Hypothalamic-pituitary-gonadal Axis Research Articles

Intracerebroventricular injection of spexin stimulates the hypothalamic-pituitary-testicular axis and increases the secretion of male reproductive hormones in rats

BackgroundMale reproductive functions are regulated in the hypothalamic-pituitary-gonadal (HPG) axis. Any problem in this axis would lead to the deterioration of reproductive functions. The present study aimed to investigate the effects of intracerebroventricular (icv) Spexin (SPX) infusion on the HPG axis in detail. Methods40 Wistar albino rats were divided into four groups: control, sham, SPX 30 nmol and SPX 100 nmol (n=10). 30 nmol/1 µl/hour SPX was administered icv to the rats in the SPX 30 nmol group for 7 days, while rats in the SPX 100 nmol group were administered 100 nmol/1 µl/hour SPX. On the 7th day, the rats were decapitated, blood and tissue samples were collected. Serum LH, FSH and testosterone levels were determined with the ELISA method, GnRH mRNA expression level was determined in hypothalamus with the RT-PCR method. Seminiferous tubule diameter and epithelial thickness were determined with the hematoxylin-eosin staining method. ResultsSPX infusion was increased GnRH mRNA expression in the hypothalamus tissue independent of the dose (p<0.05). Serum LH, FSH and testosterone levels in the SPX groups were increased when compared to the control and sham groups independent of the dose (p <0.05). Histological analysis revealed that SPX infusion did not lead to any changes in seminiferous epithelial thickness, while the tubule diameter increased in the SPX groups (p<0.05). ConclusionThe study findings demonstrated that icv SPX infusion stimulated the HPG axis and increased the secretion of male reproductive hormones.

P-644 Effect of Letrozole co-stimulation with gonadotropin in women with normal ovarian reserve on oocyte maturation: a Randomized controlled trial

Abstract Study question To define whether letrozole co-stimulation with gonadotropin in normal-ovarian reserve women will improve the number of oocyte maturation. Summary answer Letrozole co-stimulation in normal ovarian reserve resulted in a reduced number of MII. What is known already Letrozole functions as an aromatase inhibitor. By inhibiting this enzyme, letrozole effectively lowers estrogen levels. Thus, letrozole prevents the estrogen-negative feedback to the HPO axis, which can increase the secretion of gonadotropins from the pituitary gland to promote folliculogenesis. The application of letrozole co-stimulation in women with a normal ovarian reserve is still debated. Study design, size, duration This study is an open-labeled, randomized controlled trial. Letrozole co-stimulation with gonadotropin in women with normal ovarian reserve. The RCT was conducted at the Fertility and Reproductive Biology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Siriraj Hospital in Thailand, from March 2023 to October 2023. Participants/materials, setting, methods One hundred forty-four infertile women 18-40 years old with normal ovarian reserve (AMH 1.2-7 ng/ml, AFC ≥ 5) were random to gonadotropin co-stimulation with letrozole 5 mg once daily (n = 72) and gonadotropin alone (n = 72). The number of MII oocytes, follicle-to-oocyte index, GDF-9 and BMP-15 in follicular fluid were assessed. Main results and the role of chance Letrozole co-stimulation resulted in a significantly reduced number of MII [8 (4,12) vs 9 (5, 15.8), p = 0.042] and the rate of MII [ 71.7(60, 83.8) vs 80 (66.7, 90), p = 0.013]. However, the number of retrieved oocytes [12 (6,16.8) vs. 12 (6,16), p = 0.335] and FOI [85.7 (57.4,107.5) vs 84.2 [61.8, 112.5], p = 0.396] remained unchanged. The total dose of gonadotropin in the letrozole group was no different from the control group [1,350 (1,200, 1,650) vs 1,500 (1,350, 1,718.8) I.U., p = 0.137]. The duration of ovarian stimulation was shortened in the letrozole group compared to the control group [9 (8, 10) vs 9 (8.3, 10) days, p = 0.027]. The letrozole and control group had a similar level of GDF-9 (0.036 ± 0.003 A.U. vs. 0.028 ± 0.004 A.U., p = 0.119, letrozole and control group, respectively) and BMP-15 (0.034 ± 0.002 A.U. vs. 0.033 ± 0.004 A.U., p = 0.923, letrozole and control group respectively) in follicular fluid. Limitations, reasons for caution This study was open-label, with limited generalizability due to 91% of ovarian stimulation being strict to the research protocol (r-FSH and antagonist protocol) and no pregnancy outcome. Wider implications of the findings The study showed no benefit of letrozole co-stimulation in women with normal ovarian reserve. Trial registration number TCTR20221125002

P-449 Association of corpus luteum activity in early pregnancy and live birth after assisted reproductive technology (ART) and intrauterine insemination (IUI)

Abstract Study question What is the incidence of low corpus luteum activity in early pregnancy, and how are endogenous progesterone levels and live birth achievement associated? Summary answer Frequently occurring low corpus luteum activity (progesterone-level) in early pregnancy after ART and IUI strongly predicts pregnancy demise, though not independent of trophoblast activity (hCG-level). What is known already Ovarian stimulation and human chorion gonadotropine (hCG) administration may induce a luteal phase defect via negative feedback on the hypothalamic-pituitary-ovarian (HPO) axis. Luteal phase support (LPS) is routinely administered with bio-identical progesterone or oral dydrogesterone (DYD). DYD has high oral availability, minimal interaction with the pituitary gland, and no cross-reactivity in enzyme-linked immunosorbent assay (ELISA) with progesterone. Therefore, utilizing DYD as LPS in IVF/ICSI or ovulatory IUI cycles provides a unique perspective to assess endocrine luteal activity. While various studies explored progesterone and hCG post-IVF or IUI, none focused solely on the corpus luteum’s sole endocrine function and its outcomes. Study design, size, duration This single-center, retrospective study (with institutional review board approval) investigated hCG and progesterone serum levels after IVF/ICSI cycles or IUI cycles supported with DYD as the sole LPS. The study aims to assess their predictive value, individually and in combination, for sustaining pregnancy. Data from 189 IVF/ICSI and 198 IUI early pregnancies, respectively, with positive hCG test between January 2017 and June 2022, was extracted from the patient management system at the University Fertility Center. Participants/materials, setting, methods Included were only first IVF/ICSI and IUI treatment-cycles with serum hCG value ≥ limit of detection (0.6 IU/l) between days 9 and 16 after fresh embryo transfer or IUI, respectively. Additionally to hCG, endogenous progesterone was determined and the relationship between these and pregnancy maintenance was investigated using logistic regression analysis. Inclusion criteria encompassed hCG-triggered cycles using DYD as the sole LPS, administered at 30 and 20 mg daily for IVF/ICSI and IUI therapy, respectively. Main results and the role of chance The 10th, 25th, 50th and 75th quantiles of serum progesterone are at 0.28, 3.75, 33.0 and 98.7 µg/l in IVF/ICSI cycles and 0.48, 2.70, 18.40 and 26.6 µg/l in IUI cycles. Women in the first quartile of progesterone levels had nearly exclusively pregnancy demise: live birth rate 3/47 (7%, 95% confidence interval (CI) 1-19%) and 0/47 (0%, 95% CI 0-7.5%) in IVF/ICSI and IUI cycles, respectively. In both IVF/ICSI and IUI, progesterone and hCG were highly correlated (correlation coefficient 0.83 in both cases). Accordingly, the association of serum hCG levels with live birth achievement was similar in quartile analyses. Using receiver operating characteristic (ROC) curves and Youden’s indices, the optimal cut-off values for predicting live birth were determined as follows: 16.49 µg/l (89 % sensitivity (SN) and 59 % specificity (SP)) for IVF/ICSI and 15.89 µg/l (90 % SN and 70 % SP) for IUI therapy. Logarithmic regression analysis also revealed a significant correlation between progesterone levels and live birth in IVF/ICSI and IUI therapy, with a p-value of &amp;lt; 0.001. Limitations, reasons for caution Low progesterone in early pregnancy may be a consequence or a cause for pregnancy demise. DYD, like any other progesterone for LPS, might adversely impact corpus luteum formation and maintenance through HPO axis interaction, especially in mono-ovulatory cycles or in older women with inherently higher risk of luteal phase defect. Wider implications of the findings Ovarian stimulation and hCG-administration may induce a luteal phase defect with insufficient luteal activity in early pregnancy, even up to luteolysis, with potential consequences for pregnancy maintenance and maternal/fetal health. Future treatment protocols may require exploring an optimal luteotropic state at pregnancy’s outset, necessitating the establishment of relevant markers. Trial registration number not applicable

Genetic hypogonadal (Gnrh1hpg) mouse model uncovers influence of reproductive axis on maturation of the gut microbiome during puberty.

The gut microbiome plays a key role in human health and gut dysbiosis is linked to many sex-specific diseases including autoimmune, metabolic, and neurological disorders. Activation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty leads to sexual maturation and development of sex differences through the action of gonadal sex steroids. While the gut microbiome also undergoes sex differentiation, the mechanisms involved remain poorly understood. Using a genetic hypogonadal (hpg) mouse model, we sampled the fecal microbiome of male and female wild-type and hpg mutant mice before and after puberty to determine how microbial taxonomy and function are influenced by age, sex, and the HPG axis. We showed that HPG axis activation during puberty is required for sexual maturation of the gut microbiota composition, community structure, and metabolic functions. We also demonstrated that some sex differences in taxonomic composition and amine metabolism developed independently of the HPG axis, indicating that sex chromosomes are sufficient for certain sex differences in the gut microbiome. In addition, we showed that age, independent of HPG axis activation, led to some aspects of pubertal maturation of the gut microbiota community composition and putative functions. These results have implications for microbiome-based treatments, indicating that sex, hormonal status, and age should be considered when designing microbiome-based therapeutics.

The direct effect of SARS-CoV-2 virus vaccination on human ovarian granulosa cells explains menstrual irregularities

Following administration of the SARS-CoV-2 vaccine, many women worldwide reported short-term menstrual irregularities. Although menstrual bleeding, “the fifth vital sign”, is experienced by more than 300 million people on any given day worldwide, these changes were only partially studied. Irregular periods are important well beyond fertility and the discomfort they impose; they are associated with the risk of cardiovascular morbidity, chronic diseases, and premature mortality. Pre-clinical examination of the vaccine polymeric envelope indicates its accumulation in the ovaries. The somatic endocrine cells of the ovarian follicle - the granulosa cells (GCs)—participate in the strict hypothalamic-pituitary-ovarian (HPO) feedback loop that governs the menstrual cycle via endocrine and paracrine regulators, as AMH and Inhibins. We aimed to unravel the direct effect of the COVID-19 vaccine on GCs and link their post-vaccine activity to changes in menstrual patterns. Human primary GCs exposed in-vitro to the Pfizer COVID-19 vaccine BNT162b2, demonstrated no change in their viability but altered mRNA transcripts, specifically of the regulatory key factors: InhibinB was upregulated, whereas AMH was downregulated. We further examined pre- and post-vaccination blood samples from individual women and found a 2–3 folds change in the post-vaccination FSH/InhibinB protein level ratio, compared to their pre-vaccination values. This altered expression of InhibinB could significantly impact the HPO axis in vaccinated women and may ultimately influence the endometrium cyclicity, manifested clinically by the commonly reported changes in menstrual bleeding patterns.

Disruptions in reproductive health, sex hormonal profiles, and hypothalamic hormone receptors content in females of the C58/J mouse model of autism

Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive behaviors. Recent studies have highlighted a higher prevalence of endocrine and reproductive disturbances among females on the autism spectrum, hinting at potential disruptions within the hypothalamus-pituitary-ovary (HPO) axis. This research aims to explore the reproductive health disparities in ASD using an animal model of autism, the C58/J inbred mouse strain, with a focus on reproductive performance and hormonal profiles compared to the C57BL/6J control strain.Our findings revealed that the estrous cycle in C58/J females is disrupted, as evidenced by a lower frequency of complete cycles and a lack of cyclical release of estradiol and progesterone compared to control mice. C58/J females also exhibited poor performance in several reproductive parameters, including reproductive lifespan and fertility index. Furthermore, estrogen receptor alpha content showed a marked decrease in the hypothalamus of C58/J mice. These alterations in the estrous cycle, hormonal imbalances, and reduced reproductive function imply dysregulation in the HPO axis. Additionally, our in-silico study identified a group of genes involved in infertility carrying single-nucleotide polymorphisms (SNPs) in the C58/J strain, which also have human orthologs associated with autism. These findings could offer valuable insights into the molecular underpinnings of neuroendocrine axis disruption and reproductive issues observed in ASD.

Long-term carbaryl exposure leads to behavioral abnormalities and reproductive toxicity in male marine medaka through apoptosis-mediated HPA and HPG axes dysregulation

Carbaryl is a widely used carbamate pesticide that has been detected in the marine environment, but its effects on marine fish are still unknown. This study was aimed to investigate the effects of long-term exposure of carbaryl on male marine medaka. For this purpose, we set up five exposure concentration groups of 0, 0.1, 1, 10, and 100 µg/L for 180 days. On the one hand, we observed increased aggression and decreased ability to avoid predators in males after exposure, which was affected by the levels of HPA-axis hormones, especially decreased cortisol level. On the other hand, after exposure, HPG axis hormone levels and gene transcription levels were disturbed. Males exhibited a decreased gonadosomatic index and a notable reduction in mature sperm proportion and the F1 generation displayed a significant increase in malformation rate. Additionally, the number of apoptotic cells and the transcription level of apoptosis-related genes in the brains of male marine medaka substantially increased after exposure. Apoptosis of brain cells may be responsible for the disturbance of HPA and HPG axes, consequently leading to behavioral and reproductive abnormalities. These findings provide novel insights into evaluating the toxic effects of carbaryl on male marine medaka and emphasizing the criticality of exploring the potential environmental risks posed by carbaryl in the marine environment, thus providing toxicity value basis for further strengthening marine environmental monitoring and the protection of biological resources.

Bmal1 regulates female reproduction in mice via the hypothalamic-pituitary-ovarian axis.

The hypothalamic-pituitary-gonadal axis (HPG) is the key neuroendocrine axis involved in reproductive regulation. Brain and muscle ARNT-like protein 1 (Bmal1) participates in regulating the metabolism of various endocrine hormones. However, the regulation of Bmal1 on HPG and female fertility is unclear. This study aims to explore the regulation of female reproduction by Bmal1 via the HPG axis in mice. Bmal1-knockout (Ko) mice were generated using the CRISPR/Cas9 technology. The structure, function, and estrous cycle of ovarian in Bmal1 Ko female mice were measured. The key genes and proteins of the HPG axis involved in regulating female reproduction were examined through transcriptome analysis and then verified by RT-PCR, immunohistochemistry, and western blot. Furthermore, the fertility of female mice was detected after intervening prolactin (PRL) and progesterone (Pg) in Bmal1 ko mice. The number of offspring and ovarian weight were significantly lower in Bmal1-Ko mice than in wild-type (Wt) mice. In Bmal1-Ko mice, ovarian cells were arranged loosely and irregularly, and the total number of follicles was significantly reduced. No corpus luteum was found in the ovaries. Vaginal smears revealed that Bmal1-Ko mice had an irregular estrus cycle. In Bmal1-Ko mice, Star expression was decreased, PRL and luteinizing hormone (LH) levels were increased, and dopamine (DA) and Pg levels were decreased. Inhibition of PRL partially recovered the estrous cycle, corpus luteum formation, and Star expression in the ovaries. Pg supplementation promoted embryo implantation in Bmal1-Ko female mice. Bmal1 Ko increases serum PRL levels in female mice likely by reducing DA levels, thus affecting luteal formation, resulting in decreased Star expression and Pg production, hindering female reproduction. Inhibition of PRL or restoration of Pg can partially restore reproductive capacity in female Bmal1-Ko mice. Thus, Bmal1 may regulate female reproduction via the HPG axis in mice, suggesting that Bmal1 is a potential target to treat female infertility.

Melatonin influences reproduction in the sapphire devil Chrysiptera cyanea via regulation of dopamine 2b receptor transcription

Melatonin and dopamine participate in the regulation of reproduction-related hormone/peptide synthesis and secretion at the hypothalamic–pituitary–gonadal axis in fish. Here, we report a unique reproduction-related interaction of melatonin and dopamine in the brain of the sapphire devil Chrysiptera cyanea, a tropical damselfish with a long-day preference. We examined the expression of arylalkylamine N-acetyltransferase 2 (aanat2)—a rate-limiting enzyme of melatonin, dopamine 2b receptor (d2b), gonadotropin-releasing hormone (gnrh1), and β-subunit of follicle-stimulating hormone (fshβ) and luteinizing hormone (lhβ)—in the brain of the sapphire devil. During the reproductive season, mature females were divided into the early vitellogenesis (EV), late vitellogenesis (LV), and post-spawning (PS) stages; a day-low and night-high profile of aanat2 was observed during EV and LV but not during PS. There were nocturnal increases in gnrh1 during EV and LV as well as d2b during LV, suggesting that melatonin has a positive effect on the levels of gnrh1 and d2b transcripts in mature fish. When the brains of females in the non-breeding season were sampled at 4-h intervals, nocturnal increases in the levels of fshβ and lhβ transcripts were observed at 00:00 and 04:00, respectively. The immersion of immature fish in melatonin-containing seawater for 6 h resulted in the upregulation of fshβ and lhβ, as well as downregulation of d2b, in the brain. Additionally, in situ hybridization analysis showed that melatonin treatment lowered the signals of d2b transcripts in the ventral hypothalamus, rostral pars distalis, proximal pars distalis, and pars intermedia, suggesting that melatonin has a negative impact on the levels of d2b transcripts in the hypothalamus and pituitary of immature females; the opposite effect is likely concerning the levels of fshβ and lhβ transcripts in the pituitary. In conclusion, melatonin positively and negatively acted on the hypothalamus and pituitary in the sapphire devil; these opposite effects were related to differences in gonadal development status.

Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic-pituitary-gonadal axis1.

G protein-coupled receptors (GPCRs) are central to the functioning of the hypothalamic-pituitary-gonadal axis (HPG axis) and include the rhodopsin-like GPCR family members, neurokinin 3 receptor, kappa-opioid receptor, kisspeptin 1 receptor, gonadotropin-releasing hormone receptor, and the gonadotropin receptors, luteinizing hormone/choriogonadotropin receptor and follicle-stimulating hormone receptor. Unsurprisingly, inactivating variants of these receptors have been implicated in a spectrum of reproductive phenotypes, including failure to undergo puberty, and infertility. Clinical induction of puberty in patients harbouring such variants is possible, but restoration of fertility is not always a realisable outcome, particularly for those patients suffering from primary hypogonadism. Thus, novel pharmaceuticals and/or a fundamental change in approach to treating these patients are required. The increasing wealth of data describing the effects of coding-region genetic variants on GPCR function has highlighted that the majority appear to be dysfunctional as a result of misfolding of the encoded receptor protein, which, in turn, results in impaired receptor trafficking through the secretory pathway to the cell surface. As such, these intracellularly retained receptors may be amenable to 'rescue' using a pharmacological chaperone (PC)-based approach. PCs are small, cell permeant molecules hypothesised to interact with misfolded intracellularly retained proteins, stabilising their folding and promoting their trafficking through the secretory pathway. In support of the use of this approach as a viable therapeutic option, it has been observed that many rescued variant GPCRs retain at least a degree of functionality when 'rescued' to the cell surface. In this review, we examine the GPCR PC research landscape, focussing on the rescue of inactivating variant GPCRs with important roles in the HPG axis, and describe what is known regarding the mechanisms by which PCs restore trafficking and function. We also discuss some of the merits and obstacles associated with taking this approach forward into a clinical setting.

Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome

AimsPrecocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut–brain disease. On the other hand, the use of glycyrrhizin, a natural sweetener, has become popular in the past decade. Glycyrrhizin possesses various health benefits, but its impact on PP has yet to be investigated. We aimed to explore the protective effects of glycyrrhizin against PP in both humans (observational) and animals (interventional). Materials and methodsIn the human cohort, we investigated the association between glycyrrhizin consumption and risk of PP. In the animal experiment, we observed puberty onset after feeding danazol-induced PP rats with glycyrrizin. Blood, fecal, and hypothalamic samples were harvested to evaluate potential mechanistic pathways. We also performed a fecal microbiota transplantation to confirm to causal relationship between glycyrrhizin and PP risk. Key findingsGlycyrrhizin exhibited a protective effect against PP in children (OR 0.60, 95%CI: 0.39–0.89, p = 0.013), primarily driven by its significance in girls, while no significant effect was observed in boys. This effect was consistent with findings in rodents. These benefits were achieved through the modulation of the gut microbiome, which functionally suppressed the hypothalamic–pituitary–gonadal axis and prevented PP progression. A fecal microbiota transplantation indicated that the causal correlation between glycyrrhizin intake and PP is mediated by the gut microbiome alterations. SignificanceOur findings suggest that glycyrrhizin can protect against PP by altering the gut microbiome. Long term use of glycyrrhizin is safe and tolerable. Therefore, glycyrrhizin can serve as a safe and affordable complementary therapy for PP.

Regulating effect of Gegen Decoction on hypothalamic-pituitary-ovarian axis in mice with primary dysmenorrhea

This study aimed to explore the regulating effect of Gegen Decoction(GGD) on the hypothalamic-pituitary-ovarian axis(HPOA) dysfunction in the mouse model of primary dysmenorrhea(PD). The mouse model of PD with periodic characteristics was established by administration of estradiol benzoate and oxytocin. Mice were randomized into control, model, GGD, and ibuprofen groups. The writhing response, hypothalamus index, pituitary index, ovary index, and uterus index were observed and determined. The serum levels of prostaglandin F_(2α)(PGF_(2α)), gonadotropin-releasing hormone(GnRH), follicle-stimulating hormone(FSH), luteinizing hormone(LH), and estrogen(E_2) levels were measured by ELISA kits. Western blot and qPCR were employed to determine the protein and mRNA levels, respectively, of gonadotropin-releasing hormone receptor(GnRH-R) in the pituitary tissue, follicle-stimulating hormone receptor(FSHR) and luteinizing hormone receptor(LHR) in the ovarian tissue, and estrogen receptor(ER) in the uterine tissue. The results showed that the writhing response, serum levels of PGF_(2α), GnRH, FSH, LH, and E_2, ovarian and uterine indexes, the protein and mRNA levels of GnRH-R in the pituitary tissue, FSHR and LHR in the ovarian tissue, and ER in the uterine tissue were significantly increased in the model group compared with those in the control group. GGD inhibited the writhing response, reduced the serum levels of PGF_(2α), GnRH, FSH, LH, and E_2, decreased the ovarian and uterine indexes, and down-regulated the protein and mRNA levels of GnRH-R in the pituitary tissue, FSHR and LHR in the ovarian tissue, and ER in the uterine tissue. The data suggested that GGD can regulate the HPOA and inhibit E_2 generation in the mice experiencing recurrent PD by down-regulating the expression of proteins and genes related to HPOA axis, thus exerting the therapeutic effect on PD.

Association of salivary testosterone levels during the post-awakening period with age and symptoms suggestive of late-onset hypogonadism in men

Background The lack of association between serum testosterone levels and symptoms suggestive of hypogonadism is a significant barrier in the determination of late-onset hypogonadism (LOH) in men. This study explored whether testosterone levels increase after morning awakening, likewise the cortisol awakening response (CAR) in the hypothalamic–pituitary–adrenal (HPA) axis, and whether testosterone levels during the post-awakening period are associated with age and symptoms suggestive of late-onset hypogonadism (LOH) in men. Methods Testosterone and cortisol levels were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening, and scores of the Aging Males’ Symptoms (AMS) questionnaire were obtained from 225 healthy adult men. Results A typical CAR (an increase in cortisol level ≥ 2.5 nmol/L above individual baseline) was observed in 155 participants (the subgroup exhibiting typical CAR). In the subgroup exhibiting CAR, testosterone levels sharply increased during the post-awakening period, showing a significant negative correlation with age, total AMS score, and the scores of 11 items on the somatic, psychological, and sexual AMS subscales. Of these items, three sexual items (AMS items #15–17) were correlated with age. Meanwhile, there was no notable increase in testosterone levels and no significant correlation of testosterone levels with age and AMS score in the subgroup exhibiting no typical CAR (n = 70). Conclusions The results indicate that the hypothalamus-pituitary-gonad (HPG) axis responds to morning awakening, and determining testosterone levels during the post-awakening period in men with typical CAR may be useful for assessing HPG axis function and LOH.

Total osteocalcin levels are independently associated with worse testicular function and a higher degree of hypothalamic–pituitary–gonadal axis activation in Klinefelter syndrome

PurposeThe role of osteocalcin (OCN) in pubertal development, male hypogonadism, and the effect of testosterone (Te) replacement therapy (TRT) remains unclear. We aimed to investigate the total OCN (tOCN) concentrations in male patients with Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism.MethodsThis retrospective longitudinal study investigated 254 male patients with KS (47,XXY) between 2007 and 2021 at an academic referral center, categorized as (1) prepubertal, (2) pubertal, and (3) adults. All prepubertal patients were Te-naïve. Adult patients were subcategorized as (1) eugonadal, (2) hypogonadal, and (3) receiving TRT. We also analyzed 18 adult patients with available tOCN levels before and 3 months after TRT commencement.ResultsThe tOCN levels varied throughout the lifespan according to pubertal status, were highest in eugonadal and significantly lower in TRT subjects, correlated with both LH (p = 0.017) and FSH levels (p = 0.004) in adults, and significantly declined after 3 months of TRT (p = 0.006) in the adult KS cohort. HPG-axis hormones levels demonstrated no correlation in prepubertal boys. Adjustment for age and body mass index confirmed previous results and revealed significant inverse correlations with total Te (p = 0.004), calculated free Te (p = 0.016), the Te/LH (p = 0.010), and calculated free Te/LH ratios (p = 0.031).ConclusionIn KS, a model of male hypergonadotropic hypogonadism, tOCN levels were not associated with gonadal function during normal prepuberty and pubertal development but were associated with worse testicular function and a higher degree of HPG stimulation in adults. TRT acutely reduced tOCN levels in adults.

Body Condition in Small Ruminants—Effects of Nutrition on the Hypothalamic–Pituitary–Gonad Axis and Ovarian Activity That Controls Reproduction

Nutritional status plays a vital role in regulating ovary activity. This regulation is mediated by the hypothalamus–pituitary–gonad axis and by effects exerted directly on the ovary. Therefore, to achieve the best reproductive performance, it is essential to know how the nutritional status affects the secretion of GnRH, gonadotrophins, and sex steroid hormones. Adequate body reserves and energy balance are critical for optimal reproductive performance in sheep and goats. However, over- or under-conditioned animals experience issues like extended anestrus, irregular ovarian cycles, and reduced conception. Body condition scoring allows for the evaluation of the relationships between adiposity, nutritional status, and fertility. Acute feed deficits briefly stimulate processes, but chronic restrictions suppress pulsatile LH release, disrupting ovarian function. The process of follicle development is a very complex one which involves intricate interactions between the pituitary gonadotrophins and metabolic hormones as well as between the locally produced factors by the ovarian somatic and germ cells including the IGF system and the TGF-β superfamily members. Genotype and nutrition are factors that have an impact on follicular development, and seasonal factors are also involved. This review will give a brief overview on how the body condition can be evaluated and the effects of nutrition on the hypothalamus–pituitary–gonad axis and ovarian activity, which are responsible for reproductive regulation. This paper presents a clear and reasonable summary of the pathway that runs from the nutritional status of small ruminants to ovarian activity through the hypothalamic–pituitary–gonadal axis. This review summarizes methods for body condition evaluation in small ruminants and evidence regarding acute versus prolonged nutritional impacts on the hypothalamic–pituitary–gonadal axis and ovarian activity controlling reproduction.

Intracerebroventricular PROK2 infusion could increase the secretion of male reproductive hormones by stimulating the HPG axis.

Prokineticin 2 (PROK2), an important neuropeptide that plays a key role in the neuronal migration of gonadotropin-releasing hormone (GnRH) in the hypothalamus, is known to have regulatory effects on the gonads. In the present study, the impact of intracerebroventricular (icv) PROK2 infusion on hypothalamic-pituitary-gonadal axis (HPG) hormones, testicular tissues, and sperm concentration was investigated. Rats were randomly divided into four groups: control, sham, PROK2 1.5 and PROK2 4.5. Rats in the PROK2 1.5 and PROK2 4.5 groups were administered 1.5nmol and 4.5nmol PROK2 intracerebroventricularly for 7days via an osmotic mini pump (1µl/h), respectively. Rat blood serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone hormone levels were determined with the ELISA method in the blood samples after 7days of infusion. GnRH mRNA expression was determined with the RT-PCR in hypothalamus tissues. analyze Sperm concentration was determined, and testicular tissue was examined histologically with the hematoxylin-eosin staining method. It was observed that GnRH mRNA expression increased in both PROK2 infusion groups. Serum FSH, LH and testosterone hormone levels also increased in these groups. Although sperm concentration increased in PROK2 infusion groups when compared to the control and sham, the differences were not statistically significant. Testicular tissue seminiferous epithelial thickness was higher in the PROK2 groups when compared to the control and sham groups. The present study findings demonstrated that icv PROK2 infusion induced the HPG axis. It could be suggested that PROK2 could be a potential agent in the treatment of male infertility induced by endocrinological defects.

Expression of genes related to gonadal development and construction of gonadal DNA methylation maps of Trachinotus blochii under hypoxia

Chronic hypoxia can affect the growth and metabolism of fish and potentially impact gonadal development through epigenetic regulation. Trachinotus blochii (Golden pompano) is widely cultured near the coast and is sensitive to low oxygen conditions. We found that hypoxia and reoxygenation processes acted on multiple targets on the HPG axis, leading to endocrine disorders. Changes in the expression of key genes in the brain (gnrh), pituitary (fsh and lh), ovaries (cyp19a1a, foxl2, and er), and testes (dmrt1, ar, sox9, and gsdf) were associated with significant decreases in estrogen and testosterone levels. Hypoxia and reoxygenation lead to changes in DNA methylation levels in the gonads. Hypoxia upregulated the expression of dnmt1, dnmt3a, dnmt3b, tet1, and tet2 in females and dnmt3a and dnmt3b in males, while reoxygenation down-regulated the expression of dnmt1, dnmt3a, dnmt3b, tet1, and tet2 in males. Whole genome methylation sequencing showed that the number of differentially methylated regions was highest on chromosome 10 (5192) and lowest on chromosome 24 (275). Differentially methylated genes in females and males, as well as between males and females, were enriched in the oxytocin signaling pathway, fatty acid metabolism pathway, and HIF-1a pathway. In summary, hypoxia and reoxygenation can induce endocrine disorders, affect the expression of HPG axis genes, change the methylation pattern and modification pattern of gonad DNA, and then have potential effects on gonad development.

Chronic Lead Exposure Impairment of Hypothalamic-Pituitary-Gonadal Axis in Adult Male Wistar Rats: Biochemical and Histomorphological Evidence

Introduction: The upsurge in male infertility has been associated with impaired hypothalamic-pituitary-gonadal (HPG) axis. There is a dearth of conclusive empirical data as to the deleterious impacts of heavy metal intoxication on male reproductive functioning through the HPG axis. Objective: This study seeks to elucidate the possible effects of chronic lead exposure on HPG signalling activities via biochemical and histopathological assessment. Experimental Section/Material and Methods: Forty adult male Wistar rats were randomised into four experimental groups (n=10). Group A, the control group received standard feed and water ad libitume. In Groups B, C and D, animals were orally administered lead acetate at concentrations of 2.5% 3.0% and 3.5%, respectively, using a stock solution of 150mg/kg once daily for 35 days. After the treatment period, all animals were fasted overnight and euthanized by cervical dislocation. Blood levels of anterior pituitary hormones (FSH and LH) were analysed using standard methods. Statistical analyses was done on graph pad prism. Testicular tissue was processed routinely for histopathological analyses using different stains. Results: Hormonal assays showed no significant changes in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (p&gt;0.05) levels across groups. However, histological examination revealed alterations in testicular architecture, including disrupted spermatogonia cell arrangement and reduced Sertoli cell numbers, indicative of adverse effects on spermatogenesis. Conclusion: Chronic lead exposure adversely affects testicular histomorphology in adult male Wistar rats, potentially impacting reproductive function. While hormonal levels remain relatively unaffected, alterations in testicular structure suggest a direct impact on gonadal functions at a cellular level.

Hypogonadotropic hypogonadism in male tilapia lacking a functional rln3b gene

Relaxin 3 is a neuropeptide that plays a crucial role in reproductive functions of mammals. Previous studies have confirmed that rln3a plays an important role in the male reproduction of tilapia. To further understand the significance of its paralogous gene rln3b in male fertility, we generated a homozygous mutant line of rln3b in Nile tilapia. Our findings indicated that rln3b mutation delayed spermatogenesis and led to abnormal testes structure. Knocking out rln3b gene resulted in a decrease in sperm count, sperm motility and male fish fertility. TUNEL detection revealed a small amount of apoptosis in the testes of rln3b−/− male fish at 390 days after hatching (dah). RT-qPCR analysis demonstrated that mutation of rln3b gene caused a significant downregulation of steroid synthesis-related genes such as cyp17a1, cyp11b2, germ cell marker gene, Vasa, and gonadal somatic cell marker genes of amh and amhr2. Furthermore, we found a significant down-regulation of hypothalamic-pituitary-gonadal (HPG) axis-related genes, while a significantly up-regulation of the dopamine synthetase gene in the rln3b−/− male fish. Taken together, our data strongly suggested that Rln3b played a crucial role in the fertility of XY tilapia by regulating HPG axis genes.

Dampened HPG axis activity and improved reproductive lifespan in dummerstorf superfertile mouse lines

Dampened HPG axis activity and improved reproductive lifespan in dummerstorf superfertile mouse lines