Gonadotropin-releasing Hormone Infusion Research Articles

A Current Perspective on Delayed Puberty and Its Management

Delayed puberty is defined as the lack of development of secondary sex characteristics in childhood. Based on a review of the literature, delayed puberty can be divided into three main categories: (i) hypergonadotropic hypogonadism (congenital and acquired), (ii) permanent hypogonadotropic hypogonadism (congenital and acquired), and (iii) transient hypogonadotropic hypogonadism [constitutional delay of growth and puberty (CDGP) and functional hypogonadotropic hypogonadism (FHH)]. CDGP is the most common cause of hypogonadism in both males and females, accounting for 60% and 30% respectively. Testosterone is the primary treatment for male hypogonadism, while estrogen and progesterone are used for female hypogonadism. However, in recent years, physiological induction therapy protocols such as human chorionic gonadotropin (hCG) monotherapy, hCG + Follicle-stimulating hormone combined therapy, and gonadotropin releasing hormone infusion have been recommended for the treatment of hypogonadotropic hypogonadism to increase long-term fertility success. There is no clear consensus on treatment protocols for physiological induction treatment and its effect on fertility. This review will discuss the clinical approach to hypogonadism, as well as traditional and physiological induction protocols.

MON-LB051 Non-inferiority Clinical Trial on Gonadotropinversus Pulsatile Gonadotropin-releasing Hormone Infusion Therapy in Male Adolescent Patient with Congenital Hypogonadotropic Hypogonadism

Context We investigate the efficacy and safety of non-inferiority clinical trial for human chorionic gonadotropin/ human menopausal gonadotropin (HCG/HMG) versus pulsatile gonadotropin-releasing hormone (GnRH) which has not been evaluated on non-inferiority clinical trial in puberty boys with CHH. Objective To compare the efficacy and security of two different treatments in male adolescent patient with congenital hypogonadotropic hypogonadism (CHH) . To explore the standardization of early treatment and it is possible clinical recommended regimen. Methods For this prospective cohort nonrandomized controlled study, male adolescent CHH patients were recruited and categorized into HCG/HMG(group 1) and GnRH (group 2) groups. All patients were treated for 3-12months. The study was divided into research period (3 months of treatment) and extension period (3 to 12 months of treatment). Testicular volume (TV), penile length(PL), blood sex hormones levels, height, body weight, and other related laboratory indices were measured and evaluated. In this study, we observe the therapeutic effect within 3 months and also collect partial extended period data for providing further research experience. Results All CHH patients were treated for over 3 months. At the beginning, the average age of patients, the testicular volume, penile length, penile diameter in group 1 and group 2 were 15.3±1.9 years VS 14.2±1.5 years, 2.5±1.4ml VS 2.7±1.5ml, 4.8±1.3cm VS 4.2±1.4cm and 1.6±0.4cm VS 1.5±0.4cm. The difference of two groups was not statistically significant. After 3 months treatment, the testicular volume, penile length, penile diameter, the growth of testicular volume, the growth of penile length and the growth of penile diameter in group 1 and group 2 were 5.1±2.7ml VS 4.6±2.7ml , 6.9±1.7cm VS 5.1±1.6cm, 2.5±0.5cm VS 1.9±0.6cm,2.0±1.6 cm 和1.0±0.8cm, 0.9±0.5cmand0.3±0.4cm. The difference of two groups was not statistically significant. There was no significant difference in height, body weight, or BMI between the two treatments. Based on the principles of hypothesis-test, mean value M-0.25625, standard error(SE) = 0.69319,M±1.96, Se=-0.25625±1.3586524,(-1.161,1.10). The growth differential of testicular volume between group 1 and group 2 was less than 2ml in (P<0.05) . It can be inferred that group 1 is not inferior to group 2. There was no significant difference in efficacy comparison in some of the patients were treated after 6-12 months in both groups. There was no significant difference in side effects in both groups. Conclusions In this clinical trial, 3 months was an observation period. Short-term therapeutic indicated adolescent patients with CHH were effectively treated with HCG/HMG and GnRH. We discovered that the effect of HCG/HMG was as good as GnRH in treating adolescent boys with CHH. This therapeutic schedule can be used in more patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Differential Regulation of Gonadotropins in Response to Continuous Infusion of Native Gonadotropin-Releasing Hormone in the Winter Anovulatory Mare and Effects of Treatment With Estradiol-17β

We tested the hypotheses that in winter anovulatory mares (1) both chronic daily injections of estradiol-17β (E2) and subcutaneous E2 implants could enhance pituitary secretion of gonadotropins in response to continuous subcutaneous infusion of native gonadotropin-releasing hormone (GnRH); and (2) the secretory pattern of follicle-stimulating hormone (FSH) in response to continuous subcutaneous infusion of native GnRH is similar to that of luteinizing hormone (LH) but differs between mares that develop or fail to develop an estrogen-active, preovulatory follicle. In Experiment 1, 20 winter anovulatory mares (n = 5 per group) in early February received twice-daily injections of corn oil (control) or 5 mg of E2 with or without continuous subcutaneous treatment with native GnRH (100 μg/hr) or received GnRH only for up to 14 days. In Experiment 2, 24 winter anovulatory mares (n = 6 per group) were treated with a full-length (high dose) or quarter-length (low dose) E2 implant (Compudose) in combination with continuous GnRH infusion (100 μg/hr) for up to 28 days or served as sham controls. Mares developing 35-mm follicles were induced to ovulate with human chorionic gonadotropin. Mares not developing a 35-mm follicle within 14 days received a replacement 14-day GnRH pump. In Experiment 1, E2 enhanced the response to GnRH beginning on Day 3, with mean LH greater (P < .001) in GnRH + E2 than in GnRH only and control mares. In Experiment 2, plasma E2 and estrone sulfate were increased in association with the development of a large (35 mm) follicle but did not increase in response to either E2 implant despite marked increases in uterine edema following their insertion. A sustained increase (P < .0001) in plasma LH was observed in all GnRH-treated mares, but this effect was not modified by implant treatment. By Day 28, six of six GnRH, five of six GnRH + low E2, two of six GnRH + high E2, and zero of six control mares developed 35-mm follicles and were induced to ovulate. A marked increase (P < .0001) in plasma FSH was observed within 24 hours in all GnRH-treated mares, returning to baseline by Day 4. In summary, twice-daily injection of 5 mg E2 enhanced pituitary secretion of LH in response to continuous administration of GnRH, but commercial E2 cattle implants failed to duplicate these effects. Continuous infusion of GnRH produced a differential but consistent pattern of FSH secretion (short-term increase) compared with LH (sustained increase). Differences in ovarian responses to GnRH treatment could not be explained by variation in gonadotropin secretion.

AB029. The beneficial effects of pulsatile gonadotropin-releasing hormone pumps in the treatment of adult male idiopathic hypogonadotropic hypogonadism

BackgroundTo explore the efficacy of pulsatile gonadotropin-releasing hormone (GnRH) on patients with idiopathic hypogonadotropic hypogonadism (IHH) via a microinfusion pump.MethodsFifty-four adult male patients who were diagnosed as having IHH in our hospital between August 1, 2013 and August. 31, 2017 were included in the present study. All patients were treated with pulsatile GnRH pumps. Patient clinical parameters included secondary sex characteristics, morphology and size of external genitalia, and sex hormone concentrations. Fertility and sexual function were observed, evaluated, and recorded before and at 3, 6, and 12 months of treatment, and any adverse events during treatment were also recorded.ResultsThe mean follow-up time was 15.9 (range 2–40) months. Twenty-six patients treated with pulsatile GnRH infusion were followed over 2 years, 41 cases were followed over 1 year, 45 cases were followed over one-half year, 5 cases were followed for 3 months to one-half year, and 4 cases were followed for under 3 months. Before treatment, the mean testicular volume of male IHH patients was 3.19±1.66 mL, the luteinizing hormone (LH) level was 0.67±0.63 U/L, follicle-stimulating hormone (FSH) was 1.27±0.88 U/L, T was 0.50±0.53 ng/mL, resting penile length was 3.54±0.92 cm, penile pull length was 5.73±1.27 cm and penile circumference was 5.28±1.14 cm. After more than one-half year of continuous treatment, the mean testicular volume of 45 cases of male IHH patients was 6.22±1.85 mL, LH was 6.72±5.35 U/L, FSH was 5.48±3.23 U/L, T was 2.36±1.37 ng/mL, resting penile length was 4.77±0.68 cm, penile pull length was 7.87±1.01 cm and penile circumference was 7.55±1.09 cm; all of these were significantly increased relative to the same parameters before treatment (P<0.01). After 1 year of treatment, the mean testicular volume of 41 cases of male IHH patients was 8.78±2.24 mL, LH was 6.56±3.89 U/L, FSH was 5.04±2.49 U/L, T was 3.57±1.08 ng/mL, resting penile length was 5.70±0.69 cm, penile pull length was 9.44±1.24 cm, and the penile circumference was 8.74±1.03 cm; all of these were significantly increased compared with the same parameters prior to treatment (P<0.01). External genitalia and T concentrations were further improved compared with treatment at one-half year of treatment (P<0.05). After 2 years of treatment, the mean testicular volume of 26 cases of male IHH patients was 9.73±1.93 mL, LH was 6.12±3.22 U/L, FSH was 4.80±2.05 U/L, T was 3.81±0.68 ng/mL, the resting penile length was 6.08±0.52 cm, penile pull length was 9.63±1.07 cm and the penile circumference was 8.78±0.87 cm; all of these were significantly increased relative to the same parameters before treatment (P<0.01). External genitalia and T concentrations were further improved compared with one-half year of treatment (P<0.05). T was also further dramatically improved compared with T concentrations at 1 year of treatment. All 45 patients who were treated for at least 6 months produced ejaculates. Thirty-four of the 45 patients who had over one-half year of treatment successfully collected their semen by masturbation, and the results showed that there were spermatozoa in 27 patients. Four married patients who were treated for over 1 year impregnated their wives. Only a few minor adverse events were found, and most patients showed very good adherence to treatment.ConclusionsGnRH pulsatile pumps for the treatment of adult male IHH constitute a safe and effective strategy with ideal long-term beneficial effects. It is suggested that the GnRH pulsatile pump is the preferred treatment for IHH patients.

Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation

Background/Aims: Ovarian theca cell hyperandrogenism in women with polycystic ovary syndrome (PCOS) is compounded by androgen receptor-mediated impairment of estradiol and progesterone negative feedback regulation of episodic luteinizing hormone (LH) release. The resultant LH hypersecretion, likely the product of accelerated episodic release of gonadotropin-releasing hormone (GnRH) from the median eminence of the hypothalamus, hyperstimulates ovarian theca cell steroidogenesis, enabling testosterone (T) and androstenedione excess. Prenatally androgenized (PA) female monkeys exposed to fetal male levels of T during early-to-mid gestation, when adult, demonstrate PCOS-like traits, including high T and LH levels. This study tests the hypothesis that progesterone resistance-associated acceleration in episodic LH release contributes to PA monkey LH excess. Methods: A total of 4 PA and 3 regularly cycling, healthy control adult female rhesus monkeys of comparable age and body mass index underwent (1) a 10 h, frequent intravenous sampling assessment for LH episodic release, immediately followed by (2) IV infusion of exogenous GnRH to quantify continuing pituitary LH responsiveness, and subsequently (3) an SC injection of a progesterone receptor antagonist, mifepristone, to examine LH responses to blockade of progesterone-mediated action. Results: Compared to controls, the relatively hyperandrogenic PA females exhibited ~100% increase (p = 0.037) in LH pulse frequency, positive correlation of LH pulse amplitude (p = 0.017) with androstenedione, ~100% greater increase (p = 0.034) in acute (0–10 min) LH responses to exogenous GnRH, and an absence (p = 0.008) of modest LH elevation following acute progesterone receptor blockade suggestive of diminished progesterone negative feedback. Conclusion: Such dysregulation of LH release in PCOS-like monkeys implicates impaired feedback control of episodic release of hypothalamic GnRH reminiscent of PCOS neuroendocrinopathy.

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

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.

Clinical research of impulse GnRH infusion treatment to a patient with central secondary amenorrhea

Objective To apply continuous subcutaneous pulse infusion of gonadotropin-releasing hormone (GnRH) to treat patients with central secondary amenorrhea,and to observe the induction of spontaneous ovulation and natural fertilization.Methods Using micro-pulse infusion pumps with each 90-minute infusion of LHRH 10 μg daily,the serum LH,FSH,estrogen,and progesterone levels ; and change in endometrium and ovarian size before and after treatment were monitored.The end point is natural pregnancy.Results The levels of serum LH,FSH,and estrogen were obviously increased after 4 weeks of treatment.The natural menstrual cycle was rebuilt after 8 weeks of treatment.The patient was pregnant and the treatment was stopped by 16 weeks.The experience of pregnancy was favourable.40 weeks later,the patient delivered a healthy female infant via caesarean section.Conclusions It was the first time in China that the technology of micro GnRH pump was applied in patients with secondary central amenorrhea.The result demonstrates that this technology can perfectly simulate the physiology of hypothalamic GnRH secretion.At present,more patients are included in this research to confirm the effectiveness. Key words: Pituitary hormone pump ; GnRH impulse therapy ; Secondary amenorrhea ; Pregnancy ; Assisted reproductive technology ; In vitro fertilization

Maternal Exposure to Dioxin Imprints Sexual Immaturity of the Pups through Fixing the Status of the Reduced Expression of Hypothalamic Gonadotropin-Releasing Hormone

Our previous studies have shown that treatment of pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 1 μg/kg) at gestational day (GD) 15 reduces the pituitary synthesis of luteinizing hormone (LH) during the late fetal and early postnatal period, leading to the imprinting of defects in sexual behaviors at adulthood. However, it remains unclear how the attenuation of pituitary LH is linked to sexual immaturity. To address this issue, we performed a DNA microarray analysis to identify the gene(s) responsible for dioxin-induced sexual immaturity on the pituitary and hypothalamus of male pups, born of TCDD-treated dams, at the age of postnatal day (PND) 70. Among the reduced genes, we focused on gonadotropin-releasing hormone (GnRH) in the hypothalamus because of published evidence that it has a role in sexual behaviors. An attenuation by TCDD of GnRH expression emerged at PND4, and no subsequent return to the control level was seen. A change in neither DNA methylation nor histone acetylation accounted for the reduced expression of GnRH. Intracerebroventricular infusion of GnRH to the TCDD-exposed pups after reaching maturity restored the impairment of sexual behaviors. Supplying equine chorionic gonadotropin, an LH-mimicking hormone, to the TCDD-exposed fetuses at GD15 resulted in a recovery from the reduced expression of GnRH, as well as from the defects in sexual behavior. These results strongly suggest that maternal exposure to TCDD fixes the status of the lowered expression of GnRH in the offspring by reducing the LH-assisted steroidogenesis at the perinatal stage, and this mechanism imprints defects in sexual behaviors at adulthood.

Secretion of luteinizing hormone into pituitary venous effluent of the follicular and luteal phase mare: novel acceleration of episodic release during constant infusion of gonadotropin-releasing hormone

We tested the hypothesis that continuous infusion of native GnRH into mares during the estrous cycle, at a dose of 100 μg/h, would elevate circulating concentrations of LH without disrupting the endogenous, episodic pattern of LH release. Ten cyclic mares were assigned to one of two groups (n = 5/group): (1) Control (saline) and (2) GnRH in saline (100 μg/h). On experimental day 0 (3 to 6 d after ovulation), osmotic pumps containing saline or GnRH were placed subcutaneously and connected to a jugular infusion catheter. Blood samples were collected from jugular catheters daily and at 5-min intervals from catheters placed in the intercavernous sinus (ICS) for 8 h on experimental day 4 (luteal phase; 7 to 10 d after ovulation), followed by an additional 6-h intensive sampling period 36 h after PGF2α-induced luteal regression (experimental day 6; follicular phase). Treatment with GnRH increased (P < 0.001) concentrations of LH by 3- to 4-fold in the peripheral circulation and 4- to 5-fold in the ICS. Continuous GnRH treatment accelerated (P < 0.01) the frequency of LH release and decreased the interepisodic interval during both luteal and follicular phases. Treatment with GnRH during the luteal phase eliminated the low-frequency, long-duration pattern of episodic LH release and converted it to a high-frequency, short-duration pattern reminiscent of the follicular phase. These observations appear to be unique to the horse. Further studies that exploit this experimental model are likely to reveal novel mechanisms regulating the control of gonadotrope function in this species.

Evidence from the Agonadal Juvenile Male Rhesus Monkey (Macaca mulatta) for the View that the Action of Neurokinin B to Trigger Gonadotropin-Releasing Hormone Release Is Upstream from the Kisspeptin Receptor

Human genetics have revealed that kisspeptin signaling and neurokinin B (NKB) signaling are both required for robust pulsatile gonadotropin-releasing hormone (GnRH) release, and therefore for puberty and maintenance of adult gonadal function. How these two peptides interact to affect GnRH pulse generation remains a mystery. To address the hierarchy of the NKB and kisspeptin signaling pathways that are essential for GnRH release, two experiments were conducted using agonadal, juvenile male monkeys. Pituitary responsiveness to GnRH was first heightened by a pulsatile GnRH infusion to use the in situ pituitary as a bioassay for GnRH release. In the first experiment (n = 3), the kisspeptin receptor (KISS1R) was desensitized by a continuous 99-hour i.v. infusion of kisspeptin-10 (100 µg/h). During the last 4 h of continuous kisspeptin-10 infusion, desensitization of KISS1R was confirmed by failure of an i.v. bolus of kisspeptin-10 to elicit GnRH release. Desensitization of KISS1R was associated with a markedly blunted GnRH response to senktide. The response to senktide was progressively restored during the 72 h following termination of continuous kisspeptin-10. An analogous design was employed in the second experiment (n = 2) to desensitize the NKB receptor (neurokinin 3 receptor, NK3R) by administration of a continuous 48-hour i.v. infusion of senktide (200 µg/h). While a bolus of senktide during the last 3 h of continuous senktide administration failed to elicit GnRH release, thus confirming desensitization of NK3R, the ability of kisspeptin to stimulate GnRH was unimpaired. The foregoing findings support the view that NKB stimulation of GnRH release is upstream from KISS1R.

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

Mechanisms of FSH synthesis: what we know, what we don't, and why you should care

The pituitary gonadotropin hormones, FSH and LH, are key regulators of reproductive physiology. Though the two hormones are produced by the same cell type, often in response to the same endocrine and paracrine regulators, they sub-serve different biological functions and their synthesis and secretion are differentially regulated. This stems largely from differences in transcriptional, post-transcriptional, and post-translational regulation of their unique beta subunits. That is, both hormones are dimeric glycoproteins and share a common alpha subunit. Their unique beta subunits, however, derive from different genes encoding distinct proteins. Past and recent research indicates synthesis and release of the two hormones are subject to extensive and independent regulation. LH appears to be secreted predominantly via the regulated secretory pathway, whereas FSH release is largely constitutive. As such, investigations of FSH-beta subunit synthesis may lend direct insight into mechanisms underlying patterns of secreted FSH, more so than investigations of the LHbeta subunit. Here, we review recent investigations of transcriptional regulation of the FSH-beta subunit gene from different mammalian species, including humans. The results reveal both conserved and species-specific regulatory mechanisms that might contribute to inter-species variation in FSH release.

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

Differential diagnosis between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty in boys is challenging. Most tests use an acute GnRH stimulus, allowing only the release of previously synthesized gonadotropins. A constant GnRH infusion, inducing de novo gonadotropin synthesis, may allow a better discrimination. We evaluated the diagnostic accuracy of basal and peak gonadotropins after GnRH infusion, measured by ultrasensitive assays, to confirm the diagnosis in boys with suspected HH. We conducted a validation study following Standards for Reporting of Diagnostic Accuracy criteria at a tertiary public hospital. A GnRH i.v. infusion test was performed in 32 boys. LH and FSH were determined by immunofluorometric assay at 0-120 min. DIAGNOSIS ASCERTAINMENT: The following diagnoses were ascertained: complete HH (n = 19; testes < 4 ml at 18 yr), partial HH (n = 6; testes enlargement remained arrested for > or = 1 yr or did not reach 15 ml), and constitutional delay of puberty (n = 7; testes > or = 15 ml at 18 yr). Sensitivity, specificity, positive and negative predictive values, and diagnostic efficiency were assessed. Basal FSH less than 1.2 IU/liter confirmed HH with specificity of 1.00 (95% confidence interval = 0.59-1.00), rendering GnRH infusion unnecessary. In patients with basal FSH of at least 1.2 IU/liter, the coexistence of peak FSH less than 4.6 IU/liter and peak LH less than 5.8 IU/liter after GnRH infusion had high specificity (1.00; 95% confidence interval = 0.59-1.00) and diagnostic efficiency (76.9%) for HH. Basal FSH less than 1.2 IU/liter confirms HH, which precludes from further testing, reducing patient discomfort and healthcare system costs. In patients with basal FSH of at least 1.2 IU/liter, a GnRH infusion test has a high diagnostic efficiency.

Impact level of dihydrotestosterone on the hypothalamic‐pituitary‐leydig cell axis in men

Dihydrotestosterone (DHT) the physiologically most potent androgen cannot be aromatised into oestrogen. DHT is used as a treatment for idiopathic gynaecomastia. In order to investigate the different sites of action of DHT on the hypothalamic-pituitary-testicular axis, two groups of adult men were studied. Group I included 10 gonadotropin-releasing hormone (GnRH)-deficient men who were evaluated before and during a pulsatile infusion of GnRH alone for 2 weeks and then in association with DHT given transdermally at doses used in the treatment of gynaecomastia for further two weeks. Luteinizing hormone (LH) pulsatility was assessed at the end of each step of the study. Plasma LH levels were measured every 15 min. Plasma testosterone (T), DHT, oestradiol (E2), free alpha-subunit (FAS) of glycoproteic hormones and LH bioactivity were measured on pooled plasma samples. Group II included 12 healthy men in whom plasma T, DHT and E2 were measured before and then 24, 48 and 72 h after the injection of 5000 IU hCG alone or in combination with either DHT or the pure anti-androgen nilutamide. Two weeks separated each of the 3 hCG testing. In group I, except for bioactive/immunoreactive (B/I) LH ratio which was unchanged, GnRH treatment induced significant rises (p < 0.01) in all plasma hormone levels, LH pulse amplitude and frequency. During treatment with GnRH+DHT, plasma DHT levels increased up to 16.8 +/- 2.5 nm, while plasma hormone levels, B/I LH ratio, LH pulse amplitude and frequency were similar to those obtained with GnRH alone. In group II, the peak of hCG-induced T rise was not modified by either DHT or nilutamide. In contrast, DHT reduced by 50% (p < 0.01) the E2 peak in response to hCG. These data show that DHT exerts no direct action on the pituitary to retroregulate LH secretion and to modify either B/I LH ratio or FAS secretion. Its reducing effect on LH secretion is likely mediated at the hypothalamic level. DHT does not appear to have a physiological influence on Leydig cells steroidogenesis. Administered at therapeutic doses, DHT directly reduces testicular aromatase activity that combined with its antigonadotropic effect leads to the gain in the symptomatic treatment of gynaecomastia.

Gonadotropin-releasing hormone II: a multi-purpose neuropeptide

Close to 30 forms of gonadotropin releasing hormone (GnRH) and at least five GnRH receptors have been identified in a wide variety of vertebrates and some invertebrates. One form, now called GnRH II, has the broadest distribution and the most ancient and conserved phylogeny. The distribution of the neurons that produce this peptide are completely nonoverlapping with any other GnRH forms. Fibers that project from these neurons overlap with GnRH I cells and/or fibers in a few regions, but are primarily divergent. The musk shrew (Suncus murinus) continues to be the most tractable mammalian species to use for studies of the function of GnRH II. The brain of the musk shrew has two GnRH genes (I and II), two GnRH receptors (types-1 and -2), and two different behaviors can be influenced by central infusion of GnRH II, but not by GnRH I; receptivity and feeding. Here, we summarize research on the musk shrew relative to the behavioral functions of GnRH II. First, female musk shrews are continually sexually receptive by virtue of their lack of an ovarian and/or behavioral estrus cycle. This feature of their reproductive ecology may be related to their semi-tropical distribution and their breeding season is highly dependent on changes in the availability of food. When food is not abundant, females stop mating, but brief bouts of feeding reinstate reproductive behavior. Likewise, intake of food is related to GnRH II mRNA and peptide content in the brain; after mild food restriction both decline. When GnRH II is infused centrally, at times when its content is low, it can both enhance receptivity and inhibit food intake. Simultaneous administration of a type-1 antagonist does not change the effect of GnRH II and use of an analog (135-18) that is a specific GnRH II agonist as well as a type-1 antagonist has the same effect as the endogenous GnRH II peptide. We propose that GnRH II plays a critical role by orchestrating the coordination of reproduction with the availability of nutritional support for these activities. Humans are bombarded with copious nutritional opportunities and at present obesity is a larger threat to health in many parts of the world than is under nutrition. It is our hope that understanding neuropeptides such as GnRH II that regulate food intake can ultimately lead to products that may curb appetite and thus decrease obesity and related risks to health.

Increased hypothalamic GPR54 signaling: A potential mechanism for initiation of puberty in primates

To further study the role of GPR54 signaling in the onset of primate puberty, we used the monkey to examine the ability of kisspeptin-10 to elicit the release of gonadotropin-releasing hormone (GnRH) precociously, and we describe the expression of GPR54 and KiSS-1 in the hypothalamus during the peripubertal period. Agonadal juvenile male monkeys were implanted with a lateral cerebroventricular cannula and a jugular vein catheter. The responsiveness of the juvenile pituitary to endogenous GnRH release was heightened with a chronic pulsatile i.v. infusion of synthetic GnRH before kisspeptin-10 (112-121) injection. Intracerebroventricular (30 microg or 100 microg) or i.v. (100 microg) bolus injections of kisspeptin-10 elicited a robust GnRH discharge, as reflected by luteinizing hormone secretion, which was abolished by pretreatment with a GnRH-receptor antagonist. RNA was isolated from the hypothalamus of agonadal males before (juvenile) and after (pubertal) the pubertal resurgence of pulsatile GnRH release and from juvenile, early pubertal, and midpubertal ovary-intact females. KiSS-1 mRNA levels detected by real-time PCR increased with puberty in both male and female monkeys. In intact females, but not in agonadal males, GPR54 mRNA levels in the hypothalamus increased approximately 3-fold from the juvenile to midpubertal stage. Hybridization histochemistry indicated robust KiSS-1 and GPR54 mRNA expression in the region of the arcuate nucleus. These findings are consistent with the hypothesis that GPR54 signaling by its cognate ligand in the primate hypothalamus may be activated at the end of the juvenile phase of development and may contribute to the pubertal resurgence of pulsatile GnRH release, the central drive for puberty.

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

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 patients with hypogonadotrophic hypogonadism. Assuming that the results would be similar in women with polycystic ovary syndrome (PCOS), pulsatile GnRH has been used to induce ovulation in these women. Although ovulation and pregnancy have been achieved, the effectiveness of pulsatile GnRH in women with PCOS has not been clearly demonstrated. To assess the effectiveness of pulsatile GnRH administration in women with polycystic ovary syndrome (PCOS), in terms of ongoing pregnancy, ovulation, clinical pregnancy, ovarian hyperstimulation syndrome (OHSS), multiple pregnancy, miscarriage, and multifollicular growth. We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched 13 August 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 2, August 2001), MEDLINE (January 1966 to August 2003), EMBASE (January 1985 to August 2003) and reference lists of articles. We also contacted manufacturers and researchers in the field. All relevant published randomised clinical trials were selected for inclusion if treatment consisted of pulsatile GnRH administration versus another treatment for ovulation induction in subfertile women with PCOS. Relevant data were extracted independently by two reviewers (NB, MW). Validity was assessed in terms of method of randomisation, completeness of follow-up, presence or absence of crossover and co-intervention. All trials were screened and analysed for predetermined quality criteria. 2X2 tables were generated for all the relevant outcomes. Odds ratios were generated using the Peto method. Four randomised clinical trials involving 57 women were identified comparing four different treatments: GnRH versus HMG, GnRH and FSH versus FSH, GnRH following pretreatment with GnRH agonist (GnRHa) versus GnRH only, GnRH following pretreatment with GnRHa versus clomiphene citrate. This means that there was only one trial in any one comparison. In two studies, data of pre- and post-crossover were not described separately. All trials were small and of too short duration to show any significant differences in pregnancy results. The odds ratio for ongoing pregnancy, only described in one trial, was 7.5 (95% CI 0.44 to 127) in the comparison GnRH following pretreatment with GnRHa versus GnRH only in favour of the first group. Multiple pregnancies were not seen. Ovarian hyperstimulation syndrome was seen only in women allocated to ovulation induction with HMG. The four trials describing four different comparisons with a short follow up (1 to 3 cycles) were too small to either prove or discard the value of pulsatile GnRH treatment in patients with polycystic ovary syndrome.

Basal testicular testosterone production in endurance-trained men is suppressed.

Research indicates that endurance-trained men have lower basal testosterone concentrations than age-matched sedentary control men. The physiological cause for this finding is uncertain. Therefore, we examined the peripheral component in the hypothalamic-pituitary-testicular (H-P-T) axis in endurance-trained men to determine if their basal testicular production of testosterone was compromised. The study design was retrospective, with a case-control approach. Age-matched, trained (n=5, TRN) and sedentary control men (n=6, SED) were infused with gonadotrophin-releasing hormone (GnRH) to induce testicular testosterone production via subsequent luteinizing hormone elevations. Testosterone production rate was statistically analyzed with adjustments for confounding factors and compared between groups. The basal testosterone concentrations differed significantly between the TRN and SED groups [pooled mean values; 13.9 (3.0) nmol x l(-1) vs 23.4 (3.2) nmol x l(-1), P<0.05]. The testosterone production rate was significantly lower (approximately 20-30%; P<0.05) in the TRN men as compared with the SED men following GnRH infusion. It was concluded that the exogenous stimulated testicular production rate of endurance-trained men is suppressed. This finding may account, in part, for the lower circulating basal testosterone concentrations found in these men. The present evidence supports the hypothesis that endurance exercise training induces a degree of peripheral adaptation (i.e., testicle) in the H-P-T axis. Whether this adaptation in the axis is a permanent or transient phenomenon in these men remains to be determined.

Pituitary responsiveness to gonadotropin- and thyrotropin-releasing hormones in goats treated with recombinant bovine somatotropin

Non-lactating, crossbred Alpine goats, of similar age and body weight were used to evaluate the effects of bovine somatotropin (bST) administration on pituitary function. Following ovarian synchronization, treated goats ( n=4) received a subcutaneous injection of 160 mg rbST, three times, at 14-day intervals, while control goats ( n=4) remained uninjected. The day after the last rbST injection ovarian synchronization was repeated and the following day all animals were challenged with 50 μg gonadotropin-releasing hormone (GnRH) and 100 μg thyrotropin-releasing hormone (TRH), intravenously. Blood samples were collected at −10, 0, 30, 60, 90, 120, 180, 270 and 360 min after challenge. Additionally, blood sampling was conducted three times per week throughout the experimental period for the detection of peripheral somatotropin, progesterone, T 3 and T 4 concentrations. Treatment with rbST significantly increased somatotropin concentrations in treated animals (21.2±1.3 ng/ml) as compared to controls (5.2±0.4 ng/ml). GnRH and TRH infusions resulted in similar LH, TSH, T 3 and T 4 responses in both groups, in terms of the area under the curve (AUC), the peak value (PV) and the time to peak (PT). Plasma progesterone concentrations during the treatment period did not differ between groups. Treatment with rbST did not affect T 4 levels during the experimental period, but a highly significant effect of treatment was observed for T 3 levels, particularly after the second rbST administration (1.47±0.06 ng/ml versus 2.01±0.1 ng/ml) for the control and treated group. In conclusion, it has been shown that rbST treatment did not affect pituitary responsiveness to GnRH or TRH challenge, demonstrating that the pituitary control of ovarian and thyroid function is not influenced by bST administration.

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

In normal menstrual cycles, gonadotrophin releasing hormone (GnRH) secretion is pulsatile, with intervals of 60-120 minutes in the follicular phase. Treatment with pulsatile GnRH infusion by the intra-venous or subcutaneous route using a portable pump has been used successfully in patients with hypogonadotrophic hypogonadism. Assuming that the results would be similar in polycystic ovary syndrome (PCOS), pulsatile GnRH has been used to induce ovulation in patients with PCOS. But, although ovulation and pregnancy has been achieved, the use of pulsatile GnRH in PCOS patients is controversial. To assess the effectiveness of pulsatile GnRH administration in women with clomiphene-resistant polycystic ovary syndrome (PCOS), in terms of ovulation induction, pregnancy, miscarriage, multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). The search strategy of the Menstrual Disorders and Subfertility review group was used to identify all relevant trials. Please see Review Group details. All relevant published RCTs were selected. Non-randomised controlled trials were eligible for inclusion if treatment consisted of GnRH administration versus another treatment to induce ovulation in subfertile women with PCOS. A computerised MEDLINE and EMBASE search was used to identify randomised and non randomised controlled trials. The reference lists of all studies found were checked for relevant articles. One RCT (Bringer 1985a) and one abstract (Coelingh 1983) were identified this way. Relevant data were extracted independently by two reviewers (NB, MW). Validity was assessed in terms of method of randomization, completeness of follow-up, presence or absence of cross-over and co-intervention. All trials were screened and analysed for predetermined quality criteria. 2X2 tables were generated for all the relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique. Three RCTs and one non-randomised comparative trial were identified comparing four different treatments: GnRH versus HMG, GnRH following GnRHa pre-treatment versus no pre-treatment, GnRH and FSH versus FSH, and GnRH following GnRHa pre-treatment versus GnRH following oral contraceptive pre-treatment. This means that there was only one trial in any one comparison. In the first two studies, data of pre- and post-cross-over were not described separately. Therefore, these results could not be included in the MetaView analysis. The odds ratio for ovulation rate was 16 (95 % CI: 1.1-239) in the study comparing GnRH and FSH with FSH. When GnRH after GnRHa pre-treatment was compared with GnRH after oral contraceptive pre-treatment, an odds ratio of 7.5 (95 % CI: 1.2-46) was obtained. All trials were small and of too short duration to show any significance in pregnancy results. Per study only one to four pregnancies occurred. Multiple pregnancies were not seen. OHSS was seen only in the patients stimulated with HMG. The four trials describing four different comparisons with a short follow up (1 to 3 cycles) were too small to either prove or discard the value of pulsatile GnRH treatment in patients with polycystic ovary syndrome.