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...

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.

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)

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.

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

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Reed Michael C

2004-09-01

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

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

NARCIS (Netherlands)

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

2008-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

1999-11-01

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

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

International Nuclear Information System (INIS)

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

1999-01-01

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

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

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

Science.gov (United States)

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

2017-02-10

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

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

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

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

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

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Imre Farkas

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

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.

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

Pulsatile gonadotrophin releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome

NARCIS (Netherlands)

Bayram, N.; van Wely, M.; van der Veen, F.

2004-01-01

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

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

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

GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET

Directory of Open Access Journals (Sweden)

Depalo Raffaella

2012-04-01

Full Text Available Abstract Several protocols are actually available for in Vitro Fertilization and Embryo Transfer. The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol. The majority of randomized clinical trials clearly shows that in “in Vitro” Fertilization and Embryo Transfer, the combination of exogenous Gonadotropin plus a Gonadotropin Releasing Hormone (GnRH agonist, which is able to suppress pituitary FSH and LH secretion, is associated with increased pregnancy rate as compared with the use of gonadotropins without a GnRH agonist. Protocols with GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol. However, a different synchronization of follicular recruitment and growth occurs with GnRH agonists than with GnRH antagonists. Future developments have to be focused on timing of the administration of GnRH antagonists, by giving a great attention to new strategies of stimulation in patients in which radio-chemotherapy cycles are needed.

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

Science.gov (United States)

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

2016-06-01

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

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

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Dulka, Eden A; Moenter, Suzanne M

2017-11-01

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

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

Science.gov (United States)

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

2013-08-17

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

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

Involvement of phospholipase C and intracellular calcium signaling in the gonadotropin-releasing hormone regulation of prolactin release from lactotrophs of tilapia (Oreochromis mossambicus)

DEFF Research Database (Denmark)

Tipsmark, Christian Kølbæk; Weber, G M; Strom, C N

2005-01-01

Gonadotropin-releasing hormone (GnRH) is a potent stimulator of prolactin (PRL) secretion in various vertebrates including the tilapia, Oreochromis mossambicus. The mechanism by which GnRH regulates lactotroph cell function is poorly understood. Using the advantageous characteristics of the teleost...

Gonadotropin releasing hormone agonists: Expanding vistas

Directory of Open Access Journals (Sweden)

Navneet Magon

2011-01-01

Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

GnRH injection before artificial insemination (AI) alters follicle ...

African Journals Online (AJOL)

STORAGESEVER

2009-08-04

Aug 4, 2009 ... releasing hormone (GnRH) injection on day 6 of the estrous cycle. The estrous cycles ... follicle at the time of GnRH injection (Silcox et al., 1993;. Twagiramungu .... Waves and their Effect on pregnancy rate in the Cow. Reprod.

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

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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...

Cloning and functional analysis of promoters of three GnRH genes in a cichlid

International Nuclear Information System (INIS)

Kitahashi, Takashi; Sato, Hideki; Sakuma, Yasuo; Parhar, Ishwar S.

2005-01-01

Mechanisms regulating gonadotropin-releasing hormone (GnRH) types, a key molecule for reproductive physiology, remain unclear. In the present study, we cloned the promoters of GnRH1, GnRH2, and GnRH3 genes in the tilapia, Oreochromis niloticus; and found putative binding sites for glucocorticoid receptors, Sp1, C/EBP, GATA, and Oct-1, but not for androgen receptors in all three GnRH promoters using computer analysis. The presence of binding sites for progesterone receptors in GnRH1, estrogen receptors in GnRH1 and GnRH2, and thyroid hormone receptors in GnRH1 and GnRH3 suggests direct action of steroid hormones on GnRH types. Our observation of SOX and LINE-like sequences exclusively in GnRH1, COUP in GnRH2, and retinoid X receptors in GnRH3 suggests their role in sexual differentiation, midbrain segmentation, and visual cue integration, respectively. Thus, the characteristic binding sites for nuclear receptors and transcription factors support the notion that each GnRH type is regulated differently and has distinct physiological roles

In vitro regulation of LH biosynthesis and release by GnRH and estradiol

International Nuclear Information System (INIS)

Ramey, J.W.

1986-01-01

Anterior pituitaries were taken from female rats at random stages of the estrous cycle, enzymatically dispersed, and cultured for 48h in steroid-free α-modified Eagles medium followed by 24h in fresh medium +/- estradiol (E 2 ). The pituitary cells were then incubated in fresh medium containing radiolabeled precursors +/- gonadotropin releasing hormone (GnRH). Radioactive precursor incorporation into LH was determined by immuno-precipitation. The dose-dependent effects of E 2 (10 -11 to 10 -8 M) on 3 H-glucosamine ( 3 H-Gln) and 35 S-methionine ( 35 S-Met) incorporation into LH +/- 1 nM GnRH (4h) were investigated. GnRH (10 -9 M) and E 2 (all doses) significantly increased total 3 H-Gln LH. Moreover, E 2 at 10 -9 M and 10 -8 M significantly enhanced GnRH stimulated LH glycosylation. In contrast, addition of GnRH and/or E 2 did not significantly increase 35 S-Met incorporation into LH over a 4h period. The effects of various GnRH concentrations (10 -11 to 10 -9 M; 8h) +/- E 2 (0.05 nM) on 3 H-Gln LH and 35 S-Met LH production were also investigated. In the absence of E 2 , only 10 -9 M GnRH was effective in increasing total 3 H-Gln LH and 35 S-Met LH synthesis. However, in the presence of E 2 , all concentrations of GnRH stimulated LH synthesis with 3 H-Gln LH production responding in a dose related manner whereas 35 S-Met LH production was maximally stimulated at all doses of GnRH. In the final series of experiments, pituitary cells previously exposed to estradiol were incubated for 4 h in normal calcium or low calcium medium containing 3 H-Gln or 35 S-Met +/- GnRH. Removal of extracellular calcium completely inhibited GnRH stimulated 3 H-Gln LH and 35 S-Met LH production

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...

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

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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.

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

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Alun L Edwards

1996-01-01

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

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

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Stefan Lim

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

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

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Syed Nuruddin

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

Gonadotrophin-Releasing Hormone Agonists and Other Contraceptive Medications in Exotic Companion Animals.

Science.gov (United States)

Schoemaker, Nico J

2018-05-01

The use of a gonadotrophin-releasing hormone agonist slow-release implant (GnRH A-SRI) has become increasingly popular as an alternative for surgical contraception in many species. Although these implants have proven to be very effective in some species (eg, ferrets, rats, chicken, psittacines, and iguanas), they have been found less effective in other species (eg, male guinea pigs and rabbits, veiled chameleons, slider turtles, and leopard geckos). This review provides an overview of the available literature on the effects of GnRH A-SRIs in companion exotic animals. Copyright © 2018 Elsevier Inc. All rights reserved.

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

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

1979-12-01

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

Cumulus cells gene expression profiling in terms of oocyte maturity in controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist.

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Devjak, Rok; Fon Tacer, Klementina; Juvan, Peter; Virant Klun, Irma; Rozman, Damjana; Vrtačnik Bokal, Eda

2012-01-01

In in vitro fertilization (IVF) cycles controlled ovarian hyperstimulation (COH) is established by gonadotropins in combination with gonadotropin-releasing hormone (GnRH) agonists or antagonists, to prevent premature luteinizing hormone (LH) surge. The aim of our study was to improve the understanding of gene expression profile of cumulus cells (CC) in terms of ovarian stimulation protocol and oocyte maturity. We applied Affymetrix gene expression profiling in CC of oocytes at different maturation stages using either GnRH agonists or GnRH antagonists. Two analyses were performed: the first involved CC of immature metaphase I (MI) and mature metaphase II (MII) oocytes where 359 genes were differentially expressed, and the second involved the two GnRH analogues where no differentially expressed genes were observed at the entire transcriptome level. A further analysis of 359 differentially genes was performed, focusing on anti-Müllerian hormone receptor 2 (AMHR2), follicle stimulating hormone receptor (FSHR), vascular endothelial growth factor C (VEGFC) and serine protease inhibitor E2 (SERPINE2). Among other differentially expressed genes we observed a marked number of new genes connected to cell adhesion and neurotransmitters such as dopamine, glycine and γ-Aminobutyric acid (GABA). No differential expression in CC between the two GnRH analogues supports the findings of clinical studies where no significant difference in live birth rates between both GnRH analogues has been proven.

Studies on the relationship between thyroid hormones, ovarian hormones, GnRH and reproductive performance of egyptian buffaloes

International Nuclear Information System (INIS)

Farghaly, H.A.M.

1992-01-01

this study was carried out in the experimental farm of animal production department, faculty of agriculture, cairo university. hormonal analysis were performed in the laboratories of animal physiology unit, radiobiology department, nuclear research center, atomic energy authority (radiobiol. Dept., NRC, AEA). The aim of the study was to investigate the following : 1- post-partum reproductive activity of egyptian buffaloes and the factors affecting the resumption of ovarian activity after calving , with particular reference to the patterns of thyroid hormones (T 4 and T 3 ) and progesterone hormone.2- the effectiveness of using GnRH treatment on inducing ovarian activity after calving. 3- the effect of goitrogen administration (thiouracil) on ovarian activity during post-partum and on the response of buffaloes to GnRH treatment and their reproductive patterns

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

OpenAIRE

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

2006-01-01

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

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

NARCIS (Netherlands)

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

1988-01-01

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

Regulation versus modulation in GnRH receptor function

International Nuclear Information System (INIS)

Zolman, J.C.; Theodoropoulos, T.J.

1985-01-01

Serum luteinizing hormone (LH) concentration after exposure to gonadotropin-releasing hormone (GnRH) indicates that an instantaneous increase occurs in the rate of release of LH directly from the anterior pituitary, as measured dynamically during superfusion in vitro. On the other hand, estradiol-17 beta (E2) alone shows no such instantaneous effect on LH release rate (at least for the first four hours), in either physiologic or pharmacologic concentrations. At the same time, brief (ten to 30 minute) exposure of isolated anterior pituitary plasma membranes to physiologic concentrations of E2 significantly alters the binding of a fully biologically active 125 I-GnRH to its plasma membrane receptor protein. In order to characterize the effect of E2 on GnRH binding further, dispersed bovine anterior pituitary cells were preincubated for six hours in the presence or absence of physiologic concentrations of E2 (10(-10)M). Following preincubation in the presence of E2, the cell suspension was incubated for 30 minutes with physiologic concentrations (5 x 10(-11) - 5 x 10(-10)M) of a fully biologically active 125 I-GnRH. The treatment, at least, doubled the number of biologically important high affinity GnRH binding sites (Kd's . 7.5 x -10(-11) - 4.5 x 10(-10)M), and changed the binding capacity of some of the binding sites up to three fold, which altered the cooperativity of GnRH-receptor interaction. Thus, the interaction of E2 with GnRH at the level of GnRH receptor is mandatory for the short-term pituitary effect of E2 on LH release in vitro and in vivo

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

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Lubin, V; Charbonnel, B; Bouchard, P

1998-12-01

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

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

Gonadotrophin releasing hormone antagonist in IVF/ICSI

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M S Kamath

2008-01-01

Full Text Available Objective : To study the efficacy of gonadotrophin releasing hormone (GnRH antagonist in In-vitro-fertilization/Intracytoplasmic sperm injection (IVF/ICSI cycles. Type of Study : Observational study. Setting: Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, Tamil Nadu. Materials and Methods: GnRH antagonists were introduced into our practice in November 2005. Fifty-two women undergoing the antagonist protocol were studied and information gathered regarding patient profile, treatment parameters (total gonadotrophin dosage, duration of treatment, and oocyte yield, and outcomes in terms of embryological parameters (cleavage rates, implantation rates and clinical pregnancy. These parameters were compared with 121 women undergoing the standard long protocol. The costs between the two groups were also compared. Main Outcome : Clinical pregnancy rate. Results : The clinical pregnancy rate per embryo transfer in the antagonist group was 31.7% which was comparable to the clinical pregnancy rate in women undergoing the standard long protocol (30.63%. The costs between the two groups were comparable. Conclusions : GnRH antagonist protocol was found to be effective and comparable to the standard long protocol regimen. In addition it was simple, convenient, and patient friendly.

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

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

1993-09-01

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

Microdose Flare-up Gonadotropin-releasing Hormone (GnRH) Agonist Versus GnRH Antagonist Protocols in Poor Ovarian Responders Undergoing Intracytoplasmic Sperm Injection.

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Boza, Aysen; Cakar, Erbil; Boza, Barıs; Api, Murat; Kayatas, Semra; Sofuoglu, Kenan

2016-01-01

Microdose flare-up GnRH agonist and GnRH antagonist have become more popular in the management of poor ovarian responders (POR) in recent years; however, the optimal protocol for POR patients undergoing in vitro fertilization has still been a challenge. In this observational study design, two hundred forty four poor ovarian responders were retrospectively evaluated for their response to GnRH agonist protocol (group-1, n=135) or GnRH antagonist protocol (group-2, n=109). Clinical pregnancy rate was the primary end point and was compared between the groups. Student t-test, Mann Whitney U test and χ (2)-test were used to compare the groups. The pmicrodose flare-up protocol has favorable outcomes with respect to the number of oocytes retrieved and implantation rate; nevertheless, the clinical pregnancy rate was found to be similar in comparison to GnRH antagonist protocol in poor ovarian responders. GnRH antagonist protocol appears to be promising with significantly lower gonadotropin requirement and lower treatment cost in poor ovarian responders.

Effect of stage of development and sex on gonadotropin-releasing hormone secretion in in vitro hypothalamic perifusion.

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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.

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

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

1999-05-01

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

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

Science.gov (United States)

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

2012-09-01

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

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

International Nuclear Information System (INIS)

Kile, J.P.

1986-01-01

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

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.

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

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Ryo eNishiguchi

2012-10-01

Full Text Available Gonadotropin-releasing hormone (GnRH is an evolutionarily conserved neuropeptide with 10 amino acid residues, of which several structural variants exist. A molecular form known as GnRH2 ([His5 Trp7 Tyr8]GnRH, also known as chicken GnRH II is widely distributed in vertebrates except for rodents, and has recently been implicated in the regulation of feeding behavior in goldfish. However, the influence of GnRH2 on feeding behavior in other fish has not yet been studied. In the present study, therefore, we investigated the role of GnRH2 in the regulation of feeding behavior in a zebrafish model, and examined its involvement in food intake after intracerebroventricular (ICV administration. ICV injection of GnRH2 at 0.1 and 1 pmol/g body weight (BW induced a marked decrease of food consumption in a dose-dependent manner during 30 min after feeding. Cumulative food intake was significantly decreased by ICV injection of GnRH2 at 1 pmol/g BW during the 30-min post-treatment observation period. The anorexigenic action of GnRH2 was completely blocked by treatment with the GnRH type I receptor antagonist Antide at 50 pmol/g BW. We also examined the effect of feeding condition on the expression level of the GnRH2 transcript in the hypothalamus. Levels of GnRH2 mRNA obtained from fish that had been provided excess food for 7 days were higher than those in fish that had been fed normally. These results suggest that, in zebrafish, GnRH2 acts as an anorexigenic factor, as is the case in goldfish.

Effect of endotoxin on the expression of GnRH and GnRHR genes in the hypothalamus and anterior pituitary gland of anestrous ewes.

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Herman, Andrzej Przemysław; Tomaszewska-Zaremba, Dorota

2010-07-01

An immune/inflammatory challenge can affect reproduction at the level of the hypothalamus, pituitary gland, or gonads. Nonetheless, the major impact is thought to occur within the brain or the pituitary gland. The present study was designed to examine the effect of intravenous (i.v.) lipopolysaccharide (LPS) injection on the expression of gonadotropin-releasing hormone (GnRH) and the gonadotropin-releasing hormone receptor (GnRHR) genes in the hypothalamic structures where GnRH neurons are located as well as in the anterior pituitary gland (AP) of anestrous ewes. We also determined the effect of LPS on luteinizing hormone (LH) release. It was found that i.v. LPS injection significantly decreased GnRH and GnRHR mRNAs levels in the preoptic area (40%, ppituitary cells to GnRH stimulation. The presence of GnRH mRNA in the median eminence, the hypothalamic structure where GnRH-ergic neurons' terminals are located, suggests that the axonal transport of GnRH mRNA may occur in these neurons. This phenomenon could play an important role in the physiology of GnRH neurons. Our data demonstrate that immune stress could be important inhibitor of this process. Copyright 2010 Elsevier B.V. All rights reserved.

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

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

1990-07-01

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

Origins of gonadotropin-releasing hormone (GnRH) in vertebrates: identification of a novel GnRH in a basal vertebrate, the sea lamprey.

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Kavanaugh, Scott I; Nozaki, Masumi; Sower, Stacia A

2008-08-01

We cloned a cDNA encoding a novel (GnRH), named lamprey GnRH-II, from the sea lamprey, a basal vertebrate. The deduced amino acid sequence of the newly identified lamprey GnRH-II is QHWSHGWFPG. The architecture of the precursor is similar to that reported for other GnRH precursors consisting of a signal peptide, decapeptide, a downstream processing site, and a GnRH-associated peptide; however, the gene for lamprey GnRH-II does not have introns in comparison with the gene organization for all other vertebrate GnRHs. Lamprey GnRH-II precursor transcript was widely expressed in a variety of tissues. In situ hybridization of the brain showed expression and localization of the transcript in the hypothalamus, medulla, and olfactory regions, whereas immunohistochemistry using a specific antiserum showed only GnRH-II cell bodies and processes in the preoptic nucleus/hypothalamus areas. Lamprey GnRH-II was shown to stimulate the hypothalamic-pituitary axis using in vivo and in vitro studies. Lamprey GnRH-II was also shown to activate the inositol phosphate signaling system in COS-7 cells transiently transfected with the lamprey GnRH receptor. These studies provide evidence for a novel lamprey GnRH that has a role as a third hypothalamic GnRH. In summary, the newly discovered lamprey GnRH-II offers a new paradigm of the origin of the vertebrate GnRH family. We hypothesize that due to a genome/gene duplication event, an ancestral gene gave rise to two lineages of GnRHs: the gnathostome GnRH and lamprey GnRH-II.

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

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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

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

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

2009-01-15

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

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

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

2009-01-01

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

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

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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.

Dynamic GnRH and hCG testing

DEFF Research Database (Denmark)

Bang, A. Kirstine; Nordkap, Loa; Almstrup, Kristian

2017-01-01

OBJECTIVE: Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) stimulation tests may be used to evaluate the pituitary and testicular capacity. Our aim was to evaluate changes in follicular-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone after Gn...... influence of the tests was illustrated by results from 45 patients suspected of disordered hypothalamic-pituitary-gonadal axis. METHODS: Baseline, stimulated, relative and absolute changes in serum FSH and LH were determined by ultrasensitive TRIFMA, and testosterone was determined by LC-MS/MS. RESULTS......: For the reference group, LH and FSH increased almost 400% and 40% during GnRH testing, stimulated levels varied from 4.4 to 58.8 U/L and 0.2 to 11.8 U/L and FSH decreased in nine men. Testosterone increased approximately 110% (range: 18.7-67.6 nmol/L) during hCG testing. None of the polymorphisms had any major...

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

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

2004-09-01

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

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

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Celeste R. Wirsig-Wiechmann

2012-01-01

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

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.

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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.

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

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Lee, Gregory; Ge, Bixia

2010-07-01

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

The role of GABA in the regulation of GnRH neurons

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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.

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

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

1990-06-01

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

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

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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

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

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

2007-01-01

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

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

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

2005-05-13

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

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

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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.

A conserved non-reproductive GnRH system in chordates.

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Takehiro G Kusakabe

Full Text Available Gonadotropin-releasing hormone (GnRH is a neuroendocrine peptide that plays a central role in the vertebrate hypothalamo-pituitary axis. The roles of GnRH in the control of vertebrate reproductive functions have been established, while its non-reproductive function has been suggested but less well understood. Here we show that the tunicate Ciona intestinalis has in its non-reproductive larval stage a prominent GnRH system spanning the entire length of the nervous system. Tunicate GnRH receptors are phylogenetically closest to vertebrate GnRH receptors, yet functional analysis of the receptors revealed that these simple chordates have evolved a unique GnRH system with multiple ligands and receptor heterodimerization enabling complex regulation. One of the gnrh genes is conspicuously expressed in the motor ganglion and nerve cord, which are homologous structures to the hindbrain and spinal cord of vertebrates. Correspondingly, GnRH receptor genes were found to be expressed in the tail muscle and notochord of embryos, both of which are phylotypic axial structures along the nerve cord. Our findings suggest a novel non-reproductive role of GnRH in tunicates. Furthermore, we present evidence that GnRH-producing cells are present in the hindbrain and spinal cord of the medaka, Oryzias latipes, thereby suggesting the deep evolutionary origin of a non-reproductive GnRH system in chordates.

Six-month gonadotropin releasing hormone (GnRH agonist depots provide efficacy, safety, convenience, and comfort

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Phillips JM

2011-07-01

Full Text Available E David Crawford, Jason M PhillipsUniversity of Colorado Health Sciences Center, Aurora, CO, USAAbstract: Two different 6-month GnRH agonist depot formulations approved for palliative treatment of advanced and metastatic prostate cancer in the United States – leuprolide acetate 45 mg and triptorelinpalmoate 22.5 mg – provide patients with efficacy and safety comparable to those of existing 1-, 3-, and 4-month GnRH agonist depots. However, the 6-month formulations can increase patient convenience, comfort, and compliance by reducing the number of physician visits and injections required. At the conclusion of their pivotal trials, the 6-month formulations demonstrated efficacy rates in achieving chemical castration (serum testosterone #50 ng/dL that ranged between 93% and 99%. As with existing GnRH agonist depot formulations, hot flashes represented the most common adverse event reported in trials of 6-month leuprolide acetate or triptorelin. As such, these products may prove useful not only for their labeled indication, but also as adjuncts to other treatments such as radical prostatectomy, radiotherapy, and chemotherapy. We recommend further research, including head-to-head trials between the 6-month GnRH depots, to refine our understanding of these products.Keywords: prostate cancer, leuprorelin, leuprolide, triptorelin, 6-month depot, testosterone

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

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.

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

Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3

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Lund Eiliv

2009-07-01

Full Text Available Abstract Background Gonadotropin releasing hormone (GNRH1 triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3. Methods We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs were genotyped and used to identify haplotype-tagging SNPs (htSNPS in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II, European Prospective Investigation on Cancer and Nutrition (EPIC, Multiethnic Cohort (MEC, Nurses' Health Study (NHS, and Women's Health Study (WHS. Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone were also measured in 4713 study subjects. Results Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. Conclusion Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.

Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)

International Nuclear Information System (INIS)

Canzian, Federico; Calle, Eugenia E; Chanock, Stephen; Clavel-Chapelon, Francoise; Dossus, Laure; Feigelson, Heather Spencer; Haiman, Christopher A; Hankinson, Susan E; Hoover, Robert; Hunter, David J; Isaacs, Claudine; Kaaks, Rudolf; Lenner, Per; Lund, Eiliv; Overvad, Kim; Palli, Domenico; Pearce, Celeste Leigh; Quiros, Jose R; Riboli, Elio; Stram, Daniel O; Thomas, Gilles; Thun, Michael J; Cox, David G; Trichopoulos, Dimitrios; Gils, Carla H van; Ziegler, Regina G; Henderson, Katherine D; Henderson, Brian E; Berg, Christine; Bingham, Sheila; Boeing, Heiner; Buring, Julie

2009-01-01

Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3). We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects. Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians

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

African Journals Online (AJOL)

PRECIOUS

2009-11-16

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

Etude du rôle de l’expression du récepteur Neuropiline-1 et de l’exocytose Calcium-dépendante dans le neurone à GnRH sur le développement et la maturation du système à GnRH et la physiologie de la reproduction

OpenAIRE

Vanacker , Charlotte

2015-01-01

Fertility in mammals is the result of a long development and maturation process of the hypothalamic-pituitary-gonadal axis. The reproductive function is orchestrated by a small population of neurons, located in preoptic area of hypothalamus in rodents, and releasing in a pulsatile manner Gonadotropin-releasing hormon (GnRH) in the portal blood vessels, where it is transported to the anterior pituitary gland. GnRH neuropeptide triggers synthesis and release of the gonadotropins LH and FSH, whi...

Photoaffinity labeling of pituitary GnRH receptors: significance of the position of photolabel on the ligand

International Nuclear Information System (INIS)

Nikolics, K.; Szonyi, E.; Ramachandran, J.

1988-01-01

Photoreactive derivatives of GnRH and its analogues were prepared by incorporation of the 2-nitro-4(5)-azidophenylsulfenyl [2,4(5)-NAPS] group into amino acid residues at position 1, 3, 6, or 8 of the decapeptide sequence. The modification of Trp 3 by the 2,4-NAPS group led to a complete loss of the luteinizing hormone (LH) releasing as well as LH-release-inhibiting activity of the peptide. The [D-Lys(2,4-NAPS)] 6 analog was a very potent agonist that, after covalent attachment by photoaffinity labeling, caused prolonged LH secretion at a submaximal rate. [Orn(2,4-NAPS)] 8 -GnRH, a full agonist with a relative potency of 7% of GnRH, after photoaffinity labeling caused prolonged maximal LH release from cultured pituitary cells. In contrast, [Orn(2,5-NAPS)] 8 -GnRH, although being equipotent with the 2,4-NAPS isomer in terms of LH releasing ability, was unable to cause prolonged LH release after photoaffinity labeling. Thus, [Orn(2,4-NAPS)] 8 GnRH is very effective photolabeling ligand of the functionally significant pituitary GnRH receptor. Based on this compound, a pituitary peptidase resistant derivative, D-Phe 6 , [Orn(2,4-NAPS)] 8 -GnRH-(1-9)-ethylamide, was synthesized. This derivative showed high-affinity binding to pituitary membranes with a K/sub d/ comparable to those of other GnRH analogues. A radioiodinated form of this peptide was used for pituitary GnRH-receptor labeling. This derivative labeled 59- and 57-kDa proteins in rat and 58- and 56-kDa proteins in bovine pituitary membrane preparations, respectively. This peptide also labeled pituitary GnRH receptors in the solubilized state and therefore appears to be a suitable ligand for the isolation and further characterization of the receptor

Evaluation of GnRH analogue testing in diagnosis and management of children with pubertal disorders

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Hemchand K Prasad

2012-01-01

Full Text Available Context: Gonadotrophin releasing hormone (GnRH stimulation test is pivotal in the assessment of children with pubertal disorders. However, lack of availability and high cost often result in the test falling into disfavor. We routinely use the GnRH analogue stimulation test as an alternative at our center. Aim: To present the data on children with endocrine disorders who underwent GnRH agonist stimulation test in pediatric endocrine clinic of a tertiary care referral hospital. Setting and Design: Pediatric endocrine clinic of a tertiary care referral hospital. Retrospective analysis of case records. Materials and Methods: The details pertaining to clinical and radiological parameters and hormonal tests were retrieved from case records of 15 children who underwent GnRH agonist stimulation test from May 2010 to April 2011. Results: Indications for testing with GnRH analogue were evaluation of delayed puberty, diagnosis of precocious puberty, assessment of hormonal suppression in treatment of precocious puberty and micropenis in two, nine, three and one cases, respectively. The results of the test and clinical and radiological parameters were in concordance. The test was also crucial in diagnosing the onset of central precocious puberty in two children with congenital adrenal hyperplasia. Conclusion: GnRH agonist test is a convenient, safe test that can be performed on an out-patient basis and can help the clinicians in the correct diagnosis and appropriate treatment of various puberty-related disorders.

Characterization of 12 GnRH peptide agonists - a kinetic perspective.

Science.gov (United States)

Nederpelt, Indira; Georgi, Victoria; Schiele, Felix; Nowak-Reppel, Katrin; Fernández-Montalván, Amaury E; IJzerman, Adriaan P; Heitman, Laura H

2016-01-01

Drug-target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin-releasing hormone (GnRH) receptor for the treatment of hormone-dependent diseases. Surprisingly, the kinetic receptor-binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor-binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. A novel radioligand-binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [(125) I]-triptorelin. In addition to radioligand-binding studies, a homogeneous time-resolved FRET Tag-lite™ method was developed as an alternative assay for the same purpose. Two novel competition association assays were successfully developed and applied to determine the kinetic receptor-binding characteristics of 12 high-affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. © 2015 The British Pharmacological Society.

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

Science.gov (United States)

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

2015-05-26

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

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

OpenAIRE

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

2017-01-01

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

Non-invasive assessment of the reproductive cycle in free-ranging female African elephants (Loxodonta africana treated with a gonadotropin-releasing hormone (GnRH vaccine for inducing anoestrus

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Benavides Valades Gabriela

2012-08-01

Full Text Available Abstract Background In southern Africa, various options to manage elephant populations are being considered. Immunocontraception is considered to be the most ethically acceptable and logistically feasible method for control of smaller and confined populations. In this regard, the use of gonadotropin-releasing hormone (GnRH vaccine has not been investigated in female elephants, although it has been reported to be safe and effective in several domestic and wildlife species. The aims of this study were to monitor the oestrous cycles of free-ranging African elephant cows using faecal progestagen metabolites and to evaluate the efficacy of a GnRH vaccine to induce anoestrus in treated cows. Methods Between May 2009 - June 2010, luteal activity of 12 elephant cows was monitored non-invasively using an enzyme immunoassay detecting faecal 5alpha-reduced pregnanes (faecal progestagen metabolites, FPM on a private game reserve in South Africa. No bulls of breeding age were present on the reserve prior to and for the duration of the study. After a 3-month control period, 8 randomly-selected females were treated twice with 600 micrograms of GnRH vaccine (Improvac®, Pfizer Animal Health, Sandton, South Africa 5-7 weeks apart. Four of these females had been treated previously with the porcine zona pellucida (pZP vaccine for four years (2004-2007. Results All 12 monitored females (8 treated and 4 controls showed signs of luteal activity as evidenced by FPM concentrations exceeding individual baseline values more than once. A total of 16 oestrous cycles could be identified in 8 cows with four of these within the 13 to 17 weeks range previously reported for captive African elephants. According to the FPM concentrations the GnRH vaccine was unable to induce anoestrus in the treated cows. Overall FPM levels in samples collected during the wet season (mean 4.03 micrograms/gram dry faeces were significantly higher (P Conclusions The GnRH vaccination protocol failed

Combined Treatment with Gonadotropin-releasing Hormone Analog and Anabolic Steroid Hormone Increased Pubertal Height Gain and Adult Height in Boys with Early Puberty for Height.

Science.gov (United States)

Tanaka, Toshiaki; Naiki, Yasuhiro; Horikawa, Reiko

2012-04-01

Twenty-one boys with a height of 135 cm or less at onset of puberty were treated with a combination of GnRH analog and anabolic steroid hormone, and their pubertal height gain and adult height were compared with those of untreated 29 boys who enter puberty below 135 cm. The mean age at the start of treatment with a GnRH analog, leuprorelin acetate depot (Leuplin(®)) was 12.3 yr, a mean of 1.3 yr after the onset of puberty, and GnRH analog was administered every 3 to 5 wk thereafter for a mean duration of 4.1 yr. The anabolic steroid hormone was started approximately 1 yr after initiation of treatment with the GnRH analog. The mean pubertal height gain from onset of puberty till adult height was significantly greater in the combination treatment group (33.9 cm) than in the untreated group (26.4 cm) (ppenis and pubic hair is promoted by the anabolic steroid hormone, no psychosocial problems arose because of delayed puberty. No clinically significant adverse events appeared. Combined treatment with GnRH analog and anabolic steroid hormone significantly increased height gain during puberty and adult height in boys who entered puberty with a short stature, since the period until epiphyseal closure was extended due to deceleration of the bone age maturation by administration of the GnRH analog and the growth rate at this time was maintained by the anabolic steroid hormone.

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

Genetics of Isolated Hypogonadotropic Hypogonadism: Role of GnRH Receptor and Other Genes

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Karges Beate

2012-01-01

Full Text Available Hypothalamic gonadotropin releasing hormone (GnRH is a key player in normal puberty and sexual development and function. Genetic causes of isolated hypogonadotropic hypogonadism (IHH have been identified during the recent years affecting the synthesis, secretion, or action of GnRH. Developmental defects of GnRH neurons and the olfactory bulb are associated with hyposmia, rarely associated with the clinical phenotypes of synkinesia, cleft palate, ear anomalies, or choanal atresia, and may be due to mutations of KAL1, FGFR1/FGF8, PROKR2/PROK2, or CHD7. Impaired GnRH secretion in normosmic patients with IHH may be caused by deficient hypothalamic GPR54/KISS1, TACR3/TAC3, and leptinR/leptin signalling or mutations within the GNRH1 gene itself. Normosmic IHH is predominantly caused by inactivating mutations in the pituitary GnRH receptor inducing GnRH resistance, while mutations of the β-subunits of LH or FSH are very rare. Inheritance of GnRH deficiency may be oligogenic, explaining variable phenotypes. Future research should identify additional genes involved in the complex network of normal and disturbed puberty and reproduction.

Non-invasive assessment of the reproductive cycle in free-ranging female African elephants (Loxodonta africana) treated with a gonadotropin-releasing hormone (GnRH) vaccine for inducing anoestrus.

Science.gov (United States)

Benavides Valades, Gabriela; Ganswindt, Andre; Annandale, Henry; Schulman, Martin L; Bertschinger, Henk J

2012-08-25

In southern Africa, various options to manage elephant populations are being considered. Immunocontraception is considered to be the most ethically acceptable and logistically feasible method for control of smaller and confined populations. In this regard, the use of gonadotropin-releasing hormone (GnRH) vaccine has not been investigated in female elephants, although it has been reported to be safe and effective in several domestic and wildlife species. The aims of this study were to monitor the oestrous cycles of free-ranging African elephant cows using faecal progestagen metabolites and to evaluate the efficacy of a GnRH vaccine to induce anoestrus in treated cows. Between May 2009-June 2010, luteal activity of 12 elephant cows was monitored non-invasively using an enzyme immunoassay detecting faecal 5alpha-reduced pregnanes (faecal progestagen metabolites, FPM) on a private game reserve in South Africa. No bulls of breeding age were present on the reserve prior to and for the duration of the study. After a 3-month control period, 8 randomly-selected females were treated twice with 600 micrograms of GnRH vaccine (Improvac®, Pfizer Animal Health, Sandton, South Africa) 5-7 weeks apart. Four of these females had been treated previously with the porcine zona pellucida (pZP) vaccine for four years (2004-2007). All 12 monitored females (8 treated and 4 controls) showed signs of luteal activity as evidenced by FPM concentrations exceeding individual baseline values more than once. A total of 16 oestrous cycles could be identified in 8 cows with four of these within the 13 to 17 weeks range previously reported for captive African elephants. According to the FPM concentrations the GnRH vaccine was unable to induce anoestrus in the treated cows. Overall FPM levels in samples collected during the wet season (mean 4.03 micrograms/gram dry faeces) were significantly higher (Pelephants. These results indicate that irregular oestrous cycles occur amongst free

GnRH antagonist, cetrorelix, for pituitary suppression in modern, patient-friendly assisted reproductive technology.

Science.gov (United States)

Tur-Kaspa, Ilan; Ezcurra, Diego

2009-10-01

Gonadotropin-releasing hormone (GnRH) analogues are used routinely to prevent a premature luteinizing hormone (LH) surge in women undergoing assisted reproductive technology (ART) treatments. In contrast to GnRH agonists, antagonists produce rapid and reversible suppression of LH with no initial flare effect. To review the role of cetrorelix, the first GnRH antagonist approved for the prevention of premature LH surges during controlled ovarian stimulation in modern ART. A review of published literature on cetrorelix. Both multiple- and single-dose cetrorelix protocols were shown to be at least as effective as long GnRH agonist regimens for pituitary suppression in Phase II/III clinical trials. Furthermore, cetrorelix co-treatment resulted in similar live birth rates but a shorter duration of gonadotropin stimulation, a lower total gonadotropin dose requirement and lower incidence of ovarian hyperstimulation syndrome compared with long agonist regimens. A single-dose cetrorelix protocol further decreased the number of injections required. Preliminary studies have also produced promising data on the use of cetrorelix in modified ART protocols, such as frozen embryo transfer and donor oocyte recipient cycles. Cetrorelix offers a potential therapeutic alternative to GnRH agonists during controlled ovarian stimulation and has become an integral part of modern, patient-friendly reproductive medicine.

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.

Biphasic action of cyclic adenosine 3',5'- monophosphate in gonadotropin-releasing hormone (GnRH) analog-stimulated hormone release from GH3 cells stably transfected with GnRH receptor complementary deoxyribonucleic acid.

Science.gov (United States)

Stanislaus, D; Arora, V; Awara, W M; Conn, P M

1996-03-01

GH3 cells are a PRL-secreting adenoma cell line derived from pituitary lactotropes. These cells have been stably transfected with rat GnRH receptor complementary DNA to produce four cell lines: GGH(3)1', GGH(3)2', GGH(3)6', and GGH(3)12'. In response to either GnRH or Buserelin (a metabolically stable GnRH agonist), these cell lines synthesize PRL in a cAMP-dependent manner. Only GGH(3)6' cells desensitize in response to persistent treatment with 10(-7) g/ml Buserelin. GGH(3)1', GGH(3)2', and GGH(3)12' cells, however, can be made refractory to Buserelin stimulation by raising cAMP levels either by the addition of (Bu)2cAMP to the medium or by treatment with cholera toxin. In GGH(3) cells, low levels of cAMP fulfill the requirements for a second messenger, whereas higher levels appear to mediate the development of desensitization. The observation that in GGH(3)6' cells, cAMP production persists after the onset of desensitization is consistent with the view that the mechanism responsible for desensitization is distal to the production of cAMP. Moreover, the absence of any significant difference in the amount of cAMP produced per cell in GGH(3)2', GGH(3)6', or GGH(3)12' cells suggests that elevated cAMP production per cell does not explain the development of desensitization in GGH(3)6' cells. We suggest that Buserelin-stimulated PRL synthesis in GGH(3)6' cells is mediated by a different cAMP-dependent protein kinase pool(s) than that in nondesensitizing GGH(3) cells. Such a protein kinase A pool(s) may be more susceptible to degradation via cAMP-mediated mechanisms than the protein kinase pools mediating the Buserelin response in nondesensitizing GGH(3) cells. A similar mechanism has been reported in other systems.

Fresh versus frozen embryo transfer after gonadotropin-releasing hormone agonist trigger in gonadotropin-releasing hormone antagonist cycles among high responder women: A randomized, multi-center study

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Abbas Aflatoonian

2018-02-01

Full Text Available Background: The use of embryo cryopreservation excludes the possible detrimental effects of ovarian stimulation on the endometrium, and higher reproductive outcomes following this policy have been reported. Moreover, gonadotropin-releasing hormone agonist trigger in gonadotropin-releasing hormone (GnRH antagonist cycles as a substitute for standard human chorionic gonadotropin trigger, minimizes the risk of ovarian hyperstimulation syndrome (OHSS in fresh as well as frozen embryo transfer cycles (FET. Objective: To compare the reproductive outcomes and risk of OHSS in fresh vs frozen embryo transfer in high responder patients, undergoing in vitro fertilization triggered with a bolus of GnRH agonist. Materials and Methods: In this randomized, multi-centre study, 121 women undergoing FET and 119 women undergoing fresh ET were investigated as regards clinical pregnancy as the primary outcome and the chemical pregnancy, live birth, OHSS development, and perinatal data as secondary outcomes. Results: There were no significant differences between FET and fresh groups regarding chemical (46.4% vs. 40.2%, p=0.352, clinical (35.8% vs. 38.3%, p=0.699, and ongoing (30.3% vs. 32.7%, p=0.700 pregnancy rates, also live birth (30.3% vs. 29.9%, p=0.953, perinatal outcomes, and OHSS development (35.6% vs. 42.9%, p=0.337. No woman developed severe OHSS and no one required admission to hospital. Conclusion: Our findings suggest that GnRHa trigger followed by fresh transfer with modified luteal phase support in terms of a small human chorionic gonadotropin bolus is a good strategy to secure good live birth rates and a low risk of clinically relevant OHSS development in in vitro fertilization patients at risk of OHSS.

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

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Amy T. Desaulniers

2017-12-01

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

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

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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.

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

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Fegade, Harshal A; Umathe, Sudhir N

2016-04-01

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

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

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Wei Ling Lim

2016-08-01

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

Knockout of the Gnrh genes in zebrafish: effects on reproduction and potential compensation by reproductive and feeding-related neuropeptides.

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Marvel, Miranda; Spicer, Olivia Smith; Wong, Ten-Tsao; Zmora, Nilli; Zohar, Yonathan

2018-04-04

Gonadotropin-releasing hormone (GnRH) is known as a pivotal upstream regulator of reproduction in vertebrates. However, reproduction is not compromised in the hypophysiotropic Gnrh3 knockout line in zebrafish (gnrh3-/-). In order to determine if Gnrh2, the only other Gnrh isoform in zebrafish brains, is compensating for the loss of Gnrh3, we generated a double Gnrh knockout zebrafish line. Surprisingly, the loss of both Gnrh isoforms resulted in no major impact on reproduction, indicating that a compensatory response, outside of the Gnrh system, was evoked. A plethora of factors acting along the reproductive hypothalamus-pituitary axis were evaluated as possible compensators based on neuroanatomical and differential gene expression studies. In addition, we also examined the involvement of feeding factors in the brain as potential compensators for Gnrh2, which has known anorexigenic effects. We found that the double knockout fish exhibited upregulation of several genes in the brain, specifically gonadotropin-inhibitory hormone (gnih), secretogranin 2 (scg2), tachykinin 3a (tac3a), and pituitary adenylate cyclase-activating peptide 1 (pacap1), and downregulation of agouti-related peptide 1 (agrp1), indicating the compensation occurs outside of Gnrh cells and therefore is a non-cell autonomous response to the loss of Gnrh. While the differential expression of gnih and agrp1 in the double knockout line was confined to the periventricular nucleus and hypothalamus, respectively, the upregulation of scg2 corresponded with a broader neuronal redistribution in the lateral hypothalamus and hindbrain. In conclusion, our results demonstrate the existence of a redundant reproductive regulatory system that comes into play when Gnrh2 and Gnrh3 are lost.

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

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

2015-01-01

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

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

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

2013-11-01

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

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

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

1998-01-01

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

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

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

2005-01-01

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

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

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

2006-04-01

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

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

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Junghwan Suh

2013-12-01

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

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

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

2001-01-01

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

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

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

2010-06-01

Developmental exposure to the agricultural fungicide vinclozolin can impair reproductive function in male rabbits and was previously found to decrease the number of immunoreactive-gonadotrophin-releasing hormone (GnRH) neurones in the region of the organum vasculosum of the lamina terminalis and rostral preoptic area by postnatal week (PNW) 6. In the present study, in an aim to further examine the disruption of GnRH neurones by foetal vinclozolin exposure, pregnant rabbits were dosed orally with vinclozolin, flutamide or carrot paste vehicle for the last 2 weeks of gestation. Offspring were euthanised at birth (males and females), PNW 6 (females), PNW 26 (adult males) or PNW 30 (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 PNW 6 female brains by radioimmunoassay revealed a two-fold increase in GnRH peptide content in the mediobasal hypothalamus in vinclozolin-treated rabbits. This finding was complemented by immunofluorescence analyses, which revealed a 2.8-fold increase in GnRH immunoreactivity in the median eminence of vinclozolin compared to vehicle-treated females at PNW 30. 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 sub-acute, 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.

A Flexible Multidose GnRH Antagonist versus a Microdose Flare-Up GnRH Agonist Combined with a Flexible Multidose GnRH Antagonist Protocol in Poor Responders to IVF

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Gayem İnayet Turgay Çelik

2015-01-01

Full Text Available Objective. To compare the effectiveness of a flexible multidose gonadotropin-releasing hormone (GnRH antagonist against the effectiveness of a microdose flare-up GnRH agonist combined with a flexible multidose GnRH antagonist protocol in poor responders to in vitro fertilization (IVF. Study Design. A retrospective study in Akdeniz University, Faculty of Medicine, Department of Obstetrics and Gynecology, IVF Center, for 131 poor responders in the intracytoplasmic sperm injection-embryo transfer (ICSI-ET program between January 2006 and November 2012. The groups were compared to the patients’ characteristics, controlled ovarian stimulation (COH results, and laboratory results. Results. Combination protocol was applied to 46 patients (group 1, and a single protocol was applied to 85 patients (group 2. In group 1, the duration of the treatment was longer and the dose of FSH was higher. The cycle cancellation rate was significantly higher in group 2 (26.1% versus 38.8%. A significant difference was not observed with respect to the number and quality of oocytes and embryos or to the number of embryos transferred. There were no statistically significant differences in the hCG positivity (9.5% versus 9.4% or the clinical pregnancy rates (7.1% versus 10.6%. Conclusion. The combination protocol does not provide additional efficacy.

A Flexible Multidose GnRH Antagonist versus a Microdose Flare-Up GnRH Agonist Combined with a Flexible Multidose GnRH Antagonist Protocol in Poor Responders to IVF.

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Çelik, Gayem İnayet Turgay; Sütçü, Havva Kömür; Akpak, Yaşam Kemal; Akar, Münire Erman

2015-01-01

To compare the effectiveness of a flexible multidose gonadotropin-releasing hormone (GnRH) antagonist against the effectiveness of a microdose flare-up GnRH agonist combined with a flexible multidose GnRH antagonist protocol in poor responders to in vitro fertilization (IVF). A retrospective study in Akdeniz University, Faculty of Medicine, Department of Obstetrics and Gynecology, IVF Center, for 131 poor responders in the intracytoplasmic sperm injection-embryo transfer (ICSI-ET) program between January 2006 and November 2012. The groups were compared to the patients' characteristics, controlled ovarian stimulation (COH) results, and laboratory results. Combination protocol was applied to 46 patients (group 1), and a single protocol was applied to 85 patients (group 2). In group 1, the duration of the treatment was longer and the dose of FSH was higher. The cycle cancellation rate was significantly higher in group 2 (26.1% versus 38.8%). A significant difference was not observed with respect to the number and quality of oocytes and embryos or to the number of embryos transferred. There were no statistically significant differences in the hCG positivity (9.5% versus 9.4%) or the clinical pregnancy rates (7.1% versus 10.6%). The combination protocol does not provide additional efficacy.

Identification of Genes Enriched in GnRH Neurons by Translating Ribosome Affinity Purification and RNAseq in Mice.

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Burger, Laura L; Vanacker, Charlotte; Phumsatitpong, Chayarndorn; Wagenmaker, Elizabeth R; Wang, Luhong; Olson, David P; Moenter, Suzanne M

2018-04-01

Gonadotropin-releasing hormone (GnRH) neurons are a nexus of fertility regulation. We used translating ribosome affinity purification coupled with RNA sequencing to examine messenger RNAs of GnRH neurons in adult intact and gonadectomized (GDX) male and female mice. GnRH neuron ribosomes were tagged with green fluorescent protein (GFP) and GFP-labeled polysomes isolated by immunoprecipitation, producing one RNA fraction enhanced for GnRH neuron transcripts and one RNA fraction depleted. Complementary DNA libraries were created from each fraction and 50-base, paired-end sequencing done and differential expression (enhanced fraction/depleted fraction) determined with a threshold of >1.5- or <0.66-fold (false discovery rate P ≤ 0.05). A core of ∼840 genes was differentially expressed in GnRH neurons in all treatments, including enrichment for Gnrh1 (∼40-fold), and genes critical for GnRH neuron and/or gonadotrope development. In contrast, non-neuronal transcripts were not enriched or were de-enriched. Several epithelial markers were also enriched, consistent with the olfactory epithelial origins of GnRH neurons. Interestingly, many synaptic transmission pathways were de-enriched, in accordance with relatively low innervation of GnRH neurons. The most striking difference between intact and GDX mice of both sexes was a marked downregulation of genes associated with oxidative phosphorylation and upregulation of glucose transporters in GnRH neurons from GDX mice. This may suggest that GnRH neurons switch to an alternate fuel to increase adenosine triphosphate production in the absence of negative feedback when GnRH release is elevated. Knowledge of the GnRH neuron translatome and its regulation can guide functional studies and can be extended to disease states, such as polycystic ovary syndrome.

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

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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.

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...

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...

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

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

2010-01-01

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

Endocannabinoids and Endovanilloids: A Possible Balance in the Regulation of the Testicular GnRH Signalling

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Rosanna Chianese

2013-01-01

Full Text Available Reproductive functions are regulated both at central (brain and gonadal levels. In this respect, the endocannabinoid system (eCS has a very influential role. Interestingly, the characterization of eCS has taken many advantages from the usage of animal models different from mammals. Therefore, this review is oriented to summarize the main pieces of evidence regarding eCS coming from the anuran amphibian Rana esculenta, with particular interest to the morphofunctional relationship between eCS and gonadotropin releasing hormone (GnRH. Furthermore, a novel role for endovanilloids in the regulation of a testicular GnRH system will be also discussed.

In silico and in situ characterization of the zebrafish (Danio rerio gnrh3 (sGnRH gene

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Husebye Harald

2002-08-01

Full Text Available Abstract Background Gonadotropin releasing hormone (GnRH is responsible for stimulation of gonadotropic hormone (GtH in the hypothalamus-pituitary-gonadal axis (HPG. The regulatory mechanisms responsible for brain specificity make the promoter attractive for in silico analysis and reporter gene studies in zebrafish (Danio rerio. Results We have characterized a zebrafish [Trp7, Leu8] or salmon (s GnRH variant, gnrh3. The gene includes a 1.6 Kb upstream regulatory region and displays the conserved structure of 4 exons and 3 introns, as seen in other species. An in silico defined enhancer at -976 in the zebrafish promoter, containing adjacent binding sites for Oct-1, CREB and Sp1, was predicted in 2 mammalian and 5 teleost GnRH promoters. Reporter gene studies confirmed the importance of this enhancer for cell specific expression in zebrafish. Interestingly the promoter of human GnRH-I, known as mammalian GnRH (mGnRH, was shown capable of driving cell specific reporter gene expression in transgenic zebrafish. Conclusions The characterized zebrafish Gnrh3 decapeptide exhibits complete homology to the Atlantic salmon (Salmo salar GnRH-III variant. In silico analysis of mammalian and teleost GnRH promoters revealed a conserved enhancer possessing binding sites for Oct-1, CREB and Sp1. Transgenic and transient reporter gene expression in zebrafish larvae, confirmed the importance of the in silico defined zebrafish enhancer at -976. The capability of the human GnRH-I promoter of directing cell specific reporter gene expression in zebrafish supports orthology between GnRH-I and GnRH-III.

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

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

2004-01-01

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

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

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Malpaux Benoît

2004-11-01

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

The utility of the gonadotrophin releasing hormone (GnRH) test in the diagnosis of polycystic ovary syndrome (PCOS).

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Lewandowski, Krzysztof C; Cajdler-Łuba, Agata; Salata, Ireneusz; Bieńkiewicz, Małgorzata; Lewiński, Andrzej

2011-01-01

Polycystic ovary syndrome (PCOS) is characterised by increased frequency of hypothalamic GnRH pulses leading to a relative increase in LH synthesis by the pituitary. As GnRH stimulation can reveal a relative LH excess, we have endeavoured to assess whether GnRH test might be useful in the diagnosis of PCOS. The study involved 185 subjects: a PCOS group, n = 151, all with oligo- or amenorrhoea, aged (mean ± SD) 24.8 ± ± 5.4 years, BMI 24.5 ± 6.0 kg/m²; and regularly menstruating controls, n = 34, aged 26.6 ± 5.0 years, BMI 24.6 ± 5.5 kg/m². In 121 subjects with PCOS and in 32 controls, serum LH and FSH were measured before (0 minutes) and 30 and 60 minutes after GnRH stimulation (100 μg i.v.). Insulin resistance was assessed by HOMA and Insulin Resistance Index derived from glucose and insulin concentrations during 75 gram oral glucose tolerance test. Women with PCOS had higher testosterone (p = 0.0002), androstendione (p = 0.0021), 17OH-progesterone (p PCOS. Baseline and stimulated LH concentrations were higher in PCOS (9.09 ± 5.56 vs 4.83 ± 1.71 IU/L, 35.48 ± 31.4 vs 16.30 ± 6.68 IU/L, 33.86 ± 31.8 vs 13.45 ± 5.2 IU/L, at 0, 30 and 60 mins post GnRH, respectively, p PCOS in comparison to controls (LH0 min/FSH(₀ min) 1.59 ± 0.95 vs 0.76 ± 0.2, LH(₃₀ min) /FSH(₃₀ min) 4.07 ± 3.0 vs 1.89 ± 0.79, LH(₆₀ min)/FSH(₆₀ min) 3.56 ± 2.58 vs 1.55 ± 0.63, p 2.11 or LH(₆₀ min)/FSH(₆₀ min) > 1.72 had 78.3% and 87.5% sensitivity and 81.7% and 81.3% specificity for the diagnosis of PCOS, respectively. Women with PCOS have higher baseline and GnRH-stimulated LH concentrations. GnRH stimulation results in an increase in LH/FSH ratio in women with PCOS. Therefore we postulate that this phenomenon might be potentially useful as an additional tool in the diagnosis of PCOS.

Mental distress and personality in women undergoing GnRH agonist versus GnRH antagonist protocols for assisted reproductive technology

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Stenbæk, D. S.; Toftager, M.; Hjordt, L. V.

2015-01-01

STUDY QUESTION: Do mental distress and mood fluctuations in women undergoing GnRH agonist and GnRH antagonist protocols for assisted reproductive technology (ART) differ depending on protocol and the personality trait, neuroticism? SUMMARY ANSWER: ART treatment did not induce elevated levels...... of mental distress in either GnRH antagonist or agonist protocols but neuroticism was positively associated with increased mental distress, independent of protocols. WHAT IS KNOWN ALREADY: ART treatment may increase mental distress by mechanisms linked to sex hormone fluctuations. General psychological...... characteristics, such as personality traits indexing negative emotionality, e.g. neuroticism, are likely to affect mental distress during ART treatment. STUDY DESIGN, SIZE, DURATION: A total of 83 women undergoing their first ART cycle were consecutively randomized 1:1 to GnRH antagonist (n = 42) or GnRH agonist...

Pharmacokinetic/Pharmacodynamic Modelling of GnRH Antagonist Degarelix: A Comparison of the Non-linear Mixed-Effects Programs NONMEM and NLME

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Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg

2004-01-01

proposed by Lindstrom and Bates. The two programs were tested using clinical PK/PD data of a new gonadotropin-releasing hormone (GnRH) antagonist degarelix currently being developed for prostate cancer treatment. The pharmacokinetics of intravenous administered degarelix was analysed using a three...

Differential co-localization with choline acetyltransferase in nervus terminalis suggests functional differences for GnRH isoforms in bonnethead sharks (Sphyrna tiburo).

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Moeller, John F; Meredith, Michael

2010-12-17

The nervus terminalis (NT) is a vertebrate cranial nerve whose function in adults is unknown. In bonnethead sharks, the nerve is anatomically independent of the olfactory system, with two major cell populations within one or more ganglia along its exposed length. Most cells are immunoreactive for either gonadotropin-releasing hormone (GnRH) or RF-amide-like peptides. To define further the cell populations and connectivity, we used double-label immunocytochemistry with antisera to different isoforms of GnRH and to choline acetyltransferase (ChAT). The labeling patterns of two GnRH antisera revealed different populations of GnRH-immunoreactive (ir) cell profiles in the NT ganglion. One antiserum labeled a large group of cells and fibers, which likely contain mammalian GnRH (GnRH-I) as described in previous studies and which were ChAT immunoreactive. The other antiserum labeled large club-like structures, which were anuclear, and a sparse number of fibers, but with no clear labeling of cell bodies in the ganglion. These club structures were choline acetyltrasferase (ChAT)-negative, and preabsorption control tests suggest they may contain chicken-GnRH-II (GnRH-II) or dogfish GnRH. The second major NT ganglion cell-type was immunoreactive for RF-amides, which regulate GnRH release in other vertebrates, and may provide an intraganglionic influence on GnRH release. The immunocytochemical and anatomical differences between the two GnRH-immunoreactive profile types indicate possible functional differences for these isoforms in the NT. The club-like structures may be sites of GnRH release into the general circulation since these structures were observed near blood vessels and resembled structures seen in the median eminence of rats. Copyright © 2010 Elsevier B.V. All rights reserved.

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

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

2016-01-01

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

Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment

NARCIS (Netherlands)

N.S. Macklon (Nick); M.J.C. Eijkemans (René); M. Ludwig (Michael); R.E. Felberbaum; K. Diedrich; S. Bustion; E. Loumaye; B.C.J.M. Fauser (Bart); N.G.M. Beckers (Nicole)

2003-01-01

textabstractReplacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because

Ontogenic and sexual differences in pituitary GnRH receptors and intracellular Ca2+ mobilization induced by GnRH.

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Lacau-Mengido, I M; González Iglesias, A; Lux-Lantos, V; Libertun, C; Becú-Villalobos, D

1998-04-01

The present experiments were designed in order to elucidate the participation of the developing hypophysis in determining the changing sensitivity of gonadotrophins to gonadotropin-releasing hormone (GnRH) during ontogeny in the rat. To that end, we chose two well defined developmental ages that differ markedly in sexual and ontogenic characteristics of hypophyseal sensitivity to GnRH, 15 and 30 d. In order to study sex differences and the role of early sexual organization of the hypothalamus, experiments were carried out in males, females, and neonatally androgenized females (TP females). We evaluated (1) the characteristics of pituitary GnRH receptors, and (2) associated changes in GnRH-induced mobilization of intracellular Ca2+ (a second messenger involved in gonadotropins exocytosis). We measured binding characteristics of the GnRH analog D-Ser(TBu)6-des-Gly10-GnRH ethylamide in pituitary homogenates. We found that Kds did not vary among the different sex groups. Total number and concentration of receptors decreased in the female rat from 15-30 d of age, whereas in the male and TP female, receptors/pituitary increased, and the concentration/mg tissue did not change. Also, at 30 days of age, males presented higher content and concentration of receptors than females, and higher content than TP females. In order to evaluate if developmental and sexual differences in pituitary sensitivity to GnRH might be expressed through variations in the intracellular Ca2+ signal, we studied the mobilization of intracellular Ca2+ induced by GnRH (1 x 10(-8) to 1 x 10(-11) M) in a suspension of dispersed pituitary cells in the six groups. In cells from 15-d-old females, Ca2+ response was greater than in 30-d-old females at the doses of 10(-8) to 10(-10) M, indicating that in the infantile female rat activation of highly concentrated GnRH receptors is reflected in an increase in signal transduction mediated by Ca2+. In males and in female rats androgenized at birth, there was also

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

GnRH mRNA levels in male three-spined sticklebacks, Gasterosteus aculeatus, under different reproductive conditions.

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Shao, Yi Ta; Tseng, Yung Che; Chang, Chia-Hao; Yan, Hong Young; Hwang, Pung Pung; Borg, Bertil

2015-02-01

In vertebrates, reproduction is regulated by the brain-pituitary-gonad (BPG) axis, where the gonadotropin-releasing hormone (GnRH) is one of the key components. However, very little is known about the possible role of GnRH in the environmental and feedback control of fish reproduction. To investigate this, full-length gnrh2 (chicken GnRH II) and gnrh3 (salmon GnRH) sequences of male three-spined sticklebacks (Gasterosteus aculeatus), which are clustered with the taxa of the same GnRH type as other Euteleostei, were cloned and annotated. gnrh1 is absent in this species. The mRNA levels of gnrh2 and gnrh3 in the sticklebacks' brain were measured under breeding and post-breeding conditions as well as in castrated and sham-operated breeding fish and castrated/sham-operated fish kept under long-day (LD 16:8) and short-day (LD 8:16) conditions. Fully breeding males had considerably higher mRNA levels of gnrh2 and gnrh3 in the thalamus (Th) and in the telencephalon and preoptic area (T+POA), respectively, than post-breeding males. Sham-operated breeding males have higher gnrh3 mRNA levels than the corresponding castrated males. Moreover, higher gnrh2 mRNA levels in the Th and higher gnrh3 mRNA levels in the T+POA and hypothalamus (HypTh) were also found in long-day sham-operated males than in sham-operated fish kept under an inhibitory short day photoperiod. Nevertheless, gnrh2 and gnrh3 mRNA levels were not up-regulated in castrated males kept under long-day photoperiod, which suggests that positive feedbacks on the brain-pituitary-gonad axis are necessary for this response. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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Christian Bleux

2010-01-01

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

Neuroregulatory and neuroendocrine GnRH pathways in the hypothalamus and forebrain of the baboon.

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Marshall, P E; Goldsmith, P C

1980-07-14

The distribution of neurons containing gonadotropin-releasing hormone (GnRH) in the baboon hypothalamus and forebrain was studied immunocytochemically by light and electron microscopy. GnRH was present in the perikarya, axonal and dendritic processes of immunoreactive neurons. Three populations of GnRH neurons could be distinguished. Most of the GnRH neurons which are assumed to directly influence the anterior pituitary were in the medial basal hypothalamus. Other cells that projected to the median eminence were found scattered throughout the hypothalamus. A second, larger population of neurons apparently was not involved with control of the anterior pituitary. These neurons were generally found within afferent and efferent pathways of the hypothalamus and forebrain, and may receive external information affecting reproduction. A few neurons projecting to the median eminence were also observed sending collaterals to other brain areas. Thus, in addition to their neuroendocrine role, these cells possibly have neuroregulatory functions. The inference is made that these bifunctional neurons, together with the widely observed GnRH-GnRH cellular interactions may help to synchronize ovulation and sexual behavior.

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

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

2009-03-01

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

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

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

2004-02-12

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

The effects of a slow release GnRH agonist implant on male rabbits

DEFF Research Database (Denmark)

Goericke-Pesch, Sandra Kathrin; Groeger, Gesa; Wehrend, Axel

2015-01-01

Surgical castration is done in male pet rabbits for reproduction control, to reduce inter-male aggression and to control hyper-sexuality, territory marking and aggression against humans. Alternatives to surgical castration are requested because of a relatively great anaesthetic risk in rabbits....... Long-term application of a GnRH agonist implant results in a fully reversible "hormonal" castration in male dogs, cats, boars and many other species. Therefore, the present study using New Zealand White hybrid and German Giant rabbits aimed to investigate the effects of a 4.7mg deslorelin implant...

Microdose flare-up vs. flexible-multidose GnRH antagonist protocols for poor responder patients who underwent ICSI.

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Esinler, I

2014-01-01

To compare the performance of microdose flare-up (MF) and flexible-multidose gonadotropin-releasing hormone (GnRH) antagonist protocols in poor responder patients who underwent intracytoplasmic sperm injection (ICSI). One hundred and 12 consecutive patients (217 cycles) suspected to have poor ovarian response were enrolled. Group 1 (MF GnRH agonist group) constituted 64 patients (135 cycles) who underwent MF GnRH agonist protocol. Group 2 (flexible-multidose GnRH antagonist group) constituted 48 patients (82 cycles) who underwent flexible-multidose GnRH antagonist protocol. The duration of stimulation (d) (11.5 +/- 2.1 vs. 10.4 +/- 2.7, p or = seven blastomeres and < 10% fragmentation at day 3 (35.9% vs. 65.1%, p < 0.05) were significantly lower in Group 1 when compared to Group 2. The number of embryos transferred (2.2 +/- 1.3 vs. 2.4 +/- 0.9), the clinical pregnancy per embryo transfer (16.3% vs. 25.8%), and the implantation rate (8.6% vs. 12.2%) were comparable between groups. Although the flexible-multidose GnRH antagonist protocol produced better oocyte and embryo parameters, the clinical pregnancy rate and the implantation rates were comparable between the flexible-multidose GnRH antagonist and MF protocols in poor responder patients.

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

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Jiang-Feng Mao

2017-01-01

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

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

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

2017-04-01

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

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

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

2000-03-01

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

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

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

2016-01-01

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

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

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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.

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

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

2006-06-01

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

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

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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.

Combined Treatment with Gonadotropin-releasing Hormone Analog and Anabolic Steroid Hormone Increased Pubertal Height Gain and Adult Height in Boys with Early Puberty for Height

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Tanaka, Toshiaki; Naiki, Yasuhiro; Horikawa, Reiko

2012-01-01

Twenty-one boys with a height of 135 cm or less at onset of puberty were treated with a combination of GnRH analog and anabolic steroid hormone, and their pubertal height gain and adult height were compared with those of untreated 29 boys who enter puberty below 135 cm. The mean age at the start of treatment with a GnRH analog, leuprorelin acetate depot (Leuplin?) was 12.3 yr, a mean of 1.3 yr after the onset of puberty, and GnRH analog was administered every 3 to 5 wk thereafter for a mean d...

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

Selective enhancement of main olfactory input to the medial amygdala by GnRH.

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Blake, Camille Bond; Meredith, Michael

2010-03-04

In male hamsters mating behavior is dependent on chemosensory input from the main olfactory and vomeronasal systems, whose central pathways contain cell bodies and fibers of gonadotropin-releasing hormone (GnRH) neurons. In sexually naive males, vomeronasal organ removal (VNX), but not main olfactory lesions, impairs mating behavior. Intracerebroventricular (i.c.v.)-GnRH restores mating in sexually naive VNX males and enhances medial amygdala (Me) immediate-early gene activation by chemosensory stimulation. In sexually experienced males, VNX does not impair mating and i.c.v.-GnRH suppresses Me activation. Thus, the main olfactory system is sufficient for mating in experienced-VNX males, but not in naive-VNX males. We investigated the possibility that GnRH enhances main olfactory input to the amygdala in naive-VNX males using i.c.v.-GnRH and pharmacological stimulation (bicuculline/D,L-homocysteic acid mixture) of the main olfactory bulb (MOB). In sexually naive intact males there was a robust increase of Fos protein expression in the anteroventral medial amygdala (MeAv) with MOB stimulation, but no effect of GnRH. There was no effect of stimulation or GnRH in posterodorsal medial amygdala (MePd). In naive-VNX animals, GnRH increased Fos in MeAv and MePv. Only combined MOB stimulation and i.c.v.-GnRH produced a significant increase in Fos in the dorsal (reproduction-related) portion of MeP (MePd). When the animals were sexually experienced before VNX, a condition in which GnRH does not enhance mating, i.c.v.-GnRH combined with MOB stimulation suppressed Fos expression in MePd. This suggests a more selective effect of GnRH on olfactory input in MePd than elsewhere in medial amygdala of VNX males. 2009 Elsevier B.V. All rights reserved.

Basal testosterone concentrations after the application of a slow-release GnRH agonist implant are associated with a loss of response to buserelin, a short-term GnRH agonist, in the tom cat.

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Goericke-Pesch, Sandra; Georgiev, Plamen; Fasulkov, Ivan; Vodenicharov, Angel; Wehrend, Axel

2013-07-01

Slow-release GnRH agonist implants are considered an effective, reversible alternative to surgical castration in male tom cats. Individual differences exist regarding the onset of efficacy and might be delayed in some animals. Single measurements of testosterone (T) might result in basal concentrations also in intact male cats. Consequently, GnRH stimulation tests are performed to measure T increase in intact animals and to differentiate castrated from intact male cats. In this study, five tom cats were treated with a 4.7-mg deslorelin implant and GnRH stimulation tests using buserelin were performed before treatment and at 4-week intervals afterward until Week 20. After the last test in Week 20 all animals were castrated. Four of five animals had basal T after 4 weeks and-in contrast to pretreatment-application of buserelin did not result in any further T increase. In one animal, T was low after implant insertion, but not basal; however, a GnRH stimulation test induced a slight increase of T in Week 8 and 16 only and no response in Weeks 4, 12, and 20. Testicular volume was significantly decreased and penile spines disappeared in all cats. Testicular histology showed mixed atrophy, but also fully elongated spermatids in three of five male cats making infertility questionable. Because of the loss of the stimulatory effect of short-term GnRH application (buserelin), it can be assumed that long-term GnRH agonists also act by some mechanisms of downregulation of pituitary GnRH receptors in the tom cat. Copyright © 2013 Elsevier Inc. All rights reserved.

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

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

2016-04-01

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

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

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Shargil, A A

1987-03-01

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

Bilateral Salpingo-Oophorectomy Versus GnRH Analogue in the Adjuvant Treatment of Premenopausal Breast Cancer Patients: Cost-Effectiveness Evaluation of Breast Cancer Outcome, Ovarian Cancer Prevention and Treatment.

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Ferrandina, Gabriella; Amadio, Giulia; Marcellusi, Andrea; Azzolini, Elena; Puggina, Anna; Pastorino, Roberta; Ricciardi, Walter; Scambia, Giovanni

2017-11-01

BACKGROUND AND OBJECTIVE: There is no available evidence to recommend gonadotropin-releasing hormone (GnRH) analogue-based ovarian suppression versus bilateral salpingo-oophorectomy (BSO) in the adjuvant treatment of early breast cancer, since the two approaches are considered equivalent in terms of oncologic outcome. The role of surgical ovarian ablation has been revitalized based on the advances of minimally invasive surgery, and a better understanding of clinical and molecular basis of hereditary breast/ovarian cancer syndromes. The aim of this study is to analyze the cost-effectiveness of laparoscopic BSO and GnRH analogue administration in patients aged 40-49 years with hormone-sensitive breast cancer. A probabilistic decision tree model was developed to evaluate costs and outcomes of ovarian ablation through laparoscopic BSO, or ovarian suppression through monthly injections of GnRH analogue. Results were expressed as incremental costs per quality-adjusted life years (QALYs) gained. Laparoscopic BSO strategy was associated with a lower mean total cost per patient than GnRH treatment, and considering the difference in terms of QALYs, the incremental effectiveness did not demonstrate a notable difference between the two approaches. From the National Health Service perspective, and for a time horizon of 5 years, laparoscopic BSO was the dominant option compared to GnRH treatment; laparoscopic BSO was less expensive than GnRH, €2385 [95% confidence interval (CI) = 2044, 2753] vs €7093 (95% CI = 3409, 12,105), respectively, and more effective. Surgical ovarian ablation is more cost-effective than GnRH administration in the adjuvant treatment of hormone-sensitive breast cancer patients aged 40-49 years, and the advantage of preventing ovarian cancer through laparoscopic BSO should be considered.

Microdose GnRH Agonist Flare-Up versus Ultrashort GnRH Agonist Combined with Fixed GnRH Antagonist in Poor Responders of Assisted Reproductive Techniques Cycles.

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Eftekhar, Maryam; Mohammadian, Farnaz; Yousefnejad, Fariba; Khani, Parisa

2013-01-01

This study compares the microdose flare-up protocol to the ultrashort gonadotropinreleasing hormone (GnRH) agonist flare combined with the fixed multidose GnRH antagonist protocol in poor responders undergoing ovarian stimulation. In this randomized clinical trial, 120 women who were candidates for assisted reproductive techniques (ART) and had histories of one or more failed in vitro fertilization (IVF) cycles with three or fewer retrieved oocytes were prospectively randomized into two groups. Group I (60 patients) received the microdose flare-up regimen and group II (60 patients) received the ultrashort GnRH agonist combined with fixed GnRH antagonist. There were no significant differences between the groups in the number of used gonadotropin ampoules (p=0.591), duration of stimulation (p=0.610), number of retrieved oocytes (p=0.802), fertilization rate (p=0.456), and the number of transferred embryos (p=0.954). The clinical pregnancy rates were statistically similar in group I (10%) compared with group II (13.3%, p=0.389). According to our results, there is no significant difference between these protocols for improving the ART outcome in poor responders. Additional prospective, randomized studies with more patients is necessary to determine the best protocol (Registration Number: IRCT201105096420N1).

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.

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

2014-08-01

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

Evaluation of basal sex hormone levels for activation of the hypothalamic-pituitary-gonadal axis.

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Ding, Yu; Li, Juan; Yu, Yongguo; Yang, Peirong; Li, Huaiyuan; Shen, Yongnian; Huang, Xiaodong; Liu, Shijian

2018-03-28

This study aimed to identify the predictive value of basal sex hormone levels for activation of the hypothalamic-pituitary-gonadal (HPG) axis in girls. Gonadotropin-releasing hormone (GnRH) stimulation tests were performed and evaluated in a total of 1750 girls with development of secondary sex characteristics. Correlation analyses were conducted between basal sex hormones and peak luteinizing hormone (LH) levels ≥5 IU/L during the GnRH stimulation test. Receiver operating characteristic (ROC) curves for basal levels of LH, follicle-stimulating hormone (FSH), LH/FSH, and estradiol (E2) before the GnRH stimulation test were plotted. The area under the curve (AUC) and 95% confidence intervals (CIs) were measured for each curve. The maximum AUC value was observed for basal LH levels (0.77, 95% CI: 0.74-0.79), followed by basal FSH levels (0.73, 95% CI: 0.70-0.75), the basal LH/FSH ratio (0.68, 95% CI: 0.65-0.71), and basal E2 levels (0.61, 95% CI: 0.59-0.64). The appropriate cutoff value of basal LH levels associated with a positive response of the GnRH stimulation test was 0.35 IU/L, with a sensitivity of 63.96% and specificity of 76.3% from the ROC curves when Youden's index showed the maximum value. When 100% of patients had peak LH levels ≥5 IU/L, basal LH values were >2.72 IU/L, but the specificity was only 5.45%. Increased basal LH levels are a significant predictor of a positive response during the GnRH stimulation test for assessing activation of the HPG axis in most girls with early pubertal signs.

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

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

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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.

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

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

2013-12-01

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

The potential for castration of domestic animals by active immunization against GnRH

International Nuclear Information System (INIS)

Gonzalez, A.; Allen, A.F.; Murphy, B.D.; Mapletoft, R.J.; Cohen, R.

1990-01-01

Trials have been carried out in sheep and beef cattle in attempts to induce immunity against gonadotropin releasing hormone (GnRH), with the objective of using immunocastration as a replacement for surgical castration. Of the protein carriers used, ovalbumin and horse albumin yielded highest responses, with keyhole limpet haemocyanin (KLH) being a potent substitute for both. Different adjuvants were also used. In these trials, highest titre responses were obtained using Freund's complete (FCA) or Freund's incomplete (FIA) adjuvant in cattle and sheep. Although no adjuvant was found to yield as high a response as FCA and Alhydrogel, an aluminium hydroxide adjuvant generally yielded a high response in cattle and sheep. The results from the trials in beef calves indicate that active immunization against GnRH does not affect average daily gains, total body weight gain or carcass dressing percentage. The results suggest the potential of immunocastration as a substitute for surgical castration in cattle and sheep. (author). 30 refs, 8 figs, 2 tabs

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

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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.

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

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

1976-06-01

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

Characterization of gonadotrophin-releasing hormone precursor cDNA in the Old World mole-rat Cryptomys hottentotus pretoriae: high degree of identity with the New World guinea pig sequence.

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Kalamatianos, T; du Toit, L; Hrabovszky, E; Kalló, I; Marsh, P J; Bennett, N C; Coen, C W

2005-05-01

Regulation of pituitary gonadotrophins by the decapeptide gonadotrophin-releasing hormone 1 (GnRH1) is crucial for the development and maintenance of reproductive functions. A common amino acid sequence for this decapeptide, designated as 'mammalian' GnRH, has been identified in all mammals thus far investigated with the exception of the guinea pig, in which there are two amino acid substitutions. Among hystricognath rodents, the members of the family Bathyergidae regulate reproduction in response to diverse cues. Thus, highveld mole-rats (Cryptomys hottentotus pretoriae) are social bathyergids in which breeding is restricted to a particular season in the dominant female, but continuously suppressed in subordinate colony members. Elucidation of reproductive control in these animals will be facilitated by characterization of their GnRH1 gene. A partial sequence of GnRH1 precursor cDNA was isolated and characterized. Comparative analysis revealed the highest degree of identity (86%) to guinea pig GnRH1 precursor mRNA. Nevertheless, the deduced amino acid sequence of the mole-rat decapeptide is identical to the 'mammalian' sequence rather than that of guinea pigs. Successful detection of GnRH1-synthesizing neurones using either a guinea pig GnRH1 riboprobe or an antibody against the 'mammalian' decapeptide is consistent with the guinea pig-like sequence for the precursor and the classic 'mammalian' form for the decapeptide. The high degree of identity in the GnRH1 precursor sequence between this Old World mole-rat and the New World guinea pig is consistent with the theory that caviomorphs and phiomorphs originated from a common ancestral line in the Palaeocene to mid Eocene, some 63-45 million years ago.

Differentially expressed miRNAs after GnRH treatment and their potential roles in FSH regulation in porcine anterior pituitary cell.

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Rui-Song Ye

Full Text Available Hypothalamic gonadotropin-releasing hormone (GnRH is a major regulator of follicle-stimulating hormone (FSH secretion in gonadotrope cell in the anterior pituitary gland. microRNAs (miRNAs are small RNA molecules that control gene expression by imperfect binding to the 3'-untranslated region (3'-UTR of mRNA at the post-transcriptional level. It has been proven that miRNAs play an important role in hormone response and/or regulation. However, little is known about miRNAs in the regulation of FSH secretion. In this study, primary anterior pituitary cells were treated with 100 nM GnRH. The supernatant of pituitary cell was collected for FSH determination by enzyme-linked immunosorbent assay (ELISA at 3 hours and 6 hours post GnRH treatment respectively. Results revealed that GnRH significantly promoted FSH secretion at 3 h and 6 h post-treatment by 1.40-fold and 1.80-fold, respectively. FSHβ mRNA at 6 h post GnRH treatment significantly increased by 1.60-fold. At 6 hours, cells were collected for miRNA expression profile analysis using MiRCURY LNA Array and quantitative PCR (qPCR. Consequently, 21 up-regulated and 10 down-regulated miRNAs were identified, and qPCR verification of 10 randomly selected miRNAs showed a strong correlation with microarray results. Chromosome location analysis indicated that 8 miRNAs were mapped to chromosome 12 and 4 miRNAs to chromosome X. Target and pathway analysis showed that some miRNAs may be associated with GnRH regulation pathways. In addition, In-depth analysis indicated that 10 up-regulated and 3 down-regulated miRNAs probably target FSHβ mRNA 3'-UTR directly, including miR-361-3p, a highly conserved X-linked miRNA. Most importantly, functional experimental results showed that miR-361-3p was involved in FSH secretion regulation, and up-regulated miR-361-3p expression inhibited FSH secretion, while down-regulated miR-361-3p expression promoted FSH secretion in pig pituitary cell model. These differentially

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

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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.

Kisspeptin Activates Ankrd 26 Gene Expression in Migrating Embryonic GnRH Neurons

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Tomoko eSoga

2016-03-01

Full Text Available Kisspeptin, a newly discovered neuropeptide regulates gonadotropin-releasing hormone (GnRH. Kisspeptins are a large RF-amide family of peptides. The kisspeptin coded by kiss1 gene is a 145-amino acid- protein that is cleaved to C-terminal peptide kisspeptin-10. G-protein coupled receptor 54 (GPR54 has been identified as a kisspeptin receptor, and it is expressed in GnRH neurons and in a variety of cancer cells. In this study, enhanced green fluorescent protein (EGFP labelled GnRH cells with migratory properties, which express GPR54, served as a model to study the effects of kisspeptin on cell migration. We monitored EGFP–GnRH neuronal migration in brain slide culture of embryonic day 14 transgenic rat by live cell imaging system and studied the effects of kisspeptin-10 (1nM treatment for 36h on GnRH migration. Furthermore to determine kisspeptin-induced molecular pathways related with apoptosis, and cytoskeletal changes during neuronal migration, we studied the expression levels of candidate genes in laser captured EGFP–GnRH neurons by real time PCR. We found that there was no change in the expression level of genes related to cell proliferation and apoptosis. The expression of ankyrin repeat domain-containing protein (ankrd 26 in EGFP–GnRH neurons was up-regulated by the exposure to kisspeptin. These studies suggest that ankrd26 gene plays an unidentified role in regulating neuronal movement mediated by kisspeptin-GPR54 signaling, which could be a potential pathway to suppress cell migration.

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

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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

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

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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.

Do GnRH analogues directly affect human endometrial epithelial cell gene expression?

KAUST Repository

Zhang, Xiaomei

2010-03-04

We examined whether Gonadotrophin-releasing hormone (GnRH) analogues [leuprolide acetate (LA) and ganirelix acetate (GA)] modulate gene expression in Ishikawa cells used as surrogate for human endometrial epithelial cells in vitro. The specific aims were: (i) to study the modulatory effect of GnRH analogues by RT-PCR [in the absence and presence of E2 and P4, and cyclic adenosine monophos-phate (cAMP)] on mRNA expression of genes modulated during the window of implantation in GnRH analogues/rFSH-treated assisted reproductive technology cycles including OPTINEURIN (OPTN), CHROMATIN MODIFYING PROTEIN (CHMP1A), PROSAPOSIN (PSAP), IGFBP-5 and SORTING NEXIN 7 (SNX7), and (ii) to analyze the 5\\'-flanking regions of such genes for the presence of putative steroid-response elements [estrogen-response elements (EREs) and P4-response element (PREs)]. Ishikawa cells were cytokeratin+/vimentin2 and expressed ERa,ERb, PR and GnRH-R proteins. At 6 and 24 h, neither LA nor GA alone had an effect on gene expression. GnRH analogues alone or following E2 and/or P4 co-incubation for 24 h also had no effect on gene expression, but P4 significantly increased expression of CHMP1A.E2 + P4 treatment for 4 days, alone or followed by GA, had no effect, but E2 + P4 treatment followed by LA significantly decreased IGFBP-5 expression. The addition of 8-Br cAMP did not modify gene expression, with the exception of IGFBP-5 that was significantly increased. The GnRH analogues did not modify intracellular cAMP levels. We identified conserved EREs for OPN, CHMP1A, SNX7 and PSAP and PREs for SNX7. We conclude that GnRH analogues appear not to have major direct effects on gene expression of human endo-metrial epithelial cells in vitro. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

COMPARISON BETWEEN ESTRADIOL CYPIONATE AND GONADOTROPIN RELEASING HORMONE AS OVULATION SYNCHRONIZATION TREATMENTS FOR FIXED-TIME ARTIFICIAL INSEMINATION PROGRAMS IN BRAHMAN-CROSS HEIFERS IN A SUBTROPICAL REGION OF NORTHEASTERN MEXICO

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Miguel Angel Dominguez

2012-12-01

Full Text Available Synchronization protocols with intravaginal progesterone releasing devices (CIDR and PGF2α were evaluated, with GnRH or estradiol cypionate (ECP added for fixed-time artificial insemination (FTAI in five counties in Tamaulipas, Mexico. Brahman-cross heifers (≥15 months old were selected based on body condition (≥3 on a 5-point scale and confirmed ovarian activity. The six treatments (n = 320 each were: T1 (9-d CIDR, ECP on insertion, PGF2α on day 9, ECP on day 10, FTAI 54 h after removal; T2 (7-d CIDR, ECP on insertion, PGF2α on day 7, ECP on day 8, FTAI 54 h after removal; T3 (7-d CIDR, GnRH on insertion, PGF2α on day 7, FTAI and GnRH 48 h after removal; T4 (7-d CIDR, GnRH on insertion, PGF2α on day 6, FTAI and GnRH 48 h after removal; T5 (7-d CIDR, GnRH on insertion, PGF2α on day 7, FTAI and GnRH 60 h after removal; and T6 (7-d CIDR, GnRH on insertion, PGF2α on day 7, FTAI alone 48 h after removal. Pregnancy was diagnosed ultrasonically 45 days after FTAI. Analyses included pregnancy rates and treatment costs (hormones and handling. Pregnancy rates ranged from 31.6 ± 3.9 to 48.0 ± 10.6%; neither treatment nor county affected these rates (p > 0.05. In conclusion, the inclusion of treatment costs showed two more economical treatments (T2 using estradiol or T3 using GnRH under the nutritional, weather and handling conditions present in the tropical region of southeastern Tamaulipas.

Parity Differences in Heat Expression of Dairy Cows Synchronized with GnRH, CIDR and PGF2α during Dry Season in Zambia

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E. S. Mwaanga*, K. Choongo, H. Simukoko and C. Chama1

2012-01-01

Full Text Available A study was conducted to investigate parity differences in heat expression of dairy cows heat-synchronized during the dry season when feed scarcity is common. Cyclic cows (n=65 aged 2 to 10 years with parity range of 0 to 7 were selected from small-holder dairy farms around Lusaka. Cows were divided into 3 groups of nulliparous, primiparous and pluriparous. Heat-was synchronized using gonadotrophin releasing hormone (GnRH and controlled intra-vaginal drug releasing device (CIDR. Heat detection was observed after CIDR withdraw. The study showed a significantly (P<0.05 lower number of primiparous cows (68% coming into heat compared to nulliparous (81.8% and pluriparous cows (83.3%. It was concluded that parity influences estrus expression rate in dairy cows following synchronization with GnRH, CIDR and PGF2α during the dry season in the sub-tropics.

Dual Actions of Mammalian and Piscine Gonadotropin-Inhibitory Hormones, RFamide-Related Peptides and LPXRFamide Peptides, in the Hypothalamic–Pituitary–Gonadal Axis

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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.

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

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

Science.gov (United States)

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

2014-01-10

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

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

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

2010-01-01

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

Developmental expression of the G protein-coupled receptor 54 and three GnRH mRNAs in the teleost fish cobia.

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Mohamed, J Shaik; Benninghoff, Abby D; Holt, G Joan; Khan, Izhar A

2007-02-01

The cDNAs of the G protein-coupled receptor 54 (GPR54) and three prepro-gonadotropin-releasing hormones, GnRH-I (seabream GnRH), GnRH-II (chicken GnRH-II), and GnRH-III (salmon GnRH) were isolated and cloned from the brain of the teleost fish cobia, Rachycentron canadum. The cobia GPR54 cDNA was 95 and 51-56% identical to those of tilapia and mammalian models respectively. The GnRH cDNA sequences of cobia showed strong identities to those of tilapia, Atlantic croaker, red drum, and the seabass and seabream species. The real-time quantitative RT-PCR methods allowed detection of all three GnRH mRNAs on the first day after hatching (DAH). The GnRH-I mRNA levels, which were the lowest among the three GnRHs, increased gradually with two distinct peaks in larvae at 3 and 4 DAH. On the other hand, GnRH-II and GnRH-III mRNAs were significantly higher in larvae at 2 and 6 DAH compared with those on the preceding days. In addition, significant peaks of all the three GnRH mRNAs were observed in the brains of 26-day-old fish. The finding of higher GnRH-I and GnRH-II mRNAs in males than females at 153 DAH may be related to early puberty observed during the first year in laboratory-reared male cobia. Moreover, this study demonstrates for the first time the expression of GPR54 mRNA during larval development in a vertebrate species. The concomitant expression patterns of GPR54 and GnRH mRNAs during different stages of larval and juvenile developments, and during early puberty in male cobia suggest a potential relationship between GPR54 and multiple GnRHs during these stages of development consistent with the role of GPR54 in controlling GnRH release in mammals. The increase in GPR54 and GnRH mRNAs observed during early puberty in cobia is consistent with a similar change reported in pubertal rats. This finding together with the localization of GPR54 mRNAs on GnRH neurons in fish and mammals suggests that the GPR54-GnRH interactions may be conserved in different vertebrate groups.

Adult height after spontaneous pubertal growth or GnRH analog treatment in girls with early puberty: a meta-analysis.

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Bertelloni, Silvano; Massart, Francesco; Miccoli, Mario; Baroncelli, Giampiero I

2017-06-01

Early puberty (EP) has been defined as the onset of puberty in the low-normal range; it may be a cause for concern regarding a possible impairment of adult height (AH). This paper meta-analysed data on AH after spontaneous growth or after gonadotropin-releasing hormone (GnRH) analog treatment in girls with EP. A computerized literature search was conducted from 1980 to June 30, 2016. Only published studies in English were considered. Eight papers were selected (483 cases). In untreated girls (n = 300), predicted adult height (PAH) at start of follow-up (-0.559 SDS (95%CI -1.110 to 0.001); P = 0.050) was close to mid-parental height (MPH) (-0.557 SDS (95%CI -0.736 to -0.419); P adult height. What is New: • Untreated and GnRH analog treated girls with early puberty reached similar adult height. • Adult height was consistent with mid-parental height in both untreated and GnRH analog treated girls with early puberty.

[Effectiveness and safety of pulsatile GnRH pump therapy on female patients with IHH].

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

2015-11-10

To investigate the therapeutic effect of pulsatile GnRH (gonadorelin) pump on female patients with idiopathic hypogonadotropic hypogonadism (IHH). In this retrospective study, five female IHH patients were recruited. Patients were treated with pulsatile gonadorelin (10 µg per 90 min) via a pump for at least 12 weeks. Serum gonadotropins and sex steroid levels were measured, and menses were recorded. After one-week treatment, luteinizing hormone (LH) level increased from (2.2 ± 2.0) U/L to (5.4 ± 2.5) U/L (P=0.028), follicle-stimulating hormone(FSH) level increased from (3.7 ± 2.7) U/L to(6.3 ± 1.0) U/L (P=0.162), and estradiol (E2) level increased from (58 ± 13) pmol/L to (260 ± 97) pmol/L (P=0.011). Menstrual bleeding was observed in 4 patients after starting treatment for 35-55 days and two natural pregnancies were reported. No menstrual bleeding was reported in another patient. The frequency of pulsatile GnRH had to be adjusted according to endogenous GnRH secretion during the follicular phase of normal women and regular menses were induced. Pulsatile GnRH is effective in treating female IHH. A constant frequency of pulsatile GnRH is suitable for most of IHH patients. However, for those who failed to produce regular menses, adjusting pulsatile frequency to imitate the physiological rhythm of GnRH may be an alternative option.

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

Science.gov (United States)

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

2014-03-25

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

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

DEFF Research Database (Denmark)

Müller, J; Juul, A; Andersson, A M

2000-01-01

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

Genetic variation in total number and locations of GnRH neurons identified using in situ hybridization in a wild-source population.

Science.gov (United States)

Kaugars, Katherine E; Rivers, Charlotte I; Saha, Margaret S; Heideman, Paul D

2016-02-01

The evolution of brain function in the regulation of physiology may depend in part upon the numbers and locations of neurons. Wild populations of rodents contain natural genetic variation in the inhibition of reproduction by winter-like short photoperiod, and it has been hypothesized that this functional variation might be due in part to heritable variation in the numbers or location of gonadotropin releasing hormone (GnRH) neurons. A naturally variable wild-source population of white-footed mice was used to develop lines artificially selected for or against mature gonads in short, winter-like photoperiods. We compared a selection line that is reproductively inhibited in short photoperiod (Responsive) to a line that is weakly inhibited by short photoperiod (Nonresponsive) for differences in counts of neurons identified using in situ hybridization for GnRH mRNA. There was no effect of photoperiod, but there were 60% more GnRH neurons in total in the Nonresponsive selection line than the Responsive selection line. The lines differed specifically in numbers of GnRH neurons in more anterior regions, whereas numbers of GnRH neurons in posterior areas were not statistically different between lines. We compare these results to those of an earlier study that used immunohistochemical labeling for GnRH neurons. The results are consistent with the hypothesis that the selection lines and natural source population contain significant genetic variation in the number and location of GnRH neurons. The variation in GnRH neurons may contribute to functional variation in fertility that occurs in short photoperiods in the laboratory and in the wild source population in winter. © 2015 Wiley Periodicals, Inc.

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.

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

International Nuclear Information System (INIS)

Mahoney, Megan M.; Padmanabhan, Vasantha

2010-01-01

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

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

Science.gov (United States)

Mahoney, Megan M; Padmanabhan, Vasantha

2010-09-01

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

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

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Frederique Ruf-Zamojski

2018-02-01

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

Gonadotrophin-Releasing Hormone (GnRH Analogues in the Treatment of Mixed Mullerian Tumours of the Uterus: Two Case Reports and Review

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Michael Katesmark

1998-01-01

Full Text Available Subjects/Discussion. Two cases of clinical and radiological response of recurrent mixed Mullerian tumours following treatment with either nasal (Buserilin or intramuscular (Goserilin GnRH analogues are reported and a short review of the evidence to support this treatment option presented.

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

Tritium labeling of gonadotropin releasing hormone in its proline and histidine residues

International Nuclear Information System (INIS)

Klauschenz, E.; Bienert, M.; Egler, H.; Pleiss, U.; Niedrich, H.; Nikolics, K.

1981-01-01

3,4-dehydroproline9-GnRH prepared by solid phase peptide synthesis was tritiated catalytically under various conditions yielding 3H-GnRH with specific radioactivities in the range from 35-60 Ci/mmol and full LH releasing activity in vitro. Using palladium/alumina catalyst, the tritiation of the double bond occurs within ten minutes. Investigation of the tritium distribution between the amino acid residues showed a remarkably high incorporation of tritium into the histidine residue (11 to 37%). On the basis of this observation, the tritium labeling of GnRH and angiotensin I by direct catalytic hydrogen-tritium exchange was found to be useful for the labeling of these peptides at remarkably high specific radioactivity

Gonadotropin Releasing Hormone (GnRH) Neuron Migration: Initiation, Maintenance and Cessation as Critical Steps to Ensure Normal Reproductive Function

OpenAIRE

Wierman, Margaret E.; Kiseljak-Vassiliades, Katja; Tobet, Stuart

2010-01-01

GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over expression of candidate genes in mouse models. Importan...

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

Science.gov (United States)

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

2018-02-15

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

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

Science.gov (United States)

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

2017-12-01

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

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

Growth Hormone-Releasing Hormone in Diabetes

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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.

Corifollitropin alfa compared to daily rFSH or HP-HMG in GnRH antagonist controlled ovarian stimulation protocol for patients undergoing assisted reproduction.

Science.gov (United States)

Souza, Priscila Morais Galvão; Carvalho, Bruno Ramalho de; Nakagawa, Hitomi Miura; Rassi, Thalita Reis Esselin; Barbosa, Antônio César Paes; Silva, Adelino Amaral

2017-06-01

This study aimed to compare the outcomes of controlled ovarian stimulation (COS) with corifollitropin alfa versus daily recombinant follicle-stimulating hormone (rRFSH) or highly purified human menopausal gonadotropin (HP-HMG) in patients undergoing in vitro fertilization (IVF) cycles based on gonadotropin-releasing hormone (GnRH) antagonist protocols. The primary endpoints were total number of oocytes and mature oocytes. This retrospective study looked into 132 controlled ovarian stimulation cycles from IVF or oocyte cryopreservation performed in a private human reproduction center between January 1 and December 31, 2014. Enrollment criteria: women aged 0.05). There were no significant differences in fertilization (76.9% vs. 76.8%, p=1.0), biochemical pregnancy (66.7% vs. 47.2%, p=0.1561) or embryo implantation rates (68.7% vs. 50%, p=0.2588) between the groups using corifollitropin alfa and rFSH or HMG, respectively. Corifollitropin alfa seems to be as effective as rFSH or HP-HMG when used in the first seven days of ovulation induction for patients undergoing assisted reproduction in GnRH antagonist protocols.

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

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Musgrove Lois C

2001-11-01

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

Genomic structure and promoter functional analysis of GnRH3 gene in large yellow croaker (Larimichthys crocea).

Science.gov (United States)

Huang, Wei; Zhang, Jianshe; Liao, Zhi; Lv, Zhenming; Wu, Huifei; Zhu, Aiyi; Wu, Changwen

2016-01-15

Gonadotropin-releasing hormone III (GnRH3) is considered to be a key neurohormone in fish reproduction control. In the present study, the cDNA and genomic sequences of GnRH3 were cloned and characterized from large yellow croaker Larimichthys crocea. The cDNA encoded a protein of 99 amino acids with four functional motifs. The full-length genome sequence was composed of 3797 nucleotides, including four exons and three introns. Higher identities of amino acid sequences and conserved exon-intron organizations were found between LcGnRH3 and other GnRH3 genes. In addition, some special features of the sequences were detected in partial species. For example, two specific residues (V and A) were found in the family Sciaenidae, and the unique 75-72 bp type of the open reading frame 2 and 3 existed in the family Cyprinidae. Analysis of the 2576 bp promoter fragment of LcGnRH3 showed a number of transcription factor binding sites, such as AP1, CREB, GATA-1, HSF, FOXA2, and FOXL1. Promoter functional analysis using an EGFP reporter fusion in zebrafish larvae presented positive signals in the brain, including the olfactory region, the terminal nerve ganglion, the telencephalon, and the hypothalamus. The expression pattern was generally consistent with the endogenous GnRH3 GFP-expressing transgenic zebrafish lines, but the details were different. These results indicate that the structure and function of LcGnRH3 are generally similar to the other teleost GnRH3 genes, but there exist some distinctions among them. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

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

2016-01-01

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

Melatonin Inhibits GnRH-1, GnRH-3 and GnRH Receptor Expression in the Brain of the European Sea Bass, Dicentrarchus labrax

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José Antonio Muñoz-Cueto

2013-04-01

Full Text Available Several evidences supported the existence of melatonin effects on reproductive system in fish. In order to investigate whether melatonin is involved in the modulation of GnRH systems in the European sea bass, we have injected melatonin (0.5 µg/g body mass in male specimens. The brain mRNA transcript levels of the three GnRH forms and the five GnRH receptors present in this species were determined by real time quantitative PCR. Our findings revealed day–night variations in the brain expression of GnRH-1, GnRH-3 and several GnRH receptors (dlGnRHR-II-1c, -2a, which exhibited higher transcript levels at mid-light compared to mid-dark phase of the photocycle. Moreover, an inhibitory effect of melatonin on the nocturnal expression of GnRH-1, GnRH-3, and GnRH receptors subtypes 1c, 2a and 2b was also demonstrated. Interestingly, the inhibitory effect of melatonin affected the expression of hypophysiotrophic GnRH forms and GnRH receptors that exhibit day–night fluctuations, suggesting that exogenous melatonin reinforce physiological mechanisms already established. These interactions between melatoninergic and GnRH systems could be mediating photoperiod effects on reproductive and other rhythmic physiological events in the European sea bass.

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.

Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

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Guo S

2017-03-01

Full Text Available Song Guo,1,* Xiaowei Lu,1,* Ruihuan Gu,2 Di Zhang,3 Yijuan Sun,2 Yun Feng1 1Department of Obstetrics and Gynecology, Reproductive Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Gynecology, Shanghai Ji Ai Genetics & In Vitro Fertilization Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Gynecology and Obstetrics, Jinan Military General Hospital, Jinan, People’s Republic of China *These authors contributed equally to this work Purpose: Adenomyosis is a common, benign gynecological condition of the female reproductive tract characterized by heavy menstrual bleeding and dysmenorrhea. Gonadotropin-releasing hormone (GnRH agonists are one of the medications used in adenomyosis treatment; however, their underlying mechanisms are poorly understood. Moreover, it is difficult to obtain endometrial samples from women undergoing such treatment. To overcome this, we generated an adenomyosis mouse model, which we treated with an GnRH agonist to determine its effect on pregnancy outcomes. We also analyzed endometrial gene expression following GnRH agonist treatment to determine the mechanisms that may affect pregnancy outcome in individuals with adenomyosis.Methods: Neonatal female mice were divided into a control group, an untreated adenomyosis group, and an adenomyosis group treated with a GnRH agonist (n=6 each. The pregnancy outcome was observed and compared among the groups. Then, three randomly chosen transcriptomes from endometrial tissues from day 4 of pregnancy were analyzed between the adenomyosis group and the GnRH agonist treatment group by RNA sequencing and quantitative reverse transcription polymerase chain reaction (PCR.Results: The litter size was significantly smaller in the adenomyosis group than in the control group (7±0.28 vs 11±0.26; P<0.05. However, the average live litter

Hedgehog-PKA signaling and gnrh3 regulate the development of zebrafish gnrh3 neurons.

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Ming-Wei Kuo

Full Text Available GnRH neurons secrete GnRH that controls the development of the reproduction system. Despite many studies, the signals controlling the development of GnRH neurons from its progenitors have not been fully established. To understand the development of GnRH neurons, we examined the development of gnrh3-expressing cells using a transgenic zebrafish line that expresses green fluorescent protein (GFP and LacZ driven by the gnrh3 promoter. GFP and LacZ expression recapitulated that of gnrh3 in the olfactory region, olfactory bulb and telencephalon. Depletion of gnrh3 by morpholinos led to a reduction of GFP- and gnrh3-expressing cells, while over-expression of gnrh3 mRNA increased the number of these cells. This result indicates a positive feed-forward regulation of gnrh3 cells by gnrh3. The gnrh3 cells were absent in embryos that lack Hedgehog signaling, but their numbers were increased in embryos overexpressing shhb. We manipulated the amounts of kinase that antagonizes the Hedgehog signaling pathway, protein kinase A (PKA, by treating embryos with PKA activator forskolin or by injecting mRNAs encoding its constitutively active catalytic subunit (PKA* and dominant negative regulatory subunit (PKI into zebrafish embryos. PKA* misexpression or forskolin treatment decreased GFP cell numbers, while PKI misexpression led to ectopic production of GFP cells. Our data indicate that the Hedgehog-PKA pathway participates in the development of gnrh3-expressing neurons during embryogenesis.

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

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Schally, Andrew V; Gual, Carlos

2002-01-01

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

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

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

2013-10-01

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

Growth Hormone Supplementation in the Luteal Phase Before Microdose GnRH Agonist Flare Protocol for In Vitro Fertilization.

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Dunne, Caitlin; Seethram, Ken; Roberts, Jeffrey

2015-09-01

Growth hormone (GH) acts in both early and late follicular development to stimulate the proliferation and differentiation of granulosa cells and to increase the production of estradiol in animal and human ovaries. Investigators have therefore explored GH supplementation to improve outcomes in women undergoing in vitro fertilization, with the greatest interest in women with diminished ovarian reserve. Recent meta-analyses indicate that GH supplementation can be beneficial for poor responders undergoing IVF. In most studies, GH has been given concomitantly with gonadotropins during the follicular phase; this may not be optimal, since follicular recruitment begins during the preceding luteal phase. We therefore wished to examine the effect of GH supplementation in the luteal phase before controlled ovarian stimulation (COH) with a microdose GnRH agonist flare (MDF) protocol in women undergoing in vitro fertilization. We performed a retrospective matched case-control study of patients undergoing treatment at a private IVF facility between June 2012 and July 2013. Patients identified as poor responders to COH were offered adjuvant GH treatment as part of their ovarian stimulation regimen. The patients in the experimental group chose to take GH, 3.33 mg daily by subcutaneous injection for 14 days, before starting COH. All patients had an MDF stimulation protocol using 450 IU of follicle stimulating hormone (FSH) daily. A total of 42 women were included in the study. There were 14 women in the experimental group (GH) and 28 controls (C) matched for age, BMI, and day 3 FSH level. There was no difference between the groups in clinical pregnancy rate (GH = 29%, C = 32%, P = 0.99), number of mature oocytes retrieved (GH = 2.5, C = 5.0, P = 0.13), cycle cancellation rate (GH = 21%, C = 14%, P = 0.88), duration of COH (GH = 10.1, C = 10.1, P = 0.93), or mean peak estradiol level (GH = 4174 pmol/L, C = 5105 pmol/L, P = 0.44). The administration of growth hormone during the

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.)

Characterization and differential expression of three GnRH forms during reproductive development in cultured turbot Schophthalmus maximus

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Zhao, Chunyan; Xu, Shihong; Feng, Chengcheng; Liu, Yifan; Yang, Yang; Wang, Yanfeng; Xiao, Yongshuang; Song, Zongcheng; Liu, Qinghua; Li, Jun

2017-10-01

Turbots (Schophthalmus maximus), one of the most important economic marine flatfish species, fail to undergo final spawning and spermiation naturally under artificial farming conditions. In vertebrates, reproduction is regulated by the brain-pituitary-gonadal axis (BPG-axis), and gonadotropin releasing hormone (GnRH) is one of its key components. Therefore, to better understand the physiology of reproduction in the turbot, three of the genes encoding GnRH subtypes—sbGnRH, cGnRH-II and sGnRH—were cloned and sequenced by isolating the cDNA sequences. The localizations and patterns of expression of their mRNAs were also evaluated during seasonal gonadal development. All three mRNAs were expressed abundantly in the brain; sbGnRH and sGnRH mRNAs were also detected in the gonads and pituitary gland, and sbGnRH expression was much higher than that of sGnRH, indicating the critical role of sbGnRH in regulating the BPG-axis. Moreover, the brain expression patterns of sbGnRH and sGnRH mRNAs showed an increased trend during gonadal development, peaking in mature stages. This indicated the direct regulation of gonadal development by the GnRH system. In addition, cGnRH-II mRNA expression showed no significant variations, suggesting that cGnRH-II is not critically involved in the control of reproduction. Further, the mRNA abundances of the three GnRH forms in the breeding season were significantly higher than those in immature and post-breeding stages in all analyzed brain areas. Therefore, we propose that sbGnRH is the most important hormone for the regulation of reproduction in turbot via the BPG-axis. These results will help in better understanding the reproductive endocrine mechanisms of turbots and lay the groundwork for additional studies aimed at comparing the reproductive physiology of wild individuals with those raised under artificial conditions.

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

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

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Zhang John

2016-07-01

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

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

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

2017-01-01

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

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

Directory of Open Access Journals (Sweden)

Daniela I. Pérez Sirkin

2017-08-01

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

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

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

1986-01-01

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

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

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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.

Use of a GnRH antagonist in controlled ovarian hyperstimulation for assisted conception in women with polycystic ovary disease: a randomized, prospective, pilot study.

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Bahçeci, Mustafa; Ulug, Ulun; Ben-Shlomo, Izhar; Erden, Halit Firat; Akman, Mehmet Ali

2005-02-01

To compare the outcome of using gonadotropin-releasing hormone (GnRH) antagonists versus agonists in women with polycystic ovary disease (PCOD) who underwent controlled ovarian hyperstimulation (COH) for assisted reproductive techniques (ART). A total of 129 patients with PCOD were randomly allocated to undergo COH with a GnRH antagonist (59 patients) and GnRH agonist (leuprolide acetate) (70 patients) to prevent a premature luteinizing hormone (LH) surge. Assisted fertilization following oocyte retrieval and embryo transfer was performed. None of the cycles were cancelled due to a premature LH surge. There was no significant difference between the antagonist and agonist arms in the number of gonadotropin ampules consumed per cycle. However, in the antagonist arm a shorter duration of ovarian stimulation was recorded as compared to the agonist arm. Although similar numbers of oocytes was retrieved from both groups of patients, the quality of the oocytes, as measured by metaphase 2/total oocyte ratio, was lower in the antagonist arm as compared to the agonist arm. Pregnancy rates were 57.6% and 58.5% in the antagonist and agonist arms, respectively (p > 0.05). Implantation rates were not different (34.0% and 34.6%, respectively). The frequency of ovarian hyperstimulation syndrome also did not differ between the treatment groups (5% and 7.1%, respectively). The size of our study, on a specific subgroup of patients, does not allow a reliable conclusion regarding ART outcomefollowing the use of a GnRH antagonist versus agonist. Nevertheless, the protocol with the antagonist gave results that were as good as those of the protocol with the agonist in this PCOD patient population.

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

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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.

Brain Endothelial Cells Control Fertility through Ovarian-Steroid–Dependent Release of Semaphorin 3A

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Messina, Andrea; Casoni, Filippo; Vanacker, Charlotte; Langlet, Fanny; Hobo, Barbara; Cagnoni, Gabriella; Gallet, Sarah; Hanchate, Naresh Kumar; Mazur, Danièle; Taniguchi, Masahiko; Mazzone, Massimiliano; Verhaagen, Joost; Ciofi, Philippe; Bouret, Sébastien G.; Tamagnone, Luca; Prevot, Vincent

2014-01-01

Neuropilin-1 (Nrp1) guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH), the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3a loxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction. PMID:24618750

Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.

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Giacobini, Paolo; Parkash, Jyoti; Campagne, Céline; Messina, Andrea; Casoni, Filippo; Vanacker, Charlotte; Langlet, Fanny; Hobo, Barbara; Cagnoni, Gabriella; Gallet, Sarah; Hanchate, Naresh Kumar; Mazur, Danièle; Taniguchi, Masahiko; Mazzone, Massimiliano; Verhaagen, Joost; Ciofi, Philippe; Bouret, Sébastien G; Tamagnone, Luca; Prevot, Vincent

2014-03-01

Neuropilin-1 (Nrp1) guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH), the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3aloxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction.

Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A.

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Paolo Giacobini

2014-03-01

Full Text Available Neuropilin-1 (Nrp1 guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH, the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3aloxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction.

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...

Endocrine dynamics during pulsatile GnRH administration in patients with hypothalamic amenorrhea and polycystic ovarian disease.

Science.gov (United States)

Rossmanith, W G; Wirth, U; Benz, R; Wolf, A S

1989-01-01

The LH secretory patterns and ovarian endocrine responses have been determined during pulsatile gonadotropin-releasing hormone (GnRH) administration for induction of ovulation in patients with hypothalamic amenorrhea (HA). However, until now these endocrine dynamics during GnRH therapy have not been thoroughly investigated in patients with polycystic ovarian disease (PCOD). Seven patients with HA and 4 patients with PCOD have therefore been studied to determine changes in LH pulsatile activity and in serum sex steroid levels in response to chronic intermittent GnRH stimulation. GnRH was administered intravenously (5-10 micrograms/90 minutes) by means of a portable infusion pump. Blood samples were obtained at 15-minute intervals for 4 hours on the day before the start of GnRH stimulation (control day) and on treatment days 5, 10 and 15. LH was determined in all samples and FSH, serum androgens and estrogens were measured in baseline samples by RIA. While 8 (62%) ovulations and 5 conceptions were observed in 13 treatment cycles in patients with HA, no ovulations were achieved during 9 treatment cycles in patients with PCOD. On the control day significantly (p less than 0.05) higher basal LH and testosterone (T) levels and significantly (p less than 0.05) lower FSH levels were found in the PCOD patients. The LH pulsatile profiles of the PCOD patients showed significantly (p less than 0.05) higher pulse amplitudes and areas under the curve (integrated responses). Pulsatile GnRH administration induced a significant (p less than 0.05) increase in LH pulse amplitudes in both HA and PCOD patients, and also increased (p less than 0.05) the integrated responses in patients with HA. During the GnRH stimulation, the LH interpulse intervals of both HA and PCOD patients were found to be similar to the frequency in which exogenous GnRH was administered. FSH levels rose continuously (p less than 0.001) during stimulation in patients with HA, but remained unchanged in patients

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

Science.gov (United States)

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

2016-06-01

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

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.

Gonadotropin-releasing hormone receptor (Gnrhr gene knock out: Normal growth and development of sensory, motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice.

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Ellen R Busby

Full Text Available Gonadotropin-releasing hormone (GnRH is important in the control of reproduction, but its actions in non-reproductive processes are less well known. In this study we examined the effect of disrupting the GnRH receptor in mice to determine if growth, metabolism or behaviors that are not associated with reproduction were affected. To minimize the effects of other hormones such as FSH, LH and sex steroids, the neonatal-prepubertal period of 2 to 28 days of age was selected. The study shows that regardless of sex or phenotype in the Gnrhr gene knockout line, there was no significant difference in the daily development of motor control, sensory detection or spatial orientation among the wildtype, heterozygous or null mice. This included a series of behavioral tests for touch, vision, hearing, spatial orientation, locomotory behavior and muscle strength. Neither the daily body weight nor the final weight on day 28 of the kidney, liver and thymus relative to body weight varied significantly in any group. However by day 28, metabolic changes in the GnRH null females compared with wildtype females showed a significant reduction in inguinal fat pad weight normalized to body weight; this was accompanied by an increase in glucose compared with wildtype females shown by Student-Newman-Keuls Multiple Comparison test and Student's unpaired t tests. Our studies show that the GnRH-GnRHR system is not essential for growth or motor/sensory/orientation behavior during the first month of life prior to puberty onset. The lack of the GnRH-GnRHR axis, however, did affect females resulting in reduced subcutaneous inguinal fat pad weight and increased glucose with possible insulin resistance; the loss of the normal rise of estradiol at postnatal days 15-28 may account for the altered metabolism in the prepubertal female pups.

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

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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.

Comparison of long GnRH agonist versus GnRH antagonist protocol in poor responders

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Sadık Şahin

2014-12-01

Full Text Available Objective: To compare long GnRH agonist with GnRH antagonist protocol in poor responders. Materials and Methods: Medical charts of 531 poor responder women undergoing in-vitro fertilization (IVF cycle at Zeynep Kamil Maternity and Children’s Hospital, IVF Center were retrospectively analysed. Those who received at least 300 IU/daily gonadotropin and had ≤3 oocytes retrieved were enrolled in the study. Poor responders were categorized into two groups as those who received long GnRH agonist or GnRH antagonist regimen. Results: Treatment duration and total gonadotropin dosage were significantly higher in women undergoing the long GnRH agonist regimen compared with the GnRH antagonist regimen (p<0.001 for both. Although the number of total and mature oocytes retrieved was similar between the groups, good quality embryos were found to be higher in the GnRH antagonist regimen. The day of embryo transfer and number of transferred embryos were similar in the groups. No statistically significant differences were detected in pregnancy (10.5% vs 14.1%, clinical pregnancy (7.7% vs 10.6% and early pregnancy loss rates (27.2% vs 35% between the groups. Conclusion: GnRH antagonist regimen may be preferable to long GnRH regimen as it could decrease the cost and treatment duration in poor responders.

Hormonal responses to GnRH injection given at different stages of ...

African Journals Online (AJOL)

USER

2010-04-05

Apr 5, 2010 ... In conclusion, the results presented here indicate that. GnRH given at the beginning (days 5 to 7) or at the end. (days 15 to 17) of the estrous cycle did not alter the profile of progesterone and estradiol concentration in water buffaloes as previously described in cattle (Kohram et al., 1998a, b). REFERENCES.

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

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

2005-01-01

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

GnRH signalling pathways and GnRH-induced homologous desensitization in a gonadotrope cell line (alphaT3-1).

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Poulin, B; Rich, N; Mas, J L; Kordon, C; Enjalbert, A; Drouva, S V

1998-07-25

Exposure of the gonadotrope cells to gonadotropin-releasing hormone (GnRH) reduces their responsiveness to a new GnRH stimulation (homologous desensitization). The time frame as well as the mechanisms underlying this phenomenon are yet unclear. We studied in a gonadotrope cell line (alphaT3-1) the effects of short as well as long term GnRH pretreatments on the GnRH-induced phospholipases-C (PLC), -A2 (PLA2) and -D (PLD) activities, by measuring the production of IP3, total inositol phosphates (IPs), arachidonic acid (AA) and phosphatidylethanol (PEt) respectively. We demonstrated that although rapid desensitization of GnRH-induced IP3 formation did not occur in these cells, persistent stimulation of cells with GnRH or its analogue resulted in a time-dependent attenuation of GnRH-elicited IPs formation. GnRH-induced IPs desensitization was potentiated after direct activation of PKC by the phorbol ester TPA, suggesting the involvement of distinct mechanisms in the uncoupling exerted by either GnRH or TPA on GnRH-stimulated PI hydrolysis. The levels of individual phosphoinositides remained unchanged under any desensitization condition applied. Interestingly, while the GnRH-induced PLA2 activity was rapidly desensitized (2.5 min) after GnRH pretreatments, the neuropeptide-evoked PLD activation was affected at later times, indicating an important time-dependent contribution of these enzymatic activities in the sequential events underlying the GnRH-induced homologous desensitization processes in the gonadotropes. Under GnRH desensitization conditions, TPA was still able to induce PLD activation and to further potentiate the GnRH-evoked PLD activity. AlphaT3-1 cells possess several PKC isoforms which, except PKCzeta, were differentially down-regulated by TPA (PKCalpha, betaII, delta, epsilon, eta) or GnRH (PKCbetaII, delta, epsilon, eta). In spite of the presence of PKC inhibitors or down-regulation of PKC isoforms by TPA, the desensitizing effect of the neuropeptide on

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

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Engin Türkgeldi

2015-06-01

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

THE USE OF GnRH ANTAGONISTS IN OVARIAN STIMULATION FOR INTRAUTERINE INSEMINATION

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Mete Işıkoğlu

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.

Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.

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Brooke Tata

2014-09-01

Full Text Available Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH and follicle-stimulating hormone (FSH within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a

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

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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)

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats.

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Yan, Xiaonan; Yuan, Chun; Zhao, Nannan; Cui, Yugui; Liu, Jiayin

2014-07-01

In adolescent girls with polycystic ovary syndrome (PCOS), neuroendocrine derangements manifest after the onset of puberty, characterized by rapid LH pulse frequency. The early mechanism underlying the pubertal regulation of the GNRH/LH pulsatile release in adolescents with PCOS remains uncertain. To determine the effects of prenatal androgen exposure on the activation of GNRH neurons and generation of LH pulse at puberty, we administrated 5α-dihydrotestosterone to pregnant rats and observed serum LH levels and expression of hypothalamic genes in female offspring from postnatal 4 to 8 weeks. The 6-week-old prenatally androgenized (PNA) female rats exhibited an increase in LH pulse frequency. The hypothalamic expression of neurokinin B (Nkb (Tac2)) and Lepr mRNA levels in PNA rats increased remarkably before puberty and remained high during puberty, whereas elevated Kiss1 mRNA levels were detected only after the onset of puberty. Exogenous kisspeptin, NK3R agonist, and leptin triggered tonic stimulation of GNRH neurons and increased LH secretion in 6-week-old PNA rats. Leptin upregulated Kiss1 mRNA levels in the hypothalamus of pubertal PNA rats; however, pretreatment with a kisspeptin antagonist failed to suppress the elevated serum LH stimulated by leptin, indicating that the stimulatory effects of leptin may be conveyed indirectly to GNRH neurons via other neural components within the GNRH neuronal network, rather than through the kisspeptin-GPR54 pathway. These findings validate the hypotheses that NKB and leptin play an essential role in the activation of GNRH neurons and initiation of increased LH pulse frequency in PNA female rats at puberty and that kisspeptin may coordinate their stimulatory effects on LH release. © 2014 Society for Endocrinology.

Prospective assessment of pituitary size and shape on MR imaging after suppressive hormonal therapy in central precocious puberty

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Beek, J.T. van; Sharafuddin, M.J.A.; Kao, S.C.S. [Department of Radiology-JPP 3889, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52246 (United States); Luisiri, A. [Cardinal Glennon Children' s Hospital, St. Louis, Missouri (United States); Garibaldi, L.R. [Children' s Hospital of New Jersey, Newark Beth Israel Medical Center, Newark, New Jersey (United States); St. Barnabas Medical Center, Livingston, New Jersey (United States)

2000-07-01

Objective. The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue. Materials and methods. Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH analogue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume. Results. All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy. Conclusion. Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape. (orig.)

Prospective assessment of pituitary size and shape on MR imaging after suppressive hormonal therapy in central precocious puberty

International Nuclear Information System (INIS)

Beek, J.T. van; Sharafuddin, M.J.A.; Kao, S.C.S.; Luisiri, A.; Garibaldi, L.R.

2000-01-01

Objective. The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue. Materials and methods. Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH analogue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume. Results. All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy. Conclusion. Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape. (orig.)

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

African Journals Online (AJOL)

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

Corticotropin-releasing hormone: 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

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

International Nuclear Information System (INIS)

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

2012-01-01

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

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

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

2011-01-01

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

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.

Pregnancy outcome in delayed start antagonist versus microdose flare GnRH agonist protocol in poor responders undergoing IVF/ICSI: An RCT

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Robab Davar

2018-04-01

Full Text Available Background: Over the years, many article on different aspects of pathogenesis and management of poor ovarian responders have been published but there is no clear guideline for treating themyet. Objective: This study was designated to compare the effectiveness of a delayed start protocol with gonadotropin-releasing hormone (GnRH antagonist and microdose flare-up GnRH agonist protocol in poor ovarian responders. Materials and Methods: This randomized clinical trial consisted of 100 poor ovarian responder women in assisted reproductive technologies cycles. They were divided randomly in delayed-start antagonist protocol (with estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation and microdose flare-up GnRH agonist protocol. The main outcome was clinical pregnancy rate and second outcome was the number of retrieved oocytes, mature oocytes, 2PN number, fertilization rate, and implantation rate. Results: Fertilization rate, clinical pregnancy rate, and ongoing pregnancy rates were not significantly different between the two studied protocols. Number of retrieved oocytes (5.10±3.41 vs. 3.08±2.51 with p=0.002, mature oocytes (4.32±2.69 vs. 2.34±1.80 with p=0.003, number of 2PN (3.94±1.80 vs. 2.20±1.01 with p=0.001 and implantation rate (19.40% vs. 10.30% with p=0.022 were significantly higher in delayed antagonist group. Conclusion: The delayed-start protocol can improve ovarian response in poor responders by stimulating and synchronizing follicle development

Neuroendocrine regulation of gonadotropin secretion in seasonally breeding birds

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Takayoshi eUbuka

2013-03-01

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

A comparative therapeutic management of anoestrus in buffaloes using insulin and GnRH

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R. D. Purkayastha

2015-06-01

Full Text Available Aim: Anoestrus is one of the most common functional disorders of the reproductive cycle in buffaloes. In spite of technical advancement, there is no single cure for the management of anoestrus. Therefore, the aim of this study was to find out the efficacy of gonadotropic releasing hormone (GnRH and metabolic hormone for the management of true anoestrus in buffaloes. Materials and Methods: The experimental animals were selected on the basis of history, gyneco-clinical examinations and progesterone estimation. Deworming was done with Fenbendazole and thereafter mineral mixture was given @ 50 g per animal per day for 10 days in all the selected buffaloes before the start of treatment. The selected buffaloes were randomly divided into four groups (n=25. In Group I, buffaloes were administered 20 μg of buserelin intramuscularly. Buffaloes of Group II were administered long-acting insulin @ 0.25 IU/Kg body weight subcutaneously for 5 consecutive days. In Group III, buffaloes were treated with a combination of insulin and buserelin in the above-mentioned doses whereas buffaloes of Group IV were kept as untreated control. Results: The higher oestrus induction (64% vs. 28% was found in Group III and differed significantly (p<0.05 as compared to control group. The conception rate (69.23% vs. 66.66% was also found higher in Group III but did not differ significantly among the treated groups. The mean time taken for the onset of oestrus was recorded significantly shorter in insulin (8.80±0.69 and GnRH (7.60±0.92 days alone and as compared to other (Group III, 14.43±0.83 and Group IV, 20.57±1.69 days groups. Conclusion: The results of this study indicated better fertility response using Insulin plus Buserelin in true anoestrus buffaloes under field conditions.

Letrozole+ GnRH antagonist stimulation protocol in poor ovarian responders undergoing intracytoplasmic sperm injection cycles: An RCT

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Mahbod Ebrahimi

2017-08-01

Full Text Available Background: Gonadotropin-releasing hormone (GnRH antagonist protocol has been proposed as a potentially proper option for the patients with limited ovarian reserve. Nevertheless, there is no significant difference in terms of clinical pregnancy between the GnRH antagonist and agonist cycles. The use of aromatase inhibitors such as letrozole was suggested by some studies. Objective: The object of this study was to evaluate the efficacy of letrozole cotreatment with GnRH-antagonist protocol in ovarian stimulation of poor responder patients undergoing intracytoplasmic sperm injection. Materials and Methods: A double-blinded randomized control trial was conducted on 70 infertile women with poor ovarian response based on Bologna criteria in two groups: letrozole+GnRH-antagonist (LA group and placebo+GnRH-antagonist (PA group (n=35/each. The LA group involved at letrozole 2.5 mg daily over 5 days and recombinant human follicle stimulating hormone 225 IU/daily. The PA group received placebo over 5 days and recombinant human follicle stimulating hormone at the same starting day and dose, similar to LA group. GnRH-antagonist was introduced once one or more follicle reached ≥14 mm. The main outcome measures were the number of oocytes retrieved, fertilization rate, implantation rate, cycle cancellation rate, and clinical pregnancy rate. Results: There were no significant differences in demographic characteristics between groups. There were no significant differences between groups regarding the number of oocytes retrieved (p=0.81, number of embryos transferred (p=0.82, fertilization rate (p=0.225, implantation rate (p=0.72, total cycle cancelation rate (p=0.08, and clinical pregnancy rate (p=0.12. Conclusion: The use of letrozole in GnRH-antagonist cycles does not improve clinical outcomes in poor responder patients undergoing intracytoplasmic sperm injection.

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

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.

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

Inhibition of RM-1 prostate carcinoma and eliciting robust immune responses in the mouse model by using VEGF-M2-GnRH3-hinge-MVP vaccine.

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Wang, Yiqin; Alahdal, Murad; Ye, Jia; Jing, Liangliang; Liu, Xiaoxin; Chen, Huan; Jin, Liang; Cao, Rongyue

2018-01-23

GnRH and VEGF have been investigated as prostate carcinoma enhancers that support tumor spread and progression. Although both have documented roles in prostate carcinoma and many cancer types, the weak immunogenicity of these peptides has remained a major challenge for use in immunotherapy. Here, we describe a novel strategy to inhibit GnRH and VEGF production and assess the effect on the immune responses against these hormones using the RM-1 prostate cancer model. We designed a novel recombinant fusion protein which combined GnRH and VEGF as a vaccine against this tumor. The newly constructed fusion protein hVEGF121-M2-GnRH3-hinge-MVP contains the human vascular endothelial growth factor (hVEGF121) and three copies of GnRH in sequential linear alignment and T helper epitope MVP as an immunogenic vaccine. The effectiveness of the vaccine in eliciting an immune response and attenuating the prostate tumor growth was evaluated. Results showed that administration of a new vaccine effectively elicited humoral and cellular immune responses. We found that, a novel fusion protein, hVEGF121-M2-GnRH3-hinge-MVP, effectively inhibited growth of RM-1 prostate model and effectively promoted immune response. In conclusion, hVEGF121-M2-GnRH3-hinge-MVP is an effective dual mechanism tumor vaccine that limits RM-1 prostate growth. This vaccine may be a promising strategy for the treatment of hormone refractory prostate malignancies.

Effects of aqueous extract from Asparagus officinalis L. roots on hypothalamic-pituitary-gonadal axis hormone levels and the number of ovarian follicles in adult rats

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Hojatollah Karimi Jashni

2016-02-01

Full Text Available Background: Asparagus is a plant with high nutritional, pharmaceutical, and industrial values. Objective: The present study aimed to evaluate the effect of aqueous extract of asparagus roots on the hypothalamic-pituitary-gonadal axis hormones and oogenesis in female rats. Materials and Methods: In this experimental study, 40 adult female Wistar rats were divided into five groups, which consist 8 rats. Groups included control, sham and three experimental groups receiving different doses (100, 200, 400 mg/kg/bw of aqueous extract of asparagus roots. All dosages were administered orally for 28 days. Blood samples were taken from rats to evaluate serum levels of Gonadotropin releasing hormone (GnRH, follicular stimulating hormone (FSH, Luteinal hormone (LH, estrogen, and progesterone hormones. The ovaries were removed, weighted, sectioned, and studied by light microscope. Results: Dose-dependent aqueous extract of asparagus roots significantly increased serum levels of GnRH, FSH, LH, estrogen, and progestin hormones compared to control and sham groups. Increase in number of ovarian follicles and corpus luteum in groups treated with asparagus root extract was also observed (p<0.05. Conclusion: Asparagus roots extract stimulates secretion of hypothalamic- pituitary- gonadal axis hormones. This also positively affects oogenesis in female rats.

DECEMBER JMBR 13 - 2 correction.cdr

African Journals Online (AJOL)

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

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

Science.gov (United States)

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

2012-02-01

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

Expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in control of GnRH secretion.

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Yang, Ying; Zhou, Li-bin; Liu, Shang-quan; Tang, Jing-feng; Li, Feng-yin; Li, Rong-ying; Song, Huai-dong; Chen, Ming-dao

2005-08-01

To investigate the expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in the control of GnRH secretion. Receptors of bombesin3, cholecystokinin (CCK)-A, CCK-B, glucagon-like peptide (GLP)1, melanin-concentrating hormone (MCH)1, orexin1, orexin2, neuromedin-B, neuropeptide Y (NPY)1 and NPY5, neurotensin (NT)1, NT2, NT3, and leptin receptor long form mRNA in GT1-7 cells were detected by reversed transcriptase-polymerase chain reaction. GT1-7 cells were treated with leptin, orexin A and orexin B at a cohort of concentrations for different lengths of time, and GnRH in medium was determined by radioimmunoassay (RIA). Receptors of bombesin 3, CCK-B, GLP1, MCH1, orexin1, neuromedin-B, NPY1, NPY5, NT1, NT3, and leptin receptor long form mRNA were expressed in GT1-7 cells, of which, receptors of GLP1, neuromedin-B, NPY1, and NT3 were highly expressed. No amplified fragments of orexin2, NT2, and CCK-A receptor cDNA were generated with GT1-7 RNA, indicating that the GT1-7 cells did not express mRNA of them. Leptin induced a significant stimulation of GnRH release, the results being most significant at 0.1 nmol/L for 15 min. In contrast to other studies in hypothalamic explants, neither orexin A nor orexin B affected basal GnRH secretion over a wide range of concentrations ranging from 1 nmol/L to 500 nmol/Lat 15, 30, and 60 min. Feeding and reproductive function are closely linked. Many orexigenic and anorexigenic signals may control feeding behavior as well as alter GnRH secretion through their receptors on GnRH neurons.

Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol.

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Georg Griesinger

Full Text Available What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS based on the number of growing follicles ≥ 11 mm and/or estradiol (E2 levels?The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2 levels were less prognostic of OHSS than the number of follicles ≥ 11 mm.In comparison to long gonadotropin-releasing hormone (GnRH agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF, while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1-2% in a relatively young (aged 18 to 36 years IVF population treated in a GnRH-antagonist protocol.From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses.The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH in a gonadotropin-releasing hormone (GnRH-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG, and a combination of both, were determined.The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at

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...

Random-start GnRH antagonist for emergency fertility preservation: a self-controlled trial

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Checa MA

2015-02-01

Full Text Available Miguel A Checa,1,2 Mario Brassesco,2 Margalida Sastre,1 Manuel Gómez,2 Julio Herrero,3 Laura Marque,3 Arturo Brassesco,2 Juan José Espinós3 1Department of Obstetrics and Gynecology, Parc de Salut Mar, Universitat Autònoma de Barcelona, 2Centro de Infertilidad y Reproducción Humana (CIRH, 3Centro de Reproducción Asistida Sagrada Familia, Clínica Sagrada Familia, Barcelona, Spain Abstract: The aim of this study is to evaluate the feasibility and safety of random-start controlled ovarian hyperstimulation (COH for emergency fertility preservation, regardless of the phase of the menstrual cycle. A self-controlled pilot clinical trial (NCT01385332 was performed in an acute-care teaching hospital and in two private reproductive centers in Barcelona, Spain. Eleven egg donors participated in the study. Two random-start gonadotropin-releasing hormone (GnRH antagonist protocols were assessed in which ganirelix was initiated on either day 10 (protocol B or on day 20 (protocol C of the menstrual cycle and was continued until estradiol levels were below 60 pg/dL. These protocols were compared with a standard protocol (protocol A. The main outcome of interest was the number of metaphase 2 oocytes retrieved. Results from this study show that the number of mature oocytes retrieved was comparable across the different protocols (14.3±4.6 in the standard protocol versus 13.0±9.1 and 13.2±5.2 in protocols B and C, respectively; values expressed as mean ± standard deviation. The mean number of days needed for a GnRH antagonist to lower estradiol levels, as well as the ongoing pregnancy rates, were also similar when protocols B (stimulation in follicular phase and C (stimulation on luteal phase were compared with protocol A (standard stimulation. GnRH antagonists can be effectively used for random-start controlled ovarian hyperstimulation with an ovarian response similar to that of standard protocols, and the antagonists appear suitable for emergency

Circadian Control of the Estrogenic Circuits Regulating GnRH Secretion and the Preovulatory Luteinizing Hormone Surge

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Lance J Kriegsfeld

2012-05-01

Full Text Available Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG axis functioning. In mammals, the master circadian pacemaker in the suprachaismatic nucleus (SCN of the anterior hypothalamus coordinates reproductively-relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the GnRH system in control of the preovulatory LH surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.

Pharmacokinetics and Bioavailability of the GnRH Analogs in the Form of Solution and Zn2+-Suspension After Single Subcutaneous Injection in Female Rats.

Science.gov (United States)

Suszka-Świtek, Aleksandra; Ryszka, Florian; Dolińska, Barbara; Dec, Renata; Danch, Alojzy; Filipczyk, Łukasz; Wiaderkiewicz, Ryszard

2017-04-01

Although many synthetic gonadoliberin analogs have been developed, only a few of them, including buserelin, were introduced into clinical practice. Dalarelin, which differs from buserelin by just one aminoacid in the position 6 (D-Ala), is not widely used so far. Gonadotropin-releasing hormone (GnRH) analogs are used to treat many different illnesses and are available in different forms like solution for injection, nasal spray, microspheres, etc. Unfortunately, none of the above drug formulations can release the hormones for 24 h. We assumed that classical suspension could solve this problem. Two sets of experiments were performed. In the first one, buserelin and dalarelin were injected into mature female rats in two forms: suspension, in which the analogs are bounded by Zn 2+ ions and solution. The pharmacokinetic parameters and bioavailability of the analogs were calculated, based on their concentration in the plasma measured by high-performance liquid chromatography method (HPLC). In the second experiment, the hormones in two different forms were injected into superovulated immature female rats and then the concentration of Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) and 17β-estradiol in the serum was measured by radioimmunological method. The Extent of Biological Availability (EBA), calculated on the base of AUC 0-∞ , showed that in the form of solution buserelin and dalarelin display, respectively, only 13 and 8 % of biological availability of their suspension counterparts. Comparing both analogs, the EBA of dalarelin was half (53 %) that of buserelin delivered in the form of solution and 83 % when they were delivered in the form of suspension. The injection of buserelin or dalarelin, in the form of solution or suspension, into superovulated female rats increased LH, FSH and estradiol concentration in the serum. However, after injection of the analogs in the form of suspension, the high concentration of LH and FSH in the serum persisted

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.

Evaluation of the pituitary-gonadal response to GnRH, and adrenal status, in the leopard (Panthera pardus japonensis) and tiger (Panthera tigris).

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Brown, J L; Goodrowe, K L; Simmons, L G; Armstrong, D L; Wildt, D E

1988-01-01

Frequent blood samples were collected to study hormonal responses to GnRH in male and female leopards and tigers. Animals were anaesthetized with ketamine-HCl and blood samples were collected every 5 min for 15 min before and 160 min after i.v. administration of GnRH (1 micrograms/kg body weight) or saline. No differences in serum cortisol concentrations were observed between sexes within species, but mean cortisol was 2-fold greater in leopards than tigers. GnRH induced a rapid rise in LH in all animals (18.3 +/- 0.9 min to peak). Net LH peak height above pretreatment levels was 3-fold greater in males than conspecific females and was also greater in tigers than leopards. Serum FSH increased after GnRH, although the magnitude of response was less than that observed for LH. Basal LH and FSH and GnRH-stimulated FSH concentrations were not influenced by sex or species. Serum testosterone increased within 30-40 min after GnRH in 3/3 leopard and 1/3 tiger males. Basal testosterone was 3-fold greater in tiger than leopard males. LH pulses (1-2 pulses/3 h) were detected in 60% of saline-treated animals, suggesting pulsatile gonadotrophin secretion; however, in males concomitant testosterone pulses were not observed. These results indicate that there are marked sex and species differences in basal and GnRH-stimulated hormonal responses between felids of the genus Panthera which may be related to differences in adrenal activity.

Circadian control of kisspeptin and a gated GnRH response mediate the preovulatory luteinizing hormone surge

DEFF Research Database (Denmark)

Williams, Wilbur P; Jarjisian, Stephan G; Mikkelsen, Jens D

2011-01-01

In spontaneously ovulating rodents, the preovulatory LH surge is initiated on the day of proestrus by a timed, stimulatory signal originating from the circadian clock in the suprachiasmatic nucleus (SCN). The present studies explored whether kisspeptin is part of the essential neural circuit...... linking the SCN to the GnRH system to stimulate ovulation in Syrian hamsters (Mesocricetus auratus). Kisspeptin neurons exhibit an estrogen-dependent, daily pattern of cellular activity consistent with a role in the circadian control of the LH surge. The SCN targets kisspeptin neurons via vasopressinergic...... of ovulatory control with interactions among the circadian system, kisspeptin signaling, and a GnRH gating mechanism of control....

Expression of the GnRH and GnRH receptor (GnRH-R) genes in the hypothalamus and of the GnRH-R gene in the anterior pituitary gland of anestrous and luteal phase ewes.

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

2008-11-01

Data exists showing that seasonal changes in the innervations of GnRH cells in the hypothalamus and functions of some neural systems affecting GnRH neurons are associated with GnRH release in ewes. Consequently, we put the question as to how the expression of GnRH gene and GnRH-R gene in the hypothalamus and GnRH-R gene in the anterior pituitary gland is reflected with LH secretion in anestrous and luteal phase ewes. Analysis of GnRH gene expression by RT-PCR in anestrous ewes indicated comparable levels of GnRH mRNA in the preoptic area, anterior and ventromedial hypothalamus. GnRH-R mRNA at different concentrations was found throughout the preoptic area, anterior and ventromedial hypothalamus, stalk/median eminence and in the anterior pituitary gland. The highest GnRH-R mRNA levels were detected in the stalk/median eminence and in the anterior pituitary gland. During the luteal phase of the estrous cycle in ewes, the levels of GnRH mRNA and GnRH-R mRNA in all structures were significantly higher than in anestrous ewes. Also LH concentrations in blood plasma of luteal phase ewes were significantly higher than those of anestrous ewes. In conclusion, results from this study suggest that low expression of the GnRH and GnRH-R genes in the hypothalamus and of the GnRH-R gene in the anterior pituitary gland, amongst others, may be responsible for a decrease in LH secretion and the anovulatory state in ewes during the long photoperiod.

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

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Karolina Wojtulewicz

2017-11-01

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

A single sample GnRHa stimulation test in the diagnosis of precocious puberty

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Gonadotropin-releasing hormone (GnRH) has been the standard test for diagnosing central precocious puberty. Because GnRH is no longer available, GnRH analogues (GnRHa) are now used. Random LH concentration, measured by the third-generation immunochemiluminometric assay, is a useful screening tool ...

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

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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.

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

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Alaa kamil Abdulla

2017-07-01

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

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...

Synchronisation of the follicular wave with GnRH and PGF2α analogue for a timed breeding programme in dromedary camels (Camelus dromedarius).

Science.gov (United States)

Manjunatha, B M; Al-Bulushi, Samir; Pratap, N

2015-09-01

This study was conducted to develop a hormone protocol that precisely synchronises follicular development for a timed breeding (TB) programme in dromedary camels. To examine the effect of GnRH treatment at four known stages of follicular development, animals were treated with GnRH when the largest follicle of the wave was 4-7, 8-11, 12-17 and 18-27 mm in diameter. Transrectal ultrasonography was carried out daily up to 20 days after treatment. A hormone protocol (FWsynch) for the synchronisation of follicular wave and TB consisting of GnRH-1 (GnRH) on Day 0, PG-1 (PGF2α) on Day 7, GnRH-2 on Day 10 and PG-2 on Day 17 was initiated at four known stages of follicular development. Ovarian structures were monitored by ultrasonography. The FWsynch protocol was initiated at random stages of follicle development and animals were bred by natural mating at a fixed time at the research facility and in field. The pregnancy was diagnosed by ultrasonography. GnRH treatment in animals with a dominant follicle (DF) of ≥ 11 mm in diameter resulted in synchronous new follicular wave emergence, whereas in animals with a DF ≤ 10 mm, the treatment did not alter the development of the existing follicular wave. The FWsynch protocol was effective in synchronising the follicular wave for TB irrespective of the stage of follicular development at the beginning of the protocol. TB using FWsynch protocol resulted in a pregnancy rate of 60.2% in a research facility and 53.6% and 45.6% in normal and infertile camels respectively under field conditions. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Induction of Gonadotropins for Reproductive Control

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Elza Ibrahim Auerkari

2015-10-01

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

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

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

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

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Manfred Hallschmid

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

Does polycystic ovarian morphology influence the response to treatment with pulsatile GnRH in functional hypothalamic amenorrhea?

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Dumont, Agathe; Dewailly, Didier; Plouvier, Pauline; Catteau-Jonard, Sophie; Robin, Geoffroy

2016-04-29

Pulsatile GnRH therapy is the gold standard treatment for ovulation induction in women having functional hypothalamic amenorrhea (FHA). The use of pulsatile GnRH therapy in FHA patients with polycystic ovarian morphology (PCOM), called "FHA-PCOM", has been little studied in the literature and results remain contradictory. The aim of this study was to compare the outcomes of pulsatile GnRH therapy for ovulation induction between FHA and "FHA-PCOM" patients in order to search for an eventual impact of PCOM. Retrospective study from August 2002 to June 2015, including 27 patients with FHA and 40 "FHA-PCOM" patients (85 and 104 initiated cycles, respectively) treated by pulsatile GnRH therapy for induction ovulation. The two groups were similar except for markers of PCOM (follicle number per ovary, serum Anti-Müllerian Hormone level and ovarian area), which were significantly higher in patients with "FHA-PCOM". There was no significant difference between the groups concerning the ovarian response: with equivalent doses of GnRH, both groups had similar ovulation (80.8 vs 77.7 %, NS) and excessive response rates (12.5 vs 10.6 %, NS). There was no significant difference in on-going pregnancy rates (26.9 vs 20 % per initiated cycle, NS), as well as in miscarriage, multiple pregnancy or biochemical pregnancy rates. Pulsatile GnRH seems to be a successful and safe method for ovulation induction in "FHA-PCOM" patients. If results were confirmed by prospective studies, GnRH therapy could therefore become a first-line treatment for this specific population, just as it is for women with FHA without PCOM.

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

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

2009-06-01

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

Lactobacillus rhamnosus accelerates zebrafish backbone calcification and gonadal differentiation through effects on the GnRH and IGF systems.

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Matteo A Avella

Full Text Available Endogenous microbiota play essential roles in the host's immune system, physiology, reproduction and nutrient metabolism. We hypothesized that a continuous administration of an exogenous probiotic might also influence the host's development. Thus, we treated zebrafish from birth to sexual maturation (2-months treatment with Lactobacillus rhamnosus, a probiotic species intended for human use. We monitored for the presence of L. rhamnosus during the entire treatment. Zebrafish at 6 days post fertilization (dpf exhibited elevated gene expression levels for Insulin-like growth factors -I and -II, Peroxisome proliferator activated receptors -α and -β, VDR-α and RAR-γ when compared to untreated-10 days old zebrafish. Using a gonadotropin-releasing hormone 3 GFP transgenic zebrafish (GnRH3-GFP, higher GnRH3 expression was found at 6, 8 and 10 dpf upon L. rhamnosus treatment. The same larvae exhibited earlier backbone calcification and gonad maturation. Noteworthy in the gonad development was the presence of first testes differentiation at 3 weeks post fertilization in the treated zebrafish population -which normally occurs at 8 weeks- and a dramatic sex ratio modulation (93% females, 7% males in control vs. 55% females, 45% males in the treated group. We infer that administration of L. rhamnosus stimulated the IGF system, leading to a faster backbone calcification. Moreover we hypothesize a role for administration of L. rhamnosus on GnRH3 modulation during early larval development, which in turn affects gonadal development and sex differentiation. These findings suggest a significant role of the microbiota composition on the host organism development profile and open new perspectives in the study of probiotics usage and application.

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

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...

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

Science.gov (United States)

Park, Jina; Kim, Jae Hyun

2017-03-01

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

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

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Flóra eBálint

2016-03-01

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

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

Luteinizing hormone pulsatility in females following radiation therapy for central nervous system malignancies

International Nuclear Information System (INIS)

Brasacchio, R.A.; Constine, L.S.; Woolf, P.; Raubertas, R.F.; Veldhuis, J.D.; Muhs, A.G.

1997-01-01

Purpose: Females incidentally irradiated to the hypothalamic-pituitary axis (H/P-A) during radiation therapy (RT) for brain tumors may become oligoamenorrheic. We previously demonstrated that these women are hypoestrogenemic but frequently have near normal or only moderately decreased basal luteinizing hormone (LH) levels and maintain appropriate peak pituitary responses to exogenous gonadotropin releasing hormone (GnRH). We postulated that hypothalamic injury resulting in abnormal LH pulsatility could explain this complex of findings. This investigation intended to characterize this hypothalamic injury and test two potentially corrective pharmacologic interventions. Catecholamines (specifically dopamine) and opiates are known to suppress pituitary LH release through inhibition of the pituitary gonadotropes or of the GnRH neuronal terminals in the hypothalamus. Radiation-induced dysfunction of the catecholaminergic or opiate control mechanisms might translate into an increase in dopamine or opiate release or receptor responsiveness, which in turn would inhibit pulsatile gonadotropin secretion, leading to reduced LH pulsatility and to gonadal dysfunction. We therefore determined the pattern of LH release in normal controls and in patients, at baseline as well as after administration of the dopamine receptor antagonist metoclopramide (MCP), and the opiate-receptor antagonist naloxone (NAL). Methods: Patient eligibility criteria included RT to the H/P-A for a non-H/P-A CNS tumor, usually astrocytoma, with subsequent hypoestrogenemia and oligo-amenorrhea. Patients and normal volunteers were studied first under control conditions and then using MCP and NAL in a randomized cross-over manner at monthly intervals. Serum samples for LH determination were taken every 10 minutes for 12 hours during an overnight hospital stay. MCP (10 mg) was administered as an IV bolus every 4.5 hours, and NAL was administered as a continuous infusion (1.6 mg/hour). The following morning each

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

GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile.

Science.gov (United States)

Chaudhari, Nirja; Dawalbhakta, Mitali; Nampoothiri, Laxmipriya

2018-04-11

GnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS. PCOS was induced in rats by oral administration of letrozole (aromatase inhibitor). Following PCOS validation, animals were assessed for gonadotropin levels and their mRNA expression. Neurotrasnmitter status was evaluated by estimating their levels, their metabolism and their receptor expression in hypothalamus, pituitary, hippocampus and frontal cortex of PCOS rat model. We demonstrate that GnRH and LH inhibitory neurotransmitters - serotonin, dopamine, GABA and acetylcholine - are reduced while glutamate, a major stimulator of GnRH and LH release, is increased in the PCOS condition. Concomitant changes were observed for neurotransmitter metabolising enzymes and their receptors as well. Our results reveal that increased GnRH and LH pulsatility in PCOS condition likely result from the cumulative effect of altered GnRH stimulatory and inhibitory neurotransmitters in hypothalamic-pituitary centre. This, we hypothesise, is responsible for the depression and anxiety-like mood disorders commonly seen in PCOS women.

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

Science.gov (United States)

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

2016-06-01

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

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.

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.

GnRH receptor activation competes at a low level with growth signaling in stably transfected human breast cell lines

International Nuclear Information System (INIS)

Morgan, Kevin; Meyer, Colette; Miller, Nicola; Sims, Andrew H; Cagnan, Ilgin; Faratian, Dana; Harrison, David J; Millar, Robert P; Langdon, Simon P

2011-01-01

Gonadotrophin releasing hormone (GnRH) analogs lower estrogen levels in pre-menopausal breast cancer patients. GnRH receptor (GnRH-R) activation also directly inhibits the growth of certain cells. The applicability of GnRH anti-proliferation to breast cancer was therefore analyzed. GnRH-R expression in 298 primary breast cancer samples was measured by quantitative immunofluorescence. Levels of functional GnRH-R in breast-derived cell lines were assessed using 125 I-ligand binding and stimulation of 3 H-inositol phosphate production. Elevated levels of GnRH-R were stably expressed in cells by transfection. Effects of receptor activation on in vitro cell growth were investigated in comparison with IGF-I and EGF receptor inhibition, and correlated with intracellular signaling using western blotting. GnRH-R immunoscoring was highest in hormone receptor (triple) negative and grade 3 breast tumors. However prior to transfection, functional endogenous GnRH-R were undetectable in four commonly studied breast cancer cell lines (MCF-7, ZR-75-1, T47D and MDA-MB-231). After transfection with GnRH-R, high levels of cell surface GnRH-R were detected in SVCT and MDA-MB-231 clones while low-moderate levels of GnRH-R occurred in MCF-7 clones and ZR-75-1 clones. MCF-7 sub-clones with high levels of GnRH-R were isolated following hygromycin phosphotransferase transfection. High level cell surface GnRH-R enabled induction of high levels of 3 H-inositol phosphate and modest growth-inhibition in SVCT cells. In contrast, growth of MCF-7, ZR-75-1 or MDA-MB-231 clones was unaffected by GnRH-R activation. Cell growth was inhibited by IGF-I or EGF receptor inhibitors. IGF-I receptor inhibitor lowered levels of p-ERK1/2 in MCF-7 clones. Washout of IGF-I receptor inhibitor resulted in transient hyper-elevation of p-ERK1/2, but co-addition of GnRH-R agonist did not alter the dynamics of ERK1/2 re-phosphorylation. Breast cancers exhibit a range of GnRH-R immunostaining, with higher levels of

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.

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

Effects of Thyroid Dysfunction on Reproductive Hormones in Female Rats.

Science.gov (United States)

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

2018-05-10

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

Glucosensing by GnRH Neurons: Inhibition by Androgens and Involvement of AMP-Activated Protein Kinase

Science.gov (United States)

Roland, Alison V.

2011-01-01

GnRH neurons integrate steroidal and metabolic cues to regulate fertility centrally. Central glucoprivation reduces LH secretion, which is governed by GnRH release, suggesting GnRH neuron activity is modulated by glucose availability. Here we tested whether GnRH neurons can sense changes in extracellular glucose, and whether glucosensing is altered by the steroids dihydrotestosterone (DHT) and/or estradiol (E). Extracellular recordings were made from GnRH neurons in brain slices from ovariectomized (OVX) mice ± DHT and/or E implants. Firing rate was reduced by a switch from 4.5 to 0.2 mm glucose in cells from OVX, OVX+E, and OVX+DHT+E mice, but not OVX+DHT mice. This suggests that androgens reduce the sensitivity of GnRH neurons to changes in extracellular glucose, but E mitigates this effect. Next we investigated potential mechanisms. In the presence of the ATP-sensitive potassium channel antagonist tolbutamide, glucosensing persisted. In contrast, glucosensing was attenuated in the presence of compound C, an antagonist of AMP-activated protein kinase (AMPK), suggesting a role for AMPK in glucosensing. The AMPK activator N1-(b-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR) mimicked the effect of low glucose and was less effective in cells from DHT-treated mice. The effect of DHT to diminish responses to low glucose and AICAR was abolished by blockade of fast synaptic transmission. Both AICAR and low glucose activated a current with a reversal potential near −50 mV, suggesting a nonspecific cation current. These studies indicate that glucosensing is one mechanism by which GnRH neurons sense fuel availability and point to a novel role for AMPK in the central regulation of fertility. PMID:21393446

Gonadotropin Releasing Hormone Agonists or Antagonists for Preimplantation Genetic Diagnosis (PGD)? A Prospective Randomised Trial.

Science.gov (United States)

Verpoest, Willem; De Vos, Anick; De Rycke, Martine; Parikh, Shruti; Staessen, Catherine; Tournaye, Herman; De Vos, Michel; Vloeberghs, Veerle; Blockeel, Christophe

2017-11-10

The use of GnRH analogue medication is essential in reproductive medicine to avoid premature ovulation by pituitary suppression for the duration of ovarian stimulation by gonadotrophins. The type of pituitary suppression by either GnRH agonist analogues versus GnRH antagonist analogues may result in different embryological hence clinical results. Preimplantation genetic diagnosis is a subtype of IVF in which embryos are created for genetic diagnosis of hereditary disorders in order to avoid genetically affected children. Embryological quality hence ovarian stimulation in preimplantation genetic diagnosis is crucial as genetic selection will reduce the number of available embryos to a fraction of the total. The aim of this study was to assess the efficiency of GnRH antagonist versus GnRH agonist treatment for pituitary suppression in ovarian stimulation for PGD, by proxy of number and quality of embryos at cleavage stage available for biopsy. We conducted a prospective randomised controlled trial comparing pituitary suppression by GnRH antagonist versus GnRH agonist in ovarian stimulation for PGD. The primary outcome measure was the number of embryos of sufficient quality for biopsy at cleavage stage. Secondary outcome parameters were the number of blastocysts available of top quality, and clinical pregnancy rate. There was no difference in number of oocytes retrieved, embryos at cleavage stage available for biopsy or embryo quality. The clinical pregnancy rate was higher in the GnRH agonist group; however the sample size was insufficient to allow conclusions. The use of GnRH agonist versus antagonist treatment does not result in differences in a number of oocytes, embryos or embryo quality in ovarian stimulation for preimplantation genetic diagnosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

GnRH Analogues in the Prevention of Ovarian Hyperstimulation Syndrome

Science.gov (United States)

Alama, Pilar; Bellver, Jose; Vidal, Carmen; Giles, Juan

2013-01-01

The GnRH analogue (agonist and antagonist GnRH) changed ovarian stimulation. On the one hand, it improved chances of pregnancy to obtain more oocytes and better embryos. This leads to an ovarian hyper-response, which can be complicated by the ovarian hyperstimulation syndrome (OHSS). On the other hand, the GnRH analogue can prevent the incidence of OHSS: GnRH antagonist protocols, GnRH agonist for triggering final oocyte maturation, either together or separately, coasting, and the GnRH analogue may prove useful for avoiding OHSS in high-risk patients. We review these topics in this article. PMID:23825982

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...

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

Science.gov (United States)

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

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

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

Science.gov (United States)

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

2017-05-01

Gonadotropin-inhibitory hormone (GNIH) was discovered in quail with the ability to reduce gonadotropin expression/secretion in the pituitary. There have been few studies on GNIH orthologs in teleosts (LPXRFamide (Lpxrfa) peptides), which have provided inconsistent results. Therefore, the goal of this study was to determine the roles and modes of action by which Lpxrfa exerts its functions in the brain-pituitary axis of zebrafish (Danio rerio). We localized Lpxrfa soma to the ventral hypothalamus, with fibers extending throughout the brain and to the pituitary. In the preoptic area, Lpxrfa fibers interact with gonadotropin-releasing hormone 3 (Gnrh3) soma. In pituitary explants, zebrafish peptide Lpxrfa-3 downregulated luteinizing hormone beta subunit and common alpha subunit expression. In addition, Lpxrfa-3 reduced gnrh3 expression in brain slices, offering another pathway for Lpxrfa to exert its effects on reproduction. Receptor activation studies, in a heterologous cell-based system, revealed that all three zebrafish Lpxrfa peptides activate Lpxrf-R2 and Lpxrf-R3 via the PKA/cAMP pathway. Receptor activation studies demonstrated that, in addition to activating Lpxrf receptors, zebrafish Lpxrfa-2 and Lpxrfa-3 antagonize Kisspeptin-2 (Kiss2) activation of Kisspeptin receptor-1a (Kiss1ra). The fact that kiss1ra-expressing neurons in the preoptic area are innervated by Lpxrfa-ir fibers suggests an additional pathway for Lpxrfa action. Therefore, our results suggest that Lpxrfa may act as a reproductive inhibitory neuropeptide in the zebrafish that interacts with Gnrh3 neurons in the brain and with gonadotropes in the pituitary, while also potentially utilizing the Kiss2/Kiss1ra pathway. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Environment, human reproduction, menopause, and andropause.

OpenAIRE

Vermeulen, A

1993-01-01

As the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator is an integrator of hormonal, metabolic, and neural signals, it is not surprising that the function of the hypothalamogonadal axis is subject to the influence of a large array of environmental factors. Before puberty, the central nervous system (CNS) restrains the GnRH pulse generator. Undernutrition, low socioeconomic status, stress, and emotional deprivation, all delay puberty. During reproductive life, among peripher...

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.

The GnRH analogue triptorelin confers ovarian radio-protection to adult female rats

International Nuclear Information System (INIS)

Camats, N.; Garcia, F.; Parrilla, J.J.; Calaf, J.; Martin-Mateo, M.; Caldes, M. Garcia

2009-01-01

There is a controversy regarding the effects of the analogues of the gonadotrophin-releasing hormone (GnRH) in radiotherapy. This has led us to study the possible radio-protection of the ovarian function of a GnRH agonist analogue (GnRHa), triptorelin, in adult, female rats (Rattus norvegicus sp.). The effects of the X-irradiation on the oocytes of ovarian primordial follicles, with and without GnRHa treatment, were compared, directly in the female rats (F 0 ) with reproductive parameters, and in the somatic cells of the resulting foetuses (F 1 ) with cytogenetical parameters. In order to do this, the ovaries and uteri from 82 females were extracted for the reproductive analysis and 236 foetuses were obtained for cytogenetical analysis. The cytogenetical study was based on the data from 22,151 metaphases analysed. The cytogenetical parameters analysed to assess the existence of chromosomal instability were the number of aberrant metaphases (2234) and the number (2854) and type of structural chromosomal aberrations, including gaps and breaks. Concerning the reproductive analysis of the ovaries and the uteri, the parameters analysed were the number of corpora lutea, implantations, implantation losses and foetuses. Triptorelin confers radio-protection of the ovaries in front of chromosomal instability, which is different, with respect to the single and fractioned dose. The cytogenetical analysis shows a general decrease in most of the parameters of the triptorelin-treated groups, with respect to their controls, and some of these differences were considered to be statistically significant. The reproductive analysis indicates that there is also radio-protection by the agonist, although minor to the cytogenetical one. Only some of the analysed parameters show a statistically significant decrease in the triptorelin-treated groups.

The GnRH analogue triptorelin confers ovarian radio-protection to adult female rats

Energy Technology Data Exchange (ETDEWEB)

Camats, N. [Institut de Biotecnologia i de Biomedicina (I.B.B.), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Garcia, F. [Institut de Biotecnologia i de Biomedicina (I.B.B.), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Parrilla, J.J. [Servicio de Ginecologia y Obstetricia, Hospital Universitario Virgen de la Arrixaca, 30120 El Palmar, Murcia (Spain); Calaf, J. [Servei de Ginecologia i Obstetricia, Hospital Universitari de la Santa Creu i Sant Pau, 08025 Barcelona (Spain); Martin-Mateo, M. [Departament de Pediatria, d' Obstetricia i Ginecologia i de Medicina Preventiva, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Caldes, M. Garcia, E-mail: Montserrat.Garcia.Caldes@uab.es [Institut de Biotecnologia i de Biomedicina (I.B.B.), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain)

2009-10-02

There is a controversy regarding the effects of the analogues of the gonadotrophin-releasing hormone (GnRH) in radiotherapy. This has led us to study the possible radio-protection of the ovarian function of a GnRH agonist analogue (GnRHa), triptorelin, in adult, female rats (Rattus norvegicus sp.). The effects of the X-irradiation on the oocytes of ovarian primordial follicles, with and without GnRHa treatment, were compared, directly in the female rats (F{sub 0}) with reproductive parameters, and in the somatic cells of the resulting foetuses (F{sub 1}) with cytogenetical parameters. In order to do this, the ovaries and uteri from 82 females were extracted for the reproductive analysis and 236 foetuses were obtained for cytogenetical analysis. The cytogenetical study was based on the data from 22,151 metaphases analysed. The cytogenetical parameters analysed to assess the existence of chromosomal instability were the number of aberrant metaphases (2234) and the number (2854) and type of structural chromosomal aberrations, including gaps and breaks. Concerning the reproductive analysis of the ovaries and the uteri, the parameters analysed were the number of corpora lutea, implantations, implantation losses and foetuses. Triptorelin confers radio-protection of the ovaries in front of chromosomal instability, which is different, with respect to the single and fractioned dose. The cytogenetical analysis shows a general decrease in most of the parameters of the triptorelin-treated groups, with respect to their controls, and some of these differences were considered to be statistically significant. The reproductive analysis indicates that there is also radio-protection by the agonist, although minor to the cytogenetical one. Only some of the analysed parameters show a statistically significant decrease in the triptorelin-treated groups.

Kisspeptin levels in idiopathic hypogonadotropic hypogonadism diagnosed male patients and its relation with glucose-insulin dynamic.

Science.gov (United States)

Öztin, Hasan; Çağıltay, Eylem; Çağlayan, Sinan; Kaplan, Mustafa; Akpak, Yaşam Kemal; Karaca, Nilay; Tığlıoğlu, Mesut

2016-12-01

Male hypogonadism is defined as the deficiency of testosterone or sperm production synthesized by testicles or the deficiency of both. The reasons for hypogonadism may be primary, meaning testicular or secondary, meaning hypothalamohypophyseal. In hypogonadotropic hypogonadism (HH), there is indeficiency in gonadotropic hormones due to hypothalamic or hypophyseal reasons. Gonadotropin-releasing hormone (GnRH) is an important stimulant in releasing follicular stimulant hormone (FSH), mainly luteinizing hormone (LH). GnRH omitted is under the effect of many hormonal or stimulating factors. Kisspeptin is present in many places of the body, mostly in hypothalamic anteroventral periventricular nucleus and arcuate nucleus. Kisspeptin has a suppressor effect on the metastasis of many tumors such as breast cancer and malign melanoma metastases, and is called "metastin" for this reason. Kisspeptin is a strong stimulant of GnRH. In idiopathic hypogonadotropic hypogonadism (IHH) etiology, there is gonadotropic hormone release indeficiency which cannot be clearly described. A total of 30 male hypogonatropic hypogonadism diagnosed patients over 30 years of age who have applied to Haydarpasa Education Hospital Endocrinology and Metabolic Diseases Service were included in the study. Compared to the control group, the effect of kisspeptin on male patients with hypogonatropic hypogonadism and on insulin resistance developing in hypogonadism patients was investigated in our study. A statistically significant difference was detected between average kisspeptin measurements of the groups (p hypogonadism and has less effect on insulin resistance.

Microdose GnRH Agonist Flare-Up versus Ultrashort GnRH Agonist Combined with Fixed GnRH Antagonist in Poor Responders of Assisted Reproductive Techniques Cycles

Directory of Open Access Journals (Sweden)

Parisa Khani

2013-01-01

Full Text Available Background: This study compares the microdose flare-up protocol to the ultrashort gonadotropinreleasinghormone (GnRH agonist flare combined with the fixed multidose GnRH antagonistprotocol in poor responders undergoing ovarian stimulation.Materials and Methods: In this randomized clinical trial, 120 women who were candidates forassisted reproductive techniques (ART and had histories of one or more failed in vitro fertilization(IVF cycles with three or fewer retrieved oocytes were prospectively randomized into two groups.Group I (60 patients received the microdose flare-up regimen and group II (60 patients receivedthe ultrashort GnRH agonist combined with fixed GnRH antagonist.Results: There were no significant differences between the groups in the number of used gonadotropinampoules (p=0.591, duration of stimulation (p=0.610, number of retrieved oocytes (p=0.802,fertilization rate (p=0.456, and the number of transferred embryos (p=0.954. The clinical pregnancyrates were statistically similar in group I (10% compared with group II (13.3%, p=0.389.Conclusion: According to our results, there is no significant difference between these protocolsfor improving the ART outcome in poor responders. Additional prospective, randomizedstudies with more patients is necessary to determine the best protocol (Registration Number:IRCT201105096420N1.

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)

The pituitary-gonadal axis in healthy female dogs and bitches with gynecological disorders

NARCIS (Netherlands)

Buijtels, J.J.C.W.M.

2011-01-01

The pituitary gland produces and secretes follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in a pulsatile fashion, induced by pulses of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Different cells in the ovary are capable of secreting estradiol, testosterone and

Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol

DEFF Research Database (Denmark)

Toftager, M.; Bogstad, J; Bryndorf, T

2016-01-01

interval (CI): 0.33-0.57) compared with the traditional GnRH agonist protocol. Previous trials comparing the two protocols mainly included selected patient populations, a limited number of patients and the applied OHSS criteria differed, making direct comparisons difficult. In two recent large meta...... IV, dual-centre, open-label, RCT including 1050 women allocated to either short GnRH antagonist or long GnRH agonist protocol in a 1:1 ratio and enrolled over a 5-year period using a web-based concealed randomization code. This is a superiority study designed to detect a difference in severe OHSS...... between the two arms. None of the women had undergone previous ART treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: All infertile women referred for their first IVF/ICSI at two public fertility clinics, less than 40 years of age and with no uterine malformations were asked to participate. A total...

Women with oligo-/amenorrhoea and polycystic ovaries have identical responses to GnRH stimulation regardless of their androgen status: comparison of the Rotterdam and Androgen Excess Society diagnostic criteria.

Science.gov (United States)

Lewandowski, Krzysztof C; Cajdler-Luba, Agata; Bieńkiewicz, Małgorzata; Lewiński, Andrzej

2011-01-01

As increased frequency of gonadotrophin-releasing hormone (GnRH) pulses is characteristic for polycystic ovary syndrome (PCOS), we assessed gonadotrophin response to GnRH in women with PCOS with normal and raised androgens and in regularly menstruating controls. The study involved 155 subjects: PCOS, n=121, age (mean±SD) 24.8±5.4 yrs, BMI 24.5±6.0 kg/m2, all with oligo-/amenorrhoea and PCO morphology, and 34 controls. Gonadotrophins were measured in early follicular phase after GnRH stimulation (0, 30 and 60 minutes). Fifty four (41.9%) women with PCOS had androgens (testosterone, androstendione, dihydroepiandrosterone sulphate) within the reference range, and would fulfil the "Rotterdam", but not the Androgen Excess Society PCOS criteria. Baseline and stimulated LH concentrations were higher in PCOS (9.09±5.56 vs 4.83±1.71 IU/l, 35.48±31.4 vs 16.30±6.68 IU/l, 33.86±31.8 vs 13.45±5.2 IU/l, at 0, 30 and 60 min post GnRH, respectively, pPCOS increased further after GnRH stimulation. ROC analysis revealed that LH30min/FSH30min >2.11 or LH60min/FSH60min >1.72 had 78.3% and 87.5% sensitivity and 81.7% and 81.3% specificity for diagnosis of PCOS. Both baseline and GnRH-stimulated LH and FSH concentrations were similar in women with PCOS and raised androgens and with androgens within the reference range (p=0.71 and p=0.20 for LH and FSH, respectively). Regardless of their androgen status, women with PCO morphology and oligo-/amenorrhoea have higher baseline and GnRH-stimulated LH concentrations and higher GnRH-stimulated LH/FSH ratio than controls, suggestive of similar underlying mechanism accounting for menstrual irregularities. These observations support validity of PCOS diagnostic criteria based on the Rotterdam consensus.

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...

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 ...

Reproductive neuroendocrine pathways of social behavior

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Ishwar eParhar

2016-03-01

Full Text Available Social behaviors are key components of reproduction because they are essential for successful fertilization. Social behaviors such as courtship, mating, and aggression are strongly associated with sex steroids, such as testosterone, estradiol and progesterone. Secretion of sex steroids from the gonads is regulated by the hypothalamus-pituitary-gonadal (HPG axis in vertebrates. Gonadotropin-releasing hormone (GnRH is a pivotal hypothalamic neuropeptide that stimulates gonadotropin release from the pituitary. In recent years, the role of neuropeptides containing the C-terminal Arg-Phe-NH2 (RFamide peptides has been emphasized in vertebrate reproduction. In particular, two key RFamide peptides, kisspeptin and gonadotropin-inhibitory hormone (GnIH, emerged as critical accelerator and suppressor of gonadotropin secretion. Kisspeptin stimulates GnRH release by directly acting on GnRH neurons, whereas GnIH inhibits gonadotropin release by inhibiting kisspeptin or GnRH neurons or pituitary gonadotropes. These neuropeptides can regulate social behavior by regulating the HPG axis. However, distribution of neuronal fibers of GnRH, kisspeptin and GnIH neurons are not limited within the hypothalamus, and the existence of extra-hypothalamic neuronal fibers suggests direct control of social behavior within the brain. It has traditionally been shown that central administration of GnRH can stimulate female sexual behavior in rats. Recently, it was shown that Kiss1, one of the paralogs of kisspeptin peptide family, regulates fear responses in zebrafish and GnIH inhibits socio-sexual behavior in birds. Here we highlight recent findings regarding the role of GnRH, kisspeptin and GnIH in the regulation of social behaviors in fish, birds and mammals and discuss their importance in future biological and biomedical research.

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

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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.

LH response to GnRH blood test

Science.gov (United States)

... as release of too much hormone ( hyperprolactinemia ) Large pituitary tumors Decrease in hormones made by the endocrine glands Too much iron in the body ( hemochromatosis ) Eating disorders, such as anorexia Recent significant weight loss, such ...

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

Changes in dendritic architecture: Not your "usual suspect" in control of the onset of puberty.

OpenAIRE

Peter eHemond; Michael eO'Boyle; Vernon eGay; Zoe eHemond; Kelly eSuter; Kelly eSuter

2013-01-01

Until the recent past, the search for the underlying drive for the pubertal increase in gonadotropin-releasing hormone (GnRH) hormone from the GnRH-containing neurons in the hypothalamus was largely focused on extrinsic factors. The most recent evidence however indicates changes in the structure of GnRH neurons themselves may contribute to this fundamental event in development. Based on our studies in males, dendritic architecture is not static from birth until adulthood. Instead, dendrites ...

Changes in Dendritic Architecture: Not Your ?Usual Suspect? in Control of the Onset of Puberty in Male Rats

OpenAIRE

Hemond, Peter J.; O?Boyle, Michael P.; Hemond, Zoe; Gay, Vernon L.; Suter, Kelly

2013-01-01

Until the recent past, the search for the underlying drive for the pubertal increase in gonadotropin-releasing hormone (GnRH) hormone from the GnRH-containing neurons in the hypothalamus was largely focused on extrinsic factors. The most recent evidence however indicates changes in the structure of GnRH neurons themselves may contribute to this fundamental event in development. Based on our studies in males, dendritic architecture is not static from birth until adulthood. Instead, dendrites u...

Pregnancy outcome of “delayed start” GnRH antagonist protocol versus GnRH antagonist protocol in poor responders: A clinical trial study

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Abbas Aflatoonian

2017-08-01

Full Text Available Background: Management of poor-responding patients is still major challenge in assisted reproductive techniques (ART. Delayed-start GnRH antagonist protocol is recommended to these patients, but little is known in this regards. Objective: The goal of this study was assessment of delayed-start GnRH antagonist protocol in poor responders, and in vitro fertilization (IVF outcomes. Materials and Methods: This randomized clinical trial included sixty infertile women with Bologna criteria for ovarian poor responders who were candidate for IVF. In case group (n=30, delayed-start GnRH antagonist protocol administered estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin. Control group (n=30 treated with estrogen priming antagonist protocol. Finally, endometrial thickness, the rates of oocytes maturation, , embryo formation, and pregnancy were compared between two groups. Results: Rates of implantation, chemical, clinical, and ongoing pregnancy in delayed-start cycles were higher although was not statistically significant. Endometrial thickness was significantly higher in case group. There were no statistically significant differences in the rates of oocyte maturation, embryo formation, and IVF outcomes between two groups. Conclusion: There is no significant difference between delayed-start GnRH antagonist protocol versus GnRH antagonist protocol.

Mechanisms of Disease: the first kiss-a crucial role for kisspeptin-1 and its receptor, G-protein-coupled receptor 54, in puberty and reproduction.

Science.gov (United States)

Seminara, Stephanie B

2006-06-01

Although the hypothalamic secretion of gonadotropin-releasing hormone (GnRH) is the defining hormonal event of puberty, the physiologic mechanisms that drive secretion of GnRH at the time of sexual maturation have been difficult to identify. After puberty is initiated, the factors that modulate the frequency and amplitude of GnRH secretion in rapidly changing sex-steroid environments (i.e. the female menstrual cycle) also remain unknown. The discovery that, in both humans and mouse models, loss-of-function mutations in the gene that encodes G-protein-coupled receptor 54 result in phenotypes of hypogonadotropic hypogonadism with an absence of pubertal development has unearthed a novel pathway regulating GnRH secretion. Ligands for G-protein-coupled receptor 54 (KiSS-1R), including metastin (derived from the parent compound, kisspeptin-1) and metastin's C-terminal peptide fragments, have been shown to be powerful stimulants for GnRH release in vivo via their stimulation of G-protein-coupled receptor 54. This article reviews the discovery of the GPR54 gene, places it into the appropriate biological context, and explores the data from in vitro and in vivo studies that point to this ligand-receptor system as a major driver of GnRH secretion.

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.

Changes in dendritic architecture: not your "usual suspect" in control of the onset of puberty in male rats.

Science.gov (United States)

Hemond, Peter J; O'Boyle, Michael P; Hemond, Zoe; Gay, Vernon L; Suter, Kelly

2013-01-01

Until the recent past, the search for the underlying drive for the pubertal increase in gonadotropin-releasing hormone (GnRH) hormone from the GnRH-containing neurons in the hypothalamus was largely focused on extrinsic factors. The most recent evidence however indicates changes in the structure of GnRH neurons themselves may contribute to this fundamental event in development. Based on our studies in males, dendritic architecture is not static from birth until adulthood. Instead, dendrites undergo a dramatic remodeling during the postnatal period which is independent of testosterone and occurs before the pubertal increase in GnRH release. First, the number of dendrites emanating from somata is reduced between infancy and adulthood. Moreover, a dendrite of adult GnRH neurons invariability arises at angle of 180°from the axon as opposed to the extraordinary variability in location during infancy. In fact, in some neurons from infants, no dendrite even resides in the adult location. Thus, there is a spatially selective remodeling of primary dendrites. Secondly, dendrites of GnRH neurons from infants were highly branched prior to assuming the compact morphology of adults. Finally, other morphological aspects of GnRH neurons such as total dendritic length, the numbers of dendrite branches and the lengths of higher order branches were significantly greater in infants than adults, indicating a consolidation of dendritic arbors. Activity in multi-compartment models of GnRH neurons, suggest the impact of structure on neuronal activity is exerted with both active and passive dendrites. Thus, passive properties make a defining contribution to function. Accordingly, changes in morphology alone are likely to have functional consequences for the pattern of activity in GnRH neurons. Our findings suggest structural remodeling of dendrites during the postnatal period likely facilitates repetitive action potentials and thus, GnRH release at the time of puberty.

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

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

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

Science.gov (United States)

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

2010-03-01

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

Effects of triclosan on hormones and reproductive axis in female Yellow River carp (Cyprinus carpio): Potential mechanisms underlying estrogen effect.

Science.gov (United States)

Wang, Fan; Guo, Xiangmeng; Chen, Wanguang; Sun, Yaowen; Fan, Chaojie

2017-12-01

Triclosan (TCS), a member of the class of compounds called pharmaceutical and personal care products (PPCPs), is a broad antibacterial and antifungal agent found in a lot of consumer products. However, TCS hormone effect mechanism in teleost female fish is not clear. Female Yellow River carp (Cyprinus carpio) were exposed to 1/20, 1/10 and 1/5 LC 50 TCS (96h LC 50 of TCS to carp) under semi-static conditions for 42days. Vitellogenin (Vtg), 17β-estradiol (E 2 ), testosterone(T), estrogen receptor (Er), gonadotropin (GtH), and gonadotropin-releasing hormone (GnRH) levels were measured by enzyme-linked immunosorbent assay (ELISA). Meanwhile, we also examined the mRNA expressions of aromatase, GtHs-β, GnRH, and Er by quantitative real-time PCR (qRT-PCR). The results indicated that 1/5 LC 50 TCS induced Vtg in hepatopancreas of female carps by interference with the hypothalamic-pituitary-gonadal (HPG) axis at multiple potential loci through three mechanisms: (a) TCS exposure enhanced the mRNA expression of hypothalamus and gonadal aromatase which converts androgens into estrogens, subsequently increasing serum concentrations of E 2 to induce Vtg in hepatopancreas; (b) TCS treatment increased GnRH and GtH-β mRNA expression and secretion, causing the disturbance of reproductive endocrine and the increase of E 2 to induce Vtg in hepatopancreas; (c) TCS exposure enhanced synthesis and secretion of Er, then it bound to Er to active Vtg synthesis. These mechanisms showed that TCS may induce Vtg production in female Yellow River carp by Er-mediated and non-Er-mediated pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

EFFECT TN EWES OF OESTROGEN PRIMING AND GnRH ON LH ...

African Journals Online (AJOL)

Cyclicvariationsintheincreasedresponsivenessof thepituitaryto luteinizing hormone-releasing hormone ( LH RH) induced by LHRH . Endocrinology 9l , 13. COPPINGS, R.J. & MALVEN, P.V.. 1976. Biphasic effect of oestradiol on LH release mechanisms.

Final height in central precocious puberty after long term treatment with a slow release GnRH agonist

NARCIS (Netherlands)

Oostdijk, W; Rikken, B; Schreuder, S; Otten, Barto; Odink, R; Rouwe, C; Jansen, M; Gerver, WJ; Waelkens, J; Drop, S

1996-01-01

Objective-To study the resumption of puberty and the final height achieved in children with central precocious puberty (CPP) treated with the GnRH agonist triptorelin. Patients-31 girls and five boys with CPP who were treated with triptorelin 3.75 mg intramuscularly every four weeks. Girls were

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.

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

Science.gov (United States)

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

1987-10-01

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

The Impact of Centrally-acting Pesticidal/Environmental Toxicants on the Neuroendocrine Regulation of Reproductive Function in the Female Rodent: Revelant to Human Reproductive Risk Assessment.

Science.gov (United States)

In mammals, the secretion of gonadotropin-releasing hormone (GnRH) from the brain hypothalamic median eminence constitutes the final common path to the pituitary that results in the ovulatory surge of luteinizing hormone (LH). In rodent test species, a growing number of environme...

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.

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

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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

[Protective effect of GnRH analogues on the reproductive capacity of women with neoplasia or autoimmune disease who require chemotherapy. Final results of a phase ii clinical trial].

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Gris-Martínez, José M; Trillo-Urrutia, Lourdes; Gómez-Cabeza, Juan José; Encabo-Duró, Gloria

2016-02-05

In order to avoid the toxic effect of chemotherapy, it has been proposed to use GnRH agonist analogues (GnRHa) to inhibit the depletion of ovarian follicles. Nevertheless, there is controversy about its effectiveness. This clinical trial has been conducted with the aim to assess the protective effect of GnRH analogues on the reproductive capacity of women with malignancies or autoimmune diseases, which require chemotherapy. Open phase ii single-center clinical trial. During chemotherapy, a total of 5 doses of GnRH antagonist analogue at a dose interval of 3 days and/or a monthly dose of GnRHa were administered. Hormonal determinations prior to the start of the CT treatment were conducted during treatment and at the end of it. The inclusion of patients was prematurely concluded when incorporating the determination of anti-Müllerian hormone (AMH) as a parameter for assessing the ovarian reserve. Out of 38 patients, 23 (60.5%, 95%CI 43.4-76.0) had AMH values below normal following completion of treatment. An intermediate analysis was carried out observing that while most patients were recovering the menstrual cycle (86.6% 95%CI 71.9-95.6), they had reduced levels of AMH. Although most patients recovered their menstrual cycles, the ovarian reserve, assessed by the concentration of AMH, decreased in many patients. Therefore, we can conclude that the concomitant treatment of chemotherapy and GnRH analogues does not preserve the loss of follicular ovarian reserve. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

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

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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.

The role of brain peptides in the reproduction of blue gourami males (Trichogaster trichopterus).

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Levy, Gal; Degani, Gad

2013-10-01

In all vertebrates, reproduction and growth are closely linked and both are controlled by complex hormonal interactions at the brain-pituitary level. In this study, we focused on the reciprocal interactions between brain peptides that regulate growth and reproductive functions in a teleostei fish (blue gourami Trichogaster trichopterus). An increase in gonadotropin-releasing hormone 1 (GnRH1) gene expression was detected during ontogeny, and this peptide increased growth hormone (GH) and β follicle-stimulating hormone (βFSH) gene expression in pituitary cell culture. However, although no change in gonadotropin-releasing hormone 2 (GnRH2) gene expression during the reproductive cycle or sexual behavior was detected, a stimulatory effect of this peptide on β gonadotropins (βGtH) gene expression was observed. In addition, pituitary adenylate cyclase-activating polypeptide 38 (PACAP-38) inhibited GnRH-analog-induced βFSH gene expression, and co-treatment of cells with GnRH-analog and PACAP-38 inhibited GnRH-analog-stimulatory and PACAP-38-inhibitory effects on GH gene expression. These findings together with previous studies were used to create a model summarizing the mechanism of brain peptides (GnRH, PACAP and its related peptide) and the relationship to reproduction and growth through pituitary hormone gene expression during ontogenesis and reproductive stages in blue gourami. © 2013 Wiley Periodicals, Inc.

Supplementation with a recombinant human chorionic gonadotropin microdose leads to similar outcomes in ovarian stimulation with recombinant follicle-stimulating hormone using either a gonadotropin-releasing hormone agonist or antagonist for pituitary suppression.

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Cavagna, Mario; Maldonado, Luiz Guilherme Louzada; de Souza Bonetti, Tatiana Carvalho; de Almeida Ferreira Braga, Daniela Paes; Iaconelli, Assumpto; Borges, Edson

2010-06-01

To compare the outcomes of protocols for ovarian stimulation with recombinant hCG microdose, with GnRH agonists and antagonists for pituitary suppression. Prospective nonrandomized clinical trial. A private assisted reproduction center. We studied 182 patients undergoing intracytoplasmic sperm injection (ICSI) cycles, allocated into two groups: GnRH agonist group, in which patients received a GnRH agonist (n = 73), and a GnRH antagonist group, in which patients were administered a GnRH antagonist for pituitary suppression (n = 109). Pituitary suppression with GnRH agonist or GnRH antagonist. Ovarian stimulation carried out with recombinant FSH and supplemented with recombinant hCG microdose. Total dose of recombinant FSH and recombinant hCG administered; E(2) concentrations and endometrial width on the day of hCG trigger; number of follicles aspirated, oocytes and mature oocytes retrieved; fertilization, pregnancy (PR), implantation, and miscarriage rates. The total dose of recombinant FSH and recombinant hCG administered were similar between groups, as were the E(2) concentrations and endometrial width. The number of follicles aspirated, oocytes, and metaphase II oocytes collected were also comparable. There were no statistically significant differences in fertilization, PR, implantation, and miscarriage rates in the GnRH agonist and GnRH antagonist groups. When using recombinant hCG microdose supplementation for controlled ovarian stimulation (COS), there are no differences in laboratory or clinical outcomes with the use of either GnRH antagonist or agonist for pituitary suppression. Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Hormonal changes over the spawning cycle in the female three-spined stickleback, Gasterosteus aculeatus.

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Roufidou, Chrysoula; Schmitz, Monika; Mayer, Ian; Sebire, Marion; Katsiadaki, Ioanna; Shao, Yi Ta; Borg, Bertil

2018-02-01

Female three-spined sticklebacks are batch spawners laying eggs in a nest built by the male. We sampled female sticklebacks at different time points, when they were ready to spawn and 6, 24, 48 and 72h post-spawning (hps) with a male. Following spawning, almost all females (15 out of 19) had ovulated eggs again at Day 3 post-spawning (72hps). At sampling, plasma, brain and pituitaries were collected, and the ovary and liver were weighed. Testosterone (T) and estradiol (E2) were measured by radioimmunoassay. Moreover, the mRNA levels of follicle-stimulating hormone (fsh-β) and luteinizing hormone (lh-β) in the pituitary, and of the gonadotropin-releasing hormones (GnRHs: gnrh2, gnrh3) and kisspeptin (kiss2) and its G protein-coupled receptor (gpr54) in the brain were measured by real-time qPCR. Ovarian weights peaked in "ready to spawn" females, dropped after spawning, before again progressively increasing from 6 to 72hps. Plasma T levels showed peaks at 24 and 48hps and decreased at 72hps, while E2 levels increased already at 6hps and remained at high levels up to 48hps. There was a strong positive correlation between T and E2 levels over the spawning cycle. Pituitary lh-β mRNA levels showed a peak at 48hps, while fsh-β did not change. The neuropeptides and gpr54 did not show any changes. The changes in T and E2 over the stickleback spawning cycle were largely consistent with those found in other multiple-spawning fishes whereas the marked correlation between T and E2 does not support T having other major roles over the cycle than being a precursor for E2. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

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

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Baumann, G; Maheshwari, H

1997-11-01

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

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

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

1992-02-01

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

Fertility status of Hodgkin lymphoma patients treated with chemotherapy and adjuvant gonadotropin-releasing hormone analogues.

Science.gov (United States)

Huser, M; Smardova, L; Janku, P; Crha, I; Zakova, J; Stourac, P; Jarkovsky, J; Mayer, J; Ventruba, P

2015-08-01

Aim of this prospective observational study was to analyze fertility status of Hodgkin lymphoma (HL) patients treated with different types of chemotherapy while receiving GnRH analogues to preserve ovarian function. Fertility status was assessed among 108 females in reproductive age treated by curative chemotherapy for freshly diagnosed HL between 2005 and 2010 in university-based tertiary fertility and oncology center. All patients received GnRH analogues during chemotherapy to preserve their ovarian function. Their reproductive functions were assessed by follicle-stimulating hormone (FSH) measurement and pregnancy achievement. Ovarian function was determined separately in three groups with increasing gonadotoxicity of chemotherapy. One year following the treatment, normal ovarian function was found in 89 (82.4%) of patients. Two years after chemotherapy, 98 (90.7%) of patients retained their ovarian function, and 23 (21.3%) achieved clinical pregnancy during the follow-up period. Average FSH after chemotherapy was 11.6 ± 17.9 IU/l 1 year after the treatment resp. 9.0 ± 13.8 at the 2 years interval. There were significantly more patients with chemotherapy induced diminished ovarian reserve (chDOR) among the group receiving escalated BEACOPP chemotherapy in comparison with the other types of treatment (58.1% vs. 87.9% resp. 95.5%). The rate of chDOR is significantly higher after EB poly-chemotherapy and there is no tendency for improvement in time. The 2 + 2 chemotherapy with GnRH-a required for more advanced HL retained ovarian function significantly better after 2 years. Another important advantage of GnRH-a co-treatment is the excellent control of patient's menstrual cycle.

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

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

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Danuta Plewka

2014-01-01

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

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

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Silla Aimee J

2010-11-01

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

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.)

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.

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

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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.

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

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

1992-11-01

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

Comparison of luteal estradiol patch and gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation versus microdose gonadotropin-releasing hormone agonist protocol for patients with a history of poor in vitro fertilization outcomes.

Science.gov (United States)

Weitzman, Vanessa N; Engmann, Lawrence; DiLuigi, Andrea; Maier, Donald; Nulsen, John; Benadiva, Claudio

2009-07-01

To compare IVF outcomes in poor-responder patients undergoing stimulation after luteal phase E(2) patch/GnRH antagonist (LPG) protocol versus microdose GnRH agonist protocol. Retrospective analysis. University-based IVF center. Forty-five women undergoing ovarian stimulation for IVF using the LPG protocol were compared with 76 women stimulated with the microdose GnRH agonist protocol from May 2005 to April 2006. Cancellation rate, number of oocytes retrieved, and clinical pregnancy rates. The mean number of oocytes (9.1 +/- 4.1 vs. 8.9 +/- 4.3) and mature oocytes (6.7 +/- 3.5 vs. 6.8 +/- 3.1) retrieved were similar, as were the fertilization rates (70.0% +/- 24.2% vs. 69.9% +/- 21.5%) and the number of embryos transferred (2.5 +/- 1.1 vs. 2.7 +/- 1.3). The cancellation rate was not significantly different between the groups (13/45, 28.9% vs. 23/76, 30.3%). Likewise, there were no significant differences among the implantation rate (15.0% vs. 12.5%), clinical pregnancy rate (43.3% vs. 45.1%), and ongoing pregnancy rate per transfer (33.3% vs. 26.0%) between both groups. This study demonstrates that the use of an E(2) patch and a GnRH antagonist during the preceding luteal phase in patients with a history of failed cycles can provide similar IVF outcomes when compared with the microdose GnRH agonist protocol.

Identification of the GnRH-(1-5) Receptor and Signaling Pathway

Science.gov (United States)

2013-03-22

expression in immortalized GnRH neurons and to facilitate lordosis behavior in female rats. Interestingly, EP24.15 colocalizes with vii...expression in immortalized GnRH neurons (73) and facilitates lordosis behavior in female rats (72). Interestingly, EP24.15 is expressed along the...biologically active by facilitating lordosis behavior in ovariectomized estrogen-primed rats (72); and can increase the mRNA expression of GnRH in immortalized

Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis

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Oliveira João

2010-09-01

Full Text Available Abstract Background The effects of gonadotrophin-releasing hormone agonist (GnRH-a administered in the luteal phase remains controversial. This meta-analysis aimed to evaluate the effect of the administration of a single-dose of GnRH-a in the luteal phase on ICSI clinical outcomes. Methods The research strategy included the online search of databases. Only randomized studies were included. The outcomes analyzed were implantation rate, clinical pregnancy rate (CPR per transfer and ongoing pregnancy rate. The fixed effects model was used for odds ratio. In all trials, a single dose of GnRH-a was administered at day 5/6 after ICSI procedures. Results All cycles presented statistically significantly higher rates of implantation (P Conclusions These findings demonstrate that the luteal-phase single-dose GnRH-a administration can increase implantation rate in all cycles and CPR per transfer and ongoing pregnancy rate in cycles with GnRH antagonist ovarian stimulation protocol. Nevertheless, by considering the heterogeneity between the trials, it seems premature to recommend the use of GnRH-a in the luteal phase. Additional randomized controlled trials are necessary before evidence-based recommendations can be provided.

Targeted Mutagenesis of the Hypophysiotropic Gnrh3 in Zebrafish (Danio rerio Reveals No Effects on Reproductive Performance.

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Olivia Smith Spicer

Full Text Available Gnrh is the major neuropeptide regulator of vertebrate reproduction, triggering a cascade of events in the pituitary-gonadal axis that result in reproductive competence. Previous research in mice and humans has demonstrated that Gnrh/GNRH null mutations result in hypogonadotropic hypogonadism and infertility. The goal of this study was to eliminate gnrh3 (the hypophysiotropic Gnrh form function in zebrafish (Danio rerio to determine how ontogeny and reproductive performance are affected, as well as factors downstream of Gnrh3 along the reproductive axis. Using the TALEN technology, we developed a gnrh3-/- zebrafish line that harbors a 62 bp deletion in the gnrh3 gene. Our gnrh3-/- zebrafish line represents the first targeted and heritable mutation of a Gnrh isoform in any organism. Using immunohistochemistry, we verified that gnrh3-/- fish do not possess Gnrh3 peptide in any regions of the brain. However, other than changes in mRNA levels of pituitary gonadotropin genes (fshb, lhb, and cga during early development, which are corrected by adulthood, there were no changes in ontogeny and reproduction in gnrh3-/- fish. The gnrh3-/- zebrafish are fertile, displaying normal gametogenesis and reproductive performance in males and females. Together with our previous results that Gnrh3 cell ablation causes infertility, these results indicate that a compensatory mechanism is being activated, which is probably primed early on upon Gnrh3 neuron differentiation and possibly confined to Gnrh3 neurons. Potential compensation factors and sensitive windows of time for compensation during development and puberty should be explored.

Thyroid and male reproduction

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Anand Kumar

2014-01-01

Full Text Available Male reproduction is governed by the classical hypothalamo-hypophyseal testicular axis: Hypothalamic gonadotropin releasing hormone (GnRH, pituitary luteinizing hormone (LH and follicle stimulating hormone (FSH and the gonadal steroid, principally, testosterone. Thyroid hormones have been shown to exert a modulatory influence on this axis and consequently the sexual and spermatogenic function of man. This review will examine the modulatory influence of thyroid hormones on male reproduction.

Possible modulatory effects of male cues and social system on ...

African Journals Online (AJOL)

... circulating levels of luteinizing hormone (LH) and the response of the pituitary to an exogenous gonadotropin-releasing hormone (GnRH) challenge in two mole-rat species with induced ovulation but contrasting mating and social systems. Females were either kept in isolation, allowed only olfactory and auditory contact or ...

Fertility of Angus cross beef heifers after GnRH treatment on day 23 and timing of insemination in 14-day CIDR protocol.

Science.gov (United States)

Kasimanickam, R K; Hall, J B; Whittier, W D

2017-02-01

This study compared artificial insemination pregnancy rate (AI-PR) between 14-day CIDR-GnRH-PGF2α-GnRH and CIDR-PGF2α-GnRH synchronization protocol with two fixed AI times (56 or 72 hr after PGF2α). On day 0, heifers (n = 1311) from nine locations assigned body condition score (BCS: 1, emaciated; 9, obese), reproductive tract score (RTS: 1, immature, acyclic; 5, mature, cyclic) and temperament score (0, calm; and 1, excited) and fitted with a controlled internal drug release (CIDR, 1.38 g of progesterone) insert for 14 days. Within herd, heifers were randomly assigned either to no-GnRH group (n = 635) or to GnRH group (n = 676), and heifers in GnRH group received 100 μg of GnRH (gonadorelin hydrochloride, IM) on day 23. All heifers received 25 mg of PGF2α (dinoprost, IM) on day 30 and oestrous detection aids at the same time. Heifers were observed for oestrus thrice daily until AI. Within GnRH groups, heifers were randomly assigned to either AI-56 or AI-72 groups. Heifers in AI-56 group (n = 667) were inseminated at 56 hr (day 32 PM), and heifers in AI-72 group (n = 644) were inseminated at 72 hr (day 33 AM) after PGF2α administration. All heifers were given 100 μg of GnRH concurrently at the time AI. Controlling for BCS (p < .05), RTS (p < .05), oestrous expression (p < .001), temperament (p < .001) and GnRH treatment by time of insemination (p < .001), the AI-PR differed between GnRH treatment [GnRH (Yes - 60.9% (412/676) vs. No - 55.1% (350/635); p < .05)] and insemination time [AI-56 - 54.6% (364/667) vs. AI-72 - 61.8% (398/644); (p < .01)] groups. The GnRH treatment by AI time interaction influenced AI-PR (GnRH56 - 61.0% (208/341); GnRH72 - 60.9% (204/335); No-GnRH56 - 47.9% (156/326); No-GnRH72 - 62.8% (194/309); p < .001). In conclusion, 14-day CIDR synchronization protocol for FTAI required inclusion of GnRH on day 23 if inseminations were to be performed at 56 hr after PGF2α in order to achieve greater AI-PR. �

The African catfish, Clarias gariepinus, a model for the study of reproductive endocrinology in teleosts

NARCIS (Netherlands)

Oordt, P.G.W.J. van; Goos, H.J.Th.

1987-01-01

In their natural habitat African catfish, Clarias gariepinus, show a discontinuous reproductive cycle. This cycle follows changes in the gonadotropic activity of the pituitary. Gonadotropin release has been shown to be under dual hypothalamic control, i.e. a gonadotropin-releasing hormone (GnRH) and

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.

GnRH在性成熟高白鲑神经系统及性腺中的分布定位%An Immunocytochemical Localization of GnRH in the Nerve System and Gonad of Mature Coregonus peled

Institute of Scientific and Technical Information of China (English)

曹玉洁; 贾斌; 柳建新; 李志远; 张莉

2011-01-01

摘要：应用免疫组织化学方法，系统观察性成熟期高白鲑(Coregonus peled)神经系统及性腺中的促性腺激素释放激素( GnRH)的分布情况。结果表明，GnRH在大脑、小脑、中脑、脊髓、延髓中免疫阳性反应明显，且主要分布在神经元内。GnRH免疫阳性细胞在卵巢和精巢中均有分布，而且其阳性部位在卵巢主要分布于小生长期卵母细胞；在精巢中主要分布于间质细胞和精原细胞中。本文讨论了GnRH直接或间接参与高白鲑性腺发育成熟调节的可能性。%Immunocytochemical staining technique was used to study the expression of gonadotropin-releasing hormone (GnRH) in the nervous system and gonad of Coregonus peled. The results showed that there were GnRH immunoreactive endocrine cells in the cerebrum,cerebellum,diencephalon,medulla oblongata,and spinal cord. There were GnRH immunoreactive endocrine cells in the ovary and testis. The positive staining was observed mainly in the small growing oocyte, and in the interstitial cells and spermatogonia. The possible physiological function and morphological evidence of GnRH regulation on the development of gonad in C. Peled were discussed.

Evaluation of degarelix in the management of prostate cancer

Directory of Open Access Journals (Sweden)

Hendrik Van Poppel

2010-01-01

Full Text Available Hendrik Van PoppelDepartment of Urology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, BelgiumAbstract: Medical castration using gonadotropin-releasing hormone (GnRH receptor agonists currently provides the mainstay of androgen deprivation therapy for prostate cancer. Although effective, these agents only reduce testosterone levels after a delay of 14 to 21 days; they also cause an initial surge in testosterone that can stimulate the cancer and lead to exacerbation of symptoms (“clinical flare” in patients with advanced disease. Phase III trial data for the recently approved GnRH receptor blocker, degarelix, demonstrated that it is as effective and well tolerated as GnRH agonists. However, it has a pharmacological profile more closely matching orchiectomy, with an immediate onset of action and faster testosterone and PSA suppression, without a testosterone surge or microsurges following repeated injections. As a consequence, with this GnRH blocker, there is no risk of clinical flare and no need for concomitant antiandrogen flare protection. Degarelix therefore provides a useful addition to the hormonal armamentarium for prostate cancer and offers a valuable new treatment option for patients with hormone-sensitive advanced disease. Here, we review key preclinical and clinical data for degarelix, and look at patient-focused perspectives in the management of prostate cancer.Keywords: degarelix, GnRH receptor antagonist, GnRH receptor blocker, prostate cancer

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

Anti-Mullerian hormone levels do not predict response to pulsatile GnRH in women with hypothalamic amenorrhea.

Science.gov (United States)

Billington, Emma O; Corenblum, Bernard

2016-09-01

Pulsatile GnRH is used to induce ovulation in women with hypothalamic amenorrhea (HA), but tools to predict response are lacking. We assessed whether baseline AMH levels are associated with response to pulsatile GnRH in 16 women with HA. AMH levels were compared between non-responders and women who achieved follicular development or pregnancy. Median AMH for the cohort was 2.2 ng/mL. AMH levels were undetectable or low in four women, normal in nine and high in three. Follicular development was observed in 13 (81%) women (82% of cycles) and pregnancy achieved in 10 (63%) women (29% of cycles). All four women with low or undetectable AMH had follicular response and three achieved pregnancy. Of the 12 women with normal or high AMH, 10 had a follicular response and seven achieved pregnancy. Median AMH levels were comparable in those who achieved follicular development and those who did not (2.2 ng/mL versus 1.3 ng/mL, p = 0.78) and in those who became pregnant and those who did not (2.2 ng/mL versus 1.9 ng/mL, p = 0.52). In summary, low AMH does not preclude response to ovulation induction in women with HA, suggesting that ovarian potential may not be the primary determinant of AMH concentrations in this population.

Effect of a low dose combined oral contraceptive pill on the hormonal profile and cycle outcome following COS with a GnRH antagonist protocol in women over 35 years old.

Science.gov (United States)

Bakas, Panagiotis; Hassiakos, Dimitrios; Grigoriadis, Charalampos; Vlahos, Nikolaos F; Liapis, Angelos; Creatsas, George

2014-11-01

This prospective study examines if pre-treatment with two different doses of an oral contraceptive pill (OCP) modifies significantly the hormonal profile and/or the IVF/ICSI outcome following COS with a GnRH antagonist protocol. Infertile patients were allocated to receive either OCP containing 0.03 mg of ethinylestradiol and 3 mg of drospirenone, or OCP containing 0.02 mg of ethinylestradiol and 3 mg of drospirenone prior to initiation of controlled ovarian stimulation (COS) with recombinant gonadotropins on a variable multi-dose antagonist protocol (Ganirelix), while the control group underwent COS without OCP pretreatment. Lower dose OCP was associated with recovery of FSH on day 3 instead of day 5, but the synchronization of the follicular cohort, the number of retrieved oocytes and the clinical pregnancy rate were similar to higher dose OCP.

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

The use of Goserelin in the management of endometriosis | Moodley ...

African Journals Online (AJOL)

Zoladex (Goserelin acetate implant) contains a synthetic decapeptide analogue of luteinising hormone releasing (GnRH) agonist analogue. Zoladex is designed for subcutaneous injection (sterile biodegradable product equivalent to 3.6mg Goserelin) ...

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)

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

Science.gov (United States)

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

1996-02-01

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

Functional hypothalamic amenorrhea and its influence on women’s health

OpenAIRE

Meczekalski, B.; Katulski, K.; Czyzyk, A.; Podfigurna-Stopa, A.; Maciejewska-Jeske, M.

2014-01-01

Introduction Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). The final consequences are complex hormonal changes manifested by profound hypoes...

Recent advancements in the hormonal stimulation of ovulation in swine

Directory of Open Access Journals (Sweden)

Knox RV

2015-10-01

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

Growth Hormone Utilization Review in a Pediatric Primary Care Setting.

Science.gov (United States)

Sayarifard, Fatemeh; Imcheh, Fereshteh Bakhshi; Badri, Shirinsadat; Faghihi, Toktam; Qorbani, Mostafa; Radfar, Mania

2017-01-01

One of the main problems facing public health providers and administrators in many countries is ensuring the rational use of high-cost drugs. In this regard, on-going process of medication use evaluation can be considered as a useful tool. In this study, we evaluated certain usage aspects of a highly-cost medication, that is, recombinant growth hormone (GH). This cross-sectional study conducted from August 2012 to August 2014. Children receiving GH ± gonadotropin releasing hormone (GnRH) analogs were included in the study. A researcher-designed checklist was developed to evaluate the GH utilization in these patients. Baseline demographic characteristics and background clinical and growth data, as well as any aspects of drug therapy including indications, dosing, monitoring, and discontinuation were collected from the patients' medical records. Seventy children receiving GH entered the study, of which 23 patients (32.85%) received GH and GnRH analogs simultaneously. At the baseline, 67 children (95.7%) had GH stimulation test, whereas serum insulin-like growth factor-1 (IGF-1) levels were measured in 63 (90%) patients. Sixty-seven patients (95.71%) had thyroid function test, whereas bone age was determined in 68 children (97.14%). The mean ± standard deviation of GH dose for idiopathic short stature, GH deficiency, Turner's syndrome and born small for gestational age in our study was 0.22 ± 0.025 mg/kg/week, 0.23 ± 0.04 mg/kg/week, 0.22 ± 0.015 mg/kg/week, and 0.23 ± 0.02 mg/kg/week, respectively. Height and weight of all patients were followed every 3-6 months, regularly. Thirty patients were treated with GH for at least 1 year, of which thyroid hormones and IGF-1 levels were measured annually in 25 (83.33%) and 26 (86.66%) patients, respectively; while bone age was evaluated in 13 (43.33%) children, annually. GH treatment was discontinued in 15 patients (21.42%), while financial problem was the major reason. Diagnostic tests and monitoring of height, weight

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.

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.

Evaluation of degarelix in the management of prostate cancer

International Nuclear Information System (INIS)

Van Poppel, Hendrik

2010-01-01

Medical castration using gonadotropin-releasing hormone (GnRH) receptor agonists currently provides the mainstay of androgen deprivation therapy for prostate cancer. Although effective, these agents only reduce testosterone levels after a delay of 14 to 21 days; they also cause an initial surge in testosterone that can stimulate the cancer and lead to exacerbation of symptoms (“clinical flare”) in patients with advanced disease. Phase III trial data for the recently approved GnRH receptor blocker, degarelix, demonstrated that it is as effective and well tolerated as GnRH agonists. However, it has a pharmacological profile more closely matching orchiectomy, with an immediate onset of action and faster testosterone and PSA suppression, without a testosterone surge or microsurges following repeated injections. As a consequence, with this GnRH blocker, there is no risk of clinical flare and no need for concomitant antiandrogen flare protection. Degarelix therefore provides a useful addition to the hormonal armamentarium for prostate cancer and offers a valuable new treatment option for patients with hormone-sensitive advanced disease. Here, we review key preclinical and clinical data for degarelix, and look at patient-focused perspectives in the management of prostate cancer

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...