Hypothalamic Gonadotropin-releasing Hormone Research Articles

Distinct mechanisms of electroacupuncture and manual acupuncture in modulating hypothalamic GnRH–tanycyte unit function of polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is a complex neuroendocrine disorder characterized by dysregulation of the hypothalamus. Both electroacupuncture (EA) and manual acupuncture (MA) have demonstrated therapeutic efficacy in the treatment of PCOS through improvements in hypothalamic function. However, the underlying mechanisms remain poorly understood. Gonadotropin-releasing hormone (GnRH) neurons are pivotal in regulating hypothalamic endocrine function, whereas tanycyte, a specialized glial cell type, potentially contribute to this process.MethodsA dihydrotestosterone (DHT)-induced PCOS-like mouse model was used to investigate the effects of acupuncture. Tissue clearing and three-dimensional (3D) imaging were employed to visualize the hypothalamic GnRH neuronal network and assess postacupuncture modifications. Transcriptome sequencing was performed to identify changes in the gene profiles associated with EA and MA. Rax-CreERT2 transgenic mice were utilized to investigate the molecular targets of EA in tanycytes.ResultsEA significantly alleviated neuroendocrine dysfunction in PCOS-like mice by restoring the density and coverage of GnRH axonal projections. MA displayed similar therapeutic effects but had less pronounced effects on GnRH axons. Transcriptome analysis revealed distinct mechanisms for these two approaches: EA primarily regulates neuroglial plasticity, whereas MA predominantly targets neurotransmitter regulation. Both EA and MA share a common therapeutic target in the integrin family. Functional studies in Rax-CreERT2 transgenic mice confirmed that Itgb1 plays a critical role in maintaining the balance of hypothalamic GnRH–tanycyte unit during EA treatment.ConclusionsEA exerts therapeutic effects on PCOS by targeting hypothalamic GnRH–tanycyte unit, with Itgb1 identified as a key factor. MA primarily functions through neurotransmitter regulation. These findings highlight potential hypothalamic targets and provide new insights into the distinct mechanisms of EA and MA.

Obesity and Polycystic Ovary Syndrome.

The core pathophysiology of polycystic ovary syndrome involves an overproduction of androgens primarily originating from ovarian thecal cells. Two major external triggers promote androgen overproduction in the ovaries: the increased secretion of luteinizing hormone, a consequence of aberrant hypothalamic gonadotropin-releasing hormone secretion dynamics, and compensatory hyperinsulinemia resulting from insulin resistance. Obesity interacts with polycystic ovary syndrome in multiple ways, but a major role of obesity in its pathophysiology is the exacerbation of insulin resistance. Additionally, obesity contributes to polycystic ovary syndrome by facilitating the conversion of precursor hormones to testosterone within adipose cells. Moreover, obesity can lead to relative hyperandrogenemia, which is marked by lower levels of sex hormone binding globulin and increased availability of free testosterone to target tissues. Also, obesity affects the secretion of gonadotropins, resulting in heightened luteinizing hormone secretion or increased sensitivity of thecal cells to luteinizing hormone. Obesity-related insulin resistance might be amplified by alterations in adipokine and inflammatory cytokine production. Ultimately, obesity and polycystic ovary syndrome might share a common genetic predisposition. The cornerstone of managing polycystic ovary syndrome is to address individual symptoms such as hyperandrogenism (hirsutism, acne, and female type boldness), menstrual irregularities, and infertility stemming from anovulation. However, obesity is integral to the pathophysiology of polycystic ovary syndrome and exacerbates all of its features. Therefore, lifestyle modifications aimed at weight reduction should be the primary strategy in overweight or obese women with polycystic ovary syndrome.

The Regulatory Effect of Insulin-Like Growth Factor-2 on Hypothalamic Gonadotropin-Releasing Hormone Neurons during the Pubertal Period.

The insulin-like growth factor (IGF) system plays a vital role in regulating gonadotropin-releasing hormone (GnRH), whether the IGF2 can act on the GnRH neurons during the pubertal period is unclear. Central precocious puberty (CPP) rats were induced by danazol, and when the rats met the first diestrus, they were euthanized and tissues were collected. GT1-7 cells were cultured and treated with 0, 1, 10 ng/mL IGF2 for 4 hours and the changes in GnRH were measured. Mice were injected intracerebroventricularly with IGF2 (15 ng/g, 5 μL) or with the same dose of phosphate buffered saline (PBS), after eight hours, they were euthanized and tissues collected. CPP rats had increased expression of IGF2 and GnRH mRNA and their respective proteins in the preoptic area (POA) of the hypothalamus. Treatment of GT1-7 cells with 10 ng/mL of IGF2 increased GnRH mRNA and protein expression, and GnRH concentration in the culture medium. Injection of IGF2 protein into the lateral ventricle of mice increased the expression of GnRH mRNA and protein in the POA. IGF2 may upregulate the synthesis of GnRH during the pubertal period, and may also take part in the pathology of CPP.

Estradiol affects the expression of essential molecular factors involved in luteinizing hormone secretion in the plains vizcacha

The plains vizcacha is a rodent that shows reactivation of the hypothalamic–pituitary–ovary (HPO) axis activity at mid-gestation. This process is enabled by the secretion of hypothalamic gonadotropin-releasing hormone (GnRH) at mid-gestation, followed by follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. However, a decrease in the pituitary GnRH receptor (GnRHR) expression is concomitantly determined. Moreover, an increment in the pituitary expression of estrogen receptor alpha (ERα) has been determined. This work aimed to study the impact of estradiol (E2) on GnRHR expression, the transcription factors early growth response protein-1 (Egr-1) and steroidogenic factor-1 (Sf-1), as well as on LH secretion. Three experimental approaches were performed: a physiological one with pregnant plains vizcachas, an in vivo approach with ovariectomized (OVX) animals treated with E2 (OVX + E2), and an ex vivo approach using pituitary glands exposed to a combination of GnRH and E2. Significant increased pituitary expression of Sf-1 and Egr-1 was determined at mid-gestation. Ovariectomy significantly increased adenohypophyseal expression levels of GnRHR, Egr-1, and Sf-1, as well as LH secretion. Then, OVX + E2 showed similar levels to SHAM. Adenohypophyses exposed to GnRH showed induced GnRHR, Egr-1, and Sf-1 expression, and LH secretion, while GnRH + E2 reverted these changes. The mid-gestation pituitary GnRHR decrease may result from the combination of increased E2 and GnRH secretion. Nevertheless, the increased expression of Egr-1 and Sf-1 at mid-gestation, together with LH release, suggests the tightly and complex regulatory system that takes place at mid-gestation, enabling a new progesterone surge that successfully carries the pregnancy to term. New & NoteworthyA significant increment of Sf-1 and Egr-1 at the pituitary of mid-gestating plains vizcachas was determined. Moreover, E2 reverted GnRHR, Egr-1, Sf-1, and LH increase in ovariectomized vizcachas’ pituitaries and ex vivo pituitaries exposed to GnRH. The decrease of the pituitary GnRHR at mid-gestation may result from the increased E2 and GnRH levels. A tightly and complex regulatory system may take place at mid-gestation enabling a new surge of progesterone that carries pregnancy to term.

12218 Gnrh Pulse Frequency And Irregularity Play A Role In Depression

Abstract Disclosure: J. Choi: None. M. Kim: None. Gonadotropin-releasing hormone (GnRH) has a role in hypothalamic control of depression, but the underlying patterns and relationship with downstream reproductive hormones are still unclear. Here we report that hypothalamic GnRH pulse frequency and irregularity increase before GnRH pulse amplitude slowly decreases during social defeated stress models (SDS). While mice castrated and testosterone inhibited induced depression by conducting SDS, these mice led to anti-depression effects and affected by GnRH signaling, indicating that high-frequency GnRH pulses. Regramming the endogenous GnRH pulses of depressed male mice via an optogenetic approach revealed that increasing GnRH pulses frequency causes depression acceleration, while lowering the frequency of and stabilizing GnRH pulses can slow down depression. In conclusion, GnRH pulses are important for depression in male mice. Presentation: 6/1/2024

Sex-Dependent Changes in Gonadotropin-Releasing Hormone Neuron Voltage-Gated Potassium Currents in a Mouse Model of Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, and people with TLE exhibit higher rates of reproductive endocrine dysfunction. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons regulate reproductive function in mammals by regulating gonadotropin secretion from the anterior pituitary. Previous research demonstrated GnRH neuron hyperexcitability in both sexes in the intrahippocampal kainic acid (IHKA) mouse model of TLE. Fast-inactivating A-type (I A) and delayed rectifier K-type (I K) K+ currents play critical roles in modulating neuronal excitability, including in GnRH neurons. Here, we tested the hypothesis that GnRH neuron hyperexcitability is associated with reduced I A and I K conductances. At 2 months after IHKA or control saline injection, when IHKA mice exhibit chronic epilepsy, we recorded GnRH neuron excitability, I A, and I K using whole-cell patch-clamp electrophysiology. GnRH neurons from both IHKA male and diestrus female GnRH-GFP mice exhibited hyperexcitability compared with controls. In IHKA males, although maximum I A current density was increased, I K recovery from inactivation was significantly slower, consistent with a hyperexcitability phenotype. In IHKA females, however, both I A and I K were unchanged. Sex differences were not observed in I A or I K properties in controls, but IHKA mice exhibited sex effects in I A properties. These results indicate that although the emergent phenotype of increased GnRH neuron excitability is similar in IHKA males and diestrus females, the underlying mechanisms are distinct. This study thus highlights sex-specific changes in voltage-gated K+ currents in GnRH neurons in a mouse model of TLE and suggesting potential sex differences in GnRH neuron ion channel properties.

A GnRH neuronal population in the olfactory bulb translates socially relevant odors into reproductive behavior in male mice.

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons regulate fertility and integrate hormonal status with environmental cues to ensure reproductive success. Here we show that GnRH neurons in the olfactory bulb (GnRHOB) of adult mice can mediate social recognition. Specifically, we show that GnRHOB neurons extend neurites into the vomeronasal organ and olfactory epithelium and project to the median eminence. GnRHOB neurons in males express vomeronasal and olfactory receptors, are activated by female odors and mediate gonadotropin release in response to female urine. Male preference for female odors required the presence and activation of GnRHOB neurons, was impaired after genetic inhibition or ablation of these cells and relied on GnRH signaling in the posterodorsal medial amygdala. GnRH receptor expression in amygdala kisspeptin neurons appear to be required for GnRHOB neurons' actions on male mounting behavior. Taken together, these results establish GnRHOB neurons as regulating fertility, sex recognition and mating in male mice.

ZEB1 Inhibits LHβ Subunit Transcription When Overexpressed, but Is Dispensable for LH Synthesis in Mice.

Luteinizing hormone (LH), a heterodimeric glycoprotein produced by pituitary gonadotrope cells, regulates gonadal function. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates LH synthesis and secretion. GnRH induces LHβ subunit (Lhb) expression via the transcription factor, early growth response 1 (EGR1), acting on the Lhb promoter. In contrast, overexpression of zinc finger E-box binding homeobox 1 (ZEB1) represses LH production in mice, but the underlying mechanism was not previously elucidated. Here, we observed that ZEB1 inhibited GnRH-stimulated but not basal Lhb mRNA expression in homologous murine LβT2 cells. Moreover, ZEB1 blocked GnRH and/or EGR1 induction of murine Lhb but not human LHB promoter-reporter activity in these cells. Using chimeric reporters, we mapped the species-specific ZEB1 sensitivity to sequence differences, including in Z- and E-boxes, in the proximal Lhb/LHB promoters, immediately upstream of the transcription start sites. ZEB1 bound to the murine Lhb promoter with higher affinity than to the human LHB promoter in this region. To examine ZEB1's physiological role in LH synthesis, we characterized gonadotrope-specific Zeb1 knockout mice. Loss of ZEB1 in gonadotropes did not affect LH production or secretion. Collectively, the data suggest that ZEB1, when overexpressed, can inhibit GnRH/EGR1 induction of murine Lhb transcription but does not play a necessary role in LH synthesis in mice.

Neuronal network dynamics in the posterodorsal amygdala: shaping reproductive hormone pulsatility.

Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region that is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown. Here, we employ in silico modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. We introduce and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD projections' outputs on the GnRH pulse generator's activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with in vivo optogenetics. Our study sheds light on how MePD neuronal dynamics affect the GnRH pulse generator activity and offers insights into stress-related dysregulation.

Effect of central administration of indomethacin on anandamide-induced GnRH/LH secretion in the hypothalamus of anoestrous ewes.

It is suggested that cannabinoids (CBs) may disturb reproduction through action on hypothalamic gonadotropin-releasing hormone (GnRH) neurons directly or indirectly through intermediates such as prostaglandins. The study aimed to determine the influence of intracerebroventricular (i.c.v.) injection of the endogenous cannabinoid anandamide (N-arachidonoylethanolamine - AEA), alone or with the prostaglandin synthesis inhibitor indomethacin (IND), on GnRH/luteinising hormone (LH) secretion. The purpose of the research was to clarify the role of endocannabinoids and their interaction with prostaglandins in the regulation of reproduction at the level of the hypothalamus and pituitary in anoestrous sheep. The study was performed on 24 anoestrous ewes divided into four experimental groups: a control group receiving i.c.v. injection of Ringer-Locke solution, an AEA group that received i.c.v. injection of 30 μM of AEA, an IND group receiving i.c.v. injection of 5 μM of IND and an AEA + IND group that received i.c.v. injections of 30 μM of AEA and 5 μM of IND. Anandamide stimulated GnRH protein and gene expression in the median eminence and protein expression in the preoptic area without influencing GnRH messenger RNA (mRNA) in this structure. Indomethacin reversed the changes in GnRH secretion after AEA administration. It was also found that AEA stimulated LH mRNA in the pituitary without influencing LH release. Our results support the role of endogenous cannabinoids in the regulation of reproductive processes at the central nervous system level. They may act directly on the hypothalamic GnRH neurons or indirectly through intermediates such as prostaglandins.

Longitudinal Evaluation of Reproductive Endocrine Function in Men With ACTH-Dependent Cushing Syndrome.

Hypogonadism may be caused by Cushing syndrome (CS) and may intensify its adverse consequences. This work aimed to determine the frequency of male hypogonadism before and after curative surgery for CS, and its cause. Post hoc analyses of prospective cohort studies were conducted at a clinical research center. Study participants were men with adrenocorticotropic hormone (ACTH)-dependent CS: cohort 1 (C1) (n = 8, age 32.5 ± 12 years; studied 1985-1989) and cohort 2 (C2) (n = 44, 42.7 ± 15.1 years; studied 1989-2021). Interventions included the following: C1: every 20-minute blood sampling for 24 hours before and 1 to 40 months after surgical cure. Three individuals underwent gonadotropin-releasing hormone (GnRH) stimulation tests pre and post surgery. C2: Hormone measurements at baseline and 6 and 12 months (M) post cure. Main outcome measures included the following: C1: LH, FSH, LH pulse frequency, and LH response to GnRH. C2: LH, FSH, testosterone (T), free T, free thyroxine, 3,5,3'-triiodothyronine, thyrotropin, and urine free cortisol (UFC) levels and frequency of hypogonadism pre and post surgery. C1: mean LH and LH pulse frequency increased after surgery (P < .05) without changes in LH pulse amplitude, mean FSH, or peak gonadotropin response to GnRH. C2: 82% had baseline hypogonadism (total T 205 ± 28 ng/dL). Thyroid hormone levels varied inversely with UFC and cortisol. LH, total and free T, and sex hormone-binding globulin increased at 6 and 12 M post surgery, but hypogonadism persisted in 51% at 6 M and in 26% at 12 M. Hypogonadism in men with CS is widely prevalent but reversible in approximately 75% of patients 1 year after surgical cure and appears to be mediated through suppression of hypothalamic GnRH secretion, and modulated by thyroid hormones.

O-192 Kisspeptin as a test of hypothalamic function in women presenting with oligo-amenorrhea

Abstract Study question Can kisspeptin be used as a novel tool to interrogate hypothalamic function in women presenting with oligo-amenorrhea? Summary answer The hormonal response to kisspeptin offers a novel approach for the assessment of hypothalamic function in patients presenting with oligo-amenorrhea of different aetiologies. What is known already Polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhea (FHA) are the two commonest causes of anovulation causing oligo-amenorrhea in pre-menopausal women. Additionally, congenital (CHH) and functional hypogonadotropic hypogonadism can present with similar endocrine profiles. Importantly, these conditions are caused and characterised by abnormal hypothalamic function. For instance, gonadotropin-releasing hormone (GnRH) pulsatility is increased in PCOS but reduced in FHA. Despite differences in pathophysiology, differentiating these diagnoses can be challenging in clinical practice. Kisspeptin is known to stimulate hypothalamic GnRH neurons. Thus, kisspeptin could represent a novel tool to interrogate hypothalamic function in women presenting with reproductive disorders causing oligo-amenorrhea. Study design, size, duration Single-centre, prospective, experimental study of healthy women (n = 33), women with PCOS (n = 30), FHA (n = 30), or CHH (n = 8), aged 18-35 years and not taking hormonal treatment. Participants were recruited for clinical studies between September 2019 and September 2023 and underwent two separate study visits. The visits assessed the gonadotropin response to hypothalamic stimulation with an intravenous bolus of kisspeptin-54 (9.6nmol/kg) and the pituitary response to an intravenous bolus of GnRH (100 mcg). Participants/materials, setting, methods All participants took part in two study visits. Serum luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels were measured every 15 minutes for 8 hours after administration of kisspeptin-54 and GnRH. The maximal rise in LH and FSH from baseline was compared between groups using an unpaired t-test. Receiver operator characteristic (ROC) analysis was used to assess the discriminatory potential of the hormone response to kisspeptin and GnRH. Main results and the role of chance The gonadotropin response to kisspeptin was increased in women with FHA compared to all other groups. The mean (SD) of the maximal rise in LH (IU/L) after kisspeptin was 9.7 (11.4) in healthy women, 9.7 (8.3) in women with PCOS, 17.6 (10.8) in women with FHA, and 1.0 (1.1) in women with CHH. The mean (SD) of the maximal rise in FSH (IU/L) after kisspeptin was 4.2 (3.4) in healthy women, 2.8 (2.1) in women with PCOS, 9.2 (5.6) in women with FHA, and 0.7 (0.5) in women with CHH. In lean women (BMI &amp;lt;25 kg/m2), the maximal rise in FSH after kisspeptin differentiated women with PCOS from those with FHA (area under ROC curve 0.91, p = 0.0001). Furthermore, the maximal rise in FSH after kisspeptin differentiated women with FHA from women with CHH (auROC 1.00, p &amp;lt; 0.0001), whereas the equivalent auROC for FSH rise after GnRH was 0.7 (p = 0.086). Limitations, reasons for caution Participants included in this study had clearcut diagnoses of PCOS, FHA, or CHH prior to inclusion, however this could increase the risk of spectrum bias. Whilst this study provides mechanistic insight into hypothalamic dysfunction in these conditions, further prospective validation of discriminatory thresholds in different settings is required. Wider implications of the findings The specific action of kisspeptin at hypothalamic GnRH neurons enables its use to assess hypothalamic function in patients with oligo-amenorrhea due to different anovulatory disorders. Our data suggests that the hormonal response to kisspeptin has promising diagnostic potential to aid in the evaluation of women with oligo-amenorrhea. Trial registration number ISRCTN21681316

Gonadotropin-Releasing Hormone (GnRH) and Its Agonists in Bovine Reproduction I: Structure, Biosynthesis, Physiological Effects, and Its Role in Estrous Synchronization.

GnRH is essential for the regulation of mammalian reproductive processes. It regulates the production and release of pituitary gonadotropins, thereby influencing steroidogenesis and gametogenesis. While primarily produced in the hypothalamus, GnRH is also produced in peripheral organs, such as the gonads and placenta. GnRH analogs, including agonists and antagonists, have been synthesized for the reproductive management of animals and humans. This review focuses on the functions of hypothalamic GnRH in the reproductive processes of cattle. In addition to inducing the surge release of LH, the pulsatile secretion of GnRH stimulates the pituitary gland to release FSH and LH, thereby regulating gonadal function. Various GnRH-based products have been synthesized to increase their potency and efficacy in regulating reproductive functions. This review article describes the chemical structures of GnRH and its agonists. This discussion extends to the gene expression of GnRH in the hypothalamus, highlighting its pivotal role in regulating the reproductive process. Furthermore, GnRH is involved in regulating ovarian follicular development and luteal phase support, and estrus synchronization is involved. A comprehensive understanding of the role of GnRH and its analogs in the modulation of reproductive processes is essential for optimizing animal reproduction.

Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement.

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

Central MOTS-c infusion affects reproductive hormones in obese and non-obese rats

MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and MOTS-c level is inversely correlated with markers of obesity. Obesity is a risk factor for male reproductive physiology and is expressed as an important cause of infertility. In this study, we aimed to determine the effects of MOTS-c, which has been proven in the hypothalamus and testicles, on the actors involved in the reproductive axis.In the study, 80 male Wistar-Albino rats were divided into two main groups, obese and non-obese (n = 40). Rats in the first main group were fed with fatty diet feed and obesity was induced. The second main group was fed with normal diet feed. Each main group was divided into 4 subgroups (Control, Sham, 10 and 100 µM MOTS-c). The lateral ventricles of the animals in the treatment groups were infused with 10 and 100 µM MOTS-c (solvent in Sham group) for 14 days. At the end of the experiment, hypothalamic Gonadotropin-Releasing Hormone (GnRH) gene expression level, serum testosterone, Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels were determined.MOTS-c infusion caused an increase in GnRH mRNA, protein expression levels and serum testosterone, LH and FSH levels in obese and non-obese rats (p < 0.05). MOTS-c administration more significantly upregulated hormone levels in non-obese rats (p < 0.05). MOTS-c administration increases these hormones, suggesting that MOTS-c may stimulate the reproductive axis.Our results reveal that MOTS-c plays a role in the central regulation of reproduction, as well as causes increased LH, FSH and testosterone release.

Modulating the RFamide-related peptide-3/G protein-coupled receptor 147 signaling pathway with nourishing Yin-removing fire herbal mixture to alleviate precocious puberty in female rats: An experimental study.

Precocious puberty (PP) involves early activation of the hypothalamic gonadotropin-releasing hormone (GnRH) generator. The RFamide-related peptide/G protein-coupled receptor 147 (RFRP3/GPR147) signaling pathway is vital in inhibiting GnRH and delaying puberty onset. The nourishing Yin-removing fire (NYRF) herbal mixture has shown promising results in treating PP. This study aimed to assess the impact of the NYRF herbal mixture on the RFRP3/GPR147 signaling pathway in the hypothalamus and its potential in alleviating PP in female rats. In a controlled experiment, 24 female Sprague-Dawley rats (11.20 0.69 gr, postnatal day [PD5]) were divided into normal, model, normal saline, and NYRF groups (n = 6/each). PP was induced in the model, normal saline, and NYRF groups by subcutaneous injection of danazol at PD5. The NYRF herbal mixture or normal saline was administered from PD15. Serum sex hormone levels and hypothalamic samples were collected for mRNA and protein expression at PD30. In the model group, hypothalamic GnRH and kisspeptin levels increased, while RFRP3 and GPR147 levels decreased, luteinizing hormone levels elevated, reproductive organ coefficients increased, and the vagina opened earlier compared to the normal group. Conversely, the NYRF group exhibited lower GnRH and kisspeptin levels but higher RFRP3 levels in the hypothalamus. Serum luteinizing hormone levels were reduced, reproductive organ coefficients were reduced, and the vaginal opening was delayed compared to the model and normal saline groups. The NYRF herbal mixture delayed sexual development in rats with PP by hypothalamic upregulating RFRP3 and downregulating GnRH and kisspeptin.

Postnatal feeding with high-fat combined with high-glucose diet induces precocious puberty in Sprague‒Dawley rat pups

With economic development and overnutrition, including high-fat diets (HFD) and high-glucose diets (HGD), the incidence of obesity in children is increasing, and thus, the incidence of precocious puberty is increasing. Therefore, it is of great importance to construct a suitable animal model of overnutrition-induced precocious puberty for further in-depth study. Here, we fed a HFD, HGD, or HFD combined with a HGD to pups after P-21 weaning, while weaned pups fed a normal diet served as the control group. The results showed that HFD combined with a HGD increased the body weight (BW) of weaned rat pups. In addition, a HFD, HGD, and HFD combined with a HGD lowered the age at which vaginal opening occurred and accelerated the vaginal cell cycle. Furthermore, a HFD combined with a HGD increased the weight of the uterus and ovaries of weaned rat pups. Additionally, a HFD combined with a HGD promoted the development of reproductive organs in weaned female rat pups. Ultimately, a HFD combined with a HGD was found to elevate the serum levels of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH), leptin, adiponectin, and oestradiol (E2) and increase hypothalamic GnRH, Kiss-1, and GPR54 expression levels in weaned female rat pups. The current study found that overnutrition, such as that through a HFD combined with HGD, could induce precocious puberty in weaned female rat pups. In addition, a rat model of overnutrition-induced precocious puberty was established.

Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from 2 randomized, placebo-controlled clinical tricals

Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 (KP54) can induce oocyte maturation during in vitro fertilization treatment, including in women at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported. ObjectiveTo determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (Phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (Phase-2a trial). DesignTwo randomized, placebo-controlled, parallel group, dose-finding trials. SettingClinical trials unit, Netherlands. ParticipantsHealthy women aged 18-35 years, either without (Phase-1; n=24), or with ovarian stimulation (Phase-2a; n=75). InterventionsPhase-1: Single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 μg) or placebo, (n=6 per dose).Phase-2a: Single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 μg; n=16-17 per dose), triptorelin 0.2 mg (n=5; active comparator), or placebo (n=5). Main Objectives and Outcome MeasuresPhase-1: Safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones).Phase-2a: Safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); time to ovulation assessed by transvaginal ultrasound. ResultsIn both trials, MVT-602 was safe and well-tolerated across the entire dose-range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours.In the Phase-2a trial, LH concentrations increased dose-dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3μg MVT-602 and remained above 15 IU/L for 33 hours. Time to ovulation following drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 μg), 88% (1μg), 82% (0.3μg), and 75% (0.1μg), of women after MVT-602, 100% after triptorelin, and 60% after placebo. ConclusionsMVT-602 induces LH concentrations of similar amplitude and duration as the physiological mid-cycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR. Trial RegistrationsEUDRA-CT: 2017-003812-38, 2018-001379-20

Postnatal Development and Maintenance of Functional Pituitary Gonadotrophs Is Dependent on PI4-Kinase A.

Postnatal development of functional pituitary gonadotrophs is necessary for maturation of the hypothalamic-pituitary-gonadal axis, puberty, and reproduction. Here we examined the role of PI4-kinase A, which catalyzes the biosynthesis of PI4P in mouse reproduction by knocking out this enzyme in cells expressing the gonadotropin-releasing hormone (GnRH) receptor. Knockout (KO) mice were infertile, reflecting underdeveloped gonads and reproductive tracts and lack of puberty. The number and distribution of hypothalamic GnRH neurons and Gnrh1 expression in postnatal KOs were not affected, whereas Kiss1/kisspeptin expression was increased. KO of PI4-kinase A also did not alter embryonic establishment and neonatal development and function of the gonadotroph population. However, during the postnatal period, there was a progressive loss of expression of gonadotroph-specific genes, including Fshb, Lhb, and Gnrhr, accompanied by low gonadotropin synthesis. The postnatal gonadotroph population also progressively declined, reaching approximately one-third of that observed in controls at 3 months of age. In these residual gonadotrophs, GnRH-dependent calcium signaling and calcium-dependent membrane potential changes were lost, but intracellular administration of inositol-14,5-trisphosphate rescued this signaling. These results indicate a key role for PI4-kinase A in the postnatal development and maintenance of a functional gonadotroph population.

Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments. We used adult Gnrh1cre female mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in hypophysiotropic GnRH neurons. Chronic chemogenetic activation protocol was carried out with clozapine N-oxide (CNO) i.p. injections every 48h over a month. We evaluated the reproductive and hormonal profile before, during, and two months after chemogenetic manipulations. We discovered that the overactivation of GnRH neurons was sufficient to disrupt reproductive cycles, promote hyperandrogenism, and induce ovarian dysfunction. These PCOS features were detected with a long-lasting neuroendocrine dysfunction through abnormally high luteinizing hormone (LH) pulse secretion. Additionally, the GnRH-R blockade prevented the establishment of long-term neuroendocrine dysfunction and androgen excess in these animals. Taken together, our results show that hyperactivity of hypothalamic GnRH neurons is a major driver of reproductive and hormonal impairments in PCOS and suggest that antagonizing the aberrant GnRH signaling could be an efficient therapeutic venue for the treatment of PCOS. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).