Gonadorelin

Management of infertility in women with hypothalamic hypogonadotropic hypogonadism: an expert opinion.

Geoffroy Robin, Lorraine Maitrot-Mantelet, Sophie Dubourdieu +4 more

Hypothalamic gonadotropin-releasing hormone (GnRH) plays a central role in regulating the pituitary-gonadal axis. The pulsatility of GnRH release is critical for maintaining the function of GnRH receptors and the secretion pattern of gonadotropins, namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate endocrine function and follicular growth and maturation. During the luteal phase, LH is crucial for supporting a functional corpus luteum and stimulating it to produce progesterone, estradiol and relaxin.Hypothalamic hypogonadotropic hypogonadism originates from a deficiency in GnRH secretion. Low circulating gonadotropin levels subsequently lead to reduced ovarian function and anovulation. This condition may be congenital or acquired, for example through functional hypothalamic amenorrhoea (FHA) or FHA combined with polycystic ovarian morphology (PCOM). Pulsatile GnRH therapy plays a pivotal role in restoring the physiological menstrual cycle and selecting a dominant follicle in these women, thereby inducing ovulation and achieving fertility. There is extensive literature accounting for a high ovulation rate and consequently high pregnancy and birth rates per cycle, with a lower risk of adverse outcomes.

Injectable contraceptives differentially affect the hypothalamic-pituitary-gonadal axis and amenorrhea incidence†.

Alexis J Bick, Chanel Avenant, Carole-Keza Capitaine +11 more

Hormonal contraceptives modulate the hypothalamic-pituitary-ovarian (HPO) axis; however, underlying mechanisms and differences between contraceptives are underexplored. The Women's Health Injectable Contraception and HIV trial randomised 521 women to intramuscular depot medroxyprogesterone acetate (DMPA-IM) or norethisterone enanthate (NET-EN) and showed similar decreased estradiol levels, but more amenorrhea for DMPA-IM users. This secondary study excluded for misreporting contraceptive use for 128 participants (DMPA-IM n = 65; NET-EN n = 63). Peripheral blood serum collected at initiation and one week after the 24-week injection (25 W), at peak progestin levels, was analysed for gonadal steroids, progestins and peptide hormones. While no changes were detected in peripheral gonadotropin-releasing hormone levels, DMPA-IM decreased luteinising hormone (LH) less than NET-EN. DMPA-IM increased, while NET-EN decreased follicle-stimulating hormone (FSH). Both contraceptives substantially decreased gonadal steroid levels, more so in NET-EN users for testosterone and estradiol. Post-menopausal-like hypoestrogenic effects were greater than previously reported, consistent with the substantial reduction in LH levels. Whether reduced LH levels are due to direct pituitary, hypothalamic, or supra-hypothalamic effects by progestins, is unclear. MPA, unlike NET, increased fsh expression in LβT2 cells, likely via the glucocorticoid receptor, consistent with direct effects on the pituitary by MPA in women. Amenorrhea associated in a time-varying manner with MPA and HPO hormone levels and LH/FSH, for DMPA-IM but not NET-EN users. HPO hormone profiles differ between DMPA-IM and NET-EN users and compared to pre- and post-menopausal women. Mechanisms affecting amenorrhea likely differ between contraceptives, with lower 25 W LH/FSH being consistent with more amenorrhea for DMPA-IM.

Effects of Microplastics on the Central Reproductive Neuroendocrine System in a Sheep Model.

Patrycja Młotkowska, Bartosz Osuch, Elżbieta Marciniak +3 more

The present study investigated the impact of microplastics, specifically polystyrene microparticles (PS-MP), on the hypothalamic-pituitary-gonadal (HPG) neurohormonal axis, which regulates reproductive functions in animals and humans. The primary objective was to examine the effects of PS-MP on the expression of key genes and hormone concentrations within the gonadotropic system of sheep. Two doses of PS-MP-the lower dose (LD; 0.015 mg/kg) and the higher dose (HD; 0.15 mg/kg)-were administered intravenously every three days over two estrous cycles (34 days). Both doses significantly decreased the relative abundance of gonadotropin-releasing hormone (GnRH) transcripts in the mediobasal hypothalamus (MBH), whereas only the HD reduced GnRH mRNA levels in the preoptic area (POA). These transcript-level changes were not accompanied by detectable alterations in GnRH protein concentration. In the MBH, the expression of kisspeptin (KISS-1) and neurokinin B (NKB) genes decreased following exposure to the HD, whereas in the POA, significant decrease in expression were observed only after the LD administration. Changes in prodynorphin (PDYN) gene expression were confined to the MBH and were dose-dependent: the LD increased transcript levels, whereas the HD caused a decrease. The HD of PS-MP also significantly downregulated GnRH receptor (GnRHR) expression in the anterior pituitary (AP). Both PS-MP doses resulted in marked reductions in luteinizing hormone beta (LHβ) and follicle-stimulating hormone beta (FSHβ) subunit gene expression in the AP, without significant changes in hormone protein concentrations. Exposure to PS-MP reduced plasma LH and FSH concentrations: the lower dose reduced both hormones, while the higher dose significantly reduced mainly FSH, showing statistical differences between doses. To summarize, the present study demonstrates that PS-MP exerts a modulatory effect on the secretory activity of the central reproductive system in sheep, at both the hypothalamic and pituitary levels. Consequently, PS-MP has the potential to induce significant disruptions to the reproductive processes of large farm animals.

Neuroendocrine effects of exogenous adropin administration on the hypothalamic pituitary testicular axis in male rats.

Ersen Eraslan, Ayhan Tanyeli, Mustafa Can Güler +6 more

Obesity impairs male fertility through metabolic dysfunction, oxidative stress, and disruption of the hypothalamic-pituitary-testicular (HPT) axis. Adropin (ADR), a peptide hormone whose circulating levels are reduced in obesity, plays emerging roles in metabolic homeostasis; however, its involvement in reproductive endocrine regulation remains unclear. The present study was conducted in healthy, nonobese male rats and aimed to investigate the neuroendocrine and testicular effects of exogenous ADR administration, focusing on circulating reproductive hormones, hypothalamic regulatory peptides, and testicular antioxidant pathways.

Carbamazepine disrupts the hypothalamic-pituitary-testicular axis and induces hormonal imbalances and sperm damage through activating GABBR2 to inhibit AC/cAMP/PKA pathway.

Jingya Li, Ziao Liu, Min Pan +5 more

Carbamazepine (CBZ), a widely prescribed antiepileptic drug, is known to cause male reproductive toxicity, yet the underlying biological pathways remain poorly characterized. This study comprehensively investigated the impact of CBZ on the hypothalamic-pituitary-testicular (HPT) axis using integrated in vivo and in vitro models to decipher the precise molecular mechanisms involved. Rats subjected to long-term exposure (12 weeks) to CBZ at doses of 100, 200, and 400 mg/kg showed structural damage in the hypothalamus, pituitary, and testes. Concurrently, serum levels of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were reduced, indicating impairment of the HPT axis function. In-depth mechanistic studies demonstrated that CBZ suppressed the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway by upregulating the expression of gamma-aminobutyric acid type B receptor subunit 2 (GABBR2) protein, thereby triggering apoptosis of hypothalamic GnRH neurons. When GABBR2 was knocked down in GT1-7 cells (an immortalized mouse hypothalamic GnRH neuronal cell line), the AC/cAMP/PKA inhibition induced by CBZ was significantly attenuated, apoptosis was reduced, and GnRH secretion was partially restored. These findings indicate that activation of GABBR2, by repressing the AC/cAMP/PKA pathway, plays a pivotal role in CBZ-induced apoptosis of hypothalamic neurons, reduction of GnRH levels, and disruption of the HPT axis. This provides a new perspective for understanding CBZ-induced male reproductive toxicity.

Melatonin mitigates hormonal toxicity in cannabis-treated female Wistar rats: involvement of cannabinoid receptor.

A Oluwasola

Consumption of Cannabis sativa (CS), a well known psychoactive substance may impose threat on the hormonal activities of the body, hence, a protective measure is needed to prevent this threat. This study investigates the effects of melatonin and CS together with its receptors (cannabinoid receptors 1 and 2) on hormonal toxicity in female rats.

Magnetic resonance imaging-based adenohypophyseal volume for diagnosing hypothalamic-pituitary-gonadal axis activation in pre- and at-puberty children.

Sikang Gao, Yunyun Zhao, Weiyin Vivian Liu +9 more

Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Although the gonadotropin-releasing hormone (GnRH) stimulation test remains the diagnostic standard for evaluating HPG axis activation, its invasive nature limits clinical utility. Magnetic resonance imaging (MRI)-derived pituitary measurements offer a promising alternative, yet previous studies on two-dimensional measurements have reported limited accuracy. This study aimed to assess the value of adenohypophysis volume (aPV) and height (aPH) precisely measured with the three-dimensional (3D) CUBE T1 sequence (GE HealthCare) in diagnosing HPG axis activation.

Tissue-Slice Organ-on-Chip Culture of Hypothalamic and Pituitary of Lambs─The Role of Phoenixin-20 as a Modulator of Gonadotrophic Axis.

Michał Szlis, Bartosz Jarosław Przybył, Anna Wójcik-Gładysz

This study aimed to reconstruct the hypothalamic-pituitary axis using an organ-on-a-chip (OOC) model and to evaluate the modulatory role of phoenixin-20 (PNX) in the regulation of the gonadotrophic axis in sheep. Sixteen female Polish Merino lambs were used as tissue donors to create microfluidic chips containing paired hypothalamic and pituitary slices connected via perfused channels. This system enabled continuous medium flow and maintenance of functional neuroendocrine interactions under ex vivo conditions. The OOC platform was used to analyze changes in the expression of gonadotropin-releasing hormone (GnRH), kisspeptin (Kiss), neurokinin B (NKB), and prodynorphin (pDYN) in the hypothalamus, as well as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) expression and secretion in the pituitary. PNX treatment significantly increased hypothalamic GnRH expression, while the blockade of neuropeptide Y receptors (NPY1R and NPY5R) diminished this response, suggesting that PNX effects are at least partially mediated through NPY-dependent pathways. Moreover, PNX altered the transcription of Kiss, NKB, and pDYN, key components of the GnRH pulse generator, and modulated LHβ mRNA expression in the pituitary. Changes in the LH and FSH concentrations further supported a receptor-specific mechanism of PNX action. The developed hypothalamo-pituitary OOC model proved valuable for studying neuroendocrine control of reproduction. This system offers a physiologically relevant and ethically sustainable alternative to in vivo experiments, enabling precise investigations of molecular and hormonal mechanisms within the gonadotrophic axis.

Isolated Follicle-Stimulating Hormone (FSH) Deficiency in Male Sex: A Case Report.

Daniela M Soares, Jorge Diogo Silva, Ana Rita Soares +1 more

Follicle-stimulating hormone (FSH) is a glycoprotein hormone produced in the anterior pituitary, essential in the regulation of gonadal functions. Isolated FSH deficiency (IFD) is a rare inherited disorder, usually caused by β-subunit alterations. In men, it is frequently detected during infertility evaluation, commonly associated with spermatogenesis impairment and testicular atrophy with normal testosterone levels. We present the case of a 30-year-old male patient who was referred for breast pain and bilateral gynecomastia. Laboratory evaluation displayed primary hypothyroidism with positive thyroid autoantibodies and decreased FSH levels, with normal total testosterone and adequate luteinizing hormone (LH) levels. A gonadotropin-releasing hormone (GnRH) stimulation test demonstrated inadequate FSH response, highly suggestive of IFD. Genetic testing for FSHB mutations was negative, and whole exome sequencing revealed no recognized pathogenic variants. Semen analysis was postponed by the patient's choice. Although rare, IFD should be considered when evaluating patients with symptoms suggestive of hypogonadism. The overall prevalence of FSH-β mutations is unknown but probably underdiagnosed in male patients.

Activity Changes of the Hypothalamus-Pituitary Hormonal Axis in Peripubertal Female Rats.

Eun-Young Jeon, Sung-Ho Lee

Little is known about the regulation of gene expression related to the hypothalamus-pituitary (HP) axis around the onset of normal puberty. In the present study, we examined the expression profiles of genes in HP hormone circuit on every other day from postnatal day (PND) 29 to PND 43. Average vaginal opening (VO) date was PND 37 (66%), and the weight of reproductive organs increased significantly from PND 37. Serum steroid hormone levels significantly increased on PND 39. The appearance of a number of Graafian follicles and corpora lutea on PND 37. Generally, our polymerase chain reactions (PCR) results showed that most of the expression of hypothalamus and pituitary factors tended to increase after VO, and the patterns were rather unstable and no significant peak pattern such as LH surge shown in proestrus adults. The mRNA levels of gonadotropin-inhibitory hormone (GnIH)-GPR147 and neurokinin B(Tac)-TacR3 mostly reached a peak in the last period of the experimental schedule. In pituitary, mRNA level of gonadotropin subunits (Cgα, LH-β and FSH-β) also significantly increased on later experimental period. In conclusion, we could confirm the rapid growth and maturation of reproductive organs immediately after VO, and dynamic changes in gene expression of the HP axis factors. The gene expression patterns at peripubertal period were incomplete and unstable without showing the preovulatory LH surge-related gene expression pattern in adults. The present study on neuroendocrine control of peripubertal sexual maturation may offer a basis for understanding normo- and/or patho-physiological status of puberty.

Sex-dependent endocrine and cellular effects of the GnRH antagonist degarelix in rabbits and cell models.

Mo Zhao, Rong Wei, Yaojuan Lu +9 more

Degarelix is a long-acting gonadotropin-releasing hormone (GnRH) antagonist that suppresses gonadotropin and sex steroid secretion via competitive blockade of the GnRH receptor (GnRHR). Although its systemic endocrine effects have been clearly identified, its direct effects on non-pituitary-derived cells, as well as the roles of sex and context-dependent pharmacological properties, remain largely unexplored.

Effects of DSS-induced intestinal disruption on egg quality and brain, liver, and ovarian follicle functions in laying hens.

Muhammad Anang Aprianto, Jirapat Jaisue, Naoki Isobe +1 more

Intestinal disruptions, including morphological changes, barrier dysfunction, and inflammation, are associated with reduced egg production in laying hens. A previous study reported that oral administration of low-dose dextran sodium sulfate (DSS; 0.255 g/kg body weight) for 28 days caused slight intestinal disruption, resulting in decreased egg production and yolk size in the first week. These findings suggest that short-term DSS exposure may induce long-lasting effects on follicular development; however, the mechanisms underlying this early response remain unclear. This study aimed to investigate the mechanisms underlying the reduction in egg and yolk production during the first week. White Leghorn laying hens (350 days old) were divided into five groups: DSS-treated groups for 1 (DSS1), 2 (DSS2), and 7 (DSS7) consecutive days, and control groups receiving distilled water for 0 (CON0) and 7 (CON7) consecutive days. Egg parameters and serum corticosterone levels were assessed in the CON7 and DSS7 groups. At each time point, the birds were euthanized, and samples from the intestine, liver, granulosa cells (F1 and F5 follicles), hypothalamus, and pituitary gland were collected. Low-doses of DSS administration yielded the following results: (1) decreased claudin-1 (CLA-1) and claudin-5 (CLA-5) in the cecum in DSS1 and DSS2, while increased pro-inflammatory cytokines in the ileum and cecum in DSS2 and DSS7. (2) Increased sterol regulatory element binding protein-1 (SREBP-1), very low density lipoprotein-II (VLDL-II), and estrogen receptor alpha (Erα) in the liver in DSS7. (3) Decreased low-density lipoprotein receptor (LDLr) and lipoprotein receptor 8 (LR8) in the granulosa cells in DSS2, with increased CLA-1 and CLA-5 in DSS1; both patterns were reversed in DSS7. (4) Increased stress-related hormone synthesis in DSS1 and DSS7, and gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) gene expression in DSS1 and DSS2. These results suggest that slight intestinal disruption triggers a systemic stress response that impairs yolk precursor uptake and follicular function, leading to reduced egg weight and yolk size without affecting gonadotropin or yolk precursor production. After one week, a compensatory feedback response restored yolk precursor uptake and gonadotropin synthesis, but yolk size continued to decline. In conclusion, these findings suggest that short-term intestinal disruption serves as a key trigger for prolonged impairment of reproductive function and egg quality in laying hens.

Functional roles of NR4A transcription factors in GnRH regulation of gonadotropin gene expression and secretion in rat primary pituitary cells.

Ryota Terashima, Yuta Tomiyama, Shiro Kurusu +1 more

Gonadotropin-releasing hormone (GnRH) tightly regulates the synthesis and the release of gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), while the intracellular molecular mechanisms following GnRH signal for the regulation of transcription remains incompletely understood. In this study, we used primary culture of rat anterior pituitary cells to investigate the role of NR4A transcription factors (NR4A1, NR4A2, and NR4A3) in GnRH regulation of gonadotropin secretion. GnRH agonist stimulation rapidly and transiently increased Nr4a1, Nr4a2, and Nr4a3 expression within one hour, accompanied by a time-dependent increase in Fshb mRNA levels and the secretion of both FSH and LH. The knockdown of each Nr4a gene using siRNA significantly reduced Fshb expression under GnRH stimulation. Nr4a1 knockdown caused the most pronounced decrease in FSH secretion. Although Lhb and Cga mRNA levels were largely unaffected, LH secretion was consistently reduced following NR4A knockdown. These findings suggest that NR4A transcription factors act downstream of GnRH signaling to promote Fshb transcription and facilitate gonadotropin secretion, thereby modulating GnRH-dependent control of FSH and LH secretion.

GnRH-driven FSH synthesis and secretion are modulated through circ-ptpn4 ceRNA sequestration of let-7b-5p miRNA, which negatively controls ELK1 expression.

Yu-Xin Zhang, Ling-Ling Qiu, Zhe Zhang +8 more

During animal growth and development, the reproductive system is tightly controlled by the central nervous system through a highly conserved, self-feedback loop-the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH), which is produced in the hypothalamus and secreted into the hypophyseal portal circulation, serves as a master regulator of pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis and secretion, thereby orchestrating growth and reproductive functions. We identified circ-ptpn4 as a GnRH-responsive circular RNA (circRNA) that sequesters let-7b-5p, thereby attenuating its suppression of ELK1. This decrease in let-7b-5p availability thus allows enhanced ELK1 expression, which ultimately stimulates FSH production. In summary, we revealed a novel competing endogenous RNA (ceRNA)-dependent pathway (circ-ptpn4/let-7b-5p/ELK1) underlying GnRH-induced FSH regulation.

Unraveling the Cycle: A Scoping Review Exploring the Impact of Antidepressants on the Female Reproductive Cycle.

Shannon Weatherly, Carly D Garazi, Emma Woldenberg +2 more

Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are widely prescribed for mood disorders, including in individuals of reproductive age. While their psychiatric effects are well-documented, emerging evidence suggests these medications may influence hormonal regulation, ovulation, and menstrual cycle patterns. Potential mechanisms include disruption of the hypothalamic-pituitary-ovarian (HPO) axis, alterations in serotonergic signaling, and medication-specific hormonal fluctuations. These interactions raise important questions about the understudied reproductive impact of commonly prescribed antidepressants. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines, a comprehensive search of Ovid MEDLINE, Excerpta Medica Database (EMBASE), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were performed to identify studies examining the effects of antidepressants on ovarian function, menstrual regularity, ovulation, or hormone levels. Eligible studies included those involving individuals assigned female at birth (AFAB) of reproductive age, as well as animal models with comparable reproductive physiology. Both human and preclinical studies were considered, covering a range of antidepressant classes: SSRIs, SNRIs, atypical antidepressants, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and newer agents such as vortioxetine and vilazodone.  Out of 34 eligible studies, 16 were included in the final synthesis. SSRIs, especially fluoxetine, sertraline, paroxetine, escitalopram, and citalopram, were most frequently studied. Observational studies reported increased rates of menstrual irregularity and sexual dysfunction, particularly with chronic SSRI use. Antidepressant use was associated with reduced fecundability, even after adjusting for depression severity. Bupropion, venlafaxine, and other SNRIs showed cycle-phase-dependent pharmacokinetics and variable hormonal interactions. Antidepressant use was associated with changes in menstrual cycle length and increased cardiometabolic risk; however, they may normalize low testosterone levels in depressed women, with improvements in sexual function post-treatment. Clinical and preclinical findings indicate that SSRIs may impair ovulation through serotonergic inhibition of gonadotropin-releasing hormone (GnRH) as well as downstream suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), with some studies also noting elevated prolactin and follicular atresia. Taken together, these findings suggest a biologic basis for the observed menstrual irregularities and reduced fecundability reported in observational and cohort studies. Across studies, reproductive effects varied by antidepressant class, duration of use, and underlying mood pathology. Observed trends support a drug- and class-dependent impact on estrogen, progesterone, prolactin, and reproductive function, with additional implications for systemic health.

Synaptotagmin-1 regulates egg production by con trolling luteinizing hormone secretion in chickens.

Zhimin Cheng, Yangyang Wang, Yang Wang +7 more

Egg production represents one of the most economically critical traits in commercial poultry production, orchestrated primarily by the hypothalamus-pituitary-ovarian (HPO) axis. Synaptotagmin 1 (SYT1), a ubiquitous component of the nervous and endocrine systems, functions as a key mediator of calcium-dependent neurotransmitter release and hormone secretion. However, the functional role of SYT1 in avian reproductive performance has remained elusive. In this study, we present evidence that single nucleotide polymorphisms (SNPs) within the SYT1 gene effectively distinguish commercial laying hens from local wild breeds, as demonstrated through principal component analysis (PCA), suggesting the gene's pivotal role in selective breeding for enhanced egg production. Through genotype-phenotype correlation analyses, we identified two SNPs, rs39497549 and rs39477032, that exhibit strong associations with egg laying performance. Furthermore, tissue-specific expression levels showed profiling analysis revealed SYT1 transcript levels in pituitary and ovarian tissues of high-producing hens relative to their low-producing counterparts, and these expression levels showed strong positive correlations with circulating concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2). In addition, fluorescence in situ hybridization analyses further confirmed spatial co-localization of SYT1 and LH within anterior pituitary cells, suggesting a direct involvement of SYT1 in gonadotroph activity. Functional validation through in cultured pituitary cells revealed that gonadotropin-releasing hormone (GnRH) agonist stimulation significantly upregulated SYT1, follicle stimulating hormone beta subunit (FSHβ), and luteinizing hormone beta subunit (LHβ) mRNA, along with enhanced secretion of FSH and LH. Conversely, SYT1 knockdown attenuated GnRH-induced expression and secretion of gonadotropins, while SYT1 overexpression potentiated these effects. Additionally, SYT1 modulated steroidogenesis in ovarian granulosa cells by regulating the expression of steroidogenic enzymes and progesterone production. Taken together, our findings establish SYT1 as a master regulator of chicken egg production performance via modulation of reproductive hormone synthesis and secretion within the HPO axis. These results position SYT1 polymorphisms as promising genetic markers for selective breeding programs in commercial laying hens improving egg production traits in indigenous chicken breeds.

High-fat diet-induced obesity accelerates puberty in male rats through SMIM20/phoenixin upregulation.

Tao Xie, Wei Qin, Dan Zeng +5 more

Controversy exists regarding the relationship between obesity and pubertal onset in boys, and the underlying mechanisms remain unclear.

Outcomes of Patients With Familial Central Precocious Puberty due to Mutations of MKRN3 Gene After Treatment With Gonadotropin-Releasing Hormone Agonist.

Ziwei Chen, Wenying Li, Junqi Wang +7 more

To assess the therapeutic effects of gonadotropin-releasing hormone agonist (GnRHa) on children with familial central precocious puberty (FCPP) due to Makorin ring finger Protein 3 (MKRN3) gene mutations.

Dietary Copper on the Onset of Puberty in Rats: Possible Mechanism.

Rui Sun, Zhongshen Wang, Cheng Li +3 more

Background/Objectives: Copper is an essential trace element for physiological processes related to reproduction, but its impact on the hypothalamic-pituitary-ovarian (HPOA) axis and its specific mechanism remain unclear. Methods: In vivo study: 21-day-old female Sprague Dawley (SD) rats were randomly assigned to five groups (n = 10 per group), with all groups fed a basal diet and supplemented with CuSO4·5H2O to achieve copper ion concentrations of 0, 15, 30, 45, or 60 mg/kg in the diet. During the second phase of proestrus, blood samples, hypothalamic tissues, pituitary tissues, and ovarian tissues were collected. In vitro study: Primary mixed hypothalamic neurons were isolated and cultured from fetal SD rats on embryonic day 17. After identification by NSE immunofluorescence staining, six copper ion concentration groups (0, 15.6, 31.2, 46.8, 62.4, and 78 μmol/L) were established. The optimal copper concentration for cell viability and GnRH secretion was screened using CCK-8 assay (Sangon, Shanghai, China) and ELISA (Mlbio, Shanghai, China). On this basis, the cells were treated with different concentrations of PKC agonist (PMA) and PKC inhibitor (chelerythrine). Cell viability was evaluated by CCK-8 assay, the expression level of PKC was detected by Western blot, and the optimal concentration with no obvious toxicity was selected for subsequent mechanism research. Results: Dietary copper dose-dependently regulated rat puberty onset; the 45 mg/kg copper group had the earliest onset, and showed significantly increased levels of reproduction-related hormones (GnRH, FSH, LH, E2) in serum and HPOA axis. Hypothalamic transcriptomics revealed significantly enriched GnRH signaling pathways and GABAergic synaptic pathways. Mechanistically, this copper dose upregulated hypothalamic KISS-1, GPR54, and PKC (mRNA/protein), and downregulated GABA/GABA-R. Adding 46.8 μmol/L copper (as Cu2+, equivalent to optimal in vivo level) could activate the KISS-1/GPR54-GnRH system in hypothalamic neurons; regulating PKC activity could synchronously affect the expression of KISS-1, GPR54, GnRH, and GABA/GABA-R, with additional copper enhancing this effect in vitro experiments. Conclusions: This study demonstrates for the first time that dietary copper at 45 mg/kg promotes puberty onset in SD rats. The mechanism involves activation of the hypothalamic PKC pathway, which inhibits GABAergic neurotransmission while activating the KISS-1/GPR54-GnRH system, thereby enhancing HPOA axis activity and gonadotropin secretion.

Central administration of docosahexaenoic acid, eicosapentaenoic acid, or linoleic acid activates hypothalamic fatty acid sensing and is involved in reproductive regulation in spotted scat (Scatophagus argus).

Siqin Wang, Jie Luo, Xinghua Lin +6 more

The binding of fatty acid (FA) to fatty acid translocase (FAT/CD36) and subsequent regulation of lipid metabolism transcription factors, such as peroxisome proliferator-activated receptors α (PPARα) and sterol regulatory element-binding protein-1c (SREBP-1c), is an important hypothalamic fatty acid-sensing mechanism in vertebrates. The hypothalamus exhibits responsiveness to specific fatty acids and is involved in reproductive regulation. However, the link between FA sensing and reproductive regulation in the hypothalamus remains poorly understood teleosts. Therefore, the expression of genes involved in the FA-sensing mechanism-such as fat/cd36, pparα, and srebp1c, as well as gonadotropin-releasing hormone (GnRH: cgnrh, sgnrh, sbgnrh) in the hypothalamus-was investigated after intracranial administration and hypothalamic incubation of polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA), eicosapentanoic acid (EPA), and linoleic acid (LA) for 4 h in the spotted scat (Scatophagus argus). Compared to the control, intracranial administration and hypothalamic incubation of DHA and LA, as well as hypothalamic incubation of EPA, increased the levels of fat/cd36, pparα, and srebp1c. However, the expression of fat/cd36 and pparα was significantly decreased, and the level of srebp1c showed a downward trend only in the EPA group when co-incubated with the FAT/CD36 inhibitor Sulfo-N-succinimidyl oleate sodium (SSO), compared to incubation with EPA alone. After the application of PPARα antagonist GW6471, the expression of pparα in the hypothalamus decreased significantly in the DHA, EPA, and LA treatment groups, compared to incubation with DHA, EPA, and LA alone. Levels of fsh and lh in the pituitary gland were changed significantly after the intracranial administration of DHA, EPA, and LA. Compared to the control, the levels of cgnrh, sgnrh, and sbgnrh increased in the hypothalamus after both hypothalamic incubation and intracranial administration of EPA and LA. Levels of cgnrh increased in the hypothalamus after incubation, but not after intracranial administration of DHA. However, compared to the control, levels of sgnrh and sbgnrh increased after hypothalamic incubation with DHA and EPA. Only sgnrh levels decreased after incubation with LA in the presence of SSO compared to the FA treatment group alone. In the presence of GW6471, only sgnrh levels decreased after incubation with LA in the presence of SSO compared to the FA treatment group alone; the levels of cgnrh, sgnrh, and sbgnrh after LA incubation, the levels of sbgnrh after EPA incubation, and the levels of sbgnrh after DHA incubation were all significantly decreased compared to the control. These results showed that DHA, EPA, and LA could activate fat/cd36 and pparα, which are involved in reproductive regulation in the hypothalamus of the spotted scat. These results provide evidence that hypothalamic FA sensing is involved in regulating reproduction in teleosts.

Differential hypothalamic regulation of FSH and LH secretion from the fish pituitary by GnRH and CCK.

Naama Mizrahi, Miriam Shulman, Tomer Aiznkot +4 more

The hypothalamus-pituitary-gonad axis integrates environmental and internal signals to tune reproductive functions. We hypothesized that in fish, Gnrh predominantly stimulates luteinizing hormone (LH) secretion, while Cck selectively regulates follicle-stimulating hormone (FSH), thereby uncovering a novel role for Cck as a metabolic gatekeeper that links reproductive activity with nutritional status.

Emerging Perspectives on Gonadotropin Regulation in Vertebrates Revealed by the Discovery of FSH-RH in Teleosts.

Daichi Kayo, Shun Kenny Uehara, Muhammad Rahmad Royan +1 more

Vertebrate gonadal function is regulated by pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones are considered to be regulated by hypothalamic factor(s). Since the discovery of gonadotropin-releasing hormone (GnRH) in mammals, which stimulates the secretion of both FSH and LH, GnRH had been believed to be the sole gonadotropin-releasing hormone in vertebrates for more than 5 decades. However, recent studies have identified an alternative primary regulator of FSH in teleosts, leading to the hypothesis that FSH and LH are regulated by different factors in teleosts (dual GnRH model). This contrasts with the situation in mammals, where a single GnRH regulates both hormones (solo GnRH model). Importantly, although underlying mechanisms likely differ, both teleosts and mammals reproduce efficiently and have convergently evolved similar phenomena, including steroid feedback regulation. In this review, by comparing these taxa, we summarize mechanistic differences and propose an evolutionary scenario based on current experimental evidence.

Investigating the Impact of GNRH1 Polymorphism rs6185 in Women with Polycystic Ovary Syndrome through Association Study, Meta analysis and In silico Study.

Pallvi Thapar, Mandeep Kaur, Sukhjashanpreet Singh +3 more

Hypothalamic pituitary gonadal axis plays a pivotal role in reproductive physiology, and gonadotropin-releasing hormone 1 (GNRH1) is considered to be the candidate gene in the regulation of the hypothalamic-pituitary-gonadal axis. GNRH1 encodes the pre-proprotein that is processed proteolytically to form the peptide GnRH1. Its polymorphisms may involve in the disruption of the luteinising hormone/follicle-stimulating hormone (LH/FSH) ratio and cause polycystic ovary syndrome (PCOS).

Melatonin suppresses the seasonal estrus in female giant pandas.

He Huang, Rong Hou, David C Kersey +7 more

In mammals, the pineal gland secretes melatonin, which serves as a crucial signal for interpreting photoperiod cues. As a seasonal breeder, the giant panda typically mates during the spring. To fully elucidate melatonin's influence on the seasonal estrus of female giant pandas, we conducted an in-depth analysis of urinary hormones. First, we found that urinary melatonin and gonadotropin-releasing hormone (GnRH) levels exhibit distinct seasonal variations over the annual cycle. From January to April, melatonin levels decline sharply from their annual peak, while GnRH levels rise rapidly and remain elevated throughout February, March, and April, precisely corresponding to the giant panda breeding season. Second, during female estrus, the estrogen metabolites peak occurs near the time when melatonin levels drop to their lowest values, and an inverse correlation between melatonin and estrogen metabolites persists both before and after the estrogen metabolites peak. Our analysis of urinary hormones revealed that melatonin exerts a significant suppressive effect on urinary GnRH and estrogen metabolites production prior to the onset of the seasonal estrus in giant pandas. Given the multipotent differentiation capacity of mesenchymal stem cells, we selected cultured giant panda umbilical cord mesenchymal stem cells (UC-MSCs) as an in vitro model for further study. Initially, we characterized the expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in UC-MSCs following GnRH stimulation. Notably, these cells exhibited pituitary-like functional properties, including responsiveness to GnRH and expression of FSH and LH genes, making them suitable for modeling melatonin's effects. Subsequent experiments demonstrated that melatonin suppresses GnRH-induced LH and FSH mRNA expression in UC-MSCs in a dose-dependent manner and higher concentrations of melatonin were particularly effective. Collectively, our study not only elucidates the regulatory effects of melatonin on the seasonal estrous cycle of female giant pandas but also offers valuable new perspectives. These insights can potentially guide the development of conservation strategies for this endangered species, facilitating more targeted and effective efforts to safeguard its population.

Expression of irisin in the porcine pituitary gland during the oestrous cycle and early pregnancy: the role of GnRH, gonadotropins, and insulin.

Barbara Zarzecka, Kamil Dobrzyn, Marta Kiezun +6 more

Context Metabolic status significantly affects female reproductive function, with both excess and deficiency of body fat negatively affecting fertility. Irisin, a hormone secreted by muscle and fat tissue, is linked to metabolism and reproduction, but its role in the pituitary gland remains unclear. Aims This study investigated the expression of irisin and its receptor (integrin αV/β5) in the anterior (AP) and posterior (PP) lobes of the porcine pituitary during the oestrous cycle and early pregnancy. We hypothesised that they are localised in specific pituitary cell types and that gonadotropin-releasing hormone (GnRH), luteinising hormone (LH), follicle-stimulating hormone (FSH), and insulin modulate irisin expression and secretion by AP cells. Methods The expression of irisin and integrin αV/β5 was analysed using quantitative real-time polymerase chain reaction (qPCR) and western blotting. Immunofluorescence was used to determine colocalisation with pituitary hormones. AP cells were cultured in vitro and treated with GnRH, LH, FSH, or insulin to assess their effects on irisin protein concentrations and secretion. Key results Irisin and its receptor were expressed in both AP and PP lobes and colocalised with all major trophic cell types. Their expression varied depending on the reproductive stage. GnRH, LH, FSH, and insulin inhibited irisin secretion by AP cells during the luteal phase, whereas only insulin had an effect during the follicular phase. Conclusions Irisin and its receptor are expressed in a hormone-dependent manner and localise to specific pituitary cell types, suggesting intra-pituitary regulatory roles. Implications These findings indicated that irisin may act as a local modulator of pituitary function and reproductive hormone regulation, linking metabolic and reproductive health.

A single blood luteinizing hormone level of triptorelin stimulation test can diagnose hypothalamic-pituitary-gonadal axis activation in girls with high body mass index.

Beilei Zeng, Yinyin Huang, Yuan Zhou +4 more

Body mass index (BMI) may influence peak luteinizing hormone (PLH) levels during gonadotropin releasing hormone (GnRH) or GnRH analogues stimulation testing. BMI effects should be considered when interpreting test results for pubertal disorders in girls with overweight/obesity, but few studies have excluded it.

[Wheat-grain moxibustion at the Guanyuan point to regulate low testosterone and hypothalamic-pituitary-gonadal axis in naturally aged mice].

Meng-Fan Cui, Bing-Zhe Ma, Zhi-Yang Yin +3 more

To investigate the effects of wheat-grain moxibustion at the Guanyuan point on testosterone (T) synthesis and the hypothalamic-pituitary-gonadal (HPG) axis in naturally aged mice.