Hypothalamic-pituitary-gonadal Research Articles

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.

How Per- and Poly-Fluoroalkyl Substances Affect Gamete Viability and Fertilization Capability: Insights from the Literature.

There has been emerging research linking per- and poly-fluoroalkyl substances (PFAS) to gamete viability and fertility. PFAS, prevalent in the environment and water supplies, undergo slow degradation due to their C-F bond and a long half-life (2.3-8.5 years). In females, PFAS inhibit the hypothalamic-pituitary-gonadal (HPG) axis, reducing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, leading to the inhibition of androgen and estradiol production. PFAS have been found to cause detrimental effects on egg quality through impairing folliculogenesis. In males, PFAS can impair sperm motility and morphology: two fundamental qualities of successful fertilization. PFAS exposure has been proven to inhibit testosterone production, sperm capacitation, and acrosomal reaction. After fertilization, the results of PFAS exposure to embryos have also been investigated, showing reduced development to the blastocyst stage. The aim of this review is to report the main findings in the literature on the impact of PFAS exposure to gamete competency and fertilization capability by highlighting key studies on both male and female fertility. We report that there is significant evidence demonstrating the negative impacts on fertility after PFAS exposure. At high doses, these environmentally abundant and widespread compounds can significantly affect human fertility.

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.

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>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.

Preliminary investigation into long-term stress by isolated captivity-related changes of reproduction hormones in Cynomolgus monkey.

Stress profoundly affects physical and emotional well-being, extending its physiological influence to the female menstrual cycle, impeding the hypothalamus-pituitary-gonadal (HPG) axis, and affecting fertility by suppressing sex-stimulating hormones. In this study, we meticulously analyzed menstrual cycles and corresponding hormonal fluctuations in three female Cynomolgus monkeys. The preliminary findings indicated lower-than-normal levels of cortisol, follicle-stimulating hormone (FSH), and estradiol. Anovulatory bleeding occurred in one monkey, which could be linked to stress. In contrast to cortisol, alkaline phosphatase (ALP), which is correlated to cortisol levels, was consistently elevated in menstruating monkeys, suggesting its potential as a stress indicator. The non-menstruating group exhibited stress-related weight loss, emphasizing the observed ALP trends. Non-menstruating monkeys may experience more stress than menstruating monkeys. The implications of this study extend beyond the confines of primate studies and offer a valuable method for enhancing the welfare of female Cynomolgus monkeys.

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.

Microcystin-LR Induces Estrogenic Effects at Environmentally Relevant Concentration in Black-Spotted Pond Frogs (Pelophylax nigromaculatus): In Situ, In Vivo, In Vitro, and In Silico Investigations.

Harmful cyanobacterial blooms are frequent and intense worldwide, creating hazards for aquatic biodiversity. The potential estrogen-like effect of Microcystin-LR (MC-LR) is a growing concern. In this study, we assessed the estrogenic potency of MC-LR in black-spotted frogs through combined field and laboratory approaches. In 13 bloom areas of Zhejiang province, China, the MC-LR concentrations in water ranged from 0.87 to 8.77 μg/L and were correlated with sex hormone profiles in frogs, suggesting possible estrogenic activity of MC-LR. Tadpoles exposed to 1 μg/L, an environmentally relevant concentration, displayed a female-biased sex ratio relative to controls. Transcriptomic results revealed that MC-LR induces numerous and complex effects on gene expression across multiple endocrine axes. In addition, exposure of male adults significantly increased the estradiol (E2)/testosterone (T) ratio by 3.5-fold relative to controls. Downregulation of genes related to male reproductive endocrine function was also identified. We also showed how MC-LR enhances the expression of specific estrogen receptor (ER) proteins, which induce estrogenic effects by activating the ER pathway and hypothalamic-pituitary-gonadal (HPG) axis. In aggregate, our results reveal multiple lines of evidence demonstrating that, for amphibians, MC-LR is an estrogenic endocrine disruptor at environmentally relevant concentrations. The data presented here support the need for a shift in the MC-LR risk assessment. While hepatoxicity has historically been the focus of MC-LR risk assessments, our data clearly demonstrate that estrogenicity is a major mode of toxicity at environmental levels and that estrogenic effects should be considered for risk assessments on MC-LR going forward.

Effects of social environments on male primate HPG and HPA axis developmental programming.

Developmental plasticity is particularly important for humans and other primates because of our extended period of growth and maturation, during which our phenotypes adaptively respond to environmental cues. The hypothalamus-pituitary-gonadal (HPG) and hypothalamus-pituitary-adrenal (HPA) axes are likely to be principal targets of developmental "programming" given their roles in coordinating fitness-relevant aspects of the phenotype, including sexual development, adult reproductive and social strategies, and internal responses to the external environment. In social animals, including humans, the social environment is believed to be an important source of cues to which these axes may adaptively respond. The effects of early social environments on the HPA axis have been widely studied in humans, and to some extent, in other primates, but there are still major gaps in knowledge specifically relating to males. There has also been relatively little research examining the role that social environments play in developmental programming of the HPG axis or the HPA/HPG interface, and what does exist disproportionately focuses on females. These topics are likely understudied in males in part due to the difficulty of identifying developmental milestones in males relative to females and the general quiescence of the HPG axis prior to maturation. However, there are clear indicators that early life social environments matter for both sexes. In this review, we examine what is known about the impact of social environments on HPG and HPA axis programming during male development in humans and nonhuman primates, including the role that epigenetic mechanisms may play in this programming. We conclude by highlighting important next steps in this research area.

Clomiphene citrate and optional human chorionic gonadotropin for treating male hypogonadism arising from long-term anabolic-androgenic steroid use—A pilot study

IntroductionLong-term anabolic-androgenic steroid (AAS) use poses several health risks, including secondary hypogonadism. There is a knowledge gap on treatment targeting the hypothalamic-pituitary-gonadal (HPG) axis among men with anabolic steroid-induced hypogonadism (ASIH). This study aims to gain insights into the potential utility of endocrine therapy to restore endogenous testosterone levels and alleviate ASIH symptoms in AAS dependent men. MethodsIn this proof-of-concept, single-site, open longitudinal pilot study, AAS dependent men with continuous AAS use and a desire to permanently discontinue use, were given endocrine therapy. The treatment included 25 mg clomiphene citrate (CC) every second day for 16 weeks, transdermal testosterone daily during the first four weeks, and if indicated, human chorionic gonadotropin (hCG) injections for a maximum of eight weeks. Physical exams including blood collection and online questionnaires were completed every four and two weeks, respectively. ResultsTen participants, with median age 32 years (interquartile range 30–45), with mean ± standard deviation AAS use of 11 ± 4 years, completed the CC intervention. Seven participants received hCG as part of their treatment protocol. Mild adverse events included headaches, dizziness, and mood swings, and no serious adverse events occurred. During the intervention, there was a decrease in levels of hematocrit, hemoglobin and ALT (alanine aminotransferase), as well as an increase in serum FSH (follicle stimulating hormone), LH (luteinizing hormone) and SHBG (sex hormone binding globulin). Five of ten participants reached a total testosterone level within normal range (9–30 nmol/l). The HPG axis response varied greatly among participants, and was not aligned with the severity of ASIH related withdrawal symptoms. ConclusionsThe findings from this proof-of-concept study may guide future randomized controlled trials aiming to investigate potential endocrine therapeutic approaches to ASIH.

The analysis of growth performance and expression of growth-related genes in natural gynogenic blunt snout bream muscle derived from the blunt snout bream (Megalobrama amblycephala, ♀) × Chinese perch (Siniperca chuatsi, ♂)

Gynogenesis is an advanced breeding technique that can quickly establish pure lines, increase progenies genetic variation, cultivate strains with higher dominant traits. As a good model for cross order species hybridization, there are few reports on the study of natural gynogenetic blunt snout bream (GBSB), even on the differences in growth between gynogenesis progenies and their parent fish (blunt snout bream♀ and Chinese perch♂). In this research we compared the growth characteristics of the natural GBSB with its parents. It was found that GBSB had a faster growth rate and higher meat content than its female parent, and the diameter and density of muscle fibers were between those of paternal and maternal fish. We performed transcriptome sequencing of muscle tissues from GBSB and BSB, it identified 1353 significant DEGS in the muscle of the GBSB compared to the BSB, with 820 up- and 533 down-regulated genes. And the relative expression of myosins was notable rise in GBSB. In addition, the MRFs of gene structure, motifs, and phylogenetic relations were characterized in BSB and CP. It showed that MRFs and mstn central domain was highly conserved, but the number of conservative motifs in MRFs of CP is generally higher than that of BSB. Further, the relative expression of myosin complex, myogenic regulatory factors (MRFs), growth hormone/insulin-like growth factor (GH/IGF)-axis and most hypothalamic-pituitary-gonadal (HPG)-axis genes in GBSB were higher than that of the female fish and some were closer to that of the paternal fish. Through the distant hybridization between BSB and CP, a gynogenetic progeny with enhanced growth rate compared to the maternal fish was successfully generated. The research has contributed significant insights into the genes and molecular properties associated with muscle development, as well as their potential functional correlations in response to different functional requirements during the growth process of hybrid progeny formed by cross breeding.

The role of kisspeptin in female and male reproduction

Kisspeptin is a neuropeptide responsible for controlling the synthesis of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The G-protein-coupled receptor 54/kisspeptin 1 receptor (GPR54/KISS1R) is involved in its action. The comprehension of kisspeptin and its actions represents a significant breakthrough in the field of reproductive biology. Kisspeptins play a crucial role in the development and optimal functioning of the reproductive system in both female and male. Additionally, it contributes to the onset of puberty, regulating feedback processes, and influencing sexual desire and arousal. It regulates a number of reproductive functions in women, including ovulation, lactation, ovarian development, follicle development, oocyte maturation, and pregnancy via the hypothalamic-pituitary-gonadal (HPG) axis. Spermatogenesis, sperm function, Leydig cells, and reproductive behaviour are all impacted by it in men. Infertility and polycystic ovarian syndrome (PCOS) are among the diseases linked to kisspeptin dysregulation, according to the research. For potential future use in diagnosing and treating problems, it may be helpful to understand the mechanisms behind kisspeptin's effects on the reproductive system. This review focuses on the regulatory function of kisspeptin on the HPG axis and the impact of kisspeptin on reproductive processes in both female and male.

Effects of salinity on behavior and reproductive toxicity of BPA in adult marine medaka

Salinity is an important environmental factor influencing the toxicity of chemicals. Bisphenol A (BPA) is an environmental endocrine disruptor with adverse effects on aquatic organisms, such as fish. However, the influence of salinity on the biotoxicity of BPA and the underlying mechanism are unclear. In this study, we exposed marine medaka (Oryzias melastigma) to BPA at different salinities (0 psμ, 15 psμ, and 30 psμ) for 70days to investigate the toxic effects. At 0 psμ salinity, BPA had an inhibitory effect on the swimming behavior of female medaka. At 15 psμ salinity, exposure to BPA resulted in necrotic cells in the ovaries but not on the spermatozoa. In addition, BPA exposure changed the transcript levels of genes related to the nervous system (gap43, elavl3, gfap, mbpa, and α-tubulin) and the hypothalamic-pituitary-gonadal (HPG) axis (fshr, lhr, star, arα, cyp11a, cyp17a1, cyp19a, and erα); the expression changes differed among salinity levels. These results suggest that salinity influences the adverse effects of BPA on the nervous system and reproductive system of medaka. These results emphasize the importance of considering the impact of environmental factors when carrying out ecological risk assessment of pollutants.

Kisspeptin administration may promote precopulatory behavior in male rats independently or supplementally to testosterone and contribute to proceptive behavior in female partners, reducing mating failure

Kisspeptin is a peptide that plays an important role through its effects on the hypothalamus-pituitary–gonadal (HPG) axis. It has also been implicated in sexual behavior. The present study investigated whether the relationship between kisspeptin and sexual behavior is independent of the HPG axis, i.e., testosterone. Sexual behavior was examined after the administration of kisspeptin to gonadally intact male rats and gonadectomized male rats that received testosterone supplementation. Other male rats were also observed for sexual behavior once a week from 2 to 5 weeks after gonadectomy and receiving kisspeptin for the sixth postoperative week. Sexual behavior in female rats serving as the partner for each male was also observed. Female rats were not administered kisspeptin in the present study. The results obtained showed that the administration of kisspeptin increased precopulatory behavior in gonadally intact male rats and gonadectomized male rats that received testosterone supplementation and proceptive behavior in their female partners. Precopulatory behavior in males and receptive behavior in females increased, while copulatory behavior in males and receptive behavior in females remained unchanged. Furthermore, the administration of kisspeptin increased precopulatory behavior in gonadectomized males, but did not affect receptive behavior in females. These results suggest that kisspeptin affected males independently and/or supplementally to testosterone, and also that changes in the presence of testosterone in males had an impact on proceptive behavior in their female partners. In conclusion, kisspeptin may involve an as-yet-unidentified neural pathway in sexual desire independently of the HPG axis.

Integrated untargeted and targeted testicular metabolomics to reveal the regulated mechanism of Gushudan on the hypothalamic-pituitary-gonadal axis of kidney-yang-deficiency-syndrome rats.

Modern studies have shown that neuroendocrine disorders caused by the dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis are one of the important pathogenetic mechanisms of kidney-yang-deficiency-syndrome (KYDS). The preventive effect of Gushudan on KYDS has been reported, but its regulatory mechanisms on the HPG axis have not been elucidated. In this study, we developed an integrated untargeted and targeted metabolomics analysis strategy to investigate the regulatory mechanism of Gushudan on the HPG axis in rats with KYDS. In untargeted metabolomics, we screened 14 potential biomarkers such as glycine, lysine, and glycerol that were significantly associated with the HPG axis. To explore the effect of changes in the levels of potential biomarkers on KYDS, all of them were quantified in targeted metabolomics. With the quantitative results, correlations between potential biomarkers and testosterone, a functional indicator of the HPG axis, were explored. The results showed that oxidative stress, inflammatory response, and energy depletion, induced by metabolic disorders in rats, were responsible for the decrease in testosterone levels. Gushudan improves metabolic disorders and restores testosterone levels, thus restoring HPG axis dysfunction. This finding elucidates the special metabolic characteristics of KYDS and the therapeutic mechanism of Gushudan from a new perspective.

Reproductive toxic effects of chronic exposure to bisphenol A and its analogues in marine medaka (Oryzias melastigma)

As awareness of BPA's health risks has increased, many countries and regions have implemented strict controls on its use. Consequently, bisphenol analogues like BPF and BPAF are being increasingly used as substitutes. However, these compounds are also becoming increasingly prevalent in the environment due to production, use and disposal processes. The oceans act as a repository for various pollutants, and recent studies have revealed the extensive presence of bisphenols (BPs, including BPA, BPF, BPAF, etc.) in the marine environment, posing numerous health hazards to marine wildlife. Nevertheless, the reproductive toxicity of these chemicals on marine fish is not comprehensively comprehended yet. Thus, the histological features of the gonads and the gene expression profiles of HPG (Hypothalamic-Pituitary-Gonadal) axis-related genes in marine medaka (Oryzias melastigma) were studied after exposure to single and combined BPs for 70 days. The effects of each exposure group on spawning, embryo fertilization, and hatching in marine medaka were also assessed. Furthermore, the impacts of each exposure group on the genes related to methylation in the F2 and F3 generations were consistently investigated. BPs exposure was found to cause follicular atresia, irregular oocytes, and empty follicles in the ovary; but no significant lesions in the testis were observed. The expression of several HPG axis genes, including cyp19b, 17βhsd, 3βhsd, and fshr, resulted in significant changes compared to the control group. The quantity of eggs laid and fertilization rate decreased in all groups treated with BPs, with the BPAF-treated group showing a notable reduction in the number of eggs laid. Additionally, the hatching rate showed a more significant decline in the BPF-treated group. The analysis of methylated genes in the offspring of bisphenol-treated groups revealed significant changes in the expression of genes including amh, dnmt1, dnmt3ab, mbd2, and mecp2, indicating a potential transgenerational impact of bisphenols on phenotype through epigenetic modifications. Overall, the potential detrimental impact of bisphenol on the reproduction of marine medaka emphasizes the need for caution in considering the use of BPAF and BPF as substitutes.

Effects of glycerol monolaurate on estradiol and follicle-stimulating hormones, offspring quality, and mRNA expression of reproductive-related genes of zebrafish (Danio rerio) females.

This study aims to explore whether glycerol monolaurate (GML) can improve reproductive performance of female zebrafish (Danio rerio) and the survival percentage of their offspring. Three kinds of isonitrogenous and isolipid diets, including basal diet (control) and basal diet containing 0.75g/kg GML (L_GML) and 1.5g/kg GML (H_GML), were prepared for 4weeks feeding trial. The results show that GML increased the GSI of female zebrafish. GML also enhanced reproductive performance of female zebrafish. Specifically, GML increased spawning number and hatching rate of female zebrafish. Moreover, GML significantly increased the levels of triglycerides (TG), lauric acid, and estradiol (E2) in the ovary (P < 0.05). Follicle-stimulating hormone (FSH) levels in the ovary and brain also significantly increased in the L_GML group (P < 0.05). Besides, dietary GML regulated the hypothalamus-pituitary-gonad (HPG) axis evidenced by the changed expression levels of HPG axis-related genes in the brain and ovary of the L_GML and H_GML groups compared with the control group. Furthermore, compared with the control group, the expression levels of HPG axis-related genes (kiss2, kiss1r, kiss2r, gnrh3, gnrhr1, gnrhr3, lhβ, and esr2b) in the brain of the L_GML group were significantly increased (P < 0.05), and the expression levels of HPG axis-related genes (kiss1, kiss2, kiss2r, gnrh2, gnrh3, gnrhr4, fshβ, lhβ, esr1, esr2a, and esr2b) in the brain of the H_GML group were significantly increased (P < 0.05). These results suggest that GML may stimulate the expression of gnrh2 and gnrh3 by increasing the expression level of kiss1 and kiss2 genes in the hypothalamus, thus promoting the synthesis of FSH and E2. The expression levels of genes associated with gonadotropin receptors (fshr and lhr) and gonadal steroid hormone synthesis (cyp11a1, cyp17, and cyp19a) in the ovary were also significantly upregulated by dietary GML (P < 0.05). The increasing expression level of cyp19a also may promote the FSH synthesis. Particularly, GML enhanced the richness and diversity and regulated the species composition of intestinal microbiota in female zebrafish. Changes in certain intestinal microorganisms may be related to the expression of certain genes involved in the HPG axis. In addition, L_GML and H_GML both significantly decreased larvae mortality at 96h post fertilization and their mortality during the first-feeding period (P < 0.05), revealing the enhanced the starvation tolerance of zebrafish larvae. In summary, dietary GML regulated genes related to HPG axis to promote the synthesis of E2 and FSH and altered gut microbiota in female zebrafish, and improved the survival percentage of their offspring.

Novel insights into minipuberty and GnRH: Implications on neurodevelopment, cognition, and COVID-19 therapeutics.

In humans, the first 1000 days of life are pivotal for brain and organism development. Shortly after birth, gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus are activated, a phenomenon known as minipuberty. This phenomenon, observed in all mammals studied, influences the postnatal development of the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. This review will put into perspective the results of recent studies showing that the impact of minipuberty extends beyond reproductive function, influencing sensory and cognitive maturation. Studies in mice have revealed the role of nitric oxide (NO) in regulating minipuberty amplitude, with NO deficiency linked to cognitive and olfactory deficits. Additionally, findings indicate that cognitive and sensory defects in adulthood in a mouse model of Down syndrome are associated with an age-dependent decline of GnRH production, whose origin can be traced back to minipuberty, and point to the potential therapeutic role of pulsatile GnRH administration in cognitive disorders. Furthermore, this review delves into the repercussions of COVID-19 on GnRH production, emphasizing potential consequences for neurodevelopment and cognitive function in infected individuals. Notably, GnRH neurons appear susceptible to SARS-CoV-2 infection, raising concerns about potential long-term effects on brain development and function. In conclusion, the intricate interplay between GnRH neurons, GnRH release, and the activity of various extrahypothalamic brain circuits reveals an unexpected role for these neuroendocrine neurons in the development and maintenance of sensory and cognitive functions, supplementing their established function in reproduction. Therapeutic interventions targeting the HPG axis, such as inhaled NO therapy in infancy and pulsatile GnRH administration in adults, emerge as promising approaches for addressing neurodevelopmental cognitive disorders and pathological aging.

(PM-19) INSIGHTS INTO THE PATHOPHYSIOLOGY OF HYPERSEXUALITY: A COMPREHENSIVE LITERATURE EXPLORATION

Abstract Introduction Hypersexuality or Compulsive Sexual Behavior Disorder (CSBD) is characterized by a spectrum of sexual behaviors and fantasies marked by compulsion, obsession, and impulsivity. The pathophysiology of CSBD remains poorly understood despite the arousing of articles exploring the potential biomarkers associated with hypersexuality. Objective We aimed to review the literature regarding the investigation on CSBD pathophysiology from a neuroimaging, neuroendocrine and molecular perspective. Methods We raised papers related on neuroimaging, neuroendocrine and molecular biomarkers investigated in individuals that reached diagnosis of CSBD or similar, written in English language in the last 10 years, through PubMed, Scopus, and Web of Science with biomarkers and compulsive sexual behavior/hypersexuality key terms. Results Neuroimaging studies revealed the activation of the anterior cingulate cortex, ventral striatum, and amygdala, in individuals with CSBD. Neuroendocrine markers revealed abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, including elevated adrenocorticotropic hormone (ACTH) levels and non-suppression of dexamethasone. Findings concerning the hypothalamic-pituitary-gonadal (HPG) axis, responsible for sexual function regulation, varied among CSBD individuals, including testosterone and luteinizing hormone (LH) levels. Oxytocin levels have been noted to rise in CSBD individuals and subsequently decrease following psychotherapy. Genetic and epigenetic markers associated with CSBD suggest involvement of addiction-related genes and epigenetic modifications near the corticotropin-releasing hormone (CRH) gene. Conclusion Most of the findings point to HPA axis alterations. Molecular analysis is in the beginning, as well as more research on the HPG axis is needed. The exploration of CSBD biomarkers potentially will provide insights into its pathophysiology, diagnosis, and treatment. Financing FAPESP.

Tortoise-shell glue ameliorates male infertility through the hypothalamic-pituitary-gonadal axis in obese rats

ABSTRACT Background Male infertility is a worldwide population health concern, but its etiology remains poorly understood. Tortoise-shell glue (TSG) is widely utilized as a pharmaceutical or dietary supplement for various health ailments. This study aimed to evaluate the effects of TSG on male infertility in obese rats. Methods A male infertility with obesity rat model was established after a high-fat diet (HFD) and cyclophosphamide (CTX) treatment. The body weight, testis weight, and weight of adipose tissues around the epididymis were detected. We then evaluated spermatozoon motility and concentration and testis pathological changes. Next, we assessed the hypothalamic-pituitary-gonadal (HPG) axis. Moreover, serum metabolomics was used to identify differential metabolites. The Spearman correlation analysis was employed to assess the correlation between differential metabolites and sex hormone levels. Results Here, we demonstrated that TSG alleviated obesity and male infertility. Meanwhile, TSG restored the function of the HPG axis in obese infertility rats, including mRNA levels of GnRH, GnRHR, RFRP-3, and kisspeptin in the hypothalamus and pituitary and sex hormone levels in the serum. In addition, 16 potentially significant metabolites, such as Quinapril and Malabaricone C, were identified as significant in the therapeutic effects of TSG on male infertility. The majority of these differential metabolites exhibited recovery following TSG treatment. The further Spearman analysis demonstrated the close correlation between differential metabolites and sex hormones, especially Kamahine C. Conclusion TSG attenuated obesity and male infertility in rats through the HPG axis by regulating serum metabolites. It shows potential as a viable treatment option for male infertility.

Sex differences in luteinizing hormone aggravates Aβ deposition in APP/PS1 and Aβ1-42-induced mouse models of Alzheimer's disease

Alzheimer's disease (AD) exhibits a higher incidence rate among older women, and dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis during aging is associated with cognitive impairments and the development of dementia. luteinizing hormone (LH) has an important role in CNS function, such as mediating neuronal pregnenolone production, and modulating neuronal plasticity and cognition. The sex differences in LH and its impact on Aβ deposition in AD individuals remain unclear, with no reported specific mechanisms. Here, we show through data mining that LH-related pathways are significantly enriched in female AD patients. Additionally, LH levels are elevated in female AD patients and exhibit a negative correlation with cognitive levels but a positive correlation with AD pathology levels, and females exhibit a greater extent of AD pathology, such as Aβ deposition. In vivo, we observed that the exogenous injection of LH exacerbated behavioral impairments induced by Aβ1-42 in mice. LH injection resulted in worsened neuronal damage and increased Aβ deposition. In SH-SY5Y cells, co-administration of LH with Aβ further exacerbated Aβ-induced neuronal damage. Furthermore, LH can dose-dependently decrease the levels of NEP and LHR proteins while increasing the expression of GFAP and IBA1 in vivo and in vitro. Taken together, these results indicate that LH can exacerbate cognitive impairment and neuronal damage in mice by increasing Aβ deposition. The potential mechanism may involve the reduction of NEP and LHR expression, along with the exacerbation of Aβ-induced inflammation.