RESUMEN

The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer's disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD.

RESUMEN

BACKGROUND: The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans. METHODS: In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18-50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests. FINDINGS: 24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI -0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI -1.5 to 3.3], FSH (IU/l) -0.2 [95% CI -0.3 to 0.0] and LH (IU/l) -0.8 [95% CI -1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred. INTERPRETATION: In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters. FUNDING: Swiss National Science Foundation (PZ00P3_193206), Gottfried and Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Swiss Academy of Medical Sciences.

Asunto(s)

RESUMEN

Tris(2-chloroethyl) phosphate (TCEP), emerging as a predominant substitute for brominated flame retardants (BFRs), is now increasingly recognized as a prevalent contaminant in aquatic ecosystems. The extent of its reproductive toxicity in aquatic species, particularly in zebrafish (Danio rerio), remains insufficiently characterized. This study subjected zebrafish embryos to various concentrations of TCEP (0, 0.8, 4, 20, and 100 µg/L) over a period of 120 days, extending through sexual maturation, to assess its impact on female reproductive health. Notable reductions in body weight (0.59- and 0.76-fold) and length (0.71- and 0.77-fold) were observed at concentrations of 20 and 100 µg/L, with a concomitant decrease by 0.21- to 0.61-fold in the gonadal somatic index across all treatment groups. The reproductive output, as evidenced by egg production and hatchability, was adversely affected. Histopathological analysis suggested that TCEP exposure impedes ovarian development. Endocrine alterations were also evident, with testosterone and 11-ketotestosterone levels significantly diminished by 0.38- and 0.08-fold at the highest concentration tested, while 17ß-estradiol was elevated by 0.09- to 0.14-fold in all exposed groups. Transcriptomic profiling illuminated numerous differentially expressed genes (DEGs) integral to reproductive processes, including hormone regulation, neuroactive ligand-receptor interactions, oocyte meiosis, and progesterone-mediated maturation pathways. Collectively, these findings indicate that lifelong exposure to TCEP disrupts ovarian development and maturation in female zebrafish, alters gene expression within the hypothalamic-pituitary-gonadal axis, and perturbs sex hormone synthesis, culminating in pronounced reproductive toxicity.

Asunto(s)

RESUMEN

Infertility is becoming a major public health problem, with increasing frequency due to medical, environmental and societal causes. The increasingly late age of childbearing, growing exposure to endocrine disruptors and other reprotoxic products, and increasing number of medical reproductive dysfunctions (endometriosis, polycystic ovary syndrome, etc.) are among the most common causes. Fertility relies on fine-tuned control of both neuroendocrine function and reproductive behaviors, those are critically regulated by sex steroid hormones. Testosterone and estradiol exert organizational and activational effects throughout life to establish and activate the neural circuits underlying reproductive function. This regulation is mediated through estrogen receptors (ERs) and androgen receptor (AR). Estradiol acts mainly via nuclear estrogen receptors ERα and ERß. The aim of this review is to summarize the genetic studies that have been undertaken to comprehend the specific contribution of ERα and ERß in the neural circuits underlying the regulation of the hypothalamic-pituitary-gonadal axis and the expression of reproductive behaviors, including sexual and parental behavior. Particular emphasis will be placed on the neural role of these receptors and the underlying sex differences.

Asunto(s)

RESUMEN

Central precocious puberty (CPP) is a rare disease of poorly understood etiology. The cause is mostly idiopathic. However, congenital and acquired structural changes in the central nervous system are also involved. Prevalent organic changes in the central nervous system, especially among boys, prompt imaging assessment in each case of CPP. In addition, genetic and environmental factors have been reported. Safe and effective treatment is available. The time of treatment implementation is crucial to the successful outcome. Proper diagnosis and treatment make it possible to avoid a number of complications of untreated CPP. There are only a few studies analyzing the prevalence and risk factors for the disease. The aim of this paper is to discuss the current causes of CPP with particular consideration of neurological aspects.

RESUMEN

The endocrine system intricately regulates male sexual development and health which influences masculinization, sexual libido, muscle mass, bone density, and overall vitality. Disorders in the hypothalamic-pituitary-gonadal axis can lead to hypogonadism, gynecomastia, sexual dysfunction, and infertility. Testosterone replacement therapy can be considered for symptomatic hypogonadism but poses risks for azoospermia and polycythemia, along with uncertain impact on cardiovascular disease. Gynecomastia results from a high estrogen-to-androgen ratio, mostly from either excess estrogen or decreased androgens. Sexual dysfunction is more commonly secondary to psychological or metabolic disorders; consider workups to rule out endocrine etiologies including hypogonadism if indicated.

Asunto(s)

RESUMEN

Minipuberty is a term describing temporary, sex-specific activation of the hypothalamic-pituitary-gonadal axis, which is implicated in the development of male and female genital organs. Sons of women with low vitamin D during gestation were found to be characterized by increased activity of the reproductive axis and faster postnatal growth of genital organs. The current study assesses for the first time the course of minipuberty in female descendants of women with a vitamin D deficit. The study population included three matched groups of infant girls: children born to women with vitamin D deficiency (25OHD concentration below 50 nmol/L), offspring of women with vitamin D insufficiency (25OHD concentration between 50 and 75 nmol/L), and daughters of healthy females (25OHD concentration between 75 and 150 nmol/L). Salivary concentrations of estradiol, progesterone, 17-hydroxyprogesterone and androgens, as well as urine concentrations of FSH and LH, were assayed during the first 18 months of life (once a month in the first 6 months, bimonthly between months 6 and 12, and then every three months). At each visit, beyond hormone measurements, the investigators assessed the size of reproductive organs: ovaries, uterus and breasts. In daughters of mothers with vitamin D deficiency, concentrations of FSH, LH and estradiol were higher and detectable for a longer period of time, while ovarian volume, uterine length and breast diameter were greater than in the remaining groups. Children born to women with vitamin D insufficiency were characterized by higher FSH levels than daughters of healthy females, though the detection period was the same, and both groups differed in breast diameter. These findings suggest that low vitamin D status during gestation leads to more pronounced and longer-lasting activation of the reproductive axis, and is associated with increased dimensions of sexual organs, the magnitude of which depends on the degree of vitamin D deficit.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

AIMS: Precocious 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 METHODS: In 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 FINDINGS: Glycyrrhizin 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. SIGNIFICANCE: Our 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.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

Estrogens and androgens are typical steroid hormones and often occur together in contaminated aquatic environments, but their mixed effects in aquatic organisms have been less well reported. In this study, the endocrine disrupting effects of binary mixtures of 17ß-estradiol (E2) and testosterone (T) in western mosquitofish (Gambusia affinis) were assessed by analyzing the sex ratio, secondary sex characteristics, gonadal histology, and transcriptional expression of target genes related to the hypothalamic-pituitary-gonadal (HPG) axis in G. affinis (from embryos) continuously exposed to E2 (50 ng/L), T (T1: 50 ng/L; T2: 200 ng/L), and mixtures of both (E2 + T1: 50 + 50 ng/L; E2 + T2: 50 + 200 ng/L) for 119 d. The results showed that exposure to E2 + T1 and E2 + T2 reduced the length ratio of ray 4/6 ratio in male G. affinis, suggesting feminized phenomenon in male G. affinis. Furthermore, 16.7-38.5 % of female G. affinis showed masculinized anal fins and hemal spines when exposed to T alone and in combination with E2. Importantly, the transcriptional levels of certain target genes related to the HPG axis were significantly altered in G. affinis following exposure to E2 and T alone and in combinations. Moreover, exposure to E2 and T in combinations can lead to combined effects (such as synergistic and antagonistic effects) on the transcriptional levels of some genes. These results collectively suggest that exposure to environmentally relevant concentrations of E2 and T alone and in mixtures can impact the endocrine system of G. affinis, and may pose potential risks in aquatic systems.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

This study investigates the sex-specific role of the Hypothalamic-Pituitary-Gonadal axis in Alzheimer's disease progression, utilizing ADNI1 data for 493 individuals, analyzing plasma levels of gonadotropic and sex hormones, and examining neurodegeneration-related brain structures. We assessed plasma levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P4), and testosterone (T), along with volumetric measures of the hippocampus, entorhinal cortex, and hypothalamic subunits, to explore their correlation with Alzheimer's disease markers across different cognitive statuses and sexes. Significant cognitive status effects were observed for all volumetric measures, with a distinct sex-by-cognitive status interaction for hypothalamic volume, indicating a decrease in males but not in females across cognitive impairment stages. Regression analyses showed specific hypothalamic subunit volume related to hormone levels, accounting for up to approximately 40% of the variance (p < 0.05). The findings highlight sex differences in neurodegeneration and hormonal regulation, suggesting potential for personalized treatments and advancing the understanding of Alzheimer's disease etiology.

RESUMEN

Background: Due to myelin and axonal insults in multiple sclerosis individuals, motor coordination problems and endocrine imbalance may develop. Objective: This study aims to evaluate the role of chronic demyelination on the hypothalamic-pituitary-gonadal axis in the mouse model of multiple sclerosis. Materials and Methods: 20 adult C57/BL6 male mice were divided into 2 groups (n = 10/each) as follows: the control group (CONT) received a regular diet for 17 wk; and the experimental group (cuprizone [CPZ]) was fed with 0.2% CPZ for 12 wk and, then CPZ was withdrawn for 5 wk. Serum testosterone, histopathology of the brain and testis, and sperm analysis were evaluated. Results: The hypothalamic myelin content was significantly decreased in the arcuate nucleus following the 12 wk of CPZ consumption compared to the CONT group, and the statistical difference remained until 17 wk. Testosterone levels declined significantly in the CPZ group compared to the CONT group in the 12 th and 17 th wk. A significant decrease was observed in the height of the seminiferous epithelium and the interstitial tissue area, and the number of seminiferous epithelial cells in the CPZ group compared to the CONT group in the 12 th and 17 th wk. The sperm count, motility, and viability in the CPZ group significantly decreased compared to the CONT group in the 12 th and 17 th wk of the study. Conclusion: Chronic demyelination induced by CPZ intoxication, maybe through damage to the hypothalamus arcuate nucleus, leads to the hypothalamic-pituitary-gonadal axis disturbance and damage to the testis and spermatogenesis subsequently.

RESUMEN

BACKGROUND: Development of the gonads during fetal life is complex and vital for adult reproductive health. Cell and animal studies have shown an alarming effect of mild analgesics on germ cells in both males and females. More than 50% of pregnant women use mild analgesics during pregnancy, which potentially could compromise the reproductive health of the next generation. OBJECTIVES: We present a research protocol designed to evaluate the effect of prenatal exposure to mild analgesics and endocrine-disrupting chemicals on gonadal function in the offspring. POPULATION: Healthy, singleton pregnant women and their partners. DESIGN: The COPANA cohort is a prospective, observational pregnancy and birth cohort. METHODS: Participants were enrolled during the first trimester of pregnancy. Information on the use of mild analgesics was collected retrospectively 3 months prior to pregnancy and prospectively every 2 weeks throughout the study. We collected extensive data on lifestyle and reproductive health. Biospecimens were collected in the first trimester (maternal and paternal urine- and blood samples), in the third trimester in conjunction with a study-specific ultrasound scan (maternal urine sample), and approximately 3 months post-partum during the infant minipuberty period (maternal and infant urine- and blood samples). A comprehensive evaluation of reproductive function in the infants during the minipuberty phase was performed, including an ultrasound scan of the testis or ovaries and uterus. PRELIMINARY RESULTS: In total, 685 pregnant women and their partners were included between March 2020 and January 2022. A total of 589 infants (287 males) and their parents completed the follow-up during the minipuberty phase (December 2020-November 2022). CONCLUSIONS: The Copenhagen Analgesic Study holds the potential to provide novel and comprehensive insights into the impact of early and late prenatal exposure to mild analgesics and other endocrine-disrupting chemicals on future reproductive function in the offspring.

Asunto(s)

RESUMEN

Introduction: Pineal cysts have long been considered a benign intracranial variation. However, in our clinical practice, it has been observed that some children with central precocious puberty (CPP) who have pineal cysts experience rapid progression in adolescent development. In recent years, there has been a significant increase in the prevalence of CPP in girls, leading to more diagnoses of CPP among children with pineal cysts. Despite this, there is no consensus regarding whether pineal cysts contribute to CPP as one of its organic factors. This study aimed to analyze the clinical characteristics of pineal cysts in children with CPP and explore the potential effects of pineal cysts on puberty development. Methods: This single-center study retrospectively analyzed clinical data from girls aged 3 to 10 years who underwent head/pituitary magnetic resonance imaging at the Children's Hospital Affiliated to Zhengzhou University between 2019 and 2022. The study categorized the detection rates of pineal cysts based on systematic disease classification and compared the rates of cyst detection between girls diagnosed with CPP and those without CPP. Subsequently, CPP-diagnosed girls with pineal cysts were examined. Among CPP-diagnosed girls meeting the study's criteria, those with pineal cysts formed the 'cyst group,' while those without cysts were matched in a 1:1 ratio based on age and body mass index to form the 'non-cyst group.' Comparative analyses were conducted to assess the clinical characteristics between these two groups. CPP-diagnosed girls with cysts were further subdivided into three groups according to cyst size (≤5 mm, 5.1-9.9 mm, and ≥10 mm) to investigate potential differences in clinical characteristics among these subgroups. The study involved an analysis of clinical data from girls diagnosed with CPP and included imaging follow-ups to explore the progression of pineal cysts over time. Results: Among the 23,245 girls who underwent head/pituitary magnetic resonance imaging scans, the detection rate of pineal cysts was 3.6% (837/23,245), with most cases being associated with endocrine diseases. The detection rate of pineal cysts in CPP patients was 6.4% (262/4099), which was significantly higher than the 3.0% (575/19,146) in patients without CPP. In comparison to the non-cyst group, the cyst group exhibited statistically significant increases in estradiol levels, peak luteinizing hormone (LH) levels, peak LH/follicle-stimulating hormone (FSH) ratios, uterine body length, and cervix length (P < 0.001). As cyst size increased, there were significant rises in LH peak, peak LH/FSH ratio, uterine body length, and cervical length (P < 0.01). Estradiol levels and left ovarian volume also showed an increasing trend (P < 0.05). Among girls who underwent follow-up imaging, 26.3% (5/19) exhibited an increase in cyst size. Conclusion: Pineal cysts are relatively common in children with CPP. They may affect the pubertal development process, with larger cysts correlating to faster pubertal development. Therefore, the authors hypothesize that pineal cysts may trigger CPP in some cases, especially when the cysts are larger than 5 mm in size, as indicated by our data.

Asunto(s)

RESUMEN

In temperate-zone songbirds, the neuroanatomical changes which occur in advance of breeding, including the growth of nuclei of the vocal control system, are believed to occur downstream of gonadal recrudescence. However, evidence from wild birds is mixed. Here, we captured black-capped chickadees from the wild in early spring (March-April), summer (August-September), and winter (December-January); in addition to measuring the volumes of two vocal control nuclei (Area X and HVC), we also quantified two indicators of reproductive state (gonads and circulating gonadal steroids). Most birds captured in early spring had regressed gonads and low levels of circulating gonadal steroids, indicating these birds were not yet in full breeding condition. However, these early spring birds still had a significantly larger Area X than winter birds, while HVC did not differ in size across groups. Using data from a previously published seasonal study of black-capped chickadees (Phillmore et al., Developmental Neurobiology, 2015;75:203-216), we then compared Area X and HVC volumes from our early spring group to a breeding group of chickadees captured 3-4 weeks later in the spring. While Area X volume did not differ between the studies, breeding males in Phillmore et al. (2015) had a significantly larger HVC. Taken together, this suggests that the vernal growth of Area X occurs ahead of HVC in black-capped chickadees, and that the overall vernal changes in the vocal control system occur at least partially in advance of the breeding-associated upregulation of the hypothalamic-pituitary-gonadal axis.

RESUMEN

CONTEXT: The hypothalamic-pituitary-gonadal axis's transient activity in infancy, i.e, minipuberty, is considered crucial for male reproductive function. Historically, minipuberty has been considered a passive response triggered by the withdrawal of placental steroids at birth. However, given its potential link to adult reproductive function, we hypothesize that minipuberty is a partially genetically regulated process, suggesting a link between the genetic architecture of reproductive hormone concentrations across lifespan. OBJECTIVE: To investigate the association of UK Biobank Study-based polygenic scores (PGS) of adult total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations with trajectories of reproductive hormones concentrations in male infants. DESIGN: Prospective, longitudinal birth cohort (The COPENHAGEN Minipuberty Study, 2016-2018, ClinTrial: NCT02784184). Individual PGSs in male infants derived from published literature were calculated for total T and SHBG. The associations with mean SD scores (SDS) of reproductive hormone concentrations in infancy were tested. SETTING: Population-based. PATIENTS OR OTHER PARTICIPANTS: Healthy, male, term, singleton newborns were followed with repeated clinical examinations including blood sampling during a 1-year follow-up (n = 109). MAIN OUTCOME MEASURES: Circulating reproductive hormone concentrations. RESULTS: T-PGSadult were significant associated with mean T-SDSinfancy, mean SHBG-SDSinfancy, and mean LH-SDSinfancy (P = .02, <.001 and .03, with r2 = 0.05, 0.21 and 0.04, respectively). SHBG-PGSadult was significantly associated with mean SHBG-SDSinfancy (P < .001, r2 = 0.18). T-PGSadult explained 5% and 21% of the phenotypic variation in infancy of mean T-SDSinfancy and SHBG-SDSinfancy, respectively. CONCLUSION: Our findings suggest that the genetic architecture underlying total T and SHBG in adults also associates with hormone concentrations and their trajectories during infancy.

Asunto(s)

RESUMEN

OBJECTIVE: This study aims to explore the significant impact of environmental chemicals on disease development, focusing on their role in developing metabolic and endocrine diseases. The objective is to understand how these chemicals contribute to the increasing prevalence of precocious puberty, considering various factors, including epigenetic changes, lifestyle, and emotional disturbances. METHODS: The study employs a comprehensive review of descriptive observational studies in both human and animal models to identify a degree of causality between exposure to environmental chemicals and disease development, specifically focusing on endocrine disruption. Due to ethical constraints, direct causation studies in human subjects are not feasible; therefore, the research relies on accumulated observational data. RESULTS: Puberty is a crucial life period with marked physiological and psychological changes. The age at which sexual characteristics develop is changing in many regions. The findings indicate a correlation between exposure to endocrine-disrupting chemicals and the early onset of puberty. These chemicals have been shown to interfere with normal hormonal processes, particularly during critical developmental stages such as adolescence. The research also highlights the interaction of these chemical exposures with other factors, including nutritional history, social and lifestyle changes, and emotional stress, which together contribute to the prevalence of precocious puberty. CONCLUSION: Environmental chemicals significantly contribute to the development of certain metabolic and endocrine diseases, particularly in the rising incidence of precocious puberty. Although the evidence is mainly observational, it adequately justifies regulatory actions to reduce exposure risks. Furthermore, these findings highlight the urgent need for more research on the epigenetic effects of these chemicals and their wider impact on human health, especially during vital developmental periods.

Asunto(s)

RESUMEN

Testicular size is an excellent proxy for selecting high-fertility rams. The hypothalamus-pituitary-gonadal (HPG) axis plays an important role in regulating reproductive capacity in vertebrates, while key genes and regulatory pathways within the HPG axis associated with testicular size remain largely unknown in sheep. This study comprehensively compared the transcriptomic profiles in the hypothalamus, pituitary and testis of rams after sexual maturity between the large-testis group (LTG, testicular weight = 454.29 ± 54.24 g) and the small-testis group (STG, testicular weight = 77.29 ± 10.76 g). In total, 914, 795 and 10518 differentially expressed genes (DEGs) were identified in the hypothalamus, pituitary and testis between LTG and STG, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that these DEGs were mainly involved in the biological processes of reproduction, biological regulation, and development process. Notably, the neuroactive ligand-receptor interaction and cAMP signaling pathways, commonly enriched by the DEGs in the hypothalamus and pituitary between two groups, were considered as two key signal pathways regulating testicular development through the HPGs axis. Weighted gene co-expression network analysis (WGCNA) identified two modules that were significantly associated with testicular size, and 97 key genes were selected with high module membership (MM) and gene significance (GS) in these two modules. Finally, a protein-protein interaction (PPI) network was constructed, and ten genes with the highest degree were represented as hub genes, including FOS, NPY, SST, F2, AGT, NTS, OXT, EDN1, VIP and TAC1. Taken together, these results provide new insights into the molecular mechanism underlying the HPG axis regulating testicular size of Hu sheep.

Asunto(s)