Sex Hormone-binding Globulin Research Articles

Male hypogonadism is associated with obesity

Currently, there is a global trend of steadily increasing obesity rates. Obesity is a component of metabolic syndrome and is a risk factor for the development of a number of diseases, such as type 2 diabetes mellitus and cardiovascular pathologies. Obesity also leads to hypogonadism in men. In turn, the decrease in androgen levels leads to changes in body composition, reducing the amount of muscle tissue and increasing the content of adipose tissue, thus closing the vicious circle of obesity and hypogonadism. In young men, hypogonadism leads to erectile dysfunction, which can result in infertility. Pathogenetic mechanisms causing the development of hypogonadism in obese men include increased aromatization of testosterone to estradiol in adipose tissue, decreased production of gonadotropin-releasing hormone by the hypothalamus and gonadotropins by the adenohypophysis due to leptin resistance, decreased production of sex steroid-binding globulin and activation of the secretion of proinflammatory cytokines. The functional nature of male hypogonadism associated with obesity suggests the potential reversibility of this condition when treating obesity as the cause of its development. Several studies have shown that calorie reduction, drug therapy for obesity, and bariatric surgery help improve androgen levels in men. And the use of testosterone replacement therapy has a positive effect not only on sexual function in men, but also leads to a decrease in adipose tissue.

Persistent organic pollutants and endogenous sex-related hormones in Hispanic/Latino adults: The Hispanic Community health study/study of Latinos (HCHS/SOL).

Previous studies have demonstrated associations of persistent organic pollutants (POPs) with sex-related hormones; however, findings were inconsistent. Sex-specific impacts and pathways through which adiposity influences associations are not completely understood. We sought to evaluate sex-specific associations of POPs serum concentration with sex-related hormones and to explore pathways through which adiposity may modify associations. We studied 1073 men and 716 postmenopausal women participating in the "Persistent Organic Pollutants, Endogenous Hormones, and Diabetes in Latinos" ancillary study which is a subcohort of the "Hispanic Community Health Study/Study of Latinos." We use baseline examination data collected from 2008 to 2011 to investigate associations between eight organochlorine pesticides (OCPs), five polychlorinated biphenyls (PCB) groups, sum of polybrominated diphenyl ethers and polybrominated biphenyl 153 on sex hormone binding globulin (SHBG) and various sex-related hormone levels. We examined associations cross-sectionally using linear and logistic regression models adjusted for complex survey design and confounders. PCBs and select OCPs were associated with increased SHBG in women and decreased estradiol (E2) and/or bioavailable E2 in men. For instance, per quartile increase in serum concentrations of ∑PCBs and oxychlordane were associated with decreased levels of E2 (β=-6.36pmol/L; 95% CI: 10.7,-2.02 and β=-5.08pmol/L; 95% CI: 8.11,-2.05) and bioavailable E2 (β=-4.48pmol/L; 95% CI: 7.22,-1.73 and β=-4.23pmol/L; 95% CI: 6.17,-2.28), respectively, in men, and increased levels of SHBG (β=7.25nmol/L; 95% CI:2.02,12.8 and β=9.42nmol/L; 95% CI:4.08,15.0), respectively, in women. p,p'-DDT and β-HCCH, and o,p'-DDT were also associated with decreased testosterone (T) and bioavailable T (ng/dL) levels in men. Adiposity modified associations in men, revealing stronger inverse associations of PCBs, PBDEs, and several OCPs with LH, SHBG, E2, bioavailable E2, T, and the ratios of LH to FSH and E2 to T in those with below median body mass index and waist-to-hip ratio. Distinct patterns of hormone dysregulation with increasing POPs serum concentration were identified in men and post-menopausal women. In men but less so in postmenopausal women, adiposity modified associations of POPs serum concentration with sex-related hormones.

Association of ethylene oxide exposure with sex hormones in the general US population: a cross-sectional study.

Ethylene oxide (EO) is an environmental chemical widely used in industry and has been related to various conditions such as dyslipidemia and metabolic syndrome. However, it is not clear what effect EO has on sex hormones. This paper aims to investigate the connection between EO exposure and sex hormones. EO exposure was assessed by measuring blood levels of hemoglobin adducts of ethylene oxide (HbEO). Based on the National Health and Nutrition Examination Survey (NHANES) 2013-2016 dataset, we assessed linear and nonlinear associations between HbEO and sex hormone levels using weighted multivariate linear regression analyses and weighted generalized additive modeling approaches. We further calculated the threshold effect using a two-piecewise linear regression model. In addition, we performed subgroup analyses. In men, HbEO levels showed a U-shaped relationship with total testosterone (TT) and sex hormone binding globulin (SHBG), with inflection points ln (HbEO) (Natural logarithmic transformed value of HbEO) of 4.12 pmol/g Hb and 3.78 pmol/g Hb, respectively. HbEO levels in women showed an inverted U-shaped relationship with TT, with an inflection point ln (HbEO) of 4.54 pmol/g Hb. However, to the right of the inflection point, the relationship between HbEO and TT was not statistically significant (β =-0.09, 95%CI -0.21, 0.03). Female HbEO levels were negatively correlated with estradiol (E2) (β = -0.11, 95%CI -0.19, -0.03). In addition, we found a positive correlation between HbEO and SHBG in women with a body mass index (BMI) <25（β = 0.12, 95%CI 0.04, 0.20, P for interaction = 0.007). EO exposure leads to altered sex hormone levels in the general U.S. population, and further research is required in the future to validate our findings.

Association between sex steroid hormones and α-klotho: Results from the NHANES 2013-2016 and Mendelian randomization study.

This study aimed to explore the association and causal links between sex steroid hormones and the anti-aging protein α-Klotho, extending to investigate the mediation effects of potential mediators. Based on data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016, this study performed weighted multivariable-adjusted logistic regression to evaluate the association between sex steroid hormones and α-Klotho. Then, utilizing summary data from genome-wide association studies (GWAS), a bidirectional two-sample Mendelian randomization (MR) was conducted to assess the causal relationship between sex steroid hormones and α-Klotho. Finally, mediation analysis was conducted to delineate the influence of five identified potential mediators on the sex steroid hormones-α-Klotho association. In men, significant positive correlations with α-Klotho were consistent across both unadjusted and fully adjusted models for total testosterone (TT), bio-available testosterone (Bio-T), estradiol (E2) and sex hormone-binding globulin (SHBG) (Model 3: TT: β = 3.54, 95 % CI: 1.63-5.44, P = 0.0003; Bio-T: β = 1.74, 95 % CI: 0.73-2.74, P = 0.0007; E2: β = 0.25, 95 % CI: 0.11-0.38, P = 0.0003; SHBG: β = 0.95, 95 % CI: 0.63-1.27, P < 0.0001); In premenopausal women, we detected a potential nonlinear relationship between TT levels and α-Klotho, with α-Klotho levels rising to a peak at a TT level of 72.2 ng/mL, after which they declined. Furthermore, results from MR analyses reaffirmed positive associations of TT and Bio-T with α-Klotho in men (TT: β = 3.54, 95 % CI: 1.63-5.44, P = 0.0003; Bio-T: β = 1.74, 95 % CI: 0.73-2.74, P = 0.0007). Finally, significant mediation effects were observed for uric acid (β = 0.27, 95 % CI: 0.15-0.67, P < 0.0001) and creatinine (β = 0.05, 95 % CI: 0.01-0.16, P = 0.0060), accounting for 26.7 % and 5.23 % of the total mediation effect, respectively. In conclusion, our results demonstrate that both TT and Bio-T enhance the expression of α-Klotho in men. The positive association observed may be partly mediated by uric acid and creatinine.

Association of ultra-processed food-related metabolites with selected biochemical markers in the UK Biobank

BackgroundUltra-processed food (UPF) intake is positively associated with multiple adverse health outcomes. However, the underlying biological mechanisms remain unclear. Serum metabolites may elucidate these mechanisms. We investigated serum metabolites correlated with UPF and un/minimally processed food (UNPF) intake and evaluated their association with selected biochemical markers.MethodsCross-sectional study within the UK biobank, including a total of 72,817 participants with 24-hour recall dietary data and 134 nuclear magnetic resonance metabolites. UPF and UNPF intakes were evaluated using the NOVA classification, and related metabolites were identified using elastic net penalized regression. A UPF metabolomic signature was computed as a weighted sum of UPF-related metabolites, using elastic net coefficients as weights. Associations between UPF and UNPF-related metabolites, and serum C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), sex hormone-binding globulin (SHBG), and testosterone were examined using multiple quantile regression.ResultsElastic net model identified 17 and 15 metabolites uniquely related to UPF and UNPF intake, respectively. Acetoacetate, acetone, high-density lipoprotein (HDL) diameter, docosahexaenoic acid, linoleic acid, ω-3 fatty acids (FA), total lipids in large HDL cholesterol, and valine levels were decreased, but free cholesterol in extremely small very low-density lipoproteins (LDL), glutamine, glycine, glycoprotein acetyls, lactate, saturated FA, sphingomyelins, triglycerides in large LDL, and triglycerides in medium HDL levels were increased with high UPF intake. Opposite relationships were observed for UNPF intake. Heterogeneous associations were observed between UPF-related metabolites and CRP, IGF-1, SHBG, and testosterone levels. A UPF metabolomic signature was positively associated with CRP (regression coefficient per standard deviation, 1.45, 95% confidence interval, 1.385, 1.515) and negatively associated with IGF-1 (-3.16, -4.493, -1.827) and SHBG (-13.878, -15.291, -12.465).ConclusionA UPF metabolomic profile, including VLDL free cholesterol, saturated FA, triglycerides, glutamine, glycine, and glycoprotein acetyl was associated with inflammatory, insulin signalling, and reproductive biomarkers. This metabolomic profile should be explored as a potential mediators of UPF-disease associations, and as an objective marker of UPF intake.

Characteristics of polymorphism of genes involved in the regulation of glucose metabolism and steroid hormone synthesis in patients with polycystic ovary syndrome

Background: Polycystic ovary syndrome is an urgent problem of gynecological endocrinology. Currently, a number of genes have been studied that control glucose metabolism and are involved in the synthesis, conversion into an active form and transport of steroid hormones, mutations in which with a certain degree of reliability can serve as a diagnostic criterion for polycystic ovary syndrome. Aim: The aim of this study was to evaluate the PPARG Pro12Ala, INS 223HphI AT, and SHBG (TAAAA)n gene polymorphisms in patients with polycystic ovary syndrome and in healthy individuals. Materials and methods: The polymerase chain reaction method and restriction fragment length polymorphism analysis were used. The frequencies of alleles and genotypes of polymorphic variants were studied in 136 women with polycystic ovary syndrome and 47 women in the control group: Pro12Ala (PPARG gene), 223HphI AT, (INS gene) and (TAAAA)n repeats (SHBG gene). Results: The distribution of the allele and genotype frequencies for the PPARG (rs1801282) and INS (rs689) genes in patients with polycystic ovary syndrome and in healthy individuals did not differ. The distribution of the genotype frequencies in the group of women with polycystic ovary syndrome differed (p = 0.02) from that in the control group for the (TAAAA)n polymorphism in the SHBG gene. In the presence of a long repeat in the SHBG gene in at least one of the homologous chromosomes, the probability of a woman having polycystic ovary syndrome increases by 2.5 times. Patients with a verified A/A genotype (INS), in the presence of an SHBG gene allele with a long repeat, have a ten-fold higher risk of developing polycystic ovary syndrome than women with SHBG gene short alleles. Conclusions: Patients with long repeats in the SHBG gene are at risk for developing polycystic ovary syndrome with phenotypes A, B, and C, especially in combination with the presence of the A/A genotype, class I (INS).

Comparison of GLP-1 Receptor Agonists Combined with Metformin Versus Metformin Alone in the Management of PCOS: A Comprehensive Meta-Analysis.

This study compared the efficacy and safety of glucogan-like peptide-1 receptor agonists (GLP1RAs) combined with metformin versus metformin alone in women with polycystic ovary syndrome (PCOS). A systematic search of "PubMed", "EMBASE", "Cochrane Library", and "Web of Science", "Google Scholar" was conducted up to September 2024. Studies were included if they were RCTs investigating the combination of GLP1RAs and metformin in women diagnosed with PCOS. Eligible studies compared this combination therapy to metformin alone. Primary outcomes included changes in body weight, BMI, waist circumference, fasting glucose, HOMA-IR, androgen levels, and sex hormone-binding globulin (SHBG). Meta-analysis was performed using RevMan 5.4 software. Eight RCTs with a total of 337 participants were included. The combination of GLP1RAs and metformin resulted in significant reductions in body weight (mean difference [MD]=-1.37kg, 95% CI [-2.07, -0.67]; P = 0.0001), BMI (MD= -0.88kg/m², 95% CI [-1.37, -0.39]; P = 0.0005), waist circumference (MD= -2.46cm, 95% CI [-3.59,-1.33]; P < 0.0001), fasting glucose level (MD= -0.30, 95% CI [-0.42,-0.17]; P < 0.0001), and glucose level at 2h after OGTT (MD= -1.58, 95% CI [-2.10,-1.06]; P < 0.0001) compared to metformin alone. Improvements in insulin sensitivity (HOMA-IR) in GLP1RA + Met group were also observed (MD=-1.58, 95% CI [-2.10, -1.06]; P < 0.0001) comparing to Met group. Hormonal outcomes demonstrated an increase in SHBG (MD = 10.04, 95% CI [7.06, 13.01]; P < 0.0001). Adverse events were not different between GLP1RA + Met and Met groups. Collectivley, combination of GLP1RAs and metformin provides superior benefits over metformin alone in reducing body weight, improving insulin sensitivity, and regulating hormonal imbalances in women with PCOS.

Biomarker Assessment of Cheese Intake and Stroke Risk: A Mendelian Randomization Study.

This study explores the association of cheese consumption with stroke using a Mendelian randomization (MR) approach, which leverages genetic variations to minimize confounding. The study analyzed the impact of cheese cheese dietary habits on stroke, mediated by 44 biomarkers, including blood cells, biochemical markers, and blood pressure indicators. The findings show that cheese consumption is associated with lower stroke risk (OR = 0.715, P = 0.000279). Seven key biomarkers were identified as intermediaries in this relationship: apolipoprotein B (1.70%), aspartate aminotransferase (1.68%), cystatin C (2.50%), glucose (4.40%), sex hormone binding globulin (2.14%), urate (3.70%), and diastolic blood pressure (11.94%). These biomarkers help explain the biological pathways through which cheese intake may influence stroke risk, with diastolic blood pressure contributing the most to the protective effect. Despite these findings, the study notes limitations, such as the absence of specific data on cheese types and the emphasis on individuals of European ancestry may restrict the applicability of the findings to broader populations. Further research is required to validate these results and clarify the underlying mechanisms of the identified biomarkers in stroke prevention.

Evaluating the association between lipidome and female reproductive diseases through comprehensive Mendelian randomization analyses

This study aimed to assess the causal relationship between lipidome and female reproductive diseases (FRDs) using an advanced series of Mendelian randomization (MR) methods. This study utilized genome-wide association study (GWAS) summary statistics encompassing 179 lipidomes and six prevalent FRDs, namely polycystic ovary syndrome (PCOS), endometriosis, uterine fibroid, female infertility, uterine endometrial cancer, and ovarian cancer. The two-sample MR (TSMR) approach was employed to investigate the causal relationships, with further validation using false discovery rate (FDR) and multivariable MR (MVMR) methods. Subsequently, a range of comprehensive evaluations were performed, including sensitivity analysis, mediation MR analysis, reverse MR analysis, and steiger test. Examining 179 lipidome traits as exposures and 6 FRDs as outcomes, this study identified significant causal effects of 56 lipids on FRDs. Following multiple testing correction and MVMR validation, sphingomyelin (d38:2) was found to have a protective effect against PCOS (β = -0.104, 95% CI: -0.199 ~ -0.010, P = 0.031). Phosphatidylcholine (18:0_22:6) was associated with a decreased risk of developing uterine fibroid (β = -0.111, 95% CI: -0.201~ -0.021, P = 0.016), and sterol ester (27:1/20:3) showed significance in uterine endometrial cancer (β = -0.248, 95% CI: -0.443 ~ -0.053, P = 0.013). Conversely, phosphatidylethanolamine (18:2_0:0) was associated with increased risk of endometriosis (β = 0.183, 95% CI: 0.015 ~ 0.350, P = 0.033), while sterol ester (27:1/18:1) posed a risk influence on uterine fibroid (β = 1.007, 95% CI: 0.925 ~ 1.089, P < 0.001), and phosphatidylcholine (16:0_22:6) on uterine endometrial cancer (β = 0.229, 95% CI: 0.039 ~ 0.420, P = 0.018). Furthermore, it was determined that the causal associations between these lipidome profiles and FRDs were independent of BMI, obesity, diabetes, smoking, alcohol use, physical activity, inflammation, depression, waist-hip ratio, vitamin D, dehydroepiandrosterone sulphate, sex hormone binding globulin, and testosterone levels. Most outcomes passed consistent tests without evidence of heterogeneity, pleiotropy, or reverse causality. The results indicated a close association between specific lipidomes, particularly sphingomyelin, lysophosphatidylethanolamine, cholesterol ester, and phosphatidylcholines, with FRDs. These lipid species may potentially serve as biomarkers and future drug targets for the treatment of FRDs.

Intracellular Retention of Estradiol is Mediated by GRAM Domain-Containing Protein ASTER-B in Breast Cancer Cells.

Elevated blood levels of estrogens are associated with poor prognosis in estrogen receptor-positive (ER+) breast cancers, but the relationship between circulating blood hormone levels and intracellular hormone concentrations are not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal. While circulating E2 is sequestered by sex hormone binding globulin (SHBG), the potential mechanisms of intracellular E2 retention are poorly understood. We found that a mislocalization of a steroid-binding GRAM-domain containing protein, ASTER-B, to the nucleus, which is observed in a subset of breast cancer patients, is associated with higher cellular E2 retention. Accumulation and retention of E2 are related to the steroidal properties of E2, and require nuclear localization and steroid binding by ASTER-B, as shown using a panel of mutant ASTER-B proteins. Finally, we observed that nuclear ASTER-B-mediated E2 retention is required for sustained hormone-induced ERalpha chromatin occupancy at enhancers and gene expression, as well as subsequent cell growth responses. Our results add intracellular hormone retention as a mechanism controlling E2-dependent gene expression and downstream biological outcomes. Implications: Mislocalized nuclear ASTER-B, which binds estradiol to support the functions of ER, can provide an alternate means of enhancing the biological effects of E2 in breast cancers and may be a potential therapeutic target that addresses multiple aspects of estrogen bioavailability.

The Association of Menopausal Age with Sex Hormones and Anthropometric Measures Among Postmenopausal Women in the Multi-Ethnic Study of Atherosclerosis Study.

Introduction: We investigated associations of menopausal age category with body mass index (BMI), waist circumference, waist-hip ratio, and waist-height ratio. We also explored the moderating effect of anthropometric measures on associations of menopausal age category with prespecified sex hormones: estradiol, dehydroepiandrosterone (DHEA), sex hormone-binding globulin, bioavailable testosterone, and total testosterone-estradiol (T/E) ratio. Methods: In this cross-sectional study, we included 2,436 postmenopausal women from the Multi-Ethnic Study of Atherosclerosis who had menopausal age, anthropometric, and sex hormone data at baseline. Menopausal age was categorized as <45 years (early menopause), 45-49 years, 50-54 years (referent), and ≥55 years (late menopause). Linear models were used for analysis. Results: The mean (standard deviation) age was 64.7 (9.2) years. After multivariable adjustment, women who experienced late menopause had higher waist circumference (2.28 cm), waist-hip ratio (0.013 units), and waist-height ratio (0.014 units) but not BMI than those in the referent category. The interaction terms between menopausal age category and anthropometric measures were not significant for prespecified sex hormones (all Pinteraction >0.05). When compared with the referent category, T/E ratio was 21% (4.72 - 39.8%) higher among women with late menopause while DHEA levels were 9% (1 - 16%) higher among women who experienced menopause between 45 and 49 years in multivariable adjusted models. Conclusion: Women with late menopause had higher abdominal adiposity but not generalized adiposity when compared with those who experienced menopause between 50 and 54 years of age. Androgenicity was higher among women who experienced menopause between 45 and 49 years of age and those with late menopause, based on DHEA and T/E ratios, respectively.

Sex-specific associations of serum testosterone with gray matter volume and cerebral blood flow in midlife individuals at risk for Alzheimer's disease.

Testosterone, an essential sex steroid hormone, influences brain health by impacting neurophysiology and neuropathology throughout the lifespan in both genders. However, human research in this area is limited, particularly in women. This study examines the associations between testosterone levels, gray matter volume (GMV) and cerebral blood flow (CBF) in midlife individuals at risk for Alzheimer's disease (AD), according to sex and menopausal status. A cohort of 294 cognitively normal midlife participants, 83% female, ages 35-65 years, with an AD family history and/or Apolipoprotein E epsilon 4 (APOE-4) genotype, underwent volumetric Magnetic Resonance Imaging (MRI) to measure GMV and MR-Arterial Spin Labeling (ASL) for measurement of CBF. We used voxel-based analysis and volumes of interest to test for associations between testosterone (both total and free testosterone) and brain imaging outcomes, stratified by sex and menopausal status. Higher total and free testosterone levels were associated with larger GMV in men, with peak effects in frontal and temporal regions. Conversely, in women, higher testosterone levels correlated with higher CBF, with peak effects in frontal and limbic regions, subcortical areas and hypothalamus. Among women, associations between testosterone and GMV were observed at the premenopausal and perimenopausal stages, but not postmenopause, whereas associations of testosterone with CBF were significant starting at the perimenopausal stage and were more pronounced among hormone therapy non-users. Results were independent of age, APOE-4 status, midlife health indicators, and sex hormone-binding globulin levels. These findings indicate sex-specific neurophysiological effects of testosterone in AD-vulnerable regions in midlife individuals at risk for AD, with variations observed across sex and menopausal status. This underscores the need for further research focusing on the neuroprotective potential of testosterone in both sexes.

Exploring the link between sex hormone-binding globulin levels and prostate cancer risk: a comprehensive systematic review and meta-analysis.

Sex hormone-binding globulin (SHBG) plays a critical role in regulating androgen bioavailability and has been hypothesized to influence prostate cancer risk, though existing evidence is inconsistent. This systematic review and meta-analysis aimed to evaluate the association between SHBG levels and prostate cancer risk. A comprehensive search was conducted across PubMed, Embase, and Web of Science for studies published up to December 1, 2024. Observational studies assessing SHBG levels and prostate cancer risk were included. Effect sizes were pooled using random-effects meta-analysis. Heterogeneity was evaluated using the I2 statistic, and quality assessment was performed using the Newcastle-Ottawa Scale. Statistical analysis was performed using R software version 4.4. Sixteen studies, including 720,298 participants and 90,799 prostate cancer cases, were analyzed. The pooled odds ratio (OR) for prostate cancer risk per unit increase in SHBG was 0.907 (95% CI 0.799-1.030), indicating no statistically significant association. Substantial heterogeneity was observed among the included studies (I2 = 79%; P < 0.0001). Subgroup analyses showed no significant variation in effect sizes by study design. However, a Mendelian randomization analysis conducted in 140,254 European-descent males, including 79,148 prostate cancer cases, suggested a modest protective effect of higher SHBG levels, with an OR of 0.944 (95% CI 0.897-0.993). Sensitivity analyses confirmed the robustness of the pooled findings. This meta-analysis showed a complex relationship between SHBG levels and prostate cancer risk. While overall findings do not support a statistically significant association, higher SHBG levels may confer a protective role in specific contexts. Further research is needed to elucidate mechanisms, reduce heterogeneity, and validate SHBG as a biomarker for risk stratification.

Sex steroid hormones mediate the association between neonicotinoids and obesity among children and adolescents.

Neonicotinoids are the most widely used insecticide worldwide. Toxicological and epidemiological studies suggest that exposure to neonicotinoid may be linked to the development of childhood obesity. However, the evidence is limited. To investigate the association between neonicotinoid exposure and obesity among U.S. children and adolescents and to explore underlying mechanism mediated by serum sex steroid hormones in these associations. Data from the 2015-2016 National Health and Nutrition Examination Survey were used for the analysis. Generalized linear regression was used to investigate the association between detectable neonicotinoids and ten measures of obesity. The interaction effects of multiple neonicotinoids were determined by Chi-squared Automatic Interaction Detection method. Mediation analysis was used to assess potential mediators of sex steroid hormones, including testosterone (T), estradiol (E2), T/E2, sex hormone-binding globulin (SHBG), and free androgen index (FAI). Clothianidin (β = -0.29, 95 % CI: -0.57, -0.01) and N-desmethyl-acetamiprid (β = -0.19, 95 % CI: -0.35, -0.03) were associated with reduced VFI z-score. After stratification, 5-hydroxy-imidacloprid was positively associated with the risk of general obesity in males (OR=2.24, 95 % CI: 1.20, 4.20) with a probability of 52.5 %. FAI mediated 15 % of the association between neonicotinoid exposure and reduced risk of obesity, and SHBG mediated 30 % of the association between neonicotinoid exposure and increased risk of obesity. Neonicotinoids showed associations with obesity, but the results were mixed and sex-specific. Sex steroid hormones may play a role in mediating the effects of neonicotinoids on obesity.

The impact of intermittent fasting on fertility: A focus on polycystic ovary syndrome and reproductive outcomes in Women-A systematic review.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by hyperandrogenism, insulin resistance, and menstrual irregularities, leading to infertility in many women. Emerging evidence suggests intermittent fasting (IF), particularly time-restricted feeding (TRF), may improve reproductive and metabolic outcomes in women with PCOS by addressing core pathophysiological mechanisms. This systematic review examines the impact of IF on fertility and reproductive hormones in women with PCOS. A systematic search was conducted in PubMed, Scopus, and Cochrane Library using predefined search terms related to intermittent fasting, fertility, and PCOS. Eligible studies published between 2014 and 2024 were identified following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inclusion criteria targeted primary research evaluating the effects of IF on reproductive outcomes, menstrual irregularities, and metabolic parameters in women with PCOS. Data extraction and quality assessment were performed using the Caldwell framework. Three studies were included in the review. TRF interventions led to significant improvements in menstrual regularity, with 33-40% of participants reporting normalized cycles. Reductions in total testosterone, free androgen index, anti-Müllerian hormone (AMH), and luteinizing hormone (LH) levels were observed, alongside increased sex hormone-binding globulin (SHBG). TRF also improved insulin sensitivity, reduced body weight, and decreased inflammatory markers, all of which contribute to enhanced reproductive outcomes. Key outcomes included a 9% reduction in testosterone levels, 26% reduction in the free androgen index (FAI), and significant improvements in menstrual regularity (33-40%). Intermittent fasting, particularly TRF, shows potential as a non-pharmacological intervention to improve reproductive health and fertility in women with PCOS. By targeting hyperandrogenism, insulin resistance, and menstrual irregularities, TRF offers a promising lifestyle approach. However, larger randomized controlled trials with long-term follow-up are needed to confirm these findings and establish IF as a standard therapeutic option for PCOS management.

Causal influences of testosterone on brain structure change rate: A sex-stratified Mendelian randomization study.

The impact of testosterone levels on changes in brain structure has been reported. However, it is still unclear which specific brain region could be affected. This study approached Mendelian randomization method to reveal the causal relationship between testosterone levels and the rate of longitudinal structural changes in the brain. The testosterone-related GWAS data were determined from 425,097 European participants. The GWAS data on the rate of longitudinal structural changes in the brain came from the ENIGMA consortium, which included 15,640 all-age participants from 40 longitudinal cohorts. The inverse variance weighted was considered as the main estimate, MR Egger and weighted median methods were used to supplement IVW. A positive correlation was found between total testosterone levels and bioavailable testosterone levels in women and age-independent longitudinal changes in cerebral WM and surface area. The sex hormone-binding globulin levels were found a negative correlation with age-dependent longitudinal structural changes of cortical GM in men. Additionally, we also found that the bioavailable testosterone level in males was negatively associated with the quadratic age-dependent longitudinal change rate in the globus pallidum. We also found estradiol levels and sex hormone-binding globulin levels were negatively associated with the quadratic age-dependent longitudinal change rate of total brain in men. Moreover, we found a positive correlation between total testosterone levels and linear age-dependent longitudinal changes in the hippocampus in both males and females. The testosterone levels in different genders may have varying degrees of causal effects on the structural changes of brain regions. These findings provide evidence for the influence of the brain glandular axis on brain structure, particularly during female brain development.

SEX-SPECIFIC BIOMARKER PREDICTION OF FEMORAL NECK BONE LOSS AFTER HIP FRACTURE

Abstract Hip fracture exacerbates age-related inflammation and metabolic dysfunction, which could accelerate bone loss post-fracture. This study aimed to develop biomarker prediction models for declines in femoral neck bone mineral density (BMD) after hip fracture. Participants were Caucasian men (n=99) and women (n=75) from the Baltimore Hip Studies 7th cohort with a hip fracture who were not receiving glucocorticoids, sex-hormone therapy, or bone-active medications. Data were collected at baseline (within 15 days of admission) and 2-, 6-, and 12-months later. Biomarkers were categorized into tertiles: interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), soluble tumor necrosis factor-alpha (TNF-alpha) receptor type 1, estradiol (E), testosterone (T), intact parathyroid hormone (iPTH), sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), C-terminal telopeptide of type I collagen (CTX), and procollagen type I N-propeptide (PINP). Femoral neck BMD was measured using dual energy x-ray absorptiometry. Mixed-effects models adjusted for age, height, and weight estimated 1-year changes in femoral neck BMD after hip fracture. Bone loss was classified as accelerated for intra-individual changes that exceeded the mean decline. Logistic regression models were stratified by biological sex and implemented using stepwise selection. The area under the curve (AUC) estimate among men was 0.68, and biomarkers related to bone loss were E, IGF-1, SHBG, and CTX. Similarly, the AUC metric among women was 0.69, but identified biomarkers were IL-6, iPTH, IGF-1, and SHBG. Findings indicate that both inflammatory and hormonal biomarkers relate to accelerated bone loss post-fracture; however, there are differential associations in physiological mechanisms between men and women.

Bariatric Surgery as a Molecular Modulator: The Role of FSHR Polymorphisms in Enhancing eNOS Expression and Reproductive Hormone Dynamics in Women with Severe Obesity.

Severe obesity (BMI > 40 kg/m2) has a severe influence on vascular health and reproduction. This study looks at how bariatric surgery affects endothelial nitric oxide synthase (eNOS) expression and reproductive hormone regulation across different follicle-stimulating hormone receptor (FSHR) polymorphism groups in women with extreme obesity. Twenty-nine women with extreme obesity had bariatric surgery. Pre- and post-surgery levels of eNOS and reproductive hormones such as follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), anti-Müllerian hormone (AMH), and antral follicle count (AFC) were assessed. Patients were divided into three FSHR polymorphism groups (Ser/Ser, Asn/Asn, and Ser/Asn), and results were compared between them. Statistical techniques were used to determine changes and relationships. Bariatric surgery led to substantial increases in eNOS expression across all FSHR polymorphism groups (p < 0.0001), with the Ser/Ser group exhibiting the most variability. Prior to surgery, the Ser/Ser group had substantially higher FSH levels (7.41 ± 0.60 mIU/mL) than the Asn/Asn group (5.20 ± 0.63 mIU/mL, p < 0.001). Following surgery, FSH levels rose in the Ser/Ser group (9.45 ± 0.87 mIU/mL), with significant differences between the Ser/Ser and Ser/Asn groups (mean difference = 0.97, p = 0.019). SHBG levels had a negative connection with eNOS expression after surgery (r = -0.365, p = 0.049). AMH and AFC remained constant throughout polymorphism groups. BMI decreased uniformly, with an average of 15.2 ± 1.8 kg six months after surgery. Bariatric surgery improves vascular health and regulates reproductive hormones, especially in individuals with the Ser/Ser genotype. These findings indicate the possibility of combining genetic testing and bariatric therapies to improve infertility treatment in obese women.

Impact of Oral DHEA Supplementation on Androgen Levels in Women Using Combined Oral Contraceptives: A Randomized Study

Background: Combined oral contraceptives (COCs) reduce androgen levels, particularly Testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and increasing Sex Hormone-Binding Globulin (SHBG). This can lead to testosterone deficiency, which is associated with negative effects on well-being, mood, energy, cognitive function, sexual functioning, muscle mass, and bone density. Objective: To evaluate the effects of adding oral Dehydroepiandrosterone (DHEA) to Combined Oral Contraceptives (COCs) on the hormonal profile in Caucasian women. Materials and Methods: A randomized, double-blind, placebo-controlled trial was conducted with 35 healthy Caucasian women aged 21-35 years (BMI: 18.5-25 kg/m²) who used a COC containing 30μg ethinyl estradiol (EE) and 150μg Levonorgestrel (LNG). Participants discontinued COC use for three menstrual cycles before being randomized to receive either COCs with 50 mg/day DHEA (n=18) or placebo (n=17) for six cycles. Hormonal levels were measured at baseline and after 1, 3, and 6 months of treatment. Results: COC use significantly reduced Total Testosterone (by 56.2%), Free Testosterone (by 65.7%), Dehydroepiandrosterone, Dehydroepiandrosterone Sulfate, and Androstenedione levels while increasing SHBG concentration (P&lt;0.001). Adding DHEA to COCs restored both Free and Total Testosterone levels to baseline (P&lt;0.001). Discussion: The addition of DHEA to COCs was effective in maintaining physiological androgen levels, potentially counteracting the adverse effects of COCs on female sexual function and overall well-being. Conclusion: Adding 50 mg/day DHEA to EE/LNG-containing COCs maintains physiological levels of Free and Total Testosterone in Caucasian women, potentially mitigating the adverse effects of COCs on female sexual function. Further comprehensive clinical trials are warranted to evaluate these clinical effects.

Sex hormone-binding globulin, testosterone and type 2 diabetes risk in middle-aged African women: exploring the impact of HIV and menopause.

Sex hormone-binding globulin (SHBG) and testosterone are differentially associated with type 2 diabetes (T2D) risk. We investigated whether these associations differ by HIV and menopausal status in Black South African women living with (WLWH) and without HIV (WLWOH). Cross-sectional observational. Eighty one premenopausal (57 WLWOH, 24 WLWH) and 280 postmenopausal (236 WLWOH, 44 WLWH) women from the Middle-Aged Soweto Cohort (MASC) completed the following measures: circulating SHBG and sex hormones, body composition (dual energy x-ray absorptiometry), oral glucose tolerance test to estimate insulin sensitivity (Matsuda index), secretion (insulinogenic index, IGI) and clearance, and beta-cell function (disposition index, DI). Dysglycaemia was defined as either impaired fasting or postprandial glucose or T2D. SHBG was higher and total and free testosterone were lower in postmenopausal WLWH than WLWOH (all p≤0.023). Irrespective of HIV serostatus, SHBG was positively associated with Matsuda index, insulin clearance and DI and inversely with HOMA-IR (all p<0.011). The association between SHBG and Matsuda index was stronger in premenopausal than postmenopausal women (p=0.043 for interaction). Free testosterone (and not total testosterone) was only negatively associated with basal insulin clearance (p=0.021), and positively associated with HOMA-IR in premenopausal and not post-menopausal women (p=0.015 for interaction). We show for the first time that midlife African WLWH have higher SHBG and lower total and free testosterone than WLWOH, which corresponded to their higher beta-cell function, suggesting a putative protective effect of SHBG on T2D risk in WLWH.