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.

Ovulation induction with pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropins in a case of hypothalamic amenorrhea and diabetes insipidus.

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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.

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%...

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

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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.

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

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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

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.

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

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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.

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

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...

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

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

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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.

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

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

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.

Elevation of plasma gonadotropin concentration in response to mammalian gonadotropin releasing hormone (GRH) treatment of the male brown trout as determined by radioimmunoassay

International Nuclear Information System (INIS)

Crim, L.W.; Cluett, D.M.

1974-01-01

Rapid increase of the plasma gonadotropin concentration as measured by radioimmunoassay has been demonstrated in response to GRH treatment of the sexually mature male brown trout. Peak gonadotropin values were observed within 15 minutes of GRH treatment, however, the return to baseline values was prolonged compared with the mammalian response. These data support the concept that the brain, operating via releasing hormones, plays a role in the control of pituitary hormone secretion in fish

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

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

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.

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

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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

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.

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

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.

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.

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.

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)

[Spermatogenesis of pulsatile gonadotropin-releasing hormone infusion versus gonadotropin therapy in male idiopathic hypogonadotropic hypogonadism].

Science.gov (United States)

Huang, Bingkun; Mao, Jiangfeng; Xu, Hongli; Wang, Xi; Liu, Zhaoxiang; Nie, Min; Wu, Xueyan

2015-05-26

To compare the efficacies of pulsatile gonadotropin-releasing hormone (GnRH) versus human chorionic gonadotropin/human menopausal gonadotropin (HCG/HMG) for spermatogenesis in male idiopathic hypogonadotropic hypogonadism (IHH). For this retrospective study, a total of 92 male IHH outpatients from May 2010 to October 2014 were recruited and categorized into GnRH (n = 40) and HCG/HMG (n = 52) groups. Each subject selected one specific therapy voluntarily. The gonadotropin levels were measured in the first week and monthly post-treatment in GnRH group. And serum total testosterone (TT), testicular volume (TV) and rate of spermatogenesis were observed monthly post-treatment in two groups. Spermatogenesis, TT and TV were compared between two groups. All IHH patients were treated for over 3 months. The median follow-up periods in GnRH and HCG/HMG groups was 8.2 (3.0-18.4) and 9.2 (3.0-18.6) months respectively (P = 0.413). In GnRH group, LH ((0.5 ± 0.6) vs (3.4 ± 2.4) U/L, P treatment. In GnRH group, at the end of follow-up, TT ((1.0 ± 1.0) vs (7.4 ± 5.2) nmol/L, P treatment time for initial sperm appearance than HCG/HMG group ((6.5 ± 3.1) vs (10.8 ± 3.7) months, P = 0.001). Pulsatile GnRH requires a shorter time for initiation of spermatogenesis than gonadotropin therapy in IHH male patients.

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...

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.

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

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

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...

The gonadotropin-releasing hormone antagonist protocol--the protocol of choice for the polycystic ovary syndrome patient undergoing controlled ovarian stimulation

DEFF Research Database (Denmark)

Kol, Shahar; Homburg, Roy; Alsbjerg, Birgit

2012-01-01

Polycystic ovary syndrome (PCOS) patients are prone to develop ovarian hyperstimulation syndrome (OHSS), a condition which can be minimized or completely eliminated by the use of a gonadotropin-releasing hormone agonist (GnRHa) trigger. In this commentary paper, we maintain that the gonadotropin-...... ongoing pregnancy rates in the subsequent frozen-thawed transfer cycles....

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.

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.

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.

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

Gonadotropins, their receptors, and the regulation of testicular functions in fish

NARCIS (Netherlands)

Schulz, Rüdiger W; Vischer, H F; Cavaco, J E; Dos Santos Rocha, M.E.; Tyler, R.C.; Goos, H.J.; Bogerd, J.

The pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate steroidogenesis and spermatogenesis by activating receptors expressed by Leydig cells (LH receptor) and Sertoli cells (FSH receptor), respectively. This concept is also valid in fish, although the

Seasonal relationship between gonadotropin, growth hormone, and estrogen receptor mRNA expression in the pituitary gland of largemouth bass.

Science.gov (United States)

Martyniuk, Christopher J; Kroll, Kevin J; Porak, Wesley F; Steward, Cheree; Grier, Harry J; Denslow, Nancy D

2009-09-15

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) beta subunit and follicle stimulating hormone (FSH) beta subunit mRNA showed significant seasonal variation with levels peaking from January to April and were lowest from May to August. Male LMB showed more variation in gonadotropin subunit expression from month to month. Females had approximately 2-3 times higher gonadotropin mRNA levels in the pituitary when compared to males. All three gonadotropin mRNAs in females were positively correlated to gonadosomatic index (GSI), but only LHbeta mRNA was correlated to GSI in males. Gonadotropin mRNA expression also increased with increasing oocyte and sperm maturation. Gonadotropin beta subunit mRNA expression was positively correlated to GH mRNA in both sexes. The expression of all three ER isoforms was significantly correlated to each other in both sexes. The concurrent increase in all three ER mRNA isoforms with increasing gonadotropin mRNA in females and males suggests a prominent role for E2 feedback on pituitary gonadotropin synthesis in both sexes and that each of the three ER isoforms are likely to play a role in the pituitary during teleost reproduction.

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.

Neuroendocrine regulation of gonadotropin secretion in seasonally breeding birds

Directory of Open Access Journals (Sweden)

Takayoshi eUbuka

2013-03-01

Full Text Available Seasonally breeding birds detect environmental signals, such as light, temperature, food availability and presence of mates to time reproduction. Hypothalamic neurons integrate external and internal signals, and regulate reproduction by releasing neurohormones to the pituitary gland. The pituitary gland synthesizes and releases gonadotropins which in turn act on the gonads to stimulate gametogenesis and sex steroid secretion. Accordingly, how gonadotropin secretion is controlled by the hypothalamus is key to our understanding of the mechanisms of seasonal reproduction. A hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH, activates reproduction by stimulating gonadotropin synthesis and release. Another hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH, inhibits gonadotropin synthesis and release directly by acting on the pituitary gland or indirectly by decreasing the activity of GnRH neurons. Therefore, the next step to understand seasonal reproduction is to investigate how the activities of GnRH and GnIH neurons in the hypothalamus and their receptors in the pituitary gland are regulated by external and internal signals. It is possible that locally-produced triiodothyronine resulting from the action of type 2 iodothyronine deiodinase on thyroxine stimulates the release of gonadotropins, perhaps by action on GnRH neurons. The function of GnRH neurons is also regulated by transcription of the GnRH gene. Melatonin, a nocturnal hormone, stimulates the synthesis and release of GnIH and GnIH may therefore regulate a daily rhythm of gonadotropin secretion. GnIH may also temporally suppress gonadotropin secretion when environmental conditions are unfavorable. Environmental and social milieus fluctuate seasonally in the wild. Accordingly, complex interactions of various neuronal and hormonal systems need to be considered if we are to understand the mechanisms underlying seasonal reproduction.

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 ...

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

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...

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.

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.

Dual effect of melatonin on gonadotropin-releasing-hormone-induced Ca(2+) signaling in neonatal rat gonadotropes

Czech Academy of Sciences Publication Activity Database

Zemková, Hana; Vaněček, Jiří

2001-01-01

Roč. 74, č. 4 (2001), s. 262-269 ISSN 0028-3835 R&D Projects: GA ČR GA309/99/0213; GA ČR GA309/99/0215; GA AV ČR IAA5011103; GA AV ČR IAA5011105 Institutional research plan: CEZ:AV0Z5011922 Keywords : melatonin * gonadotropin-release hormone * calcium Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 2.144, year: 2001

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.

Pulsatile gonadotropin-releasing hormone therapy is associated with earlier spermatogenesis compared to combined gonadotropin therapy in patients with congenital hypogonadotropic hypogonadism

Directory of Open Access Journals (Sweden)

Jiang-Feng Mao

2017-01-01

Full Text Available Both pulsatile gonadotropin-releasing hormone (GnRH infusion and combined gonadotropin therapy (human chorionic gonadotropin and human menopausal gonadotropin [HCG/HMG] are effective to induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH. However, evidence is lacking as to which treatment strategy is better. This retrospective cohort study included 202 patients with CHH: twenty had received pulsatile GnRH and 182 had received HCG/HMG. Patients had received therapy for at least 12 months. The total follow-up time was 15.6 ± 5.0 months (range: 12-27 months for the GnRH group and 28.7 ± 13.0 months (range: 12-66 months for the HCG/HMG group. The median time to first sperm appearance was 6 months (95% confidence interval [CI]: 1.6-10.4 in the GnRH group versus 18 months (95% CI: 16.4-20.0 in the HCG/HMG group (P 1 × 10 6 ml−1 was 43.7% ± 20.4% (16 samples in the GnRH group versus 43.2% ± 18.1% (153 samples in the HCG/HMG group (P = 0.921. Notably, during follow-up, the GnRH group had lower serum testosterone levels than the HCG/HMG group (8.3 ± 4.6 vs 16.2 ± 8.2 nmol l−1 , P < 0.001. Our study found that pulsatile GnRH therapy was associated with earlier spermatogenesis and larger testicular size compared to combined gonadotropin therapy. Additional prospective randomized studies would be required to confirm these findings.

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.

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

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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.

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

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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.

Gonadotropin-releasing hormone for infertility in women with primary hypothalamic amenorrhea. Toward a more-interventional approach.

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Kesrouani, A; Abdallah, M A; Attieh, E; Abboud, J; Atallah, D; Makhoul, C

2001-01-01

To assess the effectiveness of a protocol of pulsatile gonadotropin releasing-hormone (GnRH) in treating infertility in women with primary hypothalamic amenorrhea. Retrospective analysis of 44 cycles treated at an infertility center. Twenty-four patients with primary hypothalamic amenorrhea were treated intravenously with pulsatile GnRH using 5 micrograms per bolus every 90 minutes. Ultrasound monitoring and cervical assessment by Insler's scoring system allowed timed injection of human chorionic gonadotropin (hCG) and intrauterine insemination if needed. Luteal support was provided with hCG. The ovulation rate was 95% with the 5-microgram dose. A single follicle was produced in 91% of cycles. The overall pregnancy rate per ovulatory cycle was 45%, and the pregnancy rate per patient was 83%. In patients treated previously with exogenous gonadotropins, poor results were observed. Only one case of mild overstimulation was reported. Pulsatile GnRH is an effective and safe method of treating infertility in women with primary hypothalamic amenorrhea, thus simulating normal ovulation; however, more-interventional management, including the qualitative estrogenic response, may lead to optimal results and increase the pregnancy rate.

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

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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.

Zebrafish adult-derived hypothalamic neurospheres generate gonadotropin-releasing hormone (GnRH neurons

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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.

Prenatal exposure to vinclozolin disrupts selective aspects of the gonadotropin-releasing hormone neuronal system of the rabbit

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Wadas, B.C.; Hartshorn, C.A.; Aurand, E.R.; Palmer, J.S.; Roselli, C.E.; Noel, M.L.; Gore, A.C.; Veeramachaneni, D.N.R.; Tobet, S.A.

2010-01-01

Developmental exposure to the agricultural fungicide vinclozolin can impair reproductive function in male rabbits and was previously found to decrease the number of immunoreactive-gonadotropin-releasing hormone (ir-GnRH) neurons in the region of the organum vasculosum of the lamina terminalis (OVLT) and rostral preoptic area (rPOA) by postnatal week (PNW) 6. To further examine the disruption of GnRH neurons by fetal vinclozolin exposure, in the current study, pregnant rabbits were dosed orall...

Gonadotropin-releasing hormone agonist triggering of oocyte maturation in assisted reproductive technology cycles

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Engin Türkgeldi

2015-06-01

Full Text Available Gonadotropin-releasing hormone agonists (GnRHa have gained increasing attention in the last decade as an alternative trigger for oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS. They provide a short luteinizing hormone (LH peak that limits the production of vascular endothelial growth factor, which is the key mediator leading to increased vascular permeability, the hallmark of OHSS. Initial studies showed similar oocyte yield and embryo quality compared with conventional human chorionic gonadotropin (hCG triggering; however, lower pregnancy rates and higher miscarriage rates were alarming in GnRHa triggered groups. Therefore, two approaches have been implemented to rescue the luteal phase in fresh transfers. Intensive luteal phase support (iLPS involves administiration of high doses of progesterone and estrogen and active patient monitoring. iLPS has been shown to provide satisfactory fertilization and clinical pregnancy rates, and to be especially useful in patients with high endogenous LH levels, such as in polycystic ovary syndrome. The other method for luteal phase rescue is low-dose hCG administiration 35 hours after GnRHa trigger. Likewise, this method results in statistically similar ongoing pregnancy rates (although slightly lower than to those of hCG triggered cycles. GnRHa triggering decreased OHSS rates dramatically, however, none of the rescue methods prevent OHSS totally. Cases were reported even in patients who underwent cryopreservation and did not receive hCG. GnRH triggering induces a follicle stimulating hormone (FSH surge, similar to natural cycles. Its possible benefits have been investigated and dual triggering, GnRHa trigger accompanied by a simultaneous low-dose hCG injection, has produced promising results that urge further exploration. Last of all, GnRHa triggering is useful in fertility preservation cycles in patients with hormone sensitive tumors. In conclusion, GnRHa triggering

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

The gonadotropin-inhibitory hormone (Lpxrfa) system's regulation of reproduction in the brain-pituitary axis of the zebrafish (Danio rerio).

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Spicer, Olivia Smith; Zmora, Nilli; Wong, Ten-Tsao; Golan, Matan; Levavi-Sivan, Berta; Gothilf, Yoav; Zohar, Yonathan

2017-05-01

Gonadotropin-inhibitory hormone (GNIH) was discovered in quail with the ability to reduce gonadotropin expression/secretion in the pituitary. There have been few studies on GNIH orthologs in teleosts (LPXRFamide (Lpxrfa) peptides), which have provided inconsistent results. Therefore, the goal of this study was to determine the roles and modes of action by which Lpxrfa exerts its functions in the brain-pituitary axis of zebrafish (Danio rerio). We localized Lpxrfa soma to the ventral hypothalamus, with fibers extending throughout the brain and to the pituitary. In the preoptic area, Lpxrfa fibers interact with gonadotropin-releasing hormone 3 (Gnrh3) soma. In pituitary explants, zebrafish peptide Lpxrfa-3 downregulated luteinizing hormone beta subunit and common alpha subunit expression. In addition, Lpxrfa-3 reduced gnrh3 expression in brain slices, offering another pathway for Lpxrfa to exert its effects on reproduction. Receptor activation studies, in a heterologous cell-based system, revealed that all three zebrafish Lpxrfa peptides activate Lpxrf-R2 and Lpxrf-R3 via the PKA/cAMP pathway. Receptor activation studies demonstrated that, in addition to activating Lpxrf receptors, zebrafish Lpxrfa-2 and Lpxrfa-3 antagonize Kisspeptin-2 (Kiss2) activation of Kisspeptin receptor-1a (Kiss1ra). The fact that kiss1ra-expressing neurons in the preoptic area are innervated by Lpxrfa-ir fibers suggests an additional pathway for Lpxrfa action. Therefore, our results suggest that Lpxrfa may act as a reproductive inhibitory neuropeptide in the zebrafish that interacts with Gnrh3 neurons in the brain and with gonadotropes in the pituitary, while also potentially utilizing the Kiss2/Kiss1ra pathway. © 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.

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.

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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.

Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells

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Carina Lund

2016-08-01

Full Text Available Gonadotropin-releasing hormone (GnRH neurons regulate human puberty and reproduction. Modeling their development and function in vitro would be of interest for both basic research and clinical translation. Here, we report a three-step protocol to differentiate human pluripotent stem cells (hPSCs into GnRH-secreting neurons. Firstly, hPSCs were differentiated to FOXG1, EMX2, and PAX6 expressing anterior neural progenitor cells (NPCs by dual SMAD inhibition. Secondly, NPCs were treated for 10 days with FGF8, which is a key ligand implicated in GnRH neuron ontogeny, and finally, the cells were matured with Notch inhibitor to bipolar TUJ1-positive neurons that robustly expressed GNRH1 and secreted GnRH decapeptide into the culture medium. The protocol was reproducible both in human embryonic stem cells and induced pluripotent stem cells, and thus provides a translational tool for investigating the mechanisms of human puberty and its disorders.

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

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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

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

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

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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.

Gonadotropin-releasing hormone 2 suppresses food intake in the zebrafish, Danio rerio

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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.

Gonadotropin-Releasing Hormone Modulates Vomeronasal Neuron Response to Male Salamander Pheromone

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Celeste R. Wirsig-Wiechmann

2012-01-01

Full Text Available Electrophysiological studies have shown that gonadotropin-releasing hormone (GnRH modifies chemosensory neurons responses to odors. We have previously demonstrated that male Plethodon shermani pheromone stimulates vomeronasal neurons in the female conspecific. In the present study we used agmatine uptake as a relative measure of the effects of GnRH on this pheromone-induced neural activation of vomeronasal neurons. Whole male pheromone extract containing 3 millimolar agmatine with or without 10 micromolar GnRH was applied to the nasolabial groove of female salamanders for 45 minutes. Immunocytochemical procedures were conducted to visualize and quantify relative agmatine uptake as measured by labeling density of activated vomeronasal neurons. The relative number of labeled neurons did not differ between the two groups: pheromone alone or pheromone-GnRH. However, vomeronasal neurons exposed to pheromone-GnRH collectively demonstrated higher labeling intensity, as a percentage above background (75% as compared with neurons exposed to pheromone alone (63%, P < 0.018. Since the labeling intensity of agmatine within neurons signifies the relative activity levels of the neurons, these results suggest that GnRH increases the response of female vomeronasal neurons to male pheromone.

Double insemination and gonadotropin-releasing hormone treatment of repeat-breeding dairy cattle.

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Stevenson, J S; Call, E P; Scoby, R K; Phatak, A P

1990-07-01

Our objective was to determine if double inseminations during the same estrous period of dairy cattle eligible for their third or fourth service (repeat breeders) would improve pregnancy rates equivalent to injections of GnRH given at the time of AI. Repeat-breeding, lactating cows from six herds (five herds in the San Joaquin Valley of central California and one herd in northeast Kansas) were assigned randomly to four treatment groups when detected in estrus: 1) single AI plus no injection, 2) single AI plus 100 micrograms GnRH at AI, 3) double AI plus no injection, or 4) double AI plus 100 micrograms of GnRH at AI. Inseminations were performed according to the a.m.-p.m. rule. The second AI for the double AI treatment was given 12 to 16 h after the first AI. Injections of GnRH were given intramuscularly immediately following the single AI or the first AI of the double AI. Pregnancy rates of cows given a single AI and hormone injection were numerically higher in all six herds than those of their herdmates given only a single AI. In five of six herds, the pregnancy rates of cows given a double AI and hormone injection were numerically higher than pregnancy rates of their herdmates given only a double AI. Overall pregnancy rates for the four treatments were 1) 112/353 (32.1%), 2) 165/406 (41.6%), 3) 119/364 (33.5%), and 4) 135/359 (37.5%). Gonadotropin-releasing hormone increased pregnancy rates of repeat breeders compared with controls given only a single AI. No further benefit beyond the single AI was accrued from the double AI treatment, with or without concurrent hormone administration.

Gonadotropin-releasing hormone immunoreactivity in the adult and fetal human olfactory system.

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Kim, K H; Patel, L; Tobet, S A; King, J C; Rubin, B S; Stopa, E G

1999-05-01

Studies in fetal brain tissue of rodents, nonhuman primates and birds have demonstrated that cells containing gonadotropin-releasing hormone (GnRH) migrate from the olfactory placode across the nasal septum into the forebrain. The purpose of this study was to examine GnRH neurons in components of the adult and fetal human olfactory system. In the adult human brain (n=4), immunoreactive GnRH was evident within diffusely scattered cell bodies and processes in the olfactory bulb, olfactory nerve, olfactory cortex, and nervus terminalis located on the anterior surface of the gyrus rectus. GnRH-immunoreactive structures showed a similar distribution in 20-week human fetal brains (n=2), indicating that the migration of GnRH neurons is complete at this time. In 10-11-week fetal brains (n=2), more cells were noted in the nasal cavity than in the brain. Our data are consistent with observations made in other species, confirming olfactory derivation and migration of GnRH neurons into the brain from the olfactory placode. Copyright 1999 Elsevier Science B.V.

Microdose gonadotropin-releasing hormone agonist in the absence of exogenous gonadotropins is not sufficient to induce multiple follicle development.

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Chung, Karine; Fogle, Robin; Bendikson, Kristin; Christenson, Kamilee; Paulson, Richard

2011-01-01

Because the effectiveness of the "microdose flare" stimulation protocol often is attributed to the dramatic endogenous gonadotropin release induced by the GnRH agonist, the aim of this study was to determine whether use of microdose GnRH agonist alone could induce multiple ovarian follicle development in normal responders. Based on these data, the duration of gonadotropin rise is approximately 24 to 48 hours and is too brief to sustain continued multiple follicle growth. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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.

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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.

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

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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.

The Forkhead Transcription Factor, FOXP3, Is Required for Normal Pituitary Gonadotropin Expression in Mice1

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Jung, Deborah O.; Jasurda, Jake S.; Egashira, Noboru; Ellsworth, Buffy S.

2012-01-01

ABSTRACT The hypothalamic-pituitary-gonadal axis is central to normal reproductive function. This pathway begins with the release of gonadotropin-releasing hormone in systematic pulses by the hypothalamus. Gonadotropin-releasing hormone is bound by receptors on gonadotroph cells in the anterior pituitary gland and stimulates the synthesis and secretion of luteinizing hormone and, to some extent, follicle-stimulating hormone. Once stimulated by these glycoprotein hormones, the gonads begin gametogenesis and the synthesis of sex hormones. In humans, mutations of the forkhead transcription factor, FOXP3, lead to an autoimmune disorder known as immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome. Mice with a mutation in the Foxp3 gene have a similar autoimmune syndrome and are infertile. To understand why FOXP3 is required for reproductive function, we are investigating the reproductive phenotype of Foxp3 mutant mice (Foxp3sf/Y). Although the gonadotroph cells appear to be intact in Foxp3sf/Y mice, luteinizing hormone beta (Lhb) and follicle-stimulating hormone beta (Fshb) expression are significantly decreased, demonstrating that these mice exhibit a hypogonadotropic hypogonadism. Hypothalamic expression of gonadotropin-releasing hormone is not significantly decreased in Foxp3sf/Y males. Treatment of Foxp3sf/Y males with a gonadotropin-releasing hormone receptor agonist does not rescue expression of Lhb or Fshb. Interestingly, we do not detect Foxp3 expression in the pituitary or hypothalamus, suggesting that the infertility seen in Foxp3sf/Y males is a secondary effect, possibly due to loss of FOXP3 in immune cells. Pituitary expression of glycoprotein hormone alpha (Cga) and prolactin (Prl) are significantly reduced in Foxp3sf/Y males, whereas the precursor for adrenocorticotropic hormone, pro-opiomelanocortin (Pomc), is increased. Human patients diagnosed with IPEX often exhibit thyroiditis due to destruction of the thyroid gland by

The nervus terminalis in amphibians: anatomy, chemistry and relationship with the hypothalamic gonadotropin-releasing hormone system.

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Muske, L E; Moore, F L

1988-01-01

The nervus terminalis (TN), a component of the olfactory system, is found in most vertebrates. The TN of some fishes and mammals contains neurons immunoreactive (ir) to gonadotropin-releasing hormone (LHRH), and to several other neuropeptides and neurotransmitter systems, but there is little information on TN chemistry in other vertebrate taxa. Using immunocytochemical techniques, we found LHRH-ir neurons in amphibian TNs. In anurans, but not in a urodele, the TN was also found to contain Phe-Met-Arg-Phe-NH2 (FMRFamide) immunoreactivity. LHRH-ir neurons of the TN and those of the septal-hypothalamic system are morphologically homogeneous and form a distinct anatomical continuum in amphibians. Based upon topographical and cytological criteria, we hypothesize that LHRH-ir systems in vertebrates might derive embryonically from the TN.

Conservation of Three-Dimensional Helix-Loop-Helix Structure through the Vertebrate Lineage Reopens the Cold Case of Gonadotropin-Releasing Hormone-Associated Peptide

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Daniela I. Pérez Sirkin; Daniela I. Pérez Sirkin; Anne-Gaëlle Lafont; Nédia Kamech; Gustavo M. Somoza; Paula G. Vissio; Paula G. Vissio; Sylvie Dufour

2017-01-01

GnRH-associated peptide (GAP) is the C-terminal portion of the gonadotropin-releasing hormone (GnRH) preprohormone. Although it was reported in mammals that GAP may act as a prolactin-inhibiting factor and can be co-secreted with GnRH into the hypophyseal portal blood, GAP has been practically out of the research circuit for about 20 years. Comparative studies highlighted the low conservation of GAP primary amino acid sequences among vertebrates, contributing to consider that this peptide onl...

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

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

1979-05-01

enhanced biological activity of the analog, therefore, may be due to its resistance to inactivation by enzymes on the pituitary cell surface. The membrane-associated inactivating enzyme could play an important role in vivo in determining the concentration of intact LHRH available at the receptor site which initiates gonadotropin release.

Induction of spermatogenesis and fertility in hypogonadotropic azoospermic men by intravenous pulsatile gonadotropin-releasing hormone (GnRH).

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Blumenfeld, Z; Makler, A; Frisch, L; Brandes, J M

1988-06-01

Gonadotropin-releasing hormone (GnRH) has only recently become a helpful tool in the medication of hypogonadotropic hypogonadism (HH). Two azoospermic patients with HH who had previously been treated with hCG/hMG because of delayed puberty and each of whom had fathered a child after previous gonadotropin therapy were referred due to secondary failure of hCG/hMG treatment to induce spermatogenesis and fertility. A pulse study where blood was drawn every 15 minutes for LH, FSH and PRL RIAs was performed in each patient, and afterwards a bolus of i.v. GnRH was injected to assess gonadotropin responsiveness. A portable GnRH pump was connected to each patient so that it administered 5-20 micrograms of GnRH i.v. every 89 minutes. Spermatogenesis was first detected after 42 and 78 days respectively in the 2 treated HH men and 4 1/2 months from the start of treatment their wives became pregnant. No thrombophlebitis or other complications of the i.v. therapy occurred. In the case of the first patient, the semen was washed and concentrated and intra-uterine inseminations were carried out in an attempt to shorten the time needed to achieve fertility. The first pregnancy was successfully terminated at 38 weeks with the delivery of 2 heterozygotic normal male babies. The second pregnancy ended in spontaneous delivery of a healthy female. We conclude that i.v. pulsatile, intermittent GnRH administration is a safe, efficient and highly successful means of treating azoospermic men with HH.

Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure.

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Dulka, Eden A; Moenter, Suzanne M

2017-11-01

Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction though pulsatile hormone release. Disruption of GnRH release as measured via luteinizing hormone (LH) pulses occurs in polycystic ovary syndrome (PCOS), and in young hyperandrogenemic girls. In adult prenatally androgenized (PNA) mice, which exhibit many aspects of PCOS, increased LH is associated with increased GnRH neuron action potential firing. How GnRH neuron activity develops over the prepubertal period and whether this is altered by sex or prenatal androgen treatment are unknown. We hypothesized GnRH neurons are active before puberty and that this activity is sexually differentiated and altered by PNA. Dams were injected with dihydrotestosterone (DHT) on days 16 to 18 post copulation to generate PNA mice. Action potential firing of GFP-identified GnRH neurons in brain slices from 1-, 2-, 3-, and 4-week-old and adult mice was monitored. GnRH neurons were active at all ages tested. In control females, activity increased with age through 3 weeks, then decreased to adult levels. In contrast, activity did not change in PNA females and was reduced at 3 weeks. Activity was higher in control females than males from 2 to 3 weeks. PNA did not affect GnRH neuron firing rate in males at any age. Short-term action potential patterns were also affected by age and PNA treatment. GnRH neurons are thus typically more active during the prepubertal period than adulthood, and PNA reduces prepubertal activity in females. Prepubertal activity may play a role in establishing sexually differentiated neuronal networks upstream of GnRH neurons; androgen-induced changes during this time may contribute to the adult PNA, and possibly PCOS, phenotype. Copyright © 2017 Endocrine Society.

Effect of cortisol on gonadotropin inhibitory hormone (GnIH) in the cinnamon clownfish, Amphiprion melanopus.

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Choi, Young Jae; Habibi, Hamid R; Kil, Gyung-Suk; Jung, Min-Min; Choi, Cheol Young

2017-04-01

Hypothalamic peptides, gonadotropin-releasing hormone (GnRH) and gonadotropin inhibitory hormone (GnIH), play pivotal roles in the control of reproduction and gonadal maturation in fish. In the present study we tested the possibility that stress-mediated reproductive dysfunction in teleost may involve changes in GnRH and GnIH activity. We studied expression of brain GnIH, GnIH-R, seabream GnRH (sbGnRH), as well as circulating levels of follicle stimulating hormone (FSH), and luteinizing hormone (LH) in the cinnamon clownfish, Amphiprion melanopus. Treatment with cortisol increased GnIH mRNA level, but reduced sbGnRH mRNA and circulating levels of LH and FSH in cinnamon clownfish. Using double immunofluorescence staining, we found expression of both GnIH and GnRH in the diencephalon region of cinnamon clownfish brain. These findings support the hypothesis that cortisol, an indicator of stress, affects reproduction, in part, by increasing GnIH in cinnamon clownfish which contributes to hypothalamic suppression of reproductive function in A. melanopus, a protandrous hermaphroditic fish. Copyright © 2017 Elsevier Inc. All rights reserved.

Ontogenic studies of the neural control of adenohypophyseal hormones in the rat: gonadotropins.

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

1990-12-01

1. Serotonergic, dopaminergic, and opioid systems controlling luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion develop with particular characteristics in the male and female prepubertal rats. 2. Serotonergic pathways evoke a maximal release of LH and FSH in female rats from day 12 to day 20 of age, but not in males of the same age. 3. Antidopaminergic drugs increase LH and FSH levels only in the female infantile rats. This effect is absent at birth and disappears after 20 days of age. 4. Naloxone markedly increases gonadotropins in 12-day-old females. 5. On the other hand, in 12-day-old male rats some neurotropic drugs such as diazepam could enhance LH levels, the effect being absent at other ages or in female littermates. 6. A period of high sensitivity of gonadotropins to neurotropic drugs is present during the second and third weeks of life of the rat and it is related to the sexual differentiation of the brain.

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.

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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.

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

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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...

Effects of a gonadotropin-releasing hormone vaccine on ovarian cyclicity and uterine morphology of an Asian elephant (Elephas maximus).

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Boedeker, Nancy C; Hayek, Lee-Ann C; Murray, Suzan; de Avila, David M; Brown, Janine L

2012-09-01

This report describes the successful use of a gonadotropin-releasing hormone (GnRH) vaccine to suppress ovarian steroidogenic activity and to treat hemorrhage and anemia associated with reproductive tract pathology in a 59-year-old Asian elephant (Elephas maximus). The Repro-BLOC GnRH vaccine was administered subcutaneously as a series of 4 boosters of increasing dose from 3 to 30 mg of recombinant ovalbumin-GnRH fusion protein given at variable intervals after initial vaccination with 3 mg protein. Efficacy was confirmed over a year after initial vaccination based on complete ovarian cycle suppression determined by serum progestagen analyses. Estrous cycle suppression was associated with a significant increase in GnRH antibody binding and subsequent decrease in serum luteinizing hormone and follicle-stimulating hormone concentrations. Ultrasonographic examinations of the reproductive tract documented a reduction in uterine size and vascularity after immunization. The hematocrit level normalized soon after the initial intrauterine hemorrhage, and no recurrence of anemia has been detected. No substantive adverse effects were associated with GnRH vaccination. The results indicate that GnRH vaccination in elephants shows potential for contraception and management of uterine pathology in older elephants.

Peri-pubertal gonadotropin-releasing hormone agonist treatment affects sex biased gene expression of amygdala in sheep.

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Nuruddin, Syed; Krogenæs, Anette; Brynildsrud, Ola Brønstad; Verhaegen, Steven; Evans, Neil P; Robinson, Jane E; Haraldsen, Ira Ronit Hebold; Ropstad, Erik

2013-12-01

The nature of hormonal involvement in pubertal brain development has attracted wide interest. Structural changes within the brain that occur during pubertal development appear mainly in regions closely linked with emotion, motivation and cognitive functions. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) receptors, results in exaggerated sex-differences in cognitive executive function and emotional control, as well as sex and hemisphere specific patterns of expression of hippocampal genes associated with synaptic plasticity and endocrine signaling. In this study, we explored effects of this treatment regime on the gene expression profile of the ovine amygdala. The study was conducted with 30 same-sex twin lambs (14 female and 16 male), half of which were treated with the GnRH agonist (GnRHa) goserelin acetate every 4th week, beginning before puberty, until approximately 50 weeks of age. Gene expression profiles of the left and right amygdala were measured using 8×15 K Agilent ovine microarrays. Differential expression of selected genes was confirmed by qRT-PCR (Quantitative real time PCR). Networking analyses and Gene Ontology (GO) Term analyses were performed with Ingenuity Pathway Analysis (IPA), version 7.5 and DAVID (Database for Annotation, Visualization and integrated Discovery) version 6.7 software packages, respectively. GnRHa treatment was associated with significant sex- and hemisphere-specific differential patterns of gene expression. GnRHa treatment was associated with differential expression of 432 (|logFC|>0.3, adj. p value expressed as a result of GnRHa treatment in the male animals. The results indicated that GnRH may, directly and/or indirectly, be involved in the regulation of sex- and hemisphere-specific differential expression of genes in the amygdala. This finding should be considered when long-term peri-pubertal GnRHa treatment is used in children. Copyright �

Resumption of menstruation and pituitary response to gonadotropin-releasing hormone in functional hypothalamic amenorrhea subjects undertaking estrogen replacement therapy.

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Shen, Z Q; Xu, J J; Lin, J F

2013-11-01

Functional hypothalamic amenorrhea (FHA) refers to a functional menstrual disorder with various causes and presentations. Recovery of menstrual cyclicity is common in long-term follow-up but the affecting factors remain unknown. To explore factors affecting the menstrual resumption and to evaluate the pituitary response to gonadotropin-releasing hormone (GnRH) in FHA. Thirty cases with FHA were recruited. All subjects were put on continuous 1 mg/day estradiol valerate orally and followed up monthly. Recovery was defined as the occurrence of at least three consecutive regular cycles. Responder referred to those who recovered within two years of therapy. Gonadotropin response to the 50 μg GnRH challenge was tested every three months. Nineteen (63.3%) subjects recovered with a mean time to recovery of 26.8 months. Time to recovery was negatively correlated with body mass index (BMI) before and by amenorrhea. Twentyone cases had undertaken therapy for more than two years and 10 of them recovered. BMI before and by amenorrhea were negatively correlated with the recovery. Significant increase of serum luteinizing hormone (LH) and LH response to GnRH were noted after recovery. Menstrual resumption was common in FHA undertaking estrogen replacement therapy (ERT). The likelihood of recovery was affected by their BMI before and by amenorrhea but not by the weight gain during therapy. Low serum LH and attenuated LH response to GnRH were the main features of pituitary deficiency in FHA. The menstrual resumption in FHA was accompanied by the recovery of serum LH and the LH response to GnRH.

Comparison of the ultrashort gonadotropin-releasing hormone agonist-antagonist protocol with microdose flare -up protocol in poor responders: a preliminary study.

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Berker, Bülent; Duvan, Candan İltemir; Kaya, Cemil; Aytaç, Ruşen; Satıroğlu, Hakan

2010-01-01

To determine the potential effect of the ultrashort gonadotropin-releasing hormone (GnRH) agonist/GnRH antagonist protocol versus the microdose GnRH agonist protocol in poor responders undergoing intracytoplasmic sperm injection (ICSI). The patients in the Agonist-Antagonist Group (n=41) were administered the ultrashort GnRH-agonist/ antagonist protocol, while the patients in the Microdose Group (n=41) were stimulated according to the microdose flare-up protocol. The mean number of mature oocytes retrieved was the primary outcome measure. Fertilization rate, implantation rate per embryo and clinical pregnancy rates were secondary outcome measures. There was no differenc between the mean number of mature oocytes retrieved in the two groups. There were also no statistical differences between the two groups in terms of peak serum E2 level, canceled cycles, endometrial thickness on hCG day, number of 2 pronucleus and number of embryos transferred. However, the total gonadotropin consumption and duration of stimulation were significantly higher with the Agonist-Antagonist Group compared with the Microdose Group. The implantation and clinical pregnancy rates were similar between the two groups. Despite the high dose of gonadotropin consumption and longer duration of stimulation with the ultrashort GnRH agonist/ antagonist protocol, it seems that the Agonist-Antagonist Protocol is not inferior to the microdose protocol in poor responders undergoing ICSI.

Sexual dimorphism of gonadotropin-releasing hormone type-III (GnRH3) neurons and hormonal sex reversal of male reproductive behavior in Mozambique tilapia.

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Kuramochi, Asami; Tsutiya, Atsuhiro; Kaneko, Toyoji; Ohtani-Kaneko, Ritsuko

2011-10-01

In tilapia, hormone treatment during the period of sexual differentiation can alter the phenotype of the gonads, indicating that endocrine factors can cause gonadal sex reversal. However, the endocrine mechanism underlying sex reversal of reproductive behaviors remains unsolved. In the present study, we detected sexual dimorphism of gonadotropin-releasing hormone type III (GnRH3) neurons in Mozambique tilapia Oreochromis mossambicus. Our immunohistochemical observations showed sex differences in the number of GnRH3 immunoreactive neurons in mature tilapia; males had a greater number of GnRH3 neurons in the terminal ganglion than females. Treatment with androgen (11-ketotestosterone (11-KT) or methyltestosterone), but not that with 17β-estradiol, increased the number of GnRH3 neurons in females to a level similar to that in males. Furthermore, male-specific nest-building behavior was induced in 70% of females treated with 11-KT within two weeks after the onset of the treatment. These results indicate androgen-dependent regulation of GnRH3 neurons and nest-building behavior, suggesting that GnRH3 is importantly involved in sex reversal of male-specific reproductive behavior.

Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat

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Wei Ling Lim

2016-08-01

Full Text Available Maternal dexamethasone (DEX; a glucocorticoid receptor agonist exposure delays pubertal onset and alters reproductive behaviour in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring’s reproductive function by disrupting the gonadotropin-releasing hormone (GnRH neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP under the control of GnRH promoter. Pregnant females were administered with DEX (0.1mg/kg or vehicle (VEH, water daily during gestation day 13-20. Confocal imaging was used to examine the spine density of EGFP-GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP-GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0 males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the post synaptic marker molecule, post-synaptic density 95 was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood.

Does the use of gonadotropin-releasing hormone antagonists in natural IVF cycles for poor responder patients cause more harm than benefit?

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Aksoy, Senai; Yakin, Kayhan; Seyhan, Ayse; Oktem, Ozgur; Alatas, Cengiz; Ata, Baris; Urman, Bulent

2016-06-01

Poor ovarian response to controlled ovarian stimulation (COS) is one of the most critical factors that substantially limits the success of assisted reproduction techniques (ARTs). Natural and modified natural cycle IVF are two options that could be considered as a last resort. Blocking gonadotropin-releasing hormone (GnRH) actions in the endometrium via GnRH receptor antagonism may have a negative impact on endometrial receptivity. We analysed IVF outcomes in 142 natural (n = 30) or modified natural (n = 112) IVF cycles performed in 82 women retrospectively. A significantly lower proportion of natural cycles reached follicular aspiration compared to modified natural cycles (56.7% vs. 85.7%, p cycles ending in embryo transfer (26.7% vs. 44.6%) was not statistically significant between natural cycle and modified natural IVF cycles. Clinical pregnancy (6.7% vs. 7.1%) and live birth rates per initiated cycle (6.7% vs. 5.4%) were similar between the two groups. Notably, the implantation rate was slightly lower in modified natural cycles (16% vs. 25%, p > 0.05). There was a trend towards higher clinical pregnancy (25% vs. 16%) and live birth (25% vs. 12%) rates per embryo transfer in natural cycles compared to modified natural cycles, but the differences did not reach statistical significance.

Afferent neuronal control of type-I gonadotropin releasing hormone (GnRH neurons in the human

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Erik eHrabovszky

2013-09-01

Full Text Available Understanding the regulation of the human menstrual cycle represents an important ultimate challenge of reproductive neuroendocrine research. However, direct translation of information from laboratory animal experiments to the human is often complicated by strikingly different and unique reproductive strategies and central regulatory mechanisms that can be present in even closely related animal species. In all mammals studied so far, type-I gonadotropin releasing hormone (GnRH synthesizing neurons form the final common output way from the hypothalamus in the neuroendocrine control of the adenohypophysis. Under various physiological and pathological conditions, hormonal and metabolic signals either regulate GnRH neurons directly or act on upstream neuronal circuitries to influence the pattern of pulsatile GnRH secretion into the hypophysial portal circulation. Neuronal afferents to GnRH cells convey important metabolic-, stress-, sex steroid-, lactational- and circadian signals to the reproductive axis, among other effects. This article gives an overview of the available neuroanatomical literature that described the afferent regulation of human GnRH neurons by peptidergic, monoaminergic and amino acidergic neuronal systems. Recent studies of human genetics provided evidence that central peptidergic signaling by kisspeptins and neurokinin B play particularly important roles in puberty onset and later, in the sex steroid-dependent feedback regulation of GnRH neurons. This review article places special emphasis on the topographic distribution, sexual dimorphism, aging-dependent neuroanatomical changes and plastic connectivity to GnRH neurons of the critically important human hypothalamic kisspeptin and neurokinin B systems.

Induction of Gonadotropins for Reproductive Control

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Elza Ibrahim Auerkari

2015-10-01

Full Text Available Much of the recent research on gonadotropin – related control processes of reproduction and reproductive maturation has concentrated on the neuronal and molecular biology of gonadotropin release. The reproductive development of healthy mammals requires appropriate fetal develompment and migration of the neural network controlling and including the gonadotropin releasing hormone (GnRH – producing neurons that are needed to regulate GnRH and luteinizing hormone (LH release. GnRH is also necessary for the development of the gonadotropin – producing pituitary gland. The fetal gonads respon to GnRH – induced LH production by producing the gonadal steroids required for further reproductive differentiation. Pubertal maturation is characterised by increases in LH levels, representing the corresponding pulsatile release of GnRH. This GnRH pulse generator appears to be an intrinsic property of the arcuate nucleus at the medial basal hypothalamus. The generator activity can be mediated by the neurotransmitter aspartate which activates neurons of the hypothalamus, inducing acuate releases of GnRH and hence initiates puberty. A major factor in human reproductive maturation is the decrease in the age of puberty, caused by improvement of nutritional conditions due to the socio – economic development. This implies that the pubertal activation of GnRH secretion depends on metabolic conditions. Of the substances that mediate the metabolic condition to the neuronal network regulating GnRH secretion, the role of the neuropeptide Y (NPY appears instrumental : for healthy mammals less food means more NPY, and accumulated NPY makes food to become sex. NPY does this by regulating the appropriate hypothalamic functions including the neuroendocrine control of gonadotropin release.

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

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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.

Neuroanatomical organization of gonadotropin-releasing hormone neurons during the oestrus cycle in the ewe

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Batailler, Martine; Caraty, Alain; Malpaux, Benoît; Tillet, Yves

2004-01-01

Background During the preovulatory surge of gonadotropin-releasing hormone (GnRH), a very large amount of the peptide is released in the hypothalamo-hypophyseal portal blood for 24-36H00. To study whether this release is linked to a modification of the morphological organization of the GnRH-containing neurons, i.e. morphological plasticity, we conducted experiments in intact ewes at 4 different times of the oestrous cycle (before the expected LH surge, during the LH surge, and on day 8 and day 15 of the subsequent luteal phase). The cycle stage was verified by determination of progesterone and LH concentrations in the peripheral blood samples collected prior to euthanasia. Results The distribution of GnRH-containing neurons throughout the preoptic area around the vascular organ of the lamina terminalis was studied following visualisation using immunohistochemistry. No difference was observed in the staining intensity for GnRH between the different groups. Clusters of GnRH-containing neurons (defined as 2 or more neurons being observed in close contact) were more numerous during the late follicular phase (43 ± 7) than during the luteal phase (25 ± 6), and the percentage of clusters was higher during the beginning of the follicular phase than during the luteal phase. There was no difference in the number of labelled neurons in each group. Conclusions These results indicate that the morphological organization of the GnRH-containing neurons in ewes is modified during the follicular phase. This transitory re-organization may contribute to the putative synchronization of these neurons during the surge. The molecular signal inducing this plasticity has not yet been identified, but oestradiol might play an important role, since in sheep it is the only signal which initiates the GnRH preovulatory surge. PMID:15555074

Neuroanatomical organization of gonadotropin-releasing hormone neurons during the oestrus cycle in the ewe

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Malpaux Benoît

2004-11-01

Full Text Available Abstract Background During the preovulatory surge of gonadotropin-releasing hormone (GnRH, a very large amount of the peptide is released in the hypothalamo-hypophyseal portal blood for 24-36H00. To study whether this release is linked to a modification of the morphological organization of the GnRH-containing neurons, i.e. morphological plasticity, we conducted experiments in intact ewes at 4 different times of the oestrous cycle (before the expected LH surge, during the LH surge, and on day 8 and day 15 of the subsequent luteal phase. The cycle stage was verified by determination of progesterone and LH concentrations in the peripheral blood samples collected prior to euthanasia. Results The distribution of GnRH-containing neurons throughout the preoptic area around the vascular organ of the lamina terminalis was studied following visualisation using immunohistochemistry. No difference was observed in the staining intensity for GnRH between the different groups. Clusters of GnRH-containing neurons (defined as 2 or more neurons being observed in close contact were more numerous during the late follicular phase (43 ± 7 than during the luteal phase (25 ± 6, and the percentage of clusters was higher during the beginning of the follicular phase than during the luteal phase. There was no difference in the number of labelled neurons in each group. Conclusions These results indicate that the morphological organization of the GnRH-containing neurons in ewes is modified during the follicular phase. This transitory re-organization may contribute to the putative synchronization of these neurons during the surge. The molecular signal inducing this plasticity has not yet been identified, but oestradiol might play an important role, since in sheep it is the only signal which initiates the GnRH preovulatory surge.

Influence of gonadotropin-releasing hormone and timing of insemination relative to estrus on pregnancy rates of dairy cattle at first service.

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Mee, M O; Stevenson, J S; Scoby, R K; Folman, Y

1990-06-01

The objective was to determine the influence of gonadotropin-releasing hormone on pregnancy rates of dairy cattle at first services, when both the timing of hormone injection and insemination were altered relative to the onset of estrus. Cows (n = 325) were assigned randomly to six groups making up a 2 X 2 X 2 incomplete factorial experiment; dose of GnRH (100 micrograms versus saline), timing [1 h (early) or 12 to 16 h (late) after first detected estrus] of AI, and timing of hormone injection (early versus late) were the three main effects. Cows were observed for estrus 4 times daily. Treatments and resulting pregnancy rates were: 1) hormone injection early plus AI early (35%), 2) hormone injection late plus AI early (34%), 3) saline injection early plus AI early (30%), 4) hormone injection late plus AI late (30%), 5) hormone injection early plus AI late (46%), and 6) saline injection late plus AI late (43%). Pregnancy rate in the first four groups (32%) was less than that in the latter two groups (44%). Concentrations of LH in serum were greater for cows given hormone or saline injections in early estrus than for cows injected with either hormone of saline during late estrus. Concentrations of LH in serum 2 h after GnRH were elevated above those of controls, whether GnRH was injected during early or late estrus. Neither concentrations of LH during estrus nor concentrations of progesterone 8 to 14 d after estrus explained the possible antifertility effect of GnRH given during late estrus.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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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.

Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone agonist with or without growth hormone

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Mo Kyung Jung

2014-12-01

Full Text Available PurposeThere is controversy surrounding the growth outcomes of treatment with gonadotropin-releasing hormone agonist (GnRHa in central precocious puberty (CPP. We analyzed height preservation after treatment with GnRHa with and without growth hormone (GH in girls with CPP.MethodsWe reviewed the medical records of 82 girls with idiopathic CPP who had been treated with GnRHa at Severance Children's Hospital from 2004 to 2014. We assessed the changes in height standard deviation score (SDS for bone age (BA, and compared adult height (AH with midparental height (MPH and predicted adult height (PAH during treatment in groups received GnRHa alone (n=59 or GnRHa plus GH (n=23.ResultsIn the GnRHa alone group, the height SDS for BA was increased during treatment. AH (160.4±4.23 cm was significantly higher than the initial PAH (156.6±3.96 cm (P<0.001, and it was similar to the MPH (159.9±3.52 cm. In the GnRHa plus GH group, the height SDS for BA was also increased during treatment. AH (159.3±5.33 cm was also higher than the initial PAH (154.6±2.55 cm (P<0.001, which was similar to the MPH (158.1±3.31 cm. Height gain was slightly higher than that in the GnRHa alone group, however it statistically showed no significant correlation with GH treatment.ConclusionIn CPP girls treated with GnRHa, the height SDS for BA was increased, and the AH was higher than the initial PAH. Combined GH treatment showed a limited increase in height gain.

Association of luteinizing hormone chorionic gonadotropin receptor gene polymorphism (rs2293275) with polycystic ovarian syndrome.

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Thathapudi, Sujatha; Kodati, Vijayalakshmi; Erukkambattu, Jayashankar; Addepally, Uma; Qurratulain, Hasan

2015-03-01

Polycystic ovaries and irregular menstruation/anovulation are important diagnostic criteria along with hyperandrogenism as per the Androgen Excess Society-2006 criteria for polycystic ovarian syndrome (PCOS). In the etiopathogenesis of PCOS, one of the candidate genes causing ovarian failure is the luteinizing hormone (LH) chorionic gonadotropin hormone receptor (LHCGR). Our aim was to study the association of LHCGR polymorphism (rs2293275) with PCOS in our study population. Genetic case-control study from multiple gynecological centers from Hyderabad, a cosmopolitan city in South India. The study involved 204 women with PCOS and 204 healthy, sex-, and age-matched controls. Anthropometric and biochemical profiles were taken in a well-designed pro forma. Isolation of deoxyribonucleic acid (DNA) and genotype analysis were done for the entire study population using the polymerase chain reaction-restriction fragment length polymorphism method followed by 12% polyacrylamide gel electrophoresis. In this study, we have demonstrated an association between LHCGR (rs2293275) polymorphism and PCOS. The frequency of the G allele was 0.60 in PCOS and 0.49 in controls (odds ratio [OR] 1.531, confidence interval [CI] 1.16-2.01, and p-value=0.0026), which indicates that the G allele is associated with PCOS in our population. The GG genotype conferred a significant risk of developing PCOS (OR 3.36, CI 1.96-5.75, and p-value<0.0001). We found a significant association of the GG allele with body-mass index, waist to hip ratio, insulin resistance, LH, and LH/follicle-stimulating hormone (FSH) ratio in PCOS when compared with controls. The AA allele showed high basal FSH levels. This study suggests that LHCGR (rs2293275) polymorphism is associated with PCOS and could be used as a relevant molecular marker to identify women with the risk of developing PCOS in our population and may provide an understanding about the etiology of PCOS.

Gonadotropin-releasing hormone receptor activates GTPase RhoA and inhibits cell invasion in the breast cancer cell line MDA-MB-231

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Aguilar-Rojas, Arturo; Huerta-Reyes, Maira; Maya-Núñez, Guadalupe; Arechavaleta-Velásco, Fabián; Conn, P Michael; Ulloa-Aguirre, Alfredo; Valdés, Jesús

2012-01-01

Gonadotropin-releasing hormone (GnRH) and its receptor (GnRHR) are both expressed by a number of malignant tumors, including those of the breast. In the latter, both behave as potent inhibitors of invasion. Nevertheless, the signaling pathways whereby the activated GnRH/GnRHR system exerts this effect have not been clearly established. In this study, we provide experimental evidence that describes components of the mechanism(s) whereby GnRH inhibits breast cancer cell invasion. Actin polymerization and substrate adhesion was measured in the highly invasive cell line, MDA-MB-231 transiently expressing the wild-type or mutant DesK191 GnRHR by fluorometry, flow cytometric analysis, and confocal microscopy, in the absence or presence of GnRH agonist. The effect of RhoA-GTP on stress fiber formation and focal adhesion assembly was measured in MDA-MB-231 cells co-expressing the GnRHRs and the GAP domain of human p190Rho GAP-A or the dominant negative mutant GAP-Y1284D. Cell invasion was determined by the transwell migration assay. Agonist-stimulated activation of the wild-type GnRHR and the highly plasma membrane expressed mutant GnRHR-DesK191 transiently transfected to MDA-MB-231 cells, favored F-actin polymerization and substrate adhesion. Confocal imaging allowed detection of an association between F-actin levels and the increase in stress fibers promoted by exposure to GnRH. Pull-down assays showed that the effects observed on actin cytoskeleton resulted from GnRH-stimulated activation of RhoA GTPase. Activation of this small G protein favored the marked increase in both cell adhesion to Collagen-I and number of focal adhesion complexes leading to inhibition of the invasion capacity of MDA-MB-231 cells as disclosed by assays in Transwell Chambers. We here show that GnRH inhibits invasion of highly invasive breast cancer-derived MDA-MB-231 cells. This effect is mediated through an increase in substrate adhesion promoted by activation of RhoA GTPase and formation of

Immunohistochemical evidence for the involvement of gonadotropin releasing hormone in neuroleptic and cataleptic effects of haloperidol in mice.

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Fegade, Harshal A; Umathe, Sudhir N

2016-04-01

Blockade of dopamine D2 receptor by haloperidol is attributed for neuroleptic and cataleptic effects; and also for the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH agonist is reported to exhibit similar behavioural effects as that of haloperidol, and pre-treatment with GnRH antagonist is shown to attenuate the effects of haloperidol, suggesting a possibility that GnRH might mediate the effects of haloperidol. To substantiate such possibility, the influence of haloperidol on GnRH immunoreactivity (GnRH-ir) in the brain was studied in vehicle/antide pre-treated mice by peroxidase-antiperoxidase method. Initially, an earlier reported antide-haloperidol interaction in rat was confirmed in mice, wherein haloperidol (250μg/kg, i.p.) exhibited suppression of conditioned avoidance response (CAR) on two-way shuttle box, and induced catalepsy in bar test; and pre-treatment with antide (50μg/kg, s.c., GnRH antagonist) attenuated both effects of haloperidol. Immunohistochemical study was carried out to identify GnRH-ir in the brain, isolated 1h after haloperidol treatment to mice pre-treated with vehicle/antide. The morphometric analysis of microphotographs of brain sections revealed that haloperidol treatment increased integrated density units of GnRH-ir in various regions of the limbic system. Considering basal GnRH-ir in vehicle treated group as 100%, the increase in GnRH-ir after haloperidol treatment was by 100.98% in the medial septum; 54.26% in the bed nucleus of the stria terminalis; 1152.85% in the anteroventral periventricular nucleus; 120.79% in the preoptic area-organum vasculosum of the lamina terminalis and 138.82% in the arcuate nucleus. Antide did not influence basal and haloperidol induced increase in GnRH-ir in any of the regions. As significant increase in GnRH-ir after haloperidol treatment was observed in such regions of the brain which are reported to directly or indirectly communicate with the hippocampus and basal

Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development.

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Miller, Nichol L G; Wevrick, Rachel; Mellon, Pamela L

2009-01-15

Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by hyperphagia, obesity and hypogonadotrophic hypogonadism, all highly suggestive of hypothalamic dysfunction. The NDN gene, encoding the MAGE family protein, necdin, maps to the PWS chromosome region and is highly expressed in mature hypothalamic neurons. Adult mice lacking necdin have reduced numbers of gonadotropin-releasing hormone (GnRH) neurons, but the mechanism for this reduction is unknown. Herein, we show that, although necdin is not expressed in an immature, migratory GnRH neuronal cell line (GN11), high levels are present in a mature GnRH neuronal cell line (GT1-7). Furthermore, overexpression of necdin activates GnRH transcription through cis elements bound by the homeodomain repressor Msx that are located in the enhancer and promoter of the GnRH gene, and knock-down of necdin expression reduces GnRH gene expression. In fact, overexpression of Necdin relieves Msx repression of GnRH transcription through these elements and necdin co-immunoprecipitates with Msx from GnRH neuronal cells, indicating that necdin may activate GnRH gene expression by preventing repression of GnRH gene expression by Msx. Finally, necdin is necessary for generation of the full complement of GnRH neurons during mouse development and extension of GnRH axons to the median eminence. Together, these results indicate that lack of necdin during development likely contributes to the hypogonadotrophic hypogonadal phenotype in individuals with PWS.

Necdin, a Prader–Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development

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Miller, Nichol L.G.; Wevrick, Rachel; Mellon, Pamela L.

2009-01-01

Prader–Willi syndrome (PWS) is a complex genetic disorder characterized by hyperphagia, obesity and hypogonadotrophic hypogonadism, all highly suggestive of hypothalamic dysfunction. The NDN gene, encoding the MAGE family protein, necdin, maps to the PWS chromosome region and is highly expressed in mature hypothalamic neurons. Adult mice lacking necdin have reduced numbers of gonadotropin-releasing hormone (GnRH) neurons, but the mechanism for this reduction is unknown. Herein, we show that, although necdin is not expressed in an immature, migratory GnRH neuronal cell line (GN11), high levels are present in a mature GnRH neuronal cell line (GT1-7). Furthermore, overexpression of necdin activates GnRH transcription through cis elements bound by the homeodomain repressor Msx that are located in the enhancer and promoter of the GnRH gene, and knock-down of necdin expression reduces GnRH gene expression. In fact, overexpression of Necdin relieves Msx repression of GnRH transcription through these elements and necdin co-immunoprecipitates with Msx from GnRH neuronal cells, indicating that necdin may activate GnRH gene expression by preventing repression of GnRH gene expression by Msx. Finally, necdin is necessary for generation of the full complement of GnRH neurons during mouse development and extension of GnRH axons to the median eminence. Together, these results indicate that lack of necdin during development likely contributes to the hypogonadotrophic hypogonadal phenotype in individuals with PWS. PMID:18930956

A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology

DEFF Research Database (Denmark)

Ezcurra, Diego; Humaidan, Peter

2014-01-01

to the purification process, thus hCG, mimicking LH action, is added to standardise the product. However, unlike LH, hCG plays a very minor role during the natural human menstrual cycle. It is secreted by the embryo and placenta, and its main role is to support implantation and pregnancy. More recently, recombinant......Gonadotropins extracted from the urine of post-menopausal women have traditionally been used to stimulate folliculogenesis in the treatment of infertility and in assisted reproductive technology (ART). Products, such as human menopausal gonadotropin (hMG), consist not only of a mixture...... of the hormones, follicle-stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotropin (hCG), but also other biologically active contaminants, such as growth factors, binding proteins and prions. The actual amount of molecular LH in hMG preparations varies considerably due...

Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph

International Nuclear Information System (INIS)

Winterer, J.; Barnes, K.M.; Lichter, A.S.; Deluca, A.M.; Loriaux, D.L.; Cutler, G.B. Jr.

1988-01-01

To test the hypothesis that the functional state of hypothalamic LHRH neurons and pituitary gonadotrophs might alter their radiosensitivity, we determined the experimental conditions under which the gonadotropin response to castration could be impaired by a single dose of cranial irradiation. Single doses of cranial irradiation greater than 2000 rads were lethal to unshielded rats. Shielding of the oropharynx and esophagus allowed the animals to survive doses up to 5000 rads. Doses between 2000 and 5000 rads had no effect on basal gonadotropin levels for as long as 3 months after irradiation. Irradiation caused a dose- and time-dependent impairment, however, in the gonadotropin response to castration. Impairment of the gonadotropin levels of castrate animals occurred in animals that were irradiated either before or after castration. However, rats irradiated in the castrate state showed a decreased susceptibility to irradiation damage. Additionally, stimulation of the pituitary by LHRH agonist (LHRHa) 3 h before irradiation significantly reduced the impairment of gonadotropin secretion 12-20 weeks after irradiation (P less than 0.05). Thus, increased functional activity of the rat hypothalamus or pituitary at the time of irradiation, induced by either castration or acute LHRHa administration, was associated with some protection against the gonadotropin-lowering effect of irradiation. Based upon these data, we hypothesize that stimulation of gonadotropin secretion at the time of therapeutic cranial irradiation in humans might protect against subsequent impairment of gonadotropin secretion

Does Gonadotropin Releasing Hormone Agonists plus add-back therapy bring an aurora to orthodontic treatment?

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Jiang Lingyong

2012-01-01

Full Text Available Introduction: Obviously, long therapy time of orthodontic treatment and a number of its adverse effects, such as pain, root resorption, enamel demineralization, periodontal disease, are the main reasons of complaints from patients. It is the first thing for an orthodontist to shorten the period of treatment and decrease the complications of orthodontic treatment as much as possible. The Hypothesis: We hypothesis Gonadotropin Releasing Hormone Agonists (GnRHa and add-back therapy can create the "therapeutic window", namely, the appropriate estrogen level and assuage the adverse effects of estrogen deficiency which should be avoided as much as possible. Evaluation of the Hypothesis: It is generally acknowledged that estrogen has direct regulating role in bone metabolism by acting on osteoblasts and osteoclasts. Estrogen deficiency can increase the rate of orthodontic tooth movement and also bring about some adverse effects. The appropriate estrogen level, which we call the "therapeutic window" in orthodontic treatment, can speed up the orthodontic tooth movement and eliminate the adverse effects as far as possible. GnRHa can be the maker of estrogen deficiency; meanwhile, add-back therapy can remove the adverse effects by estrogen deficiency. So, we believe that GnRHa plus add-back therapy could be a new adjuvant method of orthodontic treatment and be good for orthodontists and patients.

Developmental regulation of gonadotropin-releasing hormone gene expression by the MSX and DLX homeodomain protein families.

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Givens, Marjory L; Rave-Harel, Naama; Goonewardena, Vinodha D; Kurotani, Reiko; Berdy, Sara E; Swan, Christo H; Rubenstein, John L R; Robert, Benoit; Mellon, Pamela L

2005-05-13

Gonadotropin-releasing hormone (GnRH) is the central regulator of the hypothalamic-pituitary-gonadal axis, controlling sexual maturation and fertility in diverse species from fish to humans. GnRH gene expression is limited to a discrete population of neurons that migrate through the nasal region into the hypothalamus during embryonic development. The GnRH regulatory region contains four conserved homeodomain binding sites (ATTA) that are essential for basal promoter activity and cell-specific expression of the GnRH gene. MSX and DLX are members of the Antennapedia class of non-Hox homeodomain transcription factors that regulate gene expression and influence development of the craniofacial structures and anterior forebrain. Here, we report that expression patterns of the Msx and Dlx families of homeodomain transcription factors largely coincide with the migratory route of GnRH neurons and co-express with GnRH in neurons during embryonic development. In addition, MSX and DLX family members bind directly to the ATTA consensus sequences and regulate transcriptional activity of the GnRH promoter. Finally, mice lacking MSX1 or DLX1 and 2 show altered numbers of GnRH-expressing cells in regions where these factors likely function. These findings strongly support a role for MSX and DLX in contributing to spatiotemporal regulation of GnRH transcription during development.

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

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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.

The olfactory gonadotropin-releasing hormone immunoreactive system in mouse.

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Jennes, L

1986-10-29

The olfactory gonadotropin-releasing hormone (GnRH) system in mice was studied with immunofluorescence in combination with lesions of the olfactory bulb and retrograde transport of horseradish peroxidase (HRP) which was administered intravascularly, intranasally or into the subarachnoid space. GnRH-positive neurons were located in the two major branches forming the septal roots of the nervus terminalis, in the ganglion terminale, within the fascicles of the nervus terminalis throughout its extent, in a conspicuous band which connects the ventral neck of the caudal olfactory bulb with the accessory olfactory bulb and in the nasal mucosa. GnRH-positive fibers were seen in all areas in which neurons were found, i.e. in the rostral septum, the ganglion and nervus terminalis and in the nasal subepithelium. In addition, a broad bundle of fibers was observed to surround the entire caudal olfactory bulb, connecting the rostral sulcus rhinalis with the ventrocaudal olfactory bulb. Fibers were seen in close association with the main and accessory olfactory bulb, with the fila olfactoria and with the nasal mucosa. Throughout the olfactory bulb and the nasal epithelium, an association of GnRH fibers with blood vessels was apparent. Intravascular and intranasal injection of HRP resulted in labeling of certain GnRH neurons in the septal roots of the nervus terminalis, the ganglion terminale, the nervus terminalis, the caudal ventrodorsal connection and in the accessory olfactory bulb. After placement of HRP into the subarachnoid space dorsal to the accessory olfactory bulb, about 50% of the GnRH neurons in the accessory olfactory bulb and in the ventrodorsal connection were labeled with HRP. Also, a few GnRH neurons in the rostral septum, the ganglion terminale and in the fascicles of the nervus terminalis had taken up the enzyme. Lesions of the nervus terminalis caudal to the ganglion terminale resulted in sprouting of GnRH fibers at both sites of the knife cut. Lesions rostral

Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist

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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...

A neurokinin 3 receptor-selective agonist accelerates pulsatile luteinizing hormone secretion in lactating cattle.

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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.

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

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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.

Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

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Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

2015-01-01

Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

Growth Hormone Overexpression Disrupts Reproductive Status Through Actions on Leptin

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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

Developmental Regulation of Gonadotropin-releasing Hormone Gene Expression by the MSX and DLX Homeodomain Protein Families*

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Givens, Marjory L.; Rave-Harel, Naama; Goonewardena, Vinodha D.; Kurotani, Reiko; Berdy, Sara E.; Swan, Christo H.; Rubenstein, John L. R.; Robert, Benoit; Mellon, Pamela L.

2010-01-01

Gonadotropin-releasing hormone (GnRH) is the central regulator of the hypothalamic-pituitary-gonadal axis, controlling sexual maturation and fertility in diverse species from fish to humans. GnRH gene expression is limited to a discrete population of neurons that migrate through the nasal region into the hypothalamus during embryonic development. The GnRH regulatory region contains four conserved homeodomain binding sites (ATTA) that are essential for basal promoter activity and cell-specific expression of the GnRH gene. MSX and DLX are members of the Antennapedia class of non-Hox homeodomain transcription factors that regulate gene expression and influence development of the craniofacial structures and anterior forebrain. Here, we report that expression patterns of the Msx and Dlx families of homeodomain transcription factors largely coincide with the migratory route of GnRH neurons and co-express with GnRH in neurons during embryonic development. In addition, MSX and DLX family members bind directly to the ATTA consensus sequences and regulate transcriptional activity of the GnRH promoter. Finally, mice lacking MSX1 or DLX1 and 2 show altered numbers of GnRH-expressing cells in regions where these factors likely function. These findings strongly support a role for MSX and DLX in contributing to spatiotemporal regulation of GnRH transcription during development. PMID:15743757

Factors that predict a positive response on gonadotropin-releasing hormone stimulation test for diagnosing central precocious puberty in girls

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Junghwan Suh

2013-12-01

Full Text Available PurposeThe rapid increase in the incidence of precocious puberty in Korea has clinical and social significance. Gonadotropin-releasing hormone (GnRH stimulation test is required to diagnose central precocious puberty (CPP, however this test is expensive and time-consuming. This study aimed to identify factors that can predict a positive response to the GnRH stimulation test.MethodsClinical and laboratory parameters, including basal serum luteinizing hormone (LH, follicle-stimulating hormone (FSH, and estradiol (E2, were measured in 540 girls with clinical signs of CPP.ResultsTwo hundred twenty-nine of 540 girls with suspected CPP had a peak serum LH level higher than 5 IU/L (the CPP group. The CPP group had advanced bone age (P<0.001, accelerated yearly growth rate (P<0.001, increased basal levels of LH (P=0.02, FSH (P<0.001, E2 (P=0.001, and insulin-like growth factor-I levels (P<0.001 compared to the non-CPP group. In contrast, body weight (P<0.001 and body mass index (P<0.001 were lower in the CPP group. Although basal LH was significantly elevated in the CPP group compared to the non-CPP group, there was considerable overlap between the 2 groups. Cutoff values of basal LH (0.22 IU/L detected CPP with 87.8% sensitivity and 20.9% specificity.ConclusionNo single parameter can predict a positive response on the GnRH stimulation test with both high sensitivity and specificity. Therefore, multiple factors should be considered in evaluation of sexual precocity when deciding the timing of the GnRH stimulation test.

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

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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.

Early-life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

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Tomoko eSoga

2015-11-01

Full Text Available Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinising hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP-tagged GnIH-transgenic rats. Socially isolated rats were observed for anxious and depressive behaviours. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group -housing. We also inspected serotonergic fibre juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviours. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fibre juxtapositions on EGFP–GnIH neurons was also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

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

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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

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

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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.

Time- and dose-related effects of a gonadotropin-releasing hormone agonist and dopamine antagonist on reproduction in the Northern leopard frog (Lithobates pipiens).

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Vu, Maria; Weiler, Bradley; Trudeau, Vance L

2017-12-01

Gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone release to control ovulation and spermiation in vertebrates. Dopamine (DA) has a clear inhibitory role in the control of reproduction in numerous teleosts, and emerging evidence suggests that similar mechanisms may exist in amphibians. The interactions between GnRH and DA on spawning success and pituitary gene expression in the Northern leopard frog (Lithobates pipiens) were therefore investigated. Frogs were injected during the natural breeding season with a GnRH agonist [GnRH-A; (Des-Gly 10 , D-Ala 6 , Pro-NHEt 9 )-LHRH; 0.1μg/g and 0.4μg/g] alone and in combination with the dopamine receptor D2 antagonist metoclopramide (MET; 5μg/g and 10μg/g). Injected animals were allowed to breed in outdoor mesocosms. Time to amplexus and oviposition were assessed, and egg mass release, incidences of amplexus, egg mass weight, total egg numbers and fertilization rates were measured. To examine gene expression, female pituitaries were sampled at 12, 24 and 36h following injection of GnRH-A (0.4μg/g) alone and in combination with MET (10μg/g). The mRNA levels of the genes lhb, fshb, gpha, drd2 and gnrhr1 were measured using quantitative real-time PCR. Data were analyzed by a two-way ANOVA. Both GnRH-A doses increased amplexus, oviposition and fertilization alone. Co-injection of MET with GnRH-A did not further enhance spawning success. Injection of GnRH-A alone time-dependently increased expression of lhb, fshb, gpha and gnrhr1. The major effect of MET alone was to decrease expression of drd2. Importantly, the stimulatory effects of GnRH-A on lhb, gpha and gnrhr1 were potentiated by the co-injection of MET at 36h. At this time, expression of fshb was increased only in animals injected with both GnRH-A and MET. Spawning success was primarily driven by the actions of GnRH-A. The hypothesized inhibitory action of DA was supported by pituitary gene expression analysis. The results from this study provide a

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

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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

Milt-Egg Ratio in Artificial Fertilization of Pangasiid Catfish Injected by Gonadotropin Releasing Hormone-Analog (GnRH-a and Domperidone Mixture

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J. Subagja

2007-08-01

Full Text Available Study on the level of gonadotropin hormone treatments combined with latency time to induce ovulation in Pangasius djambal was conducted in the Research Instalation of Germ Plasm, Cijeruk, Bogor. This study was carried out to investigate the effect of GnRH-a and domperidone mixture on the milt production and fertilization rates of Pangasius djambal, and to determine the optimal milt-egg ratio required for artificial fertilization. Different doses of hormone i.e: 0,3; 0,5 and 0,7 ml kg"1 body weight combined with latency time of 12, 24 and 48 h after inducing hormone were applied to increase milt-production. Milt dilution was 10"1, 10~2, 10"3, 10"4, 10"5, 10"6 and 10"7and evaluated for hatching rate and normality of larvae. The results showed that mean milt production was 4,3 ml/kg body weight, and there was interaction between hormone dose of 0,5 ml/kg of body weight and latency time 12 and 24 h that giving hatching rate of 77 to 83% ( p Key words : Fertilization, milt production, domperidone, Pangasius djambal   ABSTRAK Suatu studi penyuntikan hormon gonadotropin dengan perbedaan dosis dan waktu laten terhadap spesies Pangasius djambal telah dilakukan di Instalasi Riset Plasma Nutfah Air Tawar, Cijeruk, Bogor. Tujuan penelitian ini adalah untuk mengetahui pengaruh hormon GnRH-a dan domperidon terhadap produktivitas semen ikan jantan dan viabilitasnya pada pembuahan buatan. Tujuan lainnya untuk menentukan perbandingan optimal antara jumlah spermatozoa dengan telur dalam fertilisasi buatan. Dosis hormon perlakuan untuk peningkatan produksi semen yaitu 0,3; 0,5 dan 0,7 ml.kg"1 bobot badan yang di kombinasikan dengan waktu inkubasi jantan 12, 24 dan 24 jam setelah penyuntikan hormon. Semen diencerkan mulai dari 10"', 10"2, 10"3, 10"4, 10~5, 10'6 dan 10"7, dan dilakukan pembuahan terhadap telur. Daya tetas dan abnormalitas larva dievaluasi. Hasil analisis menunjukan produksi semen rata-rata 4,3 ml/kg bobot badan, ada interaksi antara dosis hormon 0

Identification and localization of gonadotropin-inhibitory hormone (GnIH) orthologs in the hypothalamus of the red-eared slider turtle, Trachemys scripta elegans.

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Ukena, Kazuyoshi; Iwakoshi-Ukena, Eiko; Osugi, Tomohiro; Tsutsui, Kazuyoshi

2016-02-01

Gonadotropin-inhibitory hormone (GnIH) was discovered in 2000 as a novel hypothalamic neuropeptide that inhibited gonadotropin release in the Japanese quail. GnIH and its orthologs have a common C-terminal LPXRFamide (X=L or Q) motif, and have been identified in vertebrates from agnathans to humans, apart from reptiles. In the present study, we characterized a cDNA encoding GnIH orthologs in the brain of the red-eared slider turtle. The deduced precursor protein consisted of 205 amino-acid residues, encoding three putative peptide sequences that included the LPXRFamide motif at their C-termini. In addition, the precursor sequence was most similar to those of avian species. Immunoaffinity purification combined with mass spectrometry confirmed that three mature peptides were produced in the brain. In situ hybridization and immunohistochemistry showed that turtle GnIH-containing cells were restricted to the periventricular hypothalamic nucleus. Immunoreactive fibers were densely distributed in the median eminence. Thus, GnIH and related peptides may act on the pituitary to regulate pituitary hormone release in turtles as well as other vertebrates. Copyright © 2015 Elsevier Inc. All rights reserved.

76 FR 27888 - Implantation or Injectable Dosage Form New Animal Drugs; Gonadotropin Releasing Factor-Diphtheria...

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2011-05-13

... Factor-Diphtheria Toxoid Conjugate AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. [[Page... veterinary prescription use of gonadotropin releasing factor-diphtheria toxoid conjugate by subcutaneous... provides for the veterinary prescription use of IMPROVEST (gonadotropin releasing factor-diphtheria toxoid...

Stimulation of the young poor responder: comparison of the luteal estradiol/gonadotropin-releasing hormone antagonist priming protocol versus oral contraceptive microdose leuprolide.

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Shastri, Shefali M; Barbieri, Elizabeth; Kligman, Isaac; Schoyer, Katherine D; Davis, Owen K; Rosenwaks, Zev

2011-02-01

To evaluate in vitro fertilization (IVF) cycle outcomes in young poor responders treated with a luteal estradiol/gonadotropin-releasing hormone antagonist (E(2)/ANT) protocol versus an oral contraceptive pill microdose leuprolide protocol (OCP-MDL). Retrospective cohort. Academic practice. Poor responders: 186 women, aged <35 years undergoing IVF with either E(2)/ANT or OCP-MDL protocols. None. Clinical pregnancies, oocytes retrieved, cancellation rate. Patients in the E(2)/ANT group had a greater gonadotropin requirement (71.9 ± 22.2 vs. 57.6 ± 25.7) and lower E(2) level (1,178.6 ± 668 vs. 1,627 ± 889), yet achieved similar numbers of oocytes retrieved and fertilized, and a greater number of embryos transferred (2.3 ± 0.9 vs. 2.0 ± 1.1) with a better mean grade (2.14 ± .06 vs. 2.7 ± 1.8) compared with the OCP/MDL group. The E2/ANT group exhibited a trend toward improved implantation rates (30.5% vs. 21.1%) and ongoing pregnancy rates per started cycle: 44 out of 117 (37%) versus 17 out of 69 (25%). Poor responders aged <35 years may be treated with the aggressive E(2)/ANT protocol to improve cycle outcomes. Both protocols remain viable options for this group. Adequately powered, randomized clinical comparison appears justified. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

77 FR 4227 - Implantation or Injectable Dosage Form New Animal Drugs; Gonadotropin Releasing Factor Analog...

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2012-01-27

... Factor Analog-Diphtheria Toxoid Conjugate AGENCY: Food and Drug Administration, HHS. ACTION: Final rule... extends the slaughter interval for intact male swine injected with gonadotropin releasing factor analog...-322 for IMPROVEST (gonadotropin releasing factor analog-diphtheria toxoid conjugate) Sterile Solution...

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

On the blood-brain barrier to peptides: [3H]gonadotropin-releasing hormone accumulation by eighteen regions of the rat brain and by anterior pituitary

International Nuclear Information System (INIS)

Ermisch, A.; Ruehle, H.J.; Klauschenz, E.; Kretzschmar, R.

1984-01-01

After intracarotid injection of [ 3 H]gonadotropin-releasing hormone ([ 3 H]GnRH) the mean accumulation of radioactivity per unit wet weight of 18 brain samples investigated and the anterior pituitary was 0.38 +- 0.11% g -1 of the injected tracer dose. This indicates a low but measurable brain uptake of the peptide. The brain uptake of [ 3 H]GnRH in blood-brain barrier (BBB)-protected regions is 5% of that of separately investigated [ 3 H]OH. In BBB-free regions the accumulation of radioactivity was more than 25-fold higher than in BBB-protected regions. The accumulation of [ 3 H]GnRH among regions with BBB varies less than among regions with leaky endothelia. The data presented for [ 3 H]GnRH are similar to those for other peptides so far investigated. (author)

Features of natural and gonadotropin-releasing hormone antagonist-induced corpus luteum regression and effects of in vivo human chorionic gonadotropin.

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Del Canto, Felipe; Sierralta, Walter; Kohen, Paulina; Muñoz, Alex; Strauss, Jerome F; Devoto, Luigi

2007-11-01

The natural process of luteolysis and luteal regression is induced by withdrawal of gonadotropin support. The objectives of this study were: 1) to compare the functional changes and apoptotic features of natural human luteal regression and induced luteal regression; 2) to define the ultrastructural characteristics of the corpus luteum at the time of natural luteal regression and induced luteal regression; and 3) to examine the effect of human chorionic gonadotropin (hCG) on the steroidogenic response and apoptotic markers within the regressing corpus luteum. Twenty-three women with normal menstrual cycles undergoing tubal ligation donated corpus luteum at specific stages in the luteal phase. Some women received a GnRH antagonist prior to collection of corpus luteum, others received an injection of hCG with or without prior treatment with a GnRH antagonist. Main outcome measures were plasma hormone levels and analysis of excised luteal tissue for markers of apoptosis, histology, and ultrastructure. The progesterone and estradiol levels, corpus luteum DNA, and protein contents in induced luteal regression resembled those of natural luteal regression. hCG treatment raised progesterone and estradiol in both natural luteal regression and induced luteal regression. The increase in apoptosis detected in induced luteal regression by cytochrome c in the cytosol, activated caspase-3, and nuclear DNA fragmentation, was similar to that observed in natural luteal regression. The antiapoptotic protein Bcl-2 was significantly lower during natural luteal regression. The proapoptotic proteins Bax and Bak were at a constant level. Apoptotic and nonapoptotic death of luteal cells was observed in natural luteal regression and induced luteal regression at the ultrastructural level. hCG prevented apoptotic cell death, but not autophagy. The low number of apoptotic cells disclosed and the frequent autophagocytic suggest that multiple mechanisms are involved in cell death at luteal

Differential Gene Expression in Gonadotropin-Releasing Hormone Neurons of Male and Metestrous Female Mice.

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Vastagh, Csaba; Rodolosse, Annie; Solymosi, Norbert; Farkas, Imre; Auer, Herbert; Sárvári, Miklós; Liposits, Zsolt

2015-01-01

Gonadotropin-releasing hormone (GnRH) neurons play a pivotal role in the regulation of the hypothalamic-pituitary gonadal axis in a sex-specific manner. We hypothesized that the differences seen in reproductive functions of males and females are associated with a sexually dimorphic gene expression profile of GnRH neurons. We compared the transcriptome of GnRH neurons obtained from intact metestrous female and male GnRH-green fluorescent protein transgenic mice. About 1,500 individual GnRH neurons from each sex were sampled with laser capture microdissection followed by whole-transcriptome amplification for gene expression profiling. Under stringent selection criteria (fold change >1.6, adjusted p value 0.01), Affymetrix Mouse Genome 430 PM array analysis identified 543 differentially expressed genes. Sexual dimorphism was most apparent in gene clusters associated with synaptic communication, signal transduction, cell adhesion, vesicular transport and cell metabolism. To validate microarray results, 57 genes were selected, and 91% of their differential expression was confirmed by real-time PCR. Similarly, 88% of microarray results were confirmed with PCR from independent samples obtained by patch pipette harvesting and pooling of 30 GnRH neurons from each sex. We found significant differences in the expression of genes involved in vesicle priming and docking (Syt1, Cplx1), GABAergic (Gabra3, Gabrb3, Gabrg2) and glutamatergic (Gria1, Grin1, Slc17a6) neurotransmission, peptide signaling (Sstr3, Npr2, Cxcr4) and the regulation of intracellular ion homeostasis (Cacna1, Cacnb1, Cacng5, Kcnq2, Kcnc1). The striking sexual dimorphism of the GnRH neuron transcriptome we report here contributes to a better understanding of the differences in cellular mechanisms of GnRH neurons in the two sexes. © 2015 S. Karger AG, Basel.

Gonadotropin Inhibitory Hormone Down-Regulates the Brain-Pituitary Reproductive Axis of Male European Sea Bass (Dicentrarchus labrax).

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Paullada-Salmerón, José A; Cowan, Mairi; Aliaga-Guerrero, María; Morano, Francesca; Zanuy, Silvia; Muñoz-Cueto, José A

2016-06-01

Gonadotropin-inhibitory hormone (GnIH) inhibits gonadotropin synthesis and release from the pituitary of birds and mammals. However, the physiological role of orthologous GnIH peptides on the reproductive axis of fish is still uncertain, and their actions on the main neuroendocrine systems controlling reproduction (i.e., GnRHs, kisspeptins) have received little attention. In a recent study performed in the European sea bass, we cloned a cDNA encoding a precursor polypeptide that contained C-terminal MPMRFamide (sbGnIH-1) and MPQRFamide (sbGnIH-2) peptide sequences, developed a specific antiserum against sbGnIH-2, and characterized its central and pituitary GnIH projections in this species. In this study, we analyzed the effects of intracerebroventricular injection of sbGnIH-1 and sbGnIH-2 on brain and pituitary expression of reproductive hormone genes (gnrh1, gnrh2, gnrh3, kiss1, kiss2, gnih, lhbeta, fshbeta), and their receptors (gnrhr II-1a, gnrhr II-2b, kiss1r, kiss2r, and gnihr) as well as on plasma Fsh and Lh levels. In addition, we determined the effects of GnIH on pituitary somatotropin (Gh) expression. The results obtained revealed the inhibitory role of sbGnIH-2 on brain gnrh2, kiss1, kiss2, kiss1r, gnih, and gnihr transcripts and on pituitary fshbeta, lhbeta, gh, and gnrhr-II-1a expression, whereas sbGnIH-1 only down-regulated brain gnrh1 expression. However, at different doses, central administration of both sbGnIH-1 and sbGnIH-2 decreased Lh plasma levels. Our work represents the first study reporting the effects of centrally administered GnIH in fish and provides evidence of the differential actions of sbGnIH-1 and sbGnIH-2 on the reproductive axis of sea bass, the main inhibitory role being exerted by the sbGnIH-2 peptide. © 2016 by the Society for the Study of Reproduction, Inc.

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

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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.

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

Dimeric ligands for GPCRs involved in human reproduction : synthesis and biological evaluation

NARCIS (Netherlands)

Bonger, Kimberly Michelle

2008-01-01

Dimeric ligands for G-protein coupled receptors that are involved in human reproduction, namely the gonadotropin releasing hormone receptor, the luteinizing hormone receptor and the follicle-stimulating hormone receptor, were synthesized and biologically evaluated.

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.

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

Change in body mass index and insulin resistance after 1-year treatment with gonadotropin-releasing hormone agonists in girls with central precocious puberty.

Science.gov (United States)

Park, Jina; Kim, Jae Hyun

2017-03-01

Gonadotropin-releasing hormone agonist (GnRHa) is used as a therapeutic agent for central precocious puberty (CPP); however, increased obesity may subsequently occur. This study compared body mass index (BMI) and insulin resistance during the first year of GnRHa treatment for CPP. Patient group included 83 girls (aged 7.0-8.9 years) with developed breasts and a peak luteinizing hormone level of ≥5 IU/L after GnRH stimulation. Control group included 48 prepubertal girls. BMI and insulin resistance-related indices (homeostasis model assessment of insulin resistance [HOMA-IR] and quantitative insulin sensitivity check index [QUICKI]) were used to compare the groups before treatment, and among the patient group before and after GnRHa treatment. No statistical difference in BMI z -score was detected between the 2 groups before treatment. Fasting insulin and HOMA-IR were increased in the patient group; fasting glucose-to-insulin ratio and QUICKI were increased in the control group (all P resistance compared to the control group. During GnRHa treatment, normal-weight individuals showed increased BMI z -scores without increased insulin resistance; the overweight group demonstrated increased insulin resistance without significantly altered BMI z -scores. Long-term follow-up of BMI and insulin resistance changes in patients with CPP is required.

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

Predicting the effect of gonadotropin-releasing hormone (GnRH) analogue treatment on uterine leiomyomas based on MR imaging

Energy Technology Data Exchange (ETDEWEB)

Matsuno, Y.; Yamashita, Y.; Takahashi, M. [Dept. of Radiology, Kumamoto Univ. School of Medicine, Kumamoto (Japan); Katabuchi, H.; Okamura, H. [Dept. of Gynecology and Obstetrics, Kumamoto Univ. School of Medicine, Kumamoto (Japan); Kitano, Y.; Shimamura, T. [Dept. of Gynecology and Obstetrics, Amakusa Chuou General Hospital, Hondo (Japan)

1999-11-01

Purpose: To test the hypothesis that the simple assessment of signal intensity on T2-weighted MR images is predictive of the effect of hormonal treatment with gonadotropin-releasing hormone (GnRH) analogue. Material and methods: The correlation between T2-weighted MR imaging of uterine leiomyomas and histologic findings was evaluated using 85 leiomyomas from 62 females who underwent myomectomy or hysterectomy. We also correlated the pretreatment MR images features obtained in 110 women with 143 leiomyomas with the effect of GnRH analogue treatment. The size (length x width x depth) of the leiomyoma was evaluated before and at 6 months after treatment by ultrasound. Results: The proportion of leiomyoma cell fascicles and that of extracellular matrix affected signal intensities of uterine leiomyomas on T2-weighted MR images. The amount of extracellular matrix was predominant in hypointense leiomyomas on T2-weighted images, while diffuse intermediate signal leiomyomas were predominantly composed of leiomyoma cell fascicles. Marked degenerative changes were noted in leiomyomas with heterogenous hyperintensity. The homogeneously intermediate signal intensity leiomyomas showed significant size reduction after treatment (size ratio; posttreatment volume/pretreatment volume 0.29{+-}0.11). The size ratio for the hypointense tumors was 0.82{+-}0.14, and 0.82{+-}0.18 for the heterogeneously hyperintense tumors. There was a significant difference in the response to treatment between the homogeneously intermediate signal intensity leiomyomas and the hypointense or heterogeneously hyperintense leiomyomas (both p<0.01). Conclusion: Signal intensity on T2-weighted MR images depends on the amount of leiomyoma cell fascicles and extracellular matrix. Simple assessment of the MR signal intensity is useful in predicting the effect of GnRH analogue on uterine leiomyomas. (orig.)

Predicting the effect of gonadotropin-releasing hormone (GnRH) analogue treatment on uterine leiomyomas based on MR imaging

International Nuclear Information System (INIS)

Matsuno, Y.; Yamashita, Y.; Takahashi, M.; Katabuchi, H.; Okamura, H.; Kitano, Y.; Shimamura, T.

1999-01-01

Purpose: To test the hypothesis that the simple assessment of signal intensity on T2-weighted MR images is predictive of the effect of hormonal treatment with gonadotropin-releasing hormone (GnRH) analogue. Material and methods: The correlation between T2-weighted MR imaging of uterine leiomyomas and histologic findings was evaluated using 85 leiomyomas from 62 females who underwent myomectomy or hysterectomy. We also correlated the pretreatment MR images features obtained in 110 women with 143 leiomyomas with the effect of GnRH analogue treatment. The size (length x width x depth) of the leiomyoma was evaluated before and at 6 months after treatment by ultrasound. Results: The proportion of leiomyoma cell fascicles and that of extracellular matrix affected signal intensities of uterine leiomyomas on T2-weighted MR images. The amount of extracellular matrix was predominant in hypointense leiomyomas on T2-weighted images, while diffuse intermediate signal leiomyomas were predominantly composed of leiomyoma cell fascicles. Marked degenerative changes were noted in leiomyomas with heterogenous hyperintensity. The homogeneously intermediate signal intensity leiomyomas showed significant size reduction after treatment (size ratio; posttreatment volume/pretreatment volume 0.29±0.11). The size ratio for the hypointense tumors was 0.82±0.14, and 0.82±0.18 for the heterogeneously hyperintense tumors. There was a significant difference in the response to treatment between the homogeneously intermediate signal intensity leiomyomas and the hypointense or heterogeneously hyperintense leiomyomas (both p<0.01). Conclusion: Signal intensity on T2-weighted MR images depends on the amount of leiomyoma cell fascicles and extracellular matrix. Simple assessment of the MR signal intensity is useful in predicting the effect of GnRH analogue on uterine leiomyomas. (orig.)

Anti-Muellerian hormone, inhibin A, gonadotropins, and gonadotropin receptors in bull calves after partial scrotal resection, orchidectomy, and Burdizzo castration.

Science.gov (United States)

Scarlet, Dragos; Aurich, Christine; Ille, Natascha; Walter, Ingrid; Weber, Corinna; Pieler, Dagmar; Peinhopf, Walter; Wohlsein, Peter; Aurich, Jörg

2017-01-01

Eight-week-old calves were either castrated by partial scrotal resection (SR) without removing the testes (n = 10), Burdizzo (BZ) clamp (n = 10), orchidectomy (OR; n = 10), or were left gonad intact as controls (CO; n = 10). Concentrations of anti-Muellerian hormone (AMH), inhibin A, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in plasma were determined from 16 to 48 weeks of age. At 18 months, testes of SR, BZ, and CO bulls were obtained and the immunolocalization of LH and FSH receptors and AMH analyzed. Concentration of AMH in plasma of CO and SR bulls decreased with increasing age (P < 0.001). A similar AMH profile in CO and SR indicates that SR did not induce a true cryptorchid state. In groups OR and BZ, AMH was undetectable. Plasma inhibin concentration was higher in groups CO and SR than BZ and OR (P < 0.001). Plasma LH and FSH concentrations decreased over time (P < 0.001) and were higher in groups BZ and OR than SR and CO (P < 0.001). In the testes, immunolabeling for AMH existed in Sertoli cells of CO and SR but not BZ bulls. FSH receptors were localized in Sertoli cells, Leydig cells, spermatocytes, and the epididymis of CO and SR animals, whereas LH receptors were restricted to Leydig cells. In BZ animals, FSH and LH receptors and AMH were absent, indicating complete testicular degeneration. In conclusion, AMH is a more reliable marker for the presence of testicular tissue in bulls than inhibin. Scrotal resection did not induce a true inguinal cryptorchid state but affected testicular responsiveness to gonadotropic stimulation. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Aptamer based peptide enrichment for quantitative analysis of gonadotropin-releasing hormone by LC-MS/MS.

Science.gov (United States)

Richards, S L; Cawley, A T; Cavicchioli, R; Suann, C J; Pickford, R; Raftery, M J

2016-04-01

Over recent years threats to racing have expanded to include naturally occurring biological molecules, such as peptides and proteins, and their synthetic analogues. Traditionally, antibodies have been used to enable detection of these compounds as they allow purification and concentration of the analyte of interest. The rapid expansion of peptide-based therapeutics necessitates a similarly rapid development of suitable antibodies or other means of enrichment. Potential alternative enrichment strategies include the use of aptamers, which offer the significant advantage of chemical synthesis once the nucleic acid sequence is known. A method was developed for the enrichment, detection and quantitation of gonadotropin-releasing hormone (GnRH) in equine urine using aptamer-based enrichment and LC-MS/MS. The method achieved comparable limits of detection (1 pg/mL) and quantification (2.5 pg/mL) to previously published antibody-based enrichment methods. The intra- and inter-assay precision achieved was less than 10% at both 5 and 20 pg/mL, and displayed a working dynamic range of 2.5-100 pg/mL. Significant matrix enhancement (170 ± 8%) and low analytical recovery (29 ± 15%) was observed, although the use of an isotopically heavy labelled GnRH peptide, GnRH (Pro(13)C5,(15)N), as the internal standard provides compensation for these parameters. Within the current limits of detection GnRH was detectable up to 1h post administration in urine and identification of a urinary catabolite extended this detection window to 4h. Based on the results of this preliminary investigation we propose the use of aptamers as a viable alternative to antibodies in the enrichment of peptide targets from equine urine. Copyright © 2016 Elsevier B.V. All rights reserved.

Human Chorionic Gonadotropin: The Pregnancy Hormone and More

Directory of Open Access Journals (Sweden)

Charalampos Theofanakis

2017-05-01

Full Text Available To thoroughly review the uses of human chorionic gonadotropin (hCG related to the process of reproduction and also assess new, non-traditional theories. Review of the international literature and research studies. hCG and its receptor, LH/CGR, are expressed in numerous sites of the reproductive tract, both in gonadal and extra-goanadal tissues, promoting oocyte maturation, fertilization, implantation and early embryo development. Moreover, hCG seems to have a potential role as an anti-rejection agent in solid organ transplantation. Future research needs to focus extensively on the functions of hCG and its receptor LH/CGR, in an effort to reveal known, as well as unknown clinical potentials.

Effects of progesterone injection on performance, plasma hormones ...

African Journals Online (AJOL)

PRECIOUS

2009-11-16

Nov 16, 2009 ... triggers gonadotropin-releasing hormone (GnRH) release ... open period has been shown to have positive effect on inducing a preovulatory ..... release, injectable levonorgestrel and depot medroxyprogesterone acetate on.

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.

Effects of administration of gonadotropin-releasing hormone at artificial insemination on conception rates in dairy cows.

Science.gov (United States)

Shephard, R W; Morton, J M; Norman, S T

2014-01-10

A controlled trial investigating the effect on conception of administration of 250 μg of gonadotropin-releasing hormone (GnRH) at artificial insemination (AI) in dairy cows in seasonal or split calving herds was conducted. Time of detection of estrus, body condition, extent of estrous expression, treatment, breed, age and milk production from the most recent herd test of the current lactation was recorded. Cows were tested for pregnancy with fetal aging between 35 and 135 days after AI. Sixteen herds provided 2344 spring-calved cows and 3007 inseminations. Logistic regression adjusting for clustering at herd level was used to examine the effect of treatment for first (2344) and second (579) inseminations separately. For first AI, treatment significantly improved conception rate in cows with milk protein concentrations of 3.75% or greater and for cows with milk protein concentrations between 3.00% and 3.50% and less than 40 days calved; increased conception rate from 41.2% to 53.4%. Treatment reduced conception rates in cows with milk protein concentrations of 2.75% or less. Treating only cows identified as responding positively to treatment (11% of all study cows) was estimated to increase first service conception rate in herds from 48.1% to 49.4%. There was no significant effect of treatment on conception to second AI, nor any significant interactions. These findings indicate that GnRH at AI should be limited to the sub-group cows most likely to respond. The positive effect of GnRH at AI may be mediated through improved oocyte maturation and/or improved luteal function, rather than by reducing AI-to-ovulation intervals. Copyright © 2013 Elsevier B.V. All rights reserved.

A Journey through the Gonadotropin-Inhibitory Hormone System of Fish

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José A. Muñoz-Cueto

2017-10-01

Full Text Available Gonadotropin-inhibitory hormone (GnIH is a hypothalamic neuropeptide that belongs to the RFamide peptide family and was first identified in the quail brain. From the discovery of avian GnIH, orthologous GnIH peptides have been reported in a variety of vertebrates, including mammals, amphibians, teleosts and agnathans, but also in protochordates. It has been clearly established that GnIH suppresses reproduction in avian and mammalian species through its inhibitory actions on brain GnRH and pituitary gonadotropins. In addition, GnIH also appears to be involved in the regulation of feeding, growth, stress response, heart function and social behavior. These actions are mediated via G protein-coupled GnIH receptors (GnIH-Rs, of which two different subtypes, GPR147 and GPR74, have been described to date. With around 30,000 species, fish represent more than one-half of the total number of recognized living vertebrate species. In addition to this impressive biological diversity, fish are relevant because they include model species with scientific and clinical interest as well as many exploited species with economic importance. In spite of this, the study of GnIH and its physiological effects on reproduction and other physiological processes has only been approached in a few fish species, and results obtained are in some cases conflicting. In this review, we summarize the information available in the literature on GnIH sequences identified in fish, the distribution of GnIH and GnIH-Rs in central and peripheral tissues, the physiological actions of GnIH on the reproductive brain-pituitary-gonadal axis, as well as other reported effects of this neuropeptide, and existing knowledge on the regulatory mechanisms of GnIH in fish.

Kisspeptins modulate the biology of multiple populations of gonadotropin-releasing hormone neurons during embryogenesis and adulthood in zebrafish (Danio rerio).

Science.gov (United States)

Zhao, Yali; Lin, Meng-Chin A; Mock, Allan; Yang, Ming; Wayne, Nancy L

2014-01-01

Kisspeptin1 (product of the Kiss1 gene) is the key neuropeptide that gates puberty and maintains fertility by regulating the gonadotropin-releasing hormone (GnRH) neuronal system in mammals. Inactivating mutations in Kiss1 and the kisspeptin receptor (GPR54/Kiss1r) are associated with pubertal failure and infertility. Kiss2, a paralogous gene for kiss1, has been recently identified in several vertebrates including zebrafish. Using our transgenic zebrafish model system in which the GnRH3 promoter drives expression of emerald green fluorescent protein, we investigated the effects of kisspeptins on development of the GnRH neuronal system during embryogenesis and on electrical activity during adulthood. Quantitative PCR showed detectable levels of kiss1 and kiss2 mRNA by 1 day post fertilization, increasing throughout embryonic and larval development. Early treatment with Kiss1 or Kiss2 showed that both kisspeptins stimulated proliferation of trigeminal GnRH3 neurons located in the peripheral nervous system. However, only Kiss1, but not Kiss2, stimulated proliferation of terminal nerve and hypothalamic populations of GnRH3 neurons in the central nervous system. Immunohistochemical analysis of synaptic vesicle protein 2 suggested that Kiss1, but not Kiss2, increased synaptic contacts on the cell body and along the terminal nerve-GnRH3 neuronal processes during embryogenesis. In intact brain of adult zebrafish, whole-cell patch clamp recordings of GnRH3 neurons from the preoptic area and hypothalamus revealed opposite effects of Kiss1 and Kiss2 on spontaneous action potential firing frequency and membrane potential. Kiss1 increased spike frequency and depolarized membrane potential, whereas Kiss2 suppressed spike frequency and hyperpolarized membrane potential. We conclude that in zebrafish, Kiss1 is the primary stimulator of GnRH3 neuronal development in the embryo and an activator of stimulating hypophysiotropic neuron activities in the adult, while Kiss2 plays an

Effects of kisspeptin1 on electrical activity of an extrahypothalamic population of gonadotropin-releasing hormone neurons in medaka (Oryzias latipes).

Science.gov (United States)

Zhao, Yali; Wayne, Nancy L

2012-01-01

Kisspeptin (product of the kiss1 gene) is the most potent known activator of the hypothalamo-pituitary-gonadal axis. Both kiss1 and the kisspeptin receptor are highly expressed in the hypothalamus of vertebrates, and low doses of kisspeptin have a robust and long-lasting stimulatory effect on the rate of action potential firing of hypophysiotropic gonadotropin releasing hormone-1 (GnRH1) neurons in mice. Fish have multiple populations of GnRH neurons distinguished by their location in the brain and the GnRH gene that they express. GnRH3 neurons located in the terminal nerve (TN) associated with the olfactory bulb are neuromodulatory and do not play a direct role in regulating pituitary-gonadal function. In medaka fish, the electrical activity of TN-GnRH3 neurons is modulated by visual cues from conspecifics, and is thought to act as a transmitter of information from the external environment to the central nervous system. TN-GnRH3 neurons also play a role in sexual motivation and arousal states, making them an important population of neurons to study for understanding coordination of complex behaviors. We investigated the role of kisspeptin in regulating electrical activity of TN-GnRH3 neurons in adult medaka. Using electrophysiology in an intact brain preparation, we show that a relatively brief treatment with 100 nM of kisspeptin had a long-lasting stimulatory effect on the electrical activity of an extrahypothalamic population of GnRH neurons. Dose-response analysis suggests a relatively narrow activational range of this neuropeptide. Further, blocking action potential firing with tetrodotoxin and blocking synaptic transmission with a low Ca(2+)/high Mg(2+) solution inhibited the stimulatory action of kisspeptin on electrical activity, indicating that kisspeptin is acting indirectly through synaptic regulation to excite TN-GnRH3 neurons. Our findings provide a new perspective on kisspeptin's broader functions within the central nervous system, through its

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

Gonadotropin-releasing hormone antagonist use in controlled ovarian stimulation and intrauterine insemination cycles in women with polycystic ovary syndrome.

Science.gov (United States)

Ertunc, Devrim; Tok, Ekrem C; Savas, Aysun; Ozturk, Ilay; Dilek, Saffet

2010-03-01

To observe the effects of ganirelix on controlled ovarian stimulation and intrauterine insemination (COS/IUI) cycles in women with polycystic ovary syndrome (PCOS). Prospective, randomized, controlled clinical study. An academic clinical research center. Women with PCOS and anovulatory infertility undergoing COS/IUI. Recombinant FSH therapy was started on day 3. In women assigned to the control group (n = 47), treatment was continued up to the day of hCG administration. In patients assigned to receive GnRH antagonist (n = 42), ganirelix was added when the leading follicle was > or =14 mm. Pregnancy rates, serum E(2), P, and LH levels, and follicle numbers at hCG day, prevalence of premature luteinization, and cost of stimulation. Serum E(2), P, and LH levels were significantly lower in the ganirelix group. Although premature luteinization and cycle cancellation was encountered less in the ganirelix group, the pregnancy rates per cycle were similar (15.4% vs. 10.7%). Patients would pay 6,153 dollars more for each pregnancy when using ganirelix. Gonadotropin-releasing hormone antagonist resulted in more monofollicular development, less premature luteinization, and less cycle cancellation in IUI cycles of patients with PCOS; however, the cost of stimulation increased without an improvement in pregnancy rates. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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)

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.

Resurgence of Minimal Stimulation In Vitro Fertilization with A Protocol Consisting of Gonadotropin Releasing Hormone-Agonist Trigger and Vitrified-Thawed Embryo Transfer

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Zhang John

2016-07-01

Full Text Available Minimal stimulation in vitro fertilization (mini-IVF consists of a gentle controlled ovarian stimulation that aims to produce a maximum of five to six oocytes. There is a misbelief that mini-IVF severely compromises pregnancy and live birth rates. An appraisal of the literature pertaining to studies on mini-IVF protocols was performed. The advantages of minimal stimulation protocols are reported here with a focus on the use of clomiphene citrate (CC, gonadotropin releasing hormone (GnRH ago- nist trigger for oocyte maturation, and freeze-all embryo strategy. Literature review and the author’s own center data suggest that minimal ovarian stimulation protocols with GnRH agonist trigger and freeze-all embryo strategy along with single embryo transfer produce a reasonable clinical pregnancy and live birth rates in both good and poor responders. Additionally, mini-IVF offers numerous advantages such as: i. Reduction in cost and stress with fewer office visits, needle sticks, and ultrasounds, and ii. Reduction in the incidence of ovarian hyperstimulation syndrome (OHSS. Mini-IVF is re-emerging as a solution for some of the problems associated with conventional IVF, such as OHSS, cost, and patient discomfort.

The hormone level of both the testosterone and the gonadotropin. Chapter

International Nuclear Information System (INIS)

2000-01-01

Concentration of testosterone and gonadotropin hormones in blood serum was studied at 120 examined sick persons. It is shown that the statistically reliable (P<0.5) decrease of testosterone level is exhibiting under influence of radiation doses over 0.25 Gy. During radiation doses action increasing the legible tendency to of testosterone level reduction is noted. Results of pituitary gland-gonad system study in dependence of sexual dysfunctions are presented. Data evident that sexual dysfunction does not depend from suppression of hormone activity of gonads. It is revealed, that common testosterone level in sicks suffered from low radiation action was reduced. Differences in testosterone content at sicks with sexual dysfunction and without its have not been revealed

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

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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.

Brain morphology and immunohistochemical localization of the gonadotropin-releasing hormone in the bluefin tuna, Thunnus thynnus

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G Palmieri

2009-08-01

Full Text Available The present study was focused on the morphology of the diencephalic nuclei (likely involved in reproductive functions as well as on the distribution of GnRH (gonadotropin-releasing hormone in the rhinencephalon, telencephalon and the diencephalon of the brain of bluefin tuna (Thunnus thynnus by means of immunohistochemistry. Bluefin tuna has an encephalization quotient (QE similar to that of other large pelagic fish. Its brain exhibits well-developed optic tecta and corpus cerebelli. The diencephalic neuron cell bodies involved in reproductive functions are grouped in two main nuclei: the nucleus preopticus-periventricularis and the nucleus lateralis tuberis. The nucleus preopticus-periventricularis consists of the nucleus periventricularis and the nucleus preopticus consisting of a few sparse multipolar neurons in the rostral part and numerous cells closely packed and arranged in several layers in its aboral part. The nucleus lateralis tuberis is located in the ventral-lateral area of the diencephalon and is made up of a number of large multipolar neurones. Four different polyclonal primary antibodies against salmon (sGnRH, chicken (cGnRH-II (cGnRH-II 675, cGnRH-II 6 and sea bream (sbGnRH were employed in the immunohistochemical experiments. No immunoreactive structures were found with anti sbGnRH serum. sGnRH and cGnRH-II antisera revealed immunoreactivity in the perikarya of the olfactory bulbs, preopticus-periventricular nucleus, oculomotor nucleus and midbrain tegmentum. The nucleus lateralis tuberis showed immunostaining only with anti-sGnRH serum. Nerve fibres immunoreactive to cGnRH and sGnRH sera were found in the olfactory bulbs, olfactory nerve and neurohypophysis. The significance of the distribution of the GnRHimmunoreactive neuronal structures is discussed.

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

Histological organization of the central nervous system and distribution of a gonadotropin-releasing hormone-like peptide in the blue crab, Portunus pelagicus.

Science.gov (United States)

Saetan, Jirawat; Senarai, Thanyaporn; Tamtin, Montakan; Weerachatyanukul, Wattana; Chavadej, Jittipan; Hanna, Peter J; Parhar, Ishwar; Sobhon, Prasert; Sretarugsa, Prapee

2013-09-01

We present a detailed histological description of the central nervous system (CNS: brain, subesophageal ganglion, thoracic ganglia, abdominal ganglia) of the blue crab, Portunus pelagicus. Because the presence of gonadotropin-releasing hormone (GnRH) in crustaceans has been disputed, we examine the presence and localization of a GnRH-like peptide in the CNS of the blue crab by using antibodies against lamprey GnRH (lGnRH)-III, octopus GnRH (octGnRH) and tunicate GnRH (tGnRH)-I. These antibodies showed no cross-reactivity with red-pigment-concentrating hormone, adipokinetic hormone, or corazonin. In the brain, strong lGnRH-III immunoreactivity (-ir) was detected in small (7-17 μm diameter) neurons of clusters 8, 9 and 10, in medium-sized (21-36 μm diameter) neurons of clusters 6, 7 and 11 and in the anterior and posterior median protocerebral neuropils, olfactory neuropil, median and lateral antenna I neuropils, tegumentary neuropil and antenna II neuropil. In the subesophageal ganglion, lGnRH-III-ir was detected in medium-sized neurons and in the subesophageal neuropil. In the thoracic and abdominal ganglia, lGnRH-III-ir was detected in medium-sized and small neurons and in the neuropils. OctGnRH-ir was observed in neurons of the same clusters with moderate staining, particularly in the deutocerebrum, whereas tGnRH-I-ir was only detected in medium-sized neurons of cluster 11 in the brain. Thus, anti-lGnRH-III shows greater immunoreactivity in the crab CNS than anti-octGnRH and anti-tGnRH-I. Moreover, our functional bioassay demonstrates that only lGnRH-III has significant stimulatory effects on ovarian growth and maturation. We therefore conclude that, although the true identity of the crab GnRH eludes us, crabs possess a putative GnRH hormone similar to lGnRH-III. The identification and characterization of this molecule is part of our ongoing research.

Congenital gonadotropin deficiency in boys: management during childhood.

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Adan, L; Couto-Silva, A C; Trivin, C; Metz, C; Brauner, R

2004-02-01

To analyze the features of boys with congenital gonadotropin deficiency (CGD), and to determine the value of plasma inhibin B and anti-Müllerian hormone (AMH) for predicting testicular function and the effect of testosterone treatment. We followed 19 boys for CGD, including five with Kallmann syndrome. The boys were seen before 14 years of age for micropenis (9 boys) or later for delayed puberty (10 boys). No testis was palpable in the scrotum in 13 patients, bilaterally in seven of them. Luteinizing hormone (LH) peak after a gonadotropin releasing hormone (GnRH) test was between 0.5 and 5.6 U/l. Plasma inhibin B was low in the four patients evaluated at less than 1 year old. AMH was low in one of them and normal in four others. Of the older patients, three lad low plasma inhibin B and four had normal concentrations; plasma AMH was low in three of them and increased in four. Testosterone treatment restored penis length to normal in all patients. Low plasma inhibin B and AMH concentrations may indicate testicular damage in boys with CGD.

Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

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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.

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

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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.

Sequential versus simultaneous use of chemotherapy and gonadotropin-releasing hormone agonist (GnRHa) among estrogen receptor (ER)-positive premenopausal breast cancer patients: effects on ovarian function, disease-free survival, and overall survival.

Science.gov (United States)

Zhang, Ying; Ji, Yajie; Li, Jianwei; Lei, Li; Wu, Siyu; Zuo, Wenjia; Jia, Xiaoqing; Wang, Yujie; Mo, Miao; Zhang, Na; Shen, Zhenzhou; Wu, Jiong; Shao, Zhimin; Liu, Guangyu

2018-04-01

To investigate ovarian function and therapeutic efficacy among estrogen receptor (ER)-positive, premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonist (GnRHa) and chemotherapy simultaneously or sequentially. This study was a phase 3, open-label, parallel, randomized controlled trial (NCT01712893). Two hundred sixteen premenopausal patients (under 45 years) diagnosed with invasive ER-positive breast cancer were enrolled from July 2009 to May 2013 and randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment. All patients were advised to receive GnRHa for at least 2 years. The primary outcome was the incidence of early menopause, defined as amenorrhea lasting longer than 12 months after the last chemotherapy or GnRHa dose, with postmenopausal or unknown follicle-stimulating hormone and estradiol levels. The menstrual resumption period and survivals were the secondary endpoints. The median follow-up time was 56.9 months (IQR 49.5-72.4 months). One hundred and eight patients were enrolled in each group. Among them, 92 and 78 patients had complete primary endpoint data in the sequential and simultaneous groups, respectively. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group [simultaneous vs. sequential: OR 1.01 (95% CI 0.50-2.08); p = 0.969; age-adjusted OR 1.13; (95% CI 0.54-2.37); p = 0.737]. The median menstruation resumption period was 12.0 (95% CI 9.3-14.7) months and 10.3 (95% CI 8.2-12.4) months for the sequential and simultaneous groups, respectively [HR 0.83 (95% CI 0.59-1.16); p = 0.274; age-adjusted HR 0.90 (95%CI 0.64-1.27); p = 0.567]. No significant differences were evident for disease-free survival (p = 0.290) or overall survival (p = 0.514) between the two groups. For ER-positive premenopausal patients, the sequential use of GnRHa and chemotherapy showed ovarian preservation

The Effect of Oral Feeding of Tribulus terrestris L. on Sex Hormone and Gonadotropin Levels in Addicted Male Rats

Science.gov (United States)

Ghosian Moghaddam, Mohammad Hassan; Khalili, Mohsen; Maleki, Maryam; Ahmad Abadi, Mohammad Esmail

2013-01-01

Background: Opioids can exert adverse effects on the body. Morphine, an opioid drug, reduces hormone levels and fertility, and causes sexual activity disorders. Tribulus terrestris (TT) is a traditional herbal medicine used to enhance sexual activities. This study investigates the possible role of TT on sex hormones and gonadotropins with the intent to show its usefulness in treating fertility disorders in opioid users. Materials and Methods: In this experimental study, we randomly divided 48 rats into four groups: i. control, ii. TT-treated, iii. addicted and iv. TT-treated addicted. Watersoluble morphine was administrated orally for 21 days to induce addiction, after which the treated groups 2 and 4 received plant-mixed pelleted food (6.25%) orally for four weeks. At the end of the treatment period, the sex hormone and gonadotropin levels of all rats’ sera were determined by radioimmunoassay and Elisa kits. The data obtained were statistically analyzed using the one-way analysis of variance, followed by post-hoc Tukey test. P<0.05 was considered significant. Results: The addicted group had a significantly lower luteinizing hormone (LH) level than the control group (p<0.027). LH levels increased significantly in the TT-treated addicted group (p<0.031). The testosterone level in the treated addicted group was lower than the treated control group. The addicted group had a significantly low testosterone level (p<0.001). The estrogen level was significantly (p<0.002) lower in the addicted group than in the control group. In addition, there was a significant difference between the treated addicted group and the treated control group (p<0.048). The treated control group had a significant increase in its progesterone level (p<0.002). Overall, except for follicle-stimulating hormone (FSH), morphine reduced most of the gonadotropins and sexual hormones. Whereas TT caused a considerable increase (p<0.05) in the hormones in the treated addicted group, there was only a

The Effect of Oral Feeding of Tribulus terrestris L. on Sex Hormone and Gonadotropin Levels in Addicted Male Rats

Directory of Open Access Journals (Sweden)

Maryam Maleki

2013-01-01

Full Text Available Background: Opioids can exert adverse effects on the body. Morphine, an opioid drug,reduces hormone levels and fertility, and causes sexual activity disorders. Tribulus terrestris(TT is a traditional herbal medicine used to enhance sexual activities. This studyinvestigates the possible role of TT on sex hormones and gonadotropins with the intent toshow its usefulness in treating fertility disorders in opioid users.Materials and Methods: In this experimental study, we randomly divided 48 rats intofour groups: i. control, ii. TT-treated, iii. addicted and iv. TT-treated addicted. Watersolublemorphine was administrated orally for 21 days to induce addiction, after whichthe treated groups 2 and 4 received plant-mixed pelleted food (6.25% orally for fourweeks. At the end of the treatment period, the sex hormone and gonadotropin levels of allrats’ sera were determined by radioimmunoassay and Elisa kits. The data obtained werestatistically analyzed using the one-way analysis of variance, followed by post-hoc Tukeytest. P<0.05 was considered significant.Results: The addicted group had a significantly lower luteinizing hormone (LH levelthan the control group (p<0.027. LH levels increased significantly in the TT-treated addictedgroup (p<0.031. The testosterone level in the treated addicted group was lowerthan the treated control group. The addicted group had a significantly low testosteronelevel (p<0.001. The estrogen level was significantly (p<0.002 lower in the addictedgroup than in the control group. In addition, there was a significant difference betweenthe treated addicted group and the treated control group (p<0.048. The treated controlgroup had a significant increase in its progesterone level (p<0.002. Overall, except forfollicle-stimulating hormone (FSH, morphine reduced most of the gonadotropins andsexual hormones. Whereas TT caused a considerable increase (p<0.05 in the hormonesin the treated addicted group, there was only a slight increase in

Premenstrual Exacerbation of Life-Threatening Asthma: Effect of Gonadotrophin Releasing Hormone Analogue Therapy

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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.

Kisspeptins modulate the biology of multiple populations of gonadotropin-releasing hormone neurons during embryogenesis and adulthood in zebrafish (Danio rerio.

Directory of Open Access Journals (Sweden)

Yali Zhao

Full Text Available Kisspeptin1 (product of the Kiss1 gene is the key neuropeptide that gates puberty and maintains fertility by regulating the gonadotropin-releasing hormone (GnRH neuronal system in mammals. Inactivating mutations in Kiss1 and the kisspeptin receptor (GPR54/Kiss1r are associated with pubertal failure and infertility. Kiss2, a paralogous gene for kiss1, has been recently identified in several vertebrates including zebrafish. Using our transgenic zebrafish model system in which the GnRH3 promoter drives expression of emerald green fluorescent protein, we investigated the effects of kisspeptins on development of the GnRH neuronal system during embryogenesis and on electrical activity during adulthood. Quantitative PCR showed detectable levels of kiss1 and kiss2 mRNA by 1 day post fertilization, increasing throughout embryonic and larval development. Early treatment with Kiss1 or Kiss2 showed that both kisspeptins stimulated proliferation of trigeminal GnRH3 neurons located in the peripheral nervous system. However, only Kiss1, but not Kiss2, stimulated proliferation of terminal nerve and hypothalamic populations of GnRH3 neurons in the central nervous system. Immunohistochemical analysis of synaptic vesicle protein 2 suggested that Kiss1, but not Kiss2, increased synaptic contacts on the cell body and along the terminal nerve-GnRH3 neuronal processes during embryogenesis. In intact brain of adult zebrafish, whole-cell patch clamp recordings of GnRH3 neurons from the preoptic area and hypothalamus revealed opposite effects of Kiss1 and Kiss2 on spontaneous action potential firing frequency and membrane potential. Kiss1 increased spike frequency and depolarized membrane potential, whereas Kiss2 suppressed spike frequency and hyperpolarized membrane potential. We conclude that in zebrafish, Kiss1 is the primary stimulator of GnRH3 neuronal development in the embryo and an activator of stimulating hypophysiotropic neuron activities in the adult, while

Human pituitary and placental hormones control human insulin-like growth factor II secretion in human granulosa cells

International Nuclear Information System (INIS)

Ramasharma, K.; Li, C.H.

1987-01-01

Human granulosa cells cultured with calf serum actively proliferated for 18-20 generations and secreted progesterone into the medium; progesterone levels appeared to decline with increase in generation number. Cells cultured under serum-free conditions secreted significant amounts of progesterone and insulin-like growth factor II (IGF-II). The progesterone secretion was enhanced by the addition of human follitropin, lutropin, and chorionic gonadotropin but not by growth hormone. These cells, when challenged to varying concentrations of human growth hormone, human chorionic somatomammotropin, human prolactin, chorionic gonadotropin, follitropin, and lutropin, secreted IGF-II into the medium as measured by specific IGF-II RIA. Among these human hormones, chorionic gonadotropin, follitropin, and lutropin were most effective in inducing IGF-II secretion from these cells. When synthetic lutropin-releasing hormone and α-inhibin-92 were tested, only lutropin-releasing hormone was effective in releasing IGF-II. The results described suggest that cultured human granulosa cells can proliferate and actively secrete progesterone and IGF-II into the medium. IGF-II production in human granulosa cells was influenced by a multi-hormonal complex including human growth hormone, human chorionic somatomammotropin, and prolactin

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

Effects of peripubertal gonadotropin-releasing hormone agonist on brain development in sheep--a magnetic resonance imaging study.

Science.gov (United States)

Nuruddin, Syed; Bruchhage, Muriel; Ropstad, Erik; Krogenæs, Anette; Evans, Neil P; Robinson, Jane E; Endestad, Tor; Westlye, Lars T; Madison, Cindee; Haraldsen, Ira Ronit Hebold

2013-10-01

In many species sexual dimorphisms in brain structures and functions have been documented. In ovine model, we have previously demonstrated that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) action increased sex-differences of executive emotional behavior. The structural substrate of this behavioral alteration however is unknown. In this magnetic resonance image (MRI) study on the same animals, we investigated the effects of GnRH agonist (GnRHa) treatment on the volume of total brain, hippocampus and amygdala. In total 41 brains (17 treated; 10 females and 7 males, and 24 controls; 11 females and 13 males) were included in the MRI study. Image acquisition was performed with 3-T MRI scanner. Segmentation of the amygdala and the hippocampus was done by manual tracing and total gray and white matter volumes were estimated by means of automated brain volume segmentation of the individual T2-weighted MRI volumes. Statistical comparisons were performed with general linear models. Highly significant GnRHa treatment effects were found on the volume of left and right amygdala, indicating larger amygdalae in treated animals. Significant sex differences were found for total gray matter and right amygdala, indicating larger volumes in male compared to female animals. Additionally, we observed a significant interaction between sex and treatment on left amygdala volume, indicating stronger effects of treatment in female compared to male animals. The effects of GnRHa treatment on amygdala volumes indicate that increasing GnRH concentration during puberty may have an important impact on normal brain development in mammals. These novel findings substantiate the need for further studies investigating potential neurobiological side effects of GnRHa treatment on the brains of young animals and humans. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prenatal exposure to vinclozolin disrupts selective aspects of the gonadotropin-releasing hormone neuronal system of the rabbit

Science.gov (United States)

Wadas, B.C.; Hartshorn, C.A.; Aurand, E.R.; Palmer, J.S.; Roselli, C.E.; Noel, M.L.; Gore, A.C.; Veeramachaneni, D.N.R.; Tobet, S.A.

2010-01-01

Developmental exposure to the agricultural fungicide vinclozolin can impair reproductive function in male rabbits and was previously found to decrease the number of immunoreactive-gonadotropin-releasing hormone (ir-GnRH) neurons in the region of the organum vasculosum of the lamina terminalis (OVLT) and rostral preoptic area (rPOA) by postnatal week (PNW) 6. To further examine the disruption of GnRH neurons by fetal vinclozolin exposure, in the current study, pregnant rabbits were dosed orally with vinclozolin, flutamide, or carrot paste vehicle for the last two weeks of gestation. Offspring were euthanized at birth (males and females), PNW6 (females), PNW26 (adult males), or PNW30 (adult females) of age. At birth and in adults, brains were sectioned and processed for immunoreactive GnRH. The numbers of immunoreactive GnRH neuronal perikarya were significantly decreased in vinclozolin-treated rabbits at birth and in adult littermates. By contrast, there was an increase in GnRH immunoreactivity in the terminals in the region of the median eminence. Analysis of PNW6 female brains by radioimmunoassay (RIA) revealed a two-fold increase in GnRH peptide content in the mediobasal hypothalamus in vinclozolin-treated rabbits. This finding was complemented by immunofluorescence analyses that showed a 2.8-fold increase in GnRH immunoreactivity in the median eminence of vinclozolin compared to vehicle-treated females at PNW30. However, there was no difference between treatment groups in the measures of reproduction that were evaluated: ejaculation latency, conception rates or litter size. These results indicate that subacute, prenatal vinclozolin treatment is sufficient to create perdurable alterations in the GnRH neuronal network that forms an important input into the reproductive axis. Finally, the effect of vinclozolin on the GnRH neuronal network was not comparable to that of flutamide, suggesting that vinclozolin was not acting through anti-androgenic mechanisms. PMID

Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET.

Science.gov (United States)

Fouda, Usama M; Sayed, Ahmed M

2011-12-01

To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3-7) combined with HPuFSH-GnRHant protocol. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

Increased Progesterone/Estradiol Ratio on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilization–Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

Directory of Open Access Journals (Sweden)

Yu-Che Ou

2008-06-01

Conclusion: Premature luteinization, defined as late follicular P/E2 ratio of > 1 in long GnRHa cycles with rFSH stimulation, adversely affected ovarian responses and clinical outcomes. It seems unrelated to preovulatory luteinizing hormone (LH elevation and LH/hCG content of gonadotropins and could be associated with poor ovarian response and the presence of dysmature follicles. [Taiwan J Obstet Cynecol 2008;47(2:1 68-1 74

Hormonal changes during GnRH analogue therapy in children with central precocious puberty

DEFF Research Database (Denmark)

Müller, J; Juul, A; Andersson, A M

2000-01-01

Gonadotropin releasing hormone analogues (GnRHa) have been used for treatment of central precocious puberty (CPP) for more than 15 years. They are generally considered safe although data on potential long-term side effects are scarce. However, GnRHa therapy has profound effects on both the hypoth......Gonadotropin releasing hormone analogues (GnRHa) have been used for treatment of central precocious puberty (CPP) for more than 15 years. They are generally considered safe although data on potential long-term side effects are scarce. However, GnRHa therapy has profound effects on both...

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.

125I-luteinizing hormone (LH) binding to soluble receptors from the primate (Macaca mulatta) corpus luteum: effects of ethanol exposure

International Nuclear Information System (INIS)

Danforth, D.R.; Stouffer, R.L.

1988-01-01

In the current study, we compared the effects of ethanol on gonadotropin receptors solubilized from macaque luteal membranes to those on receptors associated with the lipid bilayer. Treatment with 1% Triton X-100 for 30 min at 4C, followed by precipitation with polyethylene glycol, resulted in recovery of 50% more binding sites for 125 I-human luteinizing hormone (hLH) than were available in particulate preparations. However, the soluble receptors displayed a 3-fold lower affinity for 125 I-hLH. Conditions which enhanced LH binding to particulates, i.e., 1-8% ethanol at 25C, decreased specific 125 I-hLH binding to soluble receptors. Steady-state LH binding to soluble receptors during incubation at 4C was half of that observed at 25C. The presence of 8% ethanol at 4C restored LH binding to levels observed in the absence of ethanol at 25C. Thus, LH binding sites in the primate corpus luteum can be effectively solubilized with Triton X-100. The different binding characteristics of particulate and soluble receptors, including the response to ethanol exposure, suggest that the lipid environment in the luteal membrane modulates the availability and affinity of gonadotropin receptors

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.

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

Evaluation of puberty by verifying spontaneous and stimulated gonadotropin values in girls.

Science.gov (United States)

Chin, Vivian L; Cai, Ziyong; Lam, Leslie; Shah, Bina; Zhou, Ping

2015-03-01

Changes in pharmacological agents and advancements in laboratory assays have changed the gonadotropin-releasing hormone analog stimulation test. To determine the best predictive model for detecting puberty in girls. Thirty-five girls, aged 2 years 7 months to 9 years 3 months, with central precocious puberty (CPP) (n=20) or premature thelarche/premature adrenarche (n=15). Diagnoses were based on clinical information, baseline hormones, bone age, and pelvic sonogram. Gonadotropins and E2 were analyzed using immunochemiluminometric assay. Logistic regression for CPP was performed. The best predictor of CPP is the E2-change model based on 3- to 24-h values, providing 80% sensitivity and 87% specificity. Three-hour luteinizing hormone (LH) provided 75% sensitivity and 87% specificity. Basal LH lowered sensitivity to 65% and specificity to 53%. The E2-change model provided the best predictive power; however, 3-h LH was more practical and convenient when evaluating puberty in girls.

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones.

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Malik, Minnie; Britten, Joy; Cox, Jeris; Patel, Amrita; Catherino, William H

2016-01-01

To determine the effect of GnRH analogues (GnRH-a) leuprolide acetate (LA) and cetrorelix acetate on gonadal hormone-regulated expression of extracellular matrix in uterine leiomyoma three-dimensional (3D) cultures. Laboratory study. University research laboratory. Women undergoing hysterectomy for symptomatic leiomyomas. The 3D cell cultures, protein analysis, Western blot, immunohistochemistry. Expression of extracellular matrix proteins, collagen 1, fibronectin, and versican in leiomyoma cells 3D cultures exposed to E2, P, LA, cetrorelix acetate, and combinations for 24- and 72-hour time points. The 3D leiomyoma cultures exposed to E2 for 24 hours demonstrated an increased expression of collagen-1 and fibronectin, which was maintained for up to 72 hours, a time point at which versican was up-regulated significantly. Although P up-regulated collagen-1 protein (1.29 ± 0.04) within 24 hours of exposure, significant increase in all extracellular matrix (ECM) proteins was observed when the gonadal hormones were used concomitantly. Significant decrease in the amount of ECM proteins was observed on use of GnRH-a, LA and cetrorelix, with 24-hour exposure. Both the compounds also significantly decreased ECM protein concentration despite the presence of E2 or both gonadal hormones. This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy. Published by Elsevier Inc.

Effect of Valsartan on the hormones of Pituitary-gonadal axis Performance in mature female Wistar Rats

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Ebrahim Hosseini

2013-02-01

Conclusion: Valsartan , as a receptor antagonist of Ang II inhibits the secretion of gonadotropin hormones and accelerates their effect on blocking the follicular cells of the female sex ,causing the reduction of female hormones.

[Anthology of the first clinical studies with hypothalamic hormones: a story of successful international cooperation].

Science.gov (United States)

Schally, Andrew V; Gual, Carlos

2002-01-01

Our early pioneering clinical trials in Mexico with natural and synthetic thyrotropin-releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Highly purified TRH of porcine origin was shown to stimulate Thyrotropin (TSH) release in hypothyroid cretins. Subsequent tests with synthetic TRH also demonstrated significant increases in plasma TSH in normal men and women as well as in patients with primary hypothyroidism and other endocrine disorders. Even more extensive clinical studies were carried out with highly purified natural porcine LH-RH. Subjects with normal basal serum levels of gonadotropins, low levels (men and women pretreated with steroids) and high levels (e.g. post menopausal women) all responded to LH-RH with a release of LH and FSH. The results of these early studies with the natural LH-RH were confirmed by the use of synthetic LH-RH. These investigations made in Mexico with TRH and LH-RH preceded all other clinical studies by a wide margin. Subsequently various clinical investigations with LH-RH agonists and antagonists were also carried out. All these studies played a major role in introducing hypothalamic-releasing hormones into clinical medicine.

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.

Expression of estrogen receptor α 36 (ESR36) in the hamster ovary throughout the estrous cycle: effects of gonadotropins.

Science.gov (United States)

Chakraborty, Prabuddha; Roy, Shyamal K

2013-01-01

Estradiol-17β (E) plays an important role in ovarian follicular development. Evidence indicates that some of the effect of E is mediated by the transmembrane estrogen receptor. In this study, we examined the spatio-temporal expression of recently discovered ERα36 (ESR36), a splice variant of Esr1 and a receptor for non-genomic E signaling, in the hamster ovary during the estrous cycle and the role of gonadotropins and ovarian steroid hormones in ESR36 expression. ESR36 expression was high on estrus (D1:0900 h) and declined precipitously by proestrus (D4:0900 h) and remained low up to D4:1600 h. Immunofluorescence findings corroborated immunoblot findings and revealed that ESR36 was expressed only in the cell membrane of both follicular and non-follicular cells, except the oocytes. Ovarian ESR36 was capable of binding to the E-affinity matrix, and have different molecular weight than that of the ESR1 or GPER. Hypophysectomy (Hx) resulted in a marked decline in ESR36 protein levels. FSH and LH, alone or combined, markedly upregulated ESR36 protein in Hx hamsters to the levels observed in D1 hamsters, but neither E nor P had any effect. Inhibition of the gonadotropin surge by phenobarbital treatment on D4:1100 h attenuated ESR36 expression in D1:0900 h ovaries, but the decline was restored by either FSH or LH replacement on D4 afternoon. This is the first report to show that ESR36, which is distinct from ESR1 or GPER is expressed in the plasma membrane of ovarian follicular and non-follicular cells, binds to E and its expression is regulated directly by the gonadotropins. In light of our previous findings, the results suggest that ovarian cells contain at least two distinct membrane estrogen receptors, such as GPER and ESR36, and strongly suggest for a non-genomic action of E regulating ovarian follicular functions.

Expression of estrogen receptor α 36 (ESR36 in the hamster ovary throughout the estrous cycle: effects of gonadotropins.

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Prabuddha Chakraborty

Full Text Available Estradiol-17β (E plays an important role in ovarian follicular development. Evidence indicates that some of the effect of E is mediated by the transmembrane estrogen receptor. In this study, we examined the spatio-temporal expression of recently discovered ERα36 (ESR36, a splice variant of Esr1 and a receptor for non-genomic E signaling, in the hamster ovary during the estrous cycle and the role of gonadotropins and ovarian steroid hormones in ESR36 expression. ESR36 expression was high on estrus (D1:0900 h and declined precipitously by proestrus (D4:0900 h and remained low up to D4:1600 h. Immunofluorescence findings corroborated immunoblot findings and revealed that ESR36 was expressed only in the cell membrane of both follicular and non-follicular cells, except the oocytes. Ovarian ESR36 was capable of binding to the E-affinity matrix, and have different molecular weight than that of the ESR1 or GPER. Hypophysectomy (Hx resulted in a marked decline in ESR36 protein levels. FSH and LH, alone or combined, markedly upregulated ESR36 protein in Hx hamsters to the levels observed in D1 hamsters, but neither E nor P had any effect. Inhibition of the gonadotropin surge by phenobarbital treatment on D4:1100 h attenuated ESR36 expression in D1:0900 h ovaries, but the decline was restored by either FSH or LH replacement on D4 afternoon. This is the first report to show that ESR36, which is distinct from ESR1 or GPER is expressed in the plasma membrane of ovarian follicular and non-follicular cells, binds to E and its expression is regulated directly by the gonadotropins. In light of our previous findings, the results suggest that ovarian cells contain at least two distinct membrane estrogen receptors, such as GPER and ESR36, and strongly suggest for a non-genomic action of E regulating ovarian follicular functions.

Suplementasi Hormon Gonadotropin Pada Medium Maturasi In Vitro Untuk Meningkatkan Perkembangan Embrio Stadium 4 Sel Kambing Bligon

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Dewi Pranatasari

2016-06-01

Full Text Available The study was carried out to investigate the effect of gonadotropin hormone supplementation into in vitro maturation medium on maturation, fertilization and embryo development of Bligon goats. This research steps consist of oocyte collection, in vitro maturation, in vitro fertilization, and in vitro embryo development. At the maturation stage the oocyte that had been collected and divided into two groups based on the maturation medium, that was tissue culture medium (TCM with supplementation of GnRH 0 IU/mL and GnRH 25 IU/mL. Oocyte and embryo morphology data were analyzed descriptively. Maturation rate and embryo development data were analyzed by using independent sample t-test. Fertilization data was analyzed descriptively. The result showed the percentages of mature oocytes from gonadotropin supplementation of 0 IU/mL and 25 IU/mL were 54.10±25.97 and 54.89±26.44%, respectively. Expansion cumulus cells surrounding the oocytes might indicated the mature oocytes. Cleavage rate of the 2 cells stage were 13,02±11,09 and 27,01±16,65%; respectively, and for the 4 cells stage were 10,16±10,01% and 16,67±14.91%. Embryos obtained from the treatment, indicated uniform of blastomeres in the size, tight, compact, intact, and round-spherical shape. It could be concluded that supplementation of gonadotropin hormone into in vitro maturation medium could not increase the rate of oocyte maturation and 4 cell embryo development, but it could increase 2 cell embryo development of Bligon goats. Hormone supplementation could improved the maturation and embryo quality.

Change in body mass index and insulin resistance after 1-year treatment with gonadotropin-releasing hormone agonists in girls with central precocious puberty

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Jina Park

2017-03-01

Full Text Available PurposeGonadotropin-releasing hormone agonist (GnRHa is used as a therapeutic agent for central precocious puberty (CPP; however, increased obesity may subsequently occur. This study compared body mass index (BMI and insulin resistance during the first year of GnRHa treatment for CPP.MethodsPatient group included 83 girls (aged 7.0–8.9 years with developed breasts and a peak luteinizing hormone level of ≥5 IU/L after GnRH stimulation. Control group included 48 prepubertal girls. BMI and insulin resistance-related indices (homeostasis model assessment of insulin resistance [HOMA-IR] and quantitative insulin sensitivity check index [QUICKI] were used to compare the groups before treatment, and among the patient group before and after GnRHa treatment.ResultsNo statistical difference in BMI z-score was detected between the 2 groups before treatment. Fasting insulin and HOMA-IR were increased in the patient group; fasting glucose-to-insulin ratio and QUICKI were increased in the control group (all P<0.001. In normal-weight subjects in the patient group, BMI z-score was significantly increased during GnRHa treatment (−0.1±0.7 vs. 0.1±0.8, P<0.001, whereas HOMA-IR and QUICKI exhibited no differences. In overweight subjects in the patient group; BMI z-score and HOMA-IR were not significantly different, whereas QUICKI was significantly decreased during GnRHa treatment (0.35±0.03 vs. 0.33±0.02, P=0.044.ConclusionGirls with CPP exhibited increased insulin resistance compared to the control group. During GnRHa treatment, normal-weight individuals showed increased BMI z-scores without increased insulin resistance; the overweight group demonstrated increased insulin resistance without significantly altered BMI z-scores. Long-term follow-up of BMI and insulin resistance changes in patients with CPP is required.

Evaluating the ovarian cancer gonadotropin hypothesis

DEFF Research Database (Denmark)

Lee, Alice W; Tyrer, Jonathan P; Doherty, Jennifer A

2015-01-01

OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment...... of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway...... genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some...

Oral contraceptive therapy for polycystic ovary disease after chronic gonadotropin-releasing agonist administration. Predictors of continued ovarian suppression.

Science.gov (United States)

Elkind-Hirsch, K E; Anania, C; Malinak, R

1996-09-01

To study the beneficial effects of oral contraceptive (OC) therapy following gonadotropin-releasing hormone agonist (GnRH-a) administration in women with polycystic ovary disease (PCOD). Twenty-three hyperandrogenic women (aged 15-39) were randomized into two groups; GnRH-a (depot every 28 days) for six months or combination therapy (GnRH-a plus OC "addback") for six months. Following six months of treatment with either therapy, all patients received OC therapy for at least six months. The hormonal state was evaluated at three-month intervals. Hormone levels of luteinizing hormone (LH), testosterone (T) and free T remained suppressed within the normal range in 11 of 17 patients (65%) during the six months of OC only therapy, while the other six patients showed "escape" from suppression, with the LH, T and free T concentrations rising to pre-GnRH-a treatment levels. Use of OC addback therapy did not potentiate the long-acting therapeutic effect of GnRH-a pretreatment; three of six patients in the escape group were pretreated with combination therapy and three with GnRH-a only. In the majority of women with PCOD, OC therapy following GnRH-a administration was effective in maintaining ovarian androgen suppression. Failure to maintain ovarian suppression in this patient population was associated with higher elevations of baseline free T concentrations.

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.)

Repeat dose of gonadotropin-releasing hormone agonist trigger in polycystic ovarian syndrome undergoing In Vitro fertilization cycles provides a better cycle outcome - a proof-of-concept study

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Krishna Deepika

2017-01-01

Full Text Available Objective: Is a single dose of gonadotropin-releasing hormone agonist (GnRHa trigger to induce final oocyte maturation in polycystic ovarian syndrome (PCOS undergoing in vitro fertilization (IVF cycles with GnRH antagonist protocol sufficient to provide optimal oocyte maturity? Design: This is a prospective, randomized, double-blind, proof-of-concept study. Setting: This study was carried out at a tertiary care center. Material and Methods: A total of 125 patients diagnosed with PCOS defined as per the ESHRE/ASRM Rotterdam criteria (2003 undergoing IVF in antagonist protocol were randomized into two groups. Group A: single dose of GnRHa 0.2 mg, 35 h prior to oocyte retrieval, and Group B: 0.2 mg GnRHa 35 h prior to oocyte retrieval + repeat dose of 0.1 mg 12 h following the 1st dose. 12 h post-trigger, luteinizing hormone (LH, progesterone (P4, and follicle-stimulating hormone (FSH values were estimated. Statistical Analysis: Continuous variables were expressed as mean ± standard deviation and categorical variables as proportions where applicable. Independent sample t-test was used for continuous variables which were normally distributed and Mann–Whitney U-test for data not normally distributed. Chi-square test or Fisher's exact test was used for categorical variables where appropriate. Odds ratio (OR with 95% confidence intervals (CIs was calculated. In addition, receiver operating characteristic curve was used to evaluate the post-trigger LH, P4, and FSH values at 12 h as predictors of oocyte maturity. Main Outcome Measures: Primary outcome: maturity rate of the oocytes. Secondary outcomes: oocyte yield, fertilization rate, availability of good quality embryos on day 3, blastocyst conversion, OHSS rates, post-trigger serum LH (IU/L, FSH (IU/L, and P4 (ng/mL levels implantation rate and clinical pregnancy rate. Results: A higher number of mature (metaphase II oocytes were obtained in Group B compared to Group A (OR of 0.47; CI: 0.38–0

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

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

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.

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...

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

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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

Effects of luteinizing hormone and human chorionic gonadotropin on corpus luteum cells in a spheroid cell culture system.

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Walz, A; Keck, C; Weber, H; Kissel, C; Pietrowski, D

2005-09-01

The human corpus luteum (CL) is a highly vascularized, temporarily active endocrine gland and consists mainly of granulosa cells (GCs), theca cells (TCs), and endothelial cells (ECs). Its cyclic growth and development takes place under the influence of gonadotropic hormones. If pregnancy does occur, human chorionic gonadotropin (hCG) takes over the function of luteinizing hormone (LH) and, in contrast to LH, extends the functional life span of the CL. In this study, we investigated the effects of hCG and LH in a spheroidal cell culture model of CL development. Our data indicate that GCs secrete factors under the control of hCG that increase sprout formation of EC-spheroids. We demonstrate that the most prominent of these factors is VEGF-A. Furthermore, we found that both LH and hCG decrease sprout formation of GC-spheroids. After forming EC-GC coculture spheroids and consequently bringing GCs and ECs in close contact, sprouting increased under the influence of hCG, however not under LH. These experiments provide evidence for an hCG dependent functional switch in the GCs after coming in contact with ECs. Moreover, it demonstrates the considerably different effects of hCG and LH on GCs although their signaling is transmitted via the same receptor.

Different gonadotropin releasing hormone agonist doses for the final oocyte maturation in high-responder patients undergoing in vitro fertilization/intra-cytoplasmic sperm injection

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Emre Goksan Pabuccu

2015-01-01

Full Text Available Context: Efficacy of gonadotropin releasing hormone agonists (GnRH-a for ovulation in high-responders. Aims: The aim of the current study is to compare the impact of different GnRH-a doses for the final oocyte maturation on cycle outcomes and ovarian hyperstimulation syndrome (OHSS rates in high-responder patients undergoing ovarian stimulation. Settings And Designs: Electronic medical records of a private in vitro fertilization center, a retrospective analysis. Subjects and Methods: A total of 77 high-responder cases were detected receiving GnRH-a. Group I consisted of 38 patients who received 1 mg of agonist and Group II consisted of 39 patients who received 2 mg of agonist. Statistical Analysis: In order to compare groups, Student′s t-test, Mann-Whitney U-test, Pearson′s Chi-square test or Fisher′s exact test were used where appropriate. A P < 0.05 was considered as statistically significant. Result: Number of retrieved oocytes (17.5 vs. 15.0, P = 0.510, implantation rates (46% vs. 55.1%, P = 0.419 and clinical pregnancy rates (42.1% vs. 38.5%, P = 0.744 were similar among groups. There were no mild or severe OHSS cases detected in Group I. Only 1 mild OHSS case was detected in Group II. Conclusion: A volume of 1 or 2 mg leuprolide acetate yields similar outcomes when used for the final oocyte maturation in high-responder patients.

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

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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.

Identification and characterization of a reptilian GnRH receptor from the leopard gecko.

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Ikemoto, T; Enomoto, M; Park, M K

2004-02-12

Gonadotropin-releasing hormone (GnRH) plays a pivotal role in the regulation of reproductive functions through interactions with its specific receptor. We describe the first molecular cloning and characterization of a full-length GnRH receptor (GnRHR) from the leopard gecko Eublepharis macularius. It has a distinct genomic structure consisting of five exons and four introns, compared with all the other reported GnRHR genes. A native GnRH form, cGnRH-II, stimulated inositol phosphate (IP) production in COS-7 cells transiently transfected with the GnRHR, in a dose dependent manner. The mRNA was expressed in all the tissues and organs examined. Molecular phylogenetic analysis revealed that the cloned GnRHR belongs to the type 2/nonmammalian I GnRHR. Low-expression levels were observed from the pituitary glands of reproductively active leopard geckos, indicating the possibility that there is at least one more type of GnRHR highly expressed in the pituitary gland for the gonadotropin secretion in this reptile.

Significant adverse reactions to long-acting gonadotropin-releasing hormone agonists for the treatment of central precocious puberty and early onset puberty

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Ji Woo Lee

2014-09-01

Full Text Available PurposeLong-acting gonadotropin-releasing hormone agonists (GnRHa are commonly used to treat central precocious puberty (CPP in Korea. Although rare, there have been reports on the characteristic of adverse reactions of GnRHa in CPP among the Korean population. This study was intended to report on our clinical experience regarding significant adverse reactions to long-acting GnRHa in CPP and early onset puberty and to evaluate the prevalence rate of serious side effects.MethodsThis retrospective study included children with CPP and early onset puberty, who were administered monthly with long-acting GnRHa (leuprolide acetate, triptorelin acetate at the outpatient clinic of Department of Pediatrics, at Inha University Hospital, between January 2011 and December 2013. We analyzed the clinical characteristics of patients who experienced significant adverse reactions and evaluated the prevalence rate.ResultsSix serious side effects (0.9% were observed among total of 621 CPP and early onset puberty children with GnRHa therapy. The number of sterile abscess formation was four in three patients (4 events of 621. Anaphylaxis occurred in only one patient, and unilateral slipped capital femoral epiphysis (SCFE in another one patient. Anaphylaxis occurred after the 6th administration of the monthly depot triptorelin acetate. Unilateral SCFE developed in GnRHa therapy.ConclusionSterile abscess formation occurred in 0.6% of CPP and early onset puberty patients from the administration of a monthly depot GnRHa therapy. The occurrences of anaphylaxis and SCFE are extremely rare, but can have serious implications on patients. Clinicians should be aware of these potential adverse effects related to GnRHa therapy in CPP.

Endotoxin-Induced Inflammation Suppresses the Effect of Melatonin on the Release of LH from the Ovine Pars Tuberalis Explants—Ex Vivo Study

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Karolina Wojtulewicz

2017-11-01

Full Text Available The secretion of the hormone melatonin reliably reflects environmental light conditions. Among numerous actions, in seasonal breeders, melatonin may regulate the secretion of the gonadotropins acting via its corresponding receptors occurring in the Pars Tuberalis (PT. However, it was previously found that the secretory activity of the pituitary may be dependent on the immune status of the animal. Therefore, this study was designed to determine the role of melatonin in the modulation of luteinizing hormone (LH secretion from the PT explants collected from saline- and endotoxin-treated ewes in the follicular phase of the oestrous cycle. Twelve Blackhead ewes were sacrificed 3 h after injection with lipopolysaccharide (LPS; 400 ng/kg or saline, and the PTs were collected. Each PT was cut into 4 explants, which were then divided into 4 groups: I, incubated with ‘pure’ medium 199; II, treated with gonadotropin-releasing hormone (GnRH (100 pg/mL; III, treated with melatonin (10 nmol/mL; and IV, incubated with GnRH and melatonin. Melatonin reduced (p < 0.05 GnRH-induced secretion of LH only in the PT from saline-treated ewes. Explants collected from LPS-treated ewes were characterized by lower (p < 0.05 GnRH-dependent response in LH release. It was also found that inflammation reduced the gene expression of the GnRH receptor and the MT1 melatonin receptors in the PT. Therefore, it was shown that inflammation affects the melatonin action on LH secretion from the PT, which may be one of the mechanisms via which immune/inflammatory challenges disturb reproduction processes in animals.

Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial.

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Zitzmann, M; Rohayem, J; Raidt, J; Kliesch, S; Kumar, N; Sitruk-Ware, R; Nieschlag, E

2017-05-01

Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone ® (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 μg/day absorbed, NETA 5 mg/10 mg, LNG 120 μg/240 μg. From an andrology outpatient clinic, 56 healthy men aged 18-50 years, with body mass index ≤33 kg × m -2 were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception. © 2017 American

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

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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

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

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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.

Pattern of human chorionic gonadotropin binding in the polycystic ovary

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Brawer, J.; Richard, M.; Farookhi, R.

1989-01-01

The histologic evolution of polycystic ovaries in the estradiol valerate-treated rat coincides with the development of a unique plasma pattern of luteinizing hormone. To assess the role of luteinizing hormone in polycystic ovaries, it is necessary to evaluate the luteinizing hormone sensitivity of the specific tissues in the polycystic ovary. Therefore, we examined the pattern of luteinizing hormone binding sites in polycystic ovaries. Rats at 4 or 8 weeks after estradiol valerate treatment each received an intrajugular injection of iodine 125-labeled human chorionic gonadotropin. Some rats also received a 1000-fold excess of unlabeled human chorionic gonadotropin in the same injection. Ovaries were prepared for autoradiography. Dense accumulations of grains occurred over the theca of normal and atretic secondary follicles in all ovaries and over clusters of secondary interstitial cells. The iodine label was variable over the typically hypertrophied theca of precystic follicles. The theca of definitive cysts showed little or no label. These results indicate that cyst formation coincides with the loss of luteinizing hormone/human chorionic gonadotropin binding to the affected follicles

Pattern of human chorionic gonadotropin binding in the polycystic ovary

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Brawer, J.; Richard, M.; Farookhi, R. (McGill Univ., Montreal, Quebec (Canada))

1989-08-01

The histologic evolution of polycystic ovaries in the estradiol valerate-treated rat coincides with the development of a unique plasma pattern of luteinizing hormone. To assess the role of luteinizing hormone in polycystic ovaries, it is necessary to evaluate the luteinizing hormone sensitivity of the specific tissues in the polycystic ovary. Therefore, we examined the pattern of luteinizing hormone binding sites in polycystic ovaries. Rats at 4 or 8 weeks after estradiol valerate treatment each received an intrajugular injection of iodine 125-labeled human chorionic gonadotropin. Some rats also received a 1000-fold excess of unlabeled human chorionic gonadotropin in the same injection. Ovaries were prepared for autoradiography. Dense accumulations of grains occurred over the theca of normal and atretic secondary follicles in all ovaries and over clusters of secondary interstitial cells. The iodine label was variable over the typically hypertrophied theca of precystic follicles. The theca of definitive cysts showed little or no label. These results indicate that cyst formation coincides with the loss of luteinizing hormone/human chorionic gonadotropin binding to the affected follicles.

GnRH-induced Ca2+ signaling patterns and gonadotropin secretion in pituitary gonadotrophs. Functional adaptations to both ordinary and extraordinary physiological demands

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María Luisa eDurán-Pastén

2013-09-01

Full Text Available Pituitary gonadotrophs are a small fraction of the anterior pituitary population, yet they synthesize gonadotropins: luteinizing (LH and follicle stimulating (FSH, essential for gametogenesis and steroidogenesis. LH is secreted via a regulated pathway while FSH release is mostly constitutive and controlled by synthesis. Although gonadotrophs fire action potentials spontaneously, the intracellular Ca2+ rises produced do not influence secretion, which is mainly driven by Gonadotropin Releasing Hormone (GnRH, a decapeptide synthesized in the hypothalamus and released in a pulsatile manner into the hypophyseal portal circulation. GnRH binding to G protein coupled receptors triggers Ca2+ mobilization from InsP3-sensitive intracellular pools, generating the global Ca2+ elevations necessary for secretion. Ca2+ signaling responses to increasing [GnRH] vary in stereotyped fashion from subthreshold to baseline spiking (oscillatory, to biphasic (spike-oscillatory or spike-plateau. This progression varies somewhat in gonadotrophs from different species and biological preparations. Both baseline spiking and biphasic GnRH-induced Ca2+ signals control LH/FSH synthesis and exocytosis. Estradiol and testosterone regulate gonadotropin secretion through feedback mechanisms, while FSH synthesis and release are influenced by activin, inhibin and follistatin. Adaptation to physiological events like the estrous cycle, involves changes in GnRH sensitivity and LH/FSH synthesis: in proestrus, estradiol feedback regulation abruptly changes from negative to positive, causing the pre-ovulatory LH surge. Similarly, when testosterone levels drop after orquiectomy the lack of negative feedback on pituitary and hypothalamus boosts both GnRH and LH secretion, gonadotrophs GnRH sensitivity increases and Ca2+ signaling patterns change. In addition, gonadotrophs proliferate and grow. These plastic changes denote a more vigorous functional adaptation in response to an extraordinary

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

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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.

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

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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

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

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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.

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.

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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.

Effects of Dietary Bacillus licheniformis on Gut Physical Barrier, Immunity, and Reproductive Hormones of Laying Hens.

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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.

Antibodies against gonadotropin-releasing hormone (GnRH) in patients with diabetes mellitus is associated with lower body weight and autonomic neuropathy.

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Berntorp, Kerstin; Frid, Anders; Alm, Ragnar; Fredrikson, Gunilla Nordin; Sjöberg, Klas; Ohlsson, Bodil

2013-08-17

Esophageal dysmotility and gastroparesis are common secondary complications in patients with diabetes mellitus. Patients with dysmotility express antibodies against gonadotropin-releasing hormone (GnRH) in serum. The aim of the present study was to scrutinize patients with diabetes mellitus with regard to the presence of GnRH antibodies, and to examine associations between antibodies and clinical findings. Thirty-nine consecutive patients with diabetes mellitus were included in the study after clinical examination and examination by esophageal manometry and gastric emptying scintigraphy. Serum was analyzed for the presence of antibodies against GnRH using an ELISA, and values are expressed as relative units (RU). Two age- and gender-matched healthy subjects per each patient served as controls. The prevalence of IgM GnRH antibodies in patients was 33% compared to 14% in controls (p = 0.027), with a higher antibody titer; 1.2 (0.6-5.0) and 0.2 (0.1-0.3) RU, respectively (p = 0.000). The expression of IgG antibodies was 15% in patients and none in controls (p = 0.000). Lower body mass index was associated with the presence of IgM antibodies (OR = 0.835, 95% CI = 0.699-0.998), and autonomic neuropathy with the presence IgG antibodies (OR = 9.000, 95% CI = 1.327-61.025). Esophageal dysmotility (69%) or gastroparesis (18%) were not associated with the presence of IgM antibodies (OR = 0.589, 95% CI = 0.143-2.424 and OR = 3.407, 95% CI = 0.633-18.350, respectively). Neither was esophageal dysmotility associated with IgG antibodies (OR = 2.500, 95% CI = 0.259-24.096). Antibodies against GnRH are more common in patients with diabetes mellitus compared with healthy controls. IgM antibodies are associated with lower body mass index and IgG antibodies are associated with autonomic neuropathy.

A Proof-of-Concept Clinical Trial of A Single Luteal Use of Long-Acting Gonadotropin-Releasing Hormone Antagonist Degarelix in Controlled Ovarian Stimulation for In Vitro Fertilization: Long Antagonist Protocol

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Evangelos G. Papanikolaou

2018-03-01

Full Text Available IntroductionA drawback of gonadotropin-releasing hormone (GnRH antagonist protocols in in vitro fertilization (IVF is that they have limited flexibility in cycle programming. This proof of concept study explored the efficacy of a single-dose, long-acting GnRH antagonist IVF protocol. Trial registration number is NCT03240159, retrospectively registered on March 08, 2017.Materials and methodsThe efficacy of a single-dose long-acting antagonist, degarelix, was explored initially in healthy donors and subsequently in infertile patients. In the first part, five healthy oocyte donors underwent ovarian stimulation with this new protocol: in the late luteal phase, at day 24, a bolus injection of degarelix was administered subcutaneously to control the LH surge in the follicular phase. Ovarian stimulation with gonadotropins was initiated subsequently from day 7 to day 10. End points were first to inhibit the LH surge later in the follicular phase and, second, to retrieve mature oocytes for IVF. In the second part, five infertile women received the same bolus injection of degarelix administered during the luteal phase at day 24. Different gonadotropin starting days (day 2 through day 8 were tested in order to observe possible differences in ovarian stimulation. In these infertile patients, fresh embryo transfers were performed to assess the pregnancy efficacy of this protocol on pregnancy outcomes and to address any possible negative effects on endometrium receptivity.ResultsIn the first part of the study, all donors were effectively downregulated with a single luteal dose of 0.5 ml of degarelix for up to 22 days until the final oocyte maturation triggering day. Mature oocytes were retrieved after 36 h from all patients and all produced 2–7 blastocysts. In the second part, all five infertile patients achieved sufficient LH downregulation and completed ovarian stimulation without any LH surge. All patients (except one with freeze all strategy had

Hormonal regulation of AMPA receptor trafficking and memory formation

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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.

Regulatory Architecture of the LβT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone

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Frederique Ruf-Zamojski

2018-02-01

Full Text Available The LβT2 mouse pituitary cell line has many characteristics of a mature gonadotrope and is a widely used model system for studying the developmental processes and the response to gonadotropin-releasing hormone (GnRH. The global epigenetic landscape, which contributes to cell-specific gene regulatory mechanisms, and the single-cell transcriptome response variation of LβT2 cells have not been previously investigated. Here, we integrate the transcriptome and genome-wide chromatin accessibility state of LβT2 cells during GnRH stimulation. In addition, we examine cell-to-cell variability in the transcriptional response to GnRH using Gel bead-in-Emulsion Drop-seq technology. Analysis of a bulk RNA-seq data set obtained 45 min after exposure to either GnRH or vehicle identified 112 transcripts that were regulated >4-fold by GnRH (FDR < 0.05. The top regulated transcripts constitute, as determined by Bayesian massive public data integration analysis, a human pituitary-relevant coordinated gene program. Chromatin accessibility [assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq] data sets generated from GnRH-treated LβT2 cells identified more than 58,000 open chromatin regions, some containing notches consistent with bound transcription factor footprints. The study of the most prominent open regions showed that 75% were in transcriptionally active promoters or introns, supporting their involvement in active transcription. Lhb, Cga, and Egr1 showed significantly open chromatin over their promoters. While Fshb was closed over its promoter, several discrete significantly open regions were found at −40 to −90 kb, which may represent novel upstream enhancers. Chromatin accessibility determined by ATAC-seq was associated with high levels of gene expression determined by RNA-seq. We obtained high-quality single-cell Gel bead-in-Emulsion Drop-seq transcriptome data, with an average of >4,000 expressed genes

[Accumulation of cyclic adenosine monophosphate in the ovary of the eel (Anguilla anguilla L.) in vitro under the effect of carp gonadotropin or ovine lutropin: kinetics and thermodependence].

Science.gov (United States)

Salmon, C; Marchelidon, J; Fontaine-Bertrand, E; Fontaine, Y A

1986-01-01

Cyclic AMP (cAMP) in pieces of eel ovary was greatly increased in vitro by the gonadotropin (cGTH) of carp, another teleost fish; after one hour at 20 degrees C, maximal stimulation = 31.7 and E.D. 50 = 0.08 micrograms/ml. Ovine lutropin (oLH) had less effect (maximal stimulation: 2.35; E.D. 50: 1.42 micrograms/ml); its action suggested that it involved a subfraction (oLH/cGTH RAc) of the receptor-adenylate cyclase (RAc) systems which mediate the action of cGTH. Another difference was the percentage of total cAMP accumulated under hormonal stimulation and released into the incubation medium; this percentage was much higher with oLH than with cGTH (47 vs 8% after one hour at 20 degrees C). This result might be explained by a localization of oLH/cGTH RAc in cells (theca ?) situated on the outside of the follicles and/or by a relative lack of cAMP binding proteins in the case of cAMP produced by oLH/cGTH RAc. Kinetic and thermodependence studies also disclosed hormone-dependent differences; at 5 degrees C, cAMP concentration was maximal after 40 min with oLH, whereas it was still increasing after 3 h with cGTH. Differences in the properties of phosphodiesterases and/or in the clearance rate of hormone-receptor (HR) complexes could explain these results. The set of RAc systems in eel ovary recognizing fish gonadotropin would then be heterogeneous; some of them would be endowed with original properties concerning receptor specificity and cAMP diffusion as well as associated phosphodiesterase activity and/or HR metabolism. We suggest that at a stage of evolution when a single sensu stricto GTH is present (instead of two in tetrapods), "isoreceptors", differing in specificity and in their fate after hormone binding, could be an important element in the fine regulation of gonadal functions.

Abrogation by human menopausal gonadotropin on testicular ...

African Journals Online (AJOL)

Cisplatin is one of the most effective chemotherapeutic agents used in the treatment of cancer cells including testicular cancer. Human Menopausal Gonadotropin (HMG) is a natural hormone necessary for human reproduction. This hormone is a leading modality of treatment for infertility as it contains equal amount of ...

Sex Hormone Receptor Repertoire in Breast Cancer

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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.

Microdose gonadotropin-releasing hormone agonist flare-up protocol versus multiple dose gonadotropin-releasing hormone antagonist protocol in poor responders undergoing intracytoplasmic sperm injection-embryo transfer cycle.

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Kahraman, Korhan; Berker, Bulent; Atabekoglu, Cem Somer; Sonmezer, Murat; Cetinkaya, Esra; Aytac, Rusen; Satiroglu, Hakan

2009-06-01

To compare the efficacy of microdose GnRH agonist (GnRH-a) flare-up and multiple dose GnRH antagonist protocols in patients who have a poor response to a long luteal GnRH-a protocol. Prospective, randomized, clinical study. University hospital. Forty-two poor responder patients undergoing intracytoplasmic sperm injection (ICSI)-embryo transfer cycle. Twenty-one patients received microdose leuprolide acetate (LA) (50 microg twice daily) starting on the second day of withdrawal bleeding. The other 21 patients received 0.25 mg of cetrorelix daily when the leading follicle reached 14 mm in diameter. Serum E(2) levels, number of growing follicles and mature oocytes, embryo quality, dose of gonadotropin used, cancellation, fertilization, implantation rate and pregnancy rate (PR). The mean serum E(2) concentration on the day of hCG administration was significantly higher in the microdose GnRH-a group than in the GnRH antagonist group (1,904 vs. 1,362 pg/mL). The clinical PRs per started cycle of microdose GnRH-a and GnRH antagonist groups were 14.2% and 9.5%, respectively. There were no statistically significant differences in the other ovulation induction characteristics, fertilization and implantation rates. Microdose GnRH-a flare-up protocol and multiple dose GnRH antagonist protocol seem to have similar efficacy in improving treatment outcomes of poor responder patients.

Follitropin receptors in rat testis. Characterization with enzymatically 125I-labeled human follitropin.

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Ketelslegers, J M; Catt, K J

1978-07-03

The interaction between enzymatically radioiodinated human follitropin and the follitropin receptors in testis homogenate was investigated in immature and adult rats. The 125I-labeled human follitropin exhibited high binding activity with specific binding of up to 17% in the presence of an excess of testis homogenate. Approx. 50% of the bound hormone could be eluted at pH 5, and the receptor purified tracer exhibited a 3.6-fold increase in binding activity when compared with the original tracer preparation. Quantitative analysis of equilibrium binding data was performed with corrections for the measured specific activity and maximum binding activity of the tracer hormone. The equilibrium association constants (Ka) determined 24 degrees C were not significantly different in immature and adult rat testis, and the mean value for Ka was 3.9 . 10(9) M-1. At 37 degrees C, the Ka value obtained using immature rat testis was 1.3 . 10(10) M-1. The association of 125I-labeled human follitropin with immature rat testis homogenate was time and temperature dependent. In the presence of an excess of unlabeled hormone, 30--60% of the preformed hormone . receptor complex was dissociated after 24 h incubation. A specific and sensitive radioligand-receptor assay for follitropin was developed using immature rat testis homogenate. The minimum detectable dose of purified human follitropin was 0.6 ng, and human urinary and pituitary follitropin, ovine follitropin and pregnant mare serum gonadotropin reacted in the assay with equivalent slopes. The potencies of highly purified pregnent mare serum gonadotropin and highly purified human follitropin were similar in the radioligand-receptor assay, consistent with the follitropin bioactivity of the equine gonadotropin.

The adipokinetic hormone receptor modulates sexual behavior, pheromone perception and pheromone production in a sex-specific and starvation-dependent manner in Drosophila melanogaster

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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.

(cGnRH-II) on plasma steroid hormone, maturation and ovulation

African Journals Online (AJOL)

PRECIOUS

2009-12-01

Dec 1, 2009 ... (LHRHa) and salmon gonadotropin-releasing hormone analogue (sGnRHa) in ..... Four out of six fish reached GVBD at 12 h after injection. Egg quality .... of the sbGnRH and cGnRH-II genes from the striped bass, Morone.

Glucocorticoid regulation of gonadotropin release from gonadotropes of ovine pituitary gland in vitro

International Nuclear Information System (INIS)

Nangalama, A.W.

1989-01-01

In order to understand the role of glucocorticoids in the regulation of gonadotropin release by the pituitary gland, the short-term effects of cortisol perifusion (1.5 h to 8 hrs) on GnRH-induced LH secretion were investigated. To determine the biochemical mechanism(s) by which cortisol can act to modulate GnRH-induced LH release, the interactions of cortisol and arachidonic acid in GnRH-stimulated LH release were examined. Cortisol perifusion for 1.5 hr had no effect on GnRH-induced LH release, but longer treatment periods (4 hr-8 hrs) significantly reduced GnRH-stimulated LH release (4.0 hr, p -4 M AA was administered for 20 min before a 10 min, 10 -10 M GnRH pulse. Like cortisol, chloroquine also failed to inhibit AA-induced LH release. Perifusion with 10 -6 M cortisol for 6.0 hours significantly (p 3 ]AA release 24% below the basal (100%) [ 3 H]AA secretion. Reduction of [ 3 H]AA release was accompanied by decreased GnRH-stimulated LH secretion

Conservation of Three-Dimensional Helix-Loop-Helix Structure through the Vertebrate Lineage Reopens the Cold Case of Gonadotropin-Releasing Hormone-Associated Peptide.

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Pérez Sirkin, Daniela I; Lafont, Anne-Gaëlle; Kamech, Nédia; Somoza, Gustavo M; Vissio, Paula G; Dufour, Sylvie

2017-01-01

GnRH-associated peptide (GAP) is the C-terminal portion of the gonadotropin-releasing hormone (GnRH) preprohormone. Although it was reported in mammals that GAP may act as a prolactin-inhibiting factor and can be co-secreted with GnRH into the hypophyseal portal blood, GAP has been practically out of the research circuit for about 20 years. Comparative studies highlighted the low conservation of GAP primary amino acid sequences among vertebrates, contributing to consider that this peptide only participates in the folding or carrying process of GnRH. Considering that the three-dimensional (3D) structure of a protein may define its function, the aim of this study was to evaluate if GAP sequences and 3D structures are conserved in the vertebrate lineage. GAP sequences from various vertebrates were retrieved from databases. Analysis of primary amino acid sequence identity and similarity, molecular phylogeny, and prediction of 3D structures were performed. Amino acid sequence comparison and phylogeny analyses confirmed the large variation of GAP sequences throughout vertebrate radiation. In contrast, prediction of the 3D structure revealed a striking conservation of the 3D structure of GAP1 (GAP associated with the hypophysiotropic type 1 GnRH), despite low amino acid sequence conservation. This GAP1 peptide presented a typical helix-loop-helix (HLH) structure in all the vertebrate species analyzed. This HLH structure could also be predicted for GAP2 in some but not all vertebrate species and in none of the GAP3 analyzed. These results allowed us to infer that selective pressures have maintained GAP1 HLH structure throughout the vertebrate lineage. The conservation of the HLH motif, known to confer biological activity to various proteins, suggests that GAP1 peptides may exert some hypophysiotropic biological functions across vertebrate radiation.

Conservation of Three-Dimensional Helix-Loop-Helix Structure through the Vertebrate Lineage Reopens the Cold Case of Gonadotropin-Releasing Hormone-Associated Peptide

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Daniela I. Pérez Sirkin

2017-08-01

Full Text Available GnRH-associated peptide (GAP is the C-terminal portion of the gonadotropin-releasing hormone (GnRH preprohormone. Although it was reported in mammals that GAP may act as a prolactin-inhibiting factor and can be co-secreted with GnRH into the hypophyseal portal blood, GAP has been practically out of the research circuit for about 20 years. Comparative studies highlighted the low conservation of GAP primary amino acid sequences among vertebrates, contributing to consider that this peptide only participates in the folding or carrying process of GnRH. Considering that the three-dimensional (3D structure of a protein may define its function, the aim of this study was to evaluate if GAP sequences and 3D structures are conserved in the vertebrate lineage. GAP sequences from various vertebrates were retrieved from databases. Analysis of primary amino acid sequence identity and similarity, molecular phylogeny, and prediction of 3D structures were performed. Amino acid sequence comparison and phylogeny analyses confirmed the large variation of GAP sequences throughout vertebrate radiation. In contrast, prediction of the 3D structure revealed a striking conservation of the 3D structure of GAP1 (GAP associated with the hypophysiotropic type 1 GnRH, despite low amino acid sequence conservation. This GAP1 peptide presented a typical helix-loop-helix (HLH structure in all the vertebrate species analyzed. This HLH structure could also be predicted for GAP2 in some but not all vertebrate species and in none of the GAP3 analyzed. These results allowed us to infer that selective pressures have maintained GAP1 HLH structure throughout the vertebrate lineage. The conservation of the HLH motif, known to confer biological activity to various proteins, suggests that GAP1 peptides may exert some hypophysiotropic biological functions across vertebrate radiation.

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

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

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.

Effects of Thyroid Dysfunction on Reproductive Hormones in Female Rats.

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Liu, Juan; Guo, Meng; Hu, Xusong; Weng, Xuechun; Tian, Ye; Xu, Kaili; Heng, Dai; Liu, Wenbo; Ding, Yu; Yang, Yanzhou; Zhang, Cheng

2018-05-10

Thyroid hormones (THs) play a critical role in the development of ovarian cells. Although the effects of THs on female reproduction are of great interest, the mechanism remains unclear. We investigated the effects of TH dysregulation on reproductive hormones in rats. Propylthiouracil (PTU) and L-thyroxine were administered to rats to induce hypo- and hyper-thyroidism, respectively, and the reproductive hormone profiles were analyzed by radioimmunoassay. Ovarian histology was evaluated with H&E staining, and gene protein level or mRNA content was analyzed by western blotting or RT-PCR. The serum levels of gonadotropin releasing hormone (GnRH) and follicle stimulating hormone (FSH) in both rat models were significantly decreased on day 21, although there were no significant changes at earlier time points. There were no significant differences in luteinizing hormone (LH) or progesterone levels between the treatment and the control groups. Both PTU and L-thyroxine treatments downregulated estradiol concentrations; however, the serum testosterone level was increased only in hypothyroid rats at day 21. In addition, the expression levels of FSH receptor, cholesterol side-chain cleavage enzyme (P450scc), and steroidogenic acute regulatory protein were decreased in both rat models. Moreover, the onset of puberty was significantly delayed in the hypothyroid group. These results provide evidence that TH dysregulation alters reproductive hormone profiles, and that the initiation of the estrous cycle is postponed in hypothyroidism.

No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial.

Science.gov (United States)

Demeestere, Isabelle; Brice, Pauline; Peccatori, Fedro A; Kentos, Alain; Dupuis, Jehan; Zachee, Pierre; Casasnovas, Olivier; Van Den Neste, Eric; Dechene, Julie; De Maertelaer, Viviane; Bron, Dominique; Englert, Yvon

2016-08-01

We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up. A total of 129 patients with lymphoma were randomly assigned to receive either triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) during chemotherapy. Ovarian function and fertility were reported after 2, 3, 4, and 5 to 7 years of follow up. The primary end point was POF, defined as at least one follicle-stimulating hormone value of > 40 IU/L after 2 years of follow up. Sixty-seven patients 26.21 ± 0.64 years of age had available data after a median follow-up time of 5.33 years in the GnRHa group and 5.58 years in the control group (P = .452). Multivariate logistic regression analysis showed a significantly increased risk of POF in patients according to age (P = .047), the conditioning regimen for hematopoietic stem cell transplant (P = .002), and the cumulative dose of cyclophosphamide > 5 g/m(2) (P = .019), but not to the coadministration of GnRHa during chemotherapy (odds ratio, 0.702; P = .651). The ovarian reserve, evaluated using anti-Müllerian hormone and follicle-stimulating hormone levels, was similar in both groups. Fifty-three percent and 43% achieved pregnancy in the GnRHa and control groups, respectively (P = .467). To the best of our knowledge, this is the first long-term analysis confirming that GnRHa is not efficient in preventing chemotherapy-induced POF in young patients with lymphoma and did not influence future pregnancy rate. These results reopen the debate about the drug's benefit in that it should not be recommended as standard for fertility preservation in patients with lymphoma. © 2016 by American Society of Clinical Oncology.

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

Evaluation of the association of vitamin D deficiency with gonadotropins and sex hormone in obese and non-obese women with polycystic ovary syndrome.

Science.gov (United States)

Velija-Ašimi, Zelija

2014-02-01

To evaluate the association of vitamin D (VD) deficiency with gonadotropins and sex hormone in obese and non-obese women with polycystic ovary syndrome (PCOS). Of the total of 140 women, thirty obese and thirty nonobese, aged 20-40 years, were included in the study. Inclusion criteria were the women with normal level of thyroid-stimulating hormone (TSH), prolactin (PRL), parathyroid hormone (PTH), and calcium, and those who had not received any medication or VD supplementation within the last 6 months. Serum 25- hydroxyvitamin D (25(OH)D), C-reactive protein (CRP), lipid profile, fasting serum glucose, basal insulin, homeostasis model analysis of insulin resistance (HOMA-IR) index, follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestrogen, total testosterone, dehidroepiandrostendion-sulphat (DHEA-S), androstendione, and sex hormone binding globulin (SHBG) were determined at follicular phase. Body mass index (BMI), weight, waist, lipids, and CRP were significantly higher in obese than in non-obese PCOS women (p=0.000). Meanwhile, insulin and HOMA-IR were also higher in the obese PCOS (p less than 0.000), and so was the fasting glucose (p=0.004). Furthermore, obese PCOS showed significantly higher level of LH (p=0.012), but lower level of progesterone (p=0.001) and androstendione (p=0.006) than in non-obese PCOS. In total 68% of PCOS women had VD deficiency but without significant difference among groups according to BMI. There was no association of VD deficiency with gonadotropins and sex hormones except SHBG. Insulin resistance was a better independent risk factor for the presence of vitamin D deficiency than SHBG. The insulin resistance and vitamin D deficiency significantly predicted the obesity risk in PCOS women.

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.

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

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.

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

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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

Ghrelin: much more than a hunger hormone

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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...

The GnRH receptor and the response of gonadotrope cells to GnRH pulse frequency code. A story of an atypical adaptation of cell function relying on a lack of receptor homologous desensitization.

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Christian Bleux

2010-01-01

Full Text Available Brain control of the reproductive system is mediated through hypothalamic gonadotropin-releasing hormone (GnRH which activates specific receptors (GnRHR present at the surface of the pituitary gonadotropes to trigger secretion of the two gonadotropins LH and FSH. A unique feature of this system is the high dependence on the secretion mode of GnRH, which is basically pulsatile but undergoes considerable fluctuations in pulse frequency pattern in response to endogenous or external factors. How the physiological fluctuations of GnRH secretion that orchestrate normal reproduction are decoded by the gonadotrope cell machinery to ultimately control gonadotropin release and/or subunit gene transcription has been the subject of intensive studies during the past decades. Surprisingly, the mammalian GnRHR is unique among G protein-coupled receptor family as it lacks the carboxy-terminal tail usually involved in classical endocytotic process. Accordingly, it does not desensitize properly and internalizes very poorly. Both this atypical intrinsic property and post-receptor events may thus contribute to decode the GnRH signal. This includes the participation of a network of signaling pathways that differently respond to GnRH together with a growing amount of genes differentially sensitive to pulse frequency. Among these are two pairs of genes, the transcription factors EGR-1 and NAB, and the regulatory factors activin and follistatin, that function as intracellular autoregulatory feedback loops controlling respectively LHbeta and FSHbeta gene expression and hence, LH and FSH synthesis. Pituitary gonadotropes thus represent a unique model of cells functionally adapted to respond to a considerably fluctuating neuroendocrine stimulation, from short individual pulses to sustained GnRH as observed at the proestrus of ovarian cycle. Altogether, the data emphasize the adaptative reciprocal complementarity of hypothalamic GnRH neurones and pituitary gonadotropes to

Toward developing recombinant gonadotropin-based hormone therapies for increasing fertility in the flatfish Senegalese sole.

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François Chauvigné

Full Text Available Captive flatfishes, such as the Senegalese sole, typically produce very low volumes of sperm. This situation is particularly prevalent in the first generation (F1 of reared sole males, which limits the development of artificial fertilization methods and the implementation of selective breeding programs. In this study, we investigated whether combined treatments with homologous recombinant follicle-stimulating (rFsh and luteinizing (rLh hormones, produced in a mammalian host system, could stimulate spermatogenesis and enhance sperm production in Senegalese sole F1 males. In an initial autumn/winter experiment, weekly intramuscular injections with increasing doses of rFsh over 9 weeks resulted in the stimulation of gonad weight, androgen release, germ cell proliferation and entry into meiosis, and the expression of different spermatogenesis-related genes, whereas a subsequent single rLh injection potentiated spermatozoa differentiation. In a second late winter/spring trial corresponding to the sole's natural prespawning and spawning periods, we tested the effect of repeated rLh injections on the amount and quality of sperm produced by males previously treated with rFsh for 4, 6, 8 or 10 weeks. These latter results showed that the combination of rFsh and rLh treatments could increase sperm production up to 7 times, and slightly improve the motility of the spermatozoa, although a high variability in the response was found. However, sustained administration of rFsh during spawning markedly diminished Leydig cell survival and the steroidogenic potential of the testis. These data suggest that in vivo application of rFsh and rLh is effective at stimulating spermatogenesis and sperm production in Senegalese sole F1 males, setting the basis for the future establishment of recombinant gonadotropin-based hormone therapies to ameliorate reproductive dysfunctions of this species.

Hormones and endocrine disruptors in human seminal plasma.

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Hampl, R; Kubatova, J; Heracek, J; Sobotka, V; Starka, L

2013-07-01

Seminal plasma represents a unique environment for maturation, nutrition, and protection of male germ cells from damaging agents. It contains an array of organic as well as inorganic chemicals, encompassing a number of biologically and immunologically active compounds, including hormones. Seminal plasma contains also various pollutants transferred from outer environment known as endocrine disruptors. They interfere with hormones at the receptor level, act as inhibitors of their biosynthesis, and affect hormone regulation.In this minireview, the main groups of hormones detected in seminal plasma are summarized. Seminal gonadal steroids were investigated mostly with aim to use them as biomarkers of impaired spermatogenesis (sperm count, motility, morphology). Concentrations of hormones in the seminal plasma often differ considerably from the blood plasma levels in dependence on their origin. In some instances (dihydrotestosterone, estradiol), their informative value is higher than determination in blood.Out of peptide hormones detected in seminal plasma, peptides of transforming growth factor beta family, especially antimullerian hormone, and oligopeptides related to thyrotropin releasing hormone have the high informative value, while assessment of seminal gonadotropins and prolactin does not bring advantage over determination in blood.Though there is a large body of information about the endocrine disruptors' impact on male reproduction, especially with their potential role in decline of male reproductive functions within the last decades, there are only scarce reports on their presence in seminal plasma. Herein, the main groups of endocrine disruptors found in seminal plasma are reviewed, and the use of their determination for investigation of fertility disorders is discussed.

Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy among patients with idiopathic and functional hypothalamic amenorrhea: a systematic review of the literature and a meta-analysis.

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Tranoulis, Anastasios; Laios, Alexandros; Pampanos, Andreas; Yannoukakos, Drakoulis; Loutradis, Dimitrios; Michala, Lina

2018-04-01

To systematically review and appraise the existing evidence in relation to the efficacy and safety of pulsatile gonadotropin-releasing hormone (pGnRH) for the treatment of women with hypothalamic amenorrhea (HA). Systematic review and meta-analysis. Not applicable. A total of 35 studies (three randomized and 32 observational) encompassing 1,002 women with HA. None. Primary outcomes: ovulation rate (OvR), pregnancy per ovulatory cycle rate (POR), and live birth per ovulatory cycle rate (LBOR). multiple gestation (MG), ovarian hyperstimulation syndrome (OHSS), and superficial thrombophlebitis (ST) rates. The summary measures were expressed as proportions and 95% confidence intervals (CI). Pulsatile GnRH treatment appears to achieve high OvRs. A trend toward high PORs and LBORs among women with HA is demonstrated. SC pGnRH achieves comparable OvR compared with IV pGnRH. The incidence of OHSS is low and of mild severity. Treatment with pGnRH is associated with low but slightly higher MG rates compared with the general population. IV administered pGnRH is rarely associated with ST. The high OvRs leading to a high rate of singleton pregnancies and the low likelihood of OHSS render the pGnRH treatment modality both effective and safe for the treatment of women with HA of either primary or secondary origin. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Pituitary Gonadotropins, Prolactin and Growth Hormone Differentially Regulate AQP1 Expression in the Porcine Ovarian Follicular Cells

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Mariusz T. Skowronski

2017-12-01

Full Text Available The present in vitro study analyzed whether the hormones that affect the ovarian follicular steroidogenesis process also participate in the regulation of AQP1 mRNA and protein expression. Granulosa (Gc and theca cells (Tc of medium and large porcine ovarian follicles were exposed to follicle-stimulating hormone (FSH, luteinizing hormone (LH, prolactin (PRL and growth hormone (GH for 24 h in separated cells and co-cultures of these cells. Real-time PCR, Western blotting, immunofluorescence and volumetric analysis were then performed. Gonadotropins, PRL and GH had a stimulatory impact on AQP1 mRNA and protein expression in Gc and Tc of medium and large ovarian cells. Moreover, swelling assays, in response to a hypotonic environment, demonstrated the functional presence of AQPs in porcine Gc and Tc. Immunofluorescence analysis showed that AQP1 protein was mainly localized in the perinuclear region of the cytoplasm, endosomes and cell membranes of Gc and Tc from medium and large follicles. It seems possible that AQP1 present in Gc and Tc cells may be implicated not only in the regulation of water homeostasis required for follicle development but also in cell proliferation and migration.

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

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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

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

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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

Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep.

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Manikkam, Mohan; Thompson, Robert C; Herkimer, Carol; Welch, Kathleen B; Flak, Jonathan; Karsch, Fred J; Padmanabhan, Vasantha

2008-04-01

The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone. Our working hypothesis was that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and, thus, hypersecretion of LH in adulthood, and that this results from altered developmental gene expression of GnRH and estradiol (E2) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone excess induced developmental changes in gene expression of pituitary GnRH and E2 receptors and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together, this series of studies suggests that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH response, leading to LH hypersecretion and acyclicity in adulthood, and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.

Production of specific antisera for radioimmunoassay of human luteinizing hormone (LH) in the presence of human chorionic gonadotropin (hCG)

International Nuclear Information System (INIS)

Thorell, J.I.; Jeppsson, S.; Holmstrom, B.

1976-01-01

A specific radioimmunoassay for LH, which measures plasma LH in the presence of human chorionic gonadotropin (hCG) is described. Rabbits were immunized with highly purified native LH. One of the antisera with a difference in its reactivity against LH and hCG was further purified by affinity chromatography on a column with hCG coupled to Sepharose 4B. The adsorbed antiserum and 125 I-LH was used in a double antibody assay. The LH standard (MRC/68/40) efficiently inhibited the binding of 125 I-LH, and the standard curve showed a sensitivity of 0.5 ng/ml in the sample. hCG up to 10,000 ng/ml did not inhibit the binding of 125 I-LH. The plasma level of LH in pregnant women in the first trimester was low (1.3 +- 0.1 ng/ml). When LH was measured in fertile or menopausal women with or without stimulation with LH/FSH releasing hormone (LH-RH)/sup x/ the results agreed to those found with our conventional LH-assay based on antiserum against hCG

Effect of rejuvenation hormones on spermatogenesis.

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Moss, Jared L; Crosnoe, Lindsey E; Kim, Edward D

2013-06-01

To review the current literature for the effect of hormones used in rejuvenation clinics on the maintenance of spermatogenesis. Review of published literature. Not applicable. Men who have undergone exogenous testosterone (T) and/or anabolic androgenic steroid (AAS) therapies. None. Semen analysis, pregnancy outcomes, and time to recovery of spermatogenesis. Exogenous testosterone and anabolic androgenic steroids suppress intratesticular testosterone production, which may lead to azoospermia or severe oligozoospermia. Therapies that protect spermatogenesis involve human chorionic gonadotropin (hCG) therapy and selective estrogen receptor modulators (SERMs). The studies examining the effect of human growth hormone (HGH) on infertile men are uncontrolled and unconvincing, but they do not appear to negatively impact spermatogenesis. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. The use of hormones for rejuvenation is increasing with the aging of the Baby Boomer population. Men desiring children at a later age may be unaware of the side-effect profile of hormones used at rejuvenation centers. Testosterone and anabolic androgenic steroids have well-established detrimental effects on spermatogenesis, but recovery may be possible with cessation. Clomiphene citrate, human growth hormone (HGH)/insulin-like growth factor-1 (IGF-1), human chorionic gonadotropin (hCG), and aromatase inhibitors do not appear to have significant negative effects on sperm production, but quality data are lacking. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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

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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.

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

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.)

A peptide mimic of an antigenic loop of alpha-human chorionic gonadotropin hormone: solution structure and interaction with a llama V-HH domain

NARCIS (Netherlands)

Ferrat, G.; Renisio, J.G.; Morelli, X.; Slootstra, J.W.; Meloen, R.; Cambillau, C.; Darbon, H.

2002-01-01

The X-ray structure of a ternary complex between human chorionic gonadotropin hormone (hCG) and two Fvs recognizing its alpha and beta subunits has been recently determined. The Fvs recognize the elongated hCG molecule by its two ends, one being the Leu-12-Cys-29 loop of the alpha subunit. We have

Effect of chronic exposure to gamma radiation and of hormonal stimulation with serum gonadotropin on catecholamine levels in hypothalamus, epiphysis and adrenals of ewes

International Nuclear Information System (INIS)

Pastorova, B.; Arendarcik, J.

1989-01-01

The effects were studied of exposure to whole body continuous irradiation and of the administration of serum gonadotropin (SG) on the concentration of catecholamines (epinephrine and norepinephrine) in the hypothalamus, epiphysis and adrenal glands of ewes during the anestric period with synchronized estrus. The first group (young barren ewes) and second group (older ewes) were exposed to continuous radiation of 60 Co for five days. The radiation was applied at a rate of 0.020 Gy per hour. After the termination of irradiation the ewes were subjected to hormonal stimulation by fractionated administration of 1500 I.U. SG. The third and fourth experimental groups of ewes were stimulated with 1500 I.U. SG without irradiation. Catecholamines were separated from the tissue supernatants by adsorption chromatography and the catecholamine contents in the eluates were determined spectrofluorometrically. Chronic exposure to gamma radiation and hormonal stimulation with SG reduced the concentration of norepinephrine in the whole hypothalamus of the sheep. A statistically significant decrease (P<0.001) was recorded in the medial and caudal hypothalamus of the adult ewes and in the rostral and caudal hypothalamus regions of the young ewes. A decrease in norepinephrine concentration, statistically significant in the caudal (P<0.01) and medial hypothalamus was recorded in the group of adult ewes after hormonal stimulation with SG without irradiation. The experimental group of young ewes responded to hormonal stimulation by a greater reduction of norepinephrine contents as compared with combined exposure to radiation and hormonal stimulation. It is assumed that the decrease in catecholamine concentration after hormonal stimulation with SG is associated with the increase in the contents of estrogens which act on the adrenergic receptors of the hypothalamus. (author). 4 figs., 21 refs

GONAD REMATURATION ON Pangasionodon hypophthalmus FEMALE THROUGH INJECTION OF PREGNANT MARE SERUM GONADOTROPIN AND HUMAN CHORIONIC GONADOTROPIN

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Evi Tahapari

2014-06-01

Full Text Available The success of spawning is influenced by internal and external factors. One of the factors that affect the var iabi li ty of Pangasianodon hypophthalmus female reproductive is the change of seasons that cause disrupted continuity of the seed availability, especially in the dry season. In the present study, combination of PMSG (pregnant mare serum gonadotropin + HCG (hormone chorionic gonadotropin hormone injections was done to induce gonad development. The treatments in this study were without hormone injections as control (A, injection of PMSG 10 IU/kg + HCG 10 IU/kg (B, and injection of PMSG 20 IU/kg HCG + 10 IU/kg (C. Injections were conducted at intervals of two weeks as many as six times. The results showed that gonad maturation generally occurs 2-4 weeks after estradiol-17 peak. PMSG + HCG hormone injections gave a significant effect on increasing the quantity and quality of eggs production. The fecundity in the A, B, C treatments, were 233,700±220,676; 300,305±24,581 and 488,433±142,228; respectively. Number of larvae produced from the A, B, C treatments, were 156,979±170,838; 229,997±18,081 and 362,713±101,850; respectively. Combination of PMSG 20 IU/kg + HCG 10 IU/kg hormone injection gave the best result on fecundity and the number of larvae production.

Circulating gonadotropins and ovarian adiponectin system are modulated by acupuncture independently of sex steroid or β-adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome.

Science.gov (United States)

Maliqueo, Manuel; Benrick, Anna; Alvi, Asif; Johansson, Julia; Sun, Miao; Labrie, Fernand; Ohlsson, Claes; Stener-Victorin, Elisabet

2015-09-05

Acupuncture with combined manual and low-frequency electrical stimulation, or electroacupuncture (EA), reduces endocrine and reproductive dysfunction in women with polycystic ovary syndrome (PCOS), likely by modulating sympathetic nerve activity or sex steroid synthesis. To test this hypothesis, we induced PCOS in rats by prepubertal implantation of continuous-release letrozole pellets (200 µg/day) or vehicle. Six weeks later, rats were treated for 5-6 weeks with low-frequency EA 5 days/week, subcutaneous injection of 17β-estradiol (2.0 µg) every fourth day, or a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg/kg) 5 days/week. Letrozole controls were handled without needle insertion or injected with sesame oil every fourth day. Estrous cyclicity, ovarian morphology, sex steroids, gonadotropins, insulin-like growth factor I, bone mineral density, and gene and protein expression in ovarian tissue were measured. Low-frequency EA induced estrous-cycle changes, decreased high levels of circulating luteinizing hormone (LH) and the LH/follicle-stimulating hormone (FSH) ratio, decreased high ovarian gene expression of adiponectin receptor 2, and increased expression of adiponectin receptor 2 protein and phosphorylation of ERK1/2. EA also increased cortical bone mineral density. Propranolol decreased ovarian expression of Foxo3, Srd5a1, and Hif1a. Estradiol decreased circulating LH, induced estrous cycle changes, and decreased ovarian expression of Adipor1, Foxo3, and Pik3r1. Further, total bone mineral density was higher in the letrozole-estradiol group. Thus, EA modulates the circulating gonadotropin levels independently of sex steroids or β-adrenergic action and affects the expression of ovarian adiponectin system. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

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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.

The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

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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

Dioxin-induced retardation of development through a reduction in the expression of pituitary hormones and possible involvement of an aryl hydrocarbon receptor in this defect: A comparative study using two strains of mice with different sensitivities to dioxin

International Nuclear Information System (INIS)

Takeda, Tomoki; Taura, Junki; Hattori, Yukiko; Ishii, Yuji; Yamada, Hideyuki

2014-01-01

We have previously revealed that treating pregnant rats with 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) reduces the expression of gonadotropins and growth hormone (GH) in the fetal and neonatal pituitary. A change in gonadotropin expression impairs the testicular expression of steroidogenic proteins in perinatal pups, and imprint defects in sexual behavior after reaching maturity. In this study, we examined whether TCDD also affects the expression of gonadotropin and GH in mice using C57BL/6J and DBA/2J strains which express the aryl hydrocarbon receptor (Ahr) exhibiting a different affinity for TCDD. When pregnant C57BL/6J mice at gestational day (GD) 12 were given oral TCDD (0.2–20 μg/kg), all doses significantly attenuated the pituitary expression of gonadotropin mRNAs in fetuses at GD18. On the other hand, in DBA/2J mice, a much higher dose of TCDD (20 μg/kg) was needed to produce a significant attenuation. Such reduction in the C57BL/6J strain continued until at least postnatal day (PND) 4. In agreement with this, TCDD reduced the testicular expression of steroidogenic proteins in C57BL/6J neonates at PND2 and 4, although the same did not occur in the fetal testis and ovary. Furthermore, TCDD reduced the perinatal expression of GH, litter size and the body weight of newborn pups only in the C57BL/6J strain. These results suggest that 1) also in mice, maternal exposure to TCDD attenuates gonadotropin-regulated steroidogenesis and GH expression leading to the impairment of pup development and sexual immaturity; and 2) Ahr activation during the late fetal and early postnatal stages is required for these defects. - Highlights: • The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on mouse growth was studied. • TCDD reduced the levels of luteinizing hormone and growth hormone in perinatal pups. • Maternal exposure to TCDD also attenuated testicular steroidogenesis in pups. • The above effects of TCDD were more pronounced in C57BL/6J than in DBA/2J

Dioxin-induced retardation of development through a reduction in the expression of pituitary hormones and possible involvement of an aryl hydrocarbon receptor in this defect: A comparative study using two strains of mice with different sensitivities to dioxin

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Takeda, Tomoki; Taura, Junki; Hattori, Yukiko; Ishii, Yuji; Yamada, Hideyuki, E-mail: hyamada@phar.kyushu-u.ac.jp

2014-08-01

We have previously revealed that treating pregnant rats with 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) reduces the expression of gonadotropins and growth hormone (GH) in the fetal and neonatal pituitary. A change in gonadotropin expression impairs the testicular expression of steroidogenic proteins in perinatal pups, and imprint defects in sexual behavior after reaching maturity. In this study, we examined whether TCDD also affects the expression of gonadotropin and GH in mice using C57BL/6J and DBA/2J strains which express the aryl hydrocarbon receptor (Ahr) exhibiting a different affinity for TCDD. When pregnant C57BL/6J mice at gestational day (GD) 12 were given oral TCDD (0.2–20 μg/kg), all doses significantly attenuated the pituitary expression of gonadotropin mRNAs in fetuses at GD18. On the other hand, in DBA/2J mice, a much higher dose of TCDD (20 μg/kg) was needed to produce a significant attenuation. Such reduction in the C57BL/6J strain continued until at least postnatal day (PND) 4. In agreement with this, TCDD reduced the testicular expression of steroidogenic proteins in C57BL/6J neonates at PND2 and 4, although the same did not occur in the fetal testis and ovary. Furthermore, TCDD reduced the perinatal expression of GH, litter size and the body weight of newborn pups only in the C57BL/6J strain. These results suggest that 1) also in mice, maternal exposure to TCDD attenuates gonadotropin-regulated steroidogenesis and GH expression leading to the impairment of pup development and sexual immaturity; and 2) Ahr activation during the late fetal and early postnatal stages is required for these defects. - Highlights: • The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on mouse growth was studied. • TCDD reduced the levels of luteinizing hormone and growth hormone in perinatal pups. • Maternal exposure to TCDD also attenuated testicular steroidogenesis in pups. • The above effects of TCDD were more pronounced in C57BL/6J than in DBA/2J

Thyroid Stimulating Hormone Receptor

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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.

Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH neurons in an estrous cycle and endocannabinoid signaling dependent manner.

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Imre Farkas

Full Text Available The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+-imaging revealed a ghrelin-triggered increase of the Ca(2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM suggesting direct action of ghrelin. Estradiol (1nM eliminated the ghrelin-evoked rise of Ca(2+-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1 antagonist AM251 (1µM and the intracellularly applied DAG-lipase inhibitor THL (10 µM, indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.

Expression and distribution of octopus gonadotropin-releasing hormone in the central nervous system and peripheral organs of the octopus (Octopus vulgaris) by in situ hybridization and immunohistochemistry.

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Iwakoshi-Ukena, Eiko; Ukena, Kazuyoshi; Takuwa-Kuroda, Kyoko; Kanda, Atshuhiro; Tsutsui, Kazuyoshi; Minakata, Hiroyuki

2004-09-20

We recently purified a peptide with structural features similar to vertebrate gonadotropin-releasing hormone (GnRH) from the brain of Octopus vulgaris, cloned a cDNA encoding the precursor protein, and named it oct-GnRH. In the current study, we investigated the expression and distribution of oct-GnRH throughout the central nervous system (CNS) and peripheral organs of Octopus by in situ hybridization on the basis of the cDNA sequence and by immunohistochemistry using a specific antiserum against oct-GnRH. Oct-GnRH mRNA-expressing cell bodies were located in 10 of 19 lobes in the supraesophageal and subesophageal parts of the CNS. Several oct-GnRH-like immunoreactive fibers were seen in all the neuropils of the CNS lobes. The sites of oct-GnRH mRNA expression and the mature peptide distribution were consistent with each other as judged by in situ hybridization and immunohistochemistry. In addition, many immunoreactive fibers were distributed in peripheral organs such as the heart, the oviduct, and the oviducal gland. Modulatory effects of oct-GnRH on the contractions of the heart and the oviduct were demonstrated. The results suggested that, in the context of reproduction, oct-GnRH is a key peptide in the subpedunculate lobe and/or posterior olfactory lobe-optic gland-gonadal axis, an octopus analogue of the hypothalamo-hypophysial-gonadal axis. It may also act as a modulatory factor in controlling higher brain functions such as feeding, memory, movement, maturation, and autonomic functions

Functional Characterization and Signaling Systems of Corazonin and Red Pigment Concentrating Hormone in the Green Shore Crab, Carcinus maenas

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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

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...

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.

Radioimmunoassay of polypeptide hormones and enzymes

International Nuclear Information System (INIS)

Felber, J.P.

1974-01-01

General principles of radioimmunoassay are reviewed. Detailed procedures are reviewed for the following hormones: insulin, pituitary hormones, gonadotropins, parathyroid hormone, ACTH, glucagon, gastrin, and peptide hormones. Radioimmunoassay of enzymes is also discussed. (U.S.)

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 ...

Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

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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.

Role of neuropeptide Y in the regulation of gonadotropin releasing hormone system in the forebrain of Clarias batrachus (Linn.): immunocytochemistry and high performance liquid chromatography-electrospray ionization-mass spectrometric analysis.

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Gaikwad, A; Biju, K C; Muthal, P L; Saha, S; Subhedar, N

2005-01-01

Although the importance of neuropeptide Y (NPY) in the regulation of gonadotropin releasing hormone (GnRH) and reproduction has been highlighted in recent years, the neuroanatomical substrate within which these substances might interact has not been fully elucidated. Present work was undertaken with a view to define the anatomical-physiological correlates underlying the role exercised by NPY in the regulation of GnRH in the forebrain of the teleost Clarias batrachus. Application of double immunocytochemistry revealed close associations as well as colocalizations of the two peptides in the olfactory receptor neurons (ORNs), olfactory nerve fibers and their terminals in the glomeruli, ganglion cells of nervus terminalis, medial olfactory tract, fibers in the area ventralis telencephali/pars supracommissuralis and cells as well as fibers in the pituitary. NPY containing axons were found to terminate in the vicinity of GnRH cells in the pituitary with light as well as electron microscopy. Double immunoelectron microscopy demonstrated gold particles for NPY and GnRH colocalized on the membrane and in dense core of the secretory granules in the cells distributed in all components of the pituitary gland. To assess the physiological implication of these observations, NPY was injected via the intracranial route and the response of GnRH immunoreactive system was evaluated by relative quantitative morphometry as well as high performance liquid chromatography (HPLC) analysis. Two hours following NPY (20 ng/g body weight) administration, a dramatic increase was observed in the GnRH immunoreactivity in the ORNs, in the fibers of the olfactory bulb (163%) and medial olfactory tract (351%). High performance liquid chromatography-electrospray ionization-mass spectrometric analysis confirmed the immunocytochemical data. Significant rise in the salmon GnRH (sGnRH)-like peptide content was observed in the olfactory organ (194.23%), olfactory bulb (146.64%), telencephalon+preoptic area

The role of endogenous opiates in athletic amenorrhea.

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Samuels, M H; Sanborn, C F; Hofeldt, F; Robbins, R

1991-03-01

We hypothesized that menstrual disturbances in female athletes arise from opioid-induced abnormalities in gonadotropin and/or prolactin (PRL) secretion. To investigate this hypothesis, we measured luteinizing hormone, follicle-stimulating hormone, and PRL levels in eumenorrheic and amenorrheic athletes during thyrotropin-releasing hormone and gonadotropin-releasing hormone tests at baseline, after naloxone infusions, after exercise to exhaustion, and after similar exercise during naloxone infusions. Contrary to our hypothesis, amenorrheic runners did not have significant alterations in basal, postexercise, or stimulated hormone levels compared with eumenorrheic runners. In addition, opioid blockade by naloxone did not enhance gonadotropin release by amenorrheic athletes.

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

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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.

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

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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

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

Revisiting available knowledge on teleostean thyroid hormone receptors.

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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.

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

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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.

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.)

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.

Increase of antitumor activity of cisplatin using agonist of gonadotropin-realising hormone and inhibitor of aromatase on the model of ascites ovarian tumor.

Science.gov (United States)

Tkalia, I G; Vorobyova, L I; Grabovoy, A N; Svintsitsky, V S; Tarasova, T O; Lukyanova, N Y; Todor, I N; Chekhun, V F

2014-09-01

To study antitumor activity of triptorelin - agonist of gonadotropin-releasing hormone and exemestane - inhibitor of aromatase in monotherapy and in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant ascites transplantable ovarian tumor (TOT), to assess therapeutic pathomorphosis and level of VEGF expression in tumor cells using diffe-rent combinations of cytostatics and hormonal drugs. 72 female Wistar rats, which underwent intraperitoneal transplantation of ascitic TOT, by 5·10(6) cells per animal, have been involved in the study. Rats were divided into 8 groups, 9 rats in each group. Histological study with assessment of therapeutic pathomorphosis in TOT and immunohistochemical study has been carried out. Survival of animals in the studied groups has been evaluated. Among animals treated in regimen of monotherapy, the most pronounced antiangiogenic activity in TOT has been observed on application of hormonal drugs (triptorelin - 39.4 ± 1.9 and exemestane - 33.9 ± 1.4%; р = 0.003), the highest grade of treatment pathomorphosis in TOT has been observed at treatment with cisplatin (11.7%; р = 0.001). Combination of triptorelin and exemestane has amplified antiangiogenic activity in TOT (12.2 ± 0.9%; р = 0.001), but has not significantly changed rates of pathomorphosis (22.1 ± 0.4%; р=0.005) and survival of animals (32.2%; р = 0.007) as compared with the same rates in rats treated with hormonal drugs in monotherapy. Significant correlation between VEGF expression and pathomorphosis has been established (relative part of viable tumor tissue (RPVTT)) in TOT (r = 0.712; р = 0.001), as well as between RPVTT and life-span of animals (r = -0.320; р = 0.007). However, lack of correlation between VEGF expression in cells of TOT and survival of rats has been determined (r = -0.194; р = 0.11). Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly high rates of therapeutic

Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism.

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Barrio, R; de Luis, D; Alonso, M; Lamas, A; Moreno, J C

1999-02-01

To evaluate the clinical and hormonal responses of adolescent males with hypogonadotropic hypogonadism (HH) in response to gonadotropin replacement with the use of long-term combined hCG and FSH therapy. Prospective clinical study. Clinical pediatric department providing tertiary care. Seven prepubertal males with isolated HH with a mean (+/-SD) age of 15.44+/-1.97 years and seven prepubertal males with panhypopituitarism-associated HH with a mean (+/-SD) age of 18.1+/-3.24 years were studied. Human chorionic gonadotropin (1,000-1,500 IU IM) and FSH (75-100 IU SC) were administered every alternate day of the week until the total induction of puberty and spermatogenesis was achieved. Serum testosterone levels, testicular volume, penis length, and sperm count were evaluated after the administration of hCG and FSH. All patients achieved normal sexual maturation and normal or nearly normal adult male levels of testosterone. The increase in testicular size was significant in both groups. Positive sperm production was assessed in four of five patients with isolated HH and in three of three patients with panhypopituitarism-associated HH. Long-term combined hCG and FSH therapy is effective in inducing puberty, increasing testicular volume, and stimulating spermatogenesis in adolescent males with isolated HH and panhypopituitarism-associated HH.

Determination of acidity constants and ionic mobilities of polyprotic peptide hormones by CZE

Czech Academy of Sciences Publication Activity Database

Šolínová, Veronika; Kašička, Václav

2013-01-01

Roč. 34, č. 18 (2013), s. 2655-2665 ISSN 0173-0835 R&D Projects: GA ČR(CZ) GAP206/12/0453; GA ČR(CZ) GA13-17224S Institutional support: RVO:61388963 Keywords : acid dissociation constant * gonadotropin-releasing hormones * ionization constant * peptides * pK(a) Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 3.161, year: 2013

Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism.

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Xu, C; Lang-Muritano, M; Phan-Hug, F; Dwyer, A A; Sykiotis, G P; Cassatella, D; Acierno, J; Mohammadi, M; Pitteloud, N

2017-08-01

Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder caused by gonadotropin-releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle-stimulating hormone both <0.5 U/L), suggestive of CHH. Genetic testing identified a de novo, heterozygous mutation in fibroblast growth factor receptor 1 (FGFR1 p.L630P). L630 resides on the ATP binding cleft of the FGFR1 tyrosine kinase domain, and L630P is predicted to cause a complete loss of receptor function. Cell-based assays confirmed that L630P abolishes FGF8 signaling activity. Identification of a loss-of-function de novo FGFR1 mutation in this patient confirms the diagnosis of CHH, allowing for a timely hormonal treatment to induce pubertal development. Therefore, genetic testing can complement clinical and hormonal assessment for a timely diagnosis of CHH in childhood. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Gonadotropin Regulation of Retinoic Acid Activity in the Testis

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Seyedmehdi Nourashrafeddin

2018-02-01

Full Text Available Initiation of spermatogenesis in primates is triggered at puberty by an increase in gonadotropins; i.e., follicle-stimulating hormone (FSH and luteinizing hormone (LH. Prior to puberty, testis of the monkey contains only undifferentiated germ cells. However, sermatogonial differentiation and spermatogenesis may be initiated prior to puberty after stimulation with exogenous LH and FSH. Retinoic acid (RA signaling is considered to be a major component that drives spermatogonial differentiation. We were interested in evaluating the relative role of LH and FSH, either alone or in combination, in regulating the retinoic acid signaling in monkey testis. Sixteen juvenile male rhesus monkeys (Macaca mulatta were infused with intermittent recombinant single chain human LH (schLH or recombinant human FSH (rhFSH or a combination of both for 11 days. We then analyzed the expression of the several putative RA signaling pathway related genes; i.e. RDH10, RDH11, ALDH1A1, ALDH1A2, CYP26B1, CRABP1, CRABP2, STRA6, STRA8 in the testis after 11 days of stimulation with vehicle, LH, FSH and combination LH/FSH using quantitative real-time PCR (qPCR. The qPCR results analysis showed that administration of gonadotropins affected a significant change in expression of some RA signaling related genes in the monkey testis. The gonadotropins, either alone or in combination dramatically increased expression of CRABP2 (p≤0.001, whereas there was a decrease in ALDH1A2 expression (p≤0.001. Moreover, combined gonadotropin treatment led to the significant decrease in CRABP1 expression (p≤0.05. These findings are the first evidence that the activity of retinoic acid signaling in the monkey testis is regulated through gonadotropins (LH/FSH levels.

Hormone Use for Therapeutic Amenorrhea and Contraception During Hematopoietic Cell Transplantation

Science.gov (United States)

Chang, Katherine; Merideth, Melissa A.; Stratton, Pamela

2015-01-01

There is a growing population of women who have or will undergo hematopoietic stem cell transplant for a variety of malignant and benign conditions. Gynecologists play an important role in addressing the gynecologic and reproductive health concerns for these women throughout the transplant process. As women undergo cell transplantation, they should avoid becoming pregnant and are at risk of uterine bleeding. Thus, counseling about and implementing hormonal treatments such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and progestin-only methods help to achieve therapeutic amenorrhea and can serve as contraception during the peritransplant period. In this commentary, we summarize the timing, risks and benefits of the hormonal options just prior, during and for the year after hematopoietic stem cell transplantation. PMID:26348182

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

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.

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 ...

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

Response of lactating dairy cows with or without purulent vaginal discharge to gonadotropin-releasing hormone and prostaglandin F2α.

Science.gov (United States)

Voelz, B E; Rocha, L; Scortegagna, F; Stevenson, J S; Mendonça, L G D

2018-02-15

Purulent vaginal discharge (PVD) is a common uterine disease in dairy cattle that has negative effects on reproductive performance. Reproductive management programs that synchronize ovulation use gonadotropin-releasing hormone (GnRH) to induce ovulation and prostaglandin F2α (PGF2α) to induce luteolysis. The objectives of this study were to evaluate ovarian response to treatment with GnRH and the odds of bearing a corpus luteum or being inseminated in dairy cows with or without PVD. Another objective was to determine the hazard of insemination after administration of PGF2α in dairy cows with or without PVD. Primiparous (n = 291) and multiparous (n = 402) cows were evaluated for PVD using a Metricheck device at 46 ± 3 and 35 ± 3 days in milk (DIM) (study day 0), respectively. On study day 14, primiparous (n = 107) and multiparous (n = 197) cows were treated with GnRH and subsequent ovulation was recorded. Primiparous (n = 178) and multiparous (n = 368) cows not inseminated by study day 21 were administered PGF2α and response to PGF2α treatment was determined by detection of estrus. Furthermore, cows were categorized by the presence of a CL or being inseminated by study days 14, 21, and 35. Overall prevalence of PVD was 28.5% and 13.4% for primiparous and multiparous cows, respectively. Projected 305-d milk yield was less (P PVD+ multiparous cows compared with PVD- multiparous cows, however, no (P = 0.26) difference was detected between primiparous PVD+ and PVD- cows. Ovulatory response to GnRH treatment was 51.8% and 47.8% for primiparous and multiparous cows, respectively. Primiparous PVD- cows tended (P = 0.06) to be less likely to ovulate to GnRH than primiparous PVD+ cows, whereas multiparous PVD+ cows were less (P = 0.04) likely to ovulate to GnRH than PVD- multiparous cows. The odds of bearing a corpus luteum or being inseminated by study days 14, 21, or 35 was not associated with PVD in primiparous cows. In contrast, the odds of bearing a corpus luteum

Effect of human chorionic gonadotropin on sexual maturation, sex steroids and thyroid hormone levels in Caspian lamprey (Caspiomyzon wagneri Kessler, 1870)

OpenAIRE

Abedi, M.; Mojazi Amiri, B.; Abdoli, A.; Javanshir, A.; Benam, S.; Namdarian, A.

2017-01-01

The objective of this study was to determine the effect of human chorionic gonadotropin (hCG) on sexual maturation, plasma sex steroids [17β-estradiol, (E2) and 17α-hydroxy progesterone (17α_OHP)] and thyroid hormones (triiodothyronine, T3 and thyroxin, T4) levels in upstream - migrating Caspian lamprey. During the experiment, 36 fish (24 females and 12 males) in spring 2013 and 36 fish (24 females and 12 males) in fall 2013 were collected from the Shirud River estuary in Mazandaran Province,...

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.

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

Presence of gonadotropin-releasing hormone-like peptide in the central nervous system and reproductive organs of the male blue swimming crab, Portunus pelagicus, and its effect on spermatogenesis.

Science.gov (United States)

Senarai, Thanyaporn; Saetan, Jirawat; Tamtin, Montakan; Weerachatyanukul, Wattana; Sobhon, Prasert; Sretarugsa, Prepee

2016-08-01

Our previous studies have demonstrated that lamprey gonadotropin-releasing hormone-III (lGnRH-III)-like peptide occurs in the central nervous system (CNS) of decapod crustaceans (Macrobrachium rosenbergii, Penaeus monodon, Portunus pelagicus), and that lGnRH-III is the most potent in stimulating ovarian maturation compared with other GnRH isoforms. In this study, we examined the localization of lGnRH-III-like peptide in the CNS and male reproductive organs of the blue swimming crab by using anti-lGnRH-III as a probe. In the brain, lGnRH-III immunoreactivity (-ir) was detected in neurons of clusters 6, 10, 11, 14/15, 16, and 17 and in many neuropils. In the subesophageal ganglion, lGnRH-III-ir was present in neurons of the dorso-lateral and ventro-medial clusters. In the thoracic ganglia, lGnRH-III-ir was observed in the large-sized neurons between the thoracic neuropils and in the ventromedial cluster of the abdominal ganglia. In the testis, lGnRH-III-ir was detected in nurse cells, hemocytes, spermatids 2, and the outer and inner zones of the acrosomes of spermatozoa. Bioassay showed that lGnRH-III significantly increased the testis-somatic index, the percentage of late stages of seminiferous tubules (stages VII-IX), the diameter of the seminiferous tubules, and the number of BrdU-labeled early germ cells compared with the control groups. Thus, lGnRH-III-like peptide exists in the male crab and possibly enhances germ cell proliferation and maturation in the testes, leading to increased sperm production.

Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

Science.gov (United States)

Carrera, M P; Ramírez-Expósito, M J; Valenzuela, M T; García, M J; Mayas, M D; Arias de Saavedra, J M; Sánchez, R; Pérez, M C; Martínez-Martos, J M

2005-02-01

Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.

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.

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

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...

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.

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...

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.

[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.

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.

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

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.

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.

Clinical and hormonal effects of chronic gonadotropin-releasing hormone agonist treatment in polycystic ovarian disease.

Science.gov (United States)

Steingold, K; De Ziegler, D; Cedars, M; Meldrum, D R; Lu, J K; Judd, H L; Chang, R J

1987-10-01

Previously, we reported that short term administration of a highly potent GnRH agonist (GnRHa) for 1 month to patients with polycystic ovarian disease (PCO) resulted in complete suppression of ovarian steroidogenesis without measurable effects on adrenal steroid production. This new study was designed to evaluate the effects of long term GnRHa administration in PCO patients with respect to their hormone secretion patterns and clinical responses. Eight PCO patients and 10 ovulatory women with endometriosis were treated daily with sc injections of [D-His6-(imBzl]),Pro9-NEt]GnRH (GnRHa; 100 micrograms) for 6 months. Their results were compared to hormone values in 8 women who had undergone bilateral oophorectomies. In response to GnRHa, PCO and ovulatory women had rises of serum LH at 1 month, after which it gradually declined to baseline. In both groups FSH secretion was suppressed throughout treatment. Serum estradiol, estrone, progesterone, 17-hydroxyprogesterone, androstenedione, and testosterone levels markedly decreased to values found in oophorectomized women by 1 month and remained low thereafter. In contrast, serum pregnenolone and 17-hydroxypregnenolone were partially suppressed, and dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol levels did not change. Clinically, hyperplastic endometrial histology in three PCO patients reverted to an inactive pattern, and proliferative endometrium in two other PCO patients became inactive in one and did not change in the other. Regression of proliferative endometrial histology occurred in all ovulatory women. Vaginal bleeding occurred in all women studied during the first month of GnRHa administration, after which all but one PCO patient became amenorrheic. Hot flashes were noted by all ovulatory women and by four of eight PCO patients. All PCO patients noted subjective reduction of skin oiliness, and five had decreased hair growth. We conclude that in premenopausal women: 1) chronic Gn

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

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

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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.

Localization of gonadotropin binding sites in human ovarian neoplasms

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Nakano, R.; Kitayama, S.; Yamoto, M.; Shima, K.; Ooshima, A.

1989-01-01

The binding of human luteinizing hormone and human follicle-stimulating hormone to ovarian tumor biopsy specimens from 29 patients was analyzed. The binding sites for human luteinizing hormone were demonstrated in one tumor of epithelial origin (mucinous cystadenoma) and in one of sex cord-stromal origin (theca cell tumor). The binding sites for human follicle-stimulating hormone were found in three tumors of epithelial origin (serous cystadenoma and mucinous cystadenoma) and in two of sex cord-stromal origin (theca cell tumor and theca-granulosa cell tumor). The surface-binding autoradiographic study revealed that the binding sites for gonadotropins were localized in the stromal tissue. The results suggest that gonadotropic hormones may play a role in the growth and differentiation of a certain type of human ovarian neoplasms

Neuropeptides linking the control of appetite with reproductive function in domestic animals

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The occurrence of puberty and maintenance of normal reproductive cycles are regulated by secretion of gonadotropin hormones from the pituitary gland, which is dependent upon the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. It is well established that secretion of...

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

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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.

Gonadotropin binding sites in human ovarian follicles and corpora lutea during the menstrual cycle

Energy Technology Data Exchange (ETDEWEB)

Shima, K.; Kitayama, S.; Nakano, R.

1987-05-01

Gonadotropin binding sites were localized by autoradiography after incubation of human ovarian sections with /sup 125/I-labeled gonadotropins. The binding sites for /sup 125/I-labeled human follicle-stimulating hormone (/sup 125/I-hFSH) were identified in the granulosa cells and in the newly formed corpora lutea. The /sup 125/I-labeled human luteinizing hormone (/sup 125/I-hLH) binding to the thecal cells increased during follicular maturation, and a dramatic increase was preferentially observed in the granulosa cells of the large preovulatory follicle. In the corpora lutea, the binding of /sup 125/I-hLH increased from the early luteal phase and decreased toward the late luteal phase. The changes in 3 beta-hydroxysteroid dehydrogenase activity in the corpora lutea corresponded to the /sup 125/I-hLH binding. Thus, the changes in gonadotropin binding sites in the follicles and corpora lutea during the menstrual cycle may help in some important way to regulate human ovarian function.

Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes.

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Marcondes, Rodrigo Rodrigues; Carvalho, Kátia Cândido; Giannocco, Gisele; Duarte, Daniele Coelho; Garcia, Natália; Soares-Junior, José Maria; da Silva, Ismael Dale Cotrim Guerreiro; Maliqueo, Manuel; Baracat, Edmund Chada; Maciel, Gustavo Arantes Rosa

2017-08-01

Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

Pathogenesis of Hyperthyroidism.

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Singh, Ishita; Hershman, Jerome M

2016-12-06

Hyperthyroidism is a form of thyrotoxicosis in which there is excess thyroid hormone synthesis and secretion. Multiple etiologies can lead to a common clinical state of "thyrotoxicosis," which is a consequence of the high thyroid hormone levels and their action on different tissues of the body. The most common cause of thyrotoxicosis is Graves' disease, an autoimmune disorder in which stimulating thyrotropin receptor antibodies bind to thyroid stimulating hormone (TSH) receptors on thyroid cells and cause overproduction of thyroid hormones. Other etiologies include: forms of thyroiditis in which inflammation causes release of preformed hormone, following thyroid gland insult that is autoimmune, infectious, mechanical or medication induced; secretion of human chorionic gonadotropin in the setting of transient gestational thyrotoxicosis and trophoblastic tumors; pituitary thyrotropin release, and exposure to extra-thyroidal sources of thyroid hormone that may be endogenous or exogenous. © 2017 American Physiological Society. Compr Physiol 7:67-79, 2017. Copyright © 2017 John Wiley & Sons, Inc.

A selective androgen receptor modulator for hormonal male contraception.

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Chen, Jiyun; Hwang, Dong Jin; Bohl, Casey E; Miller, Duane D; Dalton, James T

2005-02-01

The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies, including hormonal male contraception. The identification of an orally bioavailable SARM with the ability to mimic the central and peripheral androgenic and anabolic effects of testosterone would represent an important step toward the "male pill". We characterized the in vitro and in vivo pharmacologic activity of (S)-3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (C-6), a novel SARM developed in our laboratories. C-6 was identified as an androgen receptor (AR) agonist with high AR binding affinity (K(i) = 4.9 nM). C-6 showed tissue-selective pharmacologic activity with higher anabolic activity than androgenic activity in male rats. The doses required to maintain the weight of the prostate, seminal vesicles, and levator ani muscle to half the size of the maximum effects (i.e., ED(50)) were 0.78 +/- 0.06, 0.88 +/- 0.1, and 0.17 +/- 0.04 mg/day, respectively. As opposed to other SARMs, gonadotropin levels in C-6-treated groups were significantly lower than control values. C-6 also significantly decreased serum testosterone concentration in intact rats after 2 weeks of treatment. Marked suppression of spermatogenesis was observed after 10 weeks of treatment with C-6 in intact male rats. Pharmacokinetic studies of C-6 in male rats revealed that C-6 was well absorbed after oral administration (bioavailability 76%), with a long (6.3 h) half-life at a dose of 10 mg/kg. These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.

Combination growth hormone and gonadotropin releasing hormone analog therapy in 11beta-hydroxylase deficiency.

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Bajpai, Anurag; Kabra, Madhulika; Menon, P S N

2006-06-01

Diagnosis of 11beta-hydroxylase deficiency was made in a boy at the age of 2 1/2 years on the basis of peripheral precocious puberty, growth acceleration (height standard deviation score +4.4) with advanced skeletal maturation (bone age 8.4 years) and elevated deoxycortisol levels. Glucocorticoid supplementation led to normalization of blood pressure but was associated with progression to central precocious puberty and increase in bone age resulting in decrease in predicted adult height to 133.7 cm (target height 163 cm). The child was started on GnRH analog (triptorelin 3.75 mg every 28 days), which led to improvement in predicted adult height by 3.1 cm over 15 months. Addition of growth hormone (0.1 IU/kg/day) resulted in improvement in predicted adult height (151 cm) and height deficit (12 cm) over the next 3.6 years. Final height (151 cm) exceeded predicted height at the initiation of GnRH analog treatment by 17.3 cm. This report suggests that combination GH and GnRH analog treatment may be useful in improving height outcome in children with 11beta-hydroxylase deficiency and compromised final height.

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)

Evolutionary origin and divergence of GnIH and its homologous peptides.

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Tsutsui, Kazuyoshi; Osugi, Tomohiro

2009-03-01

Probing undiscovered hypothalamic neuropeptides that play important roles in the regulation of pituitary function in vertebrates is essential for the progress of neuroendocrinology. In 2000, we discovered a novel hypothalamic dodecapeptide inhibiting gonadotropin release in quail and termed it gonadotropin-inhibitory hormone (GnIH). GnIH acts on the pituitary and gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus via a novel G protein-coupled receptor for GnIH to inhibit gonadal development and maintenance by decreasing gonadotropin release and synthesis. Similar findings were observed in other avian species. Thus, GnIH is a key factor controlling avian reproduction. To give our findings a broader perspective, we also found GnIH homologous peptides in the hypothalamus of other vertebrates, such as mammals, reptiles, amphibians and teleosts. GnIH and its homologs share a common C-terminal LPXRFamide (X=L or Q) motif. A mammalian GnIH homolog also inhibited gonadotropin release in mammals like the GnIH action in birds. In contrast to higher vertebrates, hypophysiotropic activities of GnIH homologs were different in lower vertebrates. To clarify the evolutionary origin of GnIH and its homologs, we further sought to identify novel LPXRFamide peptides from the brain of sea lamprey and hagfish, two extant groups of the oldest lineage of vertebrates, Agnatha. In these agnathans, LPXRFamide peptide and its cDNA were identified only from the brain of hagfish. Based on these findings over the past decade, this paper summarizes the evolutionary origin and divergence of GnIH and its homologous peptides.

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

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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.

Expression and Activation of Gonadotropin Receptors

NARCIS (Netherlands)

R. Kraaij (Robert)

1996-01-01

textabstractAmong the many hormones that are produced by the anterior pituitary gland, luteinizing hormone (LH, lutropin), follicle-stimulating hormone (FSH, follitropin), and thyroidstimulating hormone (TSH, thyrotropin) form the separate family of so-called glycoprotein hormones (reviewed by

Effects of pelvic telecobalt irradiation on gonadotropin secretin

International Nuclear Information System (INIS)

Pfenninger, R.

1978-01-01

The pitnitary reaction in women operated according to Wertheim who had menstruated regularly was investigated during telecobalt irradiation. The pitnitary reaction was observed with the aid of the gonadotropin releasing factor. A dose of 25 mcg RH-LH was applied. Releasing factor examinations were carried out before exposure with functioning ovaries, after a dose of 2000 R (i.e., after 10 exposures), and after 6000 R. In the meantime, separate gonadotropin examinations were carried out continuously. A FSH reaction was observed already after 14 days, and the values were raised to almost menopause values. After this, the FSH increased further, while the LH reaction was not observed until much later. The investigation suggests an interrelation between follicle apparatus and FSH, oestrogens and LH. (orig./AJ) [de

Role of emotional processing in depressive responses to sex-hormone manipulation: a pharmacological fMRI study

DEFF Research Database (Denmark)

Henningsson, S.; Madsen, Kristoffer Hougaard; Pinborg, A.

2015-01-01

resonance imaging (fMRI) to investigate if sex-steroid hormone manipulation with a gonadotropin-releasing hormone agonist (GnRHa) influences emotional processing. Fifty-six healthy women were investigated twice: at baseline (follicular phase of menstrual cycle) and 16 +/- 3 days post intervention. At both...... sessions, fMRI-scans during exposure to faces expressing fear, anger, happiness or no emotion, depressive symptom scores and estradiol levels were acquired. The fMRI analyses focused on regions of interest for emotional processing. As expected, GnRHa initially increased and subsequently reduced estradiol...

Review: evolution of GnIH and related peptides structure and function in the chordates.

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Osugi, Tomohiro; Ubuka, Takayoshi; Tsutsui, Kazuyoshi

2014-01-01

Discovery of gonadotropin-inhibitory hormone (GnIH) in the Japanese quail in 2000 was the first to demonstrate the existence of a hypothalamic neuropeptide inhibiting gonadotropin release. We now know that GnIH regulates reproduction by inhibiting gonadotropin synthesis and release via action on the gonadotropin-releasing hormone (GnRH) system and the gonadotrope in various vertebrates. GnIH peptides identified in birds and mammals have a common LPXRF-amide (X = L or Q) motif at the C-terminus and inhibit pituitary gonadotropin secretion. However, the function and structure of GnIH peptides are diverse in fish. Goldfish GnIHs possessing a C-terminal LPXRF-amide motif have both stimulatory and inhibitory effects on gonadotropin synthesis or release. The C-terminal sequence of grass puffer and medaka GnIHs are MPQRF-amide. To investigate the evolutionary origin of GnIH and its ancestral structure and function, we searched for GnIH in agnathans, the most ancient lineage of vertebrates. We identified GnIH precursor gene and mature GnIH peptides with C-terminal QPQRF-amide or RPQRF-amide from the brain of sea lamprey. Lamprey GnIH fibers were in close proximity to GnRH-III neurons. Further, one of lamprey GnIHs stimulated the expression of lamprey GnRH-III peptide in the hypothalamus and gonadotropic hormone β mRNA expression in the pituitary. We further identified the ancestral form of GnIH, which had a C-terminal RPQRF-amide, and its receptors in amphioxus, the most basal chordate species. The amphioxus GnIH inhibited cAMP signaling in vitro. In sum, the original forms of GnIH may date back to the time of the emergence of early chordates. GnIH peptides may have had various C-terminal structures slightly different from LPXRF-amide in basal chordates, which had stimulatory and/or inhibitory functions on reproduction. The C-terminal LPXRF-amide structure and its inhibitory function on reproduction may be selected in later-evolved vertebrates, such as birds and mammals.

Review: Evolution of GnIH structure and function

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Tomohiro eOsugi

2014-08-01

Full Text Available Discovery of gonadotropin-inhibitory hormone (GnIH in the Japanese quail in 2000 was the first to demonstrate the existence of a hypothalamic neuropeptide inhibiting gonadotropin release. We now know that GnIH regulates reproduction by inhibiting gonadotropin synthesis and release via action on the gonadotropin-releasing hormone (GnRH system and the gonadotrope in various vertebrates. GnIH peptides identified in birds and mammals have a common LPXRF-amide (X = L or Q motif at the C-terminus and inhibits pituitary gonadotropin secretion. However, the function and structure of GnIH peptides were diverse in fish. Goldfish GnIHs possessing a C-terminal LPXRF-amide motif had both stimulatory and inhibitory effects on gonadotropin synthesis or release. The C-terminal sequence of grass puffer and medaka GnIHs were MPQRF-amide. To investigate the evolutionary origin of GnIH and its ancestral structure and function, we searched for GnIH in agnathans, the most ancient lineage of vertebrates. We identified GnIH precursor gene and mature GnIH peptides with C-terminal QPQRF-amide or RPQRF-amide from the brain of sea lamprey. Lamprey GnIH fibers were in close proximity to GnRH-III neurons. Further, one of lamprey GnIHs stimulated the expression of lamprey GnRH-III peptide in the hypothalamus and gonadotropic hormone β mRNA expression in the pituitary. We further identified the ancestral form of GnIH, which had a C-terminal RPQRF-amide, and its receptors in amphioxus, the most basal chordate species. The amphioxus GnIH inhibited cAMP signaling in vitro. In sum, the original forms of GnIH may date back to the time of the emergence of early chordates. GnIH peptides may have had various C-terminal structures slightly different from LPXRF-amide in basal chordates, which had stimulatory and/or inhibitory functions on reproduction. The C-terminal LPXRF-amide structure and its inhibitory function on reproduction may be selected in later-evolved vertebrates, such as

Effects of cetrorelix, a GnRH-receptor antagonist, on gonadal axis in women with functional hypothalamic amenorrhea.

Science.gov (United States)

Berardelli, Rita; Gianotti, Laura; Karamouzis, Ioannis; Picu, Andreea; Giordano, Roberta; D'Angelo, Valentina; Zinnà, Domenico; Lanfranco, Fabio; Ghigo, Ezio; Arvat, Emanuela

2011-10-01

Gonadotropin Releasing Hormone (GnRH) antagonists (GnRHa) suppress gonadotropin and sex-steroid secretion. In normal women, acute GnRHa administration induces inhibitory effect on pituitary-gonadal axis, followed by Luteinizing Hormone (LH) rebound. Functional hypothalamic amenorrhea (HA) is characterised by impaired gonadotropin secretion and hypogonadism secondary to blunted GnRH pulsatility. We studied the effects of a GnRHa, cetrorelix (CTX 3.0 mg), in six women with HA (age 30.7 ± 3.2 years; BMI 21.5 ± 1.7 kg/m(2)) and six control subjects (CS, 28.2 ± 0.6 years; 22.6 ± 0.9 kg/m(2)) on LH, Follicle-Stimulating Hormone (FSH) and oestradiol levels over 4 h (08.00-12.00 am) before, +24 h and +96 h after CTX; LH, FSH, and oestradiol were also evaluated at +6, +8, +12, +48, +72 h after CTX. CS: CTX reduced (p < 0.05) LH, FSH, and oestradiol (nadir at +12 h, +24 h, and +24 h); LH rebounded at +96 h, FSH and oestradiol recovered at +48 h and +72 h. The 4-h evaluation showed LH and FSH reduction (p < 0.05) at +24 h, with LH rebound at +96 h. HA: CTX reduced (p < 0.05) LH, FSH, and oestradiol, (nadir at +24 h, +48 h, and +48 h, recovery at +48 h, +72 h, and +96 h). The 4-h evaluation showed gonadotropin reduction (p < 0.05) 24 h after CTX, without any rebound effect. One single CTX dose still modulates gonadotropin secretion in HA. Its 'paradoxical' stimulatory effect on gonadotropins needs to be verified after prolonged administration.

Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation

DEFF Research Database (Denmark)

Frokjaer, Vibe Gedsoe; Pinborg, Anja; Holst, Klaus Kähler

2015-01-01

.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). RESULTS: Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p......BACKGROUND: An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised...... serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS...

Hormone patterns in early human gestation

International Nuclear Information System (INIS)

Mishell, D.R. Jr.; Thorneycroft, I.H.; Nagata, Y.; Murata, T.; Nakamura, R.M.

1974-01-01

Accurate measurement of the low concentration of gonadotropins and steroid hormones present in human serum has been made possible by the development of sensitive radioimmunoassay (RIA) techniques. With the use of RIA FSH and LH, progesterone and 17OH-progesterone have been previously measured in early normal pregnancy. In order to determine the daily pattern of hormone levels in early normal pregnancy, gonadotropins as well as steroid hormone levels were measured in serum samples obtained daily from three women from the time of the last menstrual period prior to conception throughout the first few months of gestation. To further identify the steroid hormone pattern in early normal pregnancy, concentrations of estradiol, progesterone, and 17OH-progesterone were measured in individual serum samples obtained from a group of 158 women with apparently normal gestations who subsequently had therapeutic abortions. (auth)

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

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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.

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)

Adjuvant Growth Hormone for Ovulation Induction with Gonadotropins in the Treatment of a Woman with Hypopituitarism

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Ariadne Daniel

2012-01-01

Full Text Available Objective. To report the prestimulation use of adjuvant GH for gonadotropin ovulation induction in a woman with hypopituitarism and GH deficiency who previously failed to respond. Design, Patients, and Measurements. A 31-year-old nulliparous woman presented with hypopituitarism and GH deficiency after failing ovulation induction with high dose gonadotropins. A trial of GH was undertaken for 5 months prior to ovulation induction resulting in normalization of IGF-I levels. Results. Women with hypopituitarism are known to have lower pregnancy rates after ovulation induction with need for higher doses of gonadotropins. A small subset of these patients do not ovulate. This patient had successful ovulation induction and pregnancy with prestimulation GH. Conclusions. This case suggests that the use of adjuvant GH in a GH-deficient patient several months before the use of human menopausal gonadotropin results in ovulation and pregnancy.

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.

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.

Characterization of actions of dopamine in the pituitary of the goldfish, Carassius auratus

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Omeljaniuk, R.J.

1988-01-01

The dopamine receptor in the goldfish (Carassius auratus) pituitary and its involvement with inhibition of gonadotropin (GtH) and {alpha}-melanocyte stimulating hormone ({alpha}-MSH) release was studied. In vitro dopamine, in a dose-related manner, inhibited spontaneous GtH and {alpha}-MSH release from superfused fragments of pars distalis (PD) and neurointermediate lob (NIL), respectively; dopamine also inhibited sGnRH-A stimulation of GtH release. Thyrotropin releasing-hormone (TRH), in a dose-related manner, stimulated {alpha}-MSH release from NIL fragments; dopamine inhibited TRH action. The stereoisomers of apomorphine were equivalent in inhibiting GtH and {alpha}-MSH release from fragments treated with releasing factors. Domperidone, in a dose-related manner, antagonized dopamine action. ({sup 3}H)-Spiperone was used to radiolabel the goldfish pituitary dopamine receptor in vitro. The binding of ({sup 3}H)-spiperone had the characteristics of a receptor: tissue specificity, dependence on tissue quantity, reversibility, saturability, displaceability, specificity of binding with various drugs and a correlation of binding with biological effects were demonstrated. This is a low-affinity, high-capacity receptor which does not show binding stereoselectivity for apomorphine; domperidone binds avidly to this receptor. The NIL contains significantly greater numbers of this receptor compared to the PD.

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

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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.

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

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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.

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

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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

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

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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.

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

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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+...

Sex-Steroid Hormone Manipulation Reduces Brain Response to Reward

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Macoveanu, Julian; Henningsson, Susanne; Pinborg, Anja

2016-01-01

's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo...... or the gonadotropin-releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex-steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map...

Hormone action. Part I. Peptide hormones

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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

Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro

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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...

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.

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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.

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

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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

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

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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.

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

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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.

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

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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.

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

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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

Use of equine chorionic gonadotropin to control reproduction of the dairy cow: a review.

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De Rensis, F; López-Gatius, F

2014-04-01

Equine chorionic gonadotropin (eCG) is a member of the glycoprotein family of hormones along with LH, FSH and thyroid-stimulating hormone. In non-equid species, eCG shows high LH- and FSH-like activities and has a high affinity for both FSH and LH receptors in the ovaries. On the granulosa and thecal cells of the follicle, eCG has long-lasting LH- and FSH-like effects that stimulate oestradiol and progesterone secretion. Thus, eCG administration in dairy cattle results in fewer atretic follicles, the recruitment of more small follicles showing an elevated growth rate, the sustained growth of medium and large follicles and improved development of the dominant and pre-ovulatory follicle. In consequence, the quality of the ensuing CL is improved, and thereby progesterone secretion increased. Based on these characteristics, eCG treatment is utilized in veterinary medicine to control the reproductive activity of the cow by i) improving reproductive performance during early post-partum stages; ii) increasing ovulation and pregnancy rates in non-cyclic cows; iii) improving the conception rate in cows showing delayed ovulation; and finally, iv) eCG is currently included in protocols for fixed-time artificial insemination since after inducing the synchrony of ovulation using a progesterone-releasing device, eCG has beneficial effects on embryo development and survival. The above effects are not always observed in cyclic animals, but they are evident in animals in which LH secretion and ovarian activity are reduced or compromised, for instance, during the early post-partum period, under seasonal heat stress, in anoestrus animals or in animals with a low body condition score. © 2014 Blackwell Verlag GmbH.

Evidence that obesity and androgens have independent and opposing effects on gonadotropin production from puberty to maturity

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Rosenfield, Robert L; Bordini, Brian

2010-01-01

Optimal fat mass is necessary for normal gonadotropin levels in adults, and both undernutrition and overnutrition suppress gonadotropins: thus, the gonadotropin response to relative adipose mass is biphasic. Adult obesity is associated with blunted luteinizing hormone (LH) pulse amplitude that is partially attributable to increased LH clearance rate. Testosterone appears to have a biphasic effect on gonadotropin production in females. Moderate elevations of testosterone appear to stimulate LH production at both the hypothalamic and pituitary level, while very high levels of testosterone suppress LH. Thus, obesity per se appears to suppress gonadotropin production, and moderate hyperandrogenemia in women appears to stimulate LH. The ordinary hypergonadotropic hyperandrogenism of obese women appears to be an exception to this model because it is usually due to polycystic ovary syndrome (PCOS), a condition in which intrinsic functional ovarian hyperandrogenism and excess adiposity share a common origin that involves insulin-resistant hyperinsulinemia. LH elevation seems to be secondary to hyperandrogenemia and is absent in the most obese cases. Overweight early pubertal girls have significant blunting of sleep-related LH production, which is the first hormonal change of puberty. The data are compatible with the possibility that excess adiposity may paradoxically subtly suppress hypothalamic-pituitary-gonadal function in early puberty although it is known to contribute to the early onset of puberty. PMID:20816944

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

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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

Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats.

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Nelson, Britta S; Black, Katelyn L; Daniel, Jill M

2016-01-01

Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In the first experiment, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In the second experiment, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In the third experiment, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.

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

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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

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

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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.

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

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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.

Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor: clinical evaluation and molecular characterization of a novel mutation.

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Frédéric Brioude

Full Text Available CONTEXT: KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH (OMIM #146110. OBJECTIVE: To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation. RESULTS: An original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 male from a consanguineous Portuguese family. This mutation, located in the seventh transmembrane domain, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs MAP kinase signaling and intracellular calcium release. In the second family, a French Caucasian male patient with nCHH was found to carry two recurrent mutations in the compound heterozygous state (p.Leu102Pro/Stop399Arg. In this man, pulsatile GnRH (Gonadotropin Releasing Hormone administration restored pulsatile LH (Luteinizing Hormone secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 miscarriages and the birth of a healthy boy. CONCLUSION: We show that a novel loss-of-function mutation (p.Tyr313His in the KISS1R gene can cause familial nCHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of gonadotropin secretion by exogenous GnRH administration further supports, in humans, the hypothalamic origin of the gonadotropin deficiency in this genetic form of nCHH.

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

Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

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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.

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.

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

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

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.

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.

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

Negative Effects of High Glucose Exposure in Human Gonadotropin-Releasing Hormone Neurons

Directory of Open Access Journals (Sweden)

Annamaria Morelli

2013-01-01

Full Text Available Metabolic disorders are often associated with male hypogonadotropic hypogonadism, suggesting that hypothalamic defects involving GnRH neurons may impair the reproductive function. Among metabolic factors hyperglycemia has been implicated in the control of the reproductive axis at central level, both in humans and in animal models. To date, little is known about the direct effects of pathological high glucose concentrations on human GnRH neurons. In this study, we investigated the high glucose effects in the human GnRH-secreting FNC-B4 cells. Gene expression profiling by qRT-PCR, confirmed that FNC-B4 cells express GnRH and several genes relevant for GnRH neuron function (KISS1R, KISS1, sex steroid and leptin receptors, FGFR1, neuropilin 2, and semaphorins, along with glucose transporters (GLUT1, GLUT3, and GLUT4. High glucose exposure (22 mM; 40 mM significantly reduced gene and protein expression of GnRH, KISS1R, KISS1, and leptin receptor, as compared to normal glucose (5 mM. Consistent with previous studies, leptin treatment significantly induced GnRH mRNA expression at 5 mM glucose, but not in the presence of high glucose concentrations. In conclusion, our findings demonstrate a deleterious direct contribution of high glucose on human GnRH neurons, thus providing new insights into pathogenic mechanisms linking metabolic disorders to reproductive dysfunctions.

Recent advancements in the hormonal stimulation of ovulation in swine

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Knox RV

2015-10-01

Full Text Available Robert V Knox Department of Animal Sciences, 360 Animal Sciences Laboratory, University of Illinois, Champaign Urbana, IL, USA Abstract: Induction of ovulation for controlled breeding is available for use around the world, and conditions for practical application appear promising. Many of the hormones available, such as human chorionic gonadotropin (hCG, gonadotropin-releasing hormone (GnRH and its analogs, as well as porcine luteinizing hormone (pLH, have been shown to be effective for advancing or synchronizing ovulation in gilts and weaned sows. Each of the hormones has unique attributes with respect to the physiology of its actions, how it is administered, its efficacy, and approval for use. The timing for induction of ovulation during the follicle phase is critical as follicle maturity changes over time, and the success of the response is determined by the stage of follicle development. Female fertility is also a primary factor affecting the success of ovulation induction and fixed time insemination protocols. Approximately 80%–90% of female pigs will develop mature follicles following weaning in sows and synchronization of estrus in gilts. However, those gilts and sows with follicles that are less developed and mature, or those that develop with abnormalities, will not respond to an ovulatory surge of LH. To address this problem, some protocols induce follicle development in all females, which can improve the overall reliability of the ovulation response. Control of ovulation is practical for use with fixed time artificial insemination and should prove highly advantageous for low-dose and single-service artificial insemination and for use with frozen-thawed and sex-sorted sperm. Keywords: artificial insemination, follicle, hormone, ovulation, swine

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.

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...

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...

Influence of Human Chorionic Gonadotropin on the Fertility Rate in ...

African Journals Online (AJOL)

An experiment was carried out on the influence of human chorionic gonadotropin hormone (hCG) on the fertility rate of rabbit does under artificial insemination. The rabbit does (7-8 months old) were used for the trial. The hCG was administered to the rabbit does at varying doses: 0, 50, 100 and 150 I.U representing ...

Chitosan-nanoconjugated hormone nanoparticles for sustained surge of gonadotropins and enhanced reproductive output in female fish.

Directory of Open Access Journals (Sweden)

Mohd Ashraf Rather

Full Text Available A controlled release delivery system helps to overcome the problem of short life of the leutinizing hormone releasing hormone (LHRH in blood and avoids use of multiple injections to enhance reproductive efficacy. Chitosan- and chitosan-gold nanoconjugates of salmon LHRH of desired size, dispersity and zeta potential were synthesized and evaluated at half the dose rate against full dose of bare LHRH for their reproductive efficacy in the female fish, Cyprinus carpio. Whereas injections of both the nanoconjugates induced controlled and sustained surge of the hormones with peak (P<0.01 at 24 hrs, surge due to bare LHRH reached its peak at 7 hrs and either remained at plateau or sharply declined thereafter. While the percentage of relative total eggs produced by fish were 130 and 67 per cent higher, that of fertilised eggs were 171 and 88 per cent higher on chitosan- and chitosan-gold nanoconjugates than bare LHRH. Chitosan nanoconjugates had a 13 per cent higher and chitosan gold preparation had a 9 per cent higher fertilization rate than bare LHRH. Histology of the ovaries also attested the pronounced effect of nanoparticles on reproductive output. This is the first report on use of chitosan-conjugated nanodelivery of gonadotropic hormone in fish.

Transcripts of genes encoding reproductive neuroendocrine hormones and androgen receptor in the brain and testis of goldfish exposed to vinclozolin, flutamide, testosterone, and their combinations.

Science.gov (United States)

Golshan, Mahdi; Habibi, Hamid R; Alavi, Sayyed Mohammad Hadi

2016-08-01

Vinclozolin (VZ) is a pesticide that acts as an anti-androgen to impair reproduction in mammals. However, VZ-induced disruption of reproduction is largely unknown in fish. In the present study, we have established a combination exposure in which adult goldfish were exposed to VZ (30 and 100 μg/L), anti-androgen flutamide (Flu, 300 μg/L), and androgen testosterone (T, 1 μg/L) to better understand effects of VZ on reproductive endocrine system. mRNA levels of kisspeptin (kiss-1 and kiss-2) and its receptor (gpr54), salmon gonadotropin-releasing hormone (gnrh3) and androgen receptor (ar) in the mid-brain, and luteinizing hormone receptor (lhr) in the testis were analyzed and compared with those of control following 10 days of exposure. kiss-1 mRNA level was increased in goldfish exposed to 100 µg/L VZ and to Flu, while kiss-2 mRNA level was increased following exposure to Flu and to combinations of 30 µg/L VZ with Flu, 100 µg/L VZ with T, and Flu with T. gpr54 mRNA level was increased in goldfish exposed to Flu and to combination of 30 µg/L VZ with Flu and 100 µg/L VZ with T. gnrh3 mRNA level was increased in goldfish exposed to 100 µg/L VZ, to Flu, and to combinations of 30 µg/L VZ with Flu, 100 µg/L VZ with T, and Flu with T. The mid-brain ar mRNA level was increased in goldfish exposed to Flu and to combinations of 30 µg/L VZ with Flu, 100 µg/L VZ with T, and Flu with T. Testicular lhr mRNA level was increased in goldfish exposed to Flu and to combination of 30 µg/L VZ with Flu. These results suggest that VZ and Flu are capable of interfering with kisspeptin and GnRH systems to alter pituitary and testicular horonal functions in adult goldfish and the brain ar mediates VZ-induced disruption of androgen production.

Estriol administration modulates luteinizing hormone secretion in women with functional hypothalamic amenorrhea.

Science.gov (United States)

Genazzani, Alessandro D; Meczekalski, Blazej; Podfigurna-Stopa, Agnieszka; Santagni, Susanna; Rattighieri, Erica; Ricchieri, Federica; Chierchia, Elisa; Simoncini, Tommaso

2012-02-01

To evaluate the influence of estriol administration on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA). Controlled clinical study. Patients with FHA in a clinical research environment. Twelve hypogonadotropic patients affected by FHA. Pulsatility study of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and a gonadotropin-releasing hormone (GnRH) test (10 μg in bolus) at baseline condition and after 8 weeks of therapy with 2 mg/day of estriol. Measurements of plasma LH, FSH, estradiol (E(2)), androstenedione (A), 17α-hydroxyprogesterone (17-OHP), cortisol, androstenedione (A), testosterone (T), thyroid-stimulating hormone (TSH), free triiodothyronine (fT(3)), free thyroxine (fT(4)), and insulin, and pulse detection. After treatment, the FHA patients showed a statistically significant increase of LH plasma levels (from 0.7 ± 0.1 mIU/mL to 3.5 ± 0.3 mIU/mL) and a statistically significant increase of LH pulse amplitude with no changes in LH pulse frequency. In addition, the LH response to the GnRH bolus was a statistically significant increase. Estriol administration induced the increase of LH plasma levels in FHA and improved GnRH-induced LH secretion. These findings suggest that estriol administration modulates the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of LH synthesis and secretion in hypogonadotropic patients with FHA. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Luteinizing hormone (LH)-responsive Cushing's syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro

NARCIS (Netherlands)

R.A. Feelders (Richard); W.W. de Herder (Wouter); S.W.J. Lamberts (Steven); L.J. Hofland (Leo); P.M. van Koetsveld (Peter); M. Verhoef-Post (Miriam); A.P.N. Themmen (Axel); F.H. de Jong (Frank); H.J. Bonjer (Jaap); A.J. Clark (Adrian); A-J. van der Lely (Aart-Jan)

2003-01-01

textabstractIn a substantial part of adrenal adenomas and hyperplasias from patients with Cushing's syndrome, cortisol production is controlled by the expression of aberrant hormone receptors on adrenocortical cells. We present in vivo and in vitro data of two patients with a

Critical evaluation of the radioiodination of follicle-stimulating-and luteinizing hormones by lactoperoxidase and its comparison with chloramine-T classical method

International Nuclear Information System (INIS)

Pinto, H.

1978-01-01

A method is described for the enzymatic radioiodination of human gonadotropins by a system consisting of lactoperoxidase, hydrogen peroxide and Na 125 I. A comparison witth the clhloramine-T modified technique was done a satisfactory specific activity (100 μCi/μg) of the labeled hormone was obtained with the enzymatic iodination, with much greater immunoreactivity and stability than after chloramine-T. As aqueous polyethylene glycol causes precipitation of antibody-bound peptide hormones with radioactive iodine with little or no precipitation of free hormones, a method of separation was developed and applied to radioimmunoassay of gonadotropins, providing several advantages over te double-antibody precipitation method. It was demonstrated that, in humans, the intravenous administration of synthetic LH-FSH/RH, stimulates the pituitary release of both LH and FSH. Results are reported now for normal women, infused with an acute load of 25μg of synthetic LH/FSH-RH and 8 hours infusion of 100μg, during the mid-follicular and luteal phases. The greatest gonadotropin responsiveness to LH/FSH-RH are found in the luteal phase during acute testing. No differences were noticed during chronic infusion as well as acute post-chronic, performed in both phases of the menstrual cycle. The possible modulating effects of steroidal secretion by the ovaries are discussed. (Author) [pt

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

Possible role of serum testosterone, gonadotropins and prolactin in patients with premature ejaculation.

Science.gov (United States)

Abu El-Hamd, M; Farah, A

2018-02-01

Premature ejaculation (PE) is the most common male sexual dysfunction. This study aimed to investigate the role of serum testosterone, gonadotropins and prolactin in patients with PE. In a prospective a case-controlled study, it was conducted on 90 male patients with PE and 90 male healthy participants as controls. Patients were evaluated by Premature Ejaculation Diagnostic Tool (PEDT) and intravaginal ejaculatory latency time (IELT). Patients with mean IELT values ≤60 s and PEDT total scores ≥11 were considered to have PE. Serum levels of total testosterone (TT), free testosterone (FT), follicle-stimulating hormone (FSH), luteinising hormone (LH) and prolactin (PL) were investigated in patients with PE and controls. There was no statistically significant difference between patients with PE and controls regarding the serum levels of TT, FT, FSH, LH and PL (p value ˃.05). There was no significant correlation between the sex hormones levels (TT, FT, FSH, LH and PL) and (age, body mass index (BMI), IELTS and total PEDT scores of the patients; p value ˃.05). This study concluded that there was no disturbance in serum levels of testosterone, gonadotropins and prolactin in patients with PE and controls. These hormones could not relate to pathogenesis of PE. © 2017 Blackwell Verlag GmbH.

Commercial radioimmunoassay for beta subunit of human chorionic gonadotropin: falsely positive determinations due to elevated serum luteinizing hormone

International Nuclear Information System (INIS)

Fowler, J.E. Jr.; Platoff, G.E.; Kubrock, C.A.; Stuzman, R.E.

1982-01-01

Among 17 men who had received seemingly curative treatment for unilateral non-seminomatous germ cell tumors for the testis and who had consistently normal serum human chorionic gonadotropin (HCG) levels at a reference laboratory, 7 (41%) had at least one falsely positive commercial serum HCG determination. To investigate the cause of these falsely positive determinations the authors measured the cross reactivity of luteinizing hormone (LH) and follicle stimulating hormone (FSH) standards in the commercial HCG assay, and studied the relationships between commercial HCG levels and serum LH levels, serum FSH levels and gonadal status in men with and without normal gonadal function. The falsely positive HCG determinations appeared to be due to elevated serum LH levels and cross reactivity of LH in the commercial HCG assay because: 1) there was substantial cross reactivity of the LH standards in the commercial assay, 2) the serum LH was elevated in four of six men with solitary testes, 3) there was a striking correlation between elevated serum LH levels and falsely elevated commercial HCG levels in ten men with solitary or absent testes, and 4) there were no falsely positive HCG determinations in 13 normal men but there were falsely positive HCG determinations in seven of ten anorchid men

Targeting Gonadotropins: An Alternative Option for Alzheimer Disease Treatment

Directory of Open Access Journals (Sweden)

Gemma Casadesus

2006-01-01

Full Text Available Recent evidence indicates that, alongside oxidative stress, dysregulation of the cell cycle in neurons susceptible to degeneration in Alzheimer disease may play a crucial role in the initiation of the disease. As such, the role of reproductive hormones, which are closely associated with the cell cycle both during development and after birth, may be of key import. While estrogen has been the primary focus, the protective effects of hormone replacement therapy on cognition and dementia only during a “crucial period” led us to expand the study of hormonal influences to other members of the hypothalamic pituitary axis. Specifically, in this review, we focus on luteinizing hormone, which is not only increased in the sera of patients with Alzheimer disease but, like estrogen, is modulated by hormone replacement therapy and also influences cognitive behavior and pathogenic processing in animal models of the disease. Targeting gonadotropins may be a useful treatment strategy for disease targeting multiple pleiotropic downstream consequences.

DECEMBER JMBR 13 - 2 correction.cdr

African Journals Online (AJOL)

Fine Print

J. E. ATAMAN, D. BAXTER-GRILLO, A.A.A. OSINUBI largely influenced by hormonal factor. Gonadotropin-releasing hormone (GnRH) from the hypothalamus, which is released in pursatile manner, stimulates luteinizing hormone (LH) and follicle stimulating hormone (FSH) release from the anterior. 4 pituitary. They both ...

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...

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

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.

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.

Pharmacologically Induced Sex Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression

DEFF Research Database (Denmark)