Paraventricular nucleus of the human hypothalamus in primary hypertension: Activation of corticotropin-releasing hormone neurons

NARCIS (Netherlands)

Goncharuk, Valeri D.; van Heerikhuize, Joop; Swaab, Dick F.; Buijs, Ruud M.

2002-01-01

By using quantitative immunohistochemical and in situ hybridization techniques, we studied corticotropin-releasing hormone (CRH)-producing neurons of the hypothalamic paraventricular nucleus (PVN) in patients who suffered from primary hypertension and died due to acute cardiac failure. The control

Ontogenesis of neurons producing luteinizing hormone-releasing hormone (LHRH) in the nervus terminalis of the rat.

Science.gov (United States)

Schwanzel-Fukuda, M; Morrell, J I; Pfaff, D W

1985-08-15

Immunoreactive luteinizing hormone-releasing hormone (LHRH) was first detected at 15 days of gestation in ganglion cells associated with the peripheral, intracranial, and central parts of the nervus terminalis of the rat. LHRH was not detected in any other structure of the central nervous system at this age. In the 17-day-old fetal rat, 62% of the total LHRH-reactive neuronal population was found in ganglion cells of the nervus terminalis. At this same age, immunoreactive beta-luteinizing hormone (beta-LH) was first seen in gonadotropes of the anterior pituitary gland. At 19 days of gestation, 31% of the total number of LHRH-reactive neurons observed in the rat brain was found in the nervus terminalis, and immunoreactive processes were first seen in the organum vasculosum of the lamina terminalis and in the median eminence. Our data indicate that from 15 to 19 days of gestation the nervus terminalis is a principal source of LHRH in the fetal rat. Presence of the decapeptide in the nervus terminalis prior to appearance of beta-LH in the anterior pituitary suggests a possible role for LHRH in this system on maturation of the gonadotropes and differentiation of the brain-pituitary-gonadal axis.

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

NARCIS (Netherlands)

G.A.C. van Haasteren (Goedele)

1995-01-01

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

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

Directory of Open Access Journals (Sweden)

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.

Internalisation of gonadotrophin-receptor complex in ovarian luteal cells

International Nuclear Information System (INIS)

Conn, P.M.; Conti, M.; Harwood, J.P.; Dufau, M.L.; Catt, K.J.

1978-01-01

Following evidence that certain protein hormones can enter target cells the present investigation was undertaken which shows that gonadotrophin-induced receptor loss may occur by a process of internalisation of the hormone-receptor complex following the initial interaction of gonadotrophin with the cell surface. Localisation studies were carried out in 33-d old female rats previously treated with pregnant mare serum gonadotrophin and human chorionic gonadotrophin (hCG) to induce ovarian luteinisation. Animals were injected with 125 I-hCG to label the ovarian receptors for luteinising hormone in vivo. Microscope autoradiographs demonstrating distribution of 125 I-hCG in ovaries at various times following injection are shown. The combined results from the autoradiographs and from solubilisation experiments were used to determine the location and nature of the hCG-receptor complex following occupancy and loss of receptors from the plasma membrane of luteinised ovarian cells. (U.K.)

Dose-dependent effects of exogenous gonadotrophins on the ...

African Journals Online (AJOL)

We compared the serwn levels of oestrogen and progesterone and the endometrial morphology of normal pregnant rats at 5,5 days' gestation with those of pregnant rats given either low (10 IU) or high (20 IU) doses of two gonadotrophins: follicle-stimulating hormone (FSH) and hwnan chorionic gonadotrophin (HCG).

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

Science.gov (United States)

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

Directory of Open Access Journals (Sweden)

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.

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

OpenAIRE

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...

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

Directory of Open Access Journals (Sweden)

Alun L Edwards

1996-01-01

Full Text Available Variability in the severity of asthma during various phases of the menstrual cycle has been frequently suspected. However, the hormonal changes that might affect mediators of bronchospasm have yet to be elucidated. The case of a 41-year-old woman suffering from longstanding asthma with life-threatening exacerbations is reported. The patient was treated with buserelin, a gonadotropin releasing hormone (GnRH analogue, which created a temporary chemical menopause and thus permitted diagnosis of a premenstrual exacerbation of asthma and offered insight into potential therapy. GnRH analogues may therefore be of value in assessing women with severe asthma suspected to vary with the menstrual cycle. The addition of estrogens and progestins at the same time as treatment with GnRH analogue may be of value in determining the role of these hormones in the pathogenesis of menstrually related exacerbations of asthma.

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.

Inhibition of septic shock in mice by an oligopeptide from the beta-chain of human chorionic gonadotrophin hormone

NARCIS (Netherlands)

Khan, N.A.; Khan, A.; Savelkoul, H.F.J.; Benner, R.

2002-01-01

Human chorionic gonadotrophin (hCG) is a heterodimeric placental glycoprotein hormone required in pregnancy. In human pregnancy urine and in commercial hCG preparations (c-hCG) it occurs in a variety of forms, including breakdown products. Several reports have suggested modulation of the immune

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

Science.gov (United States)

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.

Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons.

OpenAIRE

Flavell, D M; Wells, T; Wells, S E; Carmignac, D F; Thomas, G B; Robinson, I C

1996-01-01

Expression of human growth hormone (hGH) was targeted to growth hormone-releasing (GRF) neurons in the hypothalamus of transgenic rats. This induced dominant dwarfism by local feedback inhibition of GRF. One line, bearing a single copy of a GRF-hGH transgene, has been characterized in detail, and has been termed Tgr (for Transgenic growth-retarded). hGH was detected by immunocytochemistry in the brain, restricted to the median eminence of the hypothalamus. Low levels were also detected in the...

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

Science.gov (United States)

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

Science.gov (United States)

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

Pituitary block with gonadotrophin-releasing hormone antagonist during intrauterine insemination cycles: a systematic review and meta-analysis of randomised controlled trials.

Science.gov (United States)

Vitagliano, A; Saccone, G; Noventa, M; Borini, A; Coccia, M E; Nardelli, G B; Saccardi, C; Bifulco, G; Litta, P S; Andrisani, A

2018-06-03

Several randomised controlled trials (RCTs) have investigated the usefulness of pituitary block with gonadotrophin-releasing hormone (GnRH) antagonists during intrauterine insemination (IUI) cycles, with conflicting results. The aim of the present systematic review and meta-analysis of RCTs was to evaluate the effectiveness of GnRH antagonist administration as an intervention to improve the success of IUI cycles. Electronic databases (MEDLINE, Scopus, EMBASE, Sciencedirect) and clinical registers were searched from their inception until October 2017. Randomised controlled trials of infertile women undergoing one or more IUI stimulated cycles with GnRH antagonists compared with a control group. The primary outcomes were ongoing pregnancy/live birth rate (OPR/LBR) and clinical pregnancy rate (CPR). Pooled results were expressed as odds ratio (OR) or mean differences with 95% confidence interval (95% CI). Sources of heterogeneity were investigated through sensitivity and subgroups analysis. The body of evidence was rated using GRADE methodology. Publication bias was assessed with funnel plot, Begg's and Egger's tests. Fifteen RCTs were included (3253 IUI cycles, 2345 participants). No differences in OPR/LBR (OR 1.14, 95% CI 0.82-1.57, P = 0.44) and CPR (OR 1.28, 95% CI 0.97-1.69, P = 0.08) were found. Sensitivity and subgroup analyses did not provide statistical changes in pooled results. The body of evidence was rated as low (GRADE 2/4). No publication bias was detected. Pituitary block with GnRH antagonists does not improve OPR/LBR and CPR in women undergoing IUI cycles. Pituitary block with GnRH antagonists does not improve the success of IUI cycles. © 2018 Royal College of Obstetricians and Gynaecologists.

Differentiation of adult-type Leydig cells occurs in gonadotrophin-deficient mice

Directory of Open Access Journals (Sweden)

Charlton HM

2003-02-01

Full Text Available Abstract During mammalian testis development distinct generations of fetal and adult Leydig cells arise. Luteinising hormone (LH is required for normal adult Leydig cell function and for the establishment of normal adult Leydig cell number but its role in the process of adult Leydig cell differentiation has remained uncertain. In this study we have examined adult Leydig cell differentiation in gonadotrophin-releasing hormone (GnRH-null mice which are deficient in circulating gonadotrophins. Adult Leydig cell differentiation was assessed by measuring expression of mRNA species encoding four specific markers of adult Leydig cell differentiation in the mouse. Each of these markers (3β-hydroxysteroid dehydrogenase type VI (3βHSD VI, 17β-hydroxysteroid dehydrogenase type III (17βHSD III, prostaglandin D (PGD-synthetase and oestrogen sulphotransferase (EST is expressed only in the adult Leydig cell lineage in the normal adult animal. Real-time PCR studies showed that all four markers are expressed in adult GnRH-null mice. Localisation of 3βHSD VI and PGD-synthetase expression by in situ hybridisation confirmed that these genes are expressed in the interstitial tissue of the GnRH-null mouse. Treatment of animals with human chorionic gonadotrophin increased expression of 3βHSD VI and 17βHSD III within 12 hours further indicating that differentiated, but unstimulated cells already exist in the GnRH-null mouse. Thus, while previous studies have shown that LH is required for adult Leydig cell proliferation and activity, results from the present study show that adult Leydig cell differentiation will take place in animals deficient in LH.

Colocalization of connexin 36 and corticotropin-releasing hormone in the mouse brain

Directory of Open Access Journals (Sweden)

Ribeiro Ana C

2009-04-01

Full Text Available Abstract Background Gap junction proteins, connexins, are expressed in most endocrine and exocrine glands in the body and are at least in some glands crucial for the hormonal secretion. To what extent connexins are expressed in neurons releasing hormones or neuropeptides from or within the central nervous system is, however, unknown. Previous studies provide indirect evidence for gap junction coupling between subsets of neuropeptide-containing neurons in the paraventricular nucleus (PVN of the hypothalamus. Here we employ double labeling and retrograde tracing methods to investigate to what extent neuroendocrine and neuropeptide-containing neurons of the hypothalamus and brainstem express the neuronal gap junction protein connexin 36. Results Western blot analysis showed that connexin 36 is expressed in the PVN. In bacterial artificial chromosome transgenic mice, which specifically express the reporter gene Enhanced Green Fluorescent Protein (EGFP under the control of the connexin 36 gene promoter, EGFP expression was detected in magnocellular (neuroendocrine and in parvocellular neurons of the PVN. Although no EGFP/connexin36 expression was seen in neurons containing oxytocin or vasopressin, EGFP/connexin36 was found in subsets of PVN neurons containing corticotropin-releasing hormone (CRH, and in somatostatin neurons located along the third ventricle. Moreover, CRH neurons in brainstem areas, including the lateral parabrachial nucleus, also expressed EGFP/connexin 36. Conclusion Our data indicate that connexin 36 is expressed in subsets of neuroendocrine and CRH neurons in specific nuclei of the hypothalamus and brainstem.

Use of the gonadotrophin-releasing hormone antagonist azaline B to control the oestrous cycle in the koala (Phascolarctos cinereus).

Science.gov (United States)

Ballantyne, K; Anderson, S T; Pyne, M; Nicolson, V; Mucci, A; Lisle, A; Johnston, S D

2015-05-01

The present study examined the effectiveness of the gonadotrophin-releasing hormone (GnRH) antagonist azaline B to suppress plasma LH and 17β-oestradiol concentrations in koalas and its potential application for oestrous synchronisation. In Experiment 1, single subcutaneous injections of azaline B successfully blocked the LH response to exogenous mammalian (m) GnRH in a dose-dependent manner; specifically, 0 mg (n = 4) did not suppress the LH response, 1 mg azaline B (n = 6) suppressed the LH response for 24 h (P < 0.05), 3.3 mg azaline B (n = 8) suppressed the LH response significantly in all animals only for 3 h (P < 0.05), although in half the animals LH remained suppressed for up to 3 days, and 10 mg azaline B (n = 4) suppressed the LH response for 7 days (P < 0.05). In Experiment 2, daily 1 mg, s.c., injections of azaline B over a 10-day period during seasonal anoestrus (June-July; n = 6) suppressed (P < 0.01) the LH response to mGnRH consecutively over the 10-day treatment period and, 4 days after cessation of treatment, the LH response had not recovered. Experiment 3 was designed to test the efficacy of daily 1 mg, s.c., azaline B over 10 days to suppress plasma LH and 17β-oestradiol concentrations and ultimately synchronise timed return to oestrus during the breeding season. Although azaline B treatment did not suppress basal LH or 17β-oestradiol, oestrus was delayed in all treated females by 24.2 days, but with high variability (range 9-39 days). Overall, the present study demonstrates that the GnRH antagonist azaline B is able to inhibit the LH response in koalas to exogenous mGnRH and successfully delay the return to oestrus. However, although azaline B clearly disrupts folliculogenesis, it has not been able to effectively synchronise return to oestrus in the koala.

High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

Science.gov (United States)

Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D

2016-01-01

Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. DOI: http://dx.doi.org/10.7554/eLife.16246.001 PMID:27549338

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

Science.gov (United States)

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.

Presence of corticotrophin-releasing factor and/or tyrosine hydroxylase in cells of a neural brain-testicular pathway that are labelled by a transganglionic tracer.

Science.gov (United States)

James, P; Rivier, C; Lee, S

2008-02-01

Our laboratory has shown that male testosterone levels are not solely controlled by the release of hypothalamic gonadotrophin-releasing hormone and pituitary luteinising hormone, but are also regulated by a multisynaptic pathway connecting the brain and the testis that interferes with the testosterone response to gonadotrophins. This pathway, which is independent of the pituitary gland, is activated by an i.c.v. injection of either the stress-related peptide corticotrophin-releasing factor (CRF) or of beta-adrenoceptor agonists, both of which alter androgen release and decrease levels of the peripheral-type benzodiazepine receptor and the steroidogenic acute regulatory protein within Leydig cells. Our original studies used the retrograde transganglionic tracer pseudorabies virus (PRV) to map progression of the virus from the testes to upper brain levels. The present study aimed to extend this work by identifying the regions where CRF and catecholamine neurones represented components of the stress-activated, brain-testicular pathway that prevents testosterone increases. To this end, anaesthetised adult male rats received an intra-testicular injection of PRV. Using immunofluorescence, we identified co-labelling of PRV and either CRF or tyrosine hydroxylase (TH), the enzyme responsible for biogenic amine synthesis. Co-labelling of PRV and CRF was found in the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus (PVN) and the central amygdala. Co-labelling of PRV and TH was found in the PVN, substantia nigra, A7/Kölliker-Fuse area, area of A5, locus coeruleus, nucleus of solitary tract, area of C3, area of C2 and the area of C1/A1. These results indicate that most cell groups of the ventral noradrenergic pathway have neurones that are a part of the brain-testicular pathway. This suggests that the stress hormones CRF and catecholamines may act as neurotransmitters that signal the pathway to inhibit increases in plasma testosterone levels.

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

Science.gov (United States)

Witkin, J W

1987-01-01

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

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

Directory of Open Access Journals (Sweden)

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.

Progesterone treatment inhibits and dihydrotestosterone (DHT) treatment potentiates voltage-gated calcium currents in gonadotropin-releasing hormone (GnRH) neurons.

Science.gov (United States)

Sun, Jianli; Moenter, Suzanne M

2010-11-01

GnRH neurons are central regulators of fertility, and their activity is modulated by steroid feedback. In normal females, GnRH secretion is regulated by estradiol and progesterone (P). Excess androgens present in hyperandrogenemic fertility disorders may disrupt communication of negative feedback signals from P and/or independently stimulate GnRH release. Voltage-gated calcium channels (VGCCs) are important in regulating excitability and hormone release. Estradiol alters VGCCs in a time-of-day-dependent manner. To further elucidate ovarian steroid modulation of GnRH neuron VGCCs, we studied the effects of dihydrotestosterone (DHT) and P. Adult mice were ovariectomized (OVX) or OVX and treated with implants containing DHT (OVXD), estradiol (OVXE), estradiol and DHT (OVXED), estradiol and P (OVXEP), or estradiol, DHT, and P (OVXEDP). Macroscopic calcium current (I(Ca)) was recorded in the morning or afternoon 8-12 d after surgery using whole-cell voltage-clamp. I(Ca) was increased in afternoon vs. morning in GnRH neurons from OVXE mice but this increase was abolished in cells from OVXEP mice. I(Ca) in cells from OVXD mice was increased regardless of time of day; there was no additional effect in OVXED mice. P reduced N-type and DHT potentiated N- and R-type VGCCs; P blocked the DHT potentiation of N-type-mediated current. These data suggest P and DHT have opposing actions on VGCCs in GnRH neurons, but in the presence of both steroids, P dominates. VGCCs are targets of ovarian steroid feedback modulation of GnRH neuron activity and, more specifically, a potential mechanism whereby androgens could activate GnRH neuronal function.

Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice

Directory of Open Access Journals (Sweden)

Xin-Yuan Cao

2018-01-01

Full Text Available Triclosan (TCS, a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH, follicle-stimulating hormone (FSH and progesterone, and gonadotrophin-releasing hormone (GnRH mRNA with the lack of LH surge and elevation of prolactin (PRL. TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV and arcuate nucleus (ARC. Moreover, the estrogen (E2-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3 and thyroxine (T4 in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH and thyroid releasing hormone (TRH. In TCS mice, the treatment with Levothyroxine (L-T4 corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (≥10 mg/kg reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function.

Gonadotrophins for ovulation induction in women with polycystic ovarian syndrome

NARCIS (Netherlands)

Weiss, Nienke S.; Nahuis, Marleen; Bayram, Neriman; Mol, Ben Willem J.; van der Veen, Fulco; van Wely, Madelon

2015-01-01

Ovulation induction with follicle stimulating hormone (FSH) is the second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate (CC). To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation

Estimation of the specific activity of radioiodinated gonadotrophins: comparison of three methods

Energy Technology Data Exchange (ETDEWEB)

Englebienne, P [Centre for Research and Diagnosis in Endocrinology, Kain (Belgium); Slegers, G [Akademisch Ziekenhuis, Ghent (Belgium). Lab. voor Analytische Chemie

1983-01-14

The authors compared 3 methods for estimating the specific activity of radioiodinated gonadotrophins. Two of the methods (column recovery and isotopic dilution) gave similar results, while the third (autodisplacement) gave significantly higher estimations. In the autodisplacement method, B/T ratios, obtained when either labelled hormone alone, or labelled and unlabelled hormone, are added to the antibody, were compared as estimates of the mass of hormone iodinated. It is likely that immunologically unreactive impurities present in the labelled hormone solution invalidate such comparison.

Ovulation following gonadotrophin treatment and determination of serum estradiol and progesterone by radioimmunoassay

International Nuclear Information System (INIS)

Vesper, B.; Lisse, K.; Ittrich, G.

1979-01-01

The use of gonadotrophins to release ovulation is indicated in women with urgent desire for children and with negative response to clomiphene therapy. 69 patients treated with 100 therapeutic gonadotrophin series were examined. Estrogens and progesterone were determined by radioimmunoassay. The treatment resulted in ovulation in 54 women, 12 patients developed an ovarian reaction with an increase of estrogen, and in 34 cases no ovarian response was detectable. 6 women became pregnant during gonadotrophin therapy and further 2 after treatment

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

Luteinizing hormone/chorionic gonadotrophin receptor overexpressed in granulosa cells from polycystic ovary syndrome ovaries is functionally active.

Science.gov (United States)

Kanamarlapudi, Venkateswarlu; Gordon, Uma D; López Bernal, Andrés

2016-06-01

Polycystic ovarian syndrome (PCOS) is associated with anovulatory infertility. Luteinizing hormone/chorionic gonadotrophin receptor (LHCGR), which is critical for ovulation, has been suggested to be expressed prematurely in the ovarian follicles of women with PCOS. This study aimed to analyse the expression and activity of LHCGR in ovarian granulosa cells from PCOS patients and the involvement of ARF6 small GTPase in LHCGR internalization. Granulosa cells (GC) isolated from follicular fluid collected during oocyte retrieval from normal women (n = 19) and women with PCOS (n = 17) were used to study differences in LHCGR protein expression and activity between normal and PCOS patients. LHCGR expression is up-regulated in GC from PCOS women. LHCGR in PCOS GC is functionally active, as shown by increased cAMP production upon human gonadotrophin (HCG)-stimulation. Moreover, ARF6 is highly expressed in GC from PCOS patients and HCG-stimulation increases the concentrations of active ARF6. The inhibition of ARF6 activation attenuates HCG-induced LHCGR internalization in both normal and PCOS GC, indicating that there are no alterations in LHCGR internalisation in GC from PCOS. In conclusion, the expression and activation of LHCGR and ARF6 are up-regulated in GC from PCOS women but the mechanism of agonist-induced LHCGR internalization is unaltered. Copyright © 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Safety Extension Study Of Leuprolide Acetate (Lupron Depot) In The Treatment Of Central Precocious Puberty

Science.gov (United States)

2014-01-08

Precocious; Leuprolide Acetate; Luteinizing Hormone (LH); Gonadotrophin-releasing Hormone Agonist (GnRHa); Tanner Staging; Depot Formulation; Suppression of LH; Central Precocious Puberty (CPP); Gonadotrophin-releasing Hormone (GnRH); Lupron; GnRH Analog; Pediatrics Central Precocious Puberty

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

Science.gov (United States)

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.

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

International Nuclear Information System (INIS)

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

1985-01-01

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

Isolation and characterisation of mRNA encoding the salmon- and chicken-II type gonadotrophin-releasing hormones in the teleost fish Rutilus rutilus (Cyprinidae).

Science.gov (United States)

Penlington, M C; Williams, M A; Sumpter, J P; Rand-Weaver, M; Hoole, D; Arme, C

1997-12-01

The complementary DNAs (cDNA) encoding the [Trp7,Leu8]-gonadotrophin-releasing hormone (salmon-type GnRH; sGnRH:GeneBank accession no. u60667) and the [His5,Trp7,Tyr8]-GnRH (chicken-II-type GnRH; cGnRH-II: GeneBank accession no. u60668) precursor in the roach (Rutilus rutilus) were isolated and sequenced following reverse transcription and rapid amplification of cDNA ends (RACE). The sGnRH and cGnRH-II precursor cDNAs consisted of 439 and 628 bp, and included open reading frames of 282 and 255 bp respectively. The structures of the encoded peptides were the same as GnRHs previously identified in other vertebrates. The sGnRH and cGnRH-II precursor cDNAs, including the non-coding regions, had 88.6 and 79.9% identity respectively, to those identified in goldfish (Carassius auratus). However, significant similarity was not observed between the non-coding regions of the GnRH cDNAs of Cyprinidae and other fish. The presumed third exon, encoding partial sGnRH associated peptide (GAP) of roach, demonstrated significant nucleotide and amino acid similarity with the appropriate regions in the goldfish, but not with other species, and this may indicate functional differences of GAP between different families of fish. cGnRH-II precursor cDNAs from roach had relatively high nucleotide similarity across this GnRH variant. Cladistic analysis classified the sGnRH and cGnRH-II precursor cDNAs into three and two groups respectively. However, the divergence between nucleotide sequences within the sGnRH variant was greater than those encoding the cGnRH-II precursors. Consistent with the consensus developed from previous studies, Northern blot analysis demonstrated that expression of sGnRH and cGnRH-II was restricted to the olfactory bulbs and midbrain of roach respectively. This work forms the basis for further study on the mechanisms by which the tapeworm, Ligula intestinalis, interacts with the pituitary-gonadal axis of its fish host.

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

Science.gov (United States)

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

2014-01-01

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

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

Directory of Open Access Journals (Sweden)

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.

GnRH Neuron Activity and Pituitary Response in Estradiol-Induced vs Proestrous Luteinizing Hormone Surges in Female Mice.

Science.gov (United States)

Silveira, Marina A; Burger, Laura L; DeFazio, R Anthony; Wagenmaker, Elizabeth R; Moenter, Suzanne M

2017-02-01

During the female reproductive cycle, estradiol exerts negative and positive feedback at both the central level to alter gonadotropin-releasing hormone (GnRH) release and at the pituitary to affect response to GnRH. Many studies of the neurobiologic mechanisms underlying estradiol feedback have been done on ovariectomized, estradiol-replaced (OVX+E) mice. In this model, GnRH neuron activity depends on estradiol and time of day, increasing in estradiol-treated mice in the late afternoon, coincident with a daily luteinizing hormone (LH) surge. Amplitude of this surge appears lower than in proestrous mice, perhaps because other ovarian factors are not replaced. We hypothesized GnRH neuron activity is greater during the proestrous-preovulatory surge than the estradiol-induced surge. GnRH neuron activity was monitored by extracellular recordings from fluorescently tagged GnRH neurons in brain slices in the late afternoon from diestrous, proestrous, and OVX+E mice. Mean GnRH neuron firing rate was low on diestrus; firing rate was similarly increased in proestrous and OVX+E mice. Bursts of action potentials have been associated with hormone release in neuroendocrine systems. Examination of the patterning of action potentials revealed a shift toward longer burst duration in proestrous mice, whereas intervals between spikes were shorter in OVX+E mice. LH response to an early afternoon injection of GnRH was greater in proestrous than diestrous or OVX+E mice. These observations suggest the lower LH surge amplitude observed in the OVX+E model is likely not attributable to altered mean GnRH neuron activity, but because of reduced pituitary sensitivity, subtle shifts in action potential pattern, and/or excitation-secretion coupling in GnRH neurons. Copyright © 2017 by the Endocrine Society.

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

Visualization of oxytocin release that mediates paired pulse facilitation in hypothalamic pathways to brainstem autonomic neurons.

Directory of Open Access Journals (Sweden)

Ramón A Piñol

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

The effect of the intracervical application of follicle-stimulating hormone or luteinizing hormone on the pattern of expression of gonadotrophin receptors in the cervix of non-pregnant ewes.

Science.gov (United States)

Leethongdee, S; Khalid, M; Scaramuzzi, R J

2014-08-01

During the periovulatory period, the cervix relaxes in response to changes in circulating concentrations of reproductive hormones. The present study investigated the role of gonadotrophins in cervical function by examining the expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) and their mRNAs following intracervical treatment with either FSH or LH. Eighteen ewes were assigned to four groups, and they were then treated with progestagen sponges and PMSG to synchronize their oestrous cycles. Intracervical treatments were given 24 h after sponge removal as follows: Group 1: FSH 2 mg; Group 2: LH 2 mg; Group 3: Vehicle and Group 4: Control. Cervices were collected 54 h after sponge removal and then divided into three regions. The expression of FSHR and LHR was determined by immunohistochemistry and FSHR mRNA and LH mRNA by in situ hybridization. The expression of LHR, FSHR and their respective mRNAs was compared in six tissue layers (luminal epithelium, subepithelial stroma, circular, longitudinal and transverse muscle and serosa) and in three cervical regions (vaginal, mid and uterine). The results showed that FSH increased transcription of the FSHR gene and the levels of its receptor, but only in subepithelial stroma of the cervix. FSH also increased the levels of LHR in the cervix, but only in the muscle layers. LH had no effect on the levels of FSHR despite the fact that it did increase the level of transcription of the FSHR gene and LH also increased the levels of its own receptor in the cervix, but only in the muscle layers, and this action was independent of increased levels of transcription of the LHR gene. These findings suggest multiple levels of regulation of cervical LH and FSH receptors and that the gonadotrophins may have a role in relaxation of the cervix during oestrus by regulating their own receptors. © 2014 Blackwell Verlag GmbH.

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.

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

International Nuclear Information System (INIS)

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

1985-01-01

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

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

Science.gov (United States)

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

2014-08-01

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

Lateral hypothalamic thyrotropin-releasing hormone neurons: distribution and relationship to histochemically defined cell populations in the rat.

Science.gov (United States)

Horjales-Araujo, E; Hellysaz, A; Broberger, C

2014-09-26

The lateral hypothalamic area (LHA) constitutes a large component of the hypothalamus, and has been implicated in several aspects of motivated behavior. The LHA is of particular relevance to behavioral state control and the maintenance of arousal. Due to the cellular heterogeneity of this region, however, only some subpopulations of LHA cells have been properly anatomically characterized. Here, we have focused on cells expressing thyrotropin-releasing hormone (TRH), a peptide found in the LHA that has been implicated as a promoter of arousal. Immunofluorescence and in situ hybridization were used to map the LHA TRH population in the rat, and cells were observed to form a large ventral cluster that extended throughout almost the entire rostro-caudal axis of the hypothalamus. Almost no examples of coexistence were seen when sections were double-stained for TRH and markers of other LHA populations, including the peptides hypocretin/orexin, melanin-concentrating hormone and neurotensin. In the juxtaparaventricular area, however, a discrete group of TRH-immunoreactive cells were also stained with antisera against enkephalin and urocortin 3. Innervation from the metabolically sensitive hypothalamic arcuate nucleus was investigated by double-staining for peptide markers of the two centrally projecting groups of arcuate neurons, agouti gene-related peptide and α-melanocyte-stimulating hormone, respectively; both populations of terminals were observed forming close appositions on TRH cells in the LHA. The present study indicates that TRH-expressing cells form a unique population in the LHA that may serve as a link between metabolic signals and the generation of arousal. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

1987-03-01

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

Characterisation of monoclonal antibodies for human luteinising hormone, and mapping of antigenic determinants on the hormone

International Nuclear Information System (INIS)

Soos, M.; Siddle, K.

1983-01-01

Twelve mouse monoclonal antibodies for human luteinising hormone were produced. The affinities varied from 4 X 10 7 to 1 X 10 10 l/mol. The specificity of each antibody was assessed by determining the relative reactivities with luteinising hormone, thyroid stimulating hormone, follicle stimulating hormone and chorionic gonadotrophin. Six antibodies bound to the α-subunit as shown by similar reactivity with all hormones, and the remainder to the β-subunit as shown by specificity for luteinising hormone. This latter group of antibodies cross-reacted only weakly with thyroid stimulating hormone (approximately 10%) and follicle stimulating hormone (approximately 3%). Three of these antibodies also showed low reactivity towards chorionic gonadotrophin (<10%), though the others did not (80-300%). The ability of different antibodies to bind simultaneously to luteinising hormone was examined and it was shown that several distinct antigenic determinants existed on both subunits. The characterisation of monoclonal binding sites is discussed in relation to the use of antibodies in two-site immunoradiometric assays. (Auth.)

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

Directory of Open Access Journals (Sweden)

Kazuyoshi eTsutsui

2013-04-01

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

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

Science.gov (United States)

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

1976-06-01

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

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

GHRELIN ACTIVATES HYPOPHYSIOTROPIC CORTICOTROPIN-RELEASING FACTOR NEURONS INDEPENDENTLY OF THE ARCUATE NUCLEUS

Science.gov (United States)

Cabral, Agustina; Portiansky, Enrique; Sánchez-Jaramillo, Edith; Zigman, Jeffrey M.; Perello, Mario

2016-01-01

Previous work has established that the hormone ghrelin engages the hypothalamic-pituitary-adrenal neuroendocrine axis via activation of corticotropin-releasing factor (CRF) neurons of the hypothalamic paraventricular nucleus (PVN). The neuronal circuitry that mediates this effect of ghrelin is currently unknown. Here, we show that ghrelin-induced activation of PVN CRF neurons involved inhibition of γ-aminobutyric acid (GABA) inputs, likely via ghrelin binding sites that were localized at GABAergic terminals within the PVN. While ghrelin activated PVN CRF neurons in the presence of neuropeptide Y (NPY) receptor antagonists or in arcuate nucleus (ARC)-ablated mice, it failed to do it so in mice with ghrelin receptor expression limited to ARC agouti gene related protein (AgRP)/NPY neurons. These data support the notion that ghrelin activates PVN CRF neurons via inhibition of local GABAergic tone, in an ARC-independent manner. Furthermore, these data suggest that the neuronal circuits mediating ghrelin’s orexigenic action vs. its role as a stress signal are anatomically dissociated. PMID:26874559

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

Science.gov (United States)

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

1992-10-01

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

Nutritional Programming of Accelerated Puberty in Heifers: Involvement of Pro-Opiomelanocortin Neurones in the Arcuate Nucleus.

Science.gov (United States)

Cardoso, R C; Alves, B R C; Sharpton, S M; Williams, G L; Amstalden, M

2015-08-01

The timing of puberty and subsequent fertility in female mammals are dependent on the integration of metabolic signals by the hypothalamus. Pro-opiomelanocortin (POMC) neurones in the arcuate nucleus (ARC) comprise a critical metabolic-sensing pathway controlling the reproductive neuroendocrine axis. α-Melanocyte-stimulating hormone (αMSH), a product of the POMC gene, has excitatory effects on gonadotrophin-releasing hormone (GnRH) neurones and fibres containing αMSH project to GnRH and kisspeptin neurones. Because kisspeptin is a potent stimulator of GnRH release, αMSH may also stimulate GnRH secretion indirectly via kisspeptin neurones. In the present work, we report studies conducted in young female cattle (heifers) aiming to determine whether increased nutrient intake during the juvenile period (4-8 months of age), a strategy previously shown to advance puberty, alters POMC and KISS1 mRNA expression, as well as αMSH close contacts on GnRH and kisspeptin neurones. In Experiment 1, POMC mRNA expression, detected by in situ hybridisation, was greater (P high-gain, HG; n = 6) compared to heifers that gained 0.5 kg/day (low-gain, LG; n = 5). The number of KISS1-expressing cells in the middle ARC was reduced (P < 0.05) in HG compared to LG heifers. In Experiment 2, double-immunofluorescence showed limited αMSH-positive close contacts on GnRH neurones, and the magnitude of these inputs was not influenced by nutritional status. Conversely, a large number of kisspeptin-immunoreactive cells in the ARC were observed in close proximity to αMSH-containing varicosities. Furthermore, HG heifers (n = 5) exhibited a greater (P < 0.05) percentage of kisspeptin neurones in direct apposition to αMSH fibres and an increased (P < 0.05) number of αMSH close contacts per kisspeptin cell compared to LG heifers (n = 6). These results indicate that the POMC-kisspeptin pathway may be important in mediating the nutritional acceleration of puberty in heifers. �

Gastrointestinal hormones and their targets

DEFF Research Database (Denmark)

Rehfeld, Jens F.

2014-01-01

Gastrointestinal hormones are peptides released from endocrine cells and neurons in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gastrointestinal tract, which makes the gut the largest hormone producing organ in the body. Modern biology makes...... it feasible to conceive the hormones under five headings: The structural homology groups a majority of the hormones into nine families, each of which is assumed to originate from one ancestral gene. The individual hormone gene often has multiple phenotypes due to alternative splicing, tandem organization......, or differentiated maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gut. Gut hormone genes are also widely expressed in cells outside the gut, some only in extraintestinal endocrine cells and neurons but others also in other...

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

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

Directory of Open Access Journals (Sweden)

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.

Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles

DEFF Research Database (Denmark)

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

2013-01-01

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

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.

Male hormonal contraception: concept proven, product in sight?

Science.gov (United States)

Matthiesson, Kati L; McLachlan, Robert I

2006-01-01

Current male hormonal contraceptive (MHC) regimens act at various levels within the hypothalamic pituitary testicular axis, principally to induce the withdrawal of the pituitary gonadotrophins and in turn intratesticular androgen production and spermatogenesis. Azoospermia or severe oligozoospermia result from the inhibition of spermatogonial maturation and sperm release (spermiation). All regimens include an androgen to maintain virilization, while in many the suppression of gonadotrophins/spermatogenesis is augmented by the addition of another anti-gonadotrophic agent (progestin, GnRH antagonist). The suppression of sperm concentration to 1 x 10(6)/ml appears to provide comparable contraceptive efficacy to female hormonal methods, but the confidence intervals around these estimates remain relatively large, reflecting the limited number of exposure years reported. Also, inconsistencies in the rapidity and depth of spermatogenic suppression, potential for secondary escape of sperm into the ejaculate and onset of fertility return not readily explainable by analysis of subject serum hormone levels, germ cell number or intratesticular steroidogenesis, are apparent. As such, a better understanding of the endocrine and genetic regulation of spermatogenesis is necessary and may allow for new treatment paradigms. The development of an effective, consumer-friendly male contraceptive remains challenging, as it requires strong translational cooperation not only between basic scientists and clinicians but also between public and private sectors. At present, a prototype MHC product using a long-acting injectable testosterone and depot progestin is well advanced.

Hormonal characteristics of free-ranging female lions (Panthera leo) of the Serengeti Plains and Ngorongoro Crater.

Science.gov (United States)

Brown, J L; Bush, M; Packer, C; Pusey, A E; Monfort, S L; O'Brien, S J; Janssen, D L; Wildt, D E

1993-01-01

Pituitary responses to gonadotrophin-releasing hormone (GnRH) and prolactin and steroid secretory profiles were examined in two populations of adult, female lions in the Serengeti (one outbred in the Serengeti Plains and one inbred in the Ngorongoro Crater) to determine whether reductions in genetic variability adversely affected endocrine function. GnRH-induced gonadotrophin secretion was also examined after adrenocorticotrophic hormone (ACTH) treatment to determine whether acute increases in serum cortisol altered pituitary function. Anaesthetized lions were administered (i) saline i.v. after 10 and 100 min of blood sampling, (ii) saline at 10 min and GnRH (1 micrograms kg-1 body weight) after 100 min; or (iii) ACTH (3 micrograms kg-1) at 10 min and GnRH after 100 min of sampling. Basal serum cortisol and basal and GnRH-induced gonadotrophin secretion were similar (P > 0.05) between females of the Ngorongoro Crater and Serengeti Plains. After ACTH, serum cortisol increased two- to threefold over baseline values and the response was unaffected (P > 0.05) by location. ACTH-induced increases in serum cortisol had no effect on subsequent basal or GnRH-stimulated luteinizing hormone (LH) or follicle-stimulating hormone (FSH) secretion. Overall mean serum progesterone concentrations ranged from 0.2 to 5.4 ng ml-1 with the exception of four females (two in the Serengeti and two in the Crater; progesterone range, 18.4-46.5 ng ml-1) that were presumed pregnant (three of these females were observed nursing cubs several weeks later).(ABSTRACT TRUNCATED AT 250 WORDS)

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

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.

Penggunaan Follicle Stimulating Hormone dan Pregnant Mare Serum Gonadotrophin untuk Superovulasi pada Sapi Persilangan Brahman

Directory of Open Access Journals (Sweden)

Adrian

2009-12-01

Full Text Available Twenty cattle were used in this experiment to determine the effect of administration follicle stimulating hormone (FSH and pregnant mare serum gonadotrophin (PMSG hormones on superovulation of Brahman cross cattle. The experiment was designed into completely randomized design with 5 treatments as follows. Treatments 1 (T1: 4 mg of FSH was injected twice a day intra-ovary, T2: 8 mg of FSH was injected twice a day intra-ovary, T3: 300 IU of PMSG was injected single dose intra-ovary, T4: 600 IU of PMSG was injected single dose intra-ovary, T5: 40 mg of FSH was injected intramuscular. All experimental cattle were oestrus synchronized using 15 mg of PGF2α twice at 11-days intervals. Number of corpus luteum (CL was detected by rectal palpation at day-7 after artificial insemination. Results showed that 19 cattle (95% indicated oestrus sign. Eleven cattle (57.9% showed oestrus sign 2 days after PGF2α injection and the rest 8 cattle (42.1% oestrus sign was detected at 3 days after PGF2α injection. FSH and PMSG treatments increased significantly (P<0.05 number of CL. The highest CL number was found in T5, meanwhile number of CL in T2 and T4 were higher compared to T1 and T3. The average treatment effect could produce 6.8±5.42 CL with range 2–26 CL. On the other hand single dose treatment of 600 IU PMSG (T4 showed high significant number of non ovulatory (persistent follicle compared to other treatments (T1, T2, T3 and T5 on average number of persistent follicle 2.0±1.97 from 19 cattles. It is concluded that the best superovulation treatment was produced by injection 40 mg of FSH intra-musculary.

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

Directory of Open Access Journals (Sweden)

Musgrove Lois C

2001-11-01

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

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.

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.)

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

Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome

NARCIS (Netherlands)

Bordewijk, Esmee M.; Nahuis, Marleen; Costello, Michael F.; van der Veen, Fulco; Tso, Leopoldo O.; Mol, Ben Willem J.; van Wely, Madelon

2017-01-01

Clomiphene citrate (CC) is generally considered first-line treatment in women with anovulation due to polycystic ovary syndrome (PCOS). Ovulation induction with follicle-stimulating hormone (FSH; gonadotrophins) is second-line treatment for women who do not ovulate or conceive while taking CC.

Fracture risk in Danish men with prostate cancer

DEFF Research Database (Denmark)

Abrahamsen, Bo; Nielsen, Morten F; Eskildsen, Peter Claes

2007-01-01

To assess the risk of fracture attributable to prostate cancer, and the impact of exposure to prescribed gonadotrophin-releasing hormone agonists and antiandrogens on this risk in a nationwide, population-based case-control study.......To assess the risk of fracture attributable to prostate cancer, and the impact of exposure to prescribed gonadotrophin-releasing hormone agonists and antiandrogens on this risk in a nationwide, population-based case-control study....

Ablation of neurons expressing melanin-concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling.

Science.gov (United States)

Whiddon, Benjamin B; Palmiter, Richard D

2013-01-30

Melanin-concentrating hormone (MCH)-expressing neurons have been ascribed many roles based on studies of MCH-deficient mice. However, MCH neurons express other neurotransmitters, including GABA, nesfatin, and cocaine-amphetamine-regulated transcript. The importance of these other signaling molecules made by MCH neurons remains incompletely characterized. To determine the roles of MCH neurons in vivo, we targeted expression of the human diphtheria toxin receptor (DTR) to the gene for MCH (Pmch). Within 2 weeks of diphtheria toxin injection, heterozygous Pmch(DTR/+) mice lost 98% of their MCH neurons. These mice became lean but ate normally and were hyperactive, especially during a fast. They also responded abnormally to psychostimulants. For these phenotypes, ablation of MCH neurons recapitulated knock-out of MCH, so MCH appears to be the critical neuromodulator released by these neurons. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared with MCH-deficient mutant mice and wild-type mice. We conclude that MCH neurons regulate glucose tolerance through signaling molecules other than MCH.

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

Science.gov (United States)

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

1986-01-01

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

Peptide Hormones in the Gastrointestinal Tract

DEFF Research Database (Denmark)

Rehfeld, Jens F.

2015-01-01

Gastrointestinal hormones are peptides released from endocrine cells and neurons in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gastrointestinal tract, which makes the gut the largest hormone-producing organ in the body. Modern biology makes it feasi...

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

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...

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

Science.gov (United States)

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.

Thyroid Hormone in the CNS: Contribution of Neuron-Glia Interaction.

Science.gov (United States)

Noda, Mami

2018-01-01

The endocrine system and the central nervous system (CNS) are intimately linked. Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and neuroglia and hence for development and function of the CNS. T3 (3,3',5-triiodothyronine), an active form of TH, is important not only for neuronal development but also for differentiation of astrocytes and oligodendrocytes, and for microglial development. In adult brain, T3 affects glial morphology with sex- and age-dependent manner and therefore may affect their function, leading to influence on neuron-glia interaction. T3 is an important signaling factor that affects microglial functions such as migration and phagocytosis via complex mechanisms. Therefore, dysfunction of THs may impair glial function as well as neuronal function and thus disturb the brain, which may cause mental disorders. Investigations on molecular and cellular basis of hyperthyroidism and hypothyroidism will help us to understand changes in neuron-glia interaction and therefore consequent psychiatric symptoms. © 2018 Elsevier Inc. All rights reserved.

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.

Plasticity in neurons synthesizing wake/arousal promoting hormone hypocretin/orexin.

Science.gov (United States)

Gao, Xiao-Bing

2012-01-01

The hypothalamus is a critical brain structure regulating physiological functions essential to the survival of individuals and species. One of the striking characteristics of this brain region is the abundance of nerve cells (neurons) expressing a great numbers of neurotransmitters and neuromodulators, among which are hormones released into the blood stream through brain neuroendocrinological routes. The neurons in the lateral hypothalamus take part in intra- and extrahypothalamic circuits controlling basic physiological functions essential for the well being of animal bodies (such as cardiovascular function, respiratory function, immune responses, etc.), animal behaviors required for the maintenance of the survival of individuals (food foraging, flight, fight, etc.) and species (reproductive function), and higher brain functions (learning and memory, mental state, etc.). Hypocretin (also called orexin) comprises of two neuropeptides exclusively synthesized by neurons in the perifornical/lateral hypothalamus. Although hypocretin/orexin was initially found to enhance food intake, it is now clear that the functions mediated by hypocretin/orexin are well beyond what were originally proposed. Specifically, hypocretin/orexin is a crucial promoter of wakefulness; deficiency in the hypocretin/orexin system leads to diseases and disorders such as narcolepsy. It is clear that neurons synthesizing hypocretin/orexin are consistently under regulation originating from various parts of the brain and that the status of activity in hypocretin/orexin neurons is closely related with the nutritional and behavioral state of animals. Therefore, the demand to make adaptive changes in hypocretin/orexin neurons to accommodate the changes in the external environment and behavioral state of animals is expected. The latest developments in the studies of plasticity in hypocretin/orexin neurons under the challenges from environmental and behavioral factors have dramatically shaped the

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

Science.gov (United States)

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.

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.

Cocaine- and amphetamine-regulated transcript is present in hypothalamic neuroendocrine neurones and is released to the hypothalamic-pituitary portal circuit

DEFF Research Database (Denmark)

Larsen, P J; Seier, V; Fink-Jensen, A

2003-01-01

Cocaine- and amphetamine-regulated transcript (CART) is present in a number of hypothalamic nuclei. Besides actions in circuits regulating feeding behaviour and stress responses, the hypothalamic functions of CART are largely unknown. We report that CART immunoreactivity is present in hypothalami......, supraoptic, paraventricular (PVN) and periventricular nuclei of the hypothalamus. In the PVN, CART-positive neuroendocrine neurones were found in all of cytoarchitectonically identified nuclei. In the periventricular nucleus, approximately one-third of somatostatin cells were also CART......-immunoreactive. In the medial parvicellular subnucleus of the PVN, CART and FG coexisted with thyrotrophin-releasing hormone, whereas very few of the corticotrophin-releasing hormone containing cells were CART-immunoreactive. In the arcuate nucleus, CART was extensively colocalized with pro...

Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells.

Science.gov (United States)

Merkle, Florian T; Maroof, Asif; Wataya, Takafumi; Sasai, Yoshiki; Studer, Lorenz; Eggan, Kevin; Schier, Alexander F

2015-02-15

Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a 'self-patterning' strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases. © 2015. Published by The Company of Biologists Ltd.

Cocaine- and amphetamine-regulated transcript is present in hypothalamic neuroendocrine neurones and is released to the hypothalamic-pituitary portal circuit.

Science.gov (United States)

Larsen, P J; Seier, V; Fink-Jensen, A; Holst, J J; Warberg, J; Vrang, N

2003-03-01

Cocaine- and amphetamine-regulated transcript (CART) is present in a number of hypothalamic nuclei. Besides actions in circuits regulating feeding behaviour and stress responses, the hypothalamic functions of CART are largely unknown. We report that CART immunoreactivity is present in hypothalamic neuroendocrine neurones. Adult male rats received a systemic injection of the neuronal tracer Fluorogold (FG) 2 days before fixation, and subsequent double- and triple-labelling immunoflourescence analysis demonstrated that neuroendocrine CART-containing neurones were present in the anteroventral periventricular, supraoptic, paraventricular (PVN) and periventricular nuclei of the hypothalamus. In the PVN, CART-positive neuroendocrine neurones were found in all of cytoarchitectonically identified nuclei. In the periventricular nucleus, approximately one-third of somatostatin cells were also CART-immunoreactive. In the medial parvicellular subnucleus of the PVN, CART and FG coexisted with thyrotrophin-releasing hormone, whereas very few of the corticotrophin-releasing hormone containing cells were CART-immunoreactive. In the arcuate nucleus, CART was extensively colocalized with pro-opiomelanocortin in the ventrolateral part, but completely absent from neuroendocrine neurones of the dorsomedial part. To assess the possible role of CART as a hypothalamic-releasing factor, immunoreactive CART was measured in blood samples from the long portal vessels connecting the median eminence with the anterior pituitary gland. Adult male rats were anaesthetized and the infundibular stalk exposed via a transpharyngeal approach. The long portal vessels were transected and blood collected in 30-min periods (one prestimulatory and three poststimulatory periods). Compared to systemic venous plasma samples, baseline concentrations of immunoreactive CART were elevated in portal plasma. Exposure to sodium nitroprusside hypotension triggered a two-fold elevation of portal CART42

Pharmacoeconomy in ART: The importance of the gonadotrophin choice

Directory of Open Access Journals (Sweden)

Sandro Gerli

2010-04-01

Full Text Available Assisted Reproductive Technologies (ART have created a number of relevant economic implications. Results deriving from cost-effectiveness studies have had some important medical and social consequences. The costs of ART are specific to the healthcare system in each of the countries were the procedure is performed, reflecting the varying degrees of public and private responsibility for purchasing healthcare and total healthcare expenditure. The analysis of different cost components per treatment cycle demonstrates that the hormonal stimulation stage is the most expensive part of IVF/ICSI cycles. The use of a more costly preparation could be justified only in case of a significantly higher live birth rate. Currently, human gonadotrophins seem to be more cost-effective than recombinant preparations.

Hormonal alterations in PCOS and its influence on bone metabolism.

Science.gov (United States)

Krishnan, Abhaya; Muthusami, Sridhar

2017-02-01

According to the World Health Organization (WHO) polycystic ovary syndrome (PCOS) occurs in 4-8% of women worldwide. The prevalence of PCOS in Indian adolescents is 12.2% according to the Indian Council of Medical Research (ICMR). The National Institute of Health has documented that it affects approximately 5 million women of reproductive age in the United States. Hormonal imbalance is the characteristic of many women with polycystic ovarian syndrome (PCOS). The influence of various endocrine changes in PCOS women and their relevance to bone remains to be documented. Hormones, which include gonadotrophin-releasing hormone (GnRH), insulin, the leutinizing/follicle-stimulating hormone (LH/FSH) ratio, androgens, estrogens, growth hormones (GH), cortisol, parathyroid hormone (PTH) and calcitonin are disturbed in PCOS women. These hormones influence bone metabolism in human subjects directly as well as indirectly. The imbalance in these hormones results in increased prevalence of osteoporosis in PCOS women. Limited evidence suggests that the drugs taken during the treatment of PCOS increase the risk of bone fracture in PCOS patients through endocrine disruption. This review is aimed at the identification of the relationship between bone mineral density and hormonal changes in PCOS subjects and identifies potential areas to study bone-related disorders in PCOS women. © 2017 Society for Endocrinology.

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 ...

Role of GABA Release From Leptin Receptor-Expressing Neurons in Body Weight Regulation

Science.gov (United States)

Xu, Yuanzhong; O'Brien, William G.; Lee, Cheng-Chi; Myers, Martin G.

2012-01-01

It is well established that leptin regulates energy balance largely through isoform B leptin receptor-expressing neurons (LepR neurons) in the brain and that leptin activates one subset of LepR neurons (leptin-excited neurons) while inhibiting the other (leptin-inhibited neurons). However, the neurotransmitters released from LepR neurons that mediate leptin action in the brain are not well understood. Previous results demonstrate that leptin mainly acts on γ-aminobutyric acid (GABA)ergic neurons to reduce body weight, and that leptin activates proopiomelanocortin neuron activity by reducing GABA release onto these neurons, suggesting a body weight-promoting role for GABA released from leptin-inhibited neurons. To directly examine the role of GABA release from LepR neurons in body weight regulation, mice with disruption of GABA release specifically from LepR neurons were generated by deletion of vesicular GABA transporter in LepR neurons. Interestingly, these mice developed mild obesity on chow diet and were sensitive to diet-induced obesity, which were associated with higher food intake and lower energy expenditure. Moreover, these mice showed blunted responses in both food intake and body weight to acute leptin administration. These results demonstrate that GABA plays an important role in mediating leptin action. In combination with the previous studies that leptin reduces GABA release onto proopiomelanocortin neurons through leptin-inhibited neurons and that disruption of GABA release from agouti gene-related protein neurons, one subset of LepR-inhibited neurons, leads to a lean phenotype, our results suggest that, under our experimental conditions, GABA release from leptin-excited neuron dominates over leptin-inhibited ones. PMID:22334723

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

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

Science.gov (United States)

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

2015-11-01

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

Ewes carrying the Booroola and Vacaria prolificacy alleles respond differently to ovulation induction with equine chorionic gonadotrophin.

Science.gov (United States)

Moraes, J C F; Souza, C J H

2017-09-21

The magnitude of ovulation rate (OR) after hormonal induction in sheep should be considered when prolific genotypes are used. We investigated for the first time the effect of the Vacaria allele and its combined effect with the Booroola prolificacy mutation on OR after hormonal treatment during breeding and anoestrous season. A hundred forty-nine Ile de France crossbred ewes, raised in natural pastures in South Brazil, were used to evaluate the OR after treatment with progestagen (MAP) followed or not by equine chorionic gonadotrophin (eCG) treatment (MAP + eCG). During the breeding season, 96% MAP-treated ewes ovulated in comparison to 97% of MAP + eCG-treated females. The double heterozygous carriers (BNVN) presented the higher OR, followed by the single Vacaria (NNVN) and Booroola (BNNN) heterozygous females and least the wild-type (NNNN) ewes. During anoestrus, 96% eCG-treated ewes ovulated, in contrast to 6% treated with MAP alone. The OR of the gonadotrophin-treated females was higher in BNVN and BNNN than NNVN and NNNN ewes. An additive effect in the OR of the two mutations was observed since OR in double heterozygous ewes was similar to the sum of the effects of the alleles of the single heterozygous carrier ewes.

Synaptic glutamate release by postnatal rat serotonergic neurons in microculture.

Science.gov (United States)

Johnson, M D

1994-02-01

Serotonergic neurons are thought to play a role in depression and obsessive compulsive disorder. However, their functional transmitter repertoire is incompletely known. To investigate this repertoire, intracellular recordings were obtained from 132 cytochemically identified rat mesopontine serotonergic neurons that had re-established synapses in microcultures. Approximately 60% of the neurons evoked excitatory glutamatergic potentials in themselves or in target neurons. Glutamatergic transmission was frequently observed in microcultures containing a solitary serotonergic neuron. Evidence for co-release of serotonin and glutamate from single raphe neurons was also obtained. However, evidence for gamma-aminobutyric acid release by serotonergic neurons was observed in only two cases. These findings indicate that many cultured serotonergic neurons form glutamatergic synapses and may explain several observations in slices and in vivo.

Negative Effect of Zinc on Testes, Testosterone and Gonadotrophins Levels in Adult Male Wistar Rats

Directory of Open Access Journals (Sweden)

D. Sohrabi

2008-10-01

Full Text Available Background and ObjectivesThe toxic effects of zinc leading to sebaceous gland closure, skin eczema and blister have been previously demonstrated in other studies. The aim of this study is to determine the chronic effects of zinc chloride (ZnCl2 on testicular tissues, testosterone and gonadotrophins in adult male Wistar rats.Methods Twenty four Adult male Wistar rats were divided in to two groups of study and control with each group consisting of 12 rats. Study group rats received 10 mg/kg interaperitoneal Zinc chloride in normal saline (N.S every other day for 30 days. Control group rats received N.S during this time. Blood sample for hormonal evaluation were collected from hearts of these rats. The rats were destroyed and their testes were removed and fixed in a 10% formaldehyde and glutaraldehyde solution.ResultsThe results of this study showed a significant decrease in the level of LH and testosterone hormone among the rats in the study group compared to the control group with p< 0.001 and p< 0.01 respectively. Study of fine structure of testicular cells and tissues in the study group rats revealed swelling of mitochondria, increase in smooth endoplasmic reticulum vacuolization and lysosomic granules (Autophagic vacuoles in cytosol of their germinal cells.ConclusionBased on the results of this study consumption of large amount of compounds which contain zinc should be controlled and limited among men. There is a need for further studies to evaluate and determine the reversibility of most hormonal and physiological changes due to usage of zinc containing compounds.Keywords: Zinc Chloride; Testis; Testosterone; Gonadotrophins

GnRH neurons of young and aged female rhesus monkeys co-express GPER but are unaffected by long-term hormone replacement.

Science.gov (United States)

Naugle, Michelle M; Gore, Andrea C

2014-01-01

Menopause is caused by changes in the function of the hypothalamic-pituitary-gonadal axis that controls reproduction. Hypophysiotropic gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus orchestrate the activity of this axis and are regulated by hormonal feedback loops. The mechanisms by which GnRH responds to the primary regulatory sex steroid hormone, estradiol (E2), are still poorly understood in the context of menopause. Our goal was to determine whether the G protein-coupled estrogen receptor (GPER) is co-expressed in adult primate GnRH neurons and whether this changes with aging and/or E2 treatment. We used immunofluorescence double-labeling to characterize the co-expression of GPER in GnRH perikarya and terminals in the hypothalamus. Young and aged rhesus macaques were ovariectomized and given long-term (~2-year) hormone treatments (E2, E2 + progesterone, or vehicle) selected to mimic currently prescribed hormone replacement therapies used for the alleviation of menopausal symptoms in women. We found that about half of GnRH perikarya co-expressed GPER, while only about 12% of GnRH processes and terminals in the median eminence (ME) were double-labeled. Additionally, many GPER-labeled processes were in direct contact with GnRH neurons, often wrapped around the perikarya and processes and in close proximity in the ME. These results extend prior work by showing robust co-localization of GPER in GnRH in a clinically relevant model, and they support the possibility that GPER-mediated E2 regulation of GnRH occurs both in the soma and terminals in nonhuman primates.

The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release.

Science.gov (United States)

Rau, Andrew R; Hentges, Shane T

2017-08-02

Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these

Zinc release contributes to hypoglycemia-induced neuronal death.

Science.gov (United States)

Suh, Sang Won; Garnier, Philippe; Aoyama, Koji; Chen, Yongmei; Swanson, Raymond A

2004-08-01

Neurons exposed to zinc exhibit activation of poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme that normally participates in DNA repair but promotes cell death when extensively activated. Endogenous, vesicular zinc in brain is released to the extracellular space under conditions causing neuronal depolarization. Here, we used a rat model of insulin-induced hypoglycemia to assess the role of zinc release in PARP-1 activation and neuronal death after severe hypoglycemia. Zinc staining with N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) showed depletion of presynaptic vesicular zinc from hippocampal mossy fiber terminals and accumulation of weakly bound zinc in hippocampal CA1 cell bodies after severe hypoglycemia. Intracerebroventricular injection of the zinc chelator calcium ethylene-diamine tetraacetic acid (CaEDTA) blocked the zinc accumulation and significantly reduced hypoglycemia-induced neuronal death. CaEDTA also attenuated the accumulation of poly(ADP-ribose), the enzymatic product of PARP-1, in hippocampal neurons. These results suggest that zinc translocation is an intermediary step linking hypoglycemia to PARP-1 activation and neuronal death.

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

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

Autoradiographic localization of gonadotrophin receptors in ovaries of the common carp, Cyprinus carpio L

International Nuclear Information System (INIS)

Bieniarz, K.; Kime, D.E.

1986-01-01

Binding sites for carp gonadotrophin have been located in carp ovaries using [ 125 I]labeled gonadotrophin and autoradiography. The radioactive gonadotrophin was displaced from tissue by unlabeled gonadotrophin or carp hypophysial homogenate in a dose-dependent fashion. No binding of gonadotrophin was found in previtellogenic oocytes but binding appeared with the first indications of vitellogenesis. In the smaller vitellogenic oocytes binding was uniformly distributed in the follicular envelope, but in the largest oocytes binding was restricted to the interstitial tissue. In these more mature oocytes gonadotrophin was also found within the oocyte and appeared to migrate toward the nucleus. The relationship between binding location, steroidogenesis, and oocyte maturation is discussed. We found no evidence for specific binding of [ 125 I]thyroxine under comparable conditions

Ghrelin stimulates growth hormone release from the pituitary via hypothalamic growth hormone-releasing hormone neurons in the cichlid, Oreochromis niloticus

Science.gov (United States)

Ghrelin, a gastric peptide, is implicated in a multiplicity of biological functions, including energy homeostasis and reproduction. Neuronal systems that are involved in energy homeostasis as well as reproduction traverse the hypothalamus, however, the mechanism by which they control energy homeosta...

Submaximal doses of ghrelin do not inhibit gonadotrophin levels but stimulate prolactin secretion in postmenopausal women.

Science.gov (United States)

Messini, Christina I; Malandri, Maria; Anifandis, George; Dafopoulos, Konstantinos; Georgoulias, Panagiotis; Sveronis, Georgios; Garas, Antonios; Daponte, Alexandros; Messinis, Ioannis E

2017-07-01

An inhibitory effect of ghrelin on gonadotrophin secretion has been reported in normally menstruating women possibly modulated by endogenous oestrogen. The aim of this study was to examine the effect of ghrelin on gonadotrophin and prolactin (PRL) secretion in oestrogen-deprived postmenopausal women. Prospective intervention study. Ten healthy postmenopausal volunteer women were studied during two 15-days periods of oestrogen treatment (A and B) a month apart. Four experiments (Exp) were performed in total, two on day 1 (Exp 1A and Exp 1B) and two on day 15 (Exp 15A and Exp 15B) of the two periods. The women received in Exp 1A and in Exp 15A two iv injections of ghrelin (0.15 μg/kg at time 0 minute and 0.30 μg/kg at time 90 minutes) and in Exp1B and in Exp 15B normal saline (2 mL), respectively. Blood samples were taken at -15, 0, 30, 60, 90, 120, 150 and 180 minutes. After oestrogen treatment, late follicular phase serum oestradiol levels were attained on day 15 of periods A and B. Ghrelin administration did not affect serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), whereas it increased significantly those of growth hormone (GH) and PRL. In Exp 15A, serum PRL increment in response to ghrelin (area under the curve, net increment) was significantly greater than in Exp 1A (Pghrelin administration affects neither FSH nor LH levels but stimulates PRL secretion, that is amplified by exogenous oestrogen administration. © 2017 John Wiley & Sons Ltd.

Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

Science.gov (United States)

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

1989-08-01

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

[Neuronal and hormonal regulatory mechanisms of tears production and secretion].

Science.gov (United States)

Mrugacz, Małgorzata; Zywalewska, Nella; Bakunowicz-Lazarczyk, Alina

2005-01-01

The ocular surface, tear film, lacrimal glands act as a functional unit to preserve the quality of the refractive surface of the eye, and to resist injury and protect the eye against bodily and environmental conditions. Homeostasis of this functional unit involves neuronal and hormonal regulatory mechanisms. The eye appears to be a target organ for sex hormones particulary the androgen, as they modulate the immune system and trophic functions of the lacrimal and Meibomian glands.

Innervation by a GABAergic neuron depresses spontaneous release in glutamatergic neurons and unveils the clamping phenotype of synaptotagmin-1

DEFF Research Database (Denmark)

Wierda, Keimpe D B; Sørensen, Jakob Balslev

2014-01-01

The role of spontaneously occurring release events in glutamatergic and GABAergic neurons and their regulation is intensely debated. To study the interdependence of glutamatergic and GABAergic spontaneous release, we compared reciprocally connected "mixed" glutamatergic/GABAergic neuronal pairs...... from mice cultured on astrocyte islands with "homotypic" glutamatergic or GABAergic pairs and autaptic neurons. We measured mEPSC and mIPSC frequencies simultaneously from both neurons. Neuronal pairs formed both interneuronal synaptic and autaptic connections indiscriminately. We find that whereas m......EPSC and mIPSC frequencies did not deviate between autaptic and synaptic connections, the frequency of mEPSCs in mixed pairs was strongly depressed compared with either autaptic neurons or glutamatergic pairs. Simultaneous imaging of synapses, or comparison to evoked release amplitudes, showed...

Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function.

Science.gov (United States)

Zuure, Wieteke A; Roberts, Amy L; Quennell, Janette H; Anderson, Greg M

2013-11-06

The adipocyte-derived hormone leptin acts in the brain to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect, as GnRH neurons do not express leptin receptors (LEPRs). Here we test whether GABAergic or glutamatergic neurons provide the intermediate pathway between the site of leptin action and the GnRH neurons. Leptin receptors were deleted from GABA and glutamate neurons using Cre-Lox transgenics, and the downstream effects on puberty onset and reproduction were examined. Both mouse lines displayed the expected increase in body weight and region-specific loss of leptin signaling in the hypothalamus. The GABA neuron-specific LEPR knock-out females and males showed significantly delayed puberty onset. Adult fertility observations revealed that these knock-out animals have decreased fecundity. In contrast, glutamate neuron-specific LEPR knock-out mice displayed normal fertility. Assessment of the estrogenic hypothalamic-pituitary-gonadal axis regulation in females showed that leptin action on GABA neurons is not necessary for estradiol-mediated suppression of tonic luteinizing hormone secretion (an indirect measure of GnRH neuron activity) but is required for regulation of a full preovulatory-like luteinizing hormone surge. In conclusion, leptin signaling in GABAergic (but not glutamatergic neurons) plays a critical role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These results form an important step in explaining the role of central leptin signaling in the reproductive system. Limiting the leptin-to-GnRH mediators to GABAergic cells will enable future research to focus on a few specific types of neurons.

Hormonal therapy after the operation for catamenial pneumothorax - is it always necessary?

Science.gov (United States)

Subotic, D; Mikovic, Z; Atanasijadis, N; Savic, M; Moskovljevic, D; Subotic, D

2016-04-14

Our recent clinical observations put into question the routine hormonal therapy for pneumothorax recurrence prevention, in patients operated for catamenial pneumothorax (CP). Retrospective review of the treatment of four women operated for CP in a recent 32-months period. The four presented patients with CP represent 4.8 % of the overall number of patients operated for spontaneous pneumothorax and 19 % of women operated for pneumothorax in the same period. In all patients, typical multiple diaphragm holes existed. The involved part of the diaphragm was removed with diaphragm suture in three patients, whilst in one patient, a diaphragm placation was done. Endometriosis was histologically confirmed in two patients. During the follow-up period of 6-43 months, none of the patients underwent a postoperative hormonal therapy for different reasons, and in none of them the pneumothorax recurrence occurred. The clinical course of these patients, with the absence of the pneumothorax recurrence despite the omission of the hormonal treatment, suggests that the appropriateness of the routine hormonal treatment with gonadotrophin-releasing hormone analogues for 6-12 months, should be reconsidered and re-evaluated in further studies.

Mathematical modeling of gonadotropin-releasing hormone signaling.

Science.gov (United States)

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

2017-07-05

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

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

Science.gov (United States)

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

2017-10-26

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

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.

THYROID HORMONE TREATED ASTROCYTES INDUCE MATURATION OF CEREBRAL CORTICAL NEURONS THROUGH MODULATION OF PROTEOGLYCAN LEVELS

Directory of Open Access Journals (Sweden)

Romulo Sperduto Dezonne

2013-08-01

Full Text Available Proper brain neuronal circuitry formation and synapse development is dependent on specific cues, either genetic or epigenetic, provided by the surrounding neural environment. Within these signals, thyroid hormones (T3 and T4 play crucial role in several steps of brain morphogenesis including proliferation of progenitor cells, neuronal differentiation, maturation, migration, and synapse formation. The lack of thyroid hormones during childhood is associated with several impair neuronal connections, cognitive deficits, and mental disorders. Many of the thyroid hormones effects are mediated by astrocytes, although the mechanisms underlying these events are still unknown. In this work, we investigated the effect of 3, 5, 3’-triiodothyronine-treated (T3-treated astrocytes on cerebral cortex neuronal differentiation. Culture of neural progenitors from embryonic cerebral cortex mice onto T3-treated astrocyte monolayers yielded an increment in neuronal population, followed by enhancement of neuronal maturation, arborization and neurite outgrowth. In addition, real time PCR assays revealed an increase in the levels of the heparan sulfate proteoglycans, Glypican 1 (GPC-1 and Syndecans 3 e 4 (SDC-3 e SDC-4, followed by a decrease in the levels of the chondroitin sulfate proteoglycan, Versican. Disruption of glycosaminoglycan chains by chondroitinase AC or heparanase III completely abolished the effects of T3-treated astrocytes on neuronal morphogenesis. Our work provides evidence that astrocytes are key mediators of T3 actions on cerebral cortex neuronal development and identified potential molecules and pathways involved in neurite extension; which might eventually contribute to a better understanding of axonal regeneration, synapse formation and neuronal circuitry recover.

Growth hormone-releasing factor stimulates proliferation of somatotrophs in vitro

DEFF Research Database (Denmark)

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

1986-01-01

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

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

Science.gov (United States)

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

1993-09-01

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

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

Science.gov (United States)

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

1988-03-01

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

Thyroid Hormone and Blood Metabolites Concentration of Gilts Superovulated Prior to Mating

Directory of Open Access Journals (Sweden)

RA Mege

2009-05-01

Full Text Available An experiment was conducted to study injection of pregnant mare serum gonadotrophin (PMSG and human chorionic gonadotrophin (hCG as superovulation agent in gilts to improve thyroid hormone and blood metabolites concentraton. In this experiment, 48 gilts were assigned into four groups of twelve gilts injected with PMSG dan hCG dose levels of 0, 600, 1200 and 1800 IU/gilt. Injections were conducted three days before estrus. During gestation, gilts were placed in colony pigpen. On days 15, 35, and 70 of gestation blood collected to determine triiodothyronine, tetraiodothyronine, tryglicerides, glucose, protein and bood nitrogen urea concentration. The resuts showed that superovulation dose levels of 600 to 1200 IU/gilt increased concentration of thyroid hormone (triiodothyronine and tetraiodothyronine/thyroxin and blood metabolite (triglycerides, glucose, and protein, but decreased blood urea nitrogen in gestation ages 15, 35, and 70 days. It is concluded that superovulation with dose of 600 to 1200 IU can improve of gilts metabolite hormone and blood metabolites. (Animal Production 11(2: 88-95 (2009Key Words: gilts, superovulation, metabolite hormone, blood metabolites

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

Science.gov (United States)

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

2015-12-17

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

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

International Nuclear Information System (INIS)

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

1986-01-01

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

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

Directory of Open Access Journals (Sweden)

Manfred Hallschmid

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

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

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

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...

A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance.

Science.gov (United States)

Hoffmann, Hanne M; Mellon, Pamela L

2016-01-01

Fertility depends on the correct maturation and function of approximately 800 gonadotropin-releasing hormone (GnRH) neurons in the brain. GnRH neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates fertility. In adulthood, GnRH neurons are scattered throughout the anterior hypothalamic area and project to the median eminence, where GnRH is released into the portal vasculature to stimulate release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH then regulate gonadal steroidogenesis and gametogenesis. Absence of GnRH neurons or inappropriate GnRH release leads to infertility. Despite the critical role of GnRH neurons in fertility, we still have a limited understanding of the genes responsible for proper GnRH neuron development and function in adulthood. GnRH neurons originate in the olfactory placode then migrate into the brain. Homeodomain transcription factors expressed within GnRH neurons or along their migratory path are candidate genes for inherited infertility. Using a combined in vitro and in vivo approach, we have identified Ventral Anterior Homeobox 1 ( Vax1 ) as a novel homeodomain transcription factor responsible for GnRH neuron maturation and fertility. GnRH neuron counts in Vax1 knock-out embryos revealed Vax1 to be required for the presence of GnRH-expressing cells at embryonic day 17.5 (E17.5), but not at E13.5. To localize the effects of Vax1 on fertility, we generated Vax1 flox mice and crossed them with Gnrh cre mice to specifically delete Vax1 within GnRH neurons. GnRH staining in Vax1 flox/flox :GnRH cre mice show a total absence of GnRH expression in the adult. We performed lineage tracing in Vax1 flox/flox :GnRH cre :RosaLacZ mice which proved GnRH neurons to be alive, but incapable of expressing GnRH. The absence of GnRH leads to delayed puberty, hypogonadism and complete infertility in both sexes. Finally, using the immortalized model GnRH neuron cell lines, GN11 and

Sensitive and specific markers for insulin resistance, hyperandrogenemia, and inappropriate gonadotrophin secretion in women with polycystic ovary syndrome: a case-control study from Bahrain

Directory of Open Access Journals (Sweden)

Al-Ayadhi MA

2012-05-01

Full Text Available Jamal Golbahar,1,2,* Maha Al-Ayadhi,2,* Negalla Mohan Das,2 Khalid Gumaa,2 1Department of Molecular Medicine, Al-Jawhara Centre for Genetic Diagnosis and Research, 2Department of Medical Biochemistry, College of Medicine and Medical Sciences, AGU, Manama, Bahrain *These authors contributed equally to this articleBackground: In women with polycystic ovary syndrome (PCOS, despite a high prevalence of insulin resistance, hyperandrogenemia, and disturbances in the secretion of gonadotrophin, the principal causes of biochemical abnormalities and the best endocrine markers for PCOS have not been fully identified.Subjects and methods: Serum levels of insulin, glucose, follicle-stimulating hormone (FSH, luteinizing hormone (LH, total testosterone, estrogen, sex hormone-binding capacity (SHBG, and other related indices such as homeostasis model assessment, insulin glucose ratios, LH/FSH ratios, and the free androgen index (FAI were determined and compared in women with PCOS (n = 50 and women without PCOS (n = 50.Results: In multivariate logistic regression analyses, among all insulin resistance indices, only hyperinsulinemia (odds ratio [OR] = 2.6; confidence interval [CI]: 1.3–5.2; P = 0.008 was significantly and independently associated with PCOS when adjusted for body mass index (BMI, hyperandrogenemia, and LH/FSH ratios. The LH/FSH ratio (OR = 5.4; CI: 1.2–23.0, P = 0.03 was the only marker among those indices for inappropriate gonadotrophin secretion that significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. Among those indices for hyperandrogenemia, FAI (OR = 1.1; CI: 1.0–2.7; P = 0.02 and SHBG (OR = 1.2; CI: 1.2–3.4; P = 0.03 were significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. In addition, receiver operating characteristic analysis showed that the best predictive markers for PCOS were insulin (area under the curve [AUC] = 0.944; CI: 0.887–0

Use of fertility drugs and risk of ovarian cancer: Danish Population Based Cohort Study.

Science.gov (United States)

Jensen, Allan; Sharif, Heidi; Frederiksen, Kirsten; Kjaer, Susanne Krüger

2009-02-05

To examine the effects of fertility drugs on overall risk of ovarian cancer using data from a large cohort of infertile women. Population based cohort study. Danish hospitals and private fertility clinics. 54,362 women with infertility problems referred to all Danish fertility clinics during 1963-98. The median age at first evaluation of infertility was 30 years (range 16-55 years), and the median age at the end of follow-up was 47 (range 18-81) years. Included in the analysis were 156 women with invasive epithelial ovarian cancer (cases) and 1241 subcohort members identified in the cohort during follow-up in 2006. Effect of four groups of fertility drugs (gonadotrophins, clomifene citrate, human chorionic gonadotrophin, and gonadotrophin releasing hormone) on overall risk of ovarian cancer after adjustment for potential confounding factors. Analyses within cohort showed no overall increased risk of ovarian cancer after any use of gonadotrophins (rate ratio 0.83, 95% confidence interval 0.50 to 1.37), clomifene (1.14, 0.79 to 1.64), human chorionic gonadotrophin (0.89, 0.62 to 1.29), or gonadotrophin releasing hormone (0.80, 0.42 to 1.51). Furthermore, no associations were found between all four groups of fertility drugs and number of cycles of use, length of follow-up, or parity. No convincing association was found between use of fertility drugs and risk of ovarian cancer.

Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin-Releasing Hormone Analog.

Science.gov (United States)

Ohuchi, Kazuki; Funato, Michinori; Kato, Zenichiro; Seki, Junko; Kawase, Chizuru; Tamai, Yuya; Ono, Yoko; Nagahara, Yuki; Noda, Yasuhiro; Kameyama, Tsubasa; Ando, Shiori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki; Kaneko, Hideo

2016-02-01

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA-derived induced pluripotent stem cell (SMA-iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA-iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA-iPSCs. Using this model, we confirmed that treatment with the thyrotropin-releasing hormone (TRH) analog, 5-oxo-l-prolyl-l-histidyl-l-prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase-3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA-iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA-iPSC model. Significance: Platelet-derived growth factor (PDGF) has recently been reported to produce the greatest increase in survival motor neuron protein levels by inhibiting glycogen synthase kinase (GSK)-3β; however, motor neurons lack PDGF receptors. A human in vitro spinal muscular atrophy-derived induced pluripotent stem cell model was

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

Pengaruh Penambahan Chorionic Gonadotrophin pada Medium Maturasi terhadap Kemampuan Maturasi, Fertilisasi, dan Perkembangan Embrio secara In Vitro Kambing Peranakan Ettawa (The Effect of Chorionic Gonadotrophin Addition Into Maturation Medium on The Abili

Directory of Open Access Journals (Sweden)

Nurvina Septi Adifa

2012-02-01

the values of 40.8%, 11.4%, and 12.2% respectively. Based on the result it could be concluded that chorionic gonadotrophin addition into maturation medium had not increased ettawa crossbred oocytes maturation, fertilization, and in vitro cleavage rate. The best maturation, fertilization, and in vitro cleavage rate were found using maturation medium without any addition of chorionic gonadotrophin. (Key words: Does oocyte, Chorionic gonadotrophin, In vitro maturation, In vitro fertilization, In vitro embryo development

Adrenal Steroids: Biphasic Effects on Neurons

NARCIS (Netherlands)

Joels, M.; Karst, H.; Squire, L.R.

2009-01-01

Corticosteroid hormones are released from the adrenal gland after stress. They enter the brain and bind to high-affinity mineralocorticoid and lower affinity glucocorticoid receptors. Through these nuclear receptors, corticosteroids exert long-lasting effects on essential properties of neurons, such

The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release

OpenAIRE

Rau, Andrew R.; Hentges, Shane T.

2017-01-01

Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA re...

Differential sensitivity to nicotine among hypothalamic magnocellular neurons

DEFF Research Database (Denmark)

Mikkelsen, J D; Jacobsen, Julie; Kiss, Adrian Emil

2012-01-01

The magnocellular neurons in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) either contain vasopressin or oxytocin. Even though both hormones are released after systemic administration of nicotine, the mechanism through which the two populations of neurons are activated...... is not known. This study was carried out in the rat to investigate the effect of increasing doses of nicotine on subsets of magnocellular neurons containing either oxytocin or vasopressin....

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

Munc13 controls the location and efficiency of dense-core vesicle release in neurons.

Science.gov (United States)

van de Bospoort, Rhea; Farina, Margherita; Schmitz, Sabine K; de Jong, Arthur; de Wit, Heidi; Verhage, Matthijs; Toonen, Ruud F

2012-12-10

Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2-null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.

Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome.

Science.gov (United States)

Bordewijk, Esmée M; Nahuis, Marleen; Costello, Michael F; Van der Veen, Fulco; Tso, Leopoldo O; Mol, Ben Willem J; van Wely, Madelon

2017-01-24

Clomiphene citrate (CC) is generally considered first-line treatment in women with anovulation due to polycystic ovary syndrome (PCOS). Ovulation induction with follicle-stimulating hormone (FSH; gonadotrophins) is second-line treatment for women who do not ovulate or conceive while taking CC. Metformin may increase the effectiveness of ovulation induction with gonadotrophins and may promote safety by preventing multiple pregnancy. To determine the effectiveness and safety of metformin co-treatment during ovulation induction with gonadotrophins with respect to rates of live birth and multiple pregnancy in women with PCOS. We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and the Cumulative Index to Nursing and Allied Health Literature (CINAH) on 8 June 2016, and the reference lists of included and other relevant studies. We searched ongoing trials registries in the World Health Organization (WHO) portal and on clinicaltrials.gov on 4 September 2016. We included randomised controlled trials (RCTs) reporting data on comparison of clinical outcomes in women with PCOS undergoing ovulation induction with gonadotrophins plus metformin versus gonadotrophins alone or gonadotrophins plus placebo. We used standard methodological procedures recommended by Cochrane. Primary review outcomes were live birth rate and multiple pregnancy rate. Secondary outcomes were ovulation rate, clinical pregnancy rate, ovarian hyperstimulation syndrome (OHSS) rate, miscarriage rate, cycle cancellation rate and adverse effects. We included five RCTs (with 264 women) comparing gonadotrophins plus metformin versus gonadotrophins. The gonadotrophin used was recombinant FSH in four studies and highly purified FSH in one study. Evidence was of low quality: The main limitations were serious risk of bias due to poor reporting of study methods and blinding of participants and

Intracerebroventricular Infusion of Vasoactive Intestinal Peptide (VIP Rescues the Luteinizing Hormone Surge in Middle-Aged Female Rats

Directory of Open Access Journals (Sweden)

Yan eSun

2012-02-01

Full Text Available Reproductive aging is characterized by delayed and attenuated luteinizing hormone (LH surges apparent in middle-aged rats. The suprachiasmatic nucleus (SCN contains the circadian clock that is responsible for the timing of diverse neuroendocrine rhythms. Electrophysiological studies suggest vasoactive intestinal peptide (VIP originating from the SCN excites gonadotropin-releasing hormone (GnRH neurons and affects daily patterns of GnRH-LH release. Age-related LH surge dysfunction correlates with reduced VIP mRNA expression in the SCN and fewer GnRH neurons with VIP contacts expressing c-fos, a marker of neuronal activation, on the day of the LH surge. To determine if age-related LH surge dysfunction reflects reduced VIP availability or altered VIP responsiveness under estradiol positive feedback conditions, we assessed the effect of intracerebroventricular (icv VIP infusion on c-fos expression in GnRH neurons and on LH release in ovariohysterectomized, hormone-primed young and middle-aged rats. Icv infusion of VIP between 1300 and 1600 h significantly advanced the time of peak LH release, increased total and peak LH release, and increased the number of GnRH neurons expressing c-fos on the day of the LH surge in middle-aged rats. Surprisingly, icv infusion of VIP in young females significantly reduced the number of GnRH neurons expressing c-fos and delayed and reduced the LH surge. These observations suggest that a critical balance of VIP signaling is required to activate GnRH neurons for an appropriately timed and robust LH surge in young and middle-aged females. Age-related LH surge changes may, in part, result from decreased availability and reduced VIP-mediated neurotransmission under estradiol positive feedback conditions.

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.

Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-Neuronal–Glial Stimulation of Excitatory GABA Circuits

Science.gov (United States)

Haam, Juhee; Halmos, Katalin C.; Di, Shi

2014-01-01

Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal–glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal–glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal–glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

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

Science.gov (United States)

Martari, Marco; Salvatori, Roberto

2009-01-01

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

The olfactory gonadotropin-releasing hormone immunoreactive system in mouse.

Science.gov (United States)

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

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

Science.gov (United States)

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

2001-11-01

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

In vitro fertilisation with recombinant follicle stimulating hormone requires less IU usage compared with highly purified human menopausal gonadotrophin: results from a European retrospective observational chart review

Directory of Open Access Journals (Sweden)

Blackmore Stuart

2010-11-01

Full Text Available Abstract Background Previous studies have reported conflicting results for the comparative doses of recombinant follicle stimulating hormone (rFSH and highly purified human menopausal gonadotrophin (hMG-HP required per cycle of in vitro fertilisation (IVF; the aim of this study was to determine the average total usage of rFSH versus hMG-HP in a 'real-world' setting using routine clinical practice. Methods This retrospective chart review of databases from four European countries investigated gonadotrophin usage, oocyte and embryo yield, and pregnancy outcomes in IVF cycles (± intra-cytoplasmic sperm injection using rFSH or hMG-HP alone. Included patients met the National Institute for Health and Clinical Excellence (NICE guideline criteria for IVF and received either rFSH or hMG-HP. Statistical tests were conducted at 5% significance using Chi-square or t-tests. Results Of 30,630 IVF cycles included in this review, 74% used rFSH and 26% used hMG-HP. A significantly lower drug usage per cycle for rFSH than hMG-HP (2072.53 +/- 76.73 IU vs. 2540.14 +/- 883.08 IU, 22.6% higher for hMG-HP; p Conclusions Based on these results, IVF treatment cycles with rFSH yield statistically more oocytes (and more mature oocytes, using significantly less IU per cycle, versus hMG-HP. The incidence of all OHSS and hospitalisations due to OHSS was significantly higher in the rFSH cycles compared to the hMG-HP cycles. However, the absolute incidence of hospitalisations due to OHSS was similar to that reported previously. These results suggest that the perceived required dosage with rFSH is currently over-estimated, and the higher unit cost of rFSH may be offset by a lower required dosage compared with hMG-HP.

Pre-stimulation parameters predicting live birth after IVF in the long GnRH agonist protocol

DEFF Research Database (Denmark)

Pettersson, Göran; Andersen, Anders Nyboe; Broberg, Per

2010-01-01

This retrospective study aimed to identify novel pre-stimulation parameters associated with live birth in IVF and to develop a model for prediction of the chances of live birth at an early phase of the treatment cycle. Data were collected from a randomized trial in couples with unexplained...... infertility, tubal factor, mild male factor or other reason for infertility. All women (n=731) had undergone an IVF cycle (no intracytoplasmic sperm injection) after stimulation with human menopausal gonadotrophin or follicle-stimulating hormone following the long gonadotrophin-releasing hormone agonist...

Pre-stimulation parameters predicting live birth after IVF in the long GnRH agonist protocol

DEFF Research Database (Denmark)

Pettersson, Göran; Andersen, Anders Nyboe; Broberg, Per

2010-01-01

infertility, tubal factor, mild male factor or other reason for infertility. All women (n=731) had undergone an IVF cycle (no intracytoplasmic sperm injection) after stimulation with human menopausal gonadotrophin or follicle-stimulating hormone following the long gonadotrophin-releasing hormone agonist......This retrospective study aimed to identify novel pre-stimulation parameters associated with live birth in IVF and to develop a model for prediction of the chances of live birth at an early phase of the treatment cycle. Data were collected from a randomized trial in couples with unexplained...

Neuronal and glial release of (3H)GABA from the rat olfactory bulb

Energy Technology Data Exchange (ETDEWEB)

Jaffe, E.H.; Cuello, A.C.

1981-12-01

Neuronal versus glial components of the (3H)gamma-aminobutyric acid ((3H)GABA) release studies were performed with two different microdissected layers of the olfactory bulb of the rat. In some experiments substantia nigra was used as a GABAergic axonal system and the trigeminal ganglia as a peripheral glial model. Spontaneous release of (3H)GABA was always lower in neuronal elements as compared with glial cells. A veratridine-evoked release was observed from the ONL but not from the trigeminal ganglia. Tetrodotoxin (TTX) abolished the veratridine-evoked release from the ONL, which also showed a partial inhibition when high magnesium concentrations were used in a Ca2+-free solution. beta-Alanine was strongly exchanged with (3H)GABA from the ONL of animals with the olfactory nerve lesioned and from animals with no lesion; but only a small heteroexchange was found from the external plexiform layer. The beta-alanine heteroexchange was able to deplete the releasable GABA store from the ONL of lesioned animals. In nonlesioned animals and the external plexiform layer, the veratridine-stimulated release of (3H)GABA was not significantly reduced after the beta-alanine heteroexchange. Stimulation of the (3H)GABA release by high concentrations of potassium elicited a higher release rate from axonal terminals than from dendrites or glia. Neurones and glia showed a similar inhibition of (3H)GABA release when a high magnesium concentration was added to a calcium-free solution. When D-600 was used as a calcium-flux blocker no inhibition of the release was observed in glial cells, whereas an almost complete blockage was found in both neuronal preparations (substantia nigra and EPL). These results provide further evidence for differential release mechanisms of GABA from CNS neurones and glial cells.

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

African Journals Online (AJOL)

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

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

OpenAIRE

Morelli, Annamaria; Comeglio, Paolo; Sarchielli, Erica; Cellai, Ilaria; Vignozzi, Linda; Vannelli, Gabriella B.; Maggi, Mario

2013-01-01

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...

FSH inhibits the augmentation by oestradiol of the pituitary responsiveness to GnRH in the female rat

NARCIS (Netherlands)

Schuiling, GA; Valkhof, N; Koiter, TR

The effect of follicle stimulating hormone (FSH) treatment on the pituitary response to gonadotrophin-releasing hormone (GnRH) was studied in rats in various reproductive conditions. A 3-day treatment of cycling rats with FSH (Metrodin(R); 10 IU/injection) lowered the spontaneous pre-ovulatory

Neurons Containing Orexin or Melanin Concentrating Hormone Reciprocally Regulate Wake and Sleep

Directory of Open Access Journals (Sweden)

Roda Rani eKonadhode

2015-01-01

Full Text Available There is considerable amount of data on arousal neurons whereas there is a paucity of knowledge regarding neurons that make us fall asleep. Indeed, current network models of sleep-wake regulation list many arousal neuronal populations compared to only one sleep group located in the preoptic area. There are neurons outside the preoptic area that are active during sleep, but they have never been selectively manipulated. Indeed, none of the sleep-active neurons have been selectively stimulated. To close this knowledge gap we used optogenetics to selectively manipulate neurons containing melanin concentrating hormone (MCH. The MCH neurons are located in the posterior hypothalamus intermingled with the orexin arousal neurons. Our data indicated that optogenetic stimulation of MCH neurons in wildtype mice (J Neuroscience, 2013 robustly increased both non-REM and REM sleep. MCH neuron stimulation increased sleep during the animal’s normal active period, which is compelling evidence that stimulation of MCH neurons has a powerful effect in counteracting the strong arousal signal from all of the arousal neurons. The MCH neurons represent the only group of sleep-active neurons that when selectively stimulated induce sleep. From a translational perspective this is potentially useful in sleep disorders, such as insomnia, where sleep needs to be triggered against a strong arousal drive. Our studies indicate that the MCH neurons belong within an overall model of sleep-wake regulation.

INDUCTION OF GONADAL MATURATION OF POND CULTURED MALE TIGER SHRIMP, Penaeus monodon WITH DIFFERENT DOSAGES OF GONADOTROPIN RELEASING HORMONE ANALOGUE AGAINST EYE STALK ABLATION

Directory of Open Access Journals (Sweden)

Asda Laining

2016-12-01

Full Text Available Very low naturally mating rate of pond-reared tiger shrimp broodstock is probably due to the slow maturation of the male stock. The aim of this study was to evaluate the salmon gonadotrophin releasing hormone analoque (sGnRHa in stimulating the gonadal maturation of male stock of pond-reared tiger shrimp. The treatments were three dosages of sGnRHa at 0.1 (OV-1, 0.2 (OV-2, and 0.3 (OV-3 mL/kg of shrimp weight and control was eye stalk ablation (AB. The sGnRHa was administered via injection three times with one week interval. Male stocks with average initial body weight of 82.1 g were randomly distributed into four of 10 m3 concrete tanks, 26 males for each tank. Variables observed were performances of spermatophores and profiles of amino acid and fatty acid of muscle of the male stocks. After induction, number of male maturing indicated by spermatophores releasing from terminal ampullas was higher in shrimp induced with OV-1 (80.8% compared to control which was only 46.1%. Furthermore, shrimp treated OV-2 had the highest spermatophore weight of 0.16 g compared to control (0.11 g and other two groups. Amino acid profiles improved as the dose of sGnRHa increased up to 0.2 mL/kg from 61.23% for ablated male becoming 71.27% for OV-2. Total fatty acid also tended to improve by increasing the dose of hormone injection, however, the ablated male had higher total fatty acid content than that of OV-1. The present finding demonstrated that the dose of sGnRHa to stimulate the gonadal maturation of pond-reared male tiger shrimp could be applied at range between 0.1-0.2 mL/kg of shrimp weight.

The reproductive performance of dairy cows with anovulatory anoestrus that were injected with either gonadotrophin-releasing hormone or oestradiol benzoate as part of a re-treatment process after insemination

Directory of Open Access Journals (Sweden)

B.V.E. Segwagwe

2007-05-01

Full Text Available This experiment compared the reproductive performance of synchronised anoestrous dairy cows that were treated initially with a combination of progesterone and oestradiol benzoate and then with either gonadotrophin-releasing hormone (GnRH or oestradiol benzoate to resynchronise returns to service. It was hypothesised that injecting anoestrous dairy cows with GnRH 12-15 days after insemination and coinciding with the time of insertion of a controlled intravaginal progesterone-releasing (CIDR device would increase conception rates to the preceding 1st insemination compared with oestradiol benzoate treated cows; both GnRH and oestradiol benzoate would resynchronising the returns to service of those cows that did not conceive to the preceding insemination. Groups of cows in 11 herds were presented for a veterinary examination after they had not been seen in oestrus postpartum. Those cows diagnosed with anovulatory anoestrus (n = 1112 by manual rectal palpation and / or ultrasonography were enrolled in the trial. Each enrolled cow was injected with 2mg oestradiol benzoate i.m. on Day -10, (where Day 0 was the 1st day of the planned insemination concurrently with vaginal insertion of a CIDR device. The device inserted was withdrawn on Day -2 and then each cow injected i.m. with 1 mg of oestradiol benzoate on Day -1 unless it was in oestrus. Observation for oestrus preceded each insemination. Every cow that had been inseminated on Days -1,0,1 or 2 was presented for treatment for resynchrony on Day 14 (n=891. They were divided into 2 groups; those with an even number were each injected i.m. with 250 µg of a GnRH agonist (Treatment group n = 477; each of the cows with an odd number injected i.m. with 1mg of oestradiol benzoate (control group, n = 414. Each GnRH or oestradiol benzoate injection preceded reinsertion of a CIDR device previously inserted from Days -10 to -2. It was withdrawn on Day 22, 24 hours before injecting 1mg oestradiol benzoate

Immunological relatedness of gonadotrophins of various fishes as shown by radioimmunoassays

International Nuclear Information System (INIS)

Tan, E.S.P.; Dodd, J.M.

1978-01-01

Pituitary extracts and plasmas of 35 species of fish were tested in two radioimmunoassay (RIA) systems, a salmon-salmon homologous RIA and a salmon-carp heterologous RIA, in which the same antiserum, raised against salmon gonadotrophin, SG-G100, was employed. In the homologous RIA, most salmonid species tested, except for the powan and ayu, cross-reacted in a manner identical with that of the standard, SG-DEAE-3. Nonparallelism of inhibition curves were found in 13 non- salmonid species while 3 others showed non cross-reaction. In the heterologous RIA, all cyprinids, except the rudd, and all salmonids, except the ayu, as well as 9 other species, gave inhibition curves parallel to that of the standard purified carp gonadotrophin. These results may indicate that immunological properties of fish gonadotrophins do not correspond to known phylogenetic relationships of fishes

Co-release of glutamate and GABA from single vesicles in GABAergic neurons exogenously expressing VGLUT3

Directory of Open Access Journals (Sweden)

Johannes eZimmermann

2015-09-01

Full Text Available The identity of the vesicle neurotransmitter transporter expressed by a neuron largely corresponds with the primary neurotransmitter that cell releases. However, the vesicular glutamate transporter subtype 3 (VGLUT3 is mainly expressed in non-glutamatergic neurons, including cholinergic, serotonergic, or GABAergic neurons. Though a functional role for glutamate release from these non-glutamatergic neurons has been demonstrated, the interplay between VGLUT3 and the neuron’s characteristic neurotransmitter transporter, particularly in the case of GABAergic neurons, at the synaptic and vesicular level is less clear. In this study, we explore how exogenous expression of VGLUT3 in striatal GABAergic neurons affects the packaging and release of glutamate and GABA in synaptic vesicles. We found that VGLUT3 expression in isolated, autaptic GABAergic neurons leads to action potential evoked release of glutamate. Under these conditions, glutamate and GABA could be packaged together in single vesicles release either spontaneously or asynchronously. However, the presence of glutamate in GABAergic vesicles did not affect uptake of GABA itself, suggesting a lack of synergy in vesicle filling for these transmitters. Finally, we found postsynaptic detection of glutamate released from GABAergic terminals difficult when bona fide glutamatergic synapses were present, suggesting that co-released glutamate cannot induce postsynaptic glutamate receptor clustering.

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

Science.gov (United States)

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

Gonadal Steroid Hormones and the Hypothalamo-Pituitary-Adrenal Axis

OpenAIRE

Handa, Robert J.; Weiser, Michael J.

2013-01-01

The hypothalamo-pituitary-adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, pr...

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.

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

Science.gov (United States)

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.

Pituitary adenomas in mice transgenic for growth hormone-releasing hormone

DEFF Research Database (Denmark)

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

1992-01-01

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

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

NARCIS (Netherlands)

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

2012-01-01

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

Pharmacological and toxicological assessment of a potential GnRH vaccine in young-adult male pigs

NARCIS (Netherlands)

Turkstra, J.A.; Staay, van der F.J.; Stockhofe-Zurwieden, N.; Woelders, H.; Meloen, R.H.; Schuurman, T.

2011-01-01

Active immunization against gonadotrophin-releasing hormone (GnRH) is successfully applied to prevent boar taint in pork. In men, GnRH immunization could be an alternative to hormone therapy in patients with prostate cancer. In this study, a new GnRH vaccine formulation (a modified GnRH peptide

Radioimmunoassay of thyrotropin releasing hormone in plasma and urine

International Nuclear Information System (INIS)

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

1975-01-01

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

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

Science.gov (United States)

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

1996-04-01

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

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

Science.gov (United States)

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

2007-07-11

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

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

Energy Technology Data Exchange (ETDEWEB)

Wang, Jian.

1989-01-01

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

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

Science.gov (United States)

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

1992-03-01

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

Upregulation of transmitter release probability improves a conversion of synaptic analogue signals into neuronal digital spikes

Science.gov (United States)

2012-01-01

Action potentials at the neurons and graded signals at the synapses are primary codes in the brain. In terms of their functional interaction, the studies were focused on the influence of presynaptic spike patterns on synaptic activities. How the synapse dynamics quantitatively regulates the encoding of postsynaptic digital spikes remains unclear. We investigated this question at unitary glutamatergic synapses on cortical GABAergic neurons, especially the quantitative influences of release probability on synapse dynamics and neuronal encoding. Glutamate release probability and synaptic strength are proportionally upregulated by presynaptic sequential spikes. The upregulation of release probability and the efficiency of probability-driven synaptic facilitation are strengthened by elevating presynaptic spike frequency and Ca2+. The upregulation of release probability improves spike capacity and timing precision at postsynaptic neuron. These results suggest that the upregulation of presynaptic glutamate release facilitates a conversion of synaptic analogue signals into digital spikes in postsynaptic neurons, i.e., a functional compatibility between presynaptic and postsynaptic partners. PMID:22852823

The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

Directory of Open Access Journals (Sweden)

Arpad eDobolyi

2012-10-01

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

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

Science.gov (United States)

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

2006-01-01

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

Parallel expression of synaptophysin and evoked neurotransmitter release during development of cultured neurons

DEFF Research Database (Denmark)

Ehrhart-Bornstein, M; Treiman, M; Hansen, Gert Helge

1991-01-01

Primary cultures of GABAergic cerebral cortex neurons and glutamatergic cerebellar granule cells were used to study the expression of synaptophysin, a synaptic vesicle marker protein, along with the ability of each cell type to release neurotransmitter upon stimulation. The synaptophysin expression...... by quantitative immunoblotting and light microscope immunocytochemistry, respectively. In both cell types, a close parallelism was found between the temporal pattern of development in synaptophysin expression and neurotransmitter release. This temporal pattern differed between the two types of neurons....... The cerebral cortex neurons showed a biphasic time course of increase in synaptophysin content, paralleled by a biphasic pattern of development in their ability to release [3H]GABA in response to depolarization by glutamate or elevated K+ concentrations. In contrast, a monophasic, approximately linear increase...

Stimulatory effects of neuronally released norepinephrine on renin release in vitro

Energy Technology Data Exchange (ETDEWEB)

Matsumura, Yasuo; Kawazoe, Shinka; Ichihara, Toshio; Shinyama, Hiroshi; Kageyama, Masaaki; Morimoto, Shiro (Osaka Univ. of Pharmaceutical Sciences (Japan))

1988-10-01

Extracellular high potassium inhibits renin release in vitro by increasing calcium concentrations in the juxtaglomerular cells. The authors found that the decreased response of renin release from rat kidney cortical slices in high potassium solution changed to a strikingly increased one in the presence of nifedipine at doses over 10{sup {minus}6} M. They then examined the stimulatory effect of extracellular high potassium in the presence of nifedipine on renin release. The enhancement of release was significantly suppressed either by propranolol or by metoprolol but not by prazosin. High potassium plus nifedipine-induced increase in renin release was markedly attenuated by renal denervation. The enhancing effect was not observed when the slices were incubated in calcium-free medium. Divalent cations such as Cd{sup 2+}, Co{sup 2+}, and Mn{sup 2+} blocked this enhancement in a concentration-dependent manner. High potassium elicited an increase in {sup 3}H efflux from the slices preloaded with ({sup 3}H)-norepinephrine. The increasing effect was not influenced by nifedipine but was abolished by the removal of extracellular calcium or by the addition of divalent cations. These observations suggest to us that the high potassium plus nifedipine-induced increase in renin release from the slices is mediated by norepinephrine derived from renal sympathetic nerves and that this neuronally released norepinephrine stimulates renin release via activation of {beta}-adrenoceptors.

The nervus terminalis of the guinea pig: a new luteinizing hormone-releasing hormone (LHRH) neuronal system.

Science.gov (United States)

Schwanzel-Fukuda, M; Silverman, A J

1980-05-15

Immunoreactive LHRH-like material has been found in the cells and fibers of the nervus terminalis in fetal and adult guinea pig brains. LHRH-containing neurons and axons are seen in the nasal mucosa intermingled with fibers of the olfactory nerves, in ganglia along the ventromedial surfaces of the olfactory bulbs and forebrain, and in clusters surrounding perforating branches of the anterior cerebral artery in the regions of the septal nuclei and olfactory tubercle. Nonreactive neurons are found adjacent to the LHRH-positive cells in all of the ganglia. LHRH-immunoreactive cells and axons of the nervus terminalis are in intimate contact with cerebral blood vessels and the cerebrospinal fluid along the intracranial course of this nerve, deep to the meninges. The possible involvement of these structures in the neural mechanisms of sexual behavior and the neurohormonal regulation of reproductive function are discussed.

Prenatal androgenization of female mice programs an increase in firing activity of gonadotropin-releasing hormone (GnRH) neurons that is reversed by metformin treatment in adulthood.

Science.gov (United States)

Roland, Alison V; Moenter, Suzanne M

2011-02-01

Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

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

African Journals Online (AJOL)

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

Fluorescence imaging of glutamate release in neurons

International Nuclear Information System (INIS)

Wang, Ziqiang; Yeung, Edward S.

1999-01-01

A noninvasive detection scheme based on glutamate dehydrogenase (GDH) enzymatic assay combined with microscopy was developed to measure the glutamate release in cultured cells from the central nervous system (CNS). The enzyme reaction is very specific and sensitive. The detection limit with charge-coupled device (CCD) imaging is down to μM levels of glutamate with reasonable response time (∼30 s). The standard glutamate test shows a linear response over 3 orders of magnitude, from μM to 0.1 mM range. The in vitro monitoring of glutamate release from cultured neuron cells demonstrated excellent spatial and temporal resolution. (c) 1999 Society for Applied Spectroscopy

[Role of estrogen-sensitive neurons in the arcuate region of the hypothalamus in the mechanism of luteinizing hormone release].

Science.gov (United States)

Babichev, V N; Ignatkov, V Ia

1978-01-01

Experiments were conducted on rats; estradiol brought to the arcuate region of the hypothalamus by means of microionophoresis led to the increase of the region of the hypothalamus by means of microionophoresis led to the increase of the blood luteinizing hormone (LH) level during the following stages of the estral cycle-diestrus 1, diestrus 2, and the first half day of the proestrus; as to the second half of the proestrus day--estradiol decreased its level. Changes in the LH level in the hypophysis under the influence of the microionophoretic introduction of estradiol into the arcuate region occurred during the second half of the day of diestrus 2 (reduction), and during the estrus (elevation). In the majority of cases a rise of the blood level was combined with the neuron activation in the arcuate region under the influence of estradiol.

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

Science.gov (United States)

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

The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

Science.gov (United States)

Faghihi, Faramarz; Moustafa, Ahmed A.

2015-01-01

Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively) as words with length equal to three. Then the frequency of each word (here eight words) is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms. This study demonstrates the importance of cooperation of Hebbian mechanism with regulation of neurotransmitter release induced by rapid diffused retrograde

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

Science.gov (United States)

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

2016-08-03

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

Electrophysiological Properties of Melanin-Concentrating Hormone and Orexin Neurons in Adolescent Rats

Directory of Open Access Journals (Sweden)

Victoria Linehan

2018-03-01

Full Text Available Orexin and melanin-concentrating hormone (MCH neurons have complementary roles in various physiological functions including energy balance and the sleep/wake cycle. in vitro electrophysiological studies investigating these cells typically use post-weaning rodents, corresponding to adolescence. However, it is unclear whether these neurons are functionally mature at this period and whether these studies can be generalized to adult cells. Therefore, we examined the electrophysiological properties of orexin and MCH neurons in brain slices from post-weaning rats and found that MCH neurons undergo an age-dependent reduction in excitability, but not orexin neurons. Specifically, MCH neurons displayed an age-dependent hyperpolarization of the resting membrane potential (RMP, depolarizing shift of the threshold, and decrease in excitatory transmission, which reach the adult level by 7 weeks of age. In contrast, basic properties of orexin neurons were stable from 4 weeks to 14 weeks of age. Furthermore, a robust short-term facilitation of excitatory synapses was found in MCH neurons, which showed age-dependent changes during the post-weaning period. On the other hand, a strong short-term depression was observed in orexin neurons, which was similar throughout the same period. These differences in synaptic responses and age dependence likely differentially affect the network activity within the lateral hypothalamus where these cells co-exist. In summary, our study suggests that orexin neurons are electrophysiologically mature before adolescence whereas MCH neurons continue to develop until late adolescence. These changes in MCH neurons may contribute to growth spurts or consolidation of adult sleep patterns associated with adolescence. Furthermore, these results highlight the importance of considering the age of animals in studies involving MCH neurons.

The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

Directory of Open Access Journals (Sweden)

Faramarz eFaghihi

2015-04-01

Full Text Available Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively as words with length equal to three. Then the frequency of each word (here eight words is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms.

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

Discrepancies between Antimullerian Hormone and Follicle Stimulating Hormone in Assisted Reproduction

Directory of Open Access Journals (Sweden)

Munawar Hussain

2013-01-01

Full Text Available Data from 107 women undergoing their first IVF/ICSI were analyzed. Relationships between antimullerian hormone (AMH and follicle stimulating hormone (FSH were analyzed after dividing patients into four groups according to AMH/FSH levels. Concordance was noted in 57% of women (both AMH/FSH either normal or abnormal while 43%of women had discordant values (AMH/FSH one hormone normal and the other abnormal. Group 1 (AMH and FSH in normal range and group 2 (normal AMH and high FSH were younger compared to group 3 (low AMH and normal FSH and group 4 (both AMH/FSH abnormal. Group 1 showing the best oocyte yield was compared to the remaining three groups. Groups 3 and 4 required higher dose of gonadotrophins for controlled ovarian hyperstimulation showing their low ovarian reserve. There was no difference in cycle cancellation, clinical pregnancy, and live birth/ongoing pregnancy rate in all groups. These tests are useful to predict ovarian response but whether AMH is a substantially better predictor is not yet established.

Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in aged, long-term hormone-deprived female rats.

Directory of Open Access Journals (Sweden)

Tomoko Inagaki

Full Text Available Transient global forebrain ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons, and the ovarian hormone 17β-estradiol (E2 reduces neuronal loss in young and middle-aged females. The neuroprotective efficacy of E2 after a prolonged period of hormone deprivation is controversial, and few studies examine this issue in aged animals given E2 treatment after induction of ischemia.The present study investigated the neuroprotective effects of E2 administered immediately after global ischemia in aged female rats (15-18 months after 6 months of hormone deprivation. We also used electrophysiological methods to assess whether CA1 synapses in the aging hippocampus remain responsive to E2 after prolonged hormone withdrawal. Animals were ovariohysterectomized and underwent 10 min global ischemia 6 months later. A single dose of E2 (2.25 µg infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls. Ischemia also induced moderate loss of CA3/CA4 pyramidal cells. Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP was induced. The magnitude of LTP and of E2 enhancement of field excitatory postsynaptic potentials was indistinguishable from that recorded in slices from young rats.The data demonstrate that 1 acute post-ischemic infusion of E2 into the brain ventricles is neuroprotective in aged rats after 6 months of hormone deprivation; and 2 E2 enhances synaptic transmission in CA1 pyramidal neurons of aged long-term hormone deprived females. These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

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

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

Science.gov (United States)

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

The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic–Pituitary–Gonadal Axis

Directory of Open Access Journals (Sweden)

Shel-Hwa Yeo

2018-04-01

Full Text Available Kisspeptin–GPR54 signaling in the hypothalamus is required for reproduction and fertility in mammals. Kiss1 neurons are key regulators of gonadotropin-releasing hormone (GnRH release and modulation of the hypothalamic–pituitary–gonadal (HPG axis. Arcuate Kiss1 neurons project to GnRH nerve terminals in the median eminence, orchestrating the pulsatile secretion of luteinizing hormone (LH through the intricate interaction between GnRH pulse frequency and the pituitary gonadotrophs. Arcuate Kiss1 neurons, also known as KNDy neurons in rodents and ruminants because of their co-expression of neurokinin B and dynorphin represent an ideal hub to receive afferent inputs from other brain regions in response to physiological and environmental changes, which can regulate the HPG axis. This review will focus on studies performed primarily in rodent and ruminant species to explore potential afferent inputs to Kiss1 neurons with emphasis on the arcuate region but also considering the rostral periventricular region of the third ventricle (RP3V. Specifically, we will discuss how these inputs can be modulated by hormonal, metabolic, and environmental factors to control gonadotropin secretion and fertility. We also summarize the methods and techniques that can be used to study functional inputs into Kiss1 neurons.

Neurokinin B receptor antagonism decreases luteinising hormone pulse frequency and amplitude and delays puberty onset in the female rat.

Science.gov (United States)

Li, S Y; Li, X F; Hu, M H; Shao, B; Poston, L; Lightman, S L; O'Byrne, K T

2014-08-01

The neural mechanisms controlling puberty onset remain enigmatic. Humans with loss of function mutations in TAC3 or TACR3, the genes encoding neurokinin B (NKB) or its receptor, neurokinin-3 receptor (NK3R), respectively, present with severe congenital gonadotrophin deficiency and pubertal failure. Animal studies have shown ambiguous actions of NKB-NK3R signalling with respect to controlling puberty onset. The present study aimed to determine the role of endogenous NKB-NK3R signalling in the control of pulsatile luteinising hormone (LH) secretion and the timing of puberty onset, and also whether precocious pubertal onset as a result of an obesogenic diet is similarly regulated by this neuropeptide system. Prepubertal female rats, chronically implanted with i.c.v. cannulae, were administered SB222200, a NK3R antagonist, or artificial cerebrospinal fluid via an osmotic mini-pump for 14 days. SB222200 significantly delayed the onset of vaginal opening and first oestrus (as markers of puberty) compared to controls in both normal and high-fat diet fed animals. Additionally, serial blood sampling, via chronic indwelling cardiac catheters, revealed that the increase in LH pulse frequency was delayed and that the LH pulse amplitude was reduced in response to NK3R antagonism, regardless of dietary status. These data suggest that endogenous NKB-NK3R signalling plays a role in controlling the timing of puberty and the associated acceleration of gonadotrophin-releasing hormone pulse generator frequency in the female rat. © 2014 British Society for Neuroendocrinology.

Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria.

Directory of Open Access Journals (Sweden)

Leonardo M Saraiva

2010-12-01

Full Text Available Brain accumulation of the amyloid-β peptide (Aβ and oxidative stress underlie neuronal dysfunction and memory loss in Alzheimer's disease (AD. Hexokinase (HK, a key glycolytic enzyme, plays important pro-survival roles, reducing mitochondrial reactive oxygen species (ROS generation and preventing apoptosis in neurons and other cell types. Brain isozyme HKI is mainly associated with mitochondria and HK release from mitochondria causes a significant decrease in enzyme activity and triggers oxidative damage. We here investigated the relationship between Aβ-induced oxidative stress and HK activity. We found that Aβ triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Aβ oligomers further impair energy metabolism by decreasing neuronal ATP levels. Aβ-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Aβ-induced oxidative stress and neuronal death. Results suggest that Aβ-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in AD.

Conditional Viral Tract Tracing Delineates the Projections of the Distinct Kisspeptin Neuron Populations to Gonadotropin-Releasing Hormone (GnRH) Neurons in the Mouse.

Science.gov (United States)

Yip, Siew Hoong; Boehm, Ulrich; Herbison, Allan E; Campbell, Rebecca E

2015-07-01

Kisspeptin neurons play an essential role in the regulation of fertility through direct regulation of the GnRH neurons. However, the relative contributions of the two functionally distinct kisspeptin neuron subpopulations to this critical regulation are not fully understood. Here we analyzed the specific projection patterns of kisspeptin neurons originating from either the rostral periventricular nucleus of the third ventricle (RP3V) or the arcuate nucleus (ARN) using a cell-specific, viral-mediated tract-tracing approach. We stereotaxically injected a Cre-dependent recombinant adenovirus encoding farnesylated enhanced green fluorescent protein into the ARN or RP3V of adult male and female mice expressing Cre recombinase in kisspeptin neurons. Fibers from ARN kisspeptin neurons projected widely; however, we did not find any evidence for direct contact with GnRH neuron somata or proximal dendrites in either sex. In contrast, we identified RP3V kisspeptin fibers in close contact with GnRH neuron somata and dendrites in both sexes. Fibers originating from both the RP3V and ARN were observed in close contact with distal GnRH neuron processes in the ARN and in the lateral and internal aspects of the median eminence. Furthermore, GnRH nerve terminals were found in close contact with the proximal dendrites of ARN kisspeptin neurons in the ARN, and ARN kisspeptin fibers were found contacting RP3V kisspeptin neurons in both sexes. Together these data delineate selective zones of kisspeptin neuron inputs to GnRH neurons and demonstrate complex interconnections between the distinct kisspeptin populations and GnRH neurons.

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

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

Science.gov (United States)

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

2016-12-01

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

Human Chorionic Gonadotrophin as a Possible Mediator of Leiomyoma Growth during Pregnancy: Molecular Mechanisms.

Science.gov (United States)

Sarais, Veronica; Cermisoni, Greta Chiara; Schimberni, Matteo; Alteri, Alessandra; Papaleo, Enrico; Somigliana, Edgardo; Vigano', Paola

2017-09-20

Uterine fibroids are the most common gynecologic benign tumors. Studies supporting a strong pregnancy-related growth of leiomyomas generally claimed a crucial role of sex steroid hormones. However, sex steroids are unlikely the unique actors involved as estrogen and progesterone achieve a pick serum concentration in the last trimester while leiomyomas show a typical increase during the first trimester. Given the rapid exponential raise in serum human Chorionic Gonadotrophin (hCG) at the beginning of gestation, we conducted a review to assess the potential role of hCG in the striking growth of leiomyomas during initial pregnancy. Fibroid growth during initial pregnancy seems to correlate to the similar increase of serum hCG levels until 12 weeks of gestation. The presence of functional Luteinizing Hormone/human Chorionic Gonadotropin (LH/hCG) receptors was demonstrated on leiomyomas. In vitro treatment of leiomyoma cells with hCG determines an up to 500% increase in cell number after three days. Expression of cyclin E and cyclin-dependent kinase 1 was significantly increased in leiomyoma cells by hCG treatment. Moreover, upon binding to the receptor, hCG stimulates prolactin secretion in leiomyoma cells, promoting cell proliferation via the mitogen-activated protein kinase cascade. Fibroid enlargement during initial pregnancy may be regulated by serum hCG.

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...

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

Directory of Open Access Journals (Sweden)

Silla Aimee J

2011-05-01

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

Heterogeneity of protein hormones

Energy Technology Data Exchange (ETDEWEB)

Rosselin, G; Bataille, D; Laburthe, M; Duran-Garcia, S [Institut National de la Sante et de la Recherche Medicale (INSERM), Hopital Saint-Antoine, 75 - Paris (France)

1975-12-01

Radioimmunoassay measures antigenic determinants of hormonal molecules in the plasmas and tissues. These estimations carried out after fractionation in biological fluids, have revealed several immunological forms of the same hormone. The main problem is in the relationship of the various immunoreactive forms to the same hormonal sequence. The similar immunoreactive forms of high molecular weight usually have low biological activity and suggest the presence of prohormone; the suggestion of prohormonal nature depends on the chronology of the incorporation of labelled leucine and enzymatic transformation of prohormone with low biological into active hormone. The forms with high molecular weight and similar immunological activity may be of another nature. Thus, it has been shown that the biosynthetic nature of a compound such as big big insulin in the rat is doubtful owing to the absence of specific incorporation of labelled leucine into the immunoprecipitate of this fraction. The significance of low molecular weight form is still little known. An example of these forms is supplied by the existence of an alpha sub-unit of gonadotrophin present in the plasma of menopausal women. The interest of analytical methods by radio-receptor, simulation of cyclase activity in the identification of biological activity of immunoreactive forms, is discussed in relation to immunological forms ofenteroglucagon. An unusual aspect of the evolutive and adaptative character of hormonal heterogeneity is given by the gastro-intestinal hormones.

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

Science.gov (United States)

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

2012-03-01

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

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

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

Science.gov (United States)

Baumann, G; Maheshwari, H

1997-11-01

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

Download this PDF file

African Journals Online (AJOL)

USER

insemination and embryo transfer in small ... ovulation rate, average litter size, resorption rate, conception rate and embryo ... Pregnancy rate (%) ... Table I: Effects of synchronization protocolon oestrus response of yankasa sheep (mean ± sem) ... gonadotrophin releasing Hormone (GnRH) 30 .... time artificial insemination.

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

Science.gov (United States)

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

1992-02-01

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

Estrogen receptor beta and 2-arachydonoylglycerol mediate the suppressive effects of estradiol on frequency of postsynaptic currents in gonadotropin-releasing hormone neurons of metestrous mice: an acute slice electrophysiological study

Directory of Open Access Journals (Sweden)

Flóra eBálint

2016-03-01

Full Text Available Gonadotropin-releasing hormone (GnRH neurons are controlled by 17β-estradiol (E2 contributing to the steroid feedback regulation of the reproductive axis. In rodents, E2 exerts a negative feedback effect upon GnRH neurons throughout the estrus-diestrus phase of the ovarian cycle. The present study was undertaken to reveal the role of estrogen receptor subtypes in the mediation of the E2 signal and elucidate the downstream molecular machinery of suppression. The effect of E2 administration at low physiological concentration (10 pM on GnRH neurons in acute brain slices obtained from metestrous GnRH-GFP mice was studied under paradigms of blocking or activating estrogen receptor subtypes and interfering with retrograde 2-arachydonoylglycerol (2-AG signaling. Whole-cell patch clamp recordings revealed that E2 significantly diminished the frequency of spontaneous postsynaptic currents (sPSCs in GnRH neurons (49. 62±7.6% which effect was abolished by application of the ERα/β blocker Faslodex (1 µM. Pretreatment of the brain slices with cannabinoid receptor type 1 (CB1 inverse agonist AM251 (1 µM and intracellularly applied endocannabinoid synthesis blocker THL (10 µM significantly attenuated the effect of E2 on the sPSCs. E2 remained effective in the presence of TTX indicating a direct action of E2 on GnRH cells. The ERβ specific agonist DPN (10 pM also significantly decreased the frequency of miniature postsynaptic currents (mPSCs in GnRH neurons. In addition, the suppressive effect of E2 was completely blocked by the selective ERβ antagonist PHTPP (1 µM indicating that ERβ is required for the observed rapid effect of the E2. In contrast, the ERα agonist PPT (10 pM or the membrane-associated G protein-coupled estrogen receptor (GPR30 agonist G1 (10 pM had no significant effect on the frequency of mPSCs in these neurons. AM251 and THL significantly abolished the effect of E2 whereas AM251 eliminated the action of DPN on the mPSCs. These

Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals

Science.gov (United States)

Freire-Regatillo, Alejandra; Argente-Arizón, Pilar; Argente, Jesús; García-Segura, Luis Miguel; Chowen, Julie A.

2017-01-01

Although the brain is composed of numerous cell types, neurons have received the vast majority of attention in the attempt to understand how this organ functions. Neurons are indeed fundamental but, in order for them to function correctly, they rely on the surrounding “non-neuronal” cells. These different cell types, which include glia, epithelial cells, pericytes, and endothelia, supply essential substances to neurons, in addition to protecting them from dangerous substances and situations. Moreover, it is now clear that non-neuronal cells can also actively participate in determining neuronal signaling outcomes. Due to the increasing problem of obesity in industrialized countries, investigation of the central control of energy balance has greatly increased in attempts to identify new therapeutic targets. This has led to interesting advances in our understanding of how appetite and systemic metabolism are modulated by non-neuronal cells. For example, not only are nutrients and hormones transported into the brain by non-neuronal cells, but these cells can also metabolize these metabolic factors, thus modifying the signals reaching the neurons. The hypothalamus is the main integrating center of incoming metabolic and hormonal signals and interprets this information in order to control appetite and systemic metabolism. Hence, the factors transported and released from surrounding non-neuronal cells will undoubtedly influence metabolic homeostasis. This review focuses on what is known to date regarding the involvement of different cell types in the transport and metabolism of nutrients and hormones in the hypothalamus. The possible involvement of non-neuronal cells, in particular glial cells, in physiopathological outcomes of poor dietary habits and excess weight gain are also discussed. PMID:28377744

Surviving starvation: essential role of the ghrelin-growth hormone axis.

Science.gov (United States)

Goldstein, J L; Zhao, T-j; Li, R L; Sherbet, D P; Liang, G; Brown, M S

2011-01-01

After brief starvation, vertebrates maintain blood glucose by releasing fatty acids from adipose tissue. The fatty acids provide energy for gluconeogenesis in liver and are taken up by muscle, sparing glucose. After prolonged starvation, fat stores are depleted, yet blood glucose can be maintained at levels sufficient to preserve life. Using a new mouse model, we demonstrate that survival after prolonged starvation requires ghrelin, an octanoylated peptide hormone that stimulates growth hormone (GH) secretion. We studied wild-type mice and mice lacking ghrelin as a result of knockout of GOAT, the enzyme that attaches octanoate to ghrelin. Mice were fed 40% of their normal intake for 7 d. Fat stores in both lines of mice became depleted after 4 d. On day 7, mice were fasted for 23 h. In wild-type mice, ghrelin and GH rose massively, and blood sugar was maintained at ~60 mg/dL. In Goat(-/-) mice, ghrelin was undetectable and GH failed to rise appropriately. Blood sugar declined to ~20 mg/dL, and the animals were moribund. Infusion of ghrelin or GH prevented hypoglycemia. Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose. Thus, ghrelin lies at the center of a hormonal response that permits mice to survive an acute fast superimposed on chronic starvation.

Ovarian hormone deprivation reduces oxytocin expression in Paraventricular Nucleus preautonomic neurons and correlates with baroreflex impairment in rats

Directory of Open Access Journals (Sweden)

Vitor Ulisses De Melo

2016-10-01

Full Text Available The prevalence of cardiovascular diseases including hypertension increases dramatically in women after menopause, however the mechanisms involved remain incompletely understood. Oxytocinergic (OTergic neurons are largely present within the paraventricular nucleus of the hypothalamus (PVN. Several studies have shown that OTergic drive from PVN to brainstem increases baroreflex sensitivity and improves autonomic control of the circulation. Since preautonomic PVN neurons express different types of estrogen receptors, we hypothesize that ovarian hormone deprivation causes baroreflex impairment, autonomic imbalance and hypertension by negatively impacting OTergic drive and oxytocin levels in pre-autonomic neurons. Here, we assessed oxytocin gene and protein expression (qPCR and immunohistochemistry within PVN subnuclei in sham-operated and ovariectomized Wistar rats. Conscious hemodynamic recordings were used to assess resting blood pressure and heart rate and the autonomic modulation of heart and vessels was estimated by power spectral analysis. We observed that the ovarian hormone deprivation in ovariectomized rats decreased baroreflex sensitivity, increased sympathetic and reduced vagal outflows to the heart and augmented the resting blood pressure. Of note, ovariectomized rats had reduced PVN oxytocin mRNA and protein expression in all pre-autonomic PVN subnuclei. Furthermore, reduced PVN oxytocin protein levels were positively correlated with decreased baroreflex sensitivity and negatively correlated with increased LF/HF ratio. These findings suggest that reduced oxytocin expression in OTergic neurons of the PVN contributes to the baroreflex dysfunction and autonomic dysregulation observed with ovarian hormone deprivation.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice

Science.gov (United States)

Zhang, Rong; Asai, Masato; Mahoney, Carrie E; Joachim, Maria; Shen, Yuan; Gunner, Georgia; Majzoub, Joseph A

2016-01-01

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation. PMID:27595593

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

Depolarization-induced release of [(3)H]D-aspartate from GABAergic neurons caused by reversal of glutamate transporters

DEFF Research Database (Denmark)

Jensen, J B; Pickering, D S; Schousboe, A

2000-01-01

if glutamate in addition to gamma-aminobutyric acid (GABA) could be released from these cultures. The neurons were preloaded with [(3)H]D-aspartate and subsequently its release was followed during depolarization induced by a high potassium concentration or the alpha-amino-3-hydroxy-5-methyl-4......-isoxazolepropionic acid (AMPA) receptor agonists, AMPA and kainate. Depolarization of the neurons with 55 mM potassium increased the release of [(3)H]D-aspartate by more than 10-fold. When the non-specific calcium-channel blockers cobalt or lanthanum were included in the stimulation buffer with potassium......, the release of [(3)H]D-aspartate was decreased by about 40%. These results indicated that some of the released [(3)H]D-aspartate might originate from a vesicular pool. When AMPA was applied to the neurons, the release of [(3)H]D-aspartate was increased 2-fold and could not be prevented or decreased...

Improving the luteal phase after ovarian stimulation

DEFF Research Database (Denmark)

Andersen, Claus Yding; Vilbour Andersen, K

2014-01-01

The human chorionic gonadotrophin (HCG) trigger used for final follicular maturation in connection with assisted reproduction treatment combines ovulation induction and early luteal-phase stimulation of the corpora lutea. The use of a gonadotrophin-releasing hormone agonist (GnRHa) for final...... follicular maturation has, however, for the first time allowed a separation of the ovulatory signal from the early luteal-phase support. This has generated new information that may improve the currently employed luteal-phase support. Thus, combined results from a number of randomized controlled trials using...

Effect of high doses of equine chorionic gonadotrophin (eCG ...

African Journals Online (AJOL)

SAM

2014-03-19

Mar 19, 2014 ... Key words: Equine chorionic gonadotrophin, follicular, ovulation, pregnancy, estrus synchronization, goat. ... This requires that the management practices take into account .... MOET, multiple ovulation and embryo transfer; PASW®, predictive analytics software; PMSG, pregnant mare serum gonadotropin.

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

Directory of Open Access Journals (Sweden)

Silla Aimee J

2010-11-01

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

Effects of spaceflight on hypothalamic peptide systems controlling pituitary growth hormone dynamics

Science.gov (United States)

Sawchenko, P. E.; Arias, C.; Krasnov, I.; Grindeland, R. E.; Vale, W.

1992-01-01

Possible effects of reduced gravity on central hypophysiotropic systems controlling growth hormone (GH) secretion were investigated in rats flown on Cosmos 1887 and 2044 biosatellites. Immunohistochemical (IHC)staining for the growth hormone-releasing factor (GRF), somatostatin (SS), and other hypothalamic hormones was performed on hypothalami obtained from rats. IHC analysis was complemented by quantitative in situ assessments of mRNAs encoding the precursors for these hormones. Data obtained suggest that exposure to microgravity causes a preferential reduction in GRF peptide and mRNA levels in hypophysiotropic neurons, which may contribute to impared GH secretion in animals subjected to spaceflight. Effects of weightlessness are not mimicked by hindlimb suspension in this system.

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

International Nuclear Information System (INIS)

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

1975-01-01

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

GnRH Neurons on LSD: A Year of Rejecting Hypotheses That May Have Made Karl Popper Proud.

Science.gov (United States)

Moenter, Suzanne M

2018-01-01

Gonadotropin-releasing hormone (GnRH) neurons are critical to many aspects of fertility regulation, from producing episodic release critical to both sexes, to providing a central signal to induce the ovulatory cascade in females. This year saw progress through the rejection, and occasional support, of hypotheses in understanding how GnRH neurons contribute to these processes. This brief review provides one laboratory's view of new insights into possible roles for these cells in development, adult reproductive function, and what may go wrong with GnRH neurons in some cases of infertility. Copyright © 2018 Endocrine Society.

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

Science.gov (United States)

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

2015-02-01

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

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

Directory of Open Access Journals (Sweden)

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.

Urinary gonadotrophins: a useful non-invasive marker of activation of the hypothalamic pituitary-gonadal axis

Directory of Open Access Journals (Sweden)

McNeilly Jane D

2012-05-01

Full Text Available Abstract Background Non-invasive screening investigations are rarely used for assessing the activation and progression of the hypothalamic-pituitary gonadal axis through puberty. This study aimed to establish a normal range for urinary gonadotrophins in children progressing through puberty. Methods Urine samples were collected from 161 healthy school children (76 boys, 85 girls aged 4–19 yrs. Height and weight were converted to standard deviation score. Pubertal status, classified by Tanner staging, was determined by self-assessment. Urinary gonadotrophins were measured by chemiluminescent microparticle immunoassay. Results were grouped according to pubertal status (pre-pubertal or pubertal. Results Of the 161 children, 50 were pre-pubertal (28 boys; 22 girls and 111 were pubertal (48 boys; 63 girls. Overall, urinary gonadotrophins concentrations increased with pubertal maturation. All pre-pubertal children had a low urinary LH:Creatinine ratio. LH:Creatinine ratios were significantly higher in pubertal compared to pre-pubertal boys (pp = 0.006. However, LH:FSH ratios were a more consistent discriminant between pre-pubertal and pubertal states in both sexes (Boys 0.45 pubertal vs 0.1 pre-pubertal; girls 0.23 pubertal vs 0.06 pre-pubertal. Conclusion Urinary gonadotrophins analyses could be used as non-invasive integrated measurement of pubertal status which reflects clinical/physical status.

Gad1 mRNA as a reliable indicator of altered GABA release from orexigenic neurons in the hypothalamus.

Science.gov (United States)

Dicken, Matthew S; Hughes, Alexander R; Hentges, Shane T

2015-11-01

The strength of γ-aminobutyric acid (GABA)-mediated inhibitory synaptic input is a principle determinant of neuronal activity. However, because of differences in the number of GABA afferent inputs and the sites of synapses, it is difficult to directly assay for altered GABA transmission between specific cells. The present study tested the hypothesis that the level of mRNA for the GABA synthetic enzyme glutamate decarboxylase (GAD) can provide a reliable proxy for GABA release. This was tested in a mouse hypothalamic circuit important in the regulation of energy balance. Fluorescent in situ hybridization results show that the expression of Gad1 mRNA (encoding the GAD67 enzyme) was increased in hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons after an overnight fast, consistent with the ability of GABA from these neurons to stimulate food intake. Optogenetic studies confirmed that the observed increase in Gad1 mRNA correlated with an increase in the probability of GABA release from NPY/AgRP neurons onto downstream proopiomelanocortin neurons. Likewise, there was an increase in the readily releasable pool of GABA in NPY/AgRP neurons. Selective inhibition of GAD activity in NPY/AgRP neurons decreased GABA release, indicating that GAD67 activity, which is largely dictated by expression level, is a key determinant of GABA release. Altogether, it appears that Gad expression may be a reliable proxy of altered GABAergic transmission. Examining changes in Gad mRNA as a proxy for GABA release may be particularly helpful when the downstream targets are not known or when limited tools exist for detecting GABA release at a particular synapse. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Effects of GnRH immunization in sexually mature pony stallions

NARCIS (Netherlands)

Turkstra, J.A.; Meer, F.J.U.M.; Knaap, J.; Rottier, P.J.M.; Teerds, K.J.; Colenbrander, B.; Meloen, R.H.

2005-01-01

Immunization against gonadotrophin releasing hormone (GnRH) was studied as an alternative for the commonly used surgical castration in stallions. Two GnRH vaccines comprising non-mineral oil adjuvants were evaluated for their potential to induce high antibody titers directed against GnRH and

GnRHa trigger for final oocyte maturation

DEFF Research Database (Denmark)

Humaidan, Peter; Alsbjerg, Birgit

2014-01-01

Since the introduction of the gonadotrophin-releasing hormone analogues (GnRHa) protocol, it has become possible to trigger final oocyte maturation with a bolus of GnRHa. This leads to a significant reduction or complete elimination of ovarian hyperstimulation syndrome compared with human chorion...

Resveratrol Produces Neurotrophic Effects on Cultured Dopaminergic Neurons through Prompting Astroglial BDNF and GDNF Release

Directory of Open Access Journals (Sweden)

Feng Zhang

2012-01-01

Full Text Available Increasing evidence indicated astroglia-derived neurotrophic factors generation might hold a promising therapy for Parkinson’s disease (PD. Resveratrol, naturally present in red wine and grapes with potential benefit for health, is well known to possess a number of pharmacological activities. Besides the antineuroinflammatory properties, we hypothesized the neuroprotective potency of resveratrol is partially due to its additional neurotrophic effects. Here, primary rat midbrain neuron-glia cultures were applied to investigate the neurotrophic effects mediated by resveratrol on dopamine (DA neurons and further explore the role of neurotrophic factors in its actions. Results showed resveratrol produced neurotrophic effects on cultured DA neurons. Additionally, astroglia-derived neurotrophic factors release was responsible for resveratrol-mediated neurotrophic properties as evidenced by the following observations: (1 resveratrol failed to exert neurotrophic effects on DA neurons in the cultures without astroglia; (2 the astroglia-conditioned medium prepared from astroglia-enriched cultures treated with resveratrol produced neurotrophic effects in neuron-enriched cultures; (3 resveratrol increased neurotrophic factors release in the concentration- and time-dependent manners; (4 resveratrol-mediated neurotrophic effects were suppressed by blocking the action of the neurotrophic factors. Together, resveratrol could produce neurotrophic effects on DA neurons through prompting neurotrophic factors release, and these effects might open new alternative avenues for neurotrophic factor-based therapy targeting PD.

Individualised gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility

DEFF Research Database (Denmark)

Lauritsen, Mette Petri; Loft, Anne; Pinborg, Anja

2017-01-01

Objective The aim of this study was to evaluate an individualised gonadotrophin starting dose regimen for women with anovulatory infertility. Study design We included 71 normogonadotrophic anovulatory infertile women in a prospective, observational study. All underwent one ovulation induction cycle...

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

International Nuclear Information System (INIS)

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

2016-01-01

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

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

Science.gov (United States)

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

1992-11-01

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

Relationship of oestrus synchronization method, circulating hormones, luteinizing hormone and prostaglandin F-2 alpha receptors and luteal progesterone concentration to premature luteal regression in superovulated sheep.

Science.gov (United States)

Schiewe, M C; Fitz, T A; Brown, J L; Stuart, L D; Wildt, D E

1991-09-01

Ewes were treated with exogenous follicle-stimulating hormone (FSH) and oestrus was synchronized using either a dual prostaglandin F-2 alpha (PGF-2 alpha) injection regimen or pessaries impregnated with medroxy progesterone acetate (MAP). Natural cycling ewes served as controls. After oestrus or AI (Day 0), corpora lutea (CL) were enucleated surgically from the left and right ovaries on Days 3 and 6, respectively. The incidence of premature luteolysis was related (P less than 0.05) to PGF-2 alpha treatment and occurred in 7 of 8 ewes compared with 0 of 4 controls and 1 of 8 MAP-exposed females. Sheep with regressing CL had lower circulating and intraluteal progesterone concentrations and fewer total and small dissociated luteal cells on Day 3 than gonadotrophin-treated counterparts with normal CL. Progesterone concentration in the serum and luteal tissue was higher (P less than 0.05) in gonadotrophin-treated ewes with normal CL than in the controls; but luteinizing hormone (LH) receptors/cell were not different on Days 3 and 6. There were no apparent differences in the temporal patterns of circulating oestradiol-17 beta, FSH and LH. High progesterone in gonadotrophin-treated ewes with normal CL coincided with an increase in total luteal mass and numbers of cells, which were primarily reflected in more small luteal cells than in control ewes. Gonadotrophin-treated ewes with regressing CL on Day 3 tended (P less than 0.10) to have fewer small luteal cells and fewer (P less than 0.05) low-affinity PGF-2 alpha binding sites than sheep with normal CL. By Day 6, luteal integrity and cell viability was absent in ewes with prematurely regressed CL. These data demonstrate that (i) the incidence of premature luteal regression is highly correlated with the use of PGF-2 alpha; (ii) this abnormal luteal tissue is functionally competent for 2-3 days after ovulation, but deteriorates rapidly thereafter and (iii) luteal-dysfunctioning ewes experience a reduction in numbers of

Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol.

Science.gov (United States)

Lovinger, David M

2008-01-01

Nerve cells (i.e., neurons) communicate via a combination of electrical and chemical signals. Within the neuron, electrical signals driven by charged particles allow rapid conduction from one end of the cell to the other. Communication between neurons occurs at tiny gaps called synapses, where specialized parts of the two cells (i.e., the presynaptic and postsynaptic neurons) come within nanometers of one another to allow for chemical transmission. The presynaptic neuron releases a chemical (i.e., a neurotransmitter) that is received by the postsynaptic neuron's specialized proteins called neurotransmitter receptors. The neurotransmitter molecules bind to the receptor proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors exist-ligand-gated ion channels, which permit rapid ion flow directly across the outer cell membrane, and G-protein-coupled receptors, which set into motion chemical signaling events within the cell. Hundreds of molecules are known to act as neurotransmitters in the brain. Neuronal development and function also are affected by peptides known as neurotrophins and by steroid hormones. This article reviews the chemical nature, neuronal actions, receptor subtypes, and therapeutic roles of several transmitters, neurotrophins, and hormones. It focuses on neurotransmitters with important roles in acute and chronic alcohol effects on the brain, such as those that contribute to intoxication, tolerance, dependence, and neurotoxicity, as well as maintained alcohol drinking and addiction.

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

Science.gov (United States)

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

2012-01-24

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

Levodopa-induced dyskinesia is associated with increased thyrotropin releasing hormone in the dorsal striatum of hemi-parkinsonian rats.

Directory of Open Access Journals (Sweden)

Ippolita Cantuti-Castelvetri

2010-11-01

Full Text Available Dyskinesias associated with involuntary movements and painful muscle contractions are a common and severe complication of standard levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine therapy for Parkinson's disease. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition.Quantitative real-time polymerase chain reaction (PCR was employed to evaluate the molecular changes associated with L-DOPA-induced dyskinesias in Parkinson's disease. With this technique, we determined that thyrotropin releasing hormone (TRH was greatly increased in the dopamine-depleted striatum of hemi-parkinsonian rats that developed abnormal movements in response to L-DOPA therapy, relative to the levels measured in the contralateral non-dopamine-depleted striatum, and in the striatum of non-dyskinetic control rats. ProTRH immunostaining suggested that TRH peptide levels were almost absent in the dopamine-depleted striatum of control rats that did not develop dyskinesias, but in the dyskinetic rats, proTRH immunostaining was dramatically up-regulated in the striatum, particularly in the sensorimotor striatum. This up-regulation of TRH peptide affected striatal medium spiny neurons of both the direct and indirect pathways, as well as neurons in striosomes.TRH is not known to be a key striatal neuromodulator, but intrastriatal injection of TRH in experimental animals can induce abnormal movements, apparently through increasing dopamine release. Our finding of a dramatic and selective up-regulation of TRH expression in the sensorimotor striatum of dyskinetic rat models suggests a TRH-mediated regulatory mechanism that may underlie the pathologic neuroplasticity driving dopamine hyper-responsivity in Parkinson's disease.

Neurochemistry of bulbospinal presympathetic neurons of the medulla oblongata.

Science.gov (United States)

Stornetta, Ruth L

2009-11-01

This review focuses on presympathetic neurons in the medulla oblongata including the adrenergic cell groups C1-C3 in the rostral ventrolateral medulla and the serotonergic, GABAergic and glycinergic neurons in the ventromedial medulla. The phenotypes of these neurons including colocalized neuropeptides (e.g., neuropeptide Y, enkephalin, thyrotropin-releasing hormone, substance P) as well as their relative anatomical location are considered in relation to predicting their function in control of sympathetic outflow, in particular the sympathetic outflows controlling blood pressure and thermoregulation. Several explanations are considered for how the neuroeffectors coexisting in these neurons might be functioning, although their exact purpose remains unknown. Although there is abundant data on potential neurotransmitters and neuropeptides contained in the presympathetic neurons, we are still unable to predict function and physiology based solely on the phenotype of these neurons.

Transient increase in neuronal chloride concentration by neuroactive amino acids released from glioma cells

Directory of Open Access Journals (Sweden)

Cristina eBertollini

2012-11-01

Full Text Available Neuronal chloride concentration ([Cl-]i is known to be dynamically modulated and alterations in Cl- homeostasis may occur in the brain at physiological and pathological conditions, being also likely involved in glioma-related seizures. However, the mechanism leading to changes in neuronal [Cl-]i during glioma invasion are still unclear. To characterize the potential effect of glioma released soluble factors on neuronal [Cl-]i, we used genetically encoded CFP/YFP-based ratiometric Cl-Sensor transiently expressed in cultured hippocampal neurons. Exposition of neurons to glioma conditioned medium (GCM caused rapid and transient elevation of [Cl-]i, resulting in the increase of fluorescence ratio, which was strongly reduced by blockers of ionotropic glutamate receptors APV and NBQX. Furthermore, in HEK cells expressing GluR1-AMPA receptors, GCM activated ionic current with efficacy similar to those caused by glutamate, supporting the notion that GCM contains glutamate or glutamatergic agonists, which cause neuronal depolarization, activation of NMDA and AMPA/KA receptors leading to elevation of [Cl-]i. Chromatographic analysis of the GCM showed that it contained several aminoacids, including glutamate, whose release from glioma cells did not occur via the most common glial mechanisms of transport, or in response to hypoosmotic stress. GCM also contained glycine, whose action contrasted the glutamate effect. Indeed, strychnine application significantly increased GCM-induced depolarization and [Cl-]i rise. GCM-evoked [Cl-]i elevation was not inhibited by antagonists of Cl- transporters and significantly reduced in the presence of anion channels blocker NPPB, suggesting that Cl-selective channels are a major route for GCM-induced Cl- influx. Altogether, these data show that glioma released aminoacids may dynamically alter Cl- equilibrium in surrounding neurons, deeply interfering with their inhibitory balance, likely leading to physiological and

Effect of delayed sponge withdrawal on the superovulatory response ...

African Journals Online (AJOL)

progestagen sponges and superovulated with 1000 IV pregnant mare serum gonadotrophin ... recovered was 141 (recovery rate 51.5%) and the number of trans- ... Fixed-time artificial insemination (AI) was performed at 36 h ... and should not affect embryo .... releasing hormone treatment in the collection of sheep embryos.

Suppression of grasshopper sound production by nitric oxide-releasing neurons of the central complex

Science.gov (United States)

Weinrich, Anja; Kunst, Michael; Wirmer, Andrea; Holstein, Gay R.

2008-01-01

The central complex of acridid grasshoppers integrates sensory information pertinent to reproduction-related acoustic communication. Activation of nitric oxide (NO)/cyclic GMP-signaling by injection of NO donors into the central complex of restrained Chorthippus biguttulus females suppresses muscarine-stimulated sound production. In contrast, sound production is released by aminoguanidine (AG)-mediated inhibition of nitric oxide synthase (NOS) in the central body, suggesting a basal release of NO that suppresses singing in this situation. Using anti-citrulline immunocytochemistry to detect recent NO production, subtypes of columnar neurons with somata located in the pars intercerebralis and tangential neurons with somata in the ventro-median protocerebrum were distinctly labeled. Their arborizations in the central body upper division overlap with expression patterns for NOS and with the site of injection where NO donors suppress sound production. Systemic application of AG increases the responsiveness of unrestrained females to male calling songs. Identical treatment with the NOS inhibitor that increased male song-stimulated sound production in females induced a marked reduction of citrulline accumulation in central complex columnar and tangential neurons. We conclude that behavioral situations that are unfavorable for sound production (like being restrained) activate NOS-expressing central body neurons to release NO and elevate the behavioral threshold for sound production in female grasshoppers. PMID:18574586

The novel fusion proteins, GnRH-p53 and GnRHIII-p53, expression and their anti-tumor effect.

Directory of Open Access Journals (Sweden)

Peiyuan Jia

Full Text Available p53, one of the most well studied tumor suppressor factor, is responsible to a variety of damage owing to the induction of apoptosis and cell cycle arrest in the tumor cells. More than 50% of human tumors contain mutation or deletion of p53. Gonadotrophin-releasing hormone (GnRH, as the ligand of Gonadotrophin-releasing hormone receptor (GnRH-R, was used to deliver p53 into tumor cells. The p53 fusion proteins GnRH-p53 and GnRH iii-p53 were expressed and their targeted anti-tumor effects were determined. GnRH mediates its fusion proteins transformation into cancer cells. The intracellular delivery of p53 fusion proteins exerted the inhibition of the growth of H1299 cells in vitro and the reduction of tumor volume in vivo. Their anti-tumor effect was functioned by the apoptosis and cell cycle arrest induced by p53. Hence, the fusion protein could be a novel protein drug for anti-tumor therapy.

Photoperiodic Co-Regulation of Kisspeptin, Neurokinin B and Dynorphin in the Hypothalamus of a Seasonal Rodent

DEFF Research Database (Denmark)

Bartzen-Sprauer, J; Klosen, P; Ciofi, P

2014-01-01

In many species, sexual activity varies on a seasonal basis. Kisspeptin (Kp), a hypothalamic neuropeptide acting as a strong activator of gonadotrophin-releasing hormone neurones, plays a critical role in this adaptive process. Recent studies report that two other neuropeptides, namely neurokinin...... (NKB) and dynorphin (DYN), are co-expressed with Kp (and therefore termed KNDy neurones) in the arcuate nucleus and that these peptides are also considered to influence GnRH secretion. The present study aimed to establish whether hypothalamic NKB and DYN expression is photoperiod......-dependent in a seasonal rodent, the Syrian hamster, which exhibits robust seasonal rhythms in reproductive activity. The majority of Kp neurones in the arcuate nucleus co-express NKB and DYN and the expression of all three peptides is decreased under a short (compared to long) photoperiod, leading to a 60% decrease......-localise with RFRP-immunoreactive neurones, and the expression of both NKB and DYN is higher under a short photoperiod, which is opposite to the short-day inhibition of RFRP expression. In conclusion, the present study shows that NKB and DYN display different photoperiodic variations in the Syrian hamster...

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

Science.gov (United States)

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

2011-01-01

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

Primary cell culture of LHRH neurones from embryonic olfactory placode in the sheep (Ovis aries).

Science.gov (United States)

Duittoz, A H; Batailler, M; Caldani, M

1997-09-01

The aim of this study was to establish an in vitro model of ovine luteinizing hormone-releasing hormone (LHRH) neurones. Olfactory placodes from 26 day-old sheep embryos (E26) were used for explant culture. Cultures were maintained successfully up to 35 days, but were usually used at 17 days for immunocytochemistry. LHRH and neuronal markers such as neurofilament (NF) were detected by immunocytochemistry within and/or outside the explant. Three main types of LHRH positive cells are described: (1) neuroblastic LHRH and NF immunoreactive cells with round cell body and very short neurites found mainly within the explant, (2) migrating LHRH bipolar neurones with an fusiform cell body, found outside the explant, (3) network LHRH neuron, bipolar or multipolar with long neurites connecting other LHRH neurons. Cell morphology was very similar to that which has been described in the adult sheep brain. These results strongly suggest that LHRH neurones in the sheep originate from the olfactory placode. This mode may represent a useful tool to study LHRH neurones directly in the sheep.

Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep

Science.gov (United States)

Liu, Kai; Kim, Juhyun; Kim, Dong Won; Zhang, Yi Stephanie; Bao, Hechen; Denaxa, Myrto; Lim, Szu-Aun; Kim, Eileen; Liu, Chang; Wickersham, Ian R.; Pachnis, Vassilis; Hattar, Samer; Song, Juan; Brown, Solange P.; Blackshaw, Seth

2017-01-01

Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified1. Wake-promoting cell types include hypocretin and GABA (γ-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep2,3. Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep–wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep. PMID:28847002

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

International Nuclear Information System (INIS)

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

1988-01-01

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

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.

A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep

Directory of Open Access Journals (Sweden)

Salin Paul

2003-09-01

Full Text Available Abstract Background Peptidergic neurons containing the melanin-concentrating hormone (MCH and the hypocretins (or orexins are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation. Results Here we show that the MCH but not the hypocretin neurons are strongly active during PS, evidenced through combined hypocretin, MCH, and Fos immunostainings in three groups of rats (PS Control, PS Deprived and PS Recovery rats. Further, we show that ICV administration of MCH induces a dose-dependant increase in PS (up to 200% and slow wave sleep (up to 70% quantities. Conclusion These results indicate that MCH is a powerful hypnogenic factor. MCH neurons might play a key role in the state of PS via their widespread projections in the central nervous system.

Multivesicular release underlies short term synaptic potentiation independent of release probability change in the supraoptic nucleus.

Directory of Open Access Journals (Sweden)

Michelle E Quinlan

Full Text Available Magnocellular neurons of the supraoptic nucleus receive glutamatergic excitatory inputs that regulate the firing activity and hormone release from these neurons. A strong, brief activation of these excitatory inputs induces a lingering barrage of tetrodotoxin-resistant miniature EPSCs (mEPSCs that lasts for tens of minutes. This is known to accompany an immediate increase in large amplitude mEPSCs. However, it remains unknown how long this amplitude increase can last and whether it is simply a byproduct of greater release probability. Using in vitro patch clamp recording on acute rat brain slices, we found that a brief, high frequency stimulation (HFS of afferents induced a potentiation of mEPSC amplitude lasting up to 20 min. This amplitude potentiation did not correlate with changes in mEPSC frequency, suggesting that it does not reflect changes in presynaptic release probability. Nonetheless, neither postsynaptic calcium chelator nor the NMDA receptor antagonist blocked the potentiation. Together with the known calcium dependency of HFS-induced potentiation of mEPSCs, our results imply that mEPSC amplitude increase requires presynaptic calcium. Further analysis showed multimodal distribution of mEPSC amplitude, suggesting that large mEPSCs were due to multivesicular glutamate release, even at late post-HFS when the frequency is no longer elevated. In conclusion, high frequency activation of excitatory synapses induces lasting multivesicular release in the SON, which is independent of changes in release probability. This represents a novel form of synaptic plasticity that may contribute to prolonged excitatory tone necessary for generation of burst firing of magnocellular neurons.

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis.

Science.gov (United States)

Sokolowski, Jennifer D; Chabanon-Hicks, Chloe N; Han, Claudia Z; Heffron, Daniel S; Mandell, James W

2014-01-01

Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout (KO) and CX3CR1-KO mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a "find-me" signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-KO and CX3CR1-KO mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these KOs by 6 h after ethanol treatment. Collectively, this suggests that fractalkine acts as a "find me" signal released by apoptotic neurons, and subsequently plays a critical role in modulating both clearance and inflammatory cytokine gene expression after ethanol-induced apoptosis.

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis

Directory of Open Access Journals (Sweden)

Jennifer D Sokolowski

2014-11-01

Full Text Available Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout and CX3CR1-knockout mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a ‘find-me’ signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-knockout and CX3CR1-knockout mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these knockouts by 6 hours after ethanol treatment. Collectively, this suggests that fractalkine acts as a ‘find me’ signal released by apoptotic neurons, and subsequently plays a critical role in modulating both phagocytic clearance and inflammatory cytokine gene expression after

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

Science.gov (United States)

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

1991-01-01

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

RFRP neurons are critical gatekeepers for the photoperiodic control of reproduction

Directory of Open Access Journals (Sweden)

Valerie eSimonneaux

2012-12-01

Full Text Available Seasonally-breeding mammals rely on the photoperiodic signal to restrict their fertility to a certain time of the year. The photoperiodic information is translated in the brain via the pineal hormone melatonin, and it is now well established that it is the variation in the duration of the nocturnal peak of melatonin which synchronises reproduction with the seasons. The Syrian hamster is a long day breeder, and sexual activity is therefore promoted by exposure to a long day photoperiod and inhibited by exposure to a short day photoperiod. Interestingly, in this species electrolytic lesion of the mediobasal hypothalamus abolishes the short day-induced gonadal regression. We have shown that the expression of a recently discovered neuronal population, namely RFamide-related peptide (rfrp neurons, present in the mediobasal hypothalamus, is strongly down-regulated by melatonin in short day conditions, but not altered by circulating levels of sex steroids. The role of rfrp and its product RFRP-3 in the regulation of reproductive activity has been extensively studied in mammals, and our recent findings indicate that this peptide is a potent stimulator of the reproductive axis in the Syrian hamster. It induces a marked increase in GnRH neuron activity and gonadotrophin secretion, and it is able to rescue reproductive activity in short day sexually inactive hamsters. Little is known about the localisation of the RFRP-3 receptor, GPR147, in the rodent brain. Accumulating evidence suggests that RFRP-3 could be acting via two intermediates, the GnRH neurons in the preoptic area and the Kiss1 neurons in the arcuate nucleus, but future studies should aim at describing the localisation of Gpr147 in the Syrian hamster brain. Altogether our data indicate that the rfrp neuronal population within the mediobasal hypothalamus might be a serious candidate in mediating the photoperiodic effects of melatonin on the regulation of the reproductive axis.

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.

the use of a gonadotrophin releasing hormone in cattle: changes in ...

African Journals Online (AJOL)

clt. Eo. (J. B8 c) .tt . 9"o. E4 eq) a. 2 o o lr. /I. / o a. /. P.. /. /-o. /. /,o o-. /to. / o. /. /. / o t. -o/. \\o'o. / o o. /. /. ,ao l -o'"-o-o. {-t by radioimmunoassay technique of Youssefnejadian,. Florensa. Collins and Sommerville (1972), as modified by Faure (1975). Experiment 2. Bulls were introduced, under rancing conditions, to. 85 lactating ...

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.

Science.gov (United States)

Wu, Min; Dumalska, Iryna; Morozova, Elena; van den Pol, Anthony; Alreja, Meenakshi

2009-10-06

A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba(2+)-sensitive K(+) channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.

[The diagnostic value of human chorionic gonadotrophin ratio compared to single measurements of S-human chorionic gonadotrophin on the outcome of pregnancy of unknown location].

Science.gov (United States)

Majeed, Huda Galib; Lyngsø, Julie; Bor, Pinar

2014-10-13

Pregnancy of unknown location is defined by a positive pregnancy test, without visualizing of the intrauterine or extrauterine pregnancy by transvaginal sonography. We present the advantages of using human chorionic gonadotrophin (hCG) ratio instead of single measurements of S-hCG for predicting the outcomes of pregnancies of unknown location.

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

Science.gov (United States)

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

2010-12-01

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

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

DEFF Research Database (Denmark)

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

1992-01-01

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

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

DEFF Research Database (Denmark)

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

1998-01-01

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

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

Science.gov (United States)

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

1990-02-01

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

Dehydration-induced release of vasopressin involves activation of hypothalamic histaminergic neurons.

Science.gov (United States)

Kjaer, A; Knigge, U; Rouleau, A; Garbarg, M; Warberg, J

1994-08-01

The hypothalamic neurotransmitter histamine (HA) induces arginine vasopressin (AVP) release when administered centrally. We studied and characterized this effect of HA with respect to receptor involvement. In addition, we studied the possible role of hypothalamic histaminergic neurons in the mediation of a physiological stimulus (dehydration) for AVP secretion. Intracerebroventricular administration of HA, the H1-receptor agonists 2(3-bromophenyl)HA and 2-thiazolylethylamine, or the H2-receptor agonists amthamine or 4-methyl-HA stimulated AVP secretion. The stimulatory action of HA on AVP was inhibited by pretreatment with the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine. Twenty-four hours of dehydration elevated the plasma osmolality from 298 +/- 3 to 310 +/- 3 mmol/liter and increased the plasma AVP concentration 4-fold. The hypothalamic content of HA and its metabolite tele-methyl-HA was elevated in response to dehydration, indicating an increased synthesis and release of hypothalamic HA. Dehydration-induced AVP secretion was lowered when neuronal HA synthesis was inhibited by the administration of (S) alpha-fluoromethylhistidine or when the animals were pretreated with the H3-receptor agonist R(alpha)methylhistamine, which inhibits the release and synthesis of HA, the H1-receptor antagonists mepyramine and cetirizine, or the H2-receptor antagonists cimetidine and ranitidine. We conclude that HA, via activation of both H1- and H2-receptors, stimulates AVP release and that HA is a physiological regulator of AVP secretion.

Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction.

Science.gov (United States)

Bellefontaine, Nicole; Chachlaki, Konstantina; Parkash, Jyoti; Vanacker, Charlotte; Colledge, William; d'Anglemont de Tassigny, Xavier; Garthwaite, John; Bouret, Sebastien G; Prevot, Vincent

2014-06-01

The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region.

Postsynaptic Depolarization Enhances GABA Drive to Dorsomedial Hypothalamic Neurons through Somatodendritic Cholecystokinin Release.

Science.gov (United States)

Crosby, Karen M; Baimoukhametova, Dinara V; Bains, Jaideep S; Pittman, Quentin J

2015-09-23

Somatodendritically released peptides alter synaptic function through a variety of mechanisms, including autocrine actions that liberate retrograde transmitters. Cholecystokinin (CCK) is a neuropeptide expressed in neurons in the dorsomedial hypothalamic nucleus (DMH), a region implicated in satiety and stress. There are clear demonstrations that exogenous CCK modulates food intake and neuropeptide expression in the DMH, but there is no information on how endogenous CCK alters synaptic properties. Here, we provide the first report of somatodendritic release of CCK in the brain in male Sprague Dawley rats. CCK is released from DMH neurons in response to repeated postsynaptic depolarizations, and acts in an autocrine fashion on CCK2 receptors to enhance postsynaptic NMDA receptor function and liberate the retrograde transmitter, nitric oxide (NO). NO subsequently acts presynaptically to enhance GABA release through a soluble guanylate cyclase-mediated pathway. These data provide the first demonstration of synaptic actions of somatodendritically released CCK in the hypothalamus and reveal a new form of retrograde plasticity, depolarization-induced potentiation of inhibition. Significance statement: Somatodendritic signaling using endocannabinoids or nitric oxide to alter the efficacy of afferent transmission is well established. Despite early convincing evidence for somatodendritic release of neurohypophysial peptides in the hypothalamus, there is only limited evidence for this mode of release for other peptides. Here, we provide the first evidence for somatodendritic release of the satiety peptide cholecystokinin (CCK) in the brain. We also reveal a new form of synaptic plasticity in which postsynaptic depolarization results in enhancement of inhibition through the somatodendritic release of CCK. Copyright © 2015 the authors 0270-6474/15/3513160-11$15.00/0.

Corticotropin releasing hormone and imaging, rethinking the stress axis

International Nuclear Information System (INIS)

Contoreggi, Carlo

2015-01-01

The stress system provides integration of both neurochemical and somatic physiologic functions within organisms as an adaptive mechanism to changing environmental conditions throughout evolution. In mammals and primates the complexity and sophistication of these systems have surpassed other species in triaging neurochemical and physiologic signaling to maximize chances of survival. Corticotropin releasing hormone (CRH) and its related peptides and receptors have been identified over the last three decades and are fundamental molecular initiators of the stress response. They are crucial in the top down regulatory cascade over a myriad of neurochemical, neuroendocrine and sympathetic nervous system events. From neuroscience, we've seen that stress activation impacts behavior, endocrine and somatic physiology and influences neurochemical events that one can capture in real time with current imaging technologies. To delineate these effects one can demonstrate how the CRH neuronal networks infiltrate critical cognitive, emotive and autonomic regions of the central nervous system (CNS) with somatic effects. Abundant preclinical and clinical studies show inter-regulatory actions of CRH with multiple neurotransmitters/peptides. Stress, both acute and chronic has epigenetic effects which magnify genetic susceptibilities to alter neurochemistry; stress system activation can add critical variables in design and interpretation of basic and clinical neuroscience and related research. This review will attempt to provide an overview of the spectrum of known functions and speculative actions of CRH and stress responses in light of imaging technology and its interpretation. Metabolic and neuroreceptor positron emission/single photon tomography (PET/SPECT), functional magnetic resonance imaging (fMRI), anatomic MRI, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (pMRS) are technologies that can delineate basic mechanisms of neurophysiology and

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

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

Czech Academy of Sciences Publication Activity Database

Valeš, Karel; Řezáčová, Lenka; Stuchlík, Aleš

2008-01-01

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

The Nitric Oxide Donor SNAP-Induced Amino Acid Neurotransmitter Release in Cortical Neurons. Effects of Blockers of Voltage-Dependent Sodium and Calcium Channels

Science.gov (United States)

Merino, José Joaquín; Arce, Carmen; Naddaf, Ahmad; Bellver-Landete, Victor; Oset-Gasque, Maria Jesús; González, María Pilar

2014-01-01

Background The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated. Findings The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated. Conclusions Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons. PMID:24598811

The nitric oxide donor SNAP-induced amino acid neurotransmitter release in cortical neurons. Effects of blockers of voltage-dependent sodium and calcium channels.

Science.gov (United States)

Merino, José Joaquín; Arce, Carmen; Naddaf, Ahmad; Bellver-Landete, Victor; Oset-Gasque, Maria Jesús; González, María Pilar

2014-01-01

The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated. The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated. Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons.

The nitric oxide donor SNAP-induced amino acid neurotransmitter release in cortical neurons. Effects of blockers of voltage-dependent sodium and calcium channels.

Directory of Open Access Journals (Sweden)

José Joaquín Merino

Full Text Available The discovery that nitric oxide (NO functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated.The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated.Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons.

Hormonal priming, induction of ovulation and in-vitro fertilization of the endangered Wyoming toad (Bufo baxteri

Directory of Open Access Journals (Sweden)

Seratt Jessica

2006-06-01

Full Text Available Abstract The endangered Wyoming toad (Bufo baxteri is the subject of an extensive captive breeding and reintroduction program. Wyoming toads in captivity rarely ovulate spontaneously and hormonal induction is used to ovulate females or to stimulate spermiation in males. With hormonal induction, ovulation is unreliable and egg numbers are low. The sequential administration of anovulatory doses of hormones (priming has increased egg numbers and quality in both anurans and fish. Consequently, we tested the efficacy of a combination of human Chorionic Gonadotrophin (hCG and Luteinizing Hormone Releasing Hormone analogue (LHRHa administered as one dose, or two or three sequential doses to Bufo baxteri on egg numbers, fertilization and early embryo development. Spawning toads deposited eggs into Simplified Amphibian Ringers (SAR solution to enable controlled in-vitro fertilization (IVF with sperm from hormonally induced male toads. Unprimed females receiving a single mixed normally ovulatory dose of 500 IU hCG plus 4 micrograms of LHRHa produced no eggs. Whereas females primed with this dose and an anovulatory dose (100 IU hCG and 0.8 micrograms of LHRHa of the same hormones, or primed only with an anovulatory dose, spawned after then receiving an ovulatory dose. Higher total egg numbers were produced with two primings than with one priming. Moreover, two primings produced significantly more eggs from each individual female than one priming. The cleavage rate of eggs was not found to differ between one or two primings. Nevertheless, embryo development with eggs from two primings gave a significantly greater percentage neurulation and swim-up than those from one priming. Of the male toads receiving a single dose of 300 IU hCG, 80% produced spermic urine with the greatest sperm concentration 7 hours post-administration (PA. However, peak sperm motility (95% was achieved at 5 hours PA and remained relatively constant until declining 20 hours PA. In

Relevance of the radioimmunological determination of FSH, LH, and prolactine for the diagnosis and therapy of gynaecological-endocrinological discuses, studied in the patients of the hormone consultant ward of the gynaecological hospital of the University of Cologne, 1973 to 1975

International Nuclear Information System (INIS)

Gaschler, E.

1978-01-01

The physiology of the hypophysical gonadotrophins in women is described. The group of the patients is classified, and the normal curves for FSH, LH and HPR in the serum are shown. The author tries in the main part to bring the gonadotrophins in the various syndromes which brought the patients into the clinic, for a 'hormone consultation', in connection with other clinical findings and to compare also the individual syndromes with each other. We can see that the gonadotrophin determination can, in correct indication, be a valuable diagnostic aid which, even if used only once, is highly reliable, thanks to the accuracy of the radio immune-systems used today. (orig./AJ) [de

A Natural Variant of Obestatin, Q90L, Inhibits Ghrelin's Action on Food Intake and GH Secretion and Targets NPY and GHRH Neurons in Mice

OpenAIRE

Hassouna, Rim; Zizzari, Philippe; Viltart, Odile; Yang, Seung-Kwon; Gardette, Robert; Videau, Catherine; Badoer, Emilio; Epelbaum, Jacques; Tolle, Virginie

2012-01-01

BACKGROUND: Ghrelin and obestatin are two gut-derived peptides originating from the same ghrelin/obestatin prepropeptide gene (GHRL). While ghrelin stimulates growth hormone (GH) secretion and food intake and inhibits γ-aminobutyric-acid synaptic transmission onto GHRH (Growth Hormone Releasing Hormone) neurons, obestatin blocks these effects. In Humans, GHRL gene polymorphisms have been associated with pathologies linked to an unbalanced energy homeostasis. We hypothesized that one polymorph...

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 mast cell stabilizer sodium cromoglycate reduces histamine release and status epilepticus-induced neuronal damage in the rat hippocampus.

Science.gov (United States)

Valle-Dorado, María Guadalupe; Santana-Gómez, César Emmanuel; Orozco-Suárez, Sandra Adela; Rocha, Luisa

2015-05-01

Experiments were designed to evaluate changes in the histamine release, mast cell number and neuronal damage in hippocampus induced by status epilepticus. We also evaluated if sodium cromoglycate, a stabilizer of mast cells with a possible stabilizing effect on the membrane of neurons, was able to prevent the release of histamine, γ-aminobutyric acid (GABA) and glutamate during the status epilepticus. During microdialysis experiments, rats were treated with saline (SS-SE) or sodium cromoglycate (CG-SE) and 30 min later received the administration of pilocarpine to induce status epilepticus. Twenty-four hours after the status epilepticus, the brains were used to determine the neuronal damage and the number of mast cells in hippocampus. During the status epilepticus, SS-SE group showed an enhanced release of histamine (138.5%, p = 0.005), GABA (331 ± 91%, p ≤ 0.001) and glutamate (467%, p ≤ 0.001), even after diazepam administration. One day after the status epilepticus, SS-SE group demonstrated increased number of mast cells in Stratum pyramidale of CA1 (88%, p status epilepticus (p = 0.048), absence of wet-dog shakes, reduced histamine (but not GABA and glutamate) release, lower number of mast cells (p = 0.008) and reduced neuronal damage in hippocampus. Our data revealed that histamine, possibly from mast cells, is released in hippocampus during the status epilepticus. This effect may be involved in the subsequent neuronal damage and is diminished with sodium cromoglycate pretreatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

Georgopoulos, N A; Markou, K B; Pappas, A P; Protonatariou, A; Vagenakis, G A; Sykiotis, G P; Dimopoulos, P A; Tzingounis, V A

2001-12-01

Hypothalamic amenorrhea is a treatable cause of infertility. Our patient was presented with secondary amenorrhea and diabetes insipidus. Cortisol and prolactin responded normally to a combined insulin tolerance test (ITT) and thyrotropin-releasing hormone (TRH) challenge, while thyroid-stimulating hormone (TSH) response to TRH was diminished, and no response of growth hormone to ITT was detected. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels increased following gonadotropin-releasing hormone (GnRH) challenge. No response of LH to clomiphene citrate challenge was detected. Magnetic resonance imaging findings demonstrated a midline mass occupying the inferior hypothalamus, with posterior lobe not visible and thickened pituitary stalk. Ovulation induction was carried out first with combined human menopausal gonadotropins (hMG/LH/FSH) (150 IU/day) and afterwards with pulsatile GnRH (150 ng/kg/pulse). Ovulation was achieved with both pulsatile GnRH and combine gonadotropin therapy. Slightly better results were achieved with the pulsatile GnRH treatment.

EFFECT OF POST-MATING GNRH TREATMET ON SERUM PROGESTERONE, LUTEINIZING HORMONE LEVELS, DURATION OF ESTROUS CYCLE AND PREGNANCY RATES IN COWS

Directory of Open Access Journals (Sweden)

H. YILDIZ, E. KAYGUSUZOĞLU, M. KAYA1 AND M. ÇENESIZ1

2009-07-01

Full Text Available Pregnancy rate, estrous cycle lenght, serum progesterone and luteinizing hormone (LH concentrations were determined in gonadotropin releasing hormone (GnRH; 10.5 μg synthetic gonadotrophin releasing hormone agonist, receptal administered cows on day 12 post-mating (n=9 compared to control cows (n=8. Their oestrous cycles were synchronised by intramuscular administration of prostaglandin F2 alpha (its analog, cloprostenol twice at 11 days interval. Estrous exhibited cows were mated naturally. Blood samples were collected every two days from all animals. Serum progesterone and LH concentrations were measured by ELISA method. GnRH administration significantly increased serum LH concentration which reached peak levels 2-3 h after treatment. However, serum progesterone concentration was not affected. There were no differences in mean progesterone concentrations on days 12 to 24 post-mating between GnRH administrated and control pregnant cows. However, in non pregnant animals, progesterone concentrations on days 16 in the treated group were lower than control group (P<0.01. Pregnancy diagnosis in animals made by B-mode ultrasonography between the 30th and 35th day showed that 77.7% of treated cows were pregnant compared to 50% in control group. Duration of the estrous cycle in the non-pregnant animals was not affected by the treatment (control, 21.3 ± 0.8 days; treated, 22.5 ± 0.5 days. In conclusion, this study supports the use of GnRH on day 12 post-mating as a method for enhancing pregnancy rates in lactating dairy cattle.

Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons.

Science.gov (United States)

Pittman, Sherry K; Gracias, Neilia G; Fehrenbacher, Jill C

2016-05-01

Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivity was assessed using the stimulated release of calcitonin gene-related peptide (CGRP), whereas morphology of established neurites was evaluated using a high content screening system. Dorsal root ganglion cultures, maintained in the absence or presence of NGF, were treated from day 7 to day 12 in culture with paclitaxel (300nM) or EpoB (30nM). Following treatment, the release of CGRP was stimulated using capsaicin or high extracellular potassium. In the presence of NGF, EpoB mimicked the effects of paclitaxel: capsaicin-stimulated release was attenuated, potassium-stimulated release was slightly enhanced and the total peptide content was unchanged. In the absence of NGF, both paclitaxel and EpoB decreased capsaicin- and potassium-stimulated release and the total peptide content, suggesting that NGF may reverse MTA-induced hyposensitivity. Paclitaxel and EpoB both decreased neurite length and branching, and this attenuation was unaffected by NGF in the growth media. These differential effects of NGF on neuronal sensitivity and morphology suggest that neurite retraction is not a causative factor to alter neuronal sensitivity. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of GABA in the regulation of GnRH neurons

Directory of Open Access Journals (Sweden)

Miho eWatanabe

2014-11-01

Full Text Available Gonadotropin-releasing hormone (GnRH neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction.

Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects.

Science.gov (United States)

Berlanga-Acosta, Jorge; Abreu-Cruz, Angel; Herrera, Diana García-Del Barco; Mendoza-Marí, Yssel; Rodríguez-Ulloa, Arielis; García-Ojalvo, Ariana; Falcón-Cama, Viviana; Hernández-Bernal, Francisco; Beichen, Qu; Guillén-Nieto, Gerardo

2017-01-01

Growth hormone-releasing peptides (GHRPs) constitute a group of small synthetic peptides that stimulate the growth hormone secretion and the downstream axis activity. Mounting evidences since the early 1980s delineated unexpected pharmacological cardioprotective and cytoprotective properties for the GHRPs. However, despite intense basic pharmacological research, alternatives to prevent cell and tissue demise before lethal insults have remained as an empty niche in the clinical armamentarium. Here, we have rigorously reviewed the investigational development of GHRPs and their clinical niching perspectives. PubMed/MEDLINE databases, including original research and review articles, were explored. The search design was date escalated from 1980 and included articles in English only. GHRPs bind to two different receptors (GHS-R1a and CD36), which redundantly or independently exert relevant biological effects. GHRPs' binding to CD36 activates prosurvival pathways such as PI-3K/AKT1, thus reducing cellular death. Furthermore, GHRPs decrease reactive oxygen species (ROS) spillover, enhance the antioxidant defenses, and reduce inflammation. These cytoprotective abilities have been revealed in cardiac, neuronal, gastrointestinal, and hepatic cells, representing a comprehensive spectrum of protection of parenchymal organs. Antifibrotic effects have been attributed to some of the GHRPs by counteracting fibrogenic cytokines. In addition, GHRP family members have shown a potent myotropic effect by promoting anabolia and inhibiting catabolia. Finally, GHRPs exhibit a broad safety profile in preclinical and clinical settings. Despite these fragmented lines incite to envision multiple pharmacological uses for GHRPs, especially as a myocardial reperfusion damage-attenuating candidate, this family of "drugable" peptides awaits for a definitive clinical niche.

Preparation of slowly released male sex hormone drug by radiation polymerization technique and its evaluation in vivo

International Nuclear Information System (INIS)

Liu Rueizhi; Lei Shaoqiong; Li Ximing

1992-01-01

The radiation polymerization technique was used for immobilization testosterone propionate into crosslinked network of poly hydroxyethyl methacrylate to prepare slowly released male sex hormone drug which is used for testicular prosthesis. The testicular prosthesis was transplanted into the scrotum of male rabbit whose testes was excised 2 months before the transplantation. Then the level of male sex hormone in serum was measured by radioimmunoassay once a week after transplantation. The results of measurement in a period of 6 months were shown that the testicular prosthesis has a stable release of male sex hormone. The testosterone level in serum of the castrated male rabbits rises markedly and finally stabilizes at the level of 429 ± 36 ng/100 ml after transplantation. Macroscopic examination of biopsies taken from the tissues around the testicular prosthesis showed that tissue compatibility was revealed well

Effects of GnRH, a progesterone-releasing device, and energy balance on an oestrus synchronisation program in anoestrous dairy cows.

Science.gov (United States)

Sahu, S K; Cockrem, J F; Parkinson, T J; Laven, R A

2017-08-01

The aim of this research was to study the roles of the day 0 energy balance and gonadotrophin-releasing hormone (GnRH) and progesterone levels on dominant follicle (DF) and corpus luteum (CL) development during the first 7 days of a gonadotrophin-prostaglandin-gonadotrophin (GPG) + progesterone (P4) program in anoestrous dairy cows. Cows (n = 81) were allocated to one of the three treatments: (1) GPG + P4 (days 0 and 9, 100 µg GnRH; day 0-7, intravaginal P4 device; day 7, 500 µg PGF 2α ); (2) GPG (as for treatment 1 but excluding the P4 device) and (3) prostaglandin + GnRH + P4 (as for treatment 1, but excluding day 0 GnRH). DF and CL size, plasma concentrations of insulin, insulin-like growth factor-I (IGF-I) and non-esterified fatty acid (NEFA) were measured on days 0 and 7. The proportion of cows with a CL on day 7 was significantly different between groups (GPG: 78%, GPG+P4: 69%, PGF 2α + GnRH + P4: 42%, P = 0.02). The CL volume on day 7 was significantly associated with treatment, treatment by time postpartum and plasma concentrations of insulin, IGF-I and NEFA. In cows without a CL present on day 0 of an oestrus synchronisation program, removal of the day 0 GnRH treatment led to reduced CL development; however, no effect of adding progesterone was found. In contrast, in cows with a CL present on day 0 inclusion of a progesterone device led to a higher CL volume, but removal of the first GnRH injection had no effect. Response to the treatment was affected by plasma concentrations of insulin, IGF-I and NEFA. © 2017 Australian Veterinary Association.

Plasma hormonal profiles and dendritic spine density and morphology in the hippocampal CA1 stratum radiatum, evidenced by light microscopy, of virgin and postpartum female rats.

Science.gov (United States)

Brusco, Janaína; Wittmann, Raul; de Azevedo, Márcia S; Lucion, Aldo B; Franci, Celso R; Giovenardi, Márcia; Rasia-Filho, Alberto A

2008-06-27

Successful reproduction requires that changes in plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oxytocin (OT), estrogen (E(2)) and progesterone (P(4)) occur together with the display of maternal behaviors. Ovarian steroids and environmental stimuli can affect the dendritic spines in the rat hippocampus. Here, studying Wistar rats, it is described: (a) the sequential and concomitant changes in the hormonal profile of females at postpartum days (PP) 4, 8, 12, 16, 20 and 24, comparing to estrous cycle referential values; (b) the dendritic spine density in the stratum radiatum of CA1 (CA1-SR) Golgi-impregnated neurons in virgin females across the estrous cycle and in multiparous age-matched ones; and (c) the proportion of different types of spines in the CA1-SR of virgin and postpartum females, both in diestrus. Plasma levels of gonadotrophins and ovarian hormones remained low along PP while LH increased and PRL decreased near the end of the lactating period. The lowest dendritic spine density was found in virgin females in estrus when compared to diestrus and proestrus phases or to postpartum females in diestrus (p0.4). There were no differences in the proportions of the different spine types in nulliparous and postpartum females (p>0.2). Results suggest that medium layer CA1-SR spines undergo rapid modifications in Wistar females across the estrous cycle (not quite comparable to Sprague-Dawley data or to hormonal substitutive therapy following ovariectomy), but persistent effects of motherhood on dendritic spine density and morphology were not found in this area.

Negative Effect of Zinc on Testes, Testosterone and Gonadotrophins Levels in Adult Male Wistar Rats

Directory of Open Access Journals (Sweden)

D Sohrabi

2012-05-01

Full Text Available

Background and Objectives

The toxic effects of zinc leading to sebaceous gland closure, skin eczema and blister have been previously demonstrated in other studies. The aim of this study is to determine the chronic effects of zinc chloride (ZnCl₂   on testicular tissues, testosterone and gonadotrophins in adult male Wistar rats.

Methods

Twenty four Adult male Wistar rats were divided in to two groups of study and control with each group consisting of 12 rats. Study group rats received 10 mg/kg interaperitoneal Zinc chloride in normal saline (N.S every other day for 30 days. Control group rats received N.S during this time. Blood sample for hormonal evaluation were collected from hearts of these rats. The rats were destroyed and their testes were removed and fixed in a 10% formaldehyde and glutaraldehyde solution.

Results

The results of this study showed a significant decrease in the level of LH and testosterone hormone among the rats in the study group compared to the control group with p< 0.001  and

p< 0.01 respectively. Study of fine structure of testicular cells and tissues in the study group rats  revealed swelling of mitochondria, increase in smooth endoplasmic reticulum vacuolization and lysosomic granules (Autophagic vacuoles in cytosol of their germinal cells.

Conclusion

Based on the results of this study consumption of large amount of compounds which contain zinc should be controlled and limited among men. There is a need for further studies to evaluate and determine the reversibility of most hormonal and physiological changes due to usage of zinc containing compounds.

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)

Inhibition of rat pituitary growth hormone (GH) release by subclinical levels of lead

International Nuclear Information System (INIS)

Camoratto, A.M.; White, L.M.; Lau, Y.S.; Moriarty, C.M.

1990-01-01

Lead toxicity has been associated with short stature in children. Since growth hormone is a major regulator of growth, the effects of chronic exposure to subclinical lead levels on pituitary function were assessed. Timed pregnant rats were given 125 ppm lead (as lead nitrate) in their drinking water beginning on day 5 of gestation. After weaning, pups were continued on lead until sacrifice at 7 weeks of age. The average blood lead level at this time was 18.9 ug/dl (range 13.7-27.8). On the day of sacrifice the pituitary was removed, hemisected and incubated with vehicle or 40 nM hGRH (human growth hormone releasing hormone). Pituitaries from chronically lead-treated pups were 64% less responsive to GRH than controls. In contrast, no difference in responsiveness was observed in pituitaries from the dams. The specific binding of GRH was also examined. Control animals showed a dose-dependent displacement of 125I-GRH by unlabeled ligand (10-1000 nM). In the pituitaries of lead-treated pups binding of labeled ligand was markedly reduced by unlabeled GRH (less than 100 nM). Chronic exposure to lead had no effect on serum GH or prolactin levels or on pituitary content of GH. These data suggest that one mechanism by which lead can affect growth is by inhibition of GH release

Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model.

Science.gov (United States)

Liao, Fan; Zhang, Tony J; Mahan, Thomas E; Jiang, Hong; Holtzman, David M

2015-07-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aβ levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition. Copyright © 2014

Adenoviral vectors for highly selective gene expression in central serotonergic neurons reveal quantal characteristics of serotonin release in the rat brain

Directory of Open Access Journals (Sweden)

Teschemacher Anja G

2009-03-01

Full Text Available Abstract Background 5-hydroxytryptamine (5 HT, serotonin is one of the key neuromodulators in mammalian brain, but many fundamental properties of serotonergic neurones and 5 HT release remain unknown. The objective of this study was to generate an adenoviral vector system for selective targeting of serotonergic neurones and apply it to study quantal characteristics of 5 HT release in the rat brain. Results We have generated adenoviral vectors which incorporate a 3.6 kb fragment of the rat tryptophan hydroxylase-2 (TPH-2 gene which selectively (97% co-localisation with TPH-2 target raphe serotonergic neurones. In order to enhance the level of expression a two-step transcriptional amplification strategy was employed. This allowed direct visualization of serotonergic neurones by EGFP fluorescence. Using these vectors we have performed initial characterization of EGFP-expressing serotonergic neurones in rat organotypic brain slice cultures. Fluorescent serotonergic neurones were identified and studied using patch clamp and confocal Ca2+ imaging and had features consistent with those previously reported using post-hoc identification approaches. Fine processes of serotonergic neurones could also be visualized in un-fixed tissue and morphometric analysis suggested two putative types of axonal varicosities. We used micro-amperometry to analyse the quantal characteristics of 5 HT release and found that central 5 HT exocytosis occurs predominantly in quanta of ~28000 molecules from varicosities and ~34000 molecules from cell bodies. In addition, in somata, we observed a minority of large release events discharging on average ~800000 molecules. Conclusion For the first time quantal release of 5 HT from somato-dendritic compartments and axonal varicosities in mammalian brain has been demonstrated directly and characterised. Release from somato-dendritic and axonal compartments might have different physiological functions. Novel vectors generated in this

cAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells.

Science.gov (United States)

Inda, Carolina; Bonfiglio, Juan José; Dos Santos Claro, Paula A; Senin, Sergio A; Armando, Natalia G; Deussing, Jan M; Silberstein, Susana

2017-05-16

Corticotropin-releasing hormone receptor 1 (CRHR1) activates the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). Both cAMP sources were shown to be required for the phosphorylation of ERK1/2 triggered by activated G protein coupled receptor (GPCR) CRHR1 in neuronal and neuroendocrine contexts. Here, we show that activated CRHR1 promotes growth arrest and neurite elongation in neuronal hippocampal cells (HT22-CRHR1 cells). By characterising CRHR1 signalling mechanisms involved in the neuritogenic effect, we demonstrate that neurite outgrowth in HT22-CRHR1 cells takes place by a sAC-dependent, ERK1/2-independent signalling cascade. Both tmACs and sAC are involved in corticotropin-releasing hormone (CRH)-mediated CREB phosphorylation and c-fos induction, but only sAC-generated cAMP pools are critical for the neuritogenic effect of CRH, further highlighting the engagement of two sources of cAMP downstream of the activation of a GPCR, and reinforcing the notion that restricted cAMP microdomains may regulate independent cellular processes.

Hypersensitivity reaction with intravenous GnRH after pulsatile subcutaneous GnRH treatment in male hypogonadotrophic hypogonadism.

OpenAIRE

Popović, V.; Milosević, Z.; Djukanović, R.; Micić, D.; Nesović, M.; Manojlović, D.; Djordjević, P.; Mićić, J.

1988-01-01

Chronic pulsatile subcutaneous administration of low doses of gonadotrophin releasing hormone (GnRH) is an effective therapy for men with hypogonadotrophic hypogonadism. Hypersensitivity reactions to GnRH are rare. We wish to report hypersensitivity reactions with intravenous GnRH after low dose subcutaneous pulsatile GnRH treatment in two men with hypogonadotrophic hypogonadism due to suprasellar disease.

Use of fertility drugs and risk of ovarian cancer: Danish Population Based Cohort Study

DEFF Research Database (Denmark)

Jensen, Allan; Sharif, Heidi; Frederiksen, Kirsten

2009-01-01

OBJECTIVE: To examine the effects of fertility drugs on overall risk of ovarian cancer using data from a large cohort of infertile women. DESIGN: Population based cohort study. SETTING: Danish hospitals and private fertility clinics. PARTICIPANTS: 54,362 women with infertility problems referred...... confounding factors. RESULTS: Analyses within cohort showed no overall increased risk of ovarian cancer after any use of gonadotrophins (rate ratio 0.83, 95% confidence interval 0.50 to 1.37), clomifene (1.14, 0.79 to 1.64), human chorionic gonadotrophin (0.89, 0.62 to 1.29), or gonadotrophin releasing...... hormone (0.80, 0.42 to 1.51). Furthermore, no associations were found between all four groups of fertility drugs and number of cycles of use, length of follow-up, or parity. CONCLUSION: No convincing association was found between use of fertility drugs and risk of ovarian cancer....

Prolactin-sensitive neurons express estrogen receptor-α and depend on sex hormones for normal responsiveness to prolactin.

Science.gov (United States)

Furigo, Isadora C; Kim, Ki Woo; Nagaishi, Vanessa S; Ramos-Lobo, Angela M; de Alencar, Amanda; Pedroso, João A B; Metzger, Martin; Donato, Jose

2014-05-30

Estrogens and prolactin share important target tissues, including the gonads, brain, liver, kidneys and some types of cancer cells. Herein, we sought anatomical and functional evidence of possible crosstalk between prolactin and estrogens in the mouse brain. First, we determined the distribution of prolactin-responsive neurons that express the estrogen receptor α (ERα). A large number of prolactin-induced pSTAT5-immunoreactive neurons expressing ERα mRNA were observed in several brain areas, including the anteroventral periventricular nucleus, medial preoptic nucleus, arcuate nucleus of the hypothalamus, ventrolateral subdivision of the ventromedial nucleus of the hypothalamus (VMH), medial nucleus of the amygdala and nucleus of the solitary tract. However, although the medial preoptic area, periventricular nucleus of the hypothalamus, paraventricular nucleus of the hypothalamus, retrochiasmatic area, dorsomedial subdivision of the VMH, lateral hypothalamic area, dorsomedial nucleus of the hypothalamus and ventral premammillary nucleus contained significant numbers of prolactin-responsive neurons, these areas showed very few pSTAT5-immunoreactive cells expressing ERα mRNA. Second, we evaluated prolactin sensitivity in ovariectomized mice and observed that sex hormones are required for a normal responsiveness to prolactin as ovariectomized mice showed a lower number of prolactin-induced pSTAT5 immunoreactive neurons in all analyzed brain nuclei compared to gonad-intact females. In addition, we performed hypothalamic gene expression analyses to determine possible post-ovariectomy changes in components of prolactin signaling. We observed no significant changes in the mRNA expression of prolactin receptor, STAT5a or STAT5b. In summary, sex hormones exert a permissive role in maintaining the brain's prolactin sensitivity, most likely through post-transcriptional mechanisms. Copyright © 2014 Elsevier B.V. All rights reserved.

Role of the new growth hormone-releasing secretagogues in the diagnosis of some hypothalamopituitary pathologies.

Science.gov (United States)

Casanueva, F F; Micic, D; Pombo, M; Leal, A; Bokser, L; Zugaza, J L; Dieguez, C

1996-08-01

Growth hormone (GH)-releasing hormone (GHRH) and somatostatin have a dominant role in regulating GH secretion. However, results of studies using the new class of GH secretogogues, particularly GHRP-6, indicate that there may also be other, as yet undefined, hypothalamic mechanisms involved. Studies in adults with hypothalamopituitary disconnection (functional pituitary stalk transection), show GHRP-6-mediated GH release to be completely blocked, indicating a main action at the hypothalamic rather than the pituitary level. The synergistic effect of GHRH plus GHRP-6 administration on GH release seen in normal adults (and virtually unaffected by age, obesity, or sex) is also absent in these patients, providing further support for this conclusion. Studies of the effects of GHRP-6 in children with GH deficiency due to perinatal pituitary stalk transection have produced similar findings. It is suggested that the combined GHRH plus GHRH-6 test should be a promising tool for diagnosing GH deficiency states in both children and adults, and may identify a subgroup of patients with GH deficiency caused by interruption of the hypothalamopituitary connection.

Adiponectin Expression in the Porcine Ovary during the Oestrous Cycle and Its Effect on Ovarian Steroidogenesis

Directory of Open Access Journals (Sweden)

Anna Maleszka

2014-01-01

Full Text Available Adiponectin is an adipose-secreted hormone that regulates energy homeostasis and is also involved in the control of the reproductive system. The goal of the present study was to investigate changes in adiponectin gene and protein expression in porcine ovarian structures during the oestrous cycle and to examine the effects of in vitro administration of adiponectin on basal and gonadotrophin- and/or insulin-induced secretion of ovarian steroid hormones. Both gene and protein expression of adiponectin were enhanced during the luteal phase of the cycle. Adiponectin affected basal secretion of progesterone by luteal cells, oestradiol by granulosa cells, and testosterone by theca interna cells. The gonadotrophin/insulin-induced release of progesterone from granulosa and theca interna cells and the release of oestradiol and androstenedione from theca cells was also modified by adiponectin. In conclusion, the presence of adiponectin mRNA and protein in the porcine ovary coupled with our previous results indicating adiponectin receptors expression suggest that adiponectin may locally affect ovarian functions. The changes in adiponectin expression throughout the oestrous cycle seem to be dependent on the hormonal status of pigs related to the stage of the oestrous cycle. The effect of adiponectin on ovarian steroidogenesis suggests that this adipokine influences reproductive functions in pigs.

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.

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

Science.gov (United States)

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

Radioimmunoassay for luteinizing hormone releasing hormone in plasma

International Nuclear Information System (INIS)

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

1975-01-01

A sensitive and specific double antibody radioimmunoassay has been developed capable of measuring LH-RH in extracted human plasma. Thyrotropin releasing hormone, lysine vasopressin and most of LH-RH analogues did not appear to affect the assay. Hypothalamic extract and some of the LH-RH analogues produced displacement curves which were parallel to the curve obtained with the synthetic LH-RH. Sensitivity of the radioimmunoassay was about 3 pg per assay tube. The coefficient of variation of intraassays was 6.4%, while that of interassays was 9.6%. Exogenous LH-RH could be quantitatively extracted by acidic ethanol when varying amounts of synthetic LH-RH were added to the plasma. Immunoreactivity of LH-RH was preserved in plasma for 2 hrs in the cold but was gradually reduced thereafter. The plasma levels of LH-RH were 20 pg/ml or less in normal adults and not detectable in children. Aged males over 60 yr and postmenopausal women showed a tendency to have higher levels of plasma LH-RH. The plasma LH-RH level was significantly higher in midcycle than in the follicular or luteal stages. The disappearance rate of LH-RH from the circulation after intravenous injection could be represented as half-times of 4-6 min. Between 0.2-0.4% of the injected dose was excreted into urine within 1 hr. These results indicate that the determination of LH-RH might be a useful tool for elucidating hypothalamic-pituitary-gonad interactions. (auth.)

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...

Hepcidin Protects Neuron from Hemin-Mediated Injury by Reducing Iron

Directory of Open Access Journals (Sweden)

Yu-Fu Zhou

2017-05-01

Full Text Available Hemin plays a key role in mediating secondary neuronal injury after intracerebral hemorrhage (ICH and the cell toxicity of hemin is thought to be due to iron that is liberated when hemin is degraded. In a recent study, we demonstrated the iron regulatory hormone hepcidin reduces brain iron in iron-overloaded rats. Therefore, we hypothesized that hepcidin might be able to reduce iron and then protect neurons from hemin or iron-mediated neurotoxicity in hemin-treated neuronal cells. Here, we tested the hypothesis and demonstrated that ad-hepcidin and hepcidin peptide both have the ability to suppress the hemin-induced increase in LDH release and apoptotic cell numbers, to reduce cell iron and ferritin contents, and to inhibit expression of transferrin receptor 1, divalent metal transporter 1, and ferroportin 1 in hemin-treated neurons. We conclude that hepcidin protects neuron from hemin-mediated injury by reducing iron via inhibition of expression of iron transport proteins.

The use of anti-Müllerian hormone (AMH) for controlled ovarian stimulation in assisted reproductive technology and for fertility assessment and -counselling

DEFF Research Database (Denmark)

Pilsgaard, Fie; Grynnerup, Anna Garcia-Alix; Loessl, Kristine

2018-01-01

stimulation protocol and gonadotrophin dose can be chosen specifically for each woman enabling the so called 'individualized treatment' in line with the personalized treatment concept. Many benefits come with using AMH as a biomarker for ovarian reserve; the hormone is considered fairly cycle independent....... Currently, no international standardised assays exist. AMH is a valid predictor of the ovarian response to controlled ovarian stimulation and to some extent the chance of pregnancy in relation to assisted reproductive technology, but AMH is less optimal in prediction of spontaneous pregnancy and live birth...... after assisted reproductive technology. Accordingly, AMH can be used to optimize gonadotrophin stimulation in fertility treatment, but is not recommended as a screening tool in the general population. This article is protected by copyright. All rights reserved....

contribution of growth hormone-releasing hormone and

African Journals Online (AJOL)

The strategy used was to stimulate GH secretion in 8 young ... treatment with two oral doses of 50 mg atenolol (to inhibit .... had normal baseline thyroid-stimulating hormone (TSH) ..... production rate of 14% per decade has been documented.'".

Levels of human and rat hypothalamic growth hormone-releasing factor as determined by specific radioimmunoassay systems

International Nuclear Information System (INIS)

Audhya, T.; Manzione, M.M.; Nakane, T.; Kanie, N.; Passarelli, J.; Russo, M.; Hollander, C.S.

1985-01-01

Polyclonal antibodies to synthetic human pancreatic growth hormone-releasing factor [hpGRF(1-44)NH 2 ] and rat hypothalamic growth hormone-releasing factor [rhGRF(1-43)OH] were produced in rabbits. A subsequent booster injection by the conventional intramuscular route resulted in high-titer antibodies, which at a 1:20,000 dilution were used to develop highly sensitive and specific radioimmunoassays for these peptides. The antibody to hpGRF(1-44)NH 2 is directed against the COOH-terminal region of the molecule, as shown by its cross reactivity with various hpGRF analogues. Serial dilutions of human and rat hypothalamic extracts demonstrated parallelism with the corresponding species-specific standard and 125 I-labeled tracer. There was no cross reactivity with other neuropeptides, gastrointestinal peptides, or hypothalamic extracts of other species. Age-related changes in hypothalamic GRF content were present in rats, with a gradual increase from 2 to 16 weeks and a correlation between increasing body weight and GRF content. These radioimmunoassays will serve as important tools for understanding the regulation of growth hormone secretion in both human and rat

Biosynthesis and release of thyrotropin-releasing hormone immunoreactivity in rat pancreatic islets in organ culture. Effects of age, glucose, and streptozotocin

DEFF Research Database (Denmark)

Dolva, L O; Welinder, B S; Hanssen, K F

1983-01-01

Thyrotropin-releasing hormone immunoreactivity (TRH-IR) was measured in isolated islets and in medium from rat pancreatic islets maintained in organ culture. TRH-IR in methanol extracts of both islets and culture medium was eluted in the same position as synthetic TRH by ion-exchange and gel...... chromatography and exhibited dilution curves parallel with synthetic TRH in radioimmunoassay. [3H]Histidine was incorporated into a component that reacted with TRH antiserum and had the same retention time as synthetic TRH on reversed-phase high-performance liquid chromatography. A continuous release of TRH...

Control of oestrus and ovulation rates in Yankasa ewes

International Nuclear Information System (INIS)

Oyedipe, E.O.; Pathiraja, N.; Gyang, E.O.; Bawa, E.K.; Eduvie, L.O.

1991-01-01

Experiments were carried out in Yankasa sheep to study the efficacy of progesterone for oestrous synchronization and the effect of various gonadotrophin treatments (pregnant mare serum gonadotrophin (PMSG), human chorionic gonadotrophin (HCG) and gonadotrophin releasing hormone (GnRH)) on ovulation rates and litter size, and to elucidate responses by monitoring progesterone concentration. Preliminary studies showed normal progesterone profiles during the cycle, and a mean ovulation rate and litter size of 1.36 ± 0.34 and 1.23 respectively. Following synchronization with progesterone pessaries, PMSG dosage influenced ovulation rates. When 500 IU PMSG was given to ewes, HCG injection had an additive effect of increasing ovulation rate. Plasma progesterone concentrations showed significant treatment effects, being increased in relation to an increase in ovulation rates. Ovulation in Yankasa ewes occurred between 30-32 hours from onset of oestrus. In a fertility trial, mean ovulation rates and corresponding litter size were 2.1 versus 1.8 and 1.5 versus 1.2 for PMSG treated and untreated ewes respectively. 24 refs, 8 figs, 5 tabs

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

Science.gov (United States)

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

2008-12-23

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

Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats.

Science.gov (United States)

Bokser, L; Szende, B; Schally, A V

1990-06-01

The possible protective effect of an agonist of luteinising hormone-releasing hormone (LH-RH) against the ovarian damage caused by cyclophosphamide was investigated in rats. D-Trp6-LH-RH microcapsules were injected once a month for 3 months, in a dose calculated to release 25 micrograms day-1. Control animals received the injection vehicle. Sixty days after the first injection of microcapsules, cyclophosphamide was given at a loading dose of 50 mg kg-1 followed by 5 mg kg-1 day-1 for 30 days, while the treatment with D-Trp6-LH-RH was continued. When the ovaries were examined 3 months and 5 months after discontinuation of treatment, a significant reduction in the total number of follicles (P less than 0.01) was found in non-pretreated animals given cyclophosphamide. This reduction affected mainly follicles larger than 100 microns. An irreversible disintegration and destruction of granulosa cells was also observed in this group. In animals pretreated with D-Trp6-LH-RH, administration of cyclophosphamide caused no reduction in the number and diameter of follicles. Thus, the treatment with D-Trp6-LH-RH microcapsules before and during chemotherapy prevented the ovarian injury inflicted by cyclophosphamide. The suppression of gonadal function by LH-RH analogues could be possibly utilised for the protection of the ovaries against damage caused by cytotoxic drugs.

Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

International Nuclear Information System (INIS)

Romshe, C.A.; Zipf, W.B.; Miser, A.; Miser, J.; Sotos, J.F.; Newton, W.A.

1984-01-01

We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subject's bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response

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

Synthetic Growth Hormone-Releasing Peptides (GHRPs: A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects

Directory of Open Access Journals (Sweden)

Jorge Berlanga-Acosta

2017-02-01

Full Text Available Background: Growth hormone-releasing peptides (GHRPs constitute a group of small synthetic peptides that stimulate the growth hormone secretion and the downstream axis activity. Mounting evidences since the early 1980s delineated unexpected pharmacological cardioprotective and cytoprotective properties for the GHRPs. However, despite intense basic pharmacological research, alternatives to prevent cell and tissue demise before lethal insults have remained as an empty niche in the clinical armamentarium. Here, we have rigorously reviewed the investigational development of GHRPs and their clinical niching perspectives. Methodology: PubMed/MEDLINE databases, including original research and review articles, were explored. The search design was date escalated from 1980 and included articles in English only. Results and Conclusions: GHRPs bind to two different receptors (GHS-R1a and CD36, which redundantly or independently exert relevant biological effects. GHRPs’ binding to CD36 activates prosurvival pathways such as PI-3K/AKT1, thus reducing cellular death. Furthermore, GHRPs decrease reactive oxygen species (ROS spillover, enhance the antioxidant defenses, and reduce inflammation. These cytoprotective abilities have been revealed in cardiac, neuronal, gastrointestinal, and hepatic cells, representing a comprehensive spectrum of protection of parenchymal organs. Antifibrotic effects have been attributed to some of the GHRPs by counteracting fibrogenic cytokines. In addition, GHRP family members have shown a potent myotropic effect by promoting anabolia and inhibiting catabolia. Finally, GHRPs exhibit a broad safety profile in preclinical and clinical settings. Despite these fragmented lines incite to envision multiple pharmacological uses for GHRPs, especially as a myocardial reperfusion damage-attenuating candidate, this family of “drugable” peptides awaits for a definitive clinical niche.

Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons.

Science.gov (United States)

Li, Ying; Xu, Youfen; van den Pol, Anthony N

2013-03-01

In mature neurons, GABA is the primary inhibitory neurotransmitter. In contrast, in developing neurons, GABA exerts excitatory actions, and in some neurons GABA-mediated excitatory synaptic activity is more prevalent than glutamate-mediated excitation. Hypothalamic neuropeptides that modulate cognitive arousal and energy homeostasis, hypocretin/orexin and neuropeptide Y (NPY), evoked reversed effects on synaptic actions that were dependent on presynaptic GABA release onto melanin-concentrating hormone (MCH) neurons. MCH neurons were identified by selective green fluorescent protein (GFP) expression in transgenic mice. In adults, hypocretin increased GABA release leading to reduced excitation. In contrast, in the developing brain as studied here with analysis of miniature excitatory postsynaptic currents, paired-pulse ratios, and evoked potentials, hypocretin acted presynaptically to enhance the excitatory actions of GABA. The ability of hypocretin to enhance GABA release increases inhibition in adult neurons but paradoxically enhances excitation in developing MCH neurons. In contrast, NPY attenuation of GABA release reduced inhibition in mature neurons but enhanced inhibition during development by attenuating GABA excitation. Both hypocretin and NPY also evoked direct actions on developing MCH neurons. Hypocretin excited MCH cells by activating a sodium-calcium exchanger and by reducing potassium currents; NPY reduced activity by increasing an inwardly rectifying potassium current. These data for the first time show that both hypocretin and NPY receptors are functional presynaptically during early postnatal hypothalamic development and that both neuropeptides modulate GABA actions during development with a valence of enhanced excitation or inhibition opposite to that of the adult state, potentially allowing neuropeptide modulation of use-dependent synapse stabilization.

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.

Degarelix 240/80 mg: a new treatment option for patients with advanced prostate cancer

DEFF Research Database (Denmark)

Boccon-Gibod, L.; Iversen, P.; Persson, B.E.

2009-01-01

Gonadotrophin-releasing hormone (GnRH) receptor blockers (antagonists) are the latest addition to the hormonal therapy armamentarium for patients with prostate cancer. In contrast to the GnRH agonists, GnRH blockers have an immediate onset of action and do not cause an initial surge in testosterone...... levels that can lead to clinical flare in patients with advanced disease. Degarelix (Firmagon is a new GnRH blocker that has recently been approved by the EMEA and US FDA for the treatment of men with hormone-sensitive advanced prostate cancer. In this article, we briefly review the Phase III trial data...

Treatment of idiopathic hypogonadotropic hypogonadism in men with luteinizing hormone-releasing hormone: a comparison of treatment with daily injections and with the pulsatile infusion pump.

Science.gov (United States)

Shargil, A A

1987-03-01

Thirty husbands in childless couples, aged 24 to 35 years, were treated with luteinizing hormone-releasing hormone (LH-RH) for idiopathic hypogonadotropic hypogonadism (IHH) of peripubertal (incomplete) type. They were azoospermic or oligospermic, with less than 1.5 X 10(6)/ml nonmotile spermatozoa. The diagnosis of IHH was based on clinical and laboratory features and testicular biopsy specimen study and was further supported by results of stimulation tests and gonadotropin-releasing hormone (GnRH) test. Two treatment modalities were used: subcutaneous injections of 500 micrograms LH-RH twice daily; and perpetual subcutaneous injection, via portable infusion pump, of 25 ng/kg LH-RH, at 90-minute intervals. Two patients required a short second period of pulsatile treatment to cause a second pregnancy of their spouses. The pump proved to yield better results, compared with intermittent injections, in respect to endocrine responses, spermatogenesis, and fertility capacity. Normal levels of luteinizing hormone and follicle-stimulating hormone were reached in 2 to 3 weeks and normal testosterone levels in 8 to 10 weeks from the start of treatment. Sperm counts rose to greater than 60 X 10(6)/ml viable spermatozoa with less than 15% of abnormal forms in 3 to 5 months, and the wives conceived. Of a total of 18 deliveries of healthy infants, 12 offspring were identified genetically with their fathers. Four women were still pregnant at the conclusion of the study. The pump was well tolerated, without special operational problems to the patients. Pulsatile treatment is therefore recommended in the treatment of well-diagnosed and carefully selected cases of incomplete IHH.

Arcuate AgRP neurons and the regulation of energy balance

Directory of Open Access Journals (Sweden)

Céline eCansell

2012-12-01

Full Text Available The arcuate nucleus of the hypothalamus contains at least two crucial populations of neurons that continuously monitor signals reflecting energy status and promote the appropriate behavioral and metabolic responses to changes in energy demand. Neurons making pro-opiomelanocortin (POMC decrease food intake and increase energy expenditure through activation of G protein-coupled receptors melanocortin receptors (MCR via the release of a-melanocyte stimulating hormone. A prevailing idea until recently was that the neighboring neurons expressing the orexigenic neuropeptides, agouti-related protein (AgRP and neuropeptide Y (NPY (AgRP neurons increased feeding by opposing the anorexigenic actions of the POMC neurons. AgRP neurons activation but not POMC neurons inhibition was recently demonstrated to be necessary and sufficient to promote feeding. AgRP expressing axons were identified in mesolimbic, midbrain and pontine structure where they regulate feeding but also feeding-independent functions such as reward or peripheral nutrient partitioning. Post-synaptic Gamma aminobutyric acid (GABA, lasting in a timeline similar to neuromodulation, was identified as the core mechanism by which hunger-activated neurons regulate feeding and non-food related processes in a melanocortin independent manner.

Biphasic Effect of Diabetes on Neuronal Nitric Oxide Release in Rat Mesenteric Arteries.

Directory of Open Access Journals (Sweden)

Esther Sastre

Full Text Available We analysed possible time-dependent changes in nitrergic perivascular innervation function from diabetic rats and mechanisms implicated.In endothelium-denuded mesenteric arteries from control and four- (4W and eight-week (8W streptozotocin-induced diabetic rats the vasoconstriction to EFS (electrical field stimulation was analysed before and after preincubation with L-NAME. Neuronal NO release was analysed in the absence and presence of L-arginine, tetrahydrobiopterine (BH4 and L-arginine plus BH4. Superoxide anion (O2-, peroxynitrite (ONOO- and superoxide dismutase (SOD activity were measured. Expressions of Cu-Zn SOD, nNOS, p-nNOS Ser1417, p-nNOS Ser847, and Arginase (Arg I and II were analysed.EFS response was enhanced at 4W, and to a lesser extent at 8W. L-NAME increased EFS response in control rats and at 8W, but not at 4W. NO release was decreased at 4W and restored at 8W. L-arginine or BH4 increased NO release at 4W, but not 8W. SOD activity and O2- generation were increased at both 4W and 8W. ONOO- decreased at 4W while increased at 8W. Cu-Zn SOD, nNOS and p-NOS Ser1417 expressions remained unmodified at 4W and 8W, whereas p-nNOS Ser847 was increased at 4W. ArgI was overexpressed at 4W, remaining unmodified at 8W. ArgII expression was similar in all groups.Our results show a time-dependent effect of diabetes on neuronal NO release. At 4W, diabetes induced increased O2- generation, nNOS uncoupling and overexpression of ArgI and p-nNOS Ser847, resulting in decreased NO release. At 8W, NO release was restored, involving normalisation of ArgI and p-nNOS Ser847 expressions.

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

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

OpenAIRE

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

2012-01-01

Regulation of the hypothalamic–pituitary–adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased ...

Characterization of brn1.2 and corticotropin-releasing hormone genes in zebrafish

OpenAIRE

Chandrasekar, Gayathri

2007-01-01

The zebrafish (Danio rerio), a tropical fresh water fish originally found in the rivers of India and Bangladesh has become a popular vertebrate model system over the last decade. The rapid sequencing of the zebrafish genome together with the latest advances in forward and reverse genetics has made this model organism more fascinating as it can be used to decipher the genetic mechanisms involved in the vertebrate development. Corticotropin-releasing hormone (CRH) regulates t...

An artificially induced follicle stimulating hormone surge at the time of human chorionic gonadotrophin administration in controlled ovarian stimulation cycles has no effect on cumulus expansion, fertilization rate, embryo quality and implantation rate

NARCIS (Netherlands)

Vermeiden, J. P.; Roseboom, T. J.; Goverde, A. J.; Suchartwatnachai, C.; Schoute, E.; Braat, D. D.; Schats, R.

1997-01-01

In the spontaneous menstrual cycle, the mid-cycle gonadotrophin surge causes maturation of the cumulus-oocyte complex, mucification of cumulus cells and expansion of the cumulus oophorus, resumption of meiosis and maturation of the cytoplasm of the oocyte. Whether this is an effect purely of

Evaluation of in vivo [corrected] biological activity of new agmatine analogs of growth hormone-releasing hormone (GH-RH)

Science.gov (United States)

Bokser, L; Zarandi, M; Schally, A V

1990-01-01

The effects of agmatine analogs of growth hormone releasing hormone (GH-RH) were compared to GH-RH(1-29)-NH2 after intravenous (iv) and subcutaneous (sc) administration to pentobarbital-anesthetized male rats. After the iv injection, the analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-51); [desNH2-Tyr1,D-Lys12,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-57); [desNH2-Tyr1,Ala15,D-Lys21,Nle27] GH-RH(1-28)Agm (MZ-2-75) and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GH-RH(1-28)Agm (MZ-2-87) showed a potency equivalent to 4.4, 1.9, 1.07 and 1.03 times that of GH-RH (1-29)-NH2, respectively, at 5 min and 5.6, 1.8, 1.9 and 1.8 times higher, respectively, at 15 min. After sc administration, analogs MZ-2-51, MZ-2-57 and MZ-2-75 showed to be 34.3, 14.3 and 10.5 times more potent than the parent hormone at 15 min and 179.1, 88.9 and 45.0 times more active, respectively, at 30 min. In addition, MZ-2-51 had prolonged GH-releasing activity as compared to the standard. We also compared the activity of MZ-2-51 and MZ-2-57 with their homologous L-Arg and D-Arg analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-29)-NH2 (MZ-2-117), [des-NH2Tyr1,D-Lys12, Ala15, Nle27] GH-RH(1-29)NH2 (MZ-2-123) and [desNH2-Tyr1,D-Lys12,Ala15, Nle27,D-Arg29] GH-RH(1-29)NH2 (MZ-2-135) after intramuscular (im) injection. MZ-2-51 induced a somewhat greater GH release than MZ-2-117 at 15 min, both responses being larger than the controls (p less than 0.01) at 15 and 30 min. MZ-2-57, MZ-2-123 and MZ-2-135 given i.m. were able to stimulate GH release only at 15 minutes (p less than 0.05). Animals injected i.m. with MZ-2-51, but not with MZ-2-117, showed GH levels significantly higher than the control group (p less than 0.05) at 60 min. GH-RH(1-29)NH2 had low activity intramuscularly when tested at a dose of 2.5 micrograms. No toxic effects were observed after the iv administration of 1 mg/kg of Agm GH-RH analogs. These results indicate that our Agm analogs are active iv, sc and im and that the substitutions made in these

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

Science.gov (United States)

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

2016-01-01

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

Pathology of excessive production of growth hormone.

Science.gov (United States)

Scheithauer, B W; Kovacs, K; Randall, R V; Horvath, E; Laws, E R

1986-08-01

Since its clinical description in the last century, much progress has been made in our understanding of acromegaly. From an initial description of pituitary enlargement as just another manifestation of generalized visceromegaly, the pituitary abnormality has come to be recognized, in most instances, as the underlying aetiological factor. Gigantism and acromegaly are manifestations of disordered pituitary physiology, but the lesion responsible may be hypothalamic, adenohypophyseal or ectopic in location. The best known pathological hypothalamic basis for acromegaly is represented by a neuronal malformation or 'gangliocytoma'. It usually takes the form of an intrasellar gangliocytoma or, more rarely, a hypothalamic hamartoma. The neuronal elaboration of GHRH may play a role in the development of a growth hormone adenoma; the pituitary process may pass through an intermediate stage of somatotropic hyperplasia. When acromegaly has its basis in a pituitary abnormality, the lesion is almost exclusively an adenoma; the non-tumorous adenohypophysis shows no evidence of coexistent hyperplasia. Surprisingly, such tumours are more often engaged in the formation of multiple hormones rather than GH alone. They frequently produce not only GH and prolactin, the products characteristics of cells of the acidophil line, but also glycoprotein hormones, usually TSH. The spectrum of adenomas also varies in its degree of differentiation from a histogenetically primitive lesion, the acidophil stem cell adenoma, to well-differentiated tumours of varying cellular composition and hormone content. Each adenoma type has its clinicopathological, histochemical, immunocytological and ultrastructural characteristics. The isolation and characterization of GHRH has permitted the identification of neuroendocrine tumours, most of foregut origin, elaborating this releasing hormone. Such functional tumours induce hyperplasia of pituitary somatotrophs and may, on occasion, result in the formation of

Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

Directory of Open Access Journals (Sweden)

Nicholas V. Vamvakopoulos

1995-01-01

Full Text Available This review higlghts key aspects of corticotropin releasing hormone (CRH biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h CRH gene: (1 a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic glucocorticoid administration in clinical practice and (2 a heuristic diagram to illustrate the proposed modulation of the stress response and immune/ inflammatory reaction by steroid hormones, from the perspective of the CRH system.

The role of feeding rhythm, adrenal hormones and neuronal inputs in synchronizing daily clock gene rhythms in the liver.

Science.gov (United States)

Su, Yan; Cailotto, Cathy; Foppen, Ewout; Jansen, Remi; Zhang, Zhi; Buijs, Ruud; Fliers, Eric; Kalsbeek, Andries

2016-02-15

The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to distribute rhythmic information to the periphery via neural, humoral and/or behavioral connections. Until now, feeding, corticosterone and neural inputs are considered important signals for synchronizing daily rhythms in the liver. In this study, we investigated the necessity of neural inputs as well as of the feeding and adrenal hormone rhythms for maintaining daily hepatic clock gene rhythms. Clock genes kept their daily rhythm when only one of these three signals was disrupted, or when we disrupted hepatic neuronal inputs together with the adrenal hormone rhythm or with the daily feeding rhythm. However, all clock genes studied lost their daily expression rhythm after simultaneous disruption of the feeding and adrenal hormone rhythm. These data indicate that either a daily rhythm of feeding or adrenal hormones should be present to synchronize clock gene rhythms in the liver with the SCN. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons.

Science.gov (United States)

Linehan, Victoria; Trask, Robert B; Briggs, Chantalle; Rowe, Todd M; Hirasawa, Michiru

2015-08-01

Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 μM) and high (100 μM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

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

Science.gov (United States)

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

2009-07-15

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

Acute treatment with 17beta-estradiol attenuates astrocyte-astrocyte and astrocyte-neuron communication.

Science.gov (United States)

Rao, Shilpa P; Sikdar, Sujit Kumar

2007-12-01

Astrocytes are now recognized as dynamic signaling elements in the brain. Bidirectional communication between neurons and astrocytes involves integration of neuronal inputs by astrocytes and release of gliotransmitters that modulate neuronal excitability and synaptic transmission. The ovarian steroid hormone, 17beta-estradiol, in addition to its rapid actions on neuronal electrical activity can rapidly alter astrocyte intracellular calcium concentration ([Ca2+]i) through a membrane-associated estrogen receptor. Using calcium imaging and electrophysiological techniques, we investigated the functional consequences of acute treatment with estradiol on astrocyte-astrocyte and astrocyte-neuron communication in mixed hippocampal cultures. Mechanical stimulation of an astrocyte evoked a [Ca2+]i rise in the stimulated astrocyte, which propagated to the surrounding astrocytes as a [Ca2+]i wave. Following acute treatment with estradiol, the amplitude of the [Ca2+]i elevation in astrocytes around the stimulated astrocyte was attenuated. Further, estradiol inhibited the [Ca2+]i rise in individual astrocytes in response to the metabotropic glutamate receptor agonist, trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid. Mechanical stimulation of astrocytes induced [Ca2+]i elevations and electrophysiological responses in adjacent neurons. Estradiol rapidly attenuated the astrocyte-evoked glutamate-mediated [Ca2+]i rise and slow inward current in neurons. Also, the incidence of astrocyte-induced increase in spontaneous postsynaptic current frequency was reduced in the presence of estradiol. The effects of estradiol were stereo-specific and reversible following washout. These findings may indicate that the regulation of neuronal excitability and synaptic transmission by astrocytes is sensitive to rapid estradiol-mediated hormonal control. (c) 2007 Wiley-Liss, Inc.

Non-invasive treatments of luteinizing hormone-releasing hormone for inducing spermiation in American (Bufo americanus) and Gulf Coast (Bufo valliceps) toads.

Science.gov (United States)

Rowson, Angela D.; Obringer, Amy R.; Roth, Terri L.

2001-01-01

As many as 20% of all assessed amphibian species are threatened with extinction, and captive breeding programs are becoming important components of conservation strategies for this taxon. For some species, exogenous hormone administration has been integrated into breeding protocols to improve propagation. However, most treatments are administered by an intraperitoneal injection that can be associated with some risks. The general goal of this study was to identify a non-invasive method of applying luteinizing hormone-releasing hormone (LHRH), which reliably induces sperm release in toads. Specific objectives were to 1) test the spermiation response after topical application of different LHRH doses to the abdominal seat region, 2) evaluate the effects of adding the absorption enhancers dimethyl sulfoxide (DMSO), acetone, and glyceryl monocaprylate (GMC) to the LHRH, 3) assess the spermiation response after oral delivery of LHRH in a mealworm vehicle, and 4) compare sperm characteristics and spermiation responses to treatments in two different toad species. Male American (n = 9) and Gulf Coast (n = 7) toads were rotated systematically through a series of treatments. Urine was collected and evaluated for the presence of sperm at 0, 3, 7, 12, and 24 hours post-treatment. There were no statistical differences in spermiation induction or sperm characteristics between American and Gulf Coast toads after the treatments. Oral administration of 100 &mgr;g LHRH was occasionally successful in inducing spermiation, but results appeared largely unreliable. Ventral dermal application of 100 or 10 &mgr;g LHRH in 40% DMSO were more effective (P Zoo Biol 20:63-74, 2001. Copyright 2001 Wiley-Liss, Inc.

Radioimmunoassay for 6-D-tryptophan analog of luteinizing hormone-releasing hormone: measurement of serum levels after administration of long-acting microcapsule formulations

International Nuclear Information System (INIS)

Mason-Garcia, M.; Vigh, S.; Comaru-Schally, A.M.; Redding, T.W.; Somogyvari-Vigh, A.; Horvath, J.; Schally, A.V.

1985-01-01

A sensitive and specific radioimmunoassay for [6-D-tryptophan]luteinizing hormone-releasing hormone ([D-Trp 6 ]LH-RH) was developed and used for following the rate of liberation of [D-Trp 6 ]LH-RH from a long-acting delivery systems based on a microcapsule formulation. Rabbit antibodies were generated against [D-Trp 6 ]LH-RH conjugated to bovine serum albumin with glutaraldehyde. Crossreactivity with LH-RH was less than 1%; there was no significant cross-reactivity with other peptides. The minimal detectable dose of [D-Trp 6 ]LH-RH was 2 pg per tube. In tra- and interassay coefficients of variation were 8% and 10%, respectively. The radioimmunoassay was suitable for direct determination of [D-Trp 6 ]LH-RH in serum, permitting the study of blood levels of the analog after single injections into normal men and after one-a-month administration of microcapsules to rats. In men, 90 min after subcutaneous injection of 250 μg of the peptide, serum [D-Trp 6 ]LH-RH rose to 6-12 ng/ml. Luteinizing hormone was increased 90 min and 24 hr after the administration of the analog. Several batches of microcapsules were tested in rats and the rate of release of [D-Trp 6 ]LH-RH was followed. The improved batch of microcapsules of [D-Trp 6 ]LH-RH increased serum concentrations of the analog for 30 days or longer after intramuscular injection

Effect of in ovo injection of corticotropin-releasing hormone on the timing of hatching in broiler chickens.

Science.gov (United States)

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

2017-09-01

In chicken embryos, intravenous injection of corticotropin-releasing hormone (CRH) causes the release of both corticosteroids and thyroid hormones. These hormones initiate and enhance the hatching process, raising the possibility that CRH treatment of the late chicken embryo could accelerate hatching and/or decrease the spread of hatching. We performed a series of exploratory tests to investigate whether in ovo delivery methods of CRH other than intravenous injection that are more practical in a commercial setting, affect hatching time in broilers. Corticotropin-releasing hormone was injected into the air cell, albumen, or amniotic fluid of broiler breeder eggs, in the last week of embryonic development. Average incubation duration was significantly decreased by 22 h when 2 μg of CRH was injected into the air cell on embryonic day 18 (E18) of Cobb eggs. Acceleration of hatching (but only by 8 h) was also seen for Ross chicks when CRH was injected daily into the albumen between E10 and E18. However, repeats of both experiments did not show consistent effects of CRH on hatching time; in most experiments performed, CRH did not affect hatching time. We speculate that the effectiveness of CRH uptake via these delivery methods and/or the duration and magnitude of the thyroxine and corticosterone response to CRH is not sufficient to have a substantial effect on hatching time. We therefore conclude that in ovo CRH treatment does not seem a feasible option as a practical tool to increase hatchery productivity or to investigate the effects of CRH agonists and antagonists on hatching. © 2017 Poultry Science Association Inc.

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

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

International Nuclear Information System (INIS)

Schvartz, I.; Hazum, E.

1987-01-01

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

DIDS prevents ischemic membrane degradation in cultured hippocampal neurons by inhibiting matrix metalloproteinase release.

Directory of Open Access Journals (Sweden)

Matthew E Pamenter

Full Text Available During stroke, cells in the infarct core exhibit rapid failure of their permeability barriers, which releases ions and inflammatory molecules that are deleterious to nearby tissue (the penumbra. Plasma membrane degradation is key to penumbral spread and is mediated by matrix metalloproteinases (MMPs, which are released via vesicular exocytosis into the extracellular fluid in response to stress. DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid preserves membrane integrity in neurons challenged with an in vitro ischemic penumbral mimic (ischemic solution: IS and we asked whether this action was mediated via inhibition of MMP activity. In cultured murine hippocampal neurons challenged with IS, intracellular proMMP-2 and -9 expression increased 4-10 fold and extracellular latent and active MMP isoform expression increased 2-22 fold. MMP-mediated extracellular gelatinolytic activity increased ∼20-50 fold, causing detachment of 32.1±4.5% of cells from the matrix and extensive plasma membrane degradation (>60% of cells took up vital dyes and >60% of plasma membranes were fragmented or blebbed. DIDS abolished cellular detachment and membrane degradation in neurons and the pathology-induced extracellular expression of latent and active MMPs. DIDS similarly inhibited extracellular MMP expression and cellular detachment induced by the pro-apoptotic agent staurosporine or the general proteinase agonist 4-aminophenylmercuric acetate (APMA. Conversely, DIDS-treatment did not impair stress-induced intracellular proMMP production, nor the intracellular cleavage of proMMP-2 to the active form, suggesting DIDS interferes with the vesicular extrusion of MMPs rather than directly inhibiting proteinase expression or activation. In support of this hypothesis, an antagonist of the V-type vesicular ATPase also inhibited extracellular MMP expression to a similar degree as DIDS. In addition, in a proteinase-independent model of vesicular exocytosis, DIDS

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

Hypothalamic-pituitary, ovarian and adrenal contributions to polycystic ovary syndrome.

Science.gov (United States)

Baskind, N Ellissa; Balen, Adam H

2016-11-01

Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous disorder linked with disturbances of reproductive, endocrine and metabolic function. The definition and aetiological hypotheses of PCOS are continually developing to incorporate evolving evidence of the syndrome, which appears to be both multifactorial and polygenic. The pathophysiology of PCOS encompasses inherent ovarian dysfunction that is strongly influenced by external factors including the hypothalamic-pituitary axis and hyperinsulinaemia. Neuroendocrine abnormalities including increased gonadotrophin-releasing hormone (GnRH) pulse frequency with consequent hypersecretion of luteinising hormone (LH) affects ovarian androgen synthesis, folliculogenesis and oocyte development. Disturbed ovarian-pituitary and hypothalamic feedback accentuates the gonadotrophin abnormalities, and there is emerging evidence putatively implicating dysfunction of the Kiss 1 system. Within the follicle subunit itself, there are intra-ovarian paracrine modulators, cytokines and growth factors, which appear to play a role. Adrenally derived androgens may also contribute to the pathogenesis of PCOS, but their role is less defined. Copyright © 2016. Published by Elsevier Ltd.

(13)C heteronuclear NMR studies of the interaction of cultured neurons and astrocytes and aluminum blockade of the preferential release of citrate from astrocytes.

Science.gov (United States)

Meshitsuka, Shunsuke; Aremu, David A

2008-02-01

Citrate has been identified as a major tricarboxylic acid (TCA) cycle constituent preferentially released by astrocytes. We undertook the present study to examine further the nature of metabolic compartmentation in central nervous system tissues using (13)C-labeled glucose and to provide new information on the influence of aluminum on the metabolic interaction between neurons and astrocytes. Metabolites released into the culture medium from astrocytes and neuron-astrocyte coculture, as well as the perchloric acid extracts of the cells were analyzed using 2D (1)H and (13)C NMR spectroscopy. Astrocytes released citrate into the culture medium and the released citrate was consumed by neurons in coculture. Citrate release by astrocytes was blocked in the presence of aluminum, with progressive accumulation of citrate within the cells. We propose citrate supply is a more efficient energy source than lactate for neurons to produce ATP, especially in the hypoglycemic state on account of it being a direct component of the TCA cycle. Astrocytes may be the cellular compartment for aluminum accumulation as a citrate complex in the brain.

Effect of aging on GHRF-induced growth hormone release from anterior pituitary cells in primary culture

International Nuclear Information System (INIS)

Spik, K.W.; Boyd, R.L.; Sonntag, W.E.

1991-01-01

Five criteria were developed to validate the primary cell culture model for comparison of GRF-induced release of growth hormone in pituitary tissue from aging animals. Pituitaries from young (5-mo), middle-aged (14-mo), and old (24-mo) male Fischer 344 rats were dispersed using either trypsin/trypsin inhibitor or dispase and compared with respect to the number of pituitary cells recovered, cell viability, 3H-leucine incorporation into total protein, time course for recovery of optimal response to GRF, and the dose-relationship for GRF-induced release of growth hormone 2, 4, and 6 days after dispersal. Results indicated that direct comparison of cellular responses between tissues from young, middle-aged, and old rats in primary cell culture is confounded by variations in time for recovery of optimal responses, the effects of the enzymes used for dispersal, and the methods used to express the data

The corticotropin-releasing factor-like diuretic hormone 44 (DH44) and kinin neuropeptides modulate desiccation and starvation tolerance in Drosophila melanogaster

DEFF Research Database (Denmark)

Cannell, Elizabeth; Dornan, Anthony J.; Halberg, Kenneth Agerlin

2016-01-01

Malpighian tubules are critical organs for epithelial fluid transport and stress tolerance in insects, and are under neuroendocrine control by multiple neuropeptides secreted by identified neurons. Here, we demonstrate roles for CRF-like diuretic hormone 44 (DH44) and Drosophila melanogaster kinin...

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...

The hippocampal formation: morphological changes induced by thyroid, gonadal and adrenal hormones.

Science.gov (United States)

Gould, E; Woolley, C S; McEwen, B S

1991-01-01

The hippocampal formation is of considerable interest due to its proposed role in a number of important functions, including learning and memory processes. Manipulations of thyroid, gonadal and adrenal hormones have been shown to influence hippocampal physiology as well as learning and memory. The cellular events which underlie these hormone-induced functional changes are largely unexplored. However, studies suggest that hormonal manipulations during development and in adulthood result in dramatic morphological changes within the hippocampal formation. Because neuronal physiology has been suggested to depend upon neuronal morphology, we have been determining the morphologic sensitivity of hippocampal neurons to thyroid and steroid hormones in an effort to elucidate possible structural mechanisms to account for differences in hippocampal function. In this review, hormone-induced structural changes in the developing and adult hippocampal formation are discussed, with particular emphasis on their functional relevance. Sex differences, as well as the developmental effects of thyroid hormone and glucocorticoids, are described. Moreover, the effects of ovarian steroids, thyroid hormone and glucocorticoids on neuronal morphology in the hippocampal formation of the adult rat are reviewed. These hormone-induced structural changes may account, at least in part, for previously reported hormone-induced changes in hippocampal function.

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

Science.gov (United States)

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

2005-11-01

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

Should we give up hormone treatment in menopause?

Directory of Open Access Journals (Sweden)

Mehmet Aral Atalay

2013-12-01

Full Text Available The first paper entitled intrauterine insemination (IUI was published in 1962. By time, several methods involving the technique and the ovulation induction schedules have evolved in order to improve the success rates. Although gonadotrophin releasing hormone antagonists (GnRHa is a crucial part of assisted reproductive treatments now, concerns also arouse regarding the need for the use of it in IUI cycles. These drugs may be considered in IUI programs basically in order to prevent premature LH surges and related cycle cancellations. Although administration of a GnRH antagonist almost completely abolishes premature luteinization, it does not substantially improve the pregnancy rate. The decision of using GnRH antagonists in IUI cycles should be based primarily on the local cost/benefit analysis of individual centers. It will be prudent to limit the involvement of the antagonists in ovulation induction protocols to: patients who frequently exhibit premature LH discharges and therefore either fail to complete treatment or result in unsuccessful outcome; initiated cycles intented for IUI but converted to ART; if it is not possible for logistic reasons (weekend to perform the insemination or for medical centers in which a gynecologist on call is not available and in order to decrease clinical task burden resulting from strict cycle monitoring such as serial transvaginal sonography and/or frequent urine tests.

Aβ42 oligomers selectively disrupt neuronal calcium release.

Science.gov (United States)

Lazzari, Cristian; Kipanyula, Maulilio J; Agostini, Mario; Pozzan, Tullio; Fasolato, Cristina

2015-02-01

Accumulation of amyloid-β (Aβ) peptides correlates with aging and progression of Alzheimer's disease (AD). Aβ peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca(2+) homeostasis. By cytosolic and endoplasmic reticulum Ca(2+) measurements, we here define the short-term effects of synthetic Aβ42 on neuronal Ca(2+) dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Aβ42 did not cause Ca(2+) release or Ca(2+) influx. Similarly, 1-hour treatment with Aβ42 modified neither the resting cytosolic Ca(2+) level nor the long-lasting Ca(2+) influx caused by KCl-induced depolarization. In contrast, Aβ42 oligomers, but not monomers, significantly altered Ca(2+) release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)- and caffeine-induced Ca(2+) mobilization without alteration of the total store Ca(2+) content. Ca(2+) dysregulation by Aβ42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca(2+) store dysfunction is directly involved in Aβ42 neurotoxicity and represents a potential therapeutic target in AD-like dementia. Copyright © 2015 Elsevier Inc. All rights reserved.

Melanin-concentrating hormone: unique peptide neuronal systems in the rat brain and pituitary gland

International Nuclear Information System (INIS)

Zamir, N.; Skofitsch, G.; Bannon, M.J.; Jacobowitz, D.M.

1986-01-01

A unique neuronal system was detected in the rat central nervous system by immunohistochemistry and radioimmunoassay with antibodies to salmon melanin-concentrating hormone (MCH). MCH-like immunoreactive (MCH-LI) cell bodies were confined to the hypothalamus. MCH-LI fibers were found throughout the brain but were most prevalent in hypothalamus, mesencephalon, and pons-medulla regions. High concentrations of MCH-LI were measured in the hypothalamic medial forebrain bundle (MFB), posterior hypothalamic nucleus, and nucleus of the diagonal band. Reversed-phase high-performance liquid chromatography of MFB extracts from rat brain indicate that MCH-like peptide from the rat has a different retention time than that of the salmon MCH. An osmotic stimuls (2% NaCl as drinking water for 120 hr) caused a marked increase in MCH-LI concentrations in the lateral hypothalamus and neurointermediate lobe. The present studies establish the presence of MCH-like peptide in the rat brain. The MCH-LI neuronal system is well situated to coordinate complex functions such as regulation of water intake

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

Directory of Open Access Journals (Sweden)

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.

Systematic review of hormone replacement therapy in the infertile man

Directory of Open Access Journals (Sweden)

Amr El Meliegy

2018-03-01

Full Text Available Objectives: To highlight alternative treatment options other than exogenous testosterone administration for hypogonadal men with concomitant infertility or who wish to preserve their fertility potential, as testosterone replacement therapy (TRT inhibits spermatogenesis, representing a problem for hypogonadal men of reproductive age. Materials and methods: We performed a comprehensive literature review for the years 1978–2017 via PubMed. Also abstracts from major urological/surgical conferences were reviewed. Review was consistent with the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA criteria. We used Medical Subject Heading terms for the search including ‘testosterone replacement therapy’ or ‘TRT’ and ‘male infertility’. Results: In all, 91 manuscripts were screened and the final number used for the review was 56. All studies included were performed in adults, were written in English and had an abstract available. Conclusions: Exogenous testosterone inhibits spermatogenesis. Hypogonadal men wanting to preserve their fertility and at the same time benefiting from TRT effects can be prescribed selective oestrogen receptor modulators or testosterone plus low-dose human chorionic gonadotrophin (hCG. Patients treated for infertility with hypogonadotrophic hypogonadism can be prescribed hCG alone at first followed by or in combination from the start with follicle-stimulating hormone preparations. Keywords: Gonadotrophins, Hypogonadism, Infertility, Systematic review, Testosterone therapy

Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.

Science.gov (United States)

Stark, Romana; Reichenbach, Alex; Andrews, Zane B

2015-12-15

The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin

Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control.

Science.gov (United States)

Ramírez, Sara; Gómez-Valadés, Alicia G; Schneeberger, Marc; Varela, Luis; Haddad-Tóvolli, Roberta; Altirriba, Jordi; Noguera, Eduard; Drougard, Anne; Flores-Martínez, Álvaro; Imbernón, Mónica; Chivite, Iñigo; Pozo, Macarena; Vidal-Itriago, Andrés; Garcia, Ainhoa; Cervantes, Sara; Gasa, Rosa; Nogueiras, Ruben; Gama-Pérez, Pau; Garcia-Roves, Pablo M; Cano, David A; Knauf, Claude; Servitja, Joan-Marc; Horvath, Tamas L; Gomis, Ramon; Zorzano, Antonio; Claret, Marc

2017-06-06

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release. Copyright © 2017 Elsevier Inc. All rights reserved.

The effect of intracerebroventricular injection of L-glutamate on the hypothalamic GnRH content in rat

International Nuclear Information System (INIS)

Fu Qiang; He Haoming

2001-01-01

Objective: To investigate the effect of intracerebroventricular injection of L-Glutamate (L-Glu) on hypothalamic gonadotrophin-releasing hormone (GnRH) content in male rats. Methods: The GnRH content in the supernatant of hypothalamic homogenates was measured by RIA. Results: The mean values of hypothalamic GnRH content in rat were 1.59 +- 0.41, 0.88 +- 0.34, 0.70 +- 0.42 ng/10mg wet tissue 40 min after intracerebroventricular injection of 0.01176, 0.1176, 1.176 μg/20 μl L-Glu respectively, which were significantly lower than those in controls with saline injections (P 3 H-Glu in rat at 40 min the author found that the intake of 3 H-glu by MBH was 1069.82 +- 490.33 cpm/10 mg wet tissues, the highest value among those taken by cerebrum, cerebellum, pituitary, POA and MBH itself. Conclusion: L-Glu probably participates in the regulation of functional activity of GnRH neurons in the hypothalamus

Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output.

Science.gov (United States)

Zhao, K; Ao, Y; Harper, R M; Go, V L W; Yang, H

2013-09-05

Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity. Published by Elsevier Ltd.

A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

Science.gov (United States)

Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H Sophie; Wahis, Jérôme; da Silva Gouveia, Miriam; Tang, Yan; Ciobanu, Alexandru Cristian; Triana Del Rio, Rodrigo; Roth, Lena C; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L; Mitre, Mariela; Froemke, Robert C; Chao, Moses V; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

2016-03-16

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of graded doses of goitrin, a goitrogen in rapeseed, on synthesis and release of thyroid hormone in chicks

International Nuclear Information System (INIS)

Akiba, Yukio; Matsumoto, Tatsuro

1977-01-01

Intrathyroidal metabolism in synthesis and release of thyroid hormone was investigated in chicks administered three different levels of goitrin (0.0125, 0.025 and 0.05% in the diet) for 14 days. Thyroid glands were enlarged to 2-5 times as large as that of the control in proportion to the goitrin content of the diet. Typical high radioiodine uptake goiter was demonstrated in the goitrin-administered chicks. Total thyroid 125 I content increased about twice as much as that of the control in the goitrin-administered chicks though it was depressed in 0.0065% PUT-administered chicks. Decrease of plasma PB 125 I (approximately a half of the control) was ascertained by the estimation of plasma thyroxine by radiostereoassay. In the intrathyroidal metabolism of iodine, synthesis of iodothyronines and iodination of MIT were suppressed by goitrin, but monoiodination of tyrosine was rather accelerated. The elevated ratio of thyroid iodothyronines/plasma PBI (1.5-1.7 times as much as that of the control) reveals that the depression of plasma level of thyroid hormone is more striking than the decrease in thyroid hormone in the gland in the goitrin-administered chicks. It is, therefore, suggested that goitrin has inhibitory effects not only on the biosynthesis of thyroid hormone in the gland but also on the release of thyroid hormone from the gland. (auth.)

Neuronal release of proBDNF

OpenAIRE

Yang, Jianmin; Siao, Chia-Jen; Nagappan, Guhan; Marinic, Tina; Jing, Deqiang; McGrath, Kelly; Chen, Zhe-Yu; Mark, Willie; Tessarollo, Lino; Lee, Francis S; Lu, Bai; Hempstead, Barbara L

2009-01-01

Pro–brain-derived neurotrophic factor (proBDNF) and mature BDNF utilize distinct receptors to mediate divergent neuronal actions. Using new tools to quantitate endogenous BDNF isoforms, we found that mouse neurons secrete both proBDNF and mature BDNF. The highest levels of proBDNF and p75 were observed perinatally and declined, but were still detectable, in adulthood. Thus, BDNF actions are developmentally regulated by secretion of proBDNF or mature BDNF and by local expression of p75 and Trk...

Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

Science.gov (United States)

Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

2015-07-24

One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

Effectiveness of controlled internal drug release device treatment to alleviate reproductive seasonality in anestrus lactating or dry Barki and Rahmani ewes during non-breeding season.

Science.gov (United States)

El-Mokadem, M Y; Nour El-Din, Anm; Ramadan, T A; Rashad, A M; Taha, T A; Samak, M A; Salem, M H

2018-04-01

This study aimed to evaluate the effectiveness of hormonal treatments on ovarian activity and reproductive performance in Barki and Rahmani ewes during non-breeding season. Forty-eight multiparous ewes, 24 Barki and 24 Rahmani ewes were divided into two groups, 12 lactating and 12 dry ewes for each breed. Controlled internal drug release (CIDR) device was inserted in all ewes for 14 days in conjunction with intramuscular 500 IU equine chronic gonadotrophin (eCG) at day of CIDR removal. Data were analysed using PROC MIXED of SAS for repeated measures. Breed, physiological status and days were used as fixed effects and individual ewes as random effects. Barki ewes recorded higher (p ewes. Lactating ewes recorded higher (p ewes. Number and diameter of large follicles recorded the highest (p ewes recorded longer (p ewes. In conclusion, CIDR-eCG protocol was more potent in improving ovarian activity in Barki compared to Rahmani ewes, but this protocol seems to induce hormonal imbalance in Barki ewes that resulted in increasing conception failure compared to Rahmani ewes. © 2017 Blackwell Verlag GmbH.

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.

Estrogen enhances expression of the complement C5a receptor and the C5a-agonist evoked calcium influx in hormone secreting neurons of the hypothalamus.

Science.gov (United States)

Farkas, Imre; Varju, Patricia; Szabo, Emese; Hrabovszky, Erik; Okada, Noriko; Okada, Hidechika; Liposits, Zsolt

2008-01-01

In the present study we examined presence of the complement C5a receptor (C5aR) in hypothalamic neurosecretory neurons of the rodent brain and effect of estrogen on C5aR expression. Whole cell patch clamp measurements revealed that magnocellular neurons in the supraoptic and paraventricular nuclei of hypothalamic slices of the rats responded to the C5aR-agonist PL37-MAP peptide with calcium ion current pulses. Gonadotropin-releasing hormone (GnRH) producing neurons in slices of the preoptic area of the mice also reacted to the peptide treatment with inward calcium current. PL37-MAP was able to evoke the inward ion current of GnRH neurons in slices from ovariectomized animals. The amplitude of the inward pulses became higher in slices obtained from 17beta-estradiol (E2) substituted mice. Calcium imaging experiments demonstrated that PL37-MAP increased the intracellular calcium content in the culture of the GnRH-producing GT1-7 cell line in a concentration-dependent manner. Calcium imaging also showed that E2 pretreatment elevated the PL37-MAP evoked increase of the intracellular calcium content in the GT1-7 cells. The estrogen receptor blocker Faslodex in the medium prevented the E2-evoked increase of the PL37-MAP-triggered elevation of the intracellular calcium content in the GT1-7 cells demonstrating that the effect of E2 might be related to the presence of estrogen receptor. Real-time PCR experiments revealed that E2 increased the expression of C5aR mRNA in GT1-7 neurons, suggesting that an increased C5aR synthesis could be involved in the estrogenic modulation of calcium response. These data indicate that hypothalamic neuroendocrine neurons can integrate immune and neuroendocrine functions. Our results may serve a better understanding of the inflammatory and neurodegeneratory diseases of the hypothalamus and the related neuroendocrine and autonomic compensatory responses.

Galanin does not affect the growth hormone-releasing hormone-stimulated growth hormone secretion in patients with hyperthyroidism.

Science.gov (United States)

Giustina, A; Bussi, A R; Legati, F; Bossoni, S; Licini, M; Schettino, M; Zuccato, F; Wehrenberg, W B

1992-12-01

Patients with hyperthyroidism have reduced spontaneous and stimulated growth hormone (GH) secretion. The aim of our study was to evaluate the effects of galanin, a novel neuropeptide which stimulates GH secretion in man, on the GH response to GHRH in patients with hyperthyroidism. Eight untreated hyperthyroid patients with Graves' disease (6F, 2M, aged 25-50 years) and six healthy volunteers (3F, 3M, aged 27-76 years) underwent from -10 to 30 min in random order: (i) porcine galanin, iv, 500 micrograms in 100 ml saline; or (ii) saline, iv, 100 ml. A bolus of human GHRH(1-29)NH2, 100 micrograms, was injected iv at 0 min. Hyperthyroid patients showed blunted GH peaks after GHRH+saline (10.2 +/- 2.5 micrograms/l) compared to normal subjects (20.7 +/- 4.8 micrograms/l, p hyperthyroid subjects (12.5 +/- 3 micrograms/l) compared to normal subjects (43.8 +/- 6 micrograms/l, p hyperthyroidism suggests that hyperthyroxinemia may either increase the somatostatin release by the hypothalamus or directly affect the pituitary GH secretory capacity.

Hypothalamic control of pituitary and adrenal hormones during hypothermia.

Science.gov (United States)

Okuda, C; Miyazaki, M; Kuriyama, K

1986-01-01

In order to investigate neuroendocrinological mechanisms of hypothermia, we determined the changes in plasma concentrations of corticosterone (CS), prolactin (PRL), and thyrotropin (TSH), and their correlations with alterations in hypothalamic dopamine (DA) and thyrotropin releasing hormone (TRH), in rats restrained and immersed in a water bath at various temperatures. A graded decrease of body temperature induced a progressive increase in the plasma level of CS, whereas that of PRL showed a drastic decrease. The plasma level of TSH also showed an increase during mild hypothermia (about 35 degrees C), but this increase was not evident during profound hypothermia (below 24 degrees C). The changes in these hormones were readily reversed by rewarming animals. Although DA content in the hypothalamus was not affected, its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), showed an increase following the decrease of body temperature. Pretreatment of the animals with sulpiride, a D2-antagonist, prevented the hypothermia-induced inhibition of PRL release. Hypothalamic TRH was significantly decreased during mild hypothermia, and it returned to control levels after rewarming. These results suggest that the decrease in plasma PRL induced by hypothermia may be associated with the activation of hypothalamic DA neurons, whereas the increase in plasma TSH during mild hypothermia seems to be caused by the increased release of TRH in the hypothalamus.

Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis

NARCIS (Netherlands)

J.S.E. Laven (Joop); M.J.C. Eijkemans (René); E.G. Hughes; B.C.J.M. Fauser (Bart); A.G.M.G.J. Mulders (Annemarie)

2003-01-01

textabstractA systematic review was conducted to determine whether initial screening characteristics of women with normogonadotrophic anovulatory infertility predict clinically significant outcomes of ovulation induction with gonadotrophins, and to obtain pooled estimates of their

CORTICOTROPIN-RELEASING HORMONE MICROINFUSION IN THE CENTRAL AMYGDALA DIMINISHES A CARDIAC PARASYMPATHETIC OUTFLOW UNDER STRESS-FREE CONDITIONS

NARCIS (Netherlands)

WIERSMA, A; BOHUS, B; KOOLHAAS, JM

1993-01-01

The central nucleus of the amygdala (CeA) is known to be involved in the regulation of autonomic, neuroendocrine and behavioural responses in stress situations. The CeA contains large numbers of corticotropin-releasing hormone (CRH) cell bodies. Neuroanatomical studies revealed that the majority of

Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus

NARCIS (Netherlands)

Cope, J.L.; Regev, L.; Chen, Y.; Korosi, A.; Rice, C.J.; Ji, S.; Rogge, G.A.; Wood, M.A.; Baram, T.Z.

2014-01-01

Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely-tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in hypothalamus, CRH is

[The changes of ghrelin, growth hormone, growth hormone releasing hormone and their clinical significances in patients with chronic obstructive pulmonary disease].

Science.gov (United States)

Xu, Zhi-song; Bao, Zi-yu; Wang, Zhi-ying; Yang, Guo-jun; Zhu, Dong-fang; Zhang, Li; Tan, Rong-mei

2012-07-01

To investigate the changes of plasma ghrelin, growth hormone (GH) and growth hormone releasing hormone (GHRH) and gastric ghrelin in patients with chronic obstructive pulmonary disease (COPD) and to explore their clinical significances. Plasma ghrelin, GH, GHRH, TNFα, IL-6 and C reactive protein (CRP) were measured in 40 COPD patients and 20 controls with chronic bronchitis. Correlated factors of plasma ghrelin, TNFα, IL-6, CRP were analyzed. Body composition was assessed with bioelectrical impedance analysis. The expression of gastric ghrelin in patients with COPD was detected. Plasma ghrelin was higher in the underweight patients than in the normal weight patients and in the controls [(1.78 ± 0.46) ng/L, (1.39 ± 0.46) ng/L, (1.36 ± 0.39) ng/L, respectively]. Plasma GH was lower in the underweight patients than in the normal weight patients and in the controls [(4.12 ± 0.83) µg/L, (5.17 ± 0.72)µg/L, (6.49 ± 1.13) µg/L, respectively]. Plasma GHRH was lower in the underweight patients than in the normal weight patients and in the controls [(20.43 ± 4.41) ng/L, (23.47 ± 3.97) ng/L, (27.48 ± 10.06) ng/L, respectively]. Plasma ghrelin was higher in the underweight patients than in the controls (P 0.05). Plasma ghrelin was positively correlated with TNFα and IL-6 in the underweight patients. The gastric expression of ghrelin showed no evident difference between the patients with COPD and the controls. The plasma GH in COPD patients may not be correlated with ghrelin. The plasma ghrelin level may be a useful indicator for malnutrition in COPD patients. Plasma ghrelin might be involved in the pathogenesis of CODP by affecting the body energy metabolism.

Sex and Hormonal influences on Seizures and Epilepsy

Science.gov (United States)

Velíšková, Jana; DeSantis, Kara A.

2012-01-01

Epilepsy is the third most common chronic neurological disorder. Clinical and experimental evidence supports the role of sex and influence of sex hormones on seizures and epilepsy as well as alterations of the endocrine system and levels of sex hormones by epileptiform activity. Conversely, seizures are sensitive to changes in sex hormone levels, which in turn may affect the seizure-induced neuronal damage. The effects of reproductive hormones on neuronal excitability and seizure-induced damage are complex to contradictory and depend on different mechanisms, which have to be accounted for in data interpretation. Both estradiol and progesterone/allopregnanolone may have beneficial effects for patients with epilepsy. Individualized hormonal therapy should be considered as adjunctive treatment in patients with epilepsy to improve seizure control as well as quality of life. PMID:22504305

Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.

Science.gov (United States)

Nair, Deepti; Ramesh, Vijay; Li, Richard C; Schally, Andrew V; Gozal, David

2013-11-01

Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep. © 2013 International Society for Neurochemistry.

C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication.

Science.gov (United States)

Wang, Juan; Silva, Malan; Haas, Leonard A; Morsci, Natalia S; Nguyen, Ken C Q; Hall, David H; Barr, Maureen M

2014-03-03

Cells release extracellular vesicles (ECVs) that play important roles in intercellular communication and may mediate a broad range of physiological and pathological processes. Many fundamental aspects of ECV biogenesis and signaling have yet to be determined, with ECV detection being a challenge and obstacle due to the small size (100 nm) of the ECVs. We developed an in vivo system to visualize the dynamic release of GFP-labeled ECVs. We show here that specific Caenorhabdidits elegans ciliated sensory neurons shed and release ECVs containing GFP-tagged polycystins LOV-1 and PKD-2. These ECVs are also abundant in the lumen surrounding the cilium. Electron tomography and genetic analysis indicate that ECV biogenesis occurs via budding from the plasma membrane at the ciliary base and not via fusion of multivesicular bodies. Intraflagellar transport and kinesin-3 KLP-6 are required for environmental release of PKD-2::GFP-containing ECVs. ECVs isolated from wild-type animals induce male tail-chasing behavior, while ECVs isolated from klp-6 animals and lacking PKD-2::GFP do not. We conclude that environmentally released ECVs play a role in animal communication and mating-related behaviors. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Unique "Angiotensin-Sensitive" Neuronal Population Coordinates Neuroendocrine, Cardiovascular, and Behavioral Responses to Stress.

Science.gov (United States)

de Kloet, Annette D; Wang, Lei; Pitra, Soledad; Hiller, Helmut; Smith, Justin A; Tan, Yalun; Nguyen, Dani; Cahill, Karlena M; Sumners, Colin; Stern, Javier E; Krause, Eric G

2017-03-29

Stress elicits neuroendocrine, autonomic, and behavioral responses that mitigate homeostatic imbalance and ensure survival. However, chronic engagement of such responses promotes psychological, cardiovascular, and metabolic impairments. In recent years, the renin-angiotensin system has emerged as a key mediator of stress responding and its related pathologies, but the neuronal circuits that orchestrate these interactions are not known. These studies combine the use of the Cre-recombinase/loxP system in mice with optogenetics to structurally and functionally characterize angiotensin type-1a receptor-containing neurons of the paraventricular nucleus of the hypothalamus, the goal being to determine the extent of their involvement in the regulation of stress responses. Initial studies use neuroanatomical techniques to reveal that angiotensin type-1a receptors are localized predominantly to the parvocellular neurosecretory neurons of the paraventricular nucleus of the hypothalamus. These neurons are almost exclusively glutamatergic and send dense projections to the exterior portion of the median eminence. Furthermore, these neurons largely express corticotrophin-releasing hormone or thyrotropin-releasing hormone and do not express arginine vasopressin or oxytocin. Functionally, optogenetic stimulation of these neurons promotes the activation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, as well as a rise in systolic blood pressure. When these neurons are optogenetically inhibited, the activity of these neuroendocrine axes are suppressed and anxiety-like behavior in the elevated plus maze is dampened. Collectively, these studies implicate this neuronal population in the integration and coordination of the physiological responses to stress and may therefore serve as a potential target for therapeutic intervention for stress-related pathology. SIGNIFICANCE STATEMENT Chronic stress leads to an array of physiological responses that ultimately

The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity

Directory of Open Access Journals (Sweden)

Dieter Wicher

2007-12-01

Full Text Available The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR, we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC50=11pM due to reduction of a pacemaker Ca2+ current through cAMP-inhibited pTRPγ channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca2+ concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH: PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPγ channel that is activated by AKH under conditions of food shortage.

Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

OpenAIRE

Vamvakopoulos, Nicholas V.

1995-01-01

This review higlghts key aspects of corticotropin releasing hormone (CRH) biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h) CRH gene: (1) a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic gl...

Morphological Analysis of the Axonal Projections of EGFP-Labeled Esr1-Expressing Neurons in Transgenic Female Medaka.

Science.gov (United States)

Zempo, Buntaro; Karigo, Tomomi; Kanda, Shinji; Akazome, Yasuhisa; Oka, Yoshitaka

2018-02-01

Some hypothalamic neurons expressing estrogen receptor α (Esr1) are thought to transmit a gonadal estrogen feedback signal to gonadotropin-releasing hormone 1 (GnRH1) neurons, which is the final common pathway for feedback regulation of reproductive functions. Moreover, estrogen-sensitive neurons are suggested to control sexual behaviors in coordination with reproduction. In mammals, hypothalamic estrogen-sensitive neurons release the peptide kisspeptin and regulate GnRH1 neurons. However, a growing body of evidence in nonmammalian species casts doubt on the regulation of GnRH1 neurons by kisspeptin neurons. As a step toward understanding how estrogen regulates neuronal circuits for reproduction and sex behavior in vertebrates in general, we generated a transgenic (Tg) medaka that expresses enhanced green fluorescent protein (EGFP) specifically in esr1-expressing neurons (esr1 neurons) and analyzed their axonal projections. We found that esr1 neurons in the preoptic area (POA) project to the gnrh1 neurons. We also demonstrated by transcriptome and histological analyses that these esr1 neurons are glutamatergic or γ-aminobutyric acidergic (GABAergic) but not kisspeptinergic. We therefore suggest that glutamatergic and GABAergic esr1 neurons in the POA regulate gnrh1 neurons. This hypothesis is consistent with previous studies in mice that found that glutamatergic and GABAergic transmission is critical for estrogen-dependent changes in GnRH1 neuron firing. Thus, we propose that this neuronal circuit may provide an evolutionarily conserved mechanism for regulation of reproduction. In addition, we showed that telencephalic esr1 neurons project to medulla, which may control sexual behavior. Moreover, we found that some POA-esr1 neurons coexpress progesterone receptors. These neurons may form the neuronal circuits that regulate reproduction and sex behavior in response to the serum estrogen/progesterone. Copyright © 2018 Endocrine Society.

The relationships among acculturation, biobehavioral risk, stress, corticotropin-releasing hormone, and poor birth outcomes in Hispanic women.

Science.gov (United States)

Ruiz, R Jeanne; Dolbier, Christyn L; Fleschler, Robin

2006-01-01

To determine the predictive ability of acculturation as an antecedent of stress, biobehavioral risk, corticotropin-releasing hormone levels, and poor birth outcomes in pregnant Hispanic women. A prospective, observational design with data collected at 22-25 weeks of gestation and at birth through medical record review. Public prenatal health clinics in south Texas serving low-income women. Self-identified Hispanic women who had singleton pregnancies, no major medical risk complications, and consented to answer questionnaires as well as a venipuncture and review of their prenatal and birth medical records. Gestational age, Apgar scores, length, weight, percentile size, and head circumference of the infant at birth. Significant differences were seen in infant birth weight, head circumference, and percentile size by acculturation. English acculturation predicted stress, corticotropin-releasing hormone, biobehavioral risk, and decreased gestational age at birth. Investigation must continue to understand the circumstances that give rise to the decline in birth outcomes observed in Hispanics with acculturation to the dominant English culture in the United States.

Partial hypopituitarism and Langerhans cell histiocytosis

Science.gov (United States)

Balaguruswamy, S; Chattington, P D

2011-01-01

A case of multisystem Langerhans cell histiocytosis with pituitary involvement nearly 20 years after initial presentation. A 48-year-old man had histiocytosis X 22 years ago initially involving the groin; subsequently his external auditory meatus, scalp, gum, mandibular bone, perineum and axilla were involved and treated. The pituitary gland was involved 4 years ago. A thyrotropin-releasing hormone test showed delayed response suggestive of hypothalamic disease. Prolactin levels were normal. A gonadotropin-releasing hormone test showed impaired testosterone and gonadotrophin response in keeping with pituitary disease. A glucagon stimulation test showed an impaired growth hormone response but a normal cortisol increase. MRI pituitary showed an empty sella. There was no evidence of diabetes insipidus. Bone mineral densitometry was normal. He has partial hypopituitarism needing thyroxine and testosterone replacement. He also developed type 2 diabetes mellitus 9 years ago. He is closely monitored for any development of diabetes insipidus and the need for growth hormone supplementation. PMID:22715201

An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger.

Science.gov (United States)

Krashes, Michael J; Shah, Bhavik P; Madara, Joseph C; Olson, David P; Strochlic, David E; Garfield, Alastair S; Vong, Linh; Pei, Hongjuan; Watabe-Uchida, Mitsuko; Uchida, Naoshige; Liberles, Stephen D; Lowell, Bradford B

2014-03-13

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

Evidence and possible mechanism for the permanent decline in tuberoinfundibular dopaminergic neuronal activity after chronic estradiol administration in Fischer 233 rats

International Nuclear Information System (INIS)

Gottschall, P.E.

1986-01-01

The objective of these studies was to determine if the decline in tuberoinfundibular dopaminergic (TIDA) neuronal function observed during chronic estradiol-17-β (E 2 ) administration persisted after E 2 was removed. Ovariectomized (OVX) Fischer 344 rats were implanted with an E 2 -containing Silastic capsule for 4 weeks. Anterior pituitary (AP) weight and serum prolactin was greatly increased at the end of the E 2 treatment, that persisted 4 and 26 weeks after E 2 was withdrawn. Ag the end of E 2 treatment and 4 weeks after E 2 was withdrawn, TIDA function, as evaluated by electrical stimulation of median eminence tissue in vitro after allowing for uptake of 3 H-DA, was decreased compared to OVX controls. In an attempt to elucidate the mechanism by which E 2 results in a permanent decline in TIDA function, F344 rats were given daily bromocryptine injections in addition to a 30-day E 2 treatment. TIDA neuronal release was reduced in both E 2 and E 2 and bromocryptine treated groups. However, by 30 days after discontinuing treatment only rats given E 2 alone showed a persistent decline in TIDA function. Since permanent damage to hypothalamic neurons by an enlarged AP was speculated to be the result of E 2 treatment, neurons which regulate other AP hormones may also be damaged. To evaluate this possibility, pulsatile release of prolactin, growth hormone (GH) and luteinizing hormone (LH) was evaluated in OVX control rats, chronically E 2 -treated rats, and rats 120 days after chronic E 2 treatment. Only the frequency of prolactin pulses, but not the frequency of GH and LH pulses, was reduced in rats 120 days after E 2 treatment. This suggests selectivity in the hypothalamic damage produced by the enlarged AP

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.

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.

Serum Testosterone Levels in Prostate Cancer Patients Undergoing Luteinizing Hormone-Releasing Hormone Agonist Therapy.

Science.gov (United States)

Morote, Juan; Comas, Inma; Planas, Jacques; Maldonado, Xavier; Celma, Ana; Placer, José; Ferrer, Roser; Carles, Joan; Regis, Lucas

2018-04-01

Serum testosterone measurement is recommended to assess the efficacy of androgen deprivation therapy (ADT) and to diagnose castration resistance in patients with prostate cancer (PCa). Currently, the accepted castrate level of serum testosterone is 50 ng/dL. Liquid chromatography and tandem mass spectrometry (LC MSMS) is the appropriate method to measure testosterone, especially at low levels. However, worldwide, chemiluminescent assays (CLIAs) are used in clinical laboratories, despite their lack of accuracy and reproducibility, because they are automatable, fast, sensitive, and inexpensive. We compared serum testosterone levels measured using LC MSMS and CLIAs in 126 patients with PCa undergoing luteinizing hormone-releasing hormone (LHRH) agonist therapy. The median serum testosterone level was 14.0 ng/dL (range, 2.0-67.0 ng/dL) with LC MSMS and 31.9 ng/dL (range, 10.0-91.6 ng/dL) with CLIA (P  50 ng/dL in 3 patients (2.4%). These ranges were found in 34 (27%), 72 (57.1%), and 20 (15.9%) patients when testosterone was measured using CLIA (P < .001). The castrate level of serum testosterone using LC MSMS and CLIA was 39.8 ng/dL (95% confidence interval [CI], 37.1-43.4 ng/dL) and 66.5 ng/dL (95% CI, 62.3-71.2 ng/dL), respectively. We found that CLIA overestimated the testosterone levels in PCa patients undergoing LHRH agonist therapy. Thus, the castration level was incorrectly considered inadequate with CLIA in almost 15% of patients. The true castration level of serum testosterone using an appropriate method is < 50 ng/dL. Copyright © 2017 Elsevier Inc. All rights reserved.

Hypothalamic growth hormone receptor (GHR controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb expressing neurons

Directory of Open Access Journals (Sweden)

Gillian Cady

2017-05-01

Full Text Available Objective: The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR are active in the central nervous system (CNS and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. Methods: To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (LeprEYFPΔGHR. The mice were generated by crossing the Leprcre on the cre-inducible ROSA26-EYFP mice to GHRL/L mice. Parameters of body composition and glucose homeostasis were evaluated. Results: Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in LeprEYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in LeprEYFPΔGHR mice. Conclusion: These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding. Keywords: Growth hormone receptor, Hypothalamus, Leptin receptor, Glucose production, Liver

A nonpeptidyl growth hormone secretagogue.

Science.gov (United States)

Smith, R G; Cheng, K; Schoen, W R; Pong, S S; Hickey, G; Jacks, T; Butler, B; Chan, W W; Chaung, L Y; Judith, F

1993-06-11

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.

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

OpenAIRE

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

2004-01-01

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

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.

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

DEFF Research Database (Denmark)

Vuong, T. N. L.; Ho, M. T.; Ha, T. D.

2016-01-01

-35 years, body mass index [BMI] hormone level >1.25 ng/mL, and antral follicle count >= 6). Intervention(s): Ovulation trigger with 0.2, 0.3, or 0.4 mg triptorelin in a GnRH antagonist cycle. Main Outcome Measure(s): The primary end point was number of metaphase II oocytes...... to number of metaphase II oocytes (16.0 +/- 8.5, 15.9 +/- 7.8, and 14.7 +/- 8.4, respectively), embryos (13.2 +/- 7.8, 11.7 +/- 6.9, 11.8 +/- 7.0), and number of top-quality embryos (3.8 +/- 2.9, 3.6 +/- 3.0, 4.1 +/- 3.0). Luteinizing hormone levels at 24 hours and 36 hours after trigger was significantly...

(-)Deprenyl and (-)1-phenyl-2-propylaminopentane, [(-)PPAP], act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons.

Science.gov (United States)

Knoll, J; Miklya, I; Knoll, B; Markó, R; Kelemen, K

1996-01-01

The activity of the catecholaminergic neurons in the rat brain is enhanced significantly 30 min after the subcutaneous injection of very small doses of (-)deprenyl (threshold doses: 0.01 mg/kg for noradrenergic neurons and 0.025 mg/kg for dopaminergic neurons). As a catecholaminergic activity enhancer (CAE) substance (-)deprenyl is about ten times more potent than its parent compound, (-)methamphetamine. While the (+)methamphetamine is 3-5 times more potent than (-)methamphetammine in releasing catecholamines, the (-)methamphetamine is the more potent CAE substance. The mechanism of the CAE effect of (-)deprenyl and (-)PPAP, a deprenyl-derived substance devoid of MAO inhibitory potency, was studied in rats by measuring: a) the release of catecholamines from striatum, substantia nigra, tuberculum olfactorium and locus coeruleus; b) the stimulation induced release of 3H-noradrenaline from the isolated brain stem; and c) the antagonistic effect against tetrabenazine-induced depression of learning in the shuttle box. The CAE effect was found to be unrelated: a) to the inhibition of MAO activity; b) to the inhibition of presynaptic catecholamine receptors; c) to the inhibition of the uptake of catecholamines; and d) to the release of catecholamines. It was concluded that (-)deprenyl and (-)PPAP act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons of the brain. We show that both (-)deprenyl and (-)PPAP enhance the inward Ca2+ current in sino-auricular fibers of the frog heart. (-)PPAP was much more potent than either (+)PPAP or (-)deprenyl in this test.

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

Energy Technology Data Exchange (ETDEWEB)

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

1994-04-01

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

Enhanced excitatory input to melanin concentrating hormone neurons during developmental period of high food intake is mediated by GABA.

Science.gov (United States)

Li, Ying; van den Pol, Anthony N

2009-12-02

In contrast to the local axons of GABA neurons of the cortex and hippocampus, lateral hypothalamic neurons containing melanin concentrating hormone (MCH) and GABA send long axons throughout the brain and play key roles in energy homeostasis and mental status. In adults, MCH neurons maintain a hyperpolarized membrane potential and most of the synaptic input is inhibitory. In contrast, we found that developing MCH neurons received substantially more excitatory synaptic input. Based on gramicidin-perforated patch recordings in hypothalamic slices from MCH-green fluorescent protein transgenic mice, we found that GABA was the primary excitatory synaptic transmitter in embryonic and neonatal ages up to postnatal day 10. Surprisingly, glutamate assumed only a minor excitatory role, if any. GABA plays a complex role in developing MCH neurons, with its actions conditionally dependent on a number of factors. GABA depolarization could lead to an increase in spikes either independently or in summation with other depolarizing stimuli, or alternately, depending on the relative timing of other depolarizing events, could lead to shunting inhibition. The developmental shift from depolarizing to hyperpolarizing occurred later in the dendrites than in the cell body. Early GABA depolarization was based on a Cl(-)-dependent inward current. An interesting secondary depolarization in mature neurons that followed an initial hyperpolarization was based on a bicarbonate mechanism. Thus during the early developmental period when food consumption is high, MCH neurons are more depolarized than in the adult, and an increased level of excitatory synaptic input to these orexigenic cells is mediated by GABA.

Effect of weight reduction on insulin sensitivity, sex hormone-binding globulin, sex hormones and gonadotrophins in obese children

DEFF Research Database (Denmark)

Birkebaek, N H; Lange, Aksel; Holland-Fischer, P

2010-01-01

Obesity in men is associated with reduced insulin sensitivity and hypoandrogenism, while obesity in women is associated with reduced insulin sensitivity and hyperandrogenism. In children, the effect of obesity and weight reduction on the hypothalamo-pituitary-gonadal axis is rarely investigated. ....... The aim of the present study was to investigate the effect of weight reduction in obese Caucasian children on insulin sensitivity, sex hormone-binding globulin (SHBG), DHEAS and the hypothalamo-pituitary-gonadal axis.......Obesity in men is associated with reduced insulin sensitivity and hypoandrogenism, while obesity in women is associated with reduced insulin sensitivity and hyperandrogenism. In children, the effect of obesity and weight reduction on the hypothalamo-pituitary-gonadal axis is rarely investigated...

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

Science.gov (United States)

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.

Neuronal nitric oxide synthase-deficient mice have impaired Renin release but normal blood pressure

DEFF Research Database (Denmark)

Sällström, Johan; Carlström, Mattias; Jensen, Boye L

2008-01-01

BackgroundNitric oxide deficiency is involved in the development of hypertension, but the mechanisms are currently unclear. This study was conducted to further elucidate the role of neuronal nitric oxide synthase (nNOS) in blood pressure regulation and renin release in relation to different sodiu......-116; doi:10.1038/ajh.2007.16American Journal of Hypertension (2008) 21 111-116; doi:10.1038/ajh.2007.16....

Long-Term Recordings of Arcuate Nucleus Kisspeptin Neurons Reveal Patterned Activity That Is Modulated by Gonadal Steroids in Male Mice.

Science.gov (United States)

Vanacker, Charlotte; Moya, Manuel Ricu; DeFazio, R Anthony; Johnson, Michael L; Moenter, Suzanne M

2017-10-01

Pulsatile release of gonadotropin-releasing hormone (GnRH) is key to fertility. Pulse frequency is modulated by gonadal steroids and likely arises subsequent to coordination of GnRH neuron firing activity. The source of rhythm generation and the site of steroid feedback remain critical unanswered questions. Arcuate neurons that synthesize kisspeptin, neurokinin B, and dynorphin (KNDy) may be involved in both of these processes. We tested the hypotheses that action potential firing in KNDy neurons is episodic and that gonadal steroids regulate this pattern. Targeted extracellular recordings were made of green fluorescent protein-identified KNDy neurons in brain slices from adult male mice that were intact, castrated, or castrated and treated with estradiol or dihydrotestosterone (DHT). KNDy neurons exhibited marked peaks and nadirs in action potential firing activity during recordings lasting 1 to 3.5 hours. Peaks, identified by Cluster analysis, occurred more frequently in castrated than intact mice, and either estradiol or DHT in vivo or blocking neurokinin type 3 receptor in vitro restored peak frequency to intact levels. The frequency of peaks in firing rate and estradiol regulation of this frequency is similar to that observed for GnRH neurons, whereas DHT suppressed firing in KNDy but not GnRH neurons. We further examined the patterning of action potentials to identify bursts that may be associated with increased neuromodulator release. Burst frequency and duration are increased in castrated compared with intact and steroid-treated mice. The observation that KNDy neurons fire in an episodic manner that is regulated by steroid feedback is consistent with a role for these neurons in GnRH pulse generation and regulation. Copyright © 2017 Endocrine Society.

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

Directory of Open Access Journals (Sweden)

Janice K V Tam

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

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