaction of labeled D-Trp6-LHRH with binding sites in anterior pituitaries was consistent with the presence of a single class of noncooperative receptors (Kd = 43.75 x 10(-9) M; Bmax = 5.25 pmol/mg membrane proteins). Prolonged treatment with microcapsules of D-Trp6-LHRH reduced both Bmax and Kd. Lower doses of SB-75 (23.8 and 47.6 micrograms/day) produced up-regulation, whereas the highest dose (71.4 micrograms/day) resulted in down-regulation of binding sites for LHRH in rat pituitaries. In normal Sprague-Dawley rats, treatment with microcapsules of SB-75 (25 micrograms/day) for 6 weeks produced a slight increase in the number of available binding sites (Bmax = 2.35 +/- 0.82 pmol/mg membrane protein) and a moderate decrease in

  14. Thyrotropin-releasing hormone controls mitochondrial biology in human epidermis.

    Science.gov (United States)

    Knuever, Jana; Poeggeler, Burkhard; Gáspár, Erzsébet; Klinger, Matthias; Hellwig-Burgel, Thomas; Hardenbicker, Celine; Tóth, Balázs I; Bíró, Tamás; Paus, Ralf

    2012-03-01

    Mitochondrial capacity and metabolic potential are under the control of hormones, such as thyroid hormones. The most proximal regulator of the hypothalamic-pituitary-thyroid (HPT) axis, TRH, is the key hypothalamic integrator of energy metabolism via its impact on thyroid hormone secretion. Here, we asked whether TRH directly modulates mitochondrial functions in normal, TRH-receptor-positive human epidermis. Organ-cultured human skin was treated with TRH (5-100 ng/ml) for 12-48 h. TRH significantly increased epidermal immunoreactivity for the mitochondria-selective subunit I of respiratory chain complex IV (MTCO1). This resulted from an increased MTCO1 transcription and protein synthesis and a stimulation of mitochondrial biogenesis as demonstrated by transmission electron microscopy and TRH-enhanced mitochondrial DNA synthesis. TRH also significantly stimulated the transcription of several other mitochondrial key genes (TFAM, HSP60, and BMAL1), including the master regulator of mitochondrial biogenesis (PGC-1α). TRH significantly enhanced mitochondrial complex I and IV enzyme activity and enhanced the oxygen consumption of human skin samples, which shows that the stimulated mitochondria are fully vital because the main source for cellular oxygen consumption is mitochondrial endoxidation. These findings identify TRH as a potent, novel neuroendocrine stimulator of mitochondrial activity and biogenesis in human epidermal keratinocytes in situ. Thus, human epidermis offers an excellent model for dissecting neuroendocrine controls of human mitochondrial biology under physiologically relevant conditions and for exploring corresponding clinical applications.

  15. Corticotropin-Releasing Hormone (CRH Promotes Macrophage Foam Cell Formation via Reduced Expression of ATP Binding Cassette Transporter-1 (ABCA1.

    Directory of Open Access Journals (Sweden)

    Wonkyoung Cho

    Full Text Available Atherosclerosis, the major pathology of cardiovascular disease, is caused by multiple factors involving psychological stress. Corticotropin-releasing hormone (CRH, which is released by neurosecretory cells in the hypothalamus, peripheral nerve terminals and epithelial cells, regulates various stress-related responses. Our current study aimed to verify the role of CRH in macrophage foam cell formation, the initial critical stage of atherosclerosis. Our quantitative real-time reverse transcriptase PCR (qRT-PCR, semi-quantitative reverse transcriptase PCR, and Western blot results indicate that CRH down-regulates ATP-binding cassette transporter-1 (ABCA1 and liver X receptor (LXR-α, a transcription factor for ABCA1, in murine peritoneal macrophages and human monocyte-derived macrophages. Oil-red O (ORO staining and intracellular cholesterol measurement of macrophages treated with or without oxidized LDL (oxLDL and with or without CRH (10 nM in the presence of apolipoprotein A1 (apoA1 revealed that CRH treatment promotes macrophage foam cell formation. The boron-dipyrromethene (BODIPY-conjugated cholesterol efflux assay showed that CRH treatment reduces macrophage cholesterol efflux. Western blot analysis showed that CRH-induced down-regulation of ABCA1 is dependent on phosphorylation of Akt (Ser473 induced by interaction between CRH and CRH receptor 1(CRHR1. We conclude that activation of this pathway by CRH accelerates macrophage foam cell formation and may promote stress-related atherosclerosis.

  16. Gene specific actions of thyroid hormone receptor subtypes.

    Directory of Open Access Journals (Sweden)

    Jean Z Lin

    Full Text Available There are two homologous thyroid hormone (TH receptors (TRs α and β, which are members of the nuclear hormone receptor (NR family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TRα and TRβ differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/- T(3 in two cell backgrounds (HepG2 and HeLa. We find that hundreds of genes respond to T(3 or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T(3 response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/- T(3, TR regulation patterns and T(3 dose response. Cycloheximide (CHX treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs.

  17. Lack of hormone binding in COS-7 cells expressing a mutated growth hormone receptor found in Laron dwarfism.

    Science.gov (United States)

    Edery, M; Rozakis-Adcock, M; Goujon, L; Finidori, J; Lévi-Meyrueis, C; Paly, J; Djiane, J; Postel-Vinay, M C; Kelly, P A

    1993-01-01

    A single point mutation in the growth hormone (GH) receptor gene generating a Phe-->Ser substitution in the extracellular binding domain of the receptor has been identified in one family with Laron type dwarfism. The mutation was introduced by site-directed mutagenesis into cDNAs encoding the full-length rabbit GH receptor and the extracellular domain or binding protein (BP) of the human and rabbit GH receptor, and also in cDNAs encoding the full length and the extracellular domain of the related rabbit prolactin (PRL) receptor. All constructs were transiently expressed in COS-7 cells. Both wild type and mutant full-length rabbit GH and PRL receptors, as well as GH and prolactin BPs (wild type and mutant), were detected by Western blot in cell membranes and concentrated culture media, respectively. Immunofluorescence studies showed that wild type and mutant full-length GH receptors had the same cell surface and intracellular distribution and were expressed with comparable intensities. In contrast, all mutant forms (full-length receptors or BPs), completely lost their modify the synthesis ligand. These results clearly demonstrate that this point mutation (patients with Laron syndrome) does not modify the synthesis or the intracellular pathway of receptor proteins, but rather abolishes ability of the receptor or BP to bind GH and is thus responsible for the extreme GH resistance in these patients. Images PMID:8450064

  18. Ontogenesis of neurons producing luteinizing hormone-releasing hormone (LHRH) in the nervus terminalis of the rat.

    Science.gov (United States)

    Schwanzel-Fukuda, M; Morrell, J I; Pfaff, D W

    1985-08-15

    Immunoreactive luteinizing hormone-releasing hormone (LHRH) was first detected at 15 days of gestation in ganglion cells associated with the peripheral, intracranial, and central parts of the nervus terminalis of the rat. LHRH was not detected in any other structure of the central nervous system at this age. In the 17-day-old fetal rat, 62% of the total LHRH-reactive neuronal population was found in ganglion cells of the nervus terminalis. At this same age, immunoreactive beta-luteinizing hormone (beta-LH) was first seen in gonadotropes of the anterior pituitary gland. At 19 days of gestation, 31% of the total number of LHRH-reactive neurons observed in the rat brain was found in the nervus terminalis, and immunoreactive processes were first seen in the organum vasculosum of the lamina terminalis and in the median eminence. Our data indicate that from 15 to 19 days of gestation the nervus terminalis is a principal source of LHRH in the fetal rat. Presence of the decapeptide in the nervus terminalis prior to appearance of beta-LH in the anterior pituitary suggests a possible role for LHRH in this system on maturation of the gonadotropes and differentiation of the brain-pituitary-gonadal axis.

  19. Visualization of oxytocin release that mediates paired pulse facilitation in hypothalamic pathways to brainstem autonomic neurons.

    Directory of Open Access Journals (Sweden)

    Ramón A Piñol

    Full Text Available Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2 expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV. We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs, neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection.

  20. Growth Hormone Overexpression Disrupts Reproductive Status Through Actions on Leptin

    Directory of Open Access Journals (Sweden)

    Ji Chen

    2018-03-01

    Full Text Available Growth and reproduction are closely related. Growth hormone (GH-transgenic common carp exhibit accelerated growth and delayed reproductive development, which provides an amenable model to study hormone cross talk between the growth and reproductive axes. We analyzed the energy status and reproductive development in GH-transgenic common carp by using multi-tissue RNA sequencing, real-time-PCR, Western blotting, ELISA, immunofluorescence, and in vitro incubation. The expression of gys (glycogen synthase and igfbp1 (insulin-like growth factor binding protein as well as blood glucose concentrations are lower in GH-transgenic carp. Agrp1 (agouti-related protein 1 and sla (somatolactin a, which are related to appetite and lipid catabolism, are significantly higher in GH-transgenic carp. Low glucose content and increased appetite indicate disrupted metabolic and energy deprivation status in GH-transgenic carp. Meanwhile, the expression of genes, such as gnrhr2 (gonadotropin-releasing hormone receptor 2, gthα (gonadotropin hormone, alpha polypeptide, fshβ (follicle stimulating hormone, beta polypeptide, lhβ [luteinizing hormone, beta polypeptide] in the pituitary, cyp19a1a (aromatase A in the gonad, and cyp19a1b (aromatase B in the hypothalamus, are decreased in GH-transgenic carp. In contrast, pituitary gnih (gonadotropin inhibitory hormone, drd1 (dopamine receptor D1, drd3 (dopamine receptor D3, and drd4 (dopamine receptor D4 exhibit increased expression, which were associated with the retarded reproductive development. Leptin receptor mRNA was detected by fluorescence in situ hybridization in the pituitary including the pars intermedia and proximal pars distalis, suggesting a direct effect of leptin on LH. Recombinant carp Leptin protein was shown to stimulate pituitary gthα, fshβ, lhβ expression, and ovarian germinal vesicle breakdown in vitro. In addition to neuroendocrine factors, we suggest that reduced hepatic leptin signaling to the

  1. Gonadotrophin-Releasing Hormone Agonists and Other Contraceptive Medications in Exotic Companion Animals.

    Science.gov (United States)

    Schoemaker, Nico J

    2018-05-01

    The use of a gonadotrophin-releasing hormone agonist slow-release implant (GnRH A-SRI) has become increasingly popular as an alternative for surgical contraception in many species. Although these implants have proven to be very effective in some species (eg, ferrets, rats, chicken, psittacines, and iguanas), they have been found less effective in other species (eg, male guinea pigs and rabbits, veiled chameleons, slider turtles, and leopard geckos). This review provides an overview of the available literature on the effects of GnRH A-SRIs in companion exotic animals. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Colocalization of connexin 36 and corticotropin-releasing hormone in the mouse brain

    Directory of Open Access Journals (Sweden)

    Ribeiro Ana C

    2009-04-01

    Full Text Available Abstract Background Gap junction proteins, connexins, are expressed in most endocrine and exocrine glands in the body and are at least in some glands crucial for the hormonal secretion. To what extent connexins are expressed in neurons releasing hormones or neuropeptides from or within the central nervous system is, however, unknown. Previous studies provide indirect evidence for gap junction coupling between subsets of neuropeptide-containing neurons in the paraventricular nucleus (PVN of the hypothalamus. Here we employ double labeling and retrograde tracing methods to investigate to what extent neuroendocrine and neuropeptide-containing neurons of the hypothalamus and brainstem express the neuronal gap junction protein connexin 36. Results Western blot analysis showed that connexin 36 is expressed in the PVN. In bacterial artificial chromosome transgenic mice, which specifically express the reporter gene Enhanced Green Fluorescent Protein (EGFP under the control of the connexin 36 gene promoter, EGFP expression was detected in magnocellular (neuroendocrine and in parvocellular neurons of the PVN. Although no EGFP/connexin36 expression was seen in neurons containing oxytocin or vasopressin, EGFP/connexin36 was found in subsets of PVN neurons containing corticotropin-releasing hormone (CRH, and in somatostatin neurons located along the third ventricle. Moreover, CRH neurons in brainstem areas, including the lateral parabrachial nucleus, also expressed EGFP/connexin 36. Conclusion Our data indicate that connexin 36 is expressed in subsets of neuroendocrine and CRH neurons in specific nuclei of the hypothalamus and brainstem.

  3. Gonadotropin-releasing hormone radioimmunoassay and its measurement in normal human plasma, secondary amenorrhea, and postmenopausal syndrome

    International Nuclear Information System (INIS)

    Rosenblum, N.G.; Schlaff, S.

    1976-01-01

    A sensitive and specific double antibody radioimmunoassay for gonadotropin-releasing hormone (GnRH) has been developed for measurement in ethanol extracts of human plasma. Iodinated hormone was prepared with the use of the chloramine-T method, and antibodies were developed in rabbits over a six-month period with a GnRH synthetic copolymer immunogen. A Scatchard plot revealed at least three species of antibody. The assay can measure conservatively at the 5 pg. per milliliter level and shows no cross-reactivity with other available hypothalamic and pituitary hormones. The releasing hormone was quantitatively recovered from human plasma with immunologic identity to native hormone. Unextracted plasma could not be used because of nonspecific displacement. The measurement of GnRH in individuals receiving 100 μg of intravenous bolus infusions of the synthetic decapeptide show extremely elevated values with two half-lives: one of two to four minutes and another of 35 to 40 minutes. In our experiments, we have found measurable GnRH in patients with secondary amenorrhea and at the midcycle in normal women. In the normal cycling woman during the follicular and luteal phases, GnRH was undetectable. In postmenopausal women with extreme hypoestrogenism and markedly elevated luteinizing hormone values, GnRH was also undetectable. No bursts of GnRH could be detected in normal men when sampled every ten minutes over a two-hour period and every two hours throughout the day

  4. Effect of stage of development and sex on gonadotropin-releasing hormone secretion in in vitro hypothalamic perifusion.

    Science.gov (United States)

    Lacau-Mengido, I M; González Iglesias, A; Díaz-Torga, G; Thyssen-Cano, S; Libertun, C; Becú-Villalobos, D

    1998-04-01

    Marked sexual and ontogenic differences have been described in gonadotropin regulation in the rat. These could arise from events occurring both at the hypothalamic or hypophyseal levels. The present experiments were designed to evaluate the capacity of the hypothalamus in releasing GnRH in vitro, basally and in response to depolarization with KCl, during ontogeny in the rat. To that end we chose two well-defined developmental ages that differ markedly in sexual and ontogenic characteristics of gonadotropin regulation, 15 and 30 days. We compared GnRH release from hypothalami of females, neonatal androgenized females and males. Mediobasal hypothalami were perifused in vitro, and GnRH measured in the effluent. Basal secretion of the decapeptide increased with age in the three groups with no sexual differences encountered. When studying GnRH release induced by membrane depolarization, no differences within sex or age were encountered. On the other hand FSH serum levels decreased with age in females and increased in males, and in neonatal androgenized females followed a similar pattern to that of females. LH levels were higher in infantile females than in age-matched males or androgenized females. Such patterns of gonadotropin release were therefore not correlated to either basal or K+-induced GnRH release from the hypothalamus. We conclude that sexual and ontogenic differences in gonadotropin secretion in the developing rat are not dependent on the intrinsic capability of the hypothalamus to release GnRH in response to membrane depolarization. The hormonal differences observed during development and between sexes are probably related to differences in the sensitivity of the GnRH neuron to specific secretagogue and neurotransmitter regulation, and/or to differences in hypophyseal GnRH receptors and gonadotrope sensitivity.

  5. Ovulation induction with pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropins in a case of hypothalamic amenorrhea and diabetes insipidus.

    Science.gov (United States)

    Georgopoulos, N A; Markou, K B; Pappas, A P; Protonatariou, A; Vagenakis, G A; Sykiotis, G P; Dimopoulos, P A; Tzingounis, V A

    2001-12-01

    Hypothalamic amenorrhea is a treatable cause of infertility. Our patient was presented with secondary amenorrhea and diabetes insipidus. Cortisol and prolactin responded normally to a combined insulin tolerance test (ITT) and thyrotropin-releasing hormone (TRH) challenge, while thyroid-stimulating hormone (TSH) response to TRH was diminished, and no response of growth hormone to ITT was detected. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels increased following gonadotropin-releasing hormone (GnRH) challenge. No response of LH to clomiphene citrate challenge was detected. Magnetic resonance imaging findings demonstrated a midline mass occupying the inferior hypothalamus, with posterior lobe not visible and thickened pituitary stalk. Ovulation induction was carried out first with combined human menopausal gonadotropins (hMG/LH/FSH) (150 IU/day) and afterwards with pulsatile GnRH (150 ng/kg/pulse). Ovulation was achieved with both pulsatile GnRH and combine gonadotropin therapy. Slightly better results were achieved with the pulsatile GnRH treatment.

  6. Receptors and effects of gut hormones in three osteoblastic cell lines

    Directory of Open Access Journals (Sweden)

    Wilson Peter JM

    2011-07-01

    Full Text Available Abstract Background In recent years the interest on the relationship of gut hormones to bone processes has increased and represents one of the most interesting aspects in skeletal research. The proportion of bone mass to soft tissue is a relationship that seems to be controlled by delicate and subtle regulations that imply "cross-talks" between the nutrient intake and tissues like fat. Thus, recognition of the mechanisms that integrate a gastrointestinal-fat-bone axis and its application to several aspects of human health is vital for improving treatments related to bone diseases. This work analysed the effects of gut hormones in cell cultures of three osteoblastic cell lines which represent different stages in osteoblastic development. Also, this is the first time that there is a report on the direct effects of glucagon-like peptide 2, and obestatin on osteoblast-like cells. Methods mRNA expression levels of five gut hormone receptors (glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide 1 [GLP-1], glucagon-like peptide 2 [GLP-2], ghrelin [GHR] and obestatin [OB] were analysed in three osteoblastic cell lines (Saos-2, TE-85 and MG-63 showing different stages of osteoblast development using reverse transcription and real time polymerase chain reaction. The responses to the gut peptides were studied using assays for cell viability, and biochemical bone markers: alkaline phosphatase (ALP, procollagen type 1 amino-terminal propeptides (P1NP, and osteocalcin production. Results The gut hormone receptor mRNA displayed the highest levels for GIP in Saos-2 and the lowest levels in MG-63, whereas GHR and GPR39 (the putative obestatin receptor expression was higher in TE-85 and MG-63 and lower in Saos-2. GLP-1 and GLP-2 were expressed only in MG-63 and TE-85. Treatment of gut hormones to cell lines showed differential responses: higher levels in cell viability in Saos-2 after GIP, in TE-85 and MG-63 after GLP-1, GLP-2, ghrelin and

  7. Solubilization and molecular size of atrial natriuretic hormone (ANH) receptors from rabbit aorta, renal cortex and adrenal

    International Nuclear Information System (INIS)

    Budzik, G.P.; Bush, E.N.; Holleman, W.H.

    1986-01-01

    ANH(1-28) is presumed to regulate blood pressure and fluid balance via membrane receptors coupled to particulate guanylate cyclase. ANH receptors were solubilized from rabbit aorta, renal cortex and adrenal, primary ANH targets. Plasma membranes extracted with 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate(CHAPS) yield solubilized receptors with high affinity binding of 125 I-Tyr 28 -ANH. Degradation of hormone was minimized with a broad spectrum of protease inhibitors. 125 I-ANH binding reached maximum by 1 hr at 0 0 C and was stable for at least an additional 2 hrs. Bound was separated from free ligand by HPLC gel filtration on TSK-3000SW in PBS/CHAPS. Bound hormone eluted at a MW of ∼ 200KD in each tissue preparation and was displaced by unlabelled ANH. The concentration of solubilized binding sites was proportional to densities in intact plasma membranes, i.e., adrenal > renal > aorta. Following separation of free hormone, 125 I-ANH-receptors complexes were coupled using bifunctional crosslinking reagents. SDS-PAGE analysis and autoradiography indicated a major labelled band at ∼ 150KD in each tissue preparation. The mobility of this labelled band was not sensitive to reduction before SDS-PAGE. Although these results suggest that solubilized ANH receptors from primary target tissues are very similar, microheterogeneity affecting binding affinity or signal transduction cannot as yet be excluded

  8. Requirement of tyrosine residues 333 and 338 of the growth hormone (GH) receptor for selected GH-stimulated function

    DEFF Research Database (Denmark)

    Lobie, P E; Allevato, G; Norstedt, G

    1995-01-01

    We have examined the involvement of tyrosine residues 333 and 338 of the growth hormone (GH) receptor in the cellular response to GH. Stable Chinese hamster ovary (CHO) cell clones expressing a receptor with tyrosine residues at position 333 and 338 of the receptor substituted for phenylalanine (...

  9. Preparation of slowly released male sex hormone drug by radiation polymerization technique and its evaluation in vivo

    International Nuclear Information System (INIS)

    Liu Rueizhi; Lei Shaoqiong; Li Ximing

    1992-01-01

    The radiation polymerization technique was used for immobilization testosterone propionate into crosslinked network of poly hydroxyethyl methacrylate to prepare slowly released male sex hormone drug which is used for testicular prosthesis. The testicular prosthesis was transplanted into the scrotum of male rabbit whose testes was excised 2 months before the transplantation. Then the level of male sex hormone in serum was measured by radioimmunoassay once a week after transplantation. The results of measurement in a period of 6 months were shown that the testicular prosthesis has a stable release of male sex hormone. The testosterone level in serum of the castrated male rabbits rises markedly and finally stabilizes at the level of 429 ± 36 ng/100 ml after transplantation. Macroscopic examination of biopsies taken from the tissues around the testicular prosthesis showed that tissue compatibility was revealed well

  10. Action of specific thyroid hormone receptor α(1) and β(1) antagonists in the central and peripheral regulation of thyroid hormone metabolism in the rat.

    Science.gov (United States)

    van Beeren, Hermina C; Kwakkel, Joan; Ackermans, Mariëtte T; Wiersinga, Wilmar M; Fliers, Eric; Boelen, Anita

    2012-12-01

    The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) α(1) and β(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TRα(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TRα(1) or TRβ(1) regulated genes in central and peripheral thyroid hormone metabolism. Three groups of male rats received either Amio, Dron, or vehicle by daily intragastric administration for 2 weeks. We assessed the effects of treatment on triiodothyronine (T(3)) and thyroxine (T(4)) plasma and tissue concentrations, deiodinase type 1, 2, and 3 mRNA expressions and activities, and thyroid hormone transporters monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10), and organic anion transporter 1C1 (OATP1C1). Amio treatment decreased serum T(3), while serum T(4) and thyrotropin (TSH) increased compared to Dron-treated and control rats. At the central level of the hypothalamus-pituitary-thyroid axis, Amio treatment decreased hypothalamic thyrotropin releasing hormone (TRH) expression, while increasing pituitary TSHβ and MCT10 mRNA expression. Amio decreased the pituitary D2 activity. By contrast, Dron treatment resulted in decreased hypothalamic TRH mRNA expression only. Upon Amio treatment, liver T(3) concentration decreased substantially compared to Dron and control rats (50%, p<0.01), but liver T(4) concentration was unaffected. In addition, liver D1, mRNA, and activity decreased, while the D3 activity and mRNA increased. Liver MCT8, MCT10, and OATP1C1 mRNA expression were similar between groups. Our results suggest an important role for TRα1 in the regulation of hypothalamic TRH mRNA expression, whereas TRβ plays a dominant role in pituitary and liver thyroid

  11. Role of cardiac volume receptors in the control of ADH release during acute simulated weightlessness in man

    Science.gov (United States)

    Convertino, V. A.; Benjamin, B. A.; Keil, L. C.; Sandler, H.

    1984-01-01

    Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes, designed to induce central blood volume shifts in ten cardiac and one heart-lung transplant recipients, to assess the contribution of cardiac volume receptors in the control of ADH release during the initial acute phase of exposure to weightlessness. Each subject underwent 15 min of a sitting-control period (C) followed by 30 min of 6 deg headdown tilt (T) and 30 min of resumed sitting (S). Venous blood samples and cardiac dimensions were taken at 0 and 15 min of C; 5, 15, and 30 min of T; and 5, 15, and 30 min of S. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Heart rate and blood pressure were recorded every two min. Plasma osmolality was not altered by posture changes. Mean left ventricular end-diastolic volume increased (P less than 0.05) from 90 ml in C to 106 ml in T and returned to 87 ml in S. Plasma ADH was reduced by 20 percent (P less than 0.05) with T, and returned to control levels with S. These responses were similar in six normal cardiac-innervated control subjects. These data may suggest that cardiac volume receptors are not the primary mechanism for the control of ADH release during acute central volume shifts in man.

  12. Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital

    International Nuclear Information System (INIS)

    Schraplau, Anne; Schewe, Bettina; Neuschäfer-Rube, Frank; Ringel, Sebastian; Neuber, Corinna; Kleuser, Burkhard; Püschel, Gerhard P.

    2015-01-01

    Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR

  13. Development of a radioimmunoassay for circulating levels of gonadotropin releasing hormone

    International Nuclear Information System (INIS)

    Moodbidri, S.B.; Joshi, L.R.; Sheth, A.R.; Rao, S.S.

    1976-01-01

    A specific and sensitive radioimmunoassay system has been developed for measuring gonadotropin releasing hormone (GnRH) in unextracted human serum. Circulating levels of GnRH, LH and FSH were determined in 37 serum samples obtained from twenty normal healthy women on different days of the menstrual cycle. GnRH and LH but not FSH exhibited similar patterns during the menstrual cycle. 125 I-labelled GnRH was used in the RIA system. (author)

  14. Inhibition of rat pituitary growth hormone (GH) release by subclinical levels of lead

    International Nuclear Information System (INIS)

    Camoratto, A.M.; White, L.M.; Lau, Y.S.; Moriarty, C.M.

    1990-01-01

    Lead toxicity has been associated with short stature in children. Since growth hormone is a major regulator of growth, the effects of chronic exposure to subclinical lead levels on pituitary function were assessed. Timed pregnant rats were given 125 ppm lead (as lead nitrate) in their drinking water beginning on day 5 of gestation. After weaning, pups were continued on lead until sacrifice at 7 weeks of age. The average blood lead level at this time was 18.9 ug/dl (range 13.7-27.8). On the day of sacrifice the pituitary was removed, hemisected and incubated with vehicle or 40 nM hGRH (human growth hormone releasing hormone). Pituitaries from chronically lead-treated pups were 64% less responsive to GRH than controls. In contrast, no difference in responsiveness was observed in pituitaries from the dams. The specific binding of GRH was also examined. Control animals showed a dose-dependent displacement of 125I-GRH by unlabeled ligand (10-1000 nM). In the pituitaries of lead-treated pups binding of labeled ligand was markedly reduced by unlabeled GRH (less than 100 nM). Chronic exposure to lead had no effect on serum GH or prolactin levels or on pituitary content of GH. These data suggest that one mechanism by which lead can affect growth is by inhibition of GH release

  15. Gonadotropin-releasing hormone receptor (Gnrhr gene knock out: Normal growth and development of sensory, motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice.

    Directory of Open Access Journals (Sweden)

    Ellen R Busby

    Full Text Available Gonadotropin-releasing hormone (GnRH is important in the control of reproduction, but its actions in non-reproductive processes are less well known. In this study we examined the effect of disrupting the GnRH receptor in mice to determine if growth, metabolism or behaviors that are not associated with reproduction were affected. To minimize the effects of other hormones such as FSH, LH and sex steroids, the neonatal-prepubertal period of 2 to 28 days of age was selected. The study shows that regardless of sex or phenotype in the Gnrhr gene knockout line, there was no significant difference in the daily development of motor control, sensory detection or spatial orientation among the wildtype, heterozygous or null mice. This included a series of behavioral tests for touch, vision, hearing, spatial orientation, locomotory behavior and muscle strength. Neither the daily body weight nor the final weight on day 28 of the kidney, liver and thymus relative to body weight varied significantly in any group. However by day 28, metabolic changes in the GnRH null females compared with wildtype females showed a significant reduction in inguinal fat pad weight normalized to body weight; this was accompanied by an increase in glucose compared with wildtype females shown by Student-Newman-Keuls Multiple Comparison test and Student's unpaired t tests. Our studies show that the GnRH-GnRHR system is not essential for growth or motor/sensory/orientation behavior during the first month of life prior to puberty onset. The lack of the GnRH-GnRHR axis, however, did affect females resulting in reduced subcutaneous inguinal fat pad weight and increased glucose with possible insulin resistance; the loss of the normal rise of estradiol at postnatal days 15-28 may account for the altered metabolism in the prepubertal female pups.

  16. Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

    OpenAIRE

    McDonald, Michael P.; Wong, Rosemary; Goldstein, Gregory; Weintraub, Bruce; Cheng, Sheue-yann; Crawley, Jacqueline N.

    1998-01-01

    Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β (TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity...

  17. Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

    Science.gov (United States)

    Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

    1983-10-01

    Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

  18. Pulsatile gonadotrophin releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome

    NARCIS (Netherlands)

    Bayram, N.; van Wely, M.; van der Veen, F.

    2004-01-01

    BACKGROUND: In normal menstrual cycles, gonadotrophin releasing hormone (GnRH) secretion is pulsatile, with intervals of 60-120 minutes in the follicular phase. Treatment with pulsatile GnRH infusion by the intravenous or subcutaneous route using a portable pump has been used successfully in

  19. A neurokinin 3 receptor-selective agonist accelerates pulsatile luteinizing hormone secretion in lactating cattle.

    Science.gov (United States)

    Nakamura, Sho; Wakabayashi, Yoshihiro; Yamamura, Takashi; Ohkura, Satoshi; Matsuyama, Shuichi

    2017-07-01

    Pulsatile gonadotropin-releasing hormone (GnRH) secretion, which is indispensable for follicular development, is suppressed in lactating dairy and beef cattle. Neurokinin B (NKB) neurons in the arcuate nucleus of the hypothalamus are considered to play an essential role in generating the pulsatile mode of GnRH/luteinizing hormone (LH) secretion. The present study aimed to clarify the role of NKB-neurokinin 3 receptor (NK3R) signaling in the pulsatile pattern of GnRH/gonadotropin secretion in postpartum lactating cattle. We examined the effects of the administration of an NK3R-selective agonist, senktide, on gonadotropin secretion in lactating cattle. The lactating cattle, at approximately 7 days postpartum, were intravenously infused with senktide (30 or 300 nmol/min) or vehicle for 24 h. The administration of 30 or 300 nmol/min senktide significantly increased LH pulse frequency compared to in the control group during 0-4 or 20-24 h after infusion, respectively. Moreover, LH and follicle-stimulating hormone levels were gradually increased by 300 nmol/min administration of senktide during the 0-4-h sampling period. Ultrasonography of the ovaries was performed to identify the first postpartum ovulation in senktide-administered lactating cattle. The interval from calving to first postpartum ovulation was significantly shorter in the 300 nmol/min senktide-administered group than in the control group. Taken together, these findings suggest that senktide infusion elicits an increase in LH pulse frequency that may stimulate follicular development and, in turn, induce the first postpartum ovulation in lactating cattle. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. The liver taxis of receptor mediated lactosaminated human growth hormone

    International Nuclear Information System (INIS)

    Chen Zelian; Shi Lin; Li Tongling; Pang Qijie; He Juying; Guan Changtian

    2002-01-01

    Radiography imaging is used to assess liver taxis mechanism of anti-dwarfism drug lactosaminated human growth hormone (L-rhGH). Both L-rhGH and rhGH labelled with 131 I are used to study their biodistribution in animals (including rabbits, cocks and rats). The results show that L-rhGH is of specific hepatic targeting property, and the maximum hepatic concentration rate is 76.8%, which is two times of rhGH. Its hepatic binding is receptor mediated

  1. Role of the new growth hormone-releasing secretagogues in the diagnosis of some hypothalamopituitary pathologies.

    Science.gov (United States)

    Casanueva, F F; Micic, D; Pombo, M; Leal, A; Bokser, L; Zugaza, J L; Dieguez, C

    1996-08-01

    Growth hormone (GH)-releasing hormone (GHRH) and somatostatin have a dominant role in regulating GH secretion. However, results of studies using the new class of GH secretogogues, particularly GHRP-6, indicate that there may also be other, as yet undefined, hypothalamic mechanisms involved. Studies in adults with hypothalamopituitary disconnection (functional pituitary stalk transection), show GHRP-6-mediated GH release to be completely blocked, indicating a main action at the hypothalamic rather than the pituitary level. The synergistic effect of GHRH plus GHRP-6 administration on GH release seen in normal adults (and virtually unaffected by age, obesity, or sex) is also absent in these patients, providing further support for this conclusion. Studies of the effects of GHRP-6 in children with GH deficiency due to perinatal pituitary stalk transection have produced similar findings. It is suggested that the combined GHRH plus GHRH-6 test should be a promising tool for diagnosing GH deficiency states in both children and adults, and may identify a subgroup of patients with GH deficiency caused by interruption of the hypothalamopituitary connection.

  2. The polymorphic insertion of the luteinizing hormone receptor "insLQ" show a negative association to LHR gene expression and to the follicular fluid hormonal profile in human small antral follicles

    DEFF Research Database (Denmark)

    Borgbo, T; Chrudimska, J; Macek, M

    2018-01-01

    (AMHR2) and LHCGR, respectively, were observed for insLQ/insLQ compared to -/insLQ and the -/- genotypes. Moreover, LHCGR and CYP19a1 together with oestradiol and inhibin-B were significantly increased in -/insLQ compared to the -/- genotype. The homozygous insLQ genotype showed strong significant......The luteinizing hormone receptor (LHCGR) has a little studied polymorphic 6 bp insertion (rs4539842/insLQ). This study has evaluated the insLQ polymorphism in relation to potential associations with hormonal characteristics of human small antral follicles (hSAFs). In total, 310 hSAFs were collected...... from 86 women undergoing fertility preservation. Analysis included hormonal profile of 297 follicular fluid (FF) samples and 148 corresponding granulosa cells samples were evaluated by qPCR for selected genes. Significantly reduced and non-detectable mRNA levels of anti-Müllerian hormone receptor II...

  3. Dopamine receptors on adrenal chromaffin cells modulate calcium uptake and catecholamine release

    Energy Technology Data Exchange (ETDEWEB)

    Bigornia, L; Suozzo, M; Ryan, K A; Napp, D; Schneider, A S

    1988-10-01

    The presence of dopamine-containing cells in sympathetic ganglia, i.e., small, intensely fluorescent cells, has been known for some time. However, the role of dopamine as a peripheral neurotransmitter and its mechanism of action are not well understood. Previous studies have demonstrated the presence of D2 dopamine receptors on the surface of bovine adrenal chromaffin cells using radioligand binding methods and dopamine receptor inhibition of catecholamine release from perfused adrenal glands. In the present study, we provide evidence confirming a role of dopamine receptors as inhibitory modulators of adrenal catecholamine release from bovine chromaffin cell cultures and further show that the mechanism of modulation involves inhibition of stimulated calcium uptake. Apomorphine gave a dose-dependent inhibition (IC50 = 1 microM) of 45Ca2+ uptake stimulated by either nicotine (10 microM) or membrane depolarization with an elevated K+ level (60 mM). This inhibition was reversed by a series of specific (including stereospecific) dopamine receptor antagonists: haloperidol, spiperone, sulpiride, and (+)-butaclamol, but not (-)-butaclamol. In addition, the calcium channel agonist Bay K 8644 was used to stimulate uptake of 45Ca2+ into chromaffin cells, and this uptake was also inhibited by the dopamine receptor agonist apomorphine. The combined results suggest that dopamine receptors on adrenal chromaffin cells alter Ca2+ channel conductance, which, in turn, modulates catecholamine release.

  4. Radioimmunoassay for luteinizing hormone releasing hormone in plasma

    International Nuclear Information System (INIS)

    Saito, Shiro; Musa, Kimitaka; Oshima, Ichiyo; Yamamoto, Suzuyo; Funato, Toyohiko

    1975-01-01

    A sensitive and specific double antibody radioimmunoassay has been developed capable of measuring LH-RH in extracted human plasma. Thyrotropin releasing hormone, lysine vasopressin and most of LH-RH analogues did not appear to affect the assay. Hypothalamic extract and some of the LH-RH analogues produced displacement curves which were parallel to the curve obtained with the synthetic LH-RH. Sensitivity of the radioimmunoassay was about 3 pg per assay tube. The coefficient of variation of intraassays was 6.4%, while that of interassays was 9.6%. Exogenous LH-RH could be quantitatively extracted by acidic ethanol when varying amounts of synthetic LH-RH were added to the plasma. Immunoreactivity of LH-RH was preserved in plasma for 2 hrs in the cold but was gradually reduced thereafter. The plasma levels of LH-RH were 20 pg/ml or less in normal adults and not detectable in children. Aged males over 60 yr and postmenopausal women showed a tendency to have higher levels of plasma LH-RH. The plasma LH-RH level was significantly higher in midcycle than in the follicular or luteal stages. The disappearance rate of LH-RH from the circulation after intravenous injection could be represented as half-times of 4-6 min. Between 0.2-0.4% of the injected dose was excreted into urine within 1 hr. These results indicate that the determination of LH-RH might be a useful tool for elucidating hypothalamic-pituitary-gonad interactions. (auth.)

  5. Calcium-independent phosphatidylinositol response in gonadotropin-releasing-hormone-stimulated pituitary cells.

    OpenAIRE

    Naor, Z; Molcho, J; Zakut, H; Yavin, E

    1985-01-01

    This paper describes the effect of gonadotropin-releasing hormone (GnRH, gonadoliberin) on phospholipid metabolism in cultured rat pituitary cells. The cells were incubated with [32P]Pi to label endogenous phospholipids (10-60 min) and then stimulated with GnRH for up to 60 min. Cellular phospholipids were separated by two-dimensional t.l.c. and the radioactivity was determined. Phosphatidylinositol (PI), a minor constituent of cellular phospholipids (7.7%), was the major labelled phospholipi...

  6. Defective membrane expression of human growth hormone (GH) receptor causes Laron-type GH insensitivity syndrome.

    Science.gov (United States)

    Duquesnoy, P; Sobrier, M L; Amselem, S; Goossens, M

    1991-01-01

    Mutations in the growth hormone receptor (GHR) gene can cause growth hormone (GH) resistance. Given the sequence homology between the extracellular domain of the GHR and a soluble GH-binding protein (GH-BP), it is remarkable that GH-BP binding activity is absent from the serum of patients with Laron-type GH insensitivity, a hereditary form of severe dwarfism. We have previously identified a mutation within the extracellular domain of this receptor, replacing phenylalanine by serine at position 96 of the mature protein, in a patient with Laron syndrome. We have now investigated the effect of this Phe----Ser substitution on hormone binding activity by expressing the total human GHR cDNA and mutant form in eukaryotic cells. The wild-type protein expressed was able to bind GH but no plasma membrane binding was detectable on cells transfected with the mutant cDNA; this was also the case of cells transfected with a Phe96----Ala mutant cDNA, suggesting that the lack of binding activity is not due to a posttranslational modification of serine. Examination of the variant proteins in subcellular fractions revealed the presence of specific GH binding activity in the lysosomal fraction, whereas immunofluorescence studies located mutant proteins in the cytosol. Our findings suggest that these mutant GHRs fail to follow the correct intracellular transport pathway and underline the potential importance of this phenylalanine residue, which is conserved among the GH, prolactin, and erythropoietin receptors that belong to the same cytokine receptor superfamily. Images PMID:1719554

  7. Serotonin receptor B may lock the gate of PTTH release/synthesis in the Chinese silk moth, Antheraea pernyi; a diapause initiation/maintenance mechanism?

    Directory of Open Access Journals (Sweden)

    Qiushi Wang

    Full Text Available The release of prothoracicotropic hormone, PTTH, or its blockade is the major endocrine switch regulating the developmental channel either to metamorphosis or to pupal diapause in the Chinese silk moth, Antheraea pernyi. We have cloned cDNAs encoding two types of serotonin receptors (5HTRA and B. 5HTRA-, and 5HTRB-like immunohistochemical reactivities (-ir were colocalized with PTTH-ir in two pairs of neurosecretory cells at the dorsolateral region of the protocerebrum (DL. Therefore, the causal involvement of these receptors was suspected in PTTH release/synthesis. The level of mRNA(5HTRB responded to 10 cycles of long-day activation, falling to 40% of the original level before activation, while that of 5HTRA was not affected by long-day activation. Under LD 16:8 and 12:12, the injection of dsRNA(5HTRB resulted in early diapause termination, whereas that of dsRNA(5HTRA did not affect the rate of diapause termination. The injection of dsRNA(5HTRB induced PTTH accumulation, indicating that 5HTRB binding suppresses PTTH synthesis also. This conclusion was supported pharmacologically; the injection of luzindole, a melatonin receptor antagonist, plus 5th inhibited photoperiodic activation under LD 16:8, while that of 5,7-DHT, induced emergence in a dose dependent fashion under LD 12:12. The results suggest that 5HTRB may lock the PTTH release/synthesis, maintaining diapause. This could also work as diapause induction mechanism.

  8. Composition of cross-linked 125I-follitropin-receptor complexes

    Energy Technology Data Exchange (ETDEWEB)

    Shin, J.; Ji, T.H.

    1985-10-15

    Both of the alpha and beta subunits of intact human follitropin (FSH) were radioiodinated with SVI-sodium iodide and chloramine-T and could be resolved on sodium dodecyl sulfate-polyacrylamide gels. Radioiodinated FSH was affinity-cross-linked with a cleavable (nondisulfide) homobifunctional reagent to its membrane receptor on the porcine granulosa cell surface as well as to a Triton X-100-solubilized form of the receptor. Cross-linked samples revealed three additional bands of slower electrophoretic mobility, corresponding to 65, 83, and 117 kDa, in addition to the hormone bands. The hormone alpha beta dimer band corresponded to 43 kDa. Formation of the three bands requires the SVI-hormone to bind specifically to the receptor with subsequent cross-linking. Binding was prevented by an excess of the native hormone but not by other hormones. A monofunctional analog of the cross-linking reagent failed to produce the three bands. Reagent concentration-dependent cross-linking revealed that their formation was sequential; smaller complexes formed first and then larger ones. When gels of cross-linked complexes were treated to cleave covalent cross-links and then electrophoresed in a second dimension, 18-, 22-, and 34-kDa components were released, in addition to the alpha and beta subunits of the hormone.

  9. Discrepancy between molecular structure and ligand selectivity of a testicular follicle-stimulating hormone receptor of the African catfish (Clarias gariepinus)

    NARCIS (Netherlands)

    Bogerd, J.; Blomenröhr, M.; Andersson, E.; van der Putten, H.; Tensen, C.P.; Vischer, H F; Granneman, Joke C M; Janssen-Dommerholt, C; Goos, H.J.; Schulz, Rüdiger W

    A putative FSH receptor (FSH-R) cDNA was cloned from African catfish testis. Alignment of the deduced amino acid sequence with other (putative) glycoprotein hormone receptors and analysis of the African catfish gene indicated that the cloned receptor belonged to the FSH receptor subfamily. Catfish

  10. Premenstrual Exacerbation of Life-Threatening Asthma: Effect of Gonadotrophin Releasing Hormone Analogue Therapy

    Directory of Open Access Journals (Sweden)

    Alun L Edwards

    1996-01-01

    Full Text Available Variability in the severity of asthma during various phases of the menstrual cycle has been frequently suspected. However, the hormonal changes that might affect mediators of bronchospasm have yet to be elucidated. The case of a 41-year-old woman suffering from longstanding asthma with life-threatening exacerbations is reported. The patient was treated with buserelin, a gonadotropin releasing hormone (GnRH analogue, which created a temporary chemical menopause and thus permitted diagnosis of a premenstrual exacerbation of asthma and offered insight into potential therapy. GnRH analogues may therefore be of value in assessing women with severe asthma suspected to vary with the menstrual cycle. The addition of estrogens and progestins at the same time as treatment with GnRH analogue may be of value in determining the role of these hormones in the pathogenesis of menstrually related exacerbations of asthma.

  11. Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

    Science.gov (United States)

    Acquas, E; Di Chiara, G

    1999-10-27

    The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

  12. contribution of growth hormone-releasing hormone and

    African Journals Online (AJOL)

    The strategy used was to stimulate GH secretion in 8 young ... treatment with two oral doses of 50 mg atenolol (to inhibit .... had normal baseline thyroid-stimulating hormone (TSH) ..... production rate of 14% per decade has been documented.'".

  13. Triiodothyronine affects the alternative splicing of thyroid hormone receptor alpha mRNA

    NARCIS (Netherlands)

    Timmer, D. C.; Bakker, O.; Wiersinga, W. M.

    2003-01-01

    The c-erbAalpha gene encodes two thyroid hormone receptors, TRalpha1 and TRalpha2, that arise from alternative splicing of the TRalpha pre-mRNA. TRalpha2 is not able to bind triiodothyronine (T-3) and acts as a weak antagonist of TRs. It has been suggested that the balance of TRalpha1 to TRalpha2 is

  14. Screening of hormone-like activities in bottled waters available in Southern Spain using receptor-specific bioassays.

    Science.gov (United States)

    Real, Macarena; Molina-Molina, José-Manuel; Jiménez-Díaz, Inmaculada; Arrebola, Juan Pedro; Sáenz, José-María; Fernández, Mariana F; Olea, Nicolás

    2015-01-01

    Bottled water consumption is a putative source of human exposure to endocrine-disrupting chemicals (EDCs). Research has been conducted on the presence of chemicals with estrogen-like activity in bottled waters and on their estrogenicity, but few data are available on the presence of hormonal activities associated with other nuclear receptors (NRs). The aim of this study was to determine the presence of endocrine activities dependent on the activation of human estrogen receptor alpha (hERa) and/or androgen receptor (hAR) in water in glass or plastic bottles sold to consumers in Southern Spain. Hormone-like activities were evaluated in 29 bottled waters using receptor-specific bioassays based on reporter gene expression in PALM cells [(anti-)androgenicity] and cell proliferation assessment in MCF-7 cells [(anti-)estrogenicity] after optimized solid phase extraction (SPE). All of the water samples analyzed showed hormonal activity. This was estrogenic in 79.3% and anti-estrogenic in 37.9% of samples and was androgenic in 27.5% and anti-androgenic in 41.3%, with mean concentrations per liter of 0.113pM 17β-estradiol (E2) equivalent units (E2Eq), 11.01pM anti-estrogen (ICI 182780) equivalent units (ICI 182780Eq), 0.33pM methyltrienolone (R1881) equivalent units (R1881Eq), and 0.18nM procymidone equivalent units (ProcEq). Bottled water consumption contributes to EDC exposure. Hormone-like activities observed in waters from both plastic and glass bottles suggest that plastic packaging is not the sole source of contamination and that the source of the water and bottling process may play a role, among other factors. Further research is warranted on the cumulative effects of long-term exposure to low doses of EDCs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. [Clinical relevance of ESR1 circulating mutations detection in hormone receptor positive metastatic breast cancer].

    Science.gov (United States)

    Clatot, Florian; Perdrix, Anne; Sefrioui, David; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric

    2018-01-01

    If hormone therapy is a key treatment for hormone receptor positive advanced breast cancers, secondary resistance occurs as a rule. Recently, acquired alterations of the ESR1 gene have been identified as a mechanism of resistance on aromatase inhibitor (AI) treatment. The selective pressure by AI exposure during the metastatic setting triggers the emergence of ESR1 activating mutations. In that context, the "liquid biopsy" concept has been used to detect this molecular resistance before progression. Thus, the ESR1 circulating mutation detection will soon be used in daily practice to help monitoring patients on AI treatment and provide an early change for specific therapies that still have to be determined in prospective clinical trials. This review will present the acquired ESR1 mutations, as well as the methods used for their detection in blood and the potential clinical impact of this approach for hormone receptor positive breast cancer management. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  16. Increased circulating interleukin-8 in patients with resistance to thyroid hormone receptor alpha

    NARCIS (Netherlands)

    van der Spek, Anne H.; Surovtseva, Olga V.; Aan, Saskia; Tool, Anton T. J.; van de Geer, Annemarie; Demir, Korcan; van Gucht, Anja L. M.; van Trotsenburg, A. S. Paul; van den Berg, Timo K.; Fliers, Eric; Boelen, Anita

    2017-01-01

    Innate immune cells have recently been identified as novel thyroid hormone (TH) target cells in which intracellular TH levels appear to play an important functional role. The possible involvement of TH receptor alpha (TR alpha), which is the predominant TR in these cells, has not been studied to

  17. Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital.

    Science.gov (United States)

    Schraplau, Anne; Schewe, Bettina; Neuschäfer-Rube, Frank; Ringel, Sebastian; Neuber, Corinna; Kleuser, Burkhard; Püschel, Gerhard P

    2015-02-03

    Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR. Copyright © 2014. Published by Elsevier Ireland Ltd.

  18. Paraventricular nucleus of the human hypothalamus in primary hypertension: Activation of corticotropin-releasing hormone neurons

    NARCIS (Netherlands)

    Goncharuk, Valeri D.; van Heerikhuize, Joop; Swaab, Dick F.; Buijs, Ruud M.

    2002-01-01

    By using quantitative immunohistochemical and in situ hybridization techniques, we studied corticotropin-releasing hormone (CRH)-producing neurons of the hypothalamic paraventricular nucleus (PVN) in patients who suffered from primary hypertension and died due to acute cardiac failure. The control

  19. Identification of phenylalanine 346 in the rat growth hormone receptor as being critical for ligand-mediated internalization and down-regulation

    DEFF Research Database (Denmark)

    Allevato, G; Billestrup, N; Goujon, L

    1995-01-01

    The functional significance of growth hormone (GH) receptor (GHR) internalization is unknown; therefore, we have analyzed domains and individual amino acids in the cytoplasmic region of the rat GHR required for ligand-mediated receptor internalization, receptor down-regulation, and transcriptiona...

  20. Levels of human and rat hypothalamic growth hormone-releasing factor as determined by specific radioimmunoassay systems

    International Nuclear Information System (INIS)

    Audhya, T.; Manzione, M.M.; Nakane, T.; Kanie, N.; Passarelli, J.; Russo, M.; Hollander, C.S.

    1985-01-01

    Polyclonal antibodies to synthetic human pancreatic growth hormone-releasing factor [hpGRF(1-44)NH 2 ] and rat hypothalamic growth hormone-releasing factor [rhGRF(1-43)OH] were produced in rabbits. A subsequent booster injection by the conventional intramuscular route resulted in high-titer antibodies, which at a 1:20,000 dilution were used to develop highly sensitive and specific radioimmunoassays for these peptides. The antibody to hpGRF(1-44)NH 2 is directed against the COOH-terminal region of the molecule, as shown by its cross reactivity with various hpGRF analogues. Serial dilutions of human and rat hypothalamic extracts demonstrated parallelism with the corresponding species-specific standard and 125 I-labeled tracer. There was no cross reactivity with other neuropeptides, gastrointestinal peptides, or hypothalamic extracts of other species. Age-related changes in hypothalamic GRF content were present in rats, with a gradual increase from 2 to 16 weeks and a correlation between increasing body weight and GRF content. These radioimmunoassays will serve as important tools for understanding the regulation of growth hormone secretion in both human and rat

  1. Glycine receptors support excitatory neurotransmitter release in developing mouse visual cortex

    Science.gov (United States)

    Kunz, Portia A; Burette, Alain C; Weinberg, Richard J; Philpot, Benjamin D

    2012-01-01

    Glycine receptors (GlyRs) are found in most areas of the brain, and their dysfunction can cause severe neurological disorders. While traditionally thought of as inhibitory receptors, presynaptic-acting GlyRs (preGlyRs) can also facilitate glutamate release under certain circumstances, although the underlying molecular mechanisms are unknown. In the current study, we sought to better understand the role of GlyRs in the facilitation of excitatory neurotransmitter release in mouse visual cortex. Using whole-cell recordings, we found that preGlyRs facilitate glutamate release in developing, but not adult, visual cortex. The glycinergic enhancement of neurotransmitter release in early development depends on the high intracellular to extracellular Cl− gradient maintained by the Na+–K+–2Cl− cotransporter and requires Ca2+ entry through voltage-gated Ca2+ channels. The glycine transporter 1, localized to glial cells, regulates extracellular glycine concentration and the activation of these preGlyRs. Our findings demonstrate a developmentally regulated mechanism for controlling excitatory neurotransmitter release in the neocortex. PMID:22988142

  2. Adenosine receptors and muscarinic receptors cooperate in acetylcholine release modulation in the neuromuscular synapse.

    Science.gov (United States)

    Santafe, M M; Priego, M; Obis, T; Garcia, N; Tomàs, M; Lanuza, M A; Tomàs, J

    2015-07-01

    Adenosine receptors (ARs) are present in the motor terminals at the mouse neuromuscular junction. ARs and the presynaptic muscarinic acetylcholine receptors (mAChRs) share the functional control of the neuromuscular junction. We analysed their mutual interaction in transmitter release modulation. In electrophysiological experiments with unaltered synaptic transmission (muscles paralysed by blocking the voltage-dependent sodium channel of the muscle cells with μ-conotoxin GIIIB), we found that: (i) a collaborative action between different AR subtypes reduced synaptic depression at a moderate activity level (40 Hz); (ii) at high activity levels (100 Hz), endogenous adenosine production in the synaptic cleft was sufficient to reduce depression through A1 -type receptors (A1 Rs) and A2 A-type receptors (A2 A Rs); (iii) when the non-metabolizable 2-chloroadenosine (CADO) agonist was used, both the quantal content and depression were reduced; (iv) the protective effect of CADO on depression was mediated by A1 Rs, whereas A2 A Rs seemed to modulate A1 Rs; (v) ARs and mAChRs absolutely depended upon each other for the modulation of evoked and spontaneous acetylcholine release in basal conditions and in experimental conditions with CADO stimulation; (vi) the purinergic and muscarinic mechanisms cooperated in the control of depression by sharing a common pathway although the purinergic control was more powerful than the muscarinic control; and (vii) the imbalance of the ARs created by using subtype-selective and non-selective inhibitory and stimulatory agents uncoupled protein kinase C from evoked transmitter release. In summary, ARs (A1 Rs, A2 A Rs) and mAChRs (M1 , M2 ) cooperated in the control of activity-dependent synaptic depression and may share a common protein kinase C pathway. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  3. Identification of a novel modulator of thyroid hormone receptor-mediated action.

    Directory of Open Access Journals (Sweden)

    Bernhard G Baumgartner

    Full Text Available BACKGROUND: Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. METHODOLOGY/PRINCIPAL FINDINGS: We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TR(alpha1. This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR( alpha1 and to T(3-responsive promoters, as shown by ChIP assays. T(3 stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related. CONCLUSIONS/SIGNIFICANCE: Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease.

  4. Biosynthesis and release of thyrotropin-releasing hormone immunoreactivity in rat pancreatic islets in organ culture. Effects of age, glucose, and streptozotocin

    DEFF Research Database (Denmark)

    Dolva, L O; Welinder, B S; Hanssen, K F

    1983-01-01

    Thyrotropin-releasing hormone immunoreactivity (TRH-IR) was measured in isolated islets and in medium from rat pancreatic islets maintained in organ culture. TRH-IR in methanol extracts of both islets and culture medium was eluted in the same position as synthetic TRH by ion-exchange and gel...... chromatography and exhibited dilution curves parallel with synthetic TRH in radioimmunoassay. [3H]Histidine was incorporated into a component that reacted with TRH antiserum and had the same retention time as synthetic TRH on reversed-phase high-performance liquid chromatography. A continuous release of TRH...

  5. Corticotropin releasing hormone and imaging, rethinking the stress axis

    International Nuclear Information System (INIS)

    Contoreggi, Carlo

    2015-01-01

    The stress system provides integration of both neurochemical and somatic physiologic functions within organisms as an adaptive mechanism to changing environmental conditions throughout evolution. In mammals and primates the complexity and sophistication of these systems have surpassed other species in triaging neurochemical and physiologic signaling to maximize chances of survival. Corticotropin releasing hormone (CRH) and its related peptides and receptors have been identified over the last three decades and are fundamental molecular initiators of the stress response. They are crucial in the top down regulatory cascade over a myriad of neurochemical, neuroendocrine and sympathetic nervous system events. From neuroscience, we've seen that stress activation impacts behavior, endocrine and somatic physiology and influences neurochemical events that one can capture in real time with current imaging technologies. To delineate these effects one can demonstrate how the CRH neuronal networks infiltrate critical cognitive, emotive and autonomic regions of the central nervous system (CNS) with somatic effects. Abundant preclinical and clinical studies show inter-regulatory actions of CRH with multiple neurotransmitters/peptides. Stress, both acute and chronic has epigenetic effects which magnify genetic susceptibilities to alter neurochemistry; stress system activation can add critical variables in design and interpretation of basic and clinical neuroscience and related research. This review will attempt to provide an overview of the spectrum of known functions and speculative actions of CRH and stress responses in light of imaging technology and its interpretation. Metabolic and neuroreceptor positron emission/single photon tomography (PET/SPECT), functional magnetic resonance imaging (fMRI), anatomic MRI, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (pMRS) are technologies that can delineate basic mechanisms of neurophysiology and

  6. Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats.

    Science.gov (United States)

    Bokser, L; Szende, B; Schally, A V

    1990-06-01

    The possible protective effect of an agonist of luteinising hormone-releasing hormone (LH-RH) against the ovarian damage caused by cyclophosphamide was investigated in rats. D-Trp6-LH-RH microcapsules were injected once a month for 3 months, in a dose calculated to release 25 micrograms day-1. Control animals received the injection vehicle. Sixty days after the first injection of microcapsules, cyclophosphamide was given at a loading dose of 50 mg kg-1 followed by 5 mg kg-1 day-1 for 30 days, while the treatment with D-Trp6-LH-RH was continued. When the ovaries were examined 3 months and 5 months after discontinuation of treatment, a significant reduction in the total number of follicles (P less than 0.01) was found in non-pretreated animals given cyclophosphamide. This reduction affected mainly follicles larger than 100 microns. An irreversible disintegration and destruction of granulosa cells was also observed in this group. In animals pretreated with D-Trp6-LH-RH, administration of cyclophosphamide caused no reduction in the number and diameter of follicles. Thus, the treatment with D-Trp6-LH-RH microcapsules before and during chemotherapy prevented the ovarian injury inflicted by cyclophosphamide. The suppression of gonadal function by LH-RH analogues could be possibly utilised for the protection of the ovaries against damage caused by cytotoxic drugs.

  7. Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

    International Nuclear Information System (INIS)

    Romshe, C.A.; Zipf, W.B.; Miser, A.; Miser, J.; Sotos, J.F.; Newton, W.A.

    1984-01-01

    We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subject's bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response

  8. Putative thyroid hormone receptors in red blood cells of some reptiles.

    Science.gov (United States)

    Wong, C C; Chiu, K W

    1987-06-01

    Putative triiodothyronine (T3) receptors have been detected in the nuclei of red blood cells (RBC) in a number of reptile species. The binding characteristics of T3 receptors in vitro were dissociation constant (Kd) 9.1 to 28.58, 36.8 and 40, and 11.12 and 11.36 pM, and binding capacity (Bmax) 0.12 to 0.37, 0.17 and 0.24, and 0.19 and 0.28 fmol per million cells in the rat snake (Ptyas korros), soft-shelled turtle (Trionyx sinensis), and tokay gecko (Gekko gecko), respectively. These data were obtained in all species using in vitro incubation of whole cell according to current receptor studies on living cells. With modified technique in subsequent experiments, these values of the binding characteristics were seemingly low. The discrepancy was ascribed to the assessment of "free" fraction of hormone which would be used in subsequent calculation.

  9. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

    NARCIS (Netherlands)

    Youssef, Mohamed A. F. M.; van der Veen, Fulco; Al-Inany, Hesham G.; Griesinger, Georg; Mochtar, Monique H.; Aboulfoutouh, Ismail; Khattab, Sherif M.; van Wely, Madelon

    2011-01-01

    Background Gonadotropin-releasing hormone (GnRH) antagonist protocols for pituitary down regulation in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) allow the use of GnRH agonists for triggering final oocyte maturation. Currently, human chorionic gonadotropin (HCG) is

  10. Diverse growth hormone receptor gene mutations in Laron syndrome.

    Science.gov (United States)

    Berg, M A; Argente, J; Chernausek, S; Gracia, R; Guevara-Aguirre, J; Hopp, M; Pérez-Jurado, L; Rosenbloom, A; Toledo, S P; Francke, U

    1993-01-01

    To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), we analyzed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. We amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). We identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71 + 1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, we determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations we identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. We conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. Images Figure 1 Figure 2 PMID:8488849

  11. Aspects of dopamine and acetylcholine release induced by glutamate receptors; Aspectos das liberacoes de dopamina e acetilcolina mediadas por receptores de glutamato

    Energy Technology Data Exchange (ETDEWEB)

    Paes, Paulo Cesar de Arruda

    2002-07-01

    The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

  12. Oxytocin is a cardiovascular hormone

    Directory of Open Access Journals (Sweden)

    Gutkowska J.

    2000-01-01

    Full Text Available Oxytocin (OT, a nonapeptide, was the first hormone to have its biological activities established and chemical structure determined. It was believed that OT is released from hypothalamic nerve terminals of the posterior hypophysis into the circulation where it stimulates uterine contractions during parturition, and milk ejection during lactation. However, equivalent concentrations of OT were found in the male hypophysis, and similar stimuli of OT release were determined for both sexes, suggesting other physiological functions. Indeed, recent studies indicate that OT is involved in cognition, tolerance, adaptation and complex sexual and maternal behaviour, as well as in the regulation of cardiovascular functions. It has long been known that OT induces natriuresis and causes a fall in mean arterial pressure, both after acute and chronic treatment, but the mechanism was not clear. The discovery of the natriuretic family shed new light on this matter. Atrial natriuretic peptide (ANP, a potent natriuretic and vasorelaxant hormone, originally isolated from rat atria, has been found at other sites, including the brain. Blood volume expansion causes ANP release that is believed to be important in the induction of natriuresis and diuresis, which in turn act to reduce the increase in blood volume. Neurohypophysectomy totally abolishes the ANP response to volume expansion. This indicates that one of the major hypophyseal peptides is responsible for ANP release. The role of ANP in OT-induced natriuresis was evaluated, and we hypothesized that the cardio-renal effects of OT are mediated by the release of ANP from the heart. To support this hypothesis, we have demonstrated the presence and synthesis of OT receptors in all heart compartments and the vasculature. The functionality of these receptors has been established by the ability of OT to induce ANP release from perfused heart or atrial slices. Furthermore, we have shown that the heart and large vessels

  13. Crystal structure of the PAC1R extracellular domain unifies a consensus fold for hormone recognition by class B G-protein coupled receptors.

    Directory of Open Access Journals (Sweden)

    Shiva Kumar

    Full Text Available Pituitary adenylate cyclase activating polypeptide (PACAP is a member of the PACAP/glucagon family of peptide hormones, which controls many physiological functions in the immune, nervous, endocrine, and muscular systems. It activates adenylate cyclase by binding to its receptor, PAC1R, a member of class B G-protein coupled receptors (GPCR. Crystal structures of a number of Class B GPCR extracellular domains (ECD bound to their respective peptide hormones have revealed a consensus mechanism of hormone binding. However, the mechanism of how PACAP binds to its receptor remains controversial as an NMR structure of the PAC1R ECD/PACAP complex reveals a different topology of the ECD and a distinct mode of ligand recognition. Here we report a 1.9 Å crystal structure of the PAC1R ECD, which adopts the same fold as commonly observed for other members of Class B GPCR. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor support a model that PAC1R uses the same conserved fold of Class B GPCR ECD for PACAP binding, thus unifying the consensus mechanism of hormone binding for this family of receptors.

  14. Treatment of idiopathic hypogonadotropic hypogonadism in men with luteinizing hormone-releasing hormone: a comparison of treatment with daily injections and with the pulsatile infusion pump.

    Science.gov (United States)

    Shargil, A A

    1987-03-01

    Thirty husbands in childless couples, aged 24 to 35 years, were treated with luteinizing hormone-releasing hormone (LH-RH) for idiopathic hypogonadotropic hypogonadism (IHH) of peripubertal (incomplete) type. They were azoospermic or oligospermic, with less than 1.5 X 10(6)/ml nonmotile spermatozoa. The diagnosis of IHH was based on clinical and laboratory features and testicular biopsy specimen study and was further supported by results of stimulation tests and gonadotropin-releasing hormone (GnRH) test. Two treatment modalities were used: subcutaneous injections of 500 micrograms LH-RH twice daily; and perpetual subcutaneous injection, via portable infusion pump, of 25 ng/kg LH-RH, at 90-minute intervals. Two patients required a short second period of pulsatile treatment to cause a second pregnancy of their spouses. The pump proved to yield better results, compared with intermittent injections, in respect to endocrine responses, spermatogenesis, and fertility capacity. Normal levels of luteinizing hormone and follicle-stimulating hormone were reached in 2 to 3 weeks and normal testosterone levels in 8 to 10 weeks from the start of treatment. Sperm counts rose to greater than 60 X 10(6)/ml viable spermatozoa with less than 15% of abnormal forms in 3 to 5 months, and the wives conceived. Of a total of 18 deliveries of healthy infants, 12 offspring were identified genetically with their fathers. Four women were still pregnant at the conclusion of the study. The pump was well tolerated, without special operational problems to the patients. Pulsatile treatment is therefore recommended in the treatment of well-diagnosed and carefully selected cases of incomplete IHH.

  15. Molecular conformation, receptor binding, and hormone action of natural and synthetic estrogens and antiestrogens.

    Science.gov (United States)

    Duax, W L; Griffin, J F; Weeks, C M; Korach, K S

    1985-01-01

    The X-ray crystallographic structural determinations of synthetic estrogens and antiestrogens provide reliable information on the global minimum energy conformation of these molecules or a local minimum energy conformation that is within 1 or 2 kcal/mole of the global minimum. In favorable cases, state-of-the-art molecular mechanics calculations provide quantitative agreement with X-ray results and information on the relative energy of other local minimum energy conformations not observed crystallographically. Because the conformation of diethylstilbestrol (DES) observed in solvated crystals has an overall conformation and dipole moment more similar to estradiol it is the form more likely to bind to the receptor and produce hormone activity. Either phenol ring of DES can successfully mimic the estradiol A-ring in binding to the receptor. Indenestrol A (INDA) and indenestrol B (INDB) have nearly identical fully extended planar conformations. Either the alpha or gamma rings of these compounds may mimic the A ring of estradiol and compete for the estrogen receptor. Although there are eight distinct ways in which molecules of a racemic mixture of INDA or INDB can bind to the receptor, not all of them may be able to elicit a hormonal response. This may account for the reduced biological activity of the compounds despite their successful competition for receptor binding. The minimum energy conformations of Z-pseudodiethylstilbestrol (ZPD) and E-pseudodiethylstilbestrol (EPD) are bent in a fashion similar to that of indanestrol (INDC). These molecules have good binding affinity suggesting that the receptor does not require a flat molecule. Therefore these conformations would appear to be compatible with receptor binding, but only the Z isomer has an energetically allowed extended conformation that accounts for its observed biological activity relative to DES. PMID:3905370

  16. Growth Hormone-Releasing Peptide 6 Enhances the Healing Process and Improves the Esthetic Outcome of the Wounds

    Directory of Open Access Journals (Sweden)

    Yssel Mendoza Marí

    2016-01-01

    Full Text Available In addition to its cytoprotective effects, growth hormone-releasing peptide 6 (GHRP-6 proved to reduce liver fibrotic induration. CD36 as one of the GHRP-6 receptors appears abundantly represented in cutaneous wounds granulation tissue. The healing response in a scenario of CD36 agonistic stimulation had not been previously investigated. Excisional full-thickness wounds (6 mmØ were created in the dorsum of Wistar rats and topically treated twice a day for 5 days. The universal model of rabbit’s ears hypertrophic scars was implemented and the animals were treated daily for 30 days. Treatments for both species were based on a CMC jelly composition containing GHRP-6 400 μg/mL. Wounds response characterization included closure dynamic, RT-PCR transcriptional profile, histology, and histomorphometric procedures. The rats experiment indicated that GHRP-6 pharmacodynamics involves attenuation of immunoinflammatory mediators, their effector cells, and the reduction of the expression of fibrotic cytokines. Importantly, in the hypertrophic scars rabbit’s model, GHRP-6 intervention dramatically reduced the onset of exuberant scars by activating PPARγ and reducing the expression of fibrogenic cytokines. GHRP-6 showed no effect on the reversion of consolidated lesions. This evidence supports the notion that CD36 is an active and pharmacologically approachable receptor to attenuate wound inflammation and accelerate its closure so as to improve wound esthetic.

  17. Semi-quantitative ultrastructural analysis of the localization and neuropeptide content of gonadotropin releasing hormone nerve terminals in the median eminence throughout the estrous cycle of the rat.

    Science.gov (United States)

    Prevot, V; Dutoit, S; Croix, D; Tramu, G; Beauvillain, J C

    1998-05-01

    The ultrastructural appearance of gonadotropin releasing hormone-immunoreactive elements was studied in the external zone of the median eminence of adult female Wistar rats. On the one hand, the purpose of the study was to determine the distribution of gonadotropin releasing hormone terminals towards the parenchymatous basal lamina at the level of hypothalamo-hypophyseal portal vessels, throughout the estrous cycle. On the other hand, we have semi-quantified the gonadotropin releasing hormone content in nerve terminals or preterminals during this physiological condition. A morphometric study was coupled to a colloidal 15 mn gold postembedding immunocytochemistry procedure. Animals were killed at 09.00 on diestrus II, 0.900, 10.00, 13.00, 17.00 and 18.00 on proestrus and 09.00 on estrus (n = 4-8 rats/group). A preliminary light microscopic study was carried out to identify an antero-posterior part of median eminence strongly immunostained by anti-gonadotropin releasing hormone antibodies but which was, in addition, easily spotted. This last condition was necessary to make a good comparison between each animal. Contacts between gonadotropin releasing hormone nerve terminals and the basal lamina were observed only the day of proestrus. Such contacts, however, were rare and in the great majority of cases, gonadotropin releasing hormone terminals are separated from basal lamina by tanycytic end feet. The morphometric analysis showed no significant variation in average distance between gonadotropin releasing hormone terminals and capillaries throughout the estrous cycle. Consequently, it did not appear that a large neuroglial plasticity exists during the estrous cycle. However, the observation of contacts only on proestrus together with some ultrastructural images evoke the possibility of a slight plasticity. The semi-quantitative results show that the content of gonadotropin releasing hormone in the nerve endings presented two peaks on proestrus: one at 09.00 (23 +/- 5

  18. Cloning and characterization of the adipokinetic hormone receptor from the cockroach Periplaneta americana

    DEFF Research Database (Denmark)

    Hansen, Karina K; Hauser, Frank; Cazzamali, Giuseppe

    2006-01-01

    Cockroaches have long been used as insect models to investigate the actions of biologically active neuropeptides. Here, we describe the cloning and functional expression in Chinese hamster ovary cells of an adipokinetic hormone (AKH) G protein-coupled receptor from the cockroach Periplaneta...... americana. This receptor is only activated by various insect AKHs (we tested eight) and not by a library of 29 other insect or invertebrate neuropeptides and nine biogenic amines. Periplaneta has two intrinsic AKHs, Pea-AKH-1, and Pea-AKH-2. The Periplaneta AKH receptor is activated by low concentrations...... of both Pea-AKH-1 (EC50, 5 x 10(-9)M), and Pea-AKH-2 (EC50, 2 x 10(-9)M). Insects can be subdivided into two evolutionary lineages, holometabola (insects with a complete metamorphosis during development) and hemimetabola (incomplete metamorphosis). This paper describes the first AKH receptor from...

  19. BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus

    OpenAIRE

    Jeanneteau, Freddy D.; Lambert, W. Marcus; Ismaili, Naima; Bath, Kevin G.; Lee, Francis S.; Garabedian, Michael J.; Chao, Moses V.

    2012-01-01

    Regulation of the hypothalamic–pituitary–adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased ...

  20. Characterization of brn1.2 and corticotropin-releasing hormone genes in zebrafish

    OpenAIRE

    Chandrasekar, Gayathri

    2007-01-01

    The zebrafish (Danio rerio), a tropical fresh water fish originally found in the rivers of India and Bangladesh has become a popular vertebrate model system over the last decade. The rapid sequencing of the zebrafish genome together with the latest advances in forward and reverse genetics has made this model organism more fascinating as it can be used to decipher the genetic mechanisms involved in the vertebrate development. Corticotropin-releasing hormone (CRH) regulates t...

  1. Evaluation of in vivo [corrected] biological activity of new agmatine analogs of growth hormone-releasing hormone (GH-RH)

    Science.gov (United States)

    Bokser, L; Zarandi, M; Schally, A V

    1990-01-01

    The effects of agmatine analogs of growth hormone releasing hormone (GH-RH) were compared to GH-RH(1-29)-NH2 after intravenous (iv) and subcutaneous (sc) administration to pentobarbital-anesthetized male rats. After the iv injection, the analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-51); [desNH2-Tyr1,D-Lys12,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-57); [desNH2-Tyr1,Ala15,D-Lys21,Nle27] GH-RH(1-28)Agm (MZ-2-75) and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GH-RH(1-28)Agm (MZ-2-87) showed a potency equivalent to 4.4, 1.9, 1.07 and 1.03 times that of GH-RH (1-29)-NH2, respectively, at 5 min and 5.6, 1.8, 1.9 and 1.8 times higher, respectively, at 15 min. After sc administration, analogs MZ-2-51, MZ-2-57 and MZ-2-75 showed to be 34.3, 14.3 and 10.5 times more potent than the parent hormone at 15 min and 179.1, 88.9 and 45.0 times more active, respectively, at 30 min. In addition, MZ-2-51 had prolonged GH-releasing activity as compared to the standard. We also compared the activity of MZ-2-51 and MZ-2-57 with their homologous L-Arg and D-Arg analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-29)-NH2 (MZ-2-117), [des-NH2Tyr1,D-Lys12, Ala15, Nle27] GH-RH(1-29)NH2 (MZ-2-123) and [desNH2-Tyr1,D-Lys12,Ala15, Nle27,D-Arg29] GH-RH(1-29)NH2 (MZ-2-135) after intramuscular (im) injection. MZ-2-51 induced a somewhat greater GH release than MZ-2-117 at 15 min, both responses being larger than the controls (p less than 0.01) at 15 and 30 min. MZ-2-57, MZ-2-123 and MZ-2-135 given i.m. were able to stimulate GH release only at 15 minutes (p less than 0.05). Animals injected i.m. with MZ-2-51, but not with MZ-2-117, showed GH levels significantly higher than the control group (p less than 0.05) at 60 min. GH-RH(1-29)NH2 had low activity intramuscularly when tested at a dose of 2.5 micrograms. No toxic effects were observed after the iv administration of 1 mg/kg of Agm GH-RH analogs. These results indicate that our Agm analogs are active iv, sc and im and that the substitutions made in these

  2. Prognostic value of sex-hormone receptor expression in non-muscle-invasive bladder cancer.

    Science.gov (United States)

    Nam, Jong Kil; Park, Sung Woo; Lee, Sang Don; Chung, Moon Kee

    2014-09-01

    We investigated sex-hormone receptor expression as predicting factor of recurrence and progression in patients with non-muscle invasive bladder cancer. We retrospectively evaluated tumor specimens from patients treated for transitional cell carcinoma of the bladder at our institution between January 2006 and January 2011. Performing immunohistochemistry using a monoclonal androgen receptor antibody and monoclonal estrogen receptor-beta antibody on paraffin-embedded tissue sections, we assessed the relationship of immunohistochemistry results and prognostic factors such as recurrence and progression. A total of 169 patients with bladder cancer were evaluated in this study. Sixty-threepatients had expressed androgen receptors and 52 patients had estrogen receptor beta. On univariable analysis, androgen receptor expression was significant lower in recurrence rates (p=0.001), and estrogen receptor beta expression was significant higher in progression rates (p=0.004). On multivariable analysis, significant association was found between androgen receptor expression and lower recurrence rates (hazard ratio=0.500; 95% confidence interval, 0.294 to 0.852; p=0.011), but estrogen receptor beta expression was not significantly associated with progression rates. We concluded that the possibility of recurrence was low when the androgen receptor was expressed in the bladder cancer specimen and it could be the predicting factor of the stage, number of tumors, carcinoma in situ lesion and recurrence.

  3. Neurokinin B receptor antagonism decreases luteinising hormone pulse frequency and amplitude and delays puberty onset in the female rat.

    Science.gov (United States)

    Li, S Y; Li, X F; Hu, M H; Shao, B; Poston, L; Lightman, S L; O'Byrne, K T

    2014-08-01

    The neural mechanisms controlling puberty onset remain enigmatic. Humans with loss of function mutations in TAC3 or TACR3, the genes encoding neurokinin B (NKB) or its receptor, neurokinin-3 receptor (NK3R), respectively, present with severe congenital gonadotrophin deficiency and pubertal failure. Animal studies have shown ambiguous actions of NKB-NK3R signalling with respect to controlling puberty onset. The present study aimed to determine the role of endogenous NKB-NK3R signalling in the control of pulsatile luteinising hormone (LH) secretion and the timing of puberty onset, and also whether precocious pubertal onset as a result of an obesogenic diet is similarly regulated by this neuropeptide system. Prepubertal female rats, chronically implanted with i.c.v. cannulae, were administered SB222200, a NK3R antagonist, or artificial cerebrospinal fluid via an osmotic mini-pump for 14 days. SB222200 significantly delayed the onset of vaginal opening and first oestrus (as markers of puberty) compared to controls in both normal and high-fat diet fed animals. Additionally, serial blood sampling, via chronic indwelling cardiac catheters, revealed that the increase in LH pulse frequency was delayed and that the LH pulse amplitude was reduced in response to NK3R antagonism, regardless of dietary status. These data suggest that endogenous NKB-NK3R signalling plays a role in controlling the timing of puberty and the associated acceleration of gonadotrophin-releasing hormone pulse generator frequency in the female rat. © 2014 British Society for Neuroendocrinology.

  4. The Pseudo signal peptide of the corticotropin-releasing factor receptor type 2A prevents receptor oligomerization.

    Science.gov (United States)

    Teichmann, Anke; Rutz, Claudia; Kreuchwig, Annika; Krause, Gerd; Wiesner, Burkhard; Schülein, Ralf

    2012-08-03

    N-terminal signal peptides mediate the interaction of native proteins with the translocon complex of the endoplasmic reticulum membrane and are cleaved off during early protein biogenesis. The corticotropin-releasing factor receptor type 2a (CRF(2(a))R) possesses an N-terminal pseudo signal peptide, which represents a so far unique domain within the large protein family of G protein-coupled receptors (GPCRs). In contrast to a conventional signal peptide, the pseudo signal peptide remains uncleaved and consequently forms a hydrophobic extension at the N terminus of the receptor. The functional consequence of the presence of the pseudo signal peptide is not understood. Here, we have analyzed the significance of this domain for receptor dimerization/oligomerization in detail. To this end, we took the CRF(2(a))R and the homologous corticotropin-releasing factor receptor type 1 (CRF(1)R) possessing a conventional cleaved signal peptide and conducted signal peptide exchange experiments. Using single cell and single molecule imaging methods (fluorescence resonance energy transfer and fluorescence cross-correlation spectroscopy, respectively) as well as biochemical experiments, we obtained two novel findings; we could show that (i) the CRF(2(a))R is expressed exclusively as a monomer, and (ii) the presence of the pseudo signal peptide prevents its oligomerization. Thus, we have identified a novel functional domain within the GPCR protein family, which plays a role in receptor oligomerization and which may be useful to study the functional significance of this process in general.

  5. Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

    International Nuclear Information System (INIS)

    Gradishar, William J

    2016-01-01

    Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed

  6. Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

    Directory of Open Access Journals (Sweden)

    Nicholas V. Vamvakopoulos

    1995-01-01

    Full Text Available This review higlghts key aspects of corticotropin releasing hormone (CRH biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h CRH gene: (1 a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic glucocorticoid administration in clinical practice and (2 a heuristic diagram to illustrate the proposed modulation of the stress response and immune/ inflammatory reaction by steroid hormones, from the perspective of the CRH system.

  7. Genetic moderation of child maltreatment effects on depression and internalizing symptoms by serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter (NET), and corticotropin releasing hormone receptor 1 (CRHR1) genes in African American children.

    Science.gov (United States)

    Cicchetti, Dante; Rogosch, Fred A

    2014-11-01

    Genetic moderation of the effects of child maltreatment on depression and internalizing symptoms was investigated in a sample of low-income maltreated and nonmaltreated African American children (N = 1,096). Lifetime child maltreatment experiences were independently coded from Child Protective Services records and maternal report. Child depression and internalizing problems were assessed in the context of a summer research camp by self-report on the Children's Depression Inventory and adult counselor report on the Teacher Report Form. DNA was obtained from buccal cell or saliva samples and genotyped for polymorphisms of the following genes: serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter, and corticotropin releasing hormone receptor 1. Analyses of covariance with age and gender as covariates were conducted, with maltreatment status and respective polymorphism as main effects and their Gene × Environment (G × E) interactions. Maltreatment consistently was associated with higher Children's Depression Inventory and Teacher Report Form symptoms. The results for child self-report symptoms indicated a G × E interaction for BDNF and maltreatment. In addition, BDNF and triallelic 5-HTTLPR interacted with child maltreatment in a G × G × E interaction. Analyses for counselor report of child anxiety/depression symptoms on the Teacher Report Form indicated moderation of child maltreatment effects by triallelic 5-HTTLPR. These effects were elaborated based on variation in developmental timing of maltreatment experiences. Norepinephrine transporter was found to further moderate the G × E interaction of 5-HTTLPR and maltreatment status, revealing a G × G × E interaction. This G × G × E was extended by consideration of variation in maltreatment subtype experiences. Finally, G × G × E effects were observed for the co-action of BDNF and the corticotropin releasing hormone receptor 1

  8. Preparation and Characterization of an Antibody Antagonist That Targets the Porcine Growth Hormone Receptor

    Directory of Open Access Journals (Sweden)

    Huanzhong Cui

    2016-10-01

    Full Text Available A series of antagonists specifically targeting growth hormone receptors (GHR in different species, such as humans, rats, bovines, and mice, have been designed; however, there are currently no antagonists that target the porcine growth hormone (GH. Therefore, in this study, we developed and characterized a porcine GHR (pGHR antibody antagonist (denoted by AN98 via the hybridoma technique. The results from enzyme-linked immunosorbent assay, fluorescence activated cell sorter, indirect immunoinfluscent assay, and competitive receptor binding analysis showed that AN98 could specifically recognize pGHR, and further experiments indicated that AN98 could effectively inhibit pGH-induced signalling in CHO-pGHR cells and porcine hepatocytes. In addition, AN98 also inhibited GH-induced insulin-like growth factor-1 (IGF-1 secretion in porcine hepatocytes. In summary, these findings indicated that AN98, as a pGHR-specific antagonist, has potential applications in pGH-pGHR-related research on domestic pigs.

  9. Seasonal Relationship between Gonadotropin, Growth Hormone, and Estrogen Receptor mRNA Expression in the Pituitary Gland of Largemouth Bass

    OpenAIRE

    Martyniuk, Christopher J; Kroll, Kevin J.; Porak, Wesley F.; Steward, Cheree; Grier, Harry J.; Denslow, Nancy D.

    2009-01-01

    The objectives of this study were to investigate the seasonal changes in pituitary gonadotropins, growth hormone (GH), and estrogen receptor (ER) isoform mRNA in wild female and male largemouth bass (LMB) (Micropterus salmoides) from an unpolluted habitat to better understand reproductive physiology in this ecologically important species. Female pituitary luteinizing hormone (LH) β subunit and follicle-stimulating hormone (FSH) β subunit mRNA showed significant seasonal variation with levels ...

  10. Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects.

    Science.gov (United States)

    Berlanga-Acosta, Jorge; Abreu-Cruz, Angel; Herrera, Diana García-Del Barco; Mendoza-Marí, Yssel; Rodríguez-Ulloa, Arielis; García-Ojalvo, Ariana; Falcón-Cama, Viviana; Hernández-Bernal, Francisco; Beichen, Qu; Guillén-Nieto, Gerardo

    2017-01-01

    Growth hormone-releasing peptides (GHRPs) constitute a group of small synthetic peptides that stimulate the growth hormone secretion and the downstream axis activity. Mounting evidences since the early 1980s delineated unexpected pharmacological cardioprotective and cytoprotective properties for the GHRPs. However, despite intense basic pharmacological research, alternatives to prevent cell and tissue demise before lethal insults have remained as an empty niche in the clinical armamentarium. Here, we have rigorously reviewed the investigational development of GHRPs and their clinical niching perspectives. PubMed/MEDLINE databases, including original research and review articles, were explored. The search design was date escalated from 1980 and included articles in English only. GHRPs bind to two different receptors (GHS-R1a and CD36), which redundantly or independently exert relevant biological effects. GHRPs' binding to CD36 activates prosurvival pathways such as PI-3K/AKT1, thus reducing cellular death. Furthermore, GHRPs decrease reactive oxygen species (ROS) spillover, enhance the antioxidant defenses, and reduce inflammation. These cytoprotective abilities have been revealed in cardiac, neuronal, gastrointestinal, and hepatic cells, representing a comprehensive spectrum of protection of parenchymal organs. Antifibrotic effects have been attributed to some of the GHRPs by counteracting fibrogenic cytokines. In addition, GHRP family members have shown a potent myotropic effect by promoting anabolia and inhibiting catabolia. Finally, GHRPs exhibit a broad safety profile in preclinical and clinical settings. Despite these fragmented lines incite to envision multiple pharmacological uses for GHRPs, especially as a myocardial reperfusion damage-attenuating candidate, this family of "drugable" peptides awaits for a definitive clinical niche.

  11. Radioanalytical methods for the measurement of melanin concentrating hormone (MCH) and detection its receptor in rat tissues

    International Nuclear Information System (INIS)

    Lelesz, B.; Szilvassy, Z.; Varga, A.; Juhasz, B.; Nemeth, J.; Toth, G.K.; Toth, A.; Enyedi, A.; Felszeghy, E.

    2016-01-01

    In the present paper the development and application of a novel melanin concentrating hormone radioimmunoassay and receptor-binding assay are described. 125 I-labeling of melanin concentrating hormone (MCH) was performed by iodogen and the mono-iodinated peptide was separated by reversed-phase high performance liquid chromatography. Detection limit of the MCH specific assay was 0.2 fmol/ml. As a practical application of the novel radioimmunoassay, we measured the MCH concentration in different rat organs. High MCH concentrations were detected in the small intestine, pancreas, kidney, liver, trachea, hypothalamus and spinal cord. 125 I-MCH was also suitable for RBA to demonstrate the presence of MCH receptors in the rat brain. (author)

  12. Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model.

    Science.gov (United States)

    Liao, Fan; Zhang, Tony J; Mahan, Thomas E; Jiang, Hong; Holtzman, David M

    2015-07-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aβ levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition. Copyright © 2014

  13. Melanin concentrating hormone receptor 1 (MCHR1) antagonists - Still a viable approach for obesity treatment?

    DEFF Research Database (Denmark)

    Högberg, T.; Frimurer, T.M.; Sasmal, P.K.

    2012-01-01

    Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes...

  14. Pharmacological and biochemical characterization of the D-1 dopamine receptor mediating acetylcholine release in rabbit retina

    International Nuclear Information System (INIS)

    Hensler, J.G.; Cotterell, D.J.; Dubocovich, M.L.

    1987-01-01

    Superfusion with dopamine (0.1 microM-10 mM) evokes calcium-dependent [ 3 H]acetylcholine release from rabbit retina labeled in vitro with [ 3 H]choline. This effect is antagonized by the D-1 dopamine receptor antagonist SCH 23390. Activation or blockade of D-2 dopamine, alpha-2 or beta receptors did not stimulate or attenuate the release of [ 3 H]acetylcholine from rabbit retina. Dopamine receptor agonists evoke the release of [ 3 H]acetylcholine with the following order of potency: apomorphine ≤ SKF(R)82526 3 H]acetylcholine: SCH 23390 (IC50 = 1 nM) 3 H]acetylcholine release is characteristic of the D-1 dopamine receptor. These potencies were correlated with the potencies of dopamine receptor agonists and antagonists at the D-1 dopamine receptor in rabbit retina as labeled by [ 3 H]SCH 23390, or as determined by adenylate cyclase activity. [ 3 H]SCH 23390 binding in rabbit retinal membranes was stable, saturable and reversible. Scatchard analysis of [ 3 H]SCH 23390 saturation data revealed a single high affinity binding site (Kd = 0.175 +/- 0.002 nM) with a maximum binding of 482 +/- 12 fmol/mg of protein. The potencies of dopamine receptor agonists to stimulate [ 3 H]acetylcholine release were correlated with their potencies to stimulate adenylate cyclase (r = 0.784, P less than .05, n = 7) and with their affinities at [ 3 H]SCH 23390 binding sites (r = 0.755, P < .05, n = 8)

  15. Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism)

    Energy Technology Data Exchange (ETDEWEB)

    Daughaday, W.H.; Trivedi, B.

    1987-07-01

    It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, the authors have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of /sup 125/I-labeled hGH incubated with serum has been measured after gel filtration of the serum through an Ultrogel AcA 44 minicolumn. Results are expressed as percent of specifically bound /sup 125/I-hGH and as specific binding relative to that of a reference serum after correction is made for endogenous GH. The mean +/- SEM of specific binding of sera from eight normal adults (26-46 years of age) was 21.6 +/- 0.45%, and the relative specific binding was 101.1 +/- 8.6%. Sera from 11 normal children had lower specific binding of 12.5 +/- 1.95% and relative specific binding of 56.6 +/- 9.1%. Sera from three children with Laron-type dwarfism lacked any demonstrable GH binding, whereas sera from 10 other children with other types of nonpituitary short stature had normal relative specific binding. They suggest that the serum GH-binding protein is a soluble derivative of the GH receptor. Measurement of the serum GH-binding protein may permit recognition of other abnormalities of the GH receptor.

  16. Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism)

    International Nuclear Information System (INIS)

    Daughaday, W.H.; Trivedi, B.

    1987-01-01

    It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, the authors have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of 125 I-labeled hGH incubated with serum has been measured after gel filtration of the serum through an Ultrogel AcA 44 minicolumn. Results are expressed as percent of specifically bound 125 I-hGH and as specific binding relative to that of a reference serum after correction is made for endogenous GH. The mean +/- SEM of specific binding of sera from eight normal adults (26-46 years of age) was 21.6 +/- 0.45%, and the relative specific binding was 101.1 +/- 8.6%. Sera from 11 normal children had lower specific binding of 12.5 +/- 1.95% and relative specific binding of 56.6 +/- 9.1%. Sera from three children with Laron-type dwarfism lacked any demonstrable GH binding, whereas sera from 10 other children with other types of nonpituitary short stature had normal relative specific binding. They suggest that the serum GH-binding protein is a soluble derivative of the GH receptor. Measurement of the serum GH-binding protein may permit recognition of other abnormalities of the GH receptor

  17. Non-invasive treatments of luteinizing hormone-releasing hormone for inducing spermiation in American (Bufo americanus) and Gulf Coast (Bufo valliceps) toads.

    Science.gov (United States)

    Rowson, Angela D.; Obringer, Amy R.; Roth, Terri L.

    2001-01-01

    As many as 20% of all assessed amphibian species are threatened with extinction, and captive breeding programs are becoming important components of conservation strategies for this taxon. For some species, exogenous hormone administration has been integrated into breeding protocols to improve propagation. However, most treatments are administered by an intraperitoneal injection that can be associated with some risks. The general goal of this study was to identify a non-invasive method of applying luteinizing hormone-releasing hormone (LHRH), which reliably induces sperm release in toads. Specific objectives were to 1) test the spermiation response after topical application of different LHRH doses to the abdominal seat region, 2) evaluate the effects of adding the absorption enhancers dimethyl sulfoxide (DMSO), acetone, and glyceryl monocaprylate (GMC) to the LHRH, 3) assess the spermiation response after oral delivery of LHRH in a mealworm vehicle, and 4) compare sperm characteristics and spermiation responses to treatments in two different toad species. Male American (n = 9) and Gulf Coast (n = 7) toads were rotated systematically through a series of treatments. Urine was collected and evaluated for the presence of sperm at 0, 3, 7, 12, and 24 hours post-treatment. There were no statistical differences in spermiation induction or sperm characteristics between American and Gulf Coast toads after the treatments. Oral administration of 100 &mgr;g LHRH was occasionally successful in inducing spermiation, but results appeared largely unreliable. Ventral dermal application of 100 or 10 &mgr;g LHRH in 40% DMSO were more effective (P Zoo Biol 20:63-74, 2001. Copyright 2001 Wiley-Liss, Inc.

  18. Radioimmunoassay for 6-D-tryptophan analog of luteinizing hormone-releasing hormone: measurement of serum levels after administration of long-acting microcapsule formulations

    International Nuclear Information System (INIS)

    Mason-Garcia, M.; Vigh, S.; Comaru-Schally, A.M.; Redding, T.W.; Somogyvari-Vigh, A.; Horvath, J.; Schally, A.V.

    1985-01-01

    A sensitive and specific radioimmunoassay for [6-D-tryptophan]luteinizing hormone-releasing hormone ([D-Trp 6 ]LH-RH) was developed and used for following the rate of liberation of [D-Trp 6 ]LH-RH from a long-acting delivery systems based on a microcapsule formulation. Rabbit antibodies were generated against [D-Trp 6 ]LH-RH conjugated to bovine serum albumin with glutaraldehyde. Crossreactivity with LH-RH was less than 1%; there was no significant cross-reactivity with other peptides. The minimal detectable dose of [D-Trp 6 ]LH-RH was 2 pg per tube. In tra- and interassay coefficients of variation were 8% and 10%, respectively. The radioimmunoassay was suitable for direct determination of [D-Trp 6 ]LH-RH in serum, permitting the study of blood levels of the analog after single injections into normal men and after one-a-month administration of microcapsules to rats. In men, 90 min after subcutaneous injection of 250 μg of the peptide, serum [D-Trp 6 ]LH-RH rose to 6-12 ng/ml. Luteinizing hormone was increased 90 min and 24 hr after the administration of the analog. Several batches of microcapsules were tested in rats and the rate of release of [D-Trp 6 ]LH-RH was followed. The improved batch of microcapsules of [D-Trp 6 ]LH-RH increased serum concentrations of the analog for 30 days or longer after intramuscular injection

  19. Thyroid Hormone, Cancer, and Apoptosis.

    Science.gov (United States)

    Lin, Hung-Yun; Chin, Yu-Tan; Yang, Yu-Chen S H; Lai, Husan-Yu; Wang-Peng, Jacqueline; Liu, Leory F; Tang, Heng-Yuan; Davis, Paul J

    2016-06-13

    Thyroid hormones play important roles in regulating normal metabolism, development, and growth. They also stimulate cancer cell proliferation. Their metabolic and developmental effects and growth effects in normal tissues are mediated primarily by nuclear hormone receptors. A cell surface receptor for the hormone on integrin [alpha]vβ3 is the initiation site for effects on tumor cells. Clinical hypothyroidism may retard cancer growth, and hyperthyroidism was recently linked to the prevalence of certain cancers. Local levels of thyroid hormones are controlled through activation and deactivation of iodothyronine deiodinases in different organs. The relative activities of different deiodinases that exist in tissues or organs also affect the progression and development of specific types of cancers. In this review, the effects of thyroid hormone on signaling pathways in breast, brain, liver, thyroid, and colon cancers are discussed. The importance of nuclear thyroid hormone receptor isoforms and of the hormone receptor on the extracellular domain of integrin [alpha]vβ3 as potential cancer risk factors and therapeutic targets are addressed. We analyze the intracellular signaling pathways activated by thyroid hormones in cancer progression in hyperthyroidism or at physiological concentrations in the euthyroid state. Determining how to utilize the deaminated thyroid hormone analog (tetrac), and its nanoparticulate derivative to reduce risks of cancer progression, enhance therapeutic outcomes, and prevent cancer recurrence is also deliberated. © 2016 American Physiological Society. Compr Physiol 6:1221-1237, 2016. Copyright © 2016 John Wiley & Sons, Inc.

  20. Prostate-Derived Ets Transcription Factor Overexpression is Associated with Nodal Metastasis, Hormone Receptor Positivity in Invasive Breast Cancer

    Directory of Open Access Journals (Sweden)

    Simon Turcotte

    2007-10-01

    Full Text Available Prostate-derived Ets transcription factor (PDEF has recently been associated with invasive breast cancer, but no expression profile has been defined in clinical specimens. We undertook a comprehensive PDEF transcriptional expression study of 86 breast cancer clinical specimens, several cell lines, normal tissues. PDEF expression profile was analyzed according to standard clinicopathologic parameters, compared with hormonal receptor, HER-2/neu status, to the expression of the new tumor biomarker Dikkopf-1 (DKK1. Wide ranging PDEF overexpression was observed in 74% of tested tumors, at higher levels than the average expression found in normal breasts. High PDEF expression was associated with hormone receptor positivity (P < .001, moderate to good differentiation (less than grade III, P = .01, dissemination to axillary lymph nodes (P = .002. PDEF was an independent risk factor for nodal involvement (multivariate analysis, odds ratio 1.250, P = .002. It was expressed in a different subgroup compared to DKK1-expressing tumors (P < .001. Our data imply that PDEF mRNA expression could be useful in breast cancer molecular staging. Further insights into PDEF functions at the protein level, possible links with hormone receptors biology, bear great potential for new therapeutic avenues.

  1. CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action.

    Science.gov (United States)

    Degroot, Aldemar; Köfalvi, Attila; Wade, Mark R; Davis, Richard J; Rodrigues, Ricardo J; Rebola, Nelson; Cunha, Rodrigo A; Nomikos, George G

    2006-10-01

    Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct

  2. Effect of in ovo injection of corticotropin-releasing hormone on the timing of hatching in broiler chickens.

    Science.gov (United States)

    Watanabe, Yugo; Grommen, Sylvia V H; De Groef, Bert

    2017-09-01

    In chicken embryos, intravenous injection of corticotropin-releasing hormone (CRH) causes the release of both corticosteroids and thyroid hormones. These hormones initiate and enhance the hatching process, raising the possibility that CRH treatment of the late chicken embryo could accelerate hatching and/or decrease the spread of hatching. We performed a series of exploratory tests to investigate whether in ovo delivery methods of CRH other than intravenous injection that are more practical in a commercial setting, affect hatching time in broilers. Corticotropin-releasing hormone was injected into the air cell, albumen, or amniotic fluid of broiler breeder eggs, in the last week of embryonic development. Average incubation duration was significantly decreased by 22 h when 2 μg of CRH was injected into the air cell on embryonic day 18 (E18) of Cobb eggs. Acceleration of hatching (but only by 8 h) was also seen for Ross chicks when CRH was injected daily into the albumen between E10 and E18. However, repeats of both experiments did not show consistent effects of CRH on hatching time; in most experiments performed, CRH did not affect hatching time. We speculate that the effectiveness of CRH uptake via these delivery methods and/or the duration and magnitude of the thyroxine and corticosterone response to CRH is not sufficient to have a substantial effect on hatching time. We therefore conclude that in ovo CRH treatment does not seem a feasible option as a practical tool to increase hatchery productivity or to investigate the effects of CRH agonists and antagonists on hatching. © 2017 Poultry Science Association Inc.

  3. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    Energy Technology Data Exchange (ETDEWEB)

    Beildeck, Marcy E. [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States); Gelmann, Edward P. [Columbia University, Department of Medicine, New York, NY (United States); Byers, Stephen W., E-mail: byerss@georgetown.edu [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States)

    2010-07-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  4. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    International Nuclear Information System (INIS)

    Beildeck, Marcy E.; Gelmann, Edward P.; Byers, Stephen W.

    2010-01-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  5. The progesterone receptor antagonist, onapristone has differential effects on the timing and control of the luteolytic mechanism depending on timing of administration in sheep.

    Science.gov (United States)

    Mann, G E; Wathes, D C; Robinson, R S

    2013-08-25

    Cyclic ewes were treated with control vehicle or progesterone receptor antagonist (onapristone; 100mg i.m. twice daily) during either early (day 3-5) or late (day 12-14) luteal phase and plasma samples collected for hormone analysis and to determine endogenous and oxytocin induced PGF2α release. On day 14 and 17, ewes were euthanised and reproductive tracts collected for ovarian morphology and endometrium for oxytoxin and steroid hormone receptor analysis. Early treatment increased LH, but not progesterone or oestradiol, while late treatment elevated all three hormones. Early treatment delayed the up-regulation of endometrial oxytocin receptors and responsiveness to oxytocin challenge, delaying luteolysis. Late treatment advanced development of oxytocin receptors and responsiveness to oxytocin though not timing of luteolysis. Patterns of hormone receptor mRNA were differentially disrupted by treatments. Results provide mechanistic insight into hormonal control of the oestrous cycle and identify the ability of the luteolytic mechanism to dissociate from functional luteolysis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. Antidepressant effects of abscisic acid mediated by the downregulation of corticotrophin-releasing hormone gene expression in rats.

    Science.gov (United States)

    Qi, Cong-Cong; Zhang, Zhi; Fang, Hui; Liu, Ji; Zhou, Nan; Ge, Jin-Fang; Chen, Fang-Han; Xiang, Cheng-Bin; Zhou, Jiang-Ning

    2014-10-31

    Corticotrophin-releasing hormone (CRH) is considered to be the central driving force of the hypothalamic-pituitary-adrenal axis, which plays a key role in the stress response and depression. Clinical reports have suggested that excess retinoic acid (RA) is associated with depression. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share a similar molecular structure. Here, we proposed that ABA also plays a role in the regulation of CRH activity sharing with the RA signaling pathway. [3H]-ABA radioimmunoassay demonstrated that the hypothalamus of rats shows the highest concentration of ABA compared with the cortex and the hippocampus under basal conditions. Under acute stress, ABA concentrations increased in the serum, but decreased in the hypothalamus and were accompanied by increased corticosterone in the serum and c-fos expression in the hypothalamus. Moreover, chronic ABA administration increased sucrose intake and decreased the mRNA expression of CRH and retinoic acid receptor alpha (RARα) in the hypothalamus of rats. Furthermore, ABA improved the symptom of chronic unpredictable mild stress in model rats, as indicated by increased sucrose intake, increased swimming in the forced swim test, and reduced mRNA expression of CRH and RARα in the rat hypothalamus. In vitro, CRH expression decreased after ABA treatment across different neural cells. In BE(2)-C cells, ABA inhibited a series of retinoid receptor expression, including RARα, a receptor that could facilitate CRH expression directly. These results suggest that ABA may play a role in the pathogenesis of depression by downregulating CRH mRNA expression shared with the RA signaling pathway. © The Author 2014. Published by Oxford University Press on behalf of CINP.

  7. Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.

    Science.gov (United States)

    Zhao, Li-Hua; Yin, Yanting; Yang, Dehua; Liu, Bo; Hou, Li; Wang, Xiaoxi; Pal, Kuntal; Jiang, Yi; Feng, Yang; Cai, Xiaoqing; Dai, Antao; Liu, Mingyao; Wang, Ming-Wei; Melcher, Karsten; Xu, H Eric

    2016-07-15

    G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. A hormone pulse induces transient changes in the subcellular distribution and leads to a lysosomal accumulation of the estradiol receptor alpha in target tissues.

    Science.gov (United States)

    Qualmann, B; Kessels, M M; Thole, H H; Sierralta, W D

    2000-06-01

    An intrauterine pulse-stimulation with estradiol induced changes in the subcellular localization of estrogen receptor alpha in porcine endometrium, as detected with F(ab') fragments of various anti-receptor antibodies covalently linked to nanogold. The low-sterically hindered immunoreagents--recognizing different epitopes within the hormone binding domain--allowed for an efficient immunolabeling of estradiol receptor alpha, detecting it both in the cytoplasm and the nucleus of nonstimulated epithelium cells. In the cytoplasm, the receptor often seemed to be associated with actin filaments and the endoplasmatic reticulum. After the stimulation with estradiol, a predominantly nuclear localization and a labeling of nucleoli was observed. Our immunoelectron microscopy study demonstrates a localization of the receptor in cytoplasmic organelles that increased after the hormone pulse. These organelles exhibited the morphological properties of lysosomes and relocated to the perinuclear area. In analogous cytoplasmic organelles, the presence of cathepsin D was detected via indirect immunogold labeling, justifying their classification as lysosomes. Quantitative examinations revealed that not only the number of lysosomes in the proximity of the nucleus but also their immunostaining for estradiol receptor alpha increased significantly after the hormone pulse. Thus, estradiol induces both the rapid shift of receptor into the nucleus, a slower perinuclear accumulation of lysosomes and an increase of lysosomal ERalpha-immunoreactivity. These results suggest a role for lysosomes in the degradation of receptor shuttling out of the nucleus. This could serve as termination of the estradiol receptor alpha-dependent activation of target cells. This hypothesis is strengthened by the fact that the receptor content in uterine tissue declined drastically few hours after the hormone pulse.

  9. Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

    International Nuclear Information System (INIS)

    Sheng, Zhi-Guo; Tang, Yuan; Liu, Yu-Xiang; Yuan, Ye; Zhao, Bao-Quan; Chao, Xi-Juan; Zhu, Ben-Zhan

    2012-01-01

    Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10 −9 M suppresses TR or steroid receptor coactivator-1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-β1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of β3 integrin or c-Src significantly reduces BPA-induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the β3 integrin/c-Src/MAPK/TR-β1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways, followed by recruiting N-CoR/SMRT to TR-β1, providing a novel insight regarding the TH disruption effects of low concentration BPA. -- Highlights: ► Environmentally relevant concentrations of BPA suppress TR transcription. ► BPA recruits the N-CoR/SMRT to TR under the physiologic concentrations of T3/T4. ► BPA disrupts T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways.

  10. Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Sheng, Zhi-Guo [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Tang, Yuan [Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, 30 Yanzheng Street, Chongqing 400038 (China); Liu, Yu-Xiang [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Yuan, Ye; Zhao, Bao-Quan [Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850 (China); Chao, Xi-Juan [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Zhu, Ben-Zhan, E-mail: bzhu@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China)

    2012-02-15

    Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10{sup −9} M suppresses TR or steroid receptor coactivator-1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-β1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of β3 integrin or c-Src significantly reduces BPA-induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the β3 integrin/c-Src/MAPK/TR-β1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways, followed by recruiting N-CoR/SMRT to TR-β1, providing a novel insight regarding the TH disruption effects of low concentration BPA. -- Highlights: ► Environmentally relevant concentrations of BPA suppress TR transcription. ► BPA recruits the N-CoR/SMRT to TR under the physiologic concentrations of T3/T4. ► BPA disrupts T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways.

  11. Mechanisms of Disease: the first kiss-a crucial role for kisspeptin-1 and its receptor, G-protein-coupled receptor 54, in puberty and reproduction.

    Science.gov (United States)

    Seminara, Stephanie B

    2006-06-01

    Although the hypothalamic secretion of gonadotropin-releasing hormone (GnRH) is the defining hormonal event of puberty, the physiologic mechanisms that drive secretion of GnRH at the time of sexual maturation have been difficult to identify. After puberty is initiated, the factors that modulate the frequency and amplitude of GnRH secretion in rapidly changing sex-steroid environments (i.e. the female menstrual cycle) also remain unknown. The discovery that, in both humans and mouse models, loss-of-function mutations in the gene that encodes G-protein-coupled receptor 54 result in phenotypes of hypogonadotropic hypogonadism with an absence of pubertal development has unearthed a novel pathway regulating GnRH secretion. Ligands for G-protein-coupled receptor 54 (KiSS-1R), including metastin (derived from the parent compound, kisspeptin-1) and metastin's C-terminal peptide fragments, have been shown to be powerful stimulants for GnRH release in vivo via their stimulation of G-protein-coupled receptor 54. This article reviews the discovery of the GPR54 gene, places it into the appropriate biological context, and explores the data from in vitro and in vivo studies that point to this ligand-receptor system as a major driver of GnRH secretion.

  12. The adipokinetic hormone receptor modulates sexual behavior, pheromone perception and pheromone production in a sex-specific and starvation-dependent manner in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Sebastien eLebreton

    2016-01-01

    Full Text Available Food availability and nutritional status shape the reproductive activity of many animals. In rodents, hormones such as gonadotropin-releasing hormone (GnRH, restore energy homeostasis not only through regulating e.g. caloric intake and energy housekeeping, but also through modulating sex drive. We investigated whether the insect homologue of the GnRH receptor, the adipokinetic hormone receptor (AKHR modulates sexual behavior of the fruit fly Drosophila melanogaster depending on nutritional status. We found that AKHR regulates male, but not female sexual behavior in a starvation-dependent manner. Males lacking AKHR showed a severe decrease in their courtship activity when starved, as well as an increase in mating duration when fed. AKHR expression is particularly strong in the subesophageal zone (SEZ, Ito et al. 2014. We found axonal projections from AKHR-expressing neurons to higher brain centers including specific glomeruli in the antennal lobe. Among the glomeruli that received projections were those dedicated to detecting the male specific pheromone cis-vaccenyl acetate (cVA. Accordingly, responses to cVA were dependent on the nutritional status of flies. AKHR was also involved in the regulation of the production of cuticular pheromones, 7,11-heptacosadiene and 7-tricosene. This effect was observed only in females and depended on their feeding state. AKHR has therefore a dual role on both pheromone perception and production. For the first time our study shows an effect of AKHR on insect sexual behavior and physiology. Our results support the hypothesis of a conserved role of the GnRH/AKH pathway on a nutritional state-dependent regulation of reproduction in both vertebrates and invertebrates.

  13. Periodic regulation of expression of genes for kisspeptin, gonadotropin-inhibitory hormone and their receptors in the grass puffer: Implications in seasonal, daily and lunar rhythms of reproduction.

    Science.gov (United States)

    Ando, Hironori; Shahjahan, Md; Kitahashi, Takashi

    2018-04-03

    The seasonal, daily and lunar control of reproduction involves photoperiodic, circadian and lunar changes in the activity of kisspeptin, gonadotropin-inhibitory hormone (GnIH) and gonadotropin-releasing hormone (GnRH) neurons. These changes are brought through complex networks of light-, time- and non-photic signal-dependent control mechanisms, which are mostly unknown at present. The grass puffer, Takifugu alboplumbeus, a semilunar spawner, provides a unique and excellent animal model to assess this question because its spawning is synchronized with seasonal, daily and lunar cycles. In the diencephalon, the genes for kisspeptin, GnIH and their receptors showed similar expression patterns with clear seasonal and daily oscillations, suggesting that they are regulated by common mechanisms involving melatonin, circadian clock and water temperature. For implications in semilunar-synchronized spawning rhythm, melatonin receptor genes showed ultradian oscillations in expression with the period of 14.0-15.4 h in the pineal gland. This unique ultradian rhythm might be driven by circatidal clock. The possible circatidal clock and circadian clock in the pineal gland may cooperate to drive circasemilunar rhythm to regulate the expression of the kisspeptin, GnIH and their receptor genes. On the other hand, high temperature (over 28 °C) conditions, under which the expression of the kisspeptin and its receptor genes is markedly suppressed, may provide an environmental signal that terminates reproduction at the end of breeding period. Taken together, the periodic regulation of the kisspeptin, GnIH and their receptor genes by melatonin, circadian clock and water temperature may be important in the precisely-timed spawning of the grass puffer. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Effect of aging on GHRF-induced growth hormone release from anterior pituitary cells in primary culture

    International Nuclear Information System (INIS)

    Spik, K.W.; Boyd, R.L.; Sonntag, W.E.

    1991-01-01

    Five criteria were developed to validate the primary cell culture model for comparison of GRF-induced release of growth hormone in pituitary tissue from aging animals. Pituitaries from young (5-mo), middle-aged (14-mo), and old (24-mo) male Fischer 344 rats were dispersed using either trypsin/trypsin inhibitor or dispase and compared with respect to the number of pituitary cells recovered, cell viability, 3H-leucine incorporation into total protein, time course for recovery of optimal response to GRF, and the dose-relationship for GRF-induced release of growth hormone 2, 4, and 6 days after dispersal. Results indicated that direct comparison of cellular responses between tissues from young, middle-aged, and old rats in primary cell culture is confounded by variations in time for recovery of optimal responses, the effects of the enzymes used for dispersal, and the methods used to express the data

  15. Analog specificity of the thyrotropin-releasing hormone receptor in the central nervous system: possible clinical implications

    International Nuclear Information System (INIS)

    Hawkins, E.F.; Engel, W.K.

    1985-01-01

    TRH has rapid-onset (30 sec), slow-offset (1-12 days) clinical benefit in patients with amyotrophic lateral sclerosis and other motor neuron disorders. This benefit is probably receptor-mediated and may have at least 2 components. To obtain a better understanding of the various responses to TRH of the spinal lower motor neurons (LMNs) in patients, and possibly to help guide selection of additional therapeutic agents, the authors utilized rat CNS (spinal-cord and brain membranes) to analyze the ability of certain molecules to inhibit specific binding of [ 3 H]methyl TRH ([ 3 H]MeTRH) to the TRH receptor. They found: a) lack of high-affinity binding of the TRH-analog DN-1417 by spinal-cord and brain TRH receptor, despite its known strong TRH-like action physiologically on LMNs; b) lack of high-affinity binding of the TRH-product cyclo(His-Pro) by spinal cord and brain TRH receptor despite its having some strong TRH-like physiologic actions on the CNS; and c) lack of any identifiable high-affinity receptor for cyclo(His-Pro) in spinal cord and brain. From these data the authors hypothesize that the acute transmitter-like action of DN-1417, TRH, and possibly other TRH-analogs and products on LMNs is via a non-TRH receptor, such as an amine or amino acid neurotransmitter receptor, e.g. a 5-hydroxytryptamine receptor. They further postulate that the CNS TRH-receptor may modulate a trophic-like influence of TRH on LMNs

  16. The C'-terminal interaction domain of the thyroid hormone receptor confers the ability of the DNA site to dictate positive or negative transcriptional activity

    International Nuclear Information System (INIS)

    Holloway, J.M.; Glass, C.K.; Adler, S.; Nelson, C.A.; Rosenfeld, M.G.

    1990-01-01

    To investigate mechanisms responsible for positive and negative transcriptional control, the authors have utilized two types of promoters that are diffferentially regulated by thyroid hormone (T 3 ) receptors. Promoters containing the palindromic T 3 response element TCAGGTCA TGACCTGA are positively regulated by the T 3 receptor after the administration of T 3 , whereas otherwise identical promoters containing the estrogen response element TCAGGTCA CTG TGACCTGA can be regulated negatively; converse effects are observed with the estrogen receptor. They describe evidence that the transcriptional inhibitory effects of the T 3 or estrogen receptors on the estrogen or T 3 response elements, respectively, are imposed by amino acid sequences in the C'-terminal region that colocalize with dimerization and hormone-binding domains and that these sequences can transfer inhibitory functions to other classes of transcription factors. Removal of the C'-terminal dimerization and hormone-binding domains of either the αT 3 or estrogen receptors permits each receptor to act constitutively to enhance transcription on both T 3 and estrogen response elements. It is, therefore, suggested that protein-protein interactions between receptor C' termini limit the subset of DNA binding sites on which transcriptional activation occurs

  17. Involvement of phospholipase C and intracellular calcium signaling in the gonadotropin-releasing hormone regulation of prolactin release from lactotrophs of tilapia (Oreochromis mossambicus)

    DEFF Research Database (Denmark)

    Tipsmark, Christian Kølbæk; Weber, G M; Strom, C N

    2005-01-01

    Gonadotropin-releasing hormone (GnRH) is a potent stimulator of prolactin (PRL) secretion in various vertebrates including the tilapia, Oreochromis mossambicus. The mechanism by which GnRH regulates lactotroph cell function is poorly understood. Using the advantageous characteristics of the teleost...

  18. Receptors for luteinizing hormone-releasing hormone (LHRH) in benign prostatic hyperplasia (BPH) as potential molecular targets for therapy with LHRH antagonist cetrorelix.

    Science.gov (United States)

    Rozsa, Bernadett; Nadji, Mehrdad; Schally, Andrew V; Dezso, Balazs; Flasko, Tibor; Toth, Gyorgy; Mile, Melinda; Block, Norman L; Halmos, Gabor

    2011-04-01

    The majority of men will develop symptoms of benign prostatic hyperplasia (BPH) after 70 years of age. Various studies indicate that antagonists of LHRH, such as cetrorelix, exert direct inhibitory effects on BPH mediated by specific LHRH receptors. Our aim was to investigate the mRNA for LHRH and LHRH receptors and the expression of LHRH receptors in specimens of human BPH. The expression of mRNA for LHRH (n=35) and LHRH receptors (n=55) was investigated by RT-PCR in surgical specimens of BPH, using specific primers. The characteristics of binding sites for LHRH on 20 samples were determined by ligand competition assays. The LHRH receptor expression was also examined in 64 BPH specimens by immunohistochemistry. PCR products for LHRH were found in 18 of 35 (51%) BPH tissues and mRNA for LHRH receptors was detected in 39 of 55 (71%) BPH specimens. Eighteen of 20 (90%) samples showed a single class of high affinity binding sites for [D-Trp(6) ]LHRH with a mean K(d) of 4.04 nM and a mean B(max) of 527.6 fmol/mg membrane protein. LHRH antagonist cetrorelix showed high affinity binding to LHRH receptors in BPH. Positive immunohistochemical reaction for LHRH receptors was present in 42 of 64 (67%) BPH specimens. A high incidence of LHRH receptors in BPH supports the use of LHRH antagonists such as cetrorelix, for treatment of patients with lower urinary tract symptoms from BPH. Copyright © 2010 Wiley-Liss, Inc.

  19. Group I mGlu receptors potentiate synaptosomal [3H]glutamate release independently of exogenously applied arachidonic acid

    International Nuclear Information System (INIS)

    Reid, M.E.; Toms, N.J.; Bedingfield, J.S.; Roberts, P.J.

    1999-01-01

    In the current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [ 3 H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 μM) increased 4AP-evoked [ 3 H]glutamate release (143.32±2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC 50 =1.60±0.25 μM; E max =147.61±10.96% control) 4AP-evoked [ 3 H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu 1 receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 μM) and was BSA-insensitive. The selective mGlu 5 receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300μM) was without effect. DHPG (100 μM) also potentiated both 30 mM and 50 mM K + -evoked [ 3 H]glutamate release (121.60±12.77% and 121.50±4.45% control, respectively). DHPG (100 μM) failed to influence both 4AP-stimulated 45 Ca 2+ influx and 50 mM K + -induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A 1 receptor, group II/III mGlu receptors or GABA B receptor activity is unlikely since 4AP-evoked [ 3 H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-α-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu 1 receptor-like' receptor potentiates [ 3 H]glutamate release from cerebrocortical synaptosomes in the absence of exogenously applied arachidonic acid. This PKC dependent effect is unlikely to be via modulation of synaptosomal membrane

  20. Action of Specific Thyroid Hormone Receptor alpha(1) and beta(1) Antagonists in the Central and Peripheral Regulation of Thyroid Hormone Metabolism in the Rat

    NARCIS (Netherlands)

    van Beeren, Hermina C.; Kwakkel, Joan; Ackermans, Mariëtte T.; Wiersinga, Wilmar M.; Fliers, Eric; Boelen, Anita

    2012-01-01

    Background: The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) alpha(1)

  1. Pharmacological or genetic orexin 1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex

    Directory of Open Access Journals (Sweden)

    Leah eAluisio

    2014-05-01

    Full Text Available The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors. The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward and emotion. Recent studies have demonstrated that orexins and glutamate interact at the synaptic level and that orexins facilitate glutamate actions. We tested the hypothesis that orexins modulate glutamate signaling via OX1 receptors by monitoring levels of glutamate in frontal cortex of freely moving mice using enzyme coated biosensors under inhibited OX1 receptor conditions. MK-801, an NMDA receptor antagonist, was administered subcutaneously (0.178 mg/kg to indirectly disinhibit pyramidal neurons and therefore increase cortical glutamate release. In wild-type mice, pretreatment with the OX1 receptor antagonist GSK-1059865 (10 mg/kg S.C. which had no effect by itself, significantly attenuated the cortical glutamate release elicited by MK-801. OX1 receptor knockout mice had a blunted glutamate release response to MK-801 and exhibited about half of the glutamate release observed in wild-type mice in agreement with the data obtained with transient blockade of OX1 receptors. These results indicate that pharmacological (transient or genetic (permanent inhibition of the OX1 receptor similarly interfere with glutamatergic function in the cortex. Selectively targeting the OX1 receptor with an antagonist may normalize hyperglutamatergic states and thus may represent a novel therapeutic strategy for the treatment of various psychiatric disorders associated with hyperactive states.

  2. The role of nuclear hormone receptors in cutaneous wound repair.

    Science.gov (United States)

    Rieger, Sandra; Zhao, Hengguang; Martin, Paige; Abe, Koichiro; Lisse, Thomas S

    2015-01-01

    The cutaneous wound repair process involves balancing a dynamic series of events ranging from inflammation, oxidative stress, cell migration, proliferation, survival and differentiation. A complex series of secreted trophic factors, cytokines, surface and intracellular proteins are expressed in a temporospatial manner to restore skin integrity after wounding. Impaired initiation, maintenance or termination of the tissue repair processes can lead to perturbed healing, necrosis, fibrosis or even cancer. Nuclear hormone receptors (NHRs) in the cutaneous environment regulate tissue repair processes such as fibroplasia and angiogenesis. Defects in functional NHRs and their ligands are associated with the clinical phenotypes of chronic non-healing wounds and skin endocrine disorders. The functional relationship between NHRs and skin niche cells such as epidermal keratinocytes and dermal fibroblasts is pivotal for successful wound closure and permanent repair. The aim of this review is to delineate the cutaneous effects and cross-talk of various nuclear receptors upon injury towards functional tissue restoration. Copyright © 2014 John Wiley & Sons, Ltd.

  3. Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

    Science.gov (United States)

    Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

    2013-09-15

    The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Zebrafish adult-derived hypothalamic neurospheres generate gonadotropin-releasing hormone (GnRH neurons

    Directory of Open Access Journals (Sweden)

    Christian Cortés-Campos

    2015-09-01

    Full Text Available Gonadotropin-releasing hormone (GnRH is a hypothalamic decapeptide essential for fertility in vertebrates. Human male patients lacking GnRH and treated with hormone therapy can remain fertile after cessation of treatment suggesting that new GnRH neurons can be generated during adult life. We used zebrafish to investigate the neurogenic potential of the adult hypothalamus. Previously we have characterized the development of GnRH cells in the zebrafish linking genetic pathways to the differentiation of neuromodulatory and endocrine GnRH cells in specific regions of the brain. Here, we developed a new method to obtain neural progenitors from the adult hypothalamus in vitro. Using this system, we show that neurospheres derived from the adult hypothalamus can be maintained in culture and subsequently differentiate glia and neurons. Importantly, the adult derived progenitors differentiate into neurons containing GnRH and the number of cells is increased through exposure to either testosterone or GnRH, hormones used in therapeutic treatment in humans. Finally, we show in vivo that a neurogenic niche in the hypothalamus contains GnRH positive neurons. Thus, we demonstrated for the first time that neurospheres can be derived from the hypothalamus of the adult zebrafish and that these neural progenitors are capable of producing GnRH containing neurons.

  5. Fresh versus frozen embryo transfer after gonadotropin-releasing hormone agonist trigger in gonadotropin-releasing hormone antagonist cycles among high responder women: A randomized, multi-center study

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    Abbas Aflatoonian

    2018-02-01

    Full Text Available Background: The use of embryo cryopreservation excludes the possible detrimental effects of ovarian stimulation on the endometrium, and higher reproductive outcomes following this policy have been reported. Moreover, gonadotropin-releasing hormone agonist trigger in gonadotropin-releasing hormone (GnRH antagonist cycles as a substitute for standard human chorionic gonadotropin trigger, minimizes the risk of ovarian hyperstimulation syndrome (OHSS in fresh as well as frozen embryo transfer cycles (FET. Objective: To compare the reproductive outcomes and risk of OHSS in fresh vs frozen embryo transfer in high responder patients, undergoing in vitro fertilization triggered with a bolus of GnRH agonist. Materials and Methods: In this randomized, multi-centre study, 121 women undergoing FET and 119 women undergoing fresh ET were investigated as regards clinical pregnancy as the primary outcome and the chemical pregnancy, live birth, OHSS development, and perinatal data as secondary outcomes. Results: There were no significant differences between FET and fresh groups regarding chemical (46.4% vs. 40.2%, p=0.352, clinical (35.8% vs. 38.3%, p=0.699, and ongoing (30.3% vs. 32.7%, p=0.700 pregnancy rates, also live birth (30.3% vs. 29.9%, p=0.953, perinatal outcomes, and OHSS development (35.6% vs. 42.9%, p=0.337. No woman developed severe OHSS and no one required admission to hospital. Conclusion: Our findings suggest that GnRHa trigger followed by fresh transfer with modified luteal phase support in terms of a small human chorionic gonadotropin bolus is a good strategy to secure good live birth rates and a low risk of clinically relevant OHSS development in in vitro fertilization patients at risk of OHSS.

  6. Stress and Cognition: the relevance of timing, steroid receptors and sex differences

    NARCIS (Netherlands)

    Cornelisse, S.

    2013-01-01

    In response to a stressful situation the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis are activated, eventually leading to the release of catecholamines and corticosteroids. These stress hormones bind to different receptors in the brain (in case of corticosteroids,

  7. Effects of Dietary Bacillus licheniformis on Gut Physical Barrier, Immunity, and Reproductive Hormones of Laying Hens.

    Science.gov (United States)

    Wang, Yang; Du, Wei; Lei, Kai; Wang, Baikui; Wang, Yuanyuan; Zhou, Yingshan; Li, Weifen

    2017-09-01

    Previous study showed that dietary Bacillus licheniformis (B. licheniformis) administration contributes to the improvement of laying performance and egg quality in laying hens. In this study, we aimed to further evaluate its underlying mechanisms. Three hundred sixty Hy-Line Variety W-36 hens (28 weeks of age) were randomized into four groups, each group with six replications (n = 15). The control group received the basal diet and the treatment groups received the same basal diets supplemented with 0.01, 0.03, and 0.06% B. licheniformis powder (2 × 10 10  cfu/g) for an 8-week trial. The results demonstrate that B. licheniformis significantly enhance the intestinal barrier functions via decreasing gut permeability, promoting mucin-2 transcription, and regulating inflammatory cytokines. The systemic immunity of layers in B. licheniformis treatment groups is improved through modulating the specific and non-specific immunity. In addition, gene expressions of hormone receptors, including estrogen receptor α, estrogen receptor β, and follicle-stimulating hormone receptor, are also regulated by B. licheniformis. Meanwhile, compared with the control, B. licheniformis significantly increase gonadotropin-releasing hormone level, but markedly reduce ghrelin and inhibin secretions. Overall, our data suggest that dietary inclusion of B. licheniformis can improve the intestinal barrier function and systemic immunity and regulate reproductive hormone secretions, which contribute to better laying performance and egg quality of hens.

  8. Continuous recording of excretory water loss from Musca domestica using a flow-through humidity meter: hormonal control of diuresis.

    Science.gov (United States)

    Coast, Geoffrey M

    2004-05-01

    Water loss from adult male houseflies was continuously recorded using a flow-through humidity meter, which enabled losses to be apportioned between the sum of cuticular and respiratory transpiration, salivation and excretion. Transpiration accounted for >95% of water lost from sham-injected flies, compared with excretion (3.0%) and salivation (2.4%). In contrast, excretion accounted for 40% of water lost from flies injected with > or =3 microl of saline, whereas salivary losses were unchanged. Saline injections (1-5 microl) expanded the abdomen in the dorsal-ventral plane, and this expansion was positively correlated with the magnitude of the ensuing diuresis, suggesting the signal for diuretic hormone release originates from stretch receptors in abdominal tergal-sternal muscles. The effects of decapitation, severing the ventral nerve cord within the neck or ligaturing the neck, showed the head was needed to initiate and maintain diuresis, but was neither the source of diuretic hormone nor did it control the discharge of urine from the anus. These findings indicate the head is part of the neural-endocrine pathway between abdominal stretch receptors and sites for diuretic hormone release from the thoracic-abdominal ganglion mass. Evidence is presented for Musdo-K having a hormonal role in the control of diuresis, although other neuropeptides may also be implicated.

  9. Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study.

    Directory of Open Access Journals (Sweden)

    Horst Joachim Schirra

    Full Text Available BACKGROUND: Growth hormone is an important regulator of post-natal growth and metabolism. We have investigated the metabolic consequences of altered growth hormone signalling in mutant mice that have truncations at position 569 and 391 of the intracellular domain of the growth hormone receptor, and thus exhibit either low (around 30% maximum or no growth hormone-dependent STAT5 signalling respectively. These mutations result in altered liver metabolism, obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: The analysis of metabolic changes was performed using microarray analysis of liver tissue and NMR metabonomics of urine and liver tissue. Data were analyzed using multivariate statistics and Gene Ontology tools. The metabolic profiles characteristic for each of the two mutant groups and wild-type mice were identified with NMR metabonomics. We found decreased urinary levels of taurine, citrate and 2-oxoglutarate, and increased levels of trimethylamine, creatine and creatinine when compared to wild-type mice. These results indicate significant changes in lipid and choline metabolism, and were coupled with increased fat deposition, leading to obesity. The microarray analysis identified changes in expression of metabolic enzymes correlating with alterations in metabolite concentration both in urine and liver. Similarity of mutant 569 to the wild-type was seen in young mice, but the pattern of metabolites shifted to that of the 391 mutant as the 569 mice became obese after six months age. CONCLUSIONS/SIGNIFICANCE: The metabonomic observations were consistent with the parallel analysis of gene expression and pathway mapping using microarray data, identifying metabolites and gene transcripts involved in hepatic metabolism, especially for taurine, choline and creatinine metabolism. The systems biology approach applied in this study provides a coherent picture of metabolic changes resulting from impaired STAT5 signalling by the growth hormone

  10. Quantification of three steroid hormone receptors of the leopard gecko (Eublepharis macularius), a lizard with temperature-dependent sex determination: their tissue distributions and the effect of environmental change on their expressions.

    Science.gov (United States)

    Endo, Daisuke; Park, Min Kyun

    2003-12-01

    Sex steroid hormones play a central role in the reproduction of all vertebrates. These hormones function through their specific receptors, so the expression levels of the receptors may reflect the responsibility of target organs. However, there was no effective method to quantify the expression levels of these receptors in reptilian species. In this study, we established the competitive-PCR assay systems for the quantification of the mRNA expression levels of three sex steroid hormone receptors in the leopard gecko. These assay systems were successfully able to detect the mRNA expression level of each receptor in various organs of male adult leopard geckoes. The expression levels of mRNA of these receptors were highly various depending on the organs assayed. This is the first report regarding the tissue distributions of sex steroid hormone receptor expressions in reptile. The effects of environmental conditions on these hormone receptor expressions were also examined. After the low temperature and short photoperiod treatment for 6 weeks, only the androgen receptor expression was significantly increased in the testes. The competitive-PCR assay systems established in this report should be applicable for various studies of the molecular mechanism underlying the reproductive activity of the leopard gecko.

  11. Microsomal receptor for steroid hormones: functional implications for nuclear activity.

    Science.gov (United States)

    Muldoon, T G; Watson, G H; Evans, A C; Steinsapir, J

    1988-01-01

    Target tissues for steroid hormones are responsive by virtue of and to the extent of their content of functional intracellular receptors. Recent years have seen a shift in considerations of the cellular dynamics and distribution of these receptors, with current views favoring predominant intranuclear localization in the intact cell. This paper summarizes our analyses of the microsomal estrogen and androgen binding capability of rat uterine and ventral prostate tissue, respectively; these studies have revealed a set of high affinity sites that may act as a conduit for estrogen traversing the cell en route to the nucleus. These sites have many properties in common with cytosolic receptors, with the salient difference of a failure to activate to a more avid DNA-binding form under conditions which permit such activation of cytosolic receptors. The microsomal estrogen-binding proteins also have appreciable affinity for progesterone, another distinction from other known cellular estrogen receptor species. Various experimental approaches were employed to demonstrate that the microsomal receptors were not simply cytosol contaminants; the most convincing evidence is the recent successful separation of the cytosolic and microsomal forms by differential ammonium sulfate precipitation. Discrete subfractionation of subcellular components on successive sucrose gradients, with simultaneous assessments of binding capability and marker enzyme concentrations, indicates that the major portion of the binding is localized within the vesicles of the endoplasmic reticulum free of significant plasma membrane contamination. The microsomal receptors are readily solubilized by extraction with high- or low-salt-containing buffers or with steroid. The residual microsomes following such extraction have the characteristics of saturable acceptor sites for cytosolic estrogen-receptor complexes. The extent to which these sites will accept the cytosolic complexes is equal to the concentration of

  12. Recovery responses of testosterone, growth hormone, and IGF-1 after resistance exercise.

    Science.gov (United States)

    Kraemer, William J; Ratamess, Nicholas A; Nindl, Bradley C

    2017-03-01

    The complexity and redundancy of the endocrine pathways during recovery related to anabolic function in the body belie an oversimplistic approach to its study. The purpose of this review is to examine the role of resistance exercise (RE) on the recovery responses of three major anabolic hormones, testosterone, growth hormone(s), and insulin-like growth factor 1. Each hormone has a complexity related to differential pathways of action as well as interactions with binding proteins and receptor interactions. Testosterone is the primary anabolic hormone, and its concentration changes during the recovery period depending on the upregulation or downregulation of the androgen receptor. Multiple tissues beyond skeletal muscle are targeted under hormonal control and play critical roles in metabolism and physiological function. Growth hormone (GH) demonstrates differential increases in recovery with RE based on the type of GH being assayed and workout being used. IGF-1 shows variable increases in recovery with RE and is intimately linked to a host of binding proteins that are essential to its integrative actions and mediating targeting effects. The RE stress is related to recruitment of muscle tissue with the glandular release of hormones as signals to target tissues to support homeostatic mechanisms for metabolism and tissue repair during the recovery process. Anabolic hormones play a crucial role in the body's response to metabolism, repair, and adaptive capabilities especially in response to anabolic-type RE. Changes of these hormones following RE during recovery in the circulatory biocompartment of blood are reflective of the many mechanisms of action that are in play in the repair and recovery process. Copyright © 2017 the American Physiological Society.

  13. Synthetic Growth Hormone-Releasing Peptides (GHRPs: A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects

    Directory of Open Access Journals (Sweden)

    Jorge Berlanga-Acosta

    2017-02-01

    Full Text Available Background: Growth hormone-releasing peptides (GHRPs constitute a group of small synthetic peptides that stimulate the growth hormone secretion and the downstream axis activity. Mounting evidences since the early 1980s delineated unexpected pharmacological cardioprotective and cytoprotective properties for the GHRPs. However, despite intense basic pharmacological research, alternatives to prevent cell and tissue demise before lethal insults have remained as an empty niche in the clinical armamentarium. Here, we have rigorously reviewed the investigational development of GHRPs and their clinical niching perspectives. Methodology: PubMed/MEDLINE databases, including original research and review articles, were explored. The search design was date escalated from 1980 and included articles in English only. Results and Conclusions: GHRPs bind to two different receptors (GHS-R1a and CD36, which redundantly or independently exert relevant biological effects. GHRPs’ binding to CD36 activates prosurvival pathways such as PI-3K/AKT1, thus reducing cellular death. Furthermore, GHRPs decrease reactive oxygen species (ROS spillover, enhance the antioxidant defenses, and reduce inflammation. These cytoprotective abilities have been revealed in cardiac, neuronal, gastrointestinal, and hepatic cells, representing a comprehensive spectrum of protection of parenchymal organs. Antifibrotic effects have been attributed to some of the GHRPs by counteracting fibrogenic cytokines. In addition, GHRP family members have shown a potent myotropic effect by promoting anabolia and inhibiting catabolia. Finally, GHRPs exhibit a broad safety profile in preclinical and clinical settings. Despite these fragmented lines incite to envision multiple pharmacological uses for GHRPs, especially as a myocardial reperfusion damage-attenuating candidate, this family of “drugable” peptides awaits for a definitive clinical niche.

  14. Effects of graded doses of goitrin, a goitrogen in rapeseed, on synthesis and release of thyroid hormone in chicks

    International Nuclear Information System (INIS)

    Akiba, Yukio; Matsumoto, Tatsuro

    1977-01-01

    Intrathyroidal metabolism in synthesis and release of thyroid hormone was investigated in chicks administered three different levels of goitrin (0.0125, 0.025 and 0.05% in the diet) for 14 days. Thyroid glands were enlarged to 2-5 times as large as that of the control in proportion to the goitrin content of the diet. Typical high radioiodine uptake goiter was demonstrated in the goitrin-administered chicks. Total thyroid 125 I content increased about twice as much as that of the control in the goitrin-administered chicks though it was depressed in 0.0065% PUT-administered chicks. Decrease of plasma PB 125 I (approximately a half of the control) was ascertained by the estimation of plasma thyroxine by radiostereoassay. In the intrathyroidal metabolism of iodine, synthesis of iodothyronines and iodination of MIT were suppressed by goitrin, but monoiodination of tyrosine was rather accelerated. The elevated ratio of thyroid iodothyronines/plasma PBI (1.5-1.7 times as much as that of the control) reveals that the depression of plasma level of thyroid hormone is more striking than the decrease in thyroid hormone in the gland in the goitrin-administered chicks. It is, therefore, suggested that goitrin has inhibitory effects not only on the biosynthesis of thyroid hormone in the gland but also on the release of thyroid hormone from the gland. (auth.)

  15. Diacylglycerol production induced by growth hormone in Ob1771 preadipocytes arises from phosphatidylcholine breakdown

    International Nuclear Information System (INIS)

    Catalioto, R.M.; Ailhaud, G.; Negrel, R.

    1990-01-01

    Growth Hormone has recently been shown to stimulate the formation of diacylglycerol in Ob1771 mouse preadipocyte cells without increasing inositol lipid turnover. Addition of growth hormone to Ob1771 cells prelabelled with [ 3 H]glycerol or [ 3 H]choline led to a rapid, transient and stoechiometric formation of labelled diacylglycerol and phosphocholine, respectively. In contrast, no change was observed in the level of choline and phosphatidic acid whereas the release of water-soluble metabolites in [ 3 H]ethanolamine prelabelled cells exposed to growth hormone was hardly detectable. Stimulation by growth hormone of cells prelabelled with (2-palmitoyl 9, 10 [ 3 H])phosphatidylcholine also induced the production of labelled diacyglycerol. Pertussis toxin abolished both diacylglycerol and phosphocholine formation induced by growth hormone. It is concluded that growth hormone mediates diacylglycerol production in Ob1771 cells by means of phosphatidylcholine breakdown involving a phospholipase C which is likely coupled to the growth hormone receptor via a pertussis toxin-sensitive G-protein

  16. Diacylglycerol production induced by growth hormone in Ob1771 preadipocytes arises from phosphatidylcholine breakdown

    Energy Technology Data Exchange (ETDEWEB)

    Catalioto, R.M.; Ailhaud, G.; Negrel, R. (Universite de Nice-Sophia Antipolis (France))

    1990-12-31

    Growth Hormone has recently been shown to stimulate the formation of diacylglycerol in Ob1771 mouse preadipocyte cells without increasing inositol lipid turnover. Addition of growth hormone to Ob1771 cells prelabelled with ({sup 3}H)glycerol or ({sup 3}H)choline led to a rapid, transient and stoechiometric formation of labelled diacylglycerol and phosphocholine, respectively. In contrast, no change was observed in the level of choline and phosphatidic acid whereas the release of water-soluble metabolites in ({sup 3}H)ethanolamine prelabelled cells exposed to growth hormone was hardly detectable. Stimulation by growth hormone of cells prelabelled with (2-palmitoyl 9, 10 ({sup 3}H))phosphatidylcholine also induced the production of labelled diacyglycerol. Pertussis toxin abolished both diacylglycerol and phosphocholine formation induced by growth hormone. It is concluded that growth hormone mediates diacylglycerol production in Ob1771 cells by means of phosphatidylcholine breakdown involving a phospholipase C which is likely coupled to the growth hormone receptor via a pertussis toxin-sensitive G-protein.

  17. Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signaling and Stat5 activation

    DEFF Research Database (Denmark)

    Hansen, L. H.; Wang, X.; Kopchick, J J

    1996-01-01

    The binding of growth hormone (GH) to its receptor results in its dimerization followed by activation of Jak2 kinase and tyrosine phosphorylation of the GH receptor itself, as well as Jak2 and the transcription factors Stat1, -3, and -5. In order to study the role of GH receptor tyrosine phosphor...

  18. Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

    DEFF Research Database (Denmark)

    Schmidt, Lene S; Miller, Anthony D; Lester, Deranda B

    2010-01-01

    showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs. MATERIALS AND METHODS: Here, we investigate the role of M(5) receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release......-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M(5) receptor. These results support the concept that the M(5) receptor modulates effects of addictive drugs....

  19. Trialkyltin rexinoid-X receptor agonists selectively potentiate thyroid hormone induced programs of xenopus laevis metamorphosis

    NARCIS (Netherlands)

    Mengeling, Brenda J.; Murk, Albertinka J.; Furlow, J.D.

    2016-01-01

    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the

  20. A novel growth hormone receptor gene deletion mutation in a patient with primary growth hormone insensitivity syndrome (Laron syndrome).

    Science.gov (United States)

    Yamamoto, Hiroyasu; Kouhara, Haruhiko; Iida, Keiji; Chihara, Kazuo; Kasayama, Soji

    2008-04-01

    Growth hormone (GH) insensitivity syndrome (Laron syndrome) is known to be caused by genetic disorders of the GH-IGF-1 axis. Although many mutations in the GH receptor have been identified, there have been only a few reports of deletions of the GH receptor gene. A Japanese adult female patient with Laron syndrome was subjected to chromosome analysis with basic G-banding and also with a high accuracy technique. Each exon of the GH receptor gene was amplified by means of PCR. Since this patient was diagnosed with osteoporosis, the effects of alendronate on bone mineral density (BMD) were also examined. The chromosome analysis with the high accuracy technique demonstrated a large deletion of the short arm in one allele of chromosome 5 from p11 to p13.1 [46, XX, del (5) (p11-p13.1)]. PCR amplification of exons of the GH receptor gene showed that only exons 2 and 3 were amplified. Low-dose IGF-1 administration (30microg/kg body weight) failed to increase her BMD, whereas alendronate administration resulted in an increase associated with a decrease in urinary deoxypyridinoline (DPD) and serum osteocalcin concentrations. The GH receptor gene of the patient was shown to lack exons 4-10. To the best of our knowledge, this is the third case report of Laron syndrome with large GH receptor deletion. Alendronate was effective for the enhancement of BMD.

  1. Melanin-concentrating hormone and its receptor are expressed and functional in human skin.

    Science.gov (United States)

    Hoogduijn, Martin J; Ancans, Janis; Suzuki, Itaru; Estdale, Siân; Thody, Anthony J

    2002-08-23

    In this study, we have demonstrated the presence of melanin-concentrating hormone (MCH) and melanin-concentrating hormone receptor (MCHR1) transcripts in human skin. Sequence analysis confirmed that the transcripts of both genes were identical to those previously found in human brain. In culture, endothelial cells showed pro-MCH expression whereas no signal was found in keratinocytes, melanocytes, and fibroblasts. MCHR1 expression was restricted to melanocytes and melanoma cells. Stimulation of cultured human melanocytes with MCH reduced the alpha-MSH-induced increase in cAMP production. Furthermore, the melanogenic actions of alpha-MSH were inhibited by MCH. We propose that the MCH/MCHR1 signalling system is present in human skin and may have a role with the melanocortins in regulating the melanocyte.

  2. Neurotrophins and their receptors in the rat pituitary gland: regulation of BDNF and trkB mRNA levels by adrenal hormones.

    Science.gov (United States)

    Kononen, J; Soinila, S; Persson, H; Honkaniemi, J; Hökfelt, T; Pelto-Huikko, M

    1994-12-01

    We studied the expression of messenger ribonucleic acids (mRNAs) for neurotrophins and neurotrophin receptors in the rat pituitary gland and examined the influence of adrenal hormones on their mRNA levels, using in situ hybridization and Northern blot analysis. The only neurotrophin present at detectable levels in the pituitary was brain-derived neurotrophic factor (BDNF), which was observed in the anterior and intermediate lobes. Several transcripts of the putative receptor for BDNF, trkB, were present in the anterior and posterior lobes of the pituitary. A low amount of trkC mRNA was found in both the anterior and the intermediate lobe. Dexamethasone treatment decreased both BDNF and trkB mRNA levels in the anterior lobe of the pituitary. Adrenalectomy had no effect on trkB expression, but it decreased BDNF mRNA levels in comparison to the control animals. This effect could not be reversed by dexamethasone substitution, suggesting that BDNF, mRNA levels may be regulated not only by glucocorticoids but also by other adrenal hormones. These results demonstrate that BDNF, trkB and trkC are expressed in the pituitary gland and that glucocorticoids and possibly other adrenal hormones may modulate pituitary functions by regulating the expression of neurotrophic factors and their receptors. Whether BDNF acts as a secreted hormone, a trophic factor, or has autocrine/paracrine functions within the pituitary through its receptor, trkB, remains to be studied.

  3. Characterization of hormonal receptors and human epidermal growth factor receptor-2 in tissues of women with breast cancer at Muhimbili National Hospital, Dar es salaam, Tanzania.

    Science.gov (United States)

    Mwakigonja, Amos Rodger; Lushina, Nyanda Elias; Mwanga, Ally

    2017-01-01

    Breast cancer is a leading cause of morbidity and deaths among women worldwide. In Tanzania there is no published data on human epidermal growth receptor-2 (HER2/neu) expression in breast carcinoma. Hormonal receptors and HER2/neu status reportedly influence post-mastectomy adjuvant therapy and predict treatment outcome and prognosis. Here we evaluate hormonal receptors and HER-2 status in biopsies of women with breast cancer at Muhimbili National Hospital (MNH). A cross-sectional study of female breast post-modified radical mastectomy (MRM)/incisional biopsies confirmed to be carcinoma at the Histopathology Unit (January-December 2013). Tissue blocks having poor morphology, without tumor, secondary tumors, cases outside the study period and male patients were excluded. Routine staining was done followed by immunohistochemistry for estrogen (ER), and progesterone (PgR) receptors and HER2. Data analyzed using Statistical Package for Social Sciences (SPSS). A total of 218 cases were confirmed to be carcinoma including 70 meeting inclusion criteria. Age at diagnosis ranged 18-75 years and mean age was 48.36 years. Majority (64.3%) were in the 36-55 years age-group. Histologically, most (88.6%) women had invasive ductal carcinoma including 43.1% of intermediate grade. A great majority (78%) were stage three. Due to logistical constrains, 75.7% ( n  = 53/70) cases where immunostained for hormones including 43.4% (ER+), 26.4% (PgR+), and 28% (ER+/PgR+). Furthermore, 65.7% ( n  = 46/70) cases were immunostained for HER-2 and 15.2% ( n  = 7/46) were positive, 45.6% were triple negative (ER-,PgR-,HER2-), 23.9% (ER+,PgR+,HER2-) or luminal B, 2.2% (ER+,PgR-,HER2+),13% (ER-,PgR-,HER2+) and 15% (ER+,PgR-,HER2-) with none being triple positive. Hormonal receptors and HER2 expression at MNH appears to be comparable to previous Africans/African Americans reports but not with studies among Caucasians and the current proportion of triple negative breast carcinomas (TNBC) is

  4. Characterization of hormonal receptors and human epidermal growth factor receptor-2 in tissues of women with breast cancer at Muhimbili National Hospital, Dar es salaam, Tanzania

    Directory of Open Access Journals (Sweden)

    Amos Rodger Mwakigonja

    2017-11-01

    Full Text Available Abstract Background Breast cancer is a leading cause of morbidity and deaths among women worldwide. In Tanzania there is no published data on human epidermal growth receptor-2 (HER2/neu expression in breast carcinoma. Hormonal receptors and HER2/neu status reportedly influence post-mastectomy adjuvant therapy and predict treatment outcome and prognosis. Here we evaluate hormonal receptors and HER-2 status in biopsies of women with breast cancer at Muhimbili National Hospital (MNH. Methods A cross-sectional study of female breast post-modified radical mastectomy (MRM/incisional biopsies confirmed to be carcinoma at the Histopathology Unit (January–December 2013. Tissue blocks having poor morphology, without tumor, secondary tumors, cases outside the study period and male patients were excluded. Routine staining was done followed by immunohistochemistry for estrogen (ER, and progesterone (PgR receptors and HER2. Data analyzed using Statistical Package for Social Sciences (SPSS. Results A total of 218 cases were confirmed to be carcinoma including 70 meeting inclusion criteria. Age at diagnosis ranged 18–75 years and mean age was 48.36 years. Majority (64.3% were in the 36–55 years age-group. Histologically, most (88.6% women had invasive ductal carcinoma including 43.1% of intermediate grade. A great majority (78% were stage three. Due to logistical constrains, 75.7% (n = 53/70 cases where immunostained for hormones including 43.4% (ER+, 26.4% (PgR+, and 28% (ER+/PgR+. Furthermore, 65.7% (n = 46/70 cases were immunostained for HER-2 and 15.2% (n = 7/46 were positive, 45.6% were triple negative (ER-,PgR-,HER2-, 23.9% (ER+,PgR+,HER2- or luminal B, 2.2% (ER+,PgR-,HER2+,13% (ER-,PgR-,HER2+ and 15% (ER+,PgR-,HER2- with none being triple positive. Conclusions Hormonal receptors and HER2 expression at MNH appears to be comparable to previous Africans/African Americans reports but not with studies among Caucasians and the current proportion

  5. Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata

    International Nuclear Information System (INIS)

    Aceves, J.; Young, J.M.; Arias-Montano, J.A.; Floran, B.; Garcia, M.

    1997-01-01

    The release of [ 3 H]GABA from slices of rat substantia nigra pars reticulata induced by increasing extracellular K + from 6 to 15 mM in the presence of 10 μM sulpiride was inhibited by 73±3% by 1 μM SCH 23390, consistent with a large component of release dependent upon D 1 receptor activation. The histamine H 3 receptor-selective agonist immepip (1 μM) and the non-selective agonist histamine (100 μM) inhibited [ 3 H]GABA release by 78±2 and 80±2%, respectively. The inhibition by both agonists was reversed by the H 3 receptor antagonist thioperamide (1 μM). However, in the presence of 1 μM SCH 23390 depolarization-induced release of [ 3 H]GABA was not significantly decreased by 1 μM immepip. In rats depleted of dopamine by pretreatment with reserpine, immepip no longer inhibited control release of [ 3 H]GABA, but in the presence of 1 μM SKF 38393, which produced a 7±1-fold stimulation of release, immepip reduced the release to a level not statistically different from that in the presence of immepip alone. Immepip (1 μM) also inhibited the depolarization-induced release of [ 3 H]dopamine from substantia nigra pars reticulata slices, by 38±3%.The evidence is consistent with the proposition that activation of histamine H 3 receptors leads to the selective inhibition of the component of depolarization-induced [ 3 H]GABA release in substantia nigra pars reticulata slices which is dependent upon D 1 receptor activation. This appears to be largely an action at the terminals of the striatonigral GABA projection neurons, which may be enhanced by a partial inhibition of dendritic [ 3 H]dopamine release. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  6. Regulation versus modulation in GnRH receptor function

    International Nuclear Information System (INIS)

    Zolman, J.C.; Theodoropoulos, T.J.

    1985-01-01

    Serum luteinizing hormone (LH) concentration after exposure to gonadotropin-releasing hormone (GnRH) indicates that an instantaneous increase occurs in the rate of release of LH directly from the anterior pituitary, as measured dynamically during superfusion in vitro. On the other hand, estradiol-17 beta (E2) alone shows no such instantaneous effect on LH release rate (at least for the first four hours), in either physiologic or pharmacologic concentrations. At the same time, brief (ten to 30 minute) exposure of isolated anterior pituitary plasma membranes to physiologic concentrations of E2 significantly alters the binding of a fully biologically active 125 I-GnRH to its plasma membrane receptor protein. In order to characterize the effect of E2 on GnRH binding further, dispersed bovine anterior pituitary cells were preincubated for six hours in the presence or absence of physiologic concentrations of E2 (10(-10)M). Following preincubation in the presence of E2, the cell suspension was incubated for 30 minutes with physiologic concentrations (5 x 10(-11) - 5 x 10(-10)M) of a fully biologically active 125 I-GnRH. The treatment, at least, doubled the number of biologically important high affinity GnRH binding sites (Kd's . 7.5 x -10(-11) - 4.5 x 10(-10)M), and changed the binding capacity of some of the binding sites up to three fold, which altered the cooperativity of GnRH-receptor interaction. Thus, the interaction of E2 with GnRH at the level of GnRH receptor is mandatory for the short-term pituitary effect of E2 on LH release in vitro and in vivo

  7. The effect of the intracervical application of follicle-stimulating hormone or luteinizing hormone on the pattern of expression of gonadotrophin receptors in the cervix of non-pregnant ewes.

    Science.gov (United States)

    Leethongdee, S; Khalid, M; Scaramuzzi, R J

    2014-08-01

    During the periovulatory period, the cervix relaxes in response to changes in circulating concentrations of reproductive hormones. The present study investigated the role of gonadotrophins in cervical function by examining the expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) and their mRNAs following intracervical treatment with either FSH or LH. Eighteen ewes were assigned to four groups, and they were then treated with progestagen sponges and PMSG to synchronize their oestrous cycles. Intracervical treatments were given 24 h after sponge removal as follows: Group 1: FSH 2 mg; Group 2: LH 2 mg; Group 3: Vehicle and Group 4: Control. Cervices were collected 54 h after sponge removal and then divided into three regions. The expression of FSHR and LHR was determined by immunohistochemistry and FSHR mRNA and LH mRNA by in situ hybridization. The expression of LHR, FSHR and their respective mRNAs was compared in six tissue layers (luminal epithelium, subepithelial stroma, circular, longitudinal and transverse muscle and serosa) and in three cervical regions (vaginal, mid and uterine). The results showed that FSH increased transcription of the FSHR gene and the levels of its receptor, but only in subepithelial stroma of the cervix. FSH also increased the levels of LHR in the cervix, but only in the muscle layers. LH had no effect on the levels of FSHR despite the fact that it did increase the level of transcription of the FSHR gene and LH also increased the levels of its own receptor in the cervix, but only in the muscle layers, and this action was independent of increased levels of transcription of the LHR gene. These findings suggest multiple levels of regulation of cervical LH and FSH receptors and that the gonadotrophins may have a role in relaxation of the cervix during oestrus by regulating their own receptors. © 2014 Blackwell Verlag GmbH.

  8. Presynaptic membrane receptors in acetylcholine release modulation in the neuromuscular synapse.

    Science.gov (United States)

    Tomàs, Josep; Santafé, Manel M; Garcia, Neus; Lanuza, Maria A; Tomàs, Marta; Besalduch, Núria; Obis, Teresa; Priego, Mercedes; Hurtado, Erica

    2014-05-01

    Over the past few years, we have studied, in the mammalian neuromuscular junction (NMJ), the local involvement in transmitter release of the presynaptic muscarinic ACh autoreceptors (mAChRs), purinergic adenosine autoreceptors (P1Rs), and trophic factor receptors (TFRs; for neurotrophins and trophic cytokines) during development and in the adult. At any given moment, the way in which a synapse works is largely the logical outcome of the confluence of these (and other) metabotropic signalling pathways on intracellular kinases, which phosphorylate protein targets and materialize adaptive changes. We propose an integrated interpretation of the complementary function of these receptors in the adult NMJ. The activity of a given receptor group can modulate a given combination of spontaneous, evoked, and activity-dependent release characteristics. For instance, P1Rs can conserve resources by limiting spontaneous quantal leak of ACh (an A1 R action) and protect synapse function, because stimulation with adenosine reduces the magnitude of depression during repetitive activity. The overall outcome of the mAChRs seems to contribute to upkeep of spontaneous quantal output of ACh, save synapse function by decreasing the extent of evoked release (mainly an M2 action), and reduce depression. We have also identified several links among P1Rs, mAChRs, and TFRs. We found a close dependence between mAChR and some TFRs and observed that the muscarinic group has to operate correctly if the tropomyosin-related kinase B receptor (trkB) is also to operate correctly, and vice versa. Likewise, the functional integrity of mAChRs depends on P1Rs operating normally. Copyright © 2014 Wiley Periodicals, Inc.

  9. Gonadotrophin releasing hormone antagonist in IVF/ICSI

    Directory of Open Access Journals (Sweden)

    M S Kamath

    2008-01-01

    Full Text Available Objective : To study the efficacy of gonadotrophin releasing hormone (GnRH antagonist in In-vitro-fertilization/Intracytoplasmic sperm injection (IVF/ICSI cycles. Type of Study : Observational study. Setting: Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, Tamil Nadu. Materials and Methods: GnRH antagonists were introduced into our practice in November 2005. Fifty-two women undergoing the antagonist protocol were studied and information gathered regarding patient profile, treatment parameters (total gonadotrophin dosage, duration of treatment, and oocyte yield, and outcomes in terms of embryological parameters (cleavage rates, implantation rates and clinical pregnancy. These parameters were compared with 121 women undergoing the standard long protocol. The costs between the two groups were also compared. Main Outcome : Clinical pregnancy rate. Results : The clinical pregnancy rate per embryo transfer in the antagonist group was 31.7% which was comparable to the clinical pregnancy rate in women undergoing the standard long protocol (30.63%. The costs between the two groups were comparable. Conclusions : GnRH antagonist protocol was found to be effective and comparable to the standard long protocol regimen. In addition it was simple, convenient, and patient friendly.

  10. Characterization of pituitary growth hormone and its receptor in the green iguana (Iguana iguana).

    Science.gov (United States)

    Ávila-Mendoza, José; Carranza, Martha; Pérez-Rueda, Ernesto; Luna, Maricela; Arámburo, Carlos

    2014-07-01

    Pituitary growth hormone (GH) has been studied in most vertebrate groups; however, only a few studies have been carried out in reptiles. Little is known about pituitary hormones in the order Squamata, to which the green iguana (gi) belongs. In this work, we characterized the hypophysis of Iguana iguana morphologically. The somatotrophs (round cells of 7.6-10 μm containing 250- to 300-nm secretory granules where the giGH is stored) were found, by immunohistochemistry and in situ hybridization, exclusively in the caudal lobe of the pars distalis, whereas the lactotrophs were distributed only in the rostral lobe. A pituitary giGH-like protein was obtained by immuno-affinity chromatography employing a heterologous antibody against chicken GH. giGH showed molecular heterogeneity (22, 44, and 88 kDa by SDS-PAGE/Western blot under non-reducing conditions and at least four charge variants (pIs 6.2, 6.5, 6.9, 7.4) by isoelectric focusing. The pituitary giGH cDNA (1016 bp), amplified by PCR and RACE, encodes a pre-hormone of 218 aa, of which 190 aa correspond to the mature protein and 28 aa to the signal peptide. The giGH receptor cDNA was also partially sequenced. Phylogenetic analyses of the amino acid sequences of giGH and giGHR homologs in vertebrates suggest a parallel evolution and functional relationship between the GH and its receptor. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly.

    Science.gov (United States)

    Tritos, Nicholas A; Biller, Beverly M K

    2017-02-01

    To review published data on pegvisomant and its therapeutic role in acromegaly. Electronic searches of the published literature were conducted using the keywords: acromegaly, growth hormone (GH) receptor (antagonist), pegvisomant, therapy. Relevant articles (n = 141) were retrieved and considered for inclusion in this manuscript. Pegvisomant is a genetically engineered, recombinant growth hormone receptor antagonist, which is effective in normalizing serum insulin-like growth factor 1 (IGF-1) levels in the majority of patients with acromegaly and ameliorating symptoms and signs associated with GH excess. Pegvisomant does not have direct antiproliferative effects on the underlying somatotroph pituitary adenoma, which is the etiology of GH excess in the vast majority of patients with acromegaly. Therefore, patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. Pegvisomant is an effective therapeutic agent in patients with acromegaly who are not in remission after undergoing pituitary surgery. It mitigates excess GH action, as demonstrated by IGF-1 normalization, but has no direct effects on pituitary tumors causing acromegaly. Regular surveillance for possible tumor growth and adverse effects (hepatotoxicity, skin manifestations) is warranted.

  12. Synaptically released zinc triggers metabotropic signaling via a zinc-sensing receptor in the hippocampus.

    Science.gov (United States)

    Besser, Limor; Chorin, Ehud; Sekler, Israel; Silverman, William F; Atkin, Stan; Russell, James T; Hershfinkel, Michal

    2009-03-04

    Zn(2+) is coreleased with glutamate from mossy fiber terminals and can influence synaptic function. Here, we demonstrate that synaptically released Zn(2+) activates a selective postsynaptic Zn(2+)-sensing receptor (ZnR) in the CA3 region of the hippocampus. ZnR activation induced intracellular release of Ca(2+), as well as phosphorylation of extracellular-regulated kinase and Ca(2+)/calmodulin kinase II. Blockade of synaptic transmission by tetrodotoxin or CdCl inhibited the ZnR-mediated Ca(2+) rises. The responses mediated by ZnR were largely attenuated by the extracellular Zn(2+) chelator, CaEDTA, and in slices from mice lacking vesicular Zn(2+), suggesting that synaptically released Zn(2+) triggers the metabotropic activity. Knockdown of the expression of the orphan G-protein-coupled receptor 39 (GPR39) attenuated ZnR activity in a neuronal cell line. Importantly, we observed widespread GPR39 labeling in CA3 neurons, suggesting a role for this receptor in mediating ZnR signaling in the hippocampus. Our results describe a unique role for synaptic Zn(2+) acting as the physiological ligand of a metabotropic receptor and provide a novel pathway by which synaptic Zn(2+) can regulate neuronal function.

  13. Converging, Synergistic Actions of Multiple Stress Hormones Mediate Enduring Memory Impairments after Acute Simultaneous Stresses.

    Science.gov (United States)

    Chen, Yuncai; Molet, Jenny; Lauterborn, Julie C; Trieu, Brian H; Bolton, Jessica L; Patterson, Katelin P; Gall, Christine M; Lynch, Gary; Baram, Tallie Z

    2016-11-02

    Stress influences memory, an adaptive process crucial for survival. During stress, hippocampal synapses are bathed in a mixture of stress-released molecules, yet it is unknown whether or how these interact to mediate the effects of stress on memory. Here, we demonstrate novel synergistic actions of corticosterone and corticotropin-releasing hormone (CRH) on synaptic physiology and dendritic spine structure that mediate the profound effects of acute concurrent stresses on memory. Spatial memory in mice was impaired enduringly after acute concurrent stresses resulting from loss of synaptic potentiation associated with disrupted structure of synapse-bearing dendritic spines. Combined application of the stress hormones corticosterone and CRH recapitulated the physiological and structural defects provoked by acute stresses. Mechanistically, corticosterone and CRH, via their cognate receptors, acted synergistically on the spine-actin regulator RhoA, promoting its deactivation and degradation, respectively, and destabilizing spines. Accordingly, blocking the receptors of both hormones, but not each alone, rescued memory. Therefore, the synergistic actions of corticosterone and CRH at hippocampal synapses underlie memory impairments after concurrent and perhaps also single, severe acute stresses, with potential implications to spatial memory dysfunction in, for example, posttraumatic stress disorder. Stress influences memory, an adaptive process crucial for survival. During stress, adrenal corticosterone and hippocampal corticotropin-releasing hormone (CRH) permeate memory-forming hippocampal synapses, yet it is unknown whether (and how) these hormones interact to mediate effects of stress. Here, we demonstrate novel synergistic actions of corticosterone and CRH on hippocampal synaptic plasticity and spine structure that mediate the memory-disrupting effects of stress. Combined application of both hormones provoked synaptic function collapse and spine disruption

  14. [Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

    Science.gov (United States)

    Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

    2015-06-01

    Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

  15. Role of corticosteroid hormones in the dentate gyrus.

    NARCIS (Netherlands)

    Joëls, M.

    2007-01-01

    Dentate granule cells are enriched with receptors for the stress hormone corticosterone, i.e., the high-affinity mineralocorticoid receptor (MR), which is already extensively occupied with low levels of the hormone, and the glucocorticoid receptor (GR), which is particularly activated after stress.

  16. Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia

    NARCIS (Netherlands)

    Unmehopa, Unga A.; van Heerikhuize, Joop J.; Spijkstra, Wenda; Woods, John W.; Howard, Andrew D.; Zycband, Emanuel; Feighner, Scott D.; Hreniuk, Donna L.; Palyha, Oksana C.; Guan, Xiao-Ming; Macneil, Douglas J.; van der Ploeg, Lex H. T.; Swaab, Dick F.

    2005-01-01

    Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R

  17. Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia.

    NARCIS (Netherlands)

    Unmehopa, U.A.; Heerikhuize, J.J. van; Spijkstra, W.; Woods, J.W.; Howard, A.D.; Zycband, E.; Feighner, S.D.; Hreniuk, D.L.; Palyha, O.C.; Guan, X.-M.; MacNeil, D.J.; Ploeg, L.H.T.; Swaab, D.F.

    2005-01-01

    Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R

  18. Galanin does not affect the growth hormone-releasing hormone-stimulated growth hormone secretion in patients with hyperthyroidism.

    Science.gov (United States)

    Giustina, A; Bussi, A R; Legati, F; Bossoni, S; Licini, M; Schettino, M; Zuccato, F; Wehrenberg, W B

    1992-12-01

    Patients with hyperthyroidism have reduced spontaneous and stimulated growth hormone (GH) secretion. The aim of our study was to evaluate the effects of galanin, a novel neuropeptide which stimulates GH secretion in man, on the GH response to GHRH in patients with hyperthyroidism. Eight untreated hyperthyroid patients with Graves' disease (6F, 2M, aged 25-50 years) and six healthy volunteers (3F, 3M, aged 27-76 years) underwent from -10 to 30 min in random order: (i) porcine galanin, iv, 500 micrograms in 100 ml saline; or (ii) saline, iv, 100 ml. A bolus of human GHRH(1-29)NH2, 100 micrograms, was injected iv at 0 min. Hyperthyroid patients showed blunted GH peaks after GHRH+saline (10.2 +/- 2.5 micrograms/l) compared to normal subjects (20.7 +/- 4.8 micrograms/l, p hyperthyroid subjects (12.5 +/- 3 micrograms/l) compared to normal subjects (43.8 +/- 6 micrograms/l, p hyperthyroidism suggests that hyperthyroxinemia may either increase the somatostatin release by the hypothalamus or directly affect the pituitary GH secretory capacity.

  19. Hormone Receptor Expression Analyses in Neoplastic and Non-Neoplastic Canine Mammary Tissue by a Bead Based Multiplex Branched DNA Assay: A Gene Expression Study in Fresh Frozen and Formalin-Fixed, Paraffin-Embedded Samples.

    Directory of Open Access Journals (Sweden)

    Annika Mohr

    Full Text Available Immunohistochemistry (IHC is currently considered the method of choice for steroid hormone receptor status evaluation in human breast cancer and, therefore, it is commonly utilized for assessing canine mammary tumors. In case of low hormone receptor expression, IHC is limited and thus is complemented by molecular analyses. In the present study, a multiplex bDNA assay was evaluated as a method for hormone receptor gene expression detection in canine mammary tissues. Estrogen receptor (ESR1, progesterone receptor (PGR, prolactin receptor (PRLR and growth hormone receptor (GHR gene expressions were evaluated in neoplastic and non-neoplastic canine mammary tissues. A set of 119 fresh frozen and 180 formalin-fixed, paraffin-embedded (FFPE was comparatively analyzed and used for assay evaluation. Furthermore, a possible association between the hormone receptor expression in different histological subtypes of canine malignant mammary tumors and the castration status, breed and invasive growth of the tumor were analyzed. The multiplex bDNA assay proved to be more sensitive for fresh frozen specimens. Hormone receptor expression found was significantly decreased in malignant mammary tumors in comparison to non-neoplastic tissue and benign mammary tumors. Among the histological subtypes the lowest gene expression levels of ESR1, PGR and PRLR were found in solid, anaplastic and ductal carcinomas. In summary, the evaluation showed that the measurement of hormone receptors with the multiplex bDNA assay represents a practicable method for obtaining detailed quantitative information about gene expression in canine mammary tissue for future studies. Still, comparison with IHC or quantitative real-time PCR is needed for further validation of the present method.

  20. Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome.

    Science.gov (United States)

    Hui, Hamilton N T; Metherell, Louise A; Ng, K L; Savage, Martin O; Camacho-Hübner, Cecilia; Clark, Adrian J L

    2005-02-01

    Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.

  1. Identification of a novel mutation in the human growth hormone receptor gene (GHR) in a patient with Laron syndrome.

    Science.gov (United States)

    Gennero, Isabelle; Edouard, Thomas; Rashad, Mona; Bieth, Eric; Conte-Aurio, Françoise; Marin, Françoise; Tauber, Maithé; Salles, Jean Pierre; El Kholy, Mohamed

    2007-07-01

    Deletions and mutations in the growth hormone receptor (GHR) gene are the underlying etiology of Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS), an autosomal recessive disease. Most patients are distributed in or originate from Mediterranean and Middle-Eastern countries. Sixty mutations have been described so far. We report a novel mutation in the GHR gene in a patient with LS. Genomic DNA sequencing of exon 5 revealed a TT insertion at nucleotide 422 after codon 122. The insertion resulted in a frameshift introducing a premature termination codon that led to a truncated receptor. We present clinical, biochemical and molecular evidence of LS as the result of this homozygous insertion.

  2. Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons.

    OpenAIRE

    Flavell, D M; Wells, T; Wells, S E; Carmignac, D F; Thomas, G B; Robinson, I C

    1996-01-01

    Expression of human growth hormone (hGH) was targeted to growth hormone-releasing (GRF) neurons in the hypothalamus of transgenic rats. This induced dominant dwarfism by local feedback inhibition of GRF. One line, bearing a single copy of a GRF-hGH transgene, has been characterized in detail, and has been termed Tgr (for Transgenic growth-retarded). hGH was detected by immunocytochemistry in the brain, restricted to the median eminence of the hypothalamus. Low levels were also detected in the...

  3. CORTICOTROPIN-RELEASING HORMONE MICROINFUSION IN THE CENTRAL AMYGDALA DIMINISHES A CARDIAC PARASYMPATHETIC OUTFLOW UNDER STRESS-FREE CONDITIONS

    NARCIS (Netherlands)

    WIERSMA, A; BOHUS, B; KOOLHAAS, JM

    1993-01-01

    The central nucleus of the amygdala (CeA) is known to be involved in the regulation of autonomic, neuroendocrine and behavioural responses in stress situations. The CeA contains large numbers of corticotropin-releasing hormone (CRH) cell bodies. Neuroanatomical studies revealed that the majority of

  4. Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus

    NARCIS (Netherlands)

    Cope, J.L.; Regev, L.; Chen, Y.; Korosi, A.; Rice, C.J.; Ji, S.; Rogge, G.A.; Wood, M.A.; Baram, T.Z.

    2014-01-01

    Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely-tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in hypothalamus, CRH is

  5. D-2 dopamine receptor activation reduces free [3H]arachidonate release induced by hypophysiotropic peptides in anterior pituitary cells

    International Nuclear Information System (INIS)

    Canonico, P.L.

    1989-01-01

    Dopamine reduces the stimulation of intracellular [ 3 H]arachidonate release produced by the two PRL-stimulating peptides angiotensin-II and TRH. This effect is concentration dependent and is mediated by stimulation of D-2 dopamine receptors. D-2 receptor agonists (bromocriptine, dihydroergocryptine, and dihydroergocristine) inhibit the release of fatty acid induced by angiotensin-II with a potency that parallels their ability to inhibit PRL release in vitro. Conversely, the selective D-2 receptor antagonist L-sulpiride completely prevents dopamine's effect, whereas SCH 23390 (a D-1 receptor antagonist) is ineffective. The inhibitory action of dopamine does not seem to be consequent to an action on the adenylate cyclase-cAMP system, as 8-bromo-cAMP (1 mM) does not affect either basal or dopamine-inhibited [ 3 H]arachidonate release. However, a 24-h pertussis toxin pretreatment significantly reduces the action of dopamine on fatty acid release. Collectively, these results suggest that D-2 dopamine receptor-mediated inhibition of intracellular [ 3 H]arachidonate release requires the action of a GTP-binding protein, but is not a consequence of an inhibitory action on cAMP levels

  6. Sigma receptor ligand N,N'-di-(ortho-tolyl)guanidine inhibits release of acetylcholine in the guinea pig ileum.

    Science.gov (United States)

    Cambell, B G; Keana, J F; Weber, E

    1991-11-26

    The inhibition of stimulated contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation by sigma receptor ligands has been previously described. In this study, the stimulated release of [3H]acetylcholine from cholinergic nerve terminals in this same preparation was monitored in the presence and absence of sigma receptor ligands. N,N'-Di-(orthotolyl)guanidine (DTG) and other compounds selective for the sigma receptor inhibited stimulated [3H]acetylcholine release. These results suggest that their inhibition of stimulated contractions in this preparation was mediated by inhibition of acetylcholine release.

  7. [The changes of ghrelin, growth hormone, growth hormone releasing hormone and their clinical significances in patients with chronic obstructive pulmonary disease].

    Science.gov (United States)

    Xu, Zhi-song; Bao, Zi-yu; Wang, Zhi-ying; Yang, Guo-jun; Zhu, Dong-fang; Zhang, Li; Tan, Rong-mei

    2012-07-01

    To investigate the changes of plasma ghrelin, growth hormone (GH) and growth hormone releasing hormone (GHRH) and gastric ghrelin in patients with chronic obstructive pulmonary disease (COPD) and to explore their clinical significances. Plasma ghrelin, GH, GHRH, TNFα, IL-6 and C reactive protein (CRP) were measured in 40 COPD patients and 20 controls with chronic bronchitis. Correlated factors of plasma ghrelin, TNFα, IL-6, CRP were analyzed. Body composition was assessed with bioelectrical impedance analysis. The expression of gastric ghrelin in patients with COPD was detected. Plasma ghrelin was higher in the underweight patients than in the normal weight patients and in the controls [(1.78 ± 0.46) ng/L, (1.39 ± 0.46) ng/L, (1.36 ± 0.39) ng/L, respectively]. Plasma GH was lower in the underweight patients than in the normal weight patients and in the controls [(4.12 ± 0.83) µg/L, (5.17 ± 0.72)µg/L, (6.49 ± 1.13) µg/L, respectively]. Plasma GHRH was lower in the underweight patients than in the normal weight patients and in the controls [(20.43 ± 4.41) ng/L, (23.47 ± 3.97) ng/L, (27.48 ± 10.06) ng/L, respectively]. Plasma ghrelin was higher in the underweight patients than in the controls (P 0.05). Plasma ghrelin was positively correlated with TNFα and IL-6 in the underweight patients. The gastric expression of ghrelin showed no evident difference between the patients with COPD and the controls. The plasma GH in COPD patients may not be correlated with ghrelin. The plasma ghrelin level may be a useful indicator for malnutrition in COPD patients. Plasma ghrelin might be involved in the pathogenesis of CODP by affecting the body energy metabolism.

  8. Peptide hormones and lung cancer.

    Science.gov (United States)

    Moody, T W

    2006-03-01

    Several peptide hormones have been identified which alter the proliferation of lung cancer. Small cell lung cancer (SCLC), which is a neuroendocrine cancer, produces and secretes gastrin releasing peptide (GRP), neurotensin (NT) and adrenomedullin (AM) as autocrine growth factors. GRP, NT and AM bind to G-protein coupled receptors causing phosphatidylinositol turnover or elevated cAMP in SCLC cells. Addition of GRP, NT or AM to SCLC cells causes altered expression of nuclear oncogenes, such as c-fos, and stimulation of growth. Antagonists have been developed for GRP, NT and AM receptors which function as cytostatic agents and inhibit SCLC growth. Growth factor antagonists, such as the NT1 receptor antagonist SR48692, facilitate the ability of chemotherapeutic drugs to kill lung cancer cells. It remains to be determined if GRP, NT and AM receptors will served as molecular targets, for development of new therapies for the treatment of SCLC patients. Non-small cell lung cancer (NSCLC) cells also have a high density of GRP, NT, AM and epidermal growth factor (EGF) receptors. Several NSCLC patients with EGF receptor mutations respond to gefitinib, a tyrosine kinase inhibitor. Gefitinib relieves NSCLC symptoms, maintaining stable disease in patients who are not eligible for systemic chemotherapy. It is important to develop new therapeutic approaches using translational research techniques for the treatment of lung cancer patients.

  9. Transcriptomic and phenotypic profiling in developing zebrafish exposed to thyroid hormone receptor agonists

    Energy Technology Data Exchange (ETDEWEB)

    Haggard, Derik E.; Noyes, Pamela D.; Waters, Katrina M.; Tanguay, Robert L.

    2018-04-01

    There is a need to develop novel, high-throughput screening and prioritization methods to identify chemicals with adverse estrogen, androgen, and thyroid activity to protect human health and the environment and is of interest to the Endocrine Disruptor Screening Program. The current aim is to explore the utility of zebrafish as a testing paradigm to classify endocrine activity using phenotypically anchored transcriptome profiling. Transcriptome analysis was conducted on embryos exposed to 25 estrogen-, androgen-, or thyroid-active chemicals at a concentration that elicited adverse malformations or mortality at 120 hours post-fertilization in 80% of the animals exposed. Analysis of the top 1000 significant differentially expressed transcripts across all treatments identified a unique transcriptional and phenotypic profile for thyroid hormone receptor agonists, which can be used as a biomarker screen for potential thyroid hormone agonists.

  10. Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the invasiveness of endometrial cancer cells through the GnRH-I receptor and mitogen-activated protein kinase (MAPK)-dependent activation of matrix metalloproteinase (MMP)-2

    International Nuclear Information System (INIS)

    Wu, Hsien-Ming; Wang, Hsin-Shih; Huang, Hong-Yuan; Lai, Chyong-Huey; Lee, Chyi-Long; Soong, Yung-Kuei; Leung, Peter CK

    2013-01-01

    More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastases. Gonadotropin-releasing hormone (GnRH) plays an important role in reproduction. In mammals, expression of GnRH-II is higher than GnRH-I in reproductive tissues. Here, we examined the effect of a GnRH-II agonist on the motility of endometrial cancer cells and its mechanism of action in endometrial cancer therapy. Immunoblotting and immunohistochemistry (IHC) were used to determine the expression of the GnRH-I receptor protein in human endometrial cancer. The activity of MMP-2 in the conditioned medium was determined by gelatin zymography. Cell motility was assessed by invasion and migration assay. GnRH-I receptor si-RNA was applied to knockdown GnRH-I receptor. The GnRH-I receptor was expressed in the endometrial cancer cells. The GnRH-II agonist promoted cell motility in a dose-dependent manner. The GnRH-II agonist induced the phosphorylation of ERK1/2 and JNK, and the phosphorylation was abolished by ERK1/2 inhibitor (U0126) and the JNK inhibitor (SP600125). Cell motility promoted by GnRH-II agonist was suppressed in cells that were pretreated with U0126 and SP600125. Moreover, U0126 and SP600125 abolished the GnRH-II agonist-induced activation of MMP-2. The inhibition of MMP-2 with MMP-2 inhibitor (OA-Hy) suppressed the increase in cell motility in response to the GnRH-II agonist. Enhanced cell motility mediated by GnRH-II agonist was also suppressed by the knockdown of the endogenous GnRH-I receptor using siRNA. Our study indicates that GnRH-II agonist promoted cell motility of endometrial cancer cells through the GnRH-I receptor via the phosphorylation of ERK1/2 and JNK, and the subsequent, MAPK-dependent activation of MMP-2. Our findings represent a new concept regarding the mechanism of GnRH-II-induced cell motility in endometrial cancer cells and suggest the possibility of exploring GnRH-II as a potential therapeutic target for the

  11. Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.

    Science.gov (United States)

    Nair, Deepti; Ramesh, Vijay; Li, Richard C; Schally, Andrew V; Gozal, David

    2013-11-01

    Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep. © 2013 International Society for Neurochemistry.

  12. Gastrointestinal hormones and their targets

    DEFF Research Database (Denmark)

    Rehfeld, Jens F.

    2014-01-01

    Gastrointestinal hormones are peptides released from endocrine cells and neurons in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gastrointestinal tract, which makes the gut the largest hormone producing organ in the body. Modern biology makes...... it feasible to conceive the hormones under five headings: The structural homology groups a majority of the hormones into nine families, each of which is assumed to originate from one ancestral gene. The individual hormone gene often has multiple phenotypes due to alternative splicing, tandem organization......, or differentiated maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gut. Gut hormone genes are also widely expressed in cells outside the gut, some only in extraintestinal endocrine cells and neurons but others also in other...

  13. Resistance to thyroid hormone due to defective thyroid receptor alpha.

    Science.gov (United States)

    Moran, Carla; Chatterjee, Krishna

    2015-08-01

    Thyroid hormones act via nuclear receptors (TRα1, TRβ1, TRβ2) with differing tissue distribution; the role of α2 protein, derived from the same gene locus as TRα1, is unclear. Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic facies, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), growth retardation, constipation, dyspraxia and intellectual deficit. Biochemical abnormalities include low/low-normal T4 and high/high-normal T3 concentrations, a subnormal T4/T3 ratio, variably reduced reverse T3, raised muscle creatine kinase and mild anaemia. The disorder is mediated by heterozygous, loss-of-function, mutations involving either TRα1 alone or both TRα1 and α2, with no discernible phenotype attributable to defective α2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTHα, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTHα and its optimal management remain to be elucidated. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

    OpenAIRE

    Vamvakopoulos, Nicholas V.

    1995-01-01

    This review higlghts key aspects of corticotropin releasing hormone (CRH) biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h) CRH gene: (1) a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic gl...

  15. The relationships among acculturation, biobehavioral risk, stress, corticotropin-releasing hormone, and poor birth outcomes in Hispanic women.

    Science.gov (United States)

    Ruiz, R Jeanne; Dolbier, Christyn L; Fleschler, Robin

    2006-01-01

    To determine the predictive ability of acculturation as an antecedent of stress, biobehavioral risk, corticotropin-releasing hormone levels, and poor birth outcomes in pregnant Hispanic women. A prospective, observational design with data collected at 22-25 weeks of gestation and at birth through medical record review. Public prenatal health clinics in south Texas serving low-income women. Self-identified Hispanic women who had singleton pregnancies, no major medical risk complications, and consented to answer questionnaires as well as a venipuncture and review of their prenatal and birth medical records. Gestational age, Apgar scores, length, weight, percentile size, and head circumference of the infant at birth. Significant differences were seen in infant birth weight, head circumference, and percentile size by acculturation. English acculturation predicted stress, corticotropin-releasing hormone, biobehavioral risk, and decreased gestational age at birth. Investigation must continue to understand the circumstances that give rise to the decline in birth outcomes observed in Hispanics with acculturation to the dominant English culture in the United States.

  16. Modulation of Central Synapses by Astrocyte-Released ATP and Postsynaptic P2X Receptors

    Science.gov (United States)

    Pankratov, Yuriy

    2017-01-01

    Communication between neuronal and glial cells is important for neural plasticity. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. Recent data show that postsynaptic P2X receptors underlie slow neuromodulatory actions rather than fast synaptic transmission at brain synapses. Here, we review these findings with a particular focus on the release of ATP by astrocytes and the diversity of postsynaptic P2X-mediated modulation of synaptic strength and plasticity in the CNS. PMID:28845311

  17. The interaction between tropomyosin-related kinase B receptors and serine kinases modulates acetylcholine release in adult neuromuscular junctions.

    Science.gov (United States)

    Santafé, Manel M; Garcia, Neus; Tomàs, Marta; Obis, Teresa; Lanuza, Maria A; Besalduch, Nuria; Tomàs, Josep

    2014-02-21

    We conducted an electrophysiological study of the functional link between the tropomyosin-related kinase B (trkB) receptor signaling mechanism and serine-threonine kinases, both protein kinase C (PKC) and protein kinase A (PKA). We describe their coordinated role in transmitter release at the neuromuscular junction (NMJ) of the Levator auris longus muscle of the adult mouse. The trkB receptor normally seems to be coupled to stimulate ACh release because inhibiting the trkB receptor with K-252a results in a significant reduction in the size of EPPs. We found that the intracellular PKC pathway can operate as in basal conditions (to potentiate ACh release) without the involvement of the trkB receptor function, although the trkB pathway needs an operative PKC pathway if it is to couple to the release mechanism and potentiate it. To actively stimulate PKA (which also results in ACh release potentiation), the operativity of trkB is a necessary condition, and one effect of trkB may be PKA stimulation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Serum Testosterone Levels in Prostate Cancer Patients Undergoing Luteinizing Hormone-Releasing Hormone Agonist Therapy.

    Science.gov (United States)

    Morote, Juan; Comas, Inma; Planas, Jacques; Maldonado, Xavier; Celma, Ana; Placer, José; Ferrer, Roser; Carles, Joan; Regis, Lucas

    2018-04-01

    Serum testosterone measurement is recommended to assess the efficacy of androgen deprivation therapy (ADT) and to diagnose castration resistance in patients with prostate cancer (PCa). Currently, the accepted castrate level of serum testosterone is 50 ng/dL. Liquid chromatography and tandem mass spectrometry (LC MSMS) is the appropriate method to measure testosterone, especially at low levels. However, worldwide, chemiluminescent assays (CLIAs) are used in clinical laboratories, despite their lack of accuracy and reproducibility, because they are automatable, fast, sensitive, and inexpensive. We compared serum testosterone levels measured using LC MSMS and CLIAs in 126 patients with PCa undergoing luteinizing hormone-releasing hormone (LHRH) agonist therapy. The median serum testosterone level was 14.0 ng/dL (range, 2.0-67.0 ng/dL) with LC MSMS and 31.9 ng/dL (range, 10.0-91.6 ng/dL) with CLIA (P  50 ng/dL in 3 patients (2.4%). These ranges were found in 34 (27%), 72 (57.1%), and 20 (15.9%) patients when testosterone was measured using CLIA (P < .001). The castrate level of serum testosterone using LC MSMS and CLIA was 39.8 ng/dL (95% confidence interval [CI], 37.1-43.4 ng/dL) and 66.5 ng/dL (95% CI, 62.3-71.2 ng/dL), respectively. We found that CLIA overestimated the testosterone levels in PCa patients undergoing LHRH agonist therapy. Thus, the castration level was incorrectly considered inadequate with CLIA in almost 15% of patients. The true castration level of serum testosterone using an appropriate method is < 50 ng/dL. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved.

    Science.gov (United States)

    Bonfiglio, Juan José; Inda, Carolina; Refojo, Damián; Holsboer, Florian; Arzt, Eduardo; Silberstein, Susana

    2011-01-01

    Corticotropin-releasing hormone (CRH) plays a key role in adjusting the basal and stress-activated hypothalamic-pituitary-adrenal axis (HPA). CRH is also widely distributed in extrahypothalamic circuits, where it acts as a neuroregulator to integrate the complex neuroendocrine, autonomic, and behavioral adaptive response to stress. Hyperactive and/or dysregulated CRH circuits are involved in neuroendocrinological disturbances and stress-related mood disorders such as anxiety and depression. This review describes the main physiological features of the CRH network and summarizes recent relevant information concerning the molecular mechanism of CRH action obtained from signal transduction studies using cells and wild-type and transgenic mice lines. Special focus is placed on the MAPK signaling pathways triggered by CRH through the CRH receptor 1 that plays an essential role in CRH action in pituitary corticotrophs and in specific brain structures. Recent findings underpin the concept of specific CRH-signaling pathways restricted to specific anatomical areas. Understanding CRH action at molecular levels will not only provide insight into the precise CRH mechanism of action, but will also be instrumental in identifying novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders. Copyright © 2011 S. Karger AG, Basel.

  20. A nonpeptidyl growth hormone secretagogue.

    Science.gov (United States)

    Smith, R G; Cheng, K; Schoen, W R; Pong, S S; Hickey, G; Jacks, T; Butler, B; Chan, W W; Chaung, L Y; Judith, F

    1993-06-11

    A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.

  1. The little women of Loja--growth hormone-receptor deficiency in an inbred population of southern Ecuador.

    Science.gov (United States)

    Rosenbloom, A L; Guevara Aguirre, J; Rosenfeld, R G; Fielder, P J

    1990-11-15

    Laron-type dwarfism, which is characterized by the clinical appearance of isolated growth hormone deficiency with elevated serum levels of growth hormone and decreased serum levels of insulin-like growth factor I (IGF-I), has been described in approximately 50 patients. This condition is caused by a deficiency of the cellular receptor for growth hormone, and it is transmitted as an autosomal recessive trait, as indicated by an equal sex distribution and a high rate of consanguinity in affected families. We studied 20 patients (19 females and 1 male, 2 to 49 years of age), from an inbred Spanish population in southern Ecuador, who had the clinical features of Laron-type dwarfism. Seventeen patients were members of two large pedigrees. Among the 13 affected sibships, there were 19 affected and 24 unaffected female siblings and 1 affected and 21 unaffected male siblings. The patients' heights ranged from 10.0 to 6.7 SD below the normal mean height for age in the United States. In addition to the previously described features, 15 patients had limited elbow extensibility, all had blue scleras, affected adults had relatively short extremities, and all four affected women over 30 years of age had hip degeneration. Basal serum concentrations of growth hormone were elevated in all affected children (30 to 160 micrograms per liter) and normal to moderately elevated in the adults. The serum level of growth hormone-binding protein ranged from 1 to 30 percent of normal; IGF-I concentrations were low--less than or equal to 7 micrograms per liter in the children and less than or equal to 66 micrograms per liter in the adults (normal for Ecuadorean women, 98 to 238). Serum levels of IGF-II and growth hormone-dependent IGF-binding protein-3 were also low. We describe an inbred population with a high incidence of growth hormone-receptor deficiency resulting in a clinical picture resembling Laron-type dwarfism but differing principally in showing a marked predominance of affected

  2. A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation

    DEFF Research Database (Denmark)

    Chhabra, Y.; Wong, H. Y.; Nikolajsen, Louise Fletcher

    2018-01-01

    Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lu......-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2 h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.Oncogene advance online publication, 2 October 2017; doi:10.1038/onc.2017.352....

  3. Functional Characterization and Signaling Systems of Corazonin and Red Pigment Concentrating Hormone in the Green Shore Crab, Carcinus maenas

    Directory of Open Access Journals (Sweden)

    Jodi L. Alexander

    2018-01-01

    Full Text Available Neuropeptides play a central role as neurotransmitters, neuromodulators and hormones in orchestrating arthropod physiology. The post-genomic surge in identified neuropeptides and their putative receptors has not been matched by functional characterization of ligand-receptor pairs. Indeed, until very recently no G protein-coupled receptors (GPCRs had been functionally defined in any crustacean. Here we explore the structurally-related, functionally-diverse gonadotropin-releasing hormone paralogs, corazonin (CRZ and red-pigment concentrating hormone (RPCH and their G-protein coupled receptors (GPCRs in the crab, Carcinus maenas. Using aequorin luminescence to measure in vitro Ca2+ mobilization we demonstrated receptor-ligand pairings of CRZ and RPCH. CRZR-activated cell signaling in a dose-dependent manner (EC50 0.75 nM and comparative studies with insect CRZ peptides suggest that the C-terminus of this peptide is important in receptor-ligand interaction. RPCH interacted with RPCHR with extremely high sensitivity (EC50 20 pM. Neither receptor bound GnRH, nor the AKH/CRZ-related peptide. Transcript distributions of both receptors indicate that CRZR expression was, unexpectedly, restricted to the Y-organs (YO. Application of CRZ peptide to YO had no effect on ecdysteroid biosynthesis, excepting a modest stimulation in early post-molt. CRZ had no effect on heart activity, blood glucose levels, lipid mobilization or pigment distribution in chromatophores, a scenario that reflected the distribution of its mRNA. Apart from the well-known activity of RPCH as a chromatophorotropin, it also indirectly elicited hyperglycemia (which was eyestalk-dependent. RPCHR mRNA was also expressed in the ovary, indicating possible roles in reproduction. The anatomy of CRZ and RPCH neurons in the nervous system is described in detail by immunohistochemistry and in situ hybridization. Each peptide has extensive but non-overlapping distribution in the CNS, and neuroanatomy

  4. Hypothalamic-pituitary thyroid axis alterations in female mice with deletion of the neuromedin B receptor gene.

    Science.gov (United States)

    Oliveira, Karen J; Paula, Gabriela S M; Império, Guinever E; Bressane, Nina O; Magalhães, Carolina M A; Miranda-Alves, Leandro; Ortiga-Carvalho, Tania M; Pazos-Moura, Carmen C

    2014-11-01

    Neuromedin B, a peptide highly expressed at the pituitary, has been shown to act as autocrine/paracrine inhibitor of thyrotropin (TSH) release. Here we studied the thyroid axis of adult female mice lacking neuromedin B receptor (NBR-KO), compared to wild type (WT) littermates. They exhibited slight increase in serum TSH (18%), with normal pituitary expression of mRNA coding for α-glycoprotein subunit (Cga), but reduced TSH β-subunit mRNA (Tshb, 41%), lower intra-pituitary TSH content (24%) and increased thyroid hormone transporter MCT-8 (Slc16a2, 44%) and thyroid hormone receptor β mRNA expression (Thrb, 39%). NBR-KO mice exhibited normal thyroxine (T4) and reduced triiodothyronine (T3) (30%), with no alterations in the intra-thyroidal content of T4 and T3 or thyroid morphological changes. Hypothalamic thyrotropin-releasing hormone (TRH) mRNA (Trh) was increased (68%), concomitant with a reduction in type 2 deiodinase mRNA (Dio2, 30%) and no changes in MCT-8 and thyroid hormone receptor mRNA expression. NBR-KO mice exhibited a 56% higher increase in serum TSH in response to an acute single intraperitoneal injection of TRH concomitant with a non-significant increase in pituitary TRH receptor (Trhr) mRNA at basal state. The phenotype of female NBR-KO mice at the hypothalamus-pituitary axis revealed alterations in pituitary and hypothalamic gene expression, associated with reduced serum T3, and higher TSH response to TRH, with apparently normal thyroid morphology and hormonal production. Thus, results confirm that neuromedin B pathways are importantly involved in secretory pathways of TSH and revealed its participation in the in vivo regulation of gene expression of TSH β-subunit and pituitary MCT8 and Thrb and hypothalamic TRH and type 2 deiodinase. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Review of hormonal treatment of breast cancer | Abdulkareem ...

    African Journals Online (AJOL)

    This critical review focuses on the role of steroid hormones and their receptors in the development and treatment of breast cancer, with special reference to estrogen receptors, as well as mechanisms of receptor.ligand interactions, response or resistance to hormonal therapy against breast cancer, in conjunction with other ...

  6. Estrogen receptor beta and 2-arachydonoylglycerol mediate the suppressive effects of estradiol on frequency of postsynaptic currents in gonadotropin-releasing hormone neurons of metestrous mice: an acute slice electrophysiological study

    Directory of Open Access Journals (Sweden)

    Flóra eBálint

    2016-03-01

    Full Text Available Gonadotropin-releasing hormone (GnRH neurons are controlled by 17β-estradiol (E2 contributing to the steroid feedback regulation of the reproductive axis. In rodents, E2 exerts a negative feedback effect upon GnRH neurons throughout the estrus-diestrus phase of the ovarian cycle. The present study was undertaken to reveal the role of estrogen receptor subtypes in the mediation of the E2 signal and elucidate the downstream molecular machinery of suppression. The effect of E2 administration at low physiological concentration (10 pM on GnRH neurons in acute brain slices obtained from metestrous GnRH-GFP mice was studied under paradigms of blocking or activating estrogen receptor subtypes and interfering with retrograde 2-arachydonoylglycerol (2-AG signaling. Whole-cell patch clamp recordings revealed that E2 significantly diminished the frequency of spontaneous postsynaptic currents (sPSCs in GnRH neurons (49. 62±7.6% which effect was abolished by application of the ERα/β blocker Faslodex (1 µM. Pretreatment of the brain slices with cannabinoid receptor type 1 (CB1 inverse agonist AM251 (1 µM and intracellularly applied endocannabinoid synthesis blocker THL (10 µM significantly attenuated the effect of E2 on the sPSCs. E2 remained effective in the presence of TTX indicating a direct action of E2 on GnRH cells. The ERβ specific agonist DPN (10 pM also significantly decreased the frequency of miniature postsynaptic currents (mPSCs in GnRH neurons. In addition, the suppressive effect of E2 was completely blocked by the selective ERβ antagonist PHTPP (1 µM indicating that ERβ is required for the observed rapid effect of the E2. In contrast, the ERα agonist PPT (10 pM or the membrane-associated G protein-coupled estrogen receptor (GPR30 agonist G1 (10 pM had no significant effect on the frequency of mPSCs in these neurons. AM251 and THL significantly abolished the effect of E2 whereas AM251 eliminated the action of DPN on the mPSCs. These

  7. Group I mGlu receptors potentiate synaptosomal [{sup 3}H]glutamate release independently of exogenously applied arachidonic acid

    Energy Technology Data Exchange (ETDEWEB)

    Reid, M.E.; Toms, N.J.; Bedingfield, J.S.; Roberts, P.J. [Department of Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD (United Kingdom)

    1999-04-01

    In the current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [{sup 3}H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 {mu}M) increased 4AP-evoked [{sup 3}H]glutamate release (143.32{+-}2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC{sub 50}=1.60{+-}0.25 {mu}M; E{sub max}=147.61{+-}10.96% control) 4AP-evoked [{sup 3}H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu{sub 1} receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 {mu}M) and was BSA-insensitive. The selective mGlu{sub 5} receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300{mu}M) was without effect. DHPG (100 {mu}M) also potentiated both 30 mM and 50 mM K{sup +}-evoked [{sup 3}H]glutamate release (121.60{+-}12.77% and 121.50{+-}4.45% control, respectively). DHPG (100 {mu}M) failed to influence both 4AP-stimulated {sup 45}Ca{sup 2+} influx and 50 mM K{sup +}-induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A{sub 1} receptor, group II/III mGlu receptors or GABA{sub B} receptor activity is unlikely since 4AP-evoked [{sup 3}H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-{alpha}-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu{sub 1} receptor-like' receptor potentiates [{sup 3}H]glutamate release from cerebrocortical synaptosomes in the absence of

  8. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  9. Autocrine Regulation of UVA-Induced IL-6 Production via Release of ATP and Activation of P2Y Receptors

    Science.gov (United States)

    Kawano, Ayumi; Kadomatsu, Remi; Ono, Miyu; Kojima, Shuji; Tsukimoto, Mitsutoshi; Sakamoto, Hikaru

    2015-01-01

    Extracellular nucleotides, such as ATP, are released from cells in response to various stimuli and act as intercellular signaling molecules through activation of P2 receptors. Exposure to the ultraviolet radiation A (UVA) component of sunlight causes molecular and cellular damage, and in this study, we investigated the involvement of extracellular nucleotides and P2 receptors in the UVA-induced cellular response. Human keratinocyte-derived HaCaT cells were irradiated with a single dose of UVA (2.5 J/cm2), and ATP release and interleukin (IL)-6 production were measured. ATP was released from cells in response to UVA irradiation, and the release was blocked by pretreatment with inhibitors of gap junction hemichannels or P2X7 receptor antagonist. IL-6 production was increased after UVA irradiation, and this increase was inhibited by ecto-nucleotidase or by antagonists of P2Y11 or P2Y13 receptor. These results suggest that UVA-induced IL-6 production is mediated by release of ATP through hemichannels and P2X7 receptor, followed by activation of P2Y11 and P2Y13 receptors. Interestingly, P2Y11 and P2Y13 were associated with the same pattern of IL-6 production, though they trigger different intracellular signaling cascades: Ca2+-dependent and PI3K-dependent, respectively. Thus, IL-6 production in response to UVA-induced ATP release involves at least two distinct pathways, mediated by activation of P2Y11 and P2Y13 receptors. PMID:26030257

  10. Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist

    DEFF Research Database (Denmark)

    Vuong, T. N. L.; Ho, M. T.; Ha, T. D.

    2016-01-01

    -35 years, body mass index [BMI] hormone level >1.25 ng/mL, and antral follicle count >= 6). Intervention(s): Ovulation trigger with 0.2, 0.3, or 0.4 mg triptorelin in a GnRH antagonist cycle. Main Outcome Measure(s): The primary end point was number of metaphase II oocytes...... to number of metaphase II oocytes (16.0 +/- 8.5, 15.9 +/- 7.8, and 14.7 +/- 8.4, respectively), embryos (13.2 +/- 7.8, 11.7 +/- 6.9, 11.8 +/- 7.0), and number of top-quality embryos (3.8 +/- 2.9, 3.6 +/- 3.0, 4.1 +/- 3.0). Luteinizing hormone levels at 24 hours and 36 hours after trigger was significantly...

  11. Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

    Directory of Open Access Journals (Sweden)

    Gerd Krause

    2017-04-01

    Full Text Available The thyroid-stimulating hormone receptor (TSHR is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs. TSHR and its endogenous ligand thyrotropin (TSH are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016 concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other

  12. Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.

    Science.gov (United States)

    Kleinau, Gunnar; Worth, Catherine L; Kreuchwig, Annika; Biebermann, Heike; Marcinkowski, Patrick; Scheerer, Patrick; Krause, Gerd

    2017-01-01

    The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to

  13. Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

    Science.gov (United States)

    Kleinau, Gunnar; Worth, Catherine L.; Kreuchwig, Annika; Biebermann, Heike; Marcinkowski, Patrick; Scheerer, Patrick; Krause, Gerd

    2017-01-01

    The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to

  14. Dual Actions of Mammalian and Piscine Gonadotropin-Inhibitory Hormones, RFamide-Related Peptides and LPXRFamide Peptides, in the Hypothalamic–Pituitary–Gonadal Axis

    Directory of Open Access Journals (Sweden)

    Takayoshi Ubuka

    2018-01-01

    Full Text Available Gonadotropin-inhibitory hormone (GnIH is a hypothalamic neuropeptide that decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of gonadotropin-releasing hormone (GnRH neurons. GnIH is also called RFamide-related peptide in mammals or LPXRFamide peptide in fishes due to its characteristic C-terminal structure. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. Although most of the studies in mammals, birds, and fish have shown the inhibitory action of GnIH in the hypothalamic–pituitary–gonadal (HPG axis, several in vivo studies in mammals and many in vivo and in vitro studies in fish have shown its stimulatory action. In mouse, although the firing rate of the majority of GnRH neurons is decreased, a small population of GnRH neurons is stimulated by GnIH. In hamsters, GnIH inhibits luteinizing hormone (LH release in the breeding season when their endogenous LH level is high but stimulates LH release in non-breeding season when their LH level is basal. Besides different effects of GnIH on the HPG axis depending on the reproductive stages in fish, higher concentration or longer duration of GnIH administration can stimulate their HPG axis. These results suggest that GnIH action in the HPG axis is modulated by sex-steroid concentration, the action of neuroestrogen synthesized by the activity of aromatase stimulated by GnIH, estrogen membrane receptor, heteromerization and internalization of GnIH, GnRH, and estrogen membrane receptors. The inhibitory and stimulatory action of GnIH in the HPG axis may have a physiological role to maintain reproductive homeostasis according to developmental and reproductive stages.

  15. Gonadotropin-releasing hormone 2 suppresses food intake in the zebrafish, Danio rerio

    Directory of Open Access Journals (Sweden)

    Ryo eNishiguchi

    2012-10-01

    Full Text Available Gonadotropin-releasing hormone (GnRH is an evolutionarily conserved neuropeptide with 10 amino acid residues, of which several structural variants exist. A molecular form known as GnRH2 ([His5 Trp7 Tyr8]GnRH, also known as chicken GnRH II is widely distributed in vertebrates except for rodents, and has recently been implicated in the regulation of feeding behavior in goldfish. However, the influence of GnRH2 on feeding behavior in other fish has not yet been studied. In the present study, therefore, we investigated the role of GnRH2 in the regulation of feeding behavior in a zebrafish model, and examined its involvement in food intake after intracerebroventricular (ICV administration. ICV injection of GnRH2 at 0.1 and 1 pmol/g body weight (BW induced a marked decrease of food consumption in a dose-dependent manner during 30 min after feeding. Cumulative food intake was significantly decreased by ICV injection of GnRH2 at 1 pmol/g BW during the 30-min post-treatment observation period. The anorexigenic action of GnRH2 was completely blocked by treatment with the GnRH type I receptor antagonist Antide at 50 pmol/g BW. We also examined the effect of feeding condition on the expression level of the GnRH2 transcript in the hypothalamus. Levels of GnRH2 mRNA obtained from fish that had been provided excess food for 7 days were higher than those in fish that had been fed normally. These results suggest that, in zebrafish, GnRH2 acts as an anorexigenic factor, as is the case in goldfish.

  16. Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women

    NARCIS (Netherlands)

    Claessen, K. M. J. A.; Kloppenburg, M.; Kroon, H. M.; Bijsterbosch, J.; Pereira, A. M.; Romijn, J. A.; van der Straaten, T.; Nelissen, R. G. H. H.; Hofman, A.; Uitterlinden, A. G.; Duijnisveld, B. J.; Lakenberg, N.; Beekman, M.; van Meurs, J. B.; Slagboom, P. E.; Biermasz, N. R.; Meulenbelt, I.

    2014-01-01

    Background Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. Objective To study

  17. Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.; Hidalgo, J.; Milanés, M.V.; Laorden, M.L., E-mail: laorden@um.es

    2014-02-15

    Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence.

  18. Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor

    International Nuclear Information System (INIS)

    Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.; Hidalgo, J.; Milanés, M.V.; Laorden, M.L.

    2014-01-01

    Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence

  19. Crystal structure of an affinity-matured prolactin complexed to its dimerized receptor reveals the topology of hormone binding site 2

    DEFF Research Database (Denmark)

    Broutin, Isabelle; Jomain, Jean-Baptiste; Tallet, Estelle

    2010-01-01

    We report the first crystal structure of a 1:2 hormone.receptor complex that involves prolactin (PRL) as the ligand, at 3.8-A resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely relate...... and prostate cancer.......We report the first crystal structure of a 1:2 hormone.receptor complex that involves prolactin (PRL) as the ligand, at 3.8-A resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely related...... PRL receptor (PRLR) ligand. This structure allows one to draw up an exhaustive inventory of the residues involved at the PRL.PRLR site 2 interface, consistent with all previously reported site-directed mutagenesis data. We propose, with this description, an interaction model involving three structural...

  20. Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils.

    Directory of Open Access Journals (Sweden)

    Heike L Rittner

    2009-04-01

    Full Text Available In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR and/or toll like receptor (TLR agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively. Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, beta-endorphin antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim