Hypothalamic-pituitary-gonadal Axis Research Articles

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

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.

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.

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.

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.

Comparative efficacy of exercise, diet and/or pharmacological interventions on BMI, ovulation, and hormonal profile in reproductive-aged women with overweight or obesity: a systematic review and network meta-analysis

Abstract BACKGROUND The increasing prevalence of obesity worldwide poses a significant threat to reproductive function owing, in part, to hormonal disturbances caused by negative feedback between excess adiposity and the hypothalamic–pituitary–ovarian axis. Consequently, finding the most appropriate strategies to lose weight and improve ovulation in women with overweight or obesity is a clinically relevant matter that needs to be investigated. A comprehensive comparison of the independent and combined efficacy of lifestyle and/or pharmacological interventions on BMI, ovulation, and hormonal profile in women with overweight or obesity at risk of anovulatory infertility would facilitate improving fertility strategies in this population. OBJECTIVE AND RATIONALE This study aimed to evaluate the comparative efficacy of exercise, diet, and pharmacological interventions on BMI, ovulation, and hormonal profile in reproductive-aged women with overweight or obesity. SEARCH METHODS A systematic review was performed by searching PubMed, Scopus, Web of Science, PsycINFO, and Cochrane Library up to 14 December 2023, for randomized controlled trials assessing the effects of exercise, diet and/or pharmacological interventions (i.e. weight-lowering drugs or ovulation inducers) on BMI, ovulation, and/or hormonal profile in reproductive-aged women with overweight or obesity. We performed frequentist random-effect network meta-analyses and rated the certainty of the evidence. The primary outcomes were BMI and ovulation rate, and the secondary outcomes were serum reproductive hormone levels (gonadotrophins, androgens, or oestrogens). We performed sensitivity analyses, including the studies that only involved women with PCOS. OUTCOMES Among 1190 records screened, 148 full texts were assessed for eligibility resulting in 95 trials (9910 women), of which 53% presented a high or unclear risk of bias. The network meta-analyses revealed that, compared to control: diet combined with weight-lowering drugs (mean difference (MD) −2.61 kg/m2; 95% CI −3.04 to −2.19; τ2 = 0.22) and adding exercise (MD −2.35 kg/m2; 95% CI −2.81 to −1.89; τ2 = 0.22) led to the greatest decrease in BMI; exercise combined with diet and ovulation inducers (risk ratio (RR) 7.15; 95% CI 1.94–26.40; τ2 = 0.07) and exercise combined with diet and weight-lowering drugs (RR 4.80; 95% CI 1.67–13.84; τ2 = 0.07) produced the highest increase in ovulation rate; and exercise combined with diet and weight-lowering drugs was the most effective strategy in reducing testosterone levels (standardized mean difference (SMD) −2.91; 95% CI −4.07 to −1.74; τ2 = 2.25), the third most effective strategy in increasing sex hormone-binding globulin levels (SMD 2.37; 95% CI 0.99–3.76; τ2 = 2.48), and it was coupled with being ranked first in terms of free androgen index reduction (SMD −1.59; 95% CI −3.18 to 0.01; τ2 = 1.91). The surface under the cumulative ranking curve scores suggested that: diet combined with weight-lowering drugs is the strategy most likely (94%) to produce the highest BMI reduction; and exercise combined with diet and ovulation inducers is the strategy most likely (89%) to produce the highest ovulation rate improvement. The sensitivity analyses, which exclusively included studies involving women diagnosed with PCOS, were consistent with the results presented above. WIDER IMPLICATIONS Overall, the findings of this network meta-analysis indicate that the combination of exercise, diet, and pharmacological interventions is effective for weight loss, improving ovulation, and normalizing the androgen levels of women with overweight or obesity. Although higher quality studies are needed, these results support that the optimal treatment strategy for women with overweight or obesity wishing to conceive must consider exercise, diet, and pharmacological interventions during the shared decision-making process.

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.

Heavy menstrual bleeding in adolescence: who to investigate and how to manage it

Key content Adolescent heavy menstrual bleeding (HMB) is commonly related to hypothalamic pituitary ovarian axis immaturity, which improves with age. This article outlines when and how to investigate for underlying pathological causes. Medical treatment for adolescent HMB consists predominantly of hormonal contraceptives. Preparation choice depends upon patient preference, comorbidities and co‐existing conditions. Acute adolescent HMB is rare; a suggested framework for assessing and managing such cases is provided within this article. Learning objectives To understand how to clinically evaluate adolescent HMB. To understand when and how to investigate adolescent HMB. To understand the different medical treatment options for HMB, their efficacy, risks and alternatives. To understand the management of acute adolescent HMB. Ethical issues Duties of confidentiality must be balanced against safeguarding concerns.

Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies

BackgroundExposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated. ObjectiveTo investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies. MethodsIn 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed. ResultsThe LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): −2.8 (−4.2;-0.4); MEHP: −1.4 (−3.4,0.2)] and higher FSH [∑DINP: 11.8 (−0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [−4.28 (−8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: −12.22 (−21.09;-1.18); oxo-MEHP: −12.73 (−22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males. ConclusionWe observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.

(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.

Single microcystin exposure impairs the hypothalamic-pituitary-gonadal axis at different levels in female rats

Microcystin (MC) is most common cyanobacterial toxin. Few studies have evaluated the MC effects on the hypothalamic-pituitary-gonadal (HPG) axis and metabolic function. In this study, we assessed whether MC exposure results in HPG axis and metabolic changes. Female rats were exposed to a single dose of MC at environmentally relevant levels (5, 20 and 40 μg/kg). After 24 h, we evaluated reproductive and metabolic parameters for 15 days. MC reduced the hypothalamic GnRH protein expression, increased the pituitary protein expression of GnRHr and IL-6. MC reduced LH levels and increased FSH levels. MC reduced the primary follicles, increased the corpora lutea, elevated levels of anti-Müllerian hormone (AMH) and progesterone, and decreased estrogen levels. MC increased ovarian VEGFr, LHr, AMH, ED1, IL-6 and Gp91-phox protein expression. MC increased uterine area and reduced endometrial gland number. A blunted estrogen-negative feedback was observed in MC rats after ovariectomy, with no changes in LH levels compared to intact MC rats. Therefore, these data suggest that a MC leads to abnormal HPG axis function in female rats.

Reproductive endocrine disruption effect and mechanism in male zebrafish after life cycle exposure to environmental relevant triclosan

Triclosan (TCS) is a wide-spectrum antibacterial agent that is found in various water environments. It has been reported to have estrogenic effects. However, the impact of TCS exposure on the reproductive system of zebrafish (Danio rerio) throughout their life cycle is not well understood. In this study, zebrafish fertilized eggs were exposed to 0, 10, and 50 μg/L TCS for 120 days. The study investigated the effects of TCS exposure on brain and testis coefficients, the expression of genes related to the hypothalamus-pituitary-gonadal (HPG) axis, hormone levels, vitellogenin (VTG) content, histopathological sections, and performed RNA sequencing of male zebrafish. The results revealed that life cycle TCS exposure had significant effects on zebrafish reproductive parameters. It increased the testis coefficient, while decreasing the brain coefficient. TCS exposure also led to a decrease in mature spermatozoa and altered the expression of genes related to the HPG axis. Furthermore, TCS disrupted the balance of sex hormone levels and increased VTG content of male zebrafish. Transcriptome sequencing analysis indicated that TCS affected reproductive endocrine related pathways, including PPAR signaling pathway, cell cycle, GnRH signaling pathway, steroid biosynthesis, cytokine-cytokine receptor interaction, and steroid hormone biosynthesis. Protein-protein interaction (PPI) network analysis confirmed the enrichment of hub genes in these pathways, including bub1bb, ccnb1, cdc20, cdk1, mcm2, mcm5, mcm6, plk1, and ttk in the brain, as well as fabp1b.1, fabp2, fabp6, ccr7, cxcl11.8, hsd11b2, and hsd3b1 in the testis. This study sheds light on the reproductive endocrine-disrupting mechanisms of life cycle exposure to TCS.

Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement.

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: a cross-sectional study of six international referral centres

Although some male patients with congenital hypogonadotropic hypogonadism (CHH) undergo spontaneous reversal following treatment, predictors of reversal remain elusive. We aimed to assemble the largest cohort of male patients with CHH reversal to date and identify distinct classes of reversal. This multicentre cross-sectional study was conducted in six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. Adult men with CHH (ie, absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic-pituitary-gonadal [HPG] axis dysfunction) were eligible for inclusion. CHH reversal was defined as spontaneous recovery of HPG axis function off treatment. Centres provided common data elements on patient phenotype, clinical assessment, and genetics using a structured, harmonised data collection form developed by COST Action BM1105. Latent class mixture modelling (LCMM) was applied to establish whether at least two distinct classes of reversal could be identified and differentially predicted, and results were compared with a cohort of patients without CHH reversal to identify potential predictors of reversal. The primary outcome was the presence of at least two distinct classes of reversal. A total of 87 male patients with CHH reversal and 108 without CHH reversal were included in the analyses. LCMM identified two distinct reversal classes (75 [86%] in class 1 and 12 [14%] in class 2) on the basis of mean testicular volume, micropenis, and serum follicle-stimulating hormone (FSH) concentration. Classification probabilities were robust (0·998 for class 1 and 0·838 for class 2) and modelling uncertainty was low (entropy 0·90). Compared with class 1, patients in class 2 had significantly larger testicular volume (p<0·0001), no micropenis, and higher serum FSH concentrations (p=0·041), consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH. Patients without CHH reversal were more likely to have anosmia (p=0·016), cryptorchidism (p=0·0012), complete absence of puberty (testicular volume <4 cm³; p=0·0016), and two or more rare genetic variants (ie, oligogenicity; p=0·0001). Among patients who underwent genetic testing, no patients (of 75) with CHH reversal had a rare pathogenic ANOS1 variant compared with ten (11%) of 95 patients without CHH reversal. Individuals with CHH reversal had a significantly higher rate of rare variants in GNRHR than did those without reversal (nine [12%] of 75 vs three [3%] of 95; p=0·025). Applying LCMM to a large cohort of male patients with CHH reversal uncovered two distinct classes of reversal. Genetic investigation combined with careful clinical phenotyping could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder. National Institutes of Health National Center for Advancing Translational Sciences; Ministry of Health, Rome, Italy; Ministry of University, Rome, Italy; National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Josiah Macy Jr Foundation. For the Italian translation of the abstract see Supplementary Materials section.

Alleviative Effect of Rutin on Zearalenone-Induced Reproductive Toxicity in Male Mice by Preventing Spermatogenic Cell Apoptosis and Modulating Gene Expression in the Hypothalamic-Pituitary-Gonadal Axis.

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin found in many agricultural products and can cause reproductive disorders, mainly affecting spermatogenesis in male animals. Rutin (RUT) is a natural flavonoid compound recognized for its significant antioxidant, anti-inflammatory and estrogenic properties. The present study aimed to determine the protective role of RUT against ZEN-induced reproductive toxicity in male mice. Twenty-four adult Kunming male mice were divided into four groups: control, RUT (500 mg/kg RUT), ZEN (10 mg/kg ZEN), ZEN + RUT (500 mg/kg RUT + 10 mg/kg ZEN), with six replicates per treatment. The results indicated that RUT mitigated ZEN-induced disruption in spermatogenic cell arrangement, decreased spermatozoa count, and increased sperm mortality in the testes. RUT significantly restored ZEN-induced reduction in T, FSH, LH, and E2 serum levels. Moreover, RUT mitigated ZEN-induced apoptosis by increasing the mRNA expression level of bcl-2, decreasing the mRNA expression level of kiss1-r, and decreasing the protein expression level of caspase 8 in reproductive tissues. These findings indicate the protective role of RUT against ZEN-induced reproductive toxicity in male mice by regulating gonadotropin and testosterone secretions to maintain normal spermatogenesis via the HPG axis, which may provide a new application direction for RUT as a therapeutic agent to mitigate ZEN-induced reproductive toxicity.

Aspartame Intake Delayed Puberty Onset in Female Offspring Rats and Girls.

The disturbance of the hypothalamic-pituitary-gonadal (HPG) axis, gut microbiota (GM) community, and short-chain fatty acids (SCFAs) is a triggering factor for pubertal onset. The study investigates the effects of the long-term intake of aspartame on puberty and GM in animals and humans. Aspartame-fed female offspring rats result in vaginal opening time prolongation, serum estrogen reduction, and serum luteinizing hormone elevation. , 60mgkg-1 aspartame treatment decreases the mRNA levels of gonadotropin-releasing hormone (GnRH), Kiss1, and G protein-coupled receptor 54 (GPR54), increases the mRNA level of RFamide-related peptide-3 (RFRP-3), and decreases the expression of GnRH neurons in the hypothalamus. Significant differences in relative bacterial abundance at the genus levels and decreased fecal SCFA levels are noted by 60mgkg-1 aspartame treatment. Among which, Escherichia-Shigella is negatively correlated with several SCFAs. In girls, high-dose aspartame consumption decreases the risk of precocious puberty. Aspartame reduces the chance of puberty occurring earlier than usual in female offspring and girls. Particularly, 60mgkg-1 aspartame-fed female offspring delays pubertal onset through the dysregulation of HPG axis and GM composition by inhibiting the Kiss1/GPR54 system and inducing the RFRP-3. An acceptable dose of aspartame should be recommended during childhood.