Gonadotropin-releasing hormone (GnRH) is a peptide hormone forming a central component of the hypothalamic-pituitary-gonadal axis and is critical for controlling reproductive functions. Dysregulated GnRH is implicated in many steroid hormone-dependent diseases, and its receptor, GnRHR, is an attractive and clinically exploited therapeutic target. Mounting evidence suggests that beyond the hypothalamus and pituitary, GnRH and GnRHR are expressed in reproductive and non-reproductive, healthy and malignant peripheral tissues, where they act in an autocrine and paracrine manner. This review provides an updated overview of GnRH and GnRHR signalling with a focus on extrapituitary autocrine and paracrine roles in female reproductive health. We examine the molecular and cellular mechanisms of extrapituitary GnRHR signalling, including G-protein coupling profiles, and alternative cell-specific mechanisms that differ from pituitary signalling. We highlight recent data surrounding the (patho) physiological functions of local GnRH systems, including in the endometrium, ovary, placenta and breast, and their implications for hormone-dependent gynaecological conditions and cancers. Finally, we consider implications of peripheral GnRH/GnRHR systems for therapeutic innovation, including avenues for targeted or biased GnRH-based therapeutics, GnRH/GnRHR-mediated 'off target' effects of GnRH analogues, and explore future translational avenues for the treatment of both hormone-dependent and hormone-refractory diseases.

Mutations in the MECP2 gene, encoding the epigenetic reader Methyl-CpG binding protein 2, are the main cause of Rett syndrome, a rare neurodevelopmental disorder. Besides severe symptoms such as profound intellectual disability, loss of speech and motor skills, and epilepsy, loss of function of MECP2 has been associated with pubertal dysregulation, but the biological mechanisms leading to this remain unclear. Using a mouse model of Rett, in which males are hemizygous and females heterozygous for Mecp2 loss of function mutation, we assessed the onset and progression of puberty, together with increase in body weight and onset of neurological symptoms in post-weaning mice until puberty. In brain samples of young adult mice, we analysed hypothalamic Gonadotropin releasing hormone (GnRH) neurons by immunofluorescent labelling, and in plasma samples we measured circulating GnRH, LH, and testosterone concentrations. Finally, we analysed testosterone-dependent arginine-vasopressin circuits. In our mouse model we found delayed puberty in Mecp2 CD1-null males, associated with a reduced rate of weight gain, but with puberty onset occurring at a lower body weight than in wildtype controls. Despite later puberty onset, Mecp2CD1-null male mice were found to have an increased number of GnRH neurons, but displayed lower levels of circulating reproductive hormones. Consequently, Mecp2CD1-null males have deficient testosterone-dependent arginine-vasopressin innervation. In female Mecp2CD1-heterozygous mice, we found no overall significant differences in pubertal development or GnRH neurons. The lack of significant alterations in females might be related to a later onset of neurological symptoms due to heterozygosity. Our data supports that MECP2 is essential for typical pubertal development, with complete loss of Mecp2 in a male murine model resulting in abnormalities of pubertal timing related to lower body weight, with an observed increase in hypothalamic GnRH neurons.

Astrocytes play an essential role in the control of gonadotropin-releasing hormone (GnRH) neurons. However, limited information is available in non-conventional animal models. This study aimed to explore the hypothalamic astrocyte distribution in the plains vizcacha (Lagostomus maximus), a South American hystricomorph rodent with distinctive reproductive physiology, and to analyze their spatial relationship with GnRH neurons throughout the life cycle. Female plains vizcachas were evaluated during non-pregnancy (ovulating and non-ovulating) and pregnancy (early-, mid-, and late-pregnant). Plasma levels of estradiol (E2), progesterone (P4), and luteinizing hormone (LH) were determined. Astrocytes were assessed by glial fibrillary acidic protein (GFAP) immunohistochemistry in hypothalamic regions involved in reproductive control, including the medial preoptic area (mPOA), arcuate nucleus (ARC), and median eminence (ME). Their spatial relationship with GnRH-immunoreactive neurons and fibers was also analyzed. Pregnancy was associated with marked hormonal changes, including significantly elevated E2 levels and dynamic variations in P4 and LH (P < 0.01). Astrocyte distribution was largely conserved across life stages in the mPOA and ME, whereas a significant reduction in GFAP-immunoreactive area was detected in the ARC during early pregnancy. Close appositions between astrocytic processes and GnRH neurons were observed in ovulating non-pregnant and pseudo-ovulating mid-pregnant animals. In the ME, very intimate contacts between astrocytic processes and GnRH fibers in the palisade layer were detected exclusively during pregnancy. In conclusion, these findings reveal a steroid-dependent plasticity of hypothalamic astrocytes and support a key role for astrocyte-GnRH neuron interactions in the regulation of reproductive neuroendocrine function during gestation in the plains vizcacha.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) is an emerging environmental pollutant with limited research on its reproductive toxicity. In this study, female offspring mice were exposed to 6PPD-Q during gestation and lactation. The results revealed that 6PPD-Q exposure disrupted the hypothalamus-pituitary-ovary (HPO) axis in postnatal day (PND) 22 female offspring mice, leading to precocious puberty and estrous cycle irregularities, accompanied by substantial metabolic alterations. At PND 71, disturbances in the HPO axis and metabolic functions were observed. In both in vivo and in vitro experiments, 6PPD-Q was found to suppress hypothalamic gonadotropin releasing hormone (GnRH) secretion via the Kisspeptin/GPR54 pathway, inhibit pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion through the PKC/c-Raf/ERK1/2/IEGs pathway, and induce oxidative stress in human granulosa-like tumor cell line (KGN), resulting in a reduction in estradiol (E2) secretion. Collectively, this study provides novel theoretical insights into the potential reproductive toxicity and metabolic impact of 6PPD-Q.

Euploidy rates are comparable between progestin protocol ovarian stimulation and gonadotropin-releasing hormone antagonist protocol ovarian stimulation cycles.

Infertility is an increasing concern for many women and can affect both physical and emotional well-being. The central nervous system (CNS) - particularly the hypothalamus, pituitary gland, and pineal gland - plays a crucial role in female reproductive health. We conducted a narrative review of relevant studies published between 2015 and 2025, sourcing data from PubMed and Scopus. Our goal was to investigate how dysregulation of hormones from the hypothalamus, pituitary gland, and pineal gland contributes to fertility-related disorders, such as impairments in ovulation, oocyte quality, and embryo development. Both human and significant animal studies were considered to better understand how CNS hormones affect fertility. The findings emphasize the roles of key hormones, including gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), melatonin, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and vasopressin (ADH). The proper timing and balance of these hormones are vital. For instance, GnRH pulses regulate the release of LH and FSH, which are essential for ovulation and follicle development. Melatonin supports oocyte health and helps maintain the menstrual cycle, while ACTH and TSH are also involved in reproductive function. Vasopressin affects uterine activity and hormone production. Understanding these hormonal interactions may lead to better diagnostic tools and more effective treatment strategies for conditions such as polycystic ovary syndrome (PCOS) and other fertility-related disorders. Unlike previous studies, this research provides a comprehensive investigation of how CNS-mediated hormonal regulation influences female reproductive outcomes, examining the roles of all involved hormones.

Luteinizing hormone-releasing hormone agonists, used in advanced prostate cancer, can cause an initial testosterone surge and may inadequately suppress follicle-stimulating hormone, potentially promoting tumor growth. Injectable gonadotropin-releasing hormone (GnRH) antagonists avoid this surge but have drawbacks like injection-site reactions and monthly dosing. Relugolix, an oral GnRH antagonist, offers rapid testosterone suppression without flare and reduced cardiovascular risks. We report a 72-year-old man with suspected metastatic prostate cancer, presenting with severe neuritic pain and lower limb weakness. Relugolix, started before biopsy along with zoledronic acid and steroids, led to symptom relief within 24 h. This case supports Relugolix's utility in urgent hormone-sensitive metastatic prostate cancer care.

ObjectiveTo characterize interspecialty variation and areas of consensus in the understanding and clinical management of functional hypothalamic amenorrhea among physicians from different clinical specialties in China.MethodsWe conducted a nationwide, cross-sectional questionnaire survey of licensed physicians practicing in reproductive endocrinology, obstetrics and gynecology, and related specialties involved in functional hypothalamic amenorrhea care. The survey was administered anonymously via a national continuing medical education platform affiliated with the Peking Union Medical College Hospital Alliance between 1 November and 30 November 2025.ResultsA total of 2026 questionnaires were included in the final analysis, comprising 112 reproductive endocrinologists (5.5%), 1516 obstetricians-gynecologists (74.8%), and 398 physicians from other specialties (19.6%). Overall, only 62.7% of respondents recognized genetic susceptibility as a contributing factor to functional hypothalamic amenorrhea, and only 43.9% of respondents perceived that functional hypothalamic amenorrhea was generally diagnosed appropriately. Compared with physicians from other specialties, reproductive endocrinologists and obstetricians-gynecologists were significantly more likely to prioritize sex hormone evaluation, pelvic ultrasonography, and assessment of the thyroid and adrenal axes (all p < 0.01), whereas physicians from other specialties more frequently reported emphasizing assessments of energy metabolism (p < 0.01). Among women without fertility intentions, reproductive endocrinologists were more likely to report prioritizing elimination of precipitating factors (p < 0.05) and recommending hormone replacement and bone-targeted therapies (both p < 0.01). For women desiring pregnancy, reproductive endocrinologists were more likely to report recommending ovulation induction (p < 0.01), whereas physicians from other specialties reported greater support for the use of pulsatile gonadotropin-releasing hormone pumps (p < 0.01).ConclusionsVariations were observed in physicians' self-reported diagnostic and management approaches to functional hypothalamic amenorrhea across clinical specialties in China. These findings suggest the importance of promoting multidisciplinary consensus, developing standardized clinical pathways, and strengthening interdisciplinary collaboration to improve the quality of care for women with functional hypothalamic amenorrhea.

Prognostic factors and the role of GnRHa in premenopausal HR+/HER2+ breast cancer achieving pathologic complete response after neoadjuvant chemotherapy.

Endometriosis presents a multitude of challenges for individuals. Current treatment of the disease is based on pharmacotherapy that aims to relieve pain, improves future fertility, potentially slows disease progression and lessen the likelihood of recurrence. The present review outlines recent reports on the importance of Gonadotropin-Releasing Hormone antagonists/antagonists and a new prospective as a significant second- line treatment option. A review of the literature from the last 5 years was conducted. The search included the following medical subject: "endometriosis", "GnRh agonists", "GnRh antagonists", "pharmacotherapy".The articles published in English were included. Publications without full text access and duplicates were rejected. Current researches no longer focuse exclusively on finding new GnRH agonists/antagonists, but rather on maximizing their usage, in favour of the latter ones . Multiple active substances are now being combined into one tablet, which makes it easier for patients to take their medication and improves their adherence to treatment recommendations. 24 months monotherapy of linzagolix did not indicate any clinically relevant impact on overall bone condition in comparison to placebo group. Relugolix combination therapy maintained bone mass density over two years while effectively alleviating pain symptoms. Despite being effective, all of treatments may have additional negative effects. The best approach to pharmacotherapy depends on the individual patient's needs and circumstances. Taking into consideretion potential effects, an appropriate dose or a combination of the above options should be performed. The treatment options of Relugolix and Linzagolix are both promising and well-tolerated. Further researches should focuse on long-term bone health monitoring strategies and its safety profile.

Although gonadotropin-releasing hormone analogs (GnRHa) are the standard treatment for central precocious puberty (CPP), the efficacy of GnRHa monotherapy in older children (around 8years) and that of combination therapy with recombinant human growth hormone (rhGH) both remain unclear. This study aims to evaluate the real-world efficacy of each regimen. This retrospective cohort study enrolled Chinese girls with CPP. Two groups were formed: GnRHa monotherapy and GnRHa + rhGH combination therapy. Outcomes included adult height gain [AHG, final adult height (FAH) standard deviation score (SDS)- predicted adult height (PAH) SDS]，genetic height gain [GHG, FAH SDS-target height (Tht) SDS], and change in height (FAH SDS-baseline height SDS). In the GnRHa group, the mean age at treatment initiation was 8.87 ± 0.87years. After 17.87months of treatment, the AHG was 1.33 SDS (0.82, 2.00). In the GnRHa + rhGH group, the mean age at treatment initiation was 9.01 ± 0.80years. After 23.02months of GnRHa treatment and 14.02months of rhGH treatment, the group showed significantly greater AHG [1.72 SDS (1.24, 2.59)]. GnRHa monotherapy initiated after age 8 may still provide meaningful height gains, and adding rhGH is associated with improved FAH in patients with severe baseline height impairment.

Buserelin, a gonadotropin-releasing hormone agonist, reduces gonadotropin and estrogen levels and is commonly used to alleviate the symptoms of endometriosis. Vitamin D3 has been reported to exhibit anti-inflammatory and pro-apoptotic properties, which may contribute to the regression of endometrial lesions. We aimed to investigate the effects of vitamin D3 on the regression and recurrence prevention of endometrial implant sites through the induction of apoptosis comparable to buserelin acetate in an experimental rat endometriosis model. Endometrial implant size and adhesion scores were evaluated following treatment. Microscopic analyses were performed using hematoxylin-eosin-stained preparations. Apoptotic activity was assessed by TUNEL assay, along with the expression of Bcl-2 and Bax antibodies. Untreated rats exhibited larger implant volumes, severe glandular and stromal alterations, and pronounced inflammatory infiltration. In contrast, vitamin D3 and buserelin treatments reduced implant size and adhesion scores. The vitamin D3-treated group demonstrated a high density of TUNEL-positive cells. Increased expression of Bcl-2 protein was found in untreated groups whereas, increased expression of Bax protein was found in both treated groups. In conclusion, vitamin D₃ may have contributed to the regression of endometrial implants, possibly through mechanisms involving apoptotic pathways. Further studies are needed to clarify its role and to evaluate its potential clinical relevance.

Reproductive dysfunction is a major health concern affecting men and women globally, mediated by the activation of the hypothalamic pituitary adrenal (HPA) axis as well as strongly influenced by exposure to stress. Consequently, this results in suppression of the hypothalamic-pituitary-gonadal (HPG) axis, facilitated by glucocorticoid signalling. Although we have a clear understanding of glucocorticoids as the main mediators of stress-induced reproductive suppression, evidence indicates that monoaminergic pathways, particularly serotonin (5-HT) and its receptors, play pivotal roles in linking stress to reproductive regulation. Kisspeptin neurons have emerged as crucial integrators of both glucocorticoid and serotonergic signals. Current evidence from animal studies demonstrates that stress dysregulates reproductive function at multiple levels of the HPG axis. Glucocorticoids interact through combined genomic and non-genomic pathways to suppress the secretion of kisspeptin, gonadotropin-releasing hormone (GnRH), gonadotropins, as well as gonadal steroidogenesis. In addition to the well-established glucocorticoid mechanisms, monoamines such as 5-HT play a crucial role in mediating the link between stress and reproduction. Recent molecular, electrophysiological, and transcriptomic studies have highlighted the importance of the 5-HT7 receptor, which is highly expressed in kisspeptin neurons of the arcuate nucleus (ARC), where it acts as a critical excitatory driver of GnRH/LH pulse generation. Stress, however, suppresses serotonergic signalling by lowering 5-HT levels and suppressing serotonin receptor expression, including 5-HT7 receptor, thereby reducing kisspeptin and GnRH neuronal excitation. Glucocorticoid-mediated suppression of kisspeptin signalling might be a key underexplored pathway contributing to stress-mediated reproductive dysfunction, particularly when combined with stress-induced reductions in 5-HT and 5-HT receptor expression, suggesting a dual suppressive mechanism.

Animal models of enhanced fertility are rare, as most genetically modified mouse models with reproductive phenotype display subfertility or infertility. Here we describe the ovarian phenotype of the Dummerstorf line 2 (FL2) mouse strain, which exhibits high fertility and has been selectively bred for increased fertility over more than 190 generations. This long-term selection, outbred mouse line almost doubled the litter size to 21.5 (FL2) compared to 11.3 (unselected control line, ctrl) without showing any signs of growth retardation in the offspring. Here we show that FL2 females ovulate 25.0 oocytes per cycle compared to 13.2 in ctrl. FL2 mice remain in the estrus phase for a shorter period during a 12-day observation period. Follicle-stimulating hormone (FSH) levels are decreased, both in estrus and diestrus, compared to ctrl, whereas Luteinizing hormone (LH) levels are unaffected. The mRNA expression levels in the pituitary gland correspond to the gonadotropin levels in the blood. Progesterone levels are decreased in estrus in FL2. Hypothalamic expression levels of Gonadotropin-releasing hormone (GnRH) are decreased in diestrus. Holistic gene expression analysis indicates complex and differential regulation in estrus and diestrus in ovaries of FL2 compared to ctrl. Especially genes of the TGF-β pathway (such as Bmp3, Bmp7, Inhba) and the Wnt pathway (such as Sfrp4, Mkrn1) are differentially expressed in ovaries of FL2 females. These data indicate that reduced activity of the hypothalamic-pituitary-gonadal axis (in particular, lower levels of GnRH, FSH and progesterone), combined with altered gene transcription in the ovaries, leads to higher ovulation rates in order to achieve the breeding objective of improved fertility.

Association between chemotherapy use and prognosis in young patients with stage I-II ER+ /HER2-negative breast cancer according to Prosigna®: An international real-world analysis with propensity-score matching.

Long-acting gonadotropin-releasing hormone agonists (GnRHa) are standard therapy for central precocious puberty (CPP). Depot formulations (triptorelin, leuprolide) ensure sustained release via biodegradable matrices. Rare sterile injection-site abscesses may impair drug absorption and efficacy, and evidence on management is limited. Two patients (0.68 %) out of the 290 treated at our center with depot GnRHa between 2023 and 2025 developed recurrent culture-negative abscesses. They had normal immune workup and no IgE-mediated hypersensitivity or mastocytosis. Lesions caused pain, transient inflammation, and reduced efficacy. In one case, topical hydrocortisone butyrate 0.1 % for 5days post-injection resolved abscesses and restored efficacy. Sterile abscesses are a rare but relevant complication of GnRHa therapy. Early recognition and exclusion of infection/allergy are key. Our experience with a patient who showed a good response to topical corticosteroids may be relevant in offering a conservative therapeutic option to treat the abscess lesion without discontinuing GnRHa therapy.

Redox homeostasis in human follicular fluid: A comparison of modified natural cycle and controlled ovarian stimulation in idiopathic infertility.

To evaluate whether pretreatment magnetic resonance imaging (MRI) parameters can predict short-term clinical response to dienogest (DNG) in patients with adenomyosis. This retrospective study included 78 patients with MRI-diagnosed adenomyosis who underwent pelvic MRI before hormonal therapy between October 2018 and July 2025. Quantitative MRI parameters included T2 signal intensity ratios, diffusion-weighted imaging (DWI) signal intensity ratios, normalized apparent diffusion coefficient (ADC), and uterine morphological parameters. Adenomyosis subtypes were classified according to the modified Kishi criteria. Short-term clinical response was assessed primarily 3-6months after treatment initiation as a composite clinical outcome encompassing symptom improvement (dysmenorrhea, menstrual blood loss, and/or hemoglobin levels) and treatment continuation; patients were classified as responders or non-responders. Predictive analyses were restricted to the DNG cohort because only one patient in the GnRH cohort was a non-responder. Of the 78 patients, 32 received gonadotropin-releasing hormone (GnRH) agonist or antagonist therapy and 46 received DNG. In the DNG cohort, 30 patients were responders and 16 were non-responders. MRI-based adenomyosis subtype, lesion distribution, and uterine morphological parameters were not significantly associated with response in DNG-treated patients. However, absolute ADC values were significantly higher in responders (1.03 vs. 0.89 × 10⁻3mm2/s, P = 0.036), as was the ADC signal intensity ratio relative to the endometrium (ADC SIRendo: 0.92 vs. 0.85, P = 0.034). Receiver operating characteristic analysis demonstrated moderate discrimination for both parameters (area under the curve = 0.70). Optimal cut-off values were 0.951 × 10⁻3mm2/s for ADC and 0.952 for ADC SIRendo. Quantitative diffusion MRI parameters were associated with short-term clinical response to DNG, whereas conventional morphological features were not. Diffusion-weighted MRI may provide complementary imaging biomarkers for adenomyosis stratification in DNG-treated patients; prospective validation with longer follow-up is warranted.

The scarcity of robust long-term safety data has contributed to increasing restrictions on the use of gonadotropin-releasing hormone analog (GnRHa) treatment in transgender and gender diverse adolescents (TGDAs) in several countries. Methodological limitations of earlier studies have led to controversy and debate, underscoring the urgent need for high-quality evidence in this field. To present a study design using target trial emulation (TTE) to evaluate long-term safety of GnRHa treatment in TGDAs using observational data from national healthcare registries, and highlight methodological challenges. We applied a stepwise TTE approach, to emulate a randomized trial using real-world data. The main methodological challenges were identified as the selection of the control group and the definition of time zero. To address these, we engaged independent experts in causal inference to review the concept design and provide feedback on potential solutions. Expert feedback was systematically summarized and discussed. The resulting study design will select late-presenting TGDA individuals as the control group and defines time zero as the initiation of GnRHa treatment for the intervention group, with the equivalent age assigned as time zero in controls. Sensitivity analyses using alternative control groups and time zero definitions will be included to assess robustness. This approach allows for adjustment of confounders and aims to emulate the conditions of a randomized trial as closely as possible within the constraints of observational data. This discussion paper serves as a methodological example of target trial emulation with observational data to study long-term safety of GnRHa in TGDA. By transparently addressing methodological challenges and incorporating expert input, this approach offers a feasible and ethically sound alternative to RCTs, and contributes to the evidence base needed for informed clinical and policy decisions in transgender healthcare.

This study aimed to evaluate the effects of equine chorionic gonadotropin (eCG), Estradiol benzoate (EB) and Gonadotropin-releasing hormone (GnRH) on follicular dynamics and luteal characteristics of buffaloes (Bubalus bubalis). The animals were separated into four experimental groups: EB (n=10), EB+eCG (n=10), GnRH (n=10) and GnRH+eCG (n=10). Using B-mode and Power-Doppler ultrasound, follicular characteristics of the largest follicle, from day 9 until day 11, diameter of the preovulatory follicle, follicular area, total wall area of the preovulatory follicle, growth rate of the ovulatory follicle, vascularization in the wall area of the preovulatory follicle, percentage of vascularization in the wall area of the preovulatory follicle and moment of ovulation, were evaluated for follicular dynamics. Furthermore, on day 18 of the protocol, diameter of the corpus luteum, total area of the corpus luteum, vascularization of the corpus luteum, percentage of vascularization of the corpus luteum and the serum progesterone levels were also evaluated. Statistical analyses were performed using Tukey's test, Kruskal-Wallis and repeated measures ANOVA with a 5% significance level. Statistically significant differences were found for diameter of the corpus luteum with 1.78±0.12cm in the EB+eCG group and 1.62±0.11cm in the EB group (p=0.047), as well as in the Progesterone dosages between the treatments GnRH+eCG (4.09±0.94ng/mL) and GnRH (2.80±0.70ng/mL), p=0.017. Regarding the variables assessed by Power Doppler, no statistical differences were found between the experimental groups. Finally, the price analysis revealed that the EB+eCG protocol is 19% cheaper than the GnRH+eCG protocol. Therefore, EB offers better cost/benefit on the reproductive parameters of buffaloes subjected to pharmacological control of the estrous cycle.