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Objective: To explore the mechanism of acupuncture on improving ovarian hypofunction in aged rats from two perspectives: the overall regulation of the hypothalamic-pituitary-ovarian (HPO) axis and the local ovarian follicle stimulating hormone (FSH)/cyclic adenosine monophosphate (cAMP) signaling pathway., Methods: Six 3-month-old female SPF-grade Sprague-Dawley (SD) rats were selected as the blank group. Another twelve 9-month-old female SD rats were randomly divided into a model group and an acupuncture group, with six rats in each. The acupuncture group received acupuncture at "Baihui" (GV20), "Guanyuan" (CV4), and bilateral "Ciliao" (BL32) for 20 min per session, once every other day, for a total of 10 sessions. Vaginal smear tests were performed daily to observe the estrous cycle of the rats. Ovarian morphology was observed using HE staining, and follicles at various stages were counted. ELISA was used to detect levels of serum FSH, luteinizing hormone (LH), estradiol (E 2 ), anti-müllerian hormone (AMH), hypothalamic gonadotropin-releasing hormone (GnRH), pituitary FSH and LH, and ovarian cAMP. Immunohistochemistry and Western blot were used to detect the protein expression of ovarian cAMP protein kinase catalytic subunit, FSH receptor (FSHR), and P450. Real-time quantitative PCR was used to measure mRNA expression levels of FSHR and P450 in ovarian tissue., Results: Compared with the blank group, the model group showed an increased rate of estrous cycle disorder ( P <0.01), reduced granulosa cell layers with blurred boundaries and disordered arrangement, decreased numbers of developing follicles at all stages, and increased numbers of atretic follicles ( P <0.01); the serum levels of FSH and LH were increased ( P <0.01), while E 2 and AMH levels were decreased ( P <0.01); the hypothalamic GnRH and pituitary FSH and LH levels were elevated ( P <0.01), and ovarian cAMP level was decreased ( P <0.01); the positive expression and protein expression of ovarian P450, cAMP protein kinase catalytic subunit, and FSHR were reduced ( P <0.01), and ovarian FSHR and P450 mRNA expression was decreased ( P <0.01). Compared with the model group, the acupuncture group showed a reduced rate of estrous cycle disorder ( P <0.01), clear granulosa cell margins, increased numbers of primordial and secondary follicles, and decreased numbers of atretic follicles ( P <0.01); the serum FSH and LH levels were decreased ( P <0.01, P <0.05), while E 2 and AMH levels were increased ( P <0.05, P <0.01); the hypothalamic GnRH and pituitary FSH and LH levels were decreased ( P <0.01, P <0.05), and ovarian cAMP level was increased ( P <0.01); the positive expression and protein expression of ovarian P450, cAMP protein kinase catalytic subunit, and FSHR were elevated ( P <0.01), and ovarian FSHR and P450 mRNA expression was increased ( P <0.01)., Conclusion: Acupuncture could delay ovarian hypofunction in aged rats, possibly through regulating the HPO axis and the FSH/cAMP signaling pathway.

The process of follicle development is closely regulated by two pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Traditionally, folliculogenesis is considered to be divided into a gonadotropin-independent phase and a gonadotropin-dependent phase. Despite this, recent evidence has demonstrated that functional LH receptors are expressed even in smaller follicles during the phase considered to be gonadotropin independent. Luteinizing hormone promotes androgen synthesis within ovarian follicles and seems to significantly contribute to accelerate and enhance the transition from the primordial to the antral stage of folliculogenesis. Thus, LH could play a fundamental role in determining the number of recruitable antral follicles, with a direct impact on the cyclic recruitment of follicles and reproductive potential. Common clinical conditions of pituitary suppression such as hypogonadotropic hypogonadism, other than pregnancy and combined oral contraceptive use, have been considered to analyze the effect of lower serum LH levels on the functional ovarian reserve. This review outlines recent findings on the mechanisms of human follicle development, based on human and animal models, with a direct focus on possible new clinical applications., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: ALM, ML, FL and SDC have nothing to declare., (© 2025. The Author(s).)

Noradrenergic neurons are a brain network that integrate viscero-sensorial signals to modulate neural and neuroendocrine function. Although it has been known for decades that noradrenergic neural circuits influence neuroendocrine and reproductive function, the cellular and molecular players involved remain largely unknown. The objective of this review is to summarize past and current knowledge regarding the influence of brainstem noradrenergic systems on GnRH and gonadotrophin secretion. The main noradrenergic cell groups A1, A2, and A6, known as the ventrolateral medulla, nucleus of the solitary tract, and locus coeruleus, respectively, are involved in the control of reproductive neuroendocrine secretion. Current evidence suggests that brainstem noradrenergic circuits promote the generation and maintenance of the LH surge in both spontaneous (rats, sheep) and induced (rabbit, ferret) ovulators. In contrast, recent studies have established that LH pulsatile secretion is suppressed by specific activation of brainstem noradrenergic cell groups. The duality of the GnRH/LH response to noradrenaline reflects the inherent complexity of hindbrain noradrenaline neurons, which are responsive to stressors and gonadal steroids (ie, estradiol) and coexpress a variety of neurotransmitters and neuropeptides. Therefore, elucidating the organization and functionality of brainstem noradrenergic systems will provide targets for controlling reproduction and understanding the interconnection with stress., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

This study investigates the causal relationships between hormone levels and growth and development of children, focusing specifically on height disparities in cases of dwarfism. Besides utilizing double-debiased machine learning approach, the study integrates three alternative causal inference methods: partialing-out lasso linear regression, cross-fit partialing-out lasso linear regression, and post-double selection LASSO. These machine learning techniques are pivotal in identifying causal effects within observational data. The findings reveal a positive correlation between luteinizing hormone (LH) levels and adolescent height, while follicle-stimulating hormone (FSH) and the LH/FSH ratio show inverse correlations. The study underscores the significant role of hormone levels, particularly LH, in determining height, offering valuable insights that could guide future interventions or treatments for children and adolescents with dwarfism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Kisspeptin and galanin-like peptide (GALP) neurons in the hypothalamic arcuate nucleus (ARC) are involved in gonadotropin-releasing hormone (GnRH) neuron-mediated pulsatile luteinizing hormone (LH) secretion. Zucker fatty (ZF) rats display a leptin receptor gene abnormality and suppressed pulsatile LH secretion. ZF rats reportedly exhibit low hypothalamic GALP and kisspeptin expression, and GALP administration induces LH release in ZF rats. Therefore, we performed a histochemical analysis to determine whether GALP-induced LH release is mediated by kisspeptin neurons in ZF rats. All ZF rats were ovariectomized and subcutaneously implanted with an estradiol tube before the central injection of GALP or vehicle. GALP administration increased the plasma LH concentration. However, no significant difference was observed in the number of Kiss1 cells and the proportion of Fos-positive Kiss1 cells. The number of c-Fos-positive GnRH neurons significantly increased after GALP administration. Our results suggest that hypothalamic GALP neurons promote LH release by activating GnRH neurons without the activation of kisspeptin neurons in the ARC., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The gonadotropin-releasing hormone (GnRH) neurons operate as a neuronal ensemble exhibiting coordinated activity once every reproductive cycle to generate the preovulatory GnRH surge. Using GCaMP fiber photometry at the GnRH neuron distal dendrons to measure the output of this widely scattered population in female mice, we find that the onset, amplitude, and profile of GnRH neuron surge activity exhibits substantial variability from cycle to cycle both between and within individual mice. This was also evident when measuring successive proestrous luteinizing hormone surges. Studies combining short (c-Fos and c-Jun) and long (genetic robust activity marking) term indices of immediate early gene activation revealed that, while ∼50% of GnRH neurons were activated at the time of each surge, only half of these neurons had been active during the previous proestrous surge. These observations reveal marked inter- and intra-individual variability in the GnRH surge mechanism. Remarkably, different subpopulations of overlapping GnRH neurons are recruited to the ensemble each estrous cycle to generate the GnRH surge. While engendering variability in the surge mechanism itself, this likely provides substantial robustness to a key event underlying mammalian reproduction., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Yeo et al.)

Polycystic ovary syndrome (PCOS) has been noticed as a neuroendocrine syndrome manifested by reproductive hormone dysregulation involving increased luteinizing hormone (LH) pulse frequency and an increased LH to follicle-stimulating hormone ratio, yet theory is just beginning to be established. Neuroglia located in the arcuate nucleus and median eminence (ARC-ME) that are close to gonadotropin-releasing hormone (GnRH) axon terminals, comprise the blood-brain barrier and fenestrated vessels implying their putative roles in the modulation of the abnormal GnRH pulse in PCOS. This review outlines the disturbances of neuron-glia networks that underlie hypothetically the deregulation of GnRH-LH release and impaired sex hormone negative feedback in PCOS. We then discuss chronic and low-grade inflammatory status together with gut dysbiosis and how the detriments may intrude the hypothalamus by virtue of violating interfaces between the brain and periphery, which might contribute to the etiology of the impaired neural circuits in the ARC-ME to induce PCOS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ovarian tissue cryopreservation addresses critical challenges in fertility preservation for prepubertal female cancer patients, such as the lack of viable eggs and hormonal deficiencies. However, mitigating follicle and granulosa cell damage during freeze-thaw cycles remains an urgent issue. Luteinizing hormone (LH), upon binding to luteinizing hormone receptors (LHR) on granulosa cells, enhances estrogen synthesis and secretion, contributing to the growth of granulosa cells and follicles. This study examined mouse ovarian follicles and granulosa cells to identify optimal LH treatments using morphological assessments and LIVE/DEAD assays. The study found significant increases in the expression of Leucine-rich G-protein-coupled receptor 5 (Lgr5) and Forkhead box L2 (Foxl2) in mural and cumulus granulosa cells under LH influence, alongside marked reductions in active caspase-3 expression. Double immunofluorescence of Ki67 with Foxl2 and Lgr5 revealed ongoing proliferative activity in granulosa cells post freeze-thaw. In addition, LH treatment significantly boosted the expression of transforming growth factor (TGF-β) and its superfamily members in both granulosa cells and oocytes. These findings suggest that LH addition during cryopreservation can diminish damage to follicles and granulosa cells, offering new strategies to enhance the efficacy of mammalian ovarian cryopreservation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The production of spermatozoa, a process known as spermatogenesis, is primarily controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-driven testosterone. LH acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing LH activity can effectively restore spermatogenesis in males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of male infertility is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of LH activity in spermatogenesis regulation and explore available preparations for therapeutic use. We also examine the evidence regarding the effectiveness of LH-containing drugs in treating specific male infertility conditions and identify the main areas for future research. Our review highlights the critical role of LH in spermatogenesis and emphasizes the potential of LH-containing drugs in treating male infertility. However, further research is required to completely elucidate the mechanisms underlying the effects of LH activity on sperm production and to establish the most effective dosages and treatment durations., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: SCE and PH declare receipt of unrestricted research grants from Merck; and lecture fees from Merck, MedEA, and Event Planet., (© 2025. The Author(s).)

Hypothyroidism causes ovarian dysfunction and infertility in women and animals and impairs the hypothalamic expression of kisspeptin (Kp). However, kisspeptin is also expressed in the genital system, and the lack of the Kp receptor (Kiss1r) in the uterus is linked to reduced implantation rates. This study investigated the impact of hypothyroidism on the uterine expression of Kp and Kiss1r in female rats throughout the estrous cycle and the associated changes in uterine activity modulators. Hypothyroidism was induced through daily administration of propylthiouracil (PTU) over a period of 14 days. Plasma levels of LH, E 2 , and P 4 , cyclicity, body and uterine weight, uterine histomorphometry, and the gene and/or protein expression of Kiss1, Kiss1r, estrogen receptor α (ERα), progesterone receptor (PR), and thyroid hormone receptor α (TRα) were assessed. Additionally, proliferative activity (CDC-47) and the gene expression of uterine receptivity mediators ( SMO , WNT4 , BMP2 , HAND2 , MUC1 , and LIF ) were evaluated. Hypothyroidism prolonged the diestrus and increased progesterone levels during this phase, while decreasing luteinizing hormone and estradiol on proestrus. In the uterus, hypothyroidism reduced Kp immunostaining on diestrus and KISS1R mRNA levels on proestrus. These changes were accompanied by reduced endometrial glands, reduced uterine proliferative activity, and reduced ERα gene and protein expression. Additionally, hypothyroidism led to reduced uterine gene expression of LIF , BMP2 , WNT4 , and HAND2 . On the other hand, thyroid hypofunction increased uterine PR and TRα immunostaining, while it reduced PGR gene expression on diestrus. These findings demonstrate that hypothyroidism reduces the expression of Kiss1/Kiss1r system in the uterus, which is associated with disrupted uterine estrogen and progesterone signaling and reduced expression of uterine receptivity mediators across the rat estrous cycle.

Background: Gonadotropin-releasing hormone agonists (GnRHa) are commonly used in assisted reproduction technology (ART) cycles to prevent a luteinising hormone (LH) surge during controlled ovarian hyperstimulation (COH) prior to planned oocyte retrieval, thus optimising the chances of live birth. We compared the benefits and risks of the different GnRHa protocols used., Objectives: To evaluate the effectiveness and safety of different GnRHa protocols used as adjuncts to COH in women undergoing ART., Search Methods: We searched the following databases in December 2022: the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, and registries of ongoing trials. We also searched the reference lists of relevant articles and contacted experts in the field for any additional trials., Selection Criteria: We included randomised controlled trials (RCTs) comparing any two protocols of GnRHa, or variations of the protocol in terms of different doses or duration, used in in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles in subfertile women., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. Our primary outcome measures were number of live births or ongoing pregnancies and incidence of ovarian hyperstimulation syndrome (OHSS) per woman/couple randomised. Our secondary outcome measures included number of clinical pregnancies, pregnancy losses, number of oocytes retrieved, amount of gonadotropins used, and cost and acceptability of the treatment protocols., Main Results: We included 40 RCTs (4148 women). The trials evaluated 10 different comparisons between protocols. The evidence is current to December 2022. Only half of the studies reported the primary outcome of live birth or ongoing pregnancy rates. We restricted the primary analysis of live birth and ongoing pregnancy to trials with low risk of selection and reporting bias. Nineteen studies compared long and short protocols. The primary analysis restricted to trials with low risk of bias included five studies reporting on live birth or ongoing pregnancy rates. Results showed little or no difference when the long protocol was compared with a short protocol (odds ratio (OR) 1.45, 95% confidence interval (CI) 0.83 to 2.52; I² = 0%; 5 studies, 381 women; low-certainty evidence). For the same comparison, there was evidence that the long protocol may improve clinical pregnancy rates when compared to the short protocol (OR 1.56, 95% CI 1.01 to 2.40; I² = 23%; 8 studies, 552 women; low-certainty evidence). No study in this comparison reported on OHSS. We are uncertain if there is a difference between groups in terms of live birth and ongoing pregnancy rates when the following GnRHa protocols were compared: long versus ultrashort (OR 1.78, 95% CI 0.72 to 4.36; 1 study, 150 women; very low-certainty evidence); long luteal versus long follicular phase (OR 1.89, 95% CI 0.87 to 4.10; 1 study, 223 women; very low-certainty evidence); GnRHa reduced-dose versus GnRHa same-dose continued in the long protocol (OR 1.59, 95% CI 0.66 to 3.87; 1 study, 96 women; very low-certainty evidence); GnRHa administration for two versus three weeks before stimulation (OR 0.88, 95% CI 0.37 to 2.05; 1 study, 85 women; very low-certainty evidence); GnRHa continued versus discontinued after human chorionic gonadotropin (HCG) administration in the long protocol (OR 0.89, 95% CI 0.49 to 1.64; 1 study, 181 women; very low-certainty evidence); and 500 µg dose versus 80 µg dose in the short protocol (OR 0.31, 95% CI 0.10 to 0.98; 1 study, 200 women; very low-certainty evidence). Clinical pregnancy rates may improve with a 100 µg dose compared to a 25 µg dose in the short protocol (OR 2.30, 95% CI 1.06 to 5.00; 2 studies, 133 women; low-certainty evidence). Only four of the 40 included studies reported adverse events. We are uncertain of any difference in OHSS rate in the GnRHa reduced-dose versus GnRHa same-dose regimen in the long protocol (OR 0.47, 95% CI 0.04 to 5.35; 1 study, 96 women; very low-certainty evidence) or when administration of GnRHa lasted for two versus three weeks before stimulation (OR 0.93, 95% CI 0.06 to 15.37; 1 study, 85 women; very low-certainty evidence). Regarding miscarriage rates, we are uncertain of any difference when the GnRHa long protocol was administered for two versus three weeks before stimulation (OR 0.93, 95% CI 0.18 to 4.87; 1 study, 85 women; very low-certainty evidence) and when a 500 µg dose was compared with an 80 µg dose in the short protocol (OR 3.15, 95% CI 0.32 to 31.05; 1 study, 131 women; very low-certainty evidence). No studies reported on cost-effectiveness or acceptability of the different treatment protocols. The certainty of the evidence ranged from low to very low. The main limitations were failure to report live birth or ongoing pregnancy rates, poor reporting of methods in the primary studies, imprecise findings due to lack of data, and insufficient data regarding adverse events. Only eight of the 40 included studies were conducted within the last 10 years., Authors' Conclusions: When comparing long and short GnRHa protocols, we found little or no difference in live birth and ongoing pregnancy rates, but there was evidence that the long protocol may improve clinical pregnancy rates overall. We were uncertain of any difference in OHSS and miscarriage rates for all comparisons, which were reported by only two studies each. There was insufficient evidence to draw any conclusions regarding other adverse effects or the cost-effectiveness and acceptability of the different treatment protocols., (Copyright © 2025 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The gonadotropin-releasing hormone (GnRH) neurons represent the key output cells of the neural network controlling mammalian fertility. We used GCaMP fiber photometry to record the population activity of the GnRH neuron distal projections in the ventral arcuate nucleus where they merge before entering the median eminence to release GnRH into the portal vasculature. Recordings in freely behaving intact male and female mice revealed abrupt ~8 min duration increases in activity that correlated perfectly with the appearance of a subsequent pulse of luteinizing hormone (LH). The GnRH neuron dendrons also exhibited a low level of unchanging clustered, rapidly fluctuating baseline activity in males and throughout the estrous cycle in females. In female mice, a gradual increase in basal activity that exhibited ~80 min oscillations began in the afternoon of proestrus and lasted for 12 hr. This was associated with the onset of the LH surge that ended several hours before the fall in the GCaMP signal. Abrupt 8 min duration episodes of GCaMP activity continued to occur on top of the rising surge baseline before ceasing in estrus. These observations provide the first description of GnRH neuron activity in freely behaving animals. They demonstrate that three distinct patterns of oscillatory activity occur in GnRH neurons. These are comprised of low-level rapid baseline activity, abrupt 8 min duration oscillations that drive pulsatile gonadotropin secretion, and, in females, a gradual and very prolonged oscillating increase in activity responsible for the preovulatory LH surge., Competing Interests: SH, SY, JK, ZZ, AH No competing interests declared, (© 2024, Han et al.)

One in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARN KISS ) neurons that represent the GnRH pulse generator are dysfunctional in PCOS. We used here in vivo GCaMP fiber photometry and other approaches to examine the behavior of the GnRH pulse generator in two mouse models of PCOS. We began with the peripubertal androgen (PPA) mouse model of PCOS but found that it had a reduction in the frequency of ARN KISS neuron synchronization events (SEs) that drive LH pulses. Examining the prenatal androgen (PNA) model of PCOS, we observed highly variable patterns of pulse generator activity with no significant differences detected in ARN KISS neuron SEs, pulsatile LH secretion, or serum testosterone, estradiol, and progesterone concentrations. However, a machine learning approach identified that the ARN KISS neurons of acyclic PNA mice continued to exhibit cyclical patterns of activity similar to that of normal mice. The frequency of ARN KISS neuron SEs was significantly increased in algorithm-identified 'diestrous stage' PNA mice compared to controls. In addition, ARN KISS neurons exhibited reduced feedback suppression to progesterone in PNA mice and their gonadotrophs were also less sensitive to GnRH. These observations demonstrate the importance of understanding GnRH pulse generator activity in mouse models of PCOS. The existence of cyclical GnRH pulse generator activity in the acyclic PNA mouse indicates the presence of a complex phenotype with deficits at multiple levels of the hypothalamo-pituitary-gonadal axis., Competing Interests: ZZ, SH, MP, EW, RD, SV, DH, AH No competing interests declared, (© 2024, Zhou et al.)

Hypothalamic kisspeptin (Kiss1) neurons are vital for maintaining fertility in the mammal. In the female rodent, Kiss1 neurons populate the anteroventral periventricular/periventricular nuclei (Kiss1AVPV/PeN) and the arcuate nucleus (Kiss1ARH). Kiss1ARH neurons (also known as KNDy neurons since they coexpress neurokinin B and dynorphin) are considered the "pulse-generator" neurons that presynaptically excite gonadotropin-releasing hormone (GnRH) axons in the median eminence, whereas the Kiss1AVPV/PeN neurons are the "surge-generator" neurons that depolarize preoptic GnRH neurons directly to drive ovulation. Traditionally, it is believed that Kiss1ARH neurons are relatively quiet during the late follicular, preovulatory stage of the reproductive cycle due to the 17β-estradiol (E2)-mediated downregulation of the expression of the KNDy peptides. However, based on our single-cell, quantitative polymerase chain reaction and whole-cell electrophysiological recordings, we found that the messenger RNA (mRNA) expression of vesicular glutamate transporter 2 (Vglut2) mRNA and excitatory cation channels in Kiss1ARH neurons were significantly upregulated by E2, which increased the excitability and glutamate release from these "pulse-generator" neurons. Presently, we demonstrate that optogenetic stimulation of Kiss1ARH neurons releases glutamate to excite Kiss1AVPV/PeN neurons via activation of both ionotropic and metabotropic glutamate receptors. CRISPR mutagenesis of Vglut2 in Kiss1ARH neurons abolished glutamatergic neurotransmission, which significantly reduced the overall glutamatergic input to Kiss1AVPV/PeN neurons. The mutagenesis of Vglut2 in Kiss1ARH neurons abrogated the E2-induced luteinizing hormone surge and reduced the formation of corpus lutea, indicative of a reduced ovulatory drive in these Vglut2-mutated Kiss1ARH mice. Therefore, Kiss1ARH neurons appear to play a critical role in augmenting the GnRH surge through glutamatergic neurotransmission to Kiss1AVPV/PeN neurons., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Knowledge of the neuroendocrine system possibly improves the reproductive performance of captivated crustacean broodstock in aquaculture and it may substitute eyestalk ablation. In this study, we explored the luteinizing hormone (LH)-like molecule and proved the existence of the LH receptor (PpelLHR)-like mRNA in the blue swimming crab, Portunus pelagicus. Using the anti-human LH-β antibody, the immunoreactivities were found in the central nervous system (CNS) and ovary of the crab with the strongest signal in the mature ovary. The full-length PpelLHR-like mRNA sequence contained 4818 bp with deduced protein predicted as seven transmembrane G-protein coupled receptor, made of 1605 amino acids. The phylogenetic tree suggested this protein belonged to the clade of invertebrate LHR/FSHR-like proteins. The PpelLHR-like mRNA expressed in various organs and real-time qPCR revealed significantly higher expression of this mRNA in the brain and lower expression in the ovary of the mature crabs. In situ hybridization of this mRNA was demonstrated in neuronal clusters of the brain, ventral nerve cord, and in the oocyte stage 1-4 of the ovary, respectively. This study was preliminary to prove the existence of LH and its receptor in the blue swimming crab. Functional assay of this receptor should be performed as the next part of experiments to firmly conclude its appearance., Competing Interests: Declaration of competing interest This manuscript has been performed with no conflict of interest from any authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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 & NOTEWORTHY: A 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Reproductive traits are vital economic parameters in goat production, and boosting the reproductive capacity of breeding rams is crucial for enhancing the profitability of goat farming. Currently, research on the reproductive performance of Qianbei Ma goats mainly centers on investigating mechanisms associated with prolificacy and estrous ovulation in ewes, with limited emphasis on ram reproductive aspects. This study used scanning electron microscopy and enzyme-linked immunosorbent assay (ELISA) to profile the morphology of testis and the dynamic changes of Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), and Testosterone (T) in serum at different developmental stages of Qianbei Ma goats. Meanwhile, transcriptome sequencing technology was used to investigate the mRNA expression patterns in testicular tissues at different developmental stages: newborn (0 M), puberty (6 M), sexual maturity (12 M), and physical maturity (18 M). The results showed that the diameter, circumference, and area of the testicular seminiferous tubules gradually increased with age. The levels of T and LH in serum significantly increased from 0 to 6 months after birth (p < 0.05), followed by a stabilization of T levels and a significant decrease in LH levels (p < 0.05). Meanwhile, FSH shows a decreasing trend between 0 and 18 months after birth. A total of 26,437 differentially expressed genes were identified in 6 comparison groups, which involve various biological processes such as immunity, growth, metabolism, development, and reproduction, and are significantly enriched in signaling pathways related to testicular development and spermatogenesis. WGCNA analysis identified 6 regions significantly associated with testicular development and spermatogenesis, and selected 320 genes for constructing a PPI network. Ten candidate genes related to testicular development and spermatogenesis were identified, including TP53, PLK4, RPS9, PFN4, ACTB, CYP17A1, GPX4, CLDN1, AMH and DHH. Of these, the CYP17A1 gene promotes interstitial cell proliferation, and promotes T synthesis. This study provides a theoretical basis and data support for promoting efficient breeding of goats and early breeding of excellent male goats., Competing Interests: Declaration of competing interest Conflicts of Interest: All authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The pituitary gonadotropin luteinizing hormone (LH) is the primary stimulus for ovulation, luteal formation, and progesterone synthesis, regardless of species. Despite increased awareness of intracellular signaling events initiating the massive production of progesterone during the reproductive cycle and pregnancy, critical gaps exist in our knowledge of the metabolic and lipidomic pathways required for initiating and maintaining luteal progesterone synthesis. Using untargeted metabolomics and metabolic flux analysis in primary steroidogenic luteal cells, evidence is provided for rapid LHCGR-stimulation of metabolic pathways leading to increased glycolysis and oxygen consumption. Treatment with LH stimulated posttranslational modifications of enzymes involved in de novo lipogenesis. Mechanistic studies implicated a crucial role for de novo fatty acid synthesis and fatty acid oxidation in energy homeostasis, LHCGR/PKA signaling, and, consequently, progesterone production. These findings reveal novel hormone-sensitive metabolic pathways essential for maintaining LHCGR/PKA signaling and steroidogenesis. Understanding hormonal control of metabolic pathways in steroidogenic cells may help elucidate approaches for improving ovarian function and successful reproduction or identifying metabolic targets for developing nonhormonal contraceptives., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Circadian rhythm disruption (CRD), stemming from sleep disorders and/or shift work, is a risk factor for reproductive dysfunction. CRD has been reported to disturb nocturnal melatonin signaling, which plays a crucial role in female reproduction as a circadian regulator and an antioxidant. The hypothalamic-pituitary-ovarian (HPO) axis regulates female reproduction, with luteinizing hormone (LH) pulse pattern playing a pivotal role in folliculogenesis and steroidogenesis. However, the effect of CRD on the HPO axis and the involvement of melatonin remains unclear. Female CBA/CaJ mice underwent CRD modeling, which involves alternating between standard light conditions and an 8-h advance schedule every 3 days for 8 weeks, whereas control mice were maintained under a standard 12:12-h light/dark (LD) cycle. Subsequent measurements of diurnal melatonin levels, LH pulse patterns assessments via serial tail-tip blood sampling and evaluations of ovarian function were conducted. CRD altered the circadian rhythms of wheel-running activity and melatonin secretion in mice and led to an augmented LH pulse pattern, evidenced by increased LH pulse frequency, mean LH levels, and pituitary LH beta-subunit (LHβ) expression, irregular estrous cycles, abnormal luteal function, altered endocrine function, and ovarian oxidative stress. Melatonin treatment (10 mg/kg/day for 4 weeks) significantly improved the HPO axis disorder in CRD mice, decreasing the enhanced LH pulse frequency and pituitary LHβ expression. These findings were further validated using an in vitro LβT2 cell perfusion model. Furthermore, melatonin restored ovarian function and scavenged reactive oxygen species, thereby preventing apoptosis and preserving ovarian function. This study offers new insights into the impact of CRD on the HPO axis and emphasizes the potential of melatonin supplementation in mitigating its effects on female reproduction., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Ovarian aging significantly impacts female fertility, with mitochondrial dysfunction emerging as a key factor. This study investigated the effects of recombinant follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on mitochondrial function and metabolism in aging female reproductive cells. Human granulosa cells (HGL5) were treated with FSH/LH or not. Mitochondrial function was assessed through various assays, including mitochondrial mass, membrane potential, ROS levels, and ATP production. Mitochondrial dynamics and morphology were analyzed using MitoTracker staining. Cellular respiration was measured using a Seahorse Bioenergetics Analyzer. Metabolic reprogramming was evaluated through gene expression analysis and metabolite profiling. In vivo effects were studied using aging mouse oocytes. FSH/LH treatment significantly improved mitochondrial function in aging granulosa cells, increasing mitochondrial mass and membrane potential while reducing ROS levels. Mitochondrial dynamics showed a shift towards fusion and elongation. Cellular respiration, ATP production, and spare respiratory capacity were enhanced. FSH/LH-induced favorable alterations in cellular metabolism, favoring oxidative phosphorylation. In aging mouse oocytes, FSH/LH treatment improved in vitro maturation and mitochondrial health. In conclusion, FSH/LH supplementation ameliorates age-related mitochondrial dysfunction and improves cellular metabolism in aging female reproductive cells., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Life histories of oviparous species dictate high metabolic investment in the process of gonadal development leading to ovulation. In vertebrates, these two distinct processes are controlled by the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), respectively. While it was suggested that a common secretagogue, gonadotropin-releasing hormone (GnRH), oversees both functions, the generation of loss-of-function fish challenged this view. Here, we reveal that the satiety hormone cholecystokinin (CCK) is the primary regulator of this axis in zebrafish. We found that FSH cells express a CCK receptor, and our findings demonstrate that mutating this receptor results in a severe hindrance to ovarian development. Additionally, it causes a complete shutdown of both gonadotropins secretion. Using in-vivo and ex-vivo calcium imaging of gonadotrophs, we show that GnRH predominantly activates LH cells, whereas FSH cells respond to CCK stimulation, designating CCK as the bona fide FSH secretagogue. These findings indicate that the control of gametogenesis in fish was placed under different neural circuits, that are gated by CCK., Competing Interests: LH, OC, MS, TA, PF, OR, PM, MG, BL No competing interests declared, (© 2024, Hollander-Cohen et al.)

Ovulation disorders are a major cause of low pregnancy rates and infertility in humans and livestock. Kisspeptin neurons located in the anteroventral periventricular nucleus (AVPV) are responsible for the generation of the gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) surge and the consequent ovulation in female rodents. The present study aimed to examine whether purinergic neurons are direct upstream stimulators of AVPV kisspeptin neurons that trigger the GnRH/LH surge and consequent ovulation in Kiss1-Cre rats. We specifically knocked down the mRNA expression of the P2rx2 purinergic receptor in AVPV kisspeptin neurons by administering an adeno-associated virus (AAV) vector containing Cre-dependent P2rx2 short hairpin RNA (shRNA) into the AVPV region of ovariectomized (OVX) Kiss1-Cre rats treated with a proestrus level of estradiol-17β (OVX + high E2) or ovary-intact Kiss1-Cre rats. The E2-induced afternoon LH surge was significantly suppressed by AVPV kisspeptin neuron-specific knockdown of P2rx2 in OVX + high E2 Kiss1-Cre rats compared with scrambled shRNA-treated control OVX + high E2 Kiss1-Cre rats. Furthermore, the specific knockdown of P2rx2 in AVPV kisspeptin neurons largely disrupted the estrous cycle, spontaneous LH surge, and ovulation in ovary-intact Kiss1-Cre rats. These findings suggest that purinergic neurons directly stimulate AVPV kisspeptin neurons via P2X2 receptors (P2RX2) to induce the GnRH/LH surge and consequent ovulation in female rats.

In Brief: The natriuretic peptide system, particularly the C-type natriuretic peptide (CNP) and natriuretic peptide receptor 2 (NPR2), plays a critical role in regulating mammalian ovarian functions, including oocyte-cumulus cell communication and meiotic maturation. However, the contribution of natriuretic peptide receptor 3 (NPR3) to these processes has not been thoroughly investigated. Data from this study provide compelling evidence that NPR3 is involved in modulating gonadotropin signaling and regulating cumulus cell expansion in cattle., Abstract: The significant role of CNP and its receptor 2 (NPR2) in regulating oocyte meiotic maturation and facilitating communication between oocytes and surrounding cumulus cells has been well documented in various mammalian species including mice, cattle and swine. However, further investigation is needed to ascertain whether natriuretic peptide receptors (NPRs) are involved in regulating other essential ovarian functions. Hence, this study aimed to explore the potential involvement of NPRs in the regulation of cumulus expansion and oocyte meiotic maturation in bovine cumulus-oocyte complexes (COCs). The findings revealed that NPR3 mRNA abundance was downregulated by follicle-stimulating hormone and luteinizing hormone in cumulus cells of bovine COCs during in vitro maturation (IVM), while NPR2 mRNA levels were not affected by gonadotropins. Inhibition of the epidermal growth factor receptor (EGFR) during IVM of COCs prevented the NPR3 mRNA downregulation induced by gonadotropins in cumulus cells. Additionally, treatment of COCs during IVM with an NPR3 agonist (cANP4-23) inhibited cumulus expansion induced by gonadotropins. This inhibitory effect was further intensified when COCs were cotreated with cANP4-23 and CNP. These findings provide robust evidence indicating that normal cumulus expansion in bovine COCs involves an inhibitory effect of gonadotropins on NPR3 mRNA expression, which is mediated via EGFR signaling. The study also provides evidence that CNP and NPR3 interact synergistically to regulate cumulus expansion in response to gonadotropins.

Background: Gui-Ling-Ji (GLJ) described in the ancient medical book 'Yunji Qijian' is a traditional Chinese medicine formula used to improve male fertility. It is now available for the treatment of oligoasthenoteratozoospermia (OAT). However, the active ingredients and mechanism of GLJ are not clear., Purpose: The aim of this study was to clarify the active ingredients and mechanism of GLJ in OAT., Methods: Firstly, the cyclophosphamide-induced OAT rat model was established to evaluate the efficacy of GLJ. Secondly, serum/urine-based metabolomics and lipidomics and tissue-based transcriptomics were performed to discover the differential metabolites and genes in rats. Furthermore, network pharmacology was constructed to explore the associated mechanisms based on the results of multi-omics analysis. Finally, cellular experiment on testicular mesenchymal stromal cells (TM3) was used to validate the active ingredients and the key metabolic pathway., Results: Rats were administered GLJ by gavage every day for 3 weeks. Testicular damage and weight loss caused by cyclophosphamide were restored in rats, the sperm count and motility were improved, and levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) secretion were also elevated. Compared to the metabolites of OAT rats, 51 and 37 differential metabolites regulated by GLJ were identified from serum and urine respectively, 54 lipid differential metabolites regulated by GLJ were identified by lipidomics. At the same time, 23 of the 258 differential genes were found to be regulated by OAT rats and then reverse-regulated by GLJ. Network pharmacology has identified 13 pathways (Steroid hormone biosynthesis, Taurine and hypotaurine metabolism, Primary bile acid biosynthesis, Linoleic acid metabolism, Retinol metabolism, Glycerophospholipid metabolism, Ether lipid metabolism, Sphingolipid metabolism, Arachidonic acid metabolism, Glutathione metabolism, Arginine biosynthesis, Arginine and proline metabolism, D-Arginine and D-ornithine metabolism), four metabolites (arachidonic acid, oestrone sulphate, phosphatidylglycerol choline and sphingomyelin) and 15 targets (ABCB11, ALDH18A1, CCL3, CD244, CIITA, CYP2C8, DLL1, ITGA4, ESR1, AR, ABCB1, ABCC1, ALB, PLA2G1B and NOS2). GLJ, psoralen, isopsoralen, liquiritin, isoliquiritin, liquiritigenin, and ginsenoside Ro could significantly promote T secretion from TM3 cells. Additionally, arachidonic acid metabolism particularly the cyclooxygenase pathway, is closely related to the promotion of testosterone secretion by GLJ in TM3., Conclusion: GLJ has a therapeutic efficacy in cyclophosphamide-induced OAT rats, which can modulate the disorders of lipid metabolism and amino acid metabolism. Arachidonic acid metabolism may be a key pathway, and six prototype compounds are potential key active ingredients for GLJ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Study Question: What is the effect of oestrogen and progesterone at the beginning of the menstrual cycle in delaying entry into the fertile window?, Summary Answer: Both oestrogen and progesterone contribute to a delay in the onset of the fertile window., What Is Known Already: Oestrogen enhances cervical mucus secretion while progesterone inhibits it., Study Design, Size, Duration: Observational study. Daily observation of 220 menstrual cycles contributed by 88 women with no known menstrual cycle disorder., Participants/materials, Setting, Methods: Women recorded cervical mucus daily and collected first-morning urine samples for analysis of oestrone-3-glucuronide, pregnanediol-3-alpha-glucuronide (PDG), FHS, and LH. They underwent serial ovarian ultrasound examinations. The main outcome measure was the timing within the cycle of the onset of the fertile window, as identified by the appearance of mucus felt or seen at the vulva., Main Results and the Role of Chance: Low oestrogen secretion and persistent progesterone secretion during the first week of the menstrual cycle both negatively affect mucus secretion. Doubling oestrogen approximately doubled the odds of entering the fertile window (OR: 1.82 95% CI=1.23; 2.69). Increasing PDG from below 1.5 to 4 µg/mg creatinine was associated with a 2-fold decrease in the odds of entering the fertile window (OR: 0.51 95% CI=0.31; 0.82). Prolonged progesterone secretion during the first week of the menstrual cycle was also statistically significantly associated with higher LH secretion. Finally, the later onset of the fertile window was associated with statistically significant persistently elevated LH secretion during the luteal phase of the previous menstrual cycle., Limitations, Reasons for Caution: This post hoc study was conducted to assess the potential impact of residual progesterone secretion at the beginning of the menstrual cycle. It was conducted on an existing data set because of the scarcity of data available to answer the question. Analysis with other datasets with similar hormone results would be useful to confirm these findings., Wider Implications of the Findings: This study provides evidence for residual progesterone secretion in the early latency phase of some menstrual cycles, which may delay the onset of the fertile window. This progesterone secretion may be supported by subtly increased LH secretion during the few days before and after the onset of menses, which may relate to follicular waves in the luteal phase. Persistent progesterone secretion should be considered in predicting the onset of the fertile window and in assessing ovulatory dysfunction., Study Funding/competing Interest(s): The authors declare no conflicts of interest. No funding was provided for this secondary data analysis., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Reproductive success requires considerable energy investment. Research has shown that some adipokines, i.e. the hormones produced in adipose tissue, affect reproductive functions by influencing all structures of the hypothalamic-pituitary-ovarian axis. Apelin is a recently identified member of the adipokine family. To the best of the authors' knowledge, this is the first study to investigate the gene and protein expression of the apelin system (the apelin hormone and the apelin receptor, APJ) in the anterior (AP) and posterior (PP) pituitary lobes of the domestic pig during different phases of the oestrous cycle (days 2 to 3, 10 to 12, 14 to 16, and 17 to 19) and in early pregnancy (days 10 to 11, 12 to 13, 15 to 16, and 27 to 28). It was also assumed that apelin participates in the regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion and influences Akt, MAPK/Erk1/2, and AMPK signalling pathways in the AP during the oestrous cycle. Apelin, APJ mRNAs and proteins were detected in both pituitary lobes. Apelin was identified in gonadotropes, somatotropes, lactotropes, and thyrotropes. The study also revealed that apelin and APJ mRNA/protein levels fluctuate during the oestrous cycle and early gestation. Apelin affects basal, GnRH- and/or insulin-stimulated gonadotropin secretion in some phases of the cycle, as well as the phosphorylation of Akt, MAPK/Erk1/2, and AMPK proteins in AP cells. These findings suggest that apelin may be produced locally in the pituitary and that this gland is receptive to apelin's action. The study also suggest that apelin may influence female reproductive functions by controlling the release of LH and FSH from AP cells, and that it affects Akt, MAPK/Erk1/2, and AMPK signalling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Kisspeptins are reported to be the most potent activators of the hypothalamus-pituitary-gonadal (HPG) axis known to date. Kisspeptin potently elicits gonadotropin-releasing hormone (GnRH) release and luteinizing hormone (LH) secretion, even in the pre-pubertal period. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network primarily implicated in emotional behaviors alongside sexual functions. Therefore, an increasing body of studies has implicated kisspeptin as having many influences on emotional behaviors. The study was set out to explore if the kisspeptin/GPR54 signaling system is required for the anti-depressant-like effect of kisspeptin-10 (KP-10), besides the regulation of the HPG axis. To test this concept, peptide 234 (P234), a kisspeptin antagonist, was given to the male rats, and its modulatory effect on the anti-depressant-like effects of kisspeptin was investigated by using a forced swimming test (FST). The study has also sought to know whether kisspeptin can exert its effects through adrenergic and serotonergic receptors. To investigate this, the agents yohimbine (Yoh), an alpha-2 adrenergic receptor antagonist, and cyproheptadine (Cry), a non-selective 5-HT2 serotonergic receptor antagonist, were administered in the experiments. Our results indicate that, in rats, the anti-depressant-like effects of KP-10 in a modified rat FST are mediated by GPR54 receptors, since the kisspeptin antagonist peptide 234 reversed kisspeptin-induced anti-depressant-like effects. Our data also demonstrate that the anti-depressant-like effects of kisspeptin, at least in part, are mediated by an interaction of the alpha-2 adrenergic and 5-HT2 serotonergic receptors.

Diabetes mellitus disturbs kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the arcuate nucleus (ARC), which regulate pulsatile luteinizing hormone (LH) secretion in both sexes. However, it remains unclear whether a sex-specific association with the negative effects of diabetes on KNDy neurons exists. Therefore, we examined mRNA expression in KNDy neurons of diabetic male and female rats 7 weeks after streptozotocin (STZ) injection using histochemistry. In gonad-intact rats, the numbers of Kiss1 and Pdyn mRNA-expressing cells in the ARC decreased in an STZ-dose-dependent manner; moreover, no sex-dependent association with STZ treatment was observed. In males, plasma LH and sex steroid levels decreased in diabetic rats. Conversely, those of females did not vary significantly between the control and diabetic rats. Kiss1 expression in the anteroventral periventricular nucleus was slightly affected in diabetic animals but did not exhibit sex-dependent differences. In gonadectomized rats, the numbers of KNDy mRNA-expressing cells in the ARC and plasma LH levels decreased in diabetic male and female rats; however, sex-dependent differences did not exist. These results demonstrated that a sex-specific association with the negative effects of diabetes on KNDy neurons did not exist. Therefore, the stage of diabetes that induces the suppression of the hypothalamus may not vary according to sex.

Aims: Clinical data supports electroacupuncture (EA) as an effective treatment for female reproductive disorders especially gonadotropin abnormalities. This study aims to detect the mechanism of EA that improves the neuroendocrine defects particularly the luteinizing hormone (LH) surge failure in early reproductive aging females., Materials and Methods: Middle-aged ovariectomized rats primed with hormone were treated by EA at acupoints CV4 and SP6 and undergone LH assay. Morphological experiments detected the activation of Kiss1 cells in the anteroventral periventricular nucleus (AVPV). Using targeted liquid chromatography with tandem mass spectrometry (LC-MS/MS) and RNA-sequencing, we determined the concentrations of neurotransmitter metabolites and transcriptomics in AVPV., Key Findings: EA significantly increased c-Fos and c-Fos-positive Kiss1 cells in the middle-aged AVPV as well as the total and peak LH release. Targeted LC-MS/MS and RNA-sequencing of AVPV identified differential neurotransmitters in the middle-aged females including Acetylcholine chloride, 5-Hydroxyindole-3-aceticacid, Kynurenine, Histamine, L-Histidine and L-Glycine, while EA decreased the concentration of Acetylcholine chloride. Totally 1255 differentially expressed genes modulated by EA were strongly implicated in neurotransmitter transport and KEGG pathways involved neuroactive ligand-receptor interaction, glutamatergic and gamma-aminobutyric acid-mediated synapse. Specifically, the mRNAs associated with the LH surge such as hormone receptor Pgr, adrenoceptor Adra1a, neurotransmitter transporters Slc17a6 and Slc32a1, glutamate decarboxylase Gad2 and Kiss1 were markedly altered by EA., Significance: These findings showed that the age-related reduction of LH surge occurred via differential neurotransmitter metabolisms and altered transcriptions in AVPV, which proposed EA-based therapy for improving responsiveness of the hypothalamus to hormone in women with advanced age., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Mercuric chloride (HgCl 2 ) is poisonous to humans and animals and typically damages the nervous system and other organs. Mercuric chloride exposition disclosed to initiation of oxidative stress pathway can result in a defect in male fertility and testis tissue. Synthesized selenium nanoparticles (SeNPs) were characterized with a diameter range minimal than 100 nm, having the effective sets of the biological matter. The present study aimed to evaluate the effect of biosynthesized SeNPs, prepared by leek extract on Wistar rats' testicles and brain., Methods: Thirty-five Wistar male rats (120-150 g) were randomly split into five groups (n = 7), orally ingested with leek aqueous extract loaded on SeNPs, and then the animals were administered with mercury II chloride (HgCl 2 ) to induce testis injury and damage the nervous system., Results: The used dose of mercuric chloride led to oxidative stress damage in the testis of the rats which was evidenced by a decrease in testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and proliferating cell nuclear antigen (PCNA) levels, and an increase in nuclear factor-kappa B (NF-κB) and caspase-3. Also, HgCl 2 decreased the levels of dopamine (DA), serotonin (5-HT), norepinephrine (NE) and brain-derived neurotrophic factor (BDNF) in the brains of rats. In addition, A decrease was observed in the levels of antioxidant markers, B-cell lymphoma-2 (Bcl-2), as well as an increase in malondialdehyde (MDA), nitric oxide (NO), NF-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and Bax in both testes and brains. Pre-treatment with leek extract loaded on SeNPs significantly ameliorated testosterone, LH, FSH, PCNA and caspase-3 levels in the testis and DA, 5-HT, NE and BDNF in brains. Although the contents of MDA, NO, TNF-α, IL-1β, NF-κB and Bax decreased significantly in both. glutathione, glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase and Bcl-2 levels were significantly improved in both organs., Conclusion: Our findings suggest that treatment with aqueous leek extract loaded on SeNPs may offer promising prospects for the advancement of anti-inflammation activity against testis injury and also have a very key role in neurobehavioral alterations as a result of mercury toxicity. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

The aim of the study was to evaluate the effect of repeated low doses of gonadotropin-releasing hormone (GnRH) agonist buserelin once a day for 5 days on follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release, and ovarian function in dairy cows with anovulation type I. The study was conducted on 10 anovulatory Polish Holstein-Friesian cows. Cows in Group 1 (n = 5) received 4 µg of buserelin intramuscularly. once a day for 5 days. Control cows from Group 2 (n = 5) received saline. Concentrations of progesterone, FSH, and LH in the blood were analysed using radioimmunoassay (RIA). Ovarian structures were monitored weekly after the end of treatment by ultrasound for 4 weeks. Injections of buserelin increased FSH and LH concentrations. Release of FSH and LH was largely variable, but there was significant (P < 0.001) interaction between time and treatment during all treatment days. The number of follicles in the treatment group was significantly greater (P = 0.029) than in the control group on day 5, the diameter of follicles on day 12 was also larger (P < 0.01) in treated than in control cows. Ovulation occurred in 4 of the 5 treated cows, but only in 1 of the control cows in the 40 days after treatment. In conclusion, repeated low doses of GnRH analogue buserelin once a day for 5 days may increase the concentration of FSH and LH in dairy cows with anovulation type I., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Daurian ground squirrels (Spermophilus dauricus) experience various stress states during winter hibernation, but the impact on testicular function remains unclear. This study focused on the effects of changes in testicular autophagy, apoptosis, and mitochondrial homeostasis signaling pathways at various stages on the testes of Daurian ground squirrels. Results indicated that: (1) During winter hibernation, there was a significant increase in seminiferous tubule diameter and seminiferous epithelium thickness compared to summer. Spermatogonia number and testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were higher during inter-bout arousal, suggesting that the testes remained stable during hibernation. (2) An increased number of mitochondria with intact morphology were observed during hibernation, indicating that mitochondrial homeostasis may contribute to testicular stability. (3) DNA fragmentation was evident in the testes during the hibernation and inter-bout arousal stages, with the highest level of caspase3 enzyme activity detected during inter-bout arousal, together with elevated levels of Bax/Bcl-2 and Lc3 II/Lc3 I, indicating an up-regulation of apoptosis and autophagy signaling pathways during hibernation. (4) The abundance of DRP1, MFF, OPA1, and MFN2 proteins was increased, suggesting an up-regulation of mitochondrial dynamics-related pathways. Overall, testicular autophagy, apoptosis, and mitochondrial homeostasis-related signaling pathways were notably active in the extreme winter environment. The well-maintained mitochondrial morphology may favor the production of reproductive hormones and support stable testicular morphology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Hyperandrogenemia is associated with polycystic ovarian syndrome (PCOS) and imbalances in the pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Apelin and its receptor, APJ (class A, rhodopsin-like G- protein-coupled receptor), belongs to adipokines, and its expression has been shown in the pituitary. It is also well known that, hyperandrogenism and PCOS have deregulation of different adipokines. Whether hyperandrogenism also deregulates the apelin system in the pituitary has yet to be investigated. Thus, we have investigated the expression and localization of apelin and its receptor, APJ, in the letrozole-induced hyperandrogenised pituitary of female mice. Our results showed that the apelin, APJ and androgen receptor (AR) expression were upregulated in the anterior pituitary. Furthermore, the immunostaining of LH exhibited increased abundance than FSH. The circulating LH was also found to be elevated compared to FSH levels. The increased LH synthesis and secretion coincides with elevated apelin system in the pituitary of hyperandrogenised mice. Recently, a direct role of apelin has also been reported in the female pituitary, where apelin inhibits LH secretion. Thus, apelin could be one of the factors for deregulated gonadotropin secretion in hyperandrogenised conditions. However, more research is needed to fully understand the complex interactions between apelin and androgen regarding gonadotropin secretion in hyperandrogenised conditions., (© 2024 Wiley Periodicals LLC.)

Disruption of the estrous cycle affects fertility and reproductive health. Follicular dynamics are key to the regularity of the estrous cycle. We identified a novel lincRNA, HEOE, showing significant upregulation in the ovaries during the estrus phase across various pig breeds. Functional analysis revealed that HEOE is responsive to luteinizing hormone (LH) stimulation, modulating transcriptional suppression and alternative splicing in ovarian granulosa cells (GCs). This leads to increased GC apoptosis and inhibition of proliferation. Mechanistically, HEOE inhibits miR-16 maturation in the nucleus, and sequesters miR-16 in the cytoplasm, thereby collectively reducing miR-16's inhibition on ZMAT3, enhancing the expression of ZMAT3, a key factor in the p53 pathway and alternative splicing, thereby regulating follicular development. This effect was validated in both mice and pig follicles. Persistent overexpression or suppression of HEOE throughout the estrous cycle impairs cycle regularity and reduces litter size. These outcomes are associated with HEOE reduced follicular PGF2α levels and modulation of the cAMP signaling pathway. Our data, combined with public databases, indicate that the high expression of HEOE during the estrus phase is crucial for maintaining the estrous cycle. HEOE is a potential therapeutic target for regulating fertility and ensuring estrous cycle regularity in pigs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In Gnathostomes, reproduction is mainly controlled by the hypothalamic-pituitary-gonadal (HPG) axis, with the involvement of the pituitary gonadotropic hormones (GTH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which activate their cognate receptors, FSHR and LHR, expressed in gonads. Each GTH consists of a common α subunit and of a specific FSHβ or LHβ subunit. Chondrichthyes (holocephalans and elasmobranchs) is a sister group of bony vertebrates. This position is highly favorable for the understanding of the evolution of endocrine regulations of reproduction among gnathostomes. Surprisingly, the characterization of gonadotropins and their receptors is still limited in chondrichthyes. In the present study, GTH and GTHR sequences have been identified from several chondrichthyan genomes, and their primary structures were analyzed relative to human orthologs. 3D models of GTH/GTHR interaction were built, highlighting the importance of the receptor hinge region for ligand recognition. Functional hormone-receptor interactions have been studied in HEK cells using the small-spotted catshark (Scyliorhinus canicula) recombinant proteins and showed that LHR was specifically activated by LH whereas FSHR was activated by both FSH and LH. Expression profiles of GTHs and their receptors were explored by real-time PCR, in situ hybridization and immunohistochemistry during spermatogenesis, along the male genital tract and other tissues, as well as in some female tissues for comparison. Tissue-expression analyses showed that the highest levels were observed for fshr transcripts in testis and ovary and for lhr in specific extragonadal tissues. The two receptors were expressed at all stages of spermatogenesis by both germ cells and somatic cells, including undifferentiated spermatogonia, spermatocytes, spermatids, somatic precursors and Sertoli cells; differentiated Leydig cells being absent in the testis of S. canicula. Receptors were also expressed by the lymphomyeloid epigonal tissue and the testicular tubules. These results, suggest a wide range of gonadotropin-regulated functions in Elasmobranchs, as well as functional redundancy during spermatogenesis. These extended functions are discussed in an evolutionary context in which the specificity of gonadotropin signaling must have contributed to the evolution of gonadal cells' morphology and function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exogenous assaults interfere with homeostatic processes in the body by inducing stress responses. Corticosteroid-binding globulin (CBG) binds to stress hormone glucocorticoids to transport and dynamically control their availability to target tissues. In our previous study, we confirmed that CBG is locally produced by Leydig cells in the testes. Here, we explored the potential regulators of CBG using a murine Leydig tumor cell line (mLTC-1). Results indicated that luteinizing hormone (LH) and interleukin-6 (IL-6) were important factors stimulating the release of CBG from mLTC-1 cells. In addition, IL-6 stimulated mLTC-1 cells to release alpha-1 antitrypsin (AAT), a serine proteinase inhibitor (serpin) that affects CBG conformation. The results implied that any challenge that altered LH or IL-6 levels also changed the release and binding status of CBG with steroid hormones in the testicular microenvironment and modulated cellular responses to these stress hormones. In addition, secretory proteomic analysis indicated that the extracellular matrix (ECM), cytoskeleton, and proteasomes were essentially produced by the mLTC-1 cells, and LH evoked the secretion of proteins involved in binding and metabolism. These results emphasize that Leydig cells may undertake more functions than just steroidogenesis, and the regulation of Leydig cells by LH is versatile., (Copyright © 2024 Elsevier Inc. All rights reserved.)

GnRH governs reproduction by regulating pituitary gonadotropins. Unlike most vertebrates, gnrh-/- zebrafish are fertile. To elucidate the role of the hypophysiotropic-Gnrh3 and other mechanisms regulating pituitary gonadotropes, we profiled the gene expression of all individual pituitary cells of wild-type and gnrh3-/- adult female zebrafish. The single-cell RNA sequencing showed that LH and FSH gonadotropes express the 2 gonadotropin beta subunits with a ratio of 140:1 (lhb:fshb) and 4:1 (fshb:lhb), respectively. Lh gonadotropes predominantly express genes encoding receptors for GnRH (gnrhr2), thyroid hormone, estrogen, and steroidogenic factor 1. No GnRH receptor transcript was enriched in FSH gonadotropes. Instead, cholecystokinin receptor-b and galanin receptor-1b transcripts were enriched in these cells. The loss of the Gnrh3 gene in gnrh3-/- zebrafish resulted in downregulation of fshb in LH gonadotropes and upregulation of pituitary hormones like TSH, GH, prolactin, and proopiomelanocortin-a. Likewise, targeted chemogenetic ablation of Gnrh3 neurons led to a decrease in the number of fshb+, lhb + and fshb+/lhb + cells. Our studies suggest that Gnrh3 directly acts on LH gonadotropes through Gnrhr2, but the outcome of this interaction is still unknown. Gnrh3 also regulates fshb expression in both gonadotropes, most likely via a non-GnRH receptor route. Altogether, while LH secretion and synthesis are likely regulated in a GnRH-independent manner, Gnrh3 seems to play a role in the cellular organization of the pituitary. Moreover, the coexpression of lhb and fshb in both gonadotropes provides a possible explanation as to why gnrh3-/- zebrafish are fertile., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: To observe the protective effect of acupuncture on ovarian function and its impact on key molecules (Yes associated protein ［YAP］ and transcriptional coactivator with PDZ binding motif ［TAZ］) in the Hippo signaling pathway in poor ovarian response (POR) mice, in order to explore its mechanisms underlying improvement of POR by inhibiting ovarian cell apoptosis., Methods: The mice with regular motility cycle after screening were randomly divided into normal control, model and acupuncture groups, with 12 mice in each group. The POR model was established by gavage of tripterygium wilfordii polyglycoside suspension (50 mg · kg -1 ·d -1 ) for 2 weeks, and the mice of the normal control group was received an equal volume of 0.9% sodium chloride solution by gavage. The mice in the acupuncture group received manual acupuncture stimulation of bilateral "Taichong" (LR3) and "Sanyinjiao" (SP6), and "Zhongji" (CV3) and "Guanyuan" (CV4), with the filiform needles retained for 20 min, once daily for successive 10 days. The estrous cycle was determined by using vaginal exfoliated cell smear, and the body mass was detected weekly. The levels of serum anti Mullerian hormone (AMH), follicle stimulating hormone (FSH), estradiol (E2) and luteinizing hormone (LH) were measured using enzyme-linked immunosorbent assay (ELISA). Histopathological changes of the ovarian tissue were observed after H.E. staining, and the apoptosis of ovarian granulosa cells was measured using terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay. The expression levels of YAP, TAZ, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), cysteine aspartic acid specific protease-3 (Caspase-3) mRNAs and proteins were detected using real-time PCR and Western blot, respectively., Results: Compared with the normal control group, the model group had an increase in the rate of estrous cycle disorder, estrous cycle, serum FSH and LH content, and apoptosis of ovarian granulosa cells, and expression levels of Bax and Caspase-3 mRNAs and p-YAP, Bax and Caspase-3 proteins ( P <0.01), and a decrease in the body mass, number of retrieved oocytes, ovarian wet weight and ovarian index, serum AMH and E2 contents, and the expression levels of YAP, TAZ, Bcl-2 mRNAs and proteins ( P <0.01). After acupuncture intervention, modeling induced increase and decrease of indexes mentioned above were completely reversed ( P <0.05, P <0.01). H.E. staining showed deformed ovarian structure, reduced number of normal developing follicles and increased number of atretic follicles, disordered arrangement of the granulosa cells with fewer hierarchy in the model group, which was improved in the acupuncture group, such as increase in the number and improvement in the shape of normal ovarian follicles and reduction of the atretic follicles., Conclusions: Acupuncture intervention can inhibit the apoptosis of ovarian granulosa cells and improve the ovarian function of POR mice, which may be related to its effects in up-regulating the expressions of YAP, TAZ (key molecules of Hippo signaling pathway).

Estrogens act through nuclear and membrane-initiated signaling. Estrogen receptor alpha (ERα) is critical for reproduction, but the relative contribution of its nuclear and membrane signaling to the central regulation of reproduction is unclear. To address this question, two complementary approaches were used: estetrol (E 4 ) a natural estrogen acting as an agonist of nuclear ERs, but as an antagonist of their membrane fraction, and the C451A-ERα mouse lacking mERα. E 4 dose- dependently blocks ovulation in female rats, but the central mechanism underlying this effect is unknown. To determine whether E 4 acts centrally to control ovulation, its effect was tested on the positive feedback of estradiol (E 2 ) on neural circuits underlying luteinizing hormone (LH) secretion. In ovariectomized females chronically exposed to a low dose of E 2 , estradiol benzoate (EB) alone or combined with progesterone (P) induced an increase in the number of kisspeptin (Kp) and gonadotropin-releasing hormone (GnRH) neurons coexpressing Fos, a marker of neuronal activation. E 4 blocked these effects of EB, but not when combined to P. These results indicate that E 4 blocked the central induction of the positive feedback in the absence of P, suggesting an antagonistic effect of E 4 on mERα in the brain as shown in peripheral tissues. In parallel, as opposed to wild-type females, C451A-ERα females did not show the activation of Kp and GnRH neurons in response to EB unless they are treated with P. Together these effects support a role for membrane-initiated estrogen signaling in the activation of the circuit mediating the LH surge., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Faure et al.)

Puberty is the critical developmental transition to reproductive capability driven by the activation of gonadotropin-releasing hormone (GnRH) neurons. The complex neural mechanisms underlying pubertal activation of GnRH secretion still remain unknown, yet likely include kisspeptin neurons. However, kisspeptin neurons reside in several hypothalamic areas and the specific kisspeptin population timing pubertal onset remains undetermined. To investigate this, we strategically capitalized on the differential ontological expression of the Kiss1 gene in different hypothalamic nuclei to selectively ablate just arcuate kisspeptin neurons (aka KNDy neurons) during the early juvenile period, well before puberty, while sparing RP3V kisspeptin neurons. Both male and female transgenic mice with a majority of their KNDy neurons ablated (KNDy ABL ) by diphtheria toxin treatment in juvenile life demonstrated significantly delayed puberty onset and lower peripubertal LH secretion than controls. In adulthood, KNDy ABL mice demonstrated normal in vivo LH pulse frequency with lower basal and peak LH levels, suggesting that only a small subset of KNDy neurons is sufficient for normal GnRH pulse timing but more KNDy cells are needed to secrete normal LH concentrations. Unlike prior KNDy ablation studies in rats, there was no alteration in the occurrence or magnitude of estradiol-induced LH surges in KNDy ABL female mice, indicating that a complete KNDy neuronal population is not essential for normal LH surge generation. This study teases apart the contributions of different kisspeptin neural populations to the control of puberty onset, demonstrating that a majority of KNDy neurons in the arcuate nucleus are necessary for the proper timing of puberty in both sexes., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Purpose: We previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly., Methods: The clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared., Results: No differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression., Conclusions: The increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors., (© 2024. The Author(s).)

Doxorubicin (DOX) can be applied to treat several cancers. DOX-induced oxidative stress causes testicular damage. Diosmin (DIO), as a potent antioxidant, reduces many drugs' side effects. We determined DIO therapeutic effects on DOX-related testicular toxicity. Forty rats were assigned to five groups as control, DOX (2.5 mg/kg six i.p. injections at equal intervals over two weeks), DOX + DIO (25, 50, 100 mg/kg, orally, daily, for two weeks) groups. Oxidative and antioxidant markers, fertility parameters levels, sperm parameters, and a histopathological examination were analyzed. DOX group showed a significant decrease in the number of spermatogonia, primary spermatocytes, and sertoli cells, seminiferous tubular diameter, seminiferous luminal diameter, and seminiferous epithelial height. Moreover, testosterone levels, glutathione (GSH) levels, catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities showed a significant decrease. Furthermore, nitric oxide (NO) and malondialdehyde (MDA) contents and also follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels showed a significant increase in the DOX group compared to the control group. DIO improved DOX-related alterations in levels of hormones, spermatogonia, spermatocytes, and sertoli cell number, and seminiferous diameters (tubular, luminal, and epithelial height). Furthermore, GSH level, SOD, GPx, and CAT activities showed a significant increase, and MDA and NO contents showed a significant decrease in the DOX + DIO group than the DOX group. The results indicate that DIO mitigate DOX-induced testicular toxicity by its anti-oxidant activity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) control antral follicular growth by regulating several processes, such as the synthesis of hormones and signaling molecules, proliferation, survival, apoptosis, luteinization, and ovulation. To exert these effects, gonadotropins bind to their respective G s protein-coupled receptors, activating the protein kinase A (PKA) pathway or recruiting G q proteins to activate protein kinase C (PKC) signaling. Although the action mechanism of FSH and LH is clear, recently, it has been shown that both gonadotropins promote the synthesis of sphingosine-1-phosphate (S1P) in granulosa and theca cells through the activation of sphingosine kinase 1. Moreover, the inhibition of SPHKs reduces S1P synthesis, cell viability, and the proliferation of follicular cells in response to gonadotropins, and the addition of S1P to the culture medium increases the proliferation of granulosa and theca cells without apparent effects on sexual steroid synthesis. Therefore, we consider that S1P is a crucial signaling molecule that complements the canonical gonadotropin pathway to promote the proliferation and viability of granulosa and theca cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuroestrogens locally synthesized in the brain are known to play a role in sexual behaviors. However, the question of whether neuroestrogens are involved in the regulation of the gonadotropin-releasing hormone (GnRH) release is just emerging. Because previous studies in this lab indicate that neuroestradiol is also important for the pulsatile release as well as the surge release of GnRH in female rhesus monkeys, in the present study, we examined whether neuroestradiol plays a role in the estrogen-induced LH surge in orchidectomized (ORX) male rhesus monkeys. Unlike in rodents, it is known that a high dose of estrogen treatment can result in the LH surge in ORX male rhesus monkeys. Results that the administration of the aromatase inhibitor, letrozole, failed to attenuate the estrogen-induced LH surge, suggest that unlike in ovariectomized females, neuroestrogens do not play a role in the LH surge experimentally induced by the exogenous estrogen treatment in ORX male monkeys., (© 2024 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Background: The efficiency and profitability of animal farming systems are closely linked to the reproductive success of livestock, which requires effective management through biological, hormonal, and nutritional strategies. The "male effect," referring to the influence of male pheromones on female reproductive hormones, offers several benefits. This leads to improved reproductive management, better timing of breeding, and increased fertility rates. Additionally, using natural pheromones provides a non-invasive and sustainable method for managing reproduction, and it can be a cost-effective strategy, reducing the need for expensive hormonal treatments. Incorporating male pheromones into reproductive management practices can thus boost the efficiency and profitability of animal farming systems., Aim: The study's objective is to examine the influence of pheromones, extracted from Awassi ram's wool and Shami goat buck's hair, on the secretion of luteinizing hormone (LH) and Progesterone (P4) in Awassi ewes during the breeding season., Methods: The pheromones were extracted using a soaking method with dichloromethane as the solvent. The resulting organic extract was then analyzed using a Chromatec-Crystal 5,000 gas chromatography-mass spectrometry device, equipped with a quadrupole mass spectrometer. The experiment was carried out on three equal groups, each consisting of 17 subjects, during the breeding season. In Group I, 15 ml of the ram's wool extract was applied to a piece of gauze and placed in a specially designed mask that was attached directly to the nose. In the second group, a similar procedure was followed using 15 ml of the buck's hair extract. The third group consisted of Awassi rams. The LH assay was conducted immediately before the treatment and again at 1, 10, and 20 hours post-treatment, and after 5 and 30 days of treatment to assess P4 levels., Results: The study found that pheromones from Awassi rams and Shami goat bucks significantly increased the levels of LH and P4 in female Awassi sheep., Conclusion: The study concludes that the pheromones extracted from the wool of rams and Shami goat bucks can stimulate the response of female Awassi sheep. This finding opens up the possibility of using these pheromones in the reproductive management of female Awassi sheep., Competing Interests: The authors declare that there is no conflict of interest.

In mammals, secretion of tonic (pulsatile) gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) is often suppressed during lactation. Suppression of GnRH/LH pulses in lactating dams is assumed to be caused by suckling stimuli and a chronic negative energy balance due to milk production. The present study aimed to investigate whether the central enkephalin-δ opioid receptor (DOR) signaling mediated the suppression of LH secretion by acute suckling stimuli and/or chronic negative energy balance due to milk production in rats during late lactation when dams were under a heavy energy demand. On postpartum day 16, the number of Penk (enkephalin mRNA)-expressing cells in the arcuate nucleus was significantly higher in lactating rats than in non-lactating control rats. Pulsatile LH secretion was suppressed in rats with chronic suckling or acute 1-h suckling stimuli 6 h after pup removal on day 16 of lactation. Central DOR antagonism significantly increased the mean LH concentrations and the baseline of LH pulses in rats with chronic suckling but not with acute suckling stimuli on day 16 of lactation. Besides, central κ opioid receptor (KOR) antagonism increased the amplitude of LH pulses in rats with the acute suckling stimuli on day 16 of lactation. These results suggest that central DOR signaling mediates the suppression of LH secretion caused by a negative energy balance in rats receiving chronic suckling during late lactation. On the other hand, central KOR signaling likely mediates acute suckling stimuli-induced suppression of LH secretion in rats during late lactation.

Follicular wave synchronization and follicular superstimulation with FSH are commonly used in OPU-IVP programs to increase oocyte developmental competence. Factors like Growth Differentiation Factor 9 (GDF9) and Bone Morphogenetic Protein 15 (BMP15), from the TGF beta superfamily, are produced by the oocyte and modulate follicular function. The aim of this study was to analyze the FSH-induced effects on (1) embryo production in dual-purpose Simmental cattle, and (2) TGF beta-mediated effects on oocyte-granulosa cell communication. Simmental heifers (n = 12, age 484 ± 62 days) underwent two OPU-IVP cycles in a cross-over design. Follicular waves were synchronized using 0.5 mg cloprostenol on Day 0, followed by 10 μg buserelin on Day 2. Subsequently, half of the heifers were randomly assigned to receive FSH/LH (four injections of 75 IU FSHp and 75IU LHp, 12 h apart on Days 4 and 5) before the first OPU, while the remaining heifers received FSH/LH before the second OPU. At the time of OPU, i.e. 7 days after the start of synchronization, granulosa cells were collected for RT-qPCR analysis. FSH treatment did not affect the number of oocytes collected (17.3 vs. 13.3, P > 0.05), but increased the percentage of quality 1 oocytes compared to controls (45.7 % vs. 22.0 %, P < 0.001). Neither cleavage (86.4 % vs. 85.7 %), nor blastocyst (42.1 % vs. 39.3 %) rate, or the number of transferable embryos produced by IVP (4.1 vs 4.8) was influenced by FSH treatment (P > 0.05 in all cases). FSH treatment increased HIF1A and FSHR levels in granulosa cells, while STAR was decreased (P = 0.008 in all cases). FSH treatment did not affect BMP15 or GDF9 mRNA expression (P > 0.05) but appeared to modulate the expression of genes involved in the BMP signaling pathway. Transcriptional levels of BMP15 receptor (BMPR1A, P = 0.016), and its downstream signaling factor SMAD1 (P = 0.008) were affected by FSH treatment. Our results demonstrated no benefit of this FSH stimulation protocol on IVP results in Simmental heifers. Further, our results suggest that the effects of FSH on bovine oocytes during acquisition of developmental competence may be mediated through BMP, but do not involve the regulation of transcriptional availability of GDF9, providing new insights into possible paracrine effects of the oocyte on granulosa cells., Competing Interests: Declaration of Competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic-pituitary-gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the molecular mechanisms in the hypothalamus regulating sexual maturation in goats. We analyzed the serum hormone profiles and hypothalamic mRNA expression profiles of female goats during sexual development (1 day old (neonatal, D1, n = 5), 2 months old (prepuberty, M2, n = 5), 4 months old (sexual maturity, M4, n = 5), and 6 months old (breeding period, M6, n = 5)). The results indicated that from D1 to M6, serum hormone levels, including FSH, LH, progesterone, estradiol, IGF1, and leptin, exhibited an initial increase followed by a decline, peaking at M4. Furthermore, we identified a total of 508 differentially expressed genes in the hypothalamus, with a total of four distinct expression patterns. Nuclear receptor subfamily 1, group D, member 1 ( NR1D1 ), glucagon-like peptide 1 receptor ( GLP1R ), and gonadotropin-releasing hormone 1 ( GnRH-1 ) may contribute to hormone secretion, energy metabolism, and signal transduction during goat sexual maturation via circadian rhythm regulation, ECM receptor interactions, neuroactive ligand-receptor interactions, and Wnt signaling pathways. This investigation offers novel insights into the molecular mechanisms governing the hypothalamic regulation of goat sexual maturation.

In this article, we will review common pituitary disorders. There are 6 hormones secreted by the anterior pituitary gland: thyroid-stimulating hormone, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, growth hormone, and prolactin. The posterior pituitary gland stores and releases the hormones made in the hypothalamus, oxytocin and antidiuretic hormone, based on the body's needs. This article will discuss the role of these hormones, conditions and symptoms that occur with elevated or reduced hormone levels, as well as the evaluation and treatment of these pituitary disorders., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The gonadotrope cells within the pituitary control vital processes of reproduction by producing follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both external stimuli and internal regulatory factors contribute to the regulation of gonadotrope development and function. In recent years, growing evidences indicate that microRNAs (miRNAs), which regulate gene expression post-transcriptionally, play critical roles in multiple processes of gonadotrope development and function, including the syntheses of α or β subunits of FSH and LH, the secretion of LH, the regulation of GnRH signaling, and the maintenance of gonadotrope cell kinetics. Here, we review recent advances of miRNAs' expression, functions and mechanisms approached by using miRNA knockout mouse models, in silico analysis and the in vitro cultures of primary pituitary cells and gonadotrope-derived cell lines. By summarizing and discussing different roles of miRNAs in gonadotropes, this minireview helps to gain insights into the complex molecular network in gonadotropes and reproduction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)