Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women.

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, ptrend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, ptrend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, ptrend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.

Alcohol intake and endogenous sex hormones in women: Meta-analysis of cohort studies and Mendelian randomization.

BACKGROUND: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. METHODS: Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). RESULTS: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). CONCLUSIONS: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

Effects of testosterone and sex hormone binding globulin on lung function in males and females: a multivariable Mendelian Randomisation study.

BACKGROUND: Observational studies suggest that total testosterone (TT) and sex hormone-binding globulin (SHBG) may have beneficial effects on lung function, but these findings might be spurious due to confounding and reverse causation. We addressed these limitations by using multivariable Mendelian randomisation (MVMR) to investigate the independent causal effects of TT and SHBG on lung function. METHODS: We first identified genetic instruments by performing genome-wide association analyses of TT and SHBG in the large UK Biobank, separately in males and females. We then assessed the independent effects of TT and SHBG on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using one-sample MVMR. We addressed pleiotropy, which could bias MVMR, using several methods that account for it. We performed subgroup MVMR analyses by obesity, physical activity and menopausal status, and assessed associations between TT and SHBG with lung function decline. Finally, we compared the MVMR results with those of observational analyses in the UK Biobank. FINDINGS: In the MVMR analyses, there was evidence of pleiotropy, but results were consistent when accounting for it. We found a strong beneficial effect of TT on FVC and FEV1 in both males and females, but a moderate detrimental effect of SHBG on FEV1 and FEV1/FVC in males only. Subgroup analyses suggested stronger effects of TT among obese and older males. The observational analyses, in line with previous studies, agreed with MRMV for TT, but not for SHBG. INTERPRETATION: These findings suggest that testosterone improves lung function in males and females, while SHBG has an opposite independent effect in males.

A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes.

PURPOSE: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. METHODS: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. RESULTS: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. CONCLUSION: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Biomarkers to inform the management of polycystic ovary syndrome: A review of systematic reviews.

INTRODUCTION: Polycystic ovarian syndrome (PCOS) is the commonest endocrine condition affecting reproductive age women. Many biomarkers may aid assessment and management, however evidence is limited on their utility in clinical practice. We conducted a review of systematic reviews to identify the most useful biomarkers in the clinical management of PCOS. METHODS: We searched MEDLINE, EMBASE, CENTRAL and HTA until August 2023 for reviews evaluating biomarkers in PCOS women compared to healthy controls. Methodological quality was assessed using the AMSTAR2 tool. We reported pooled evidence for each biomarker with 95% confidence intervals from the most recent, up-to-date, and best quality review. RESULTS: From 3360 citations, we included 75 systematic reviews (88 biomarkers, 191,792 women). Most reviews (50/75, 67%) were moderate quality, but reported high heterogeneity (66/75, 88%). We identified 63 abnormal biomarkers in women with PCOS versus healthy controls. Of these, 22 core biomarkers could help evaluate the multisystemic impact of PCOS and inform patient management and surveillance: dehydroepiandrosterone, prolactin, sex hormone-binding globulin, total and free testosterone, anti-Mullerian hormone, systolic and diastolic blood pressure, c-reactive protein, fibrinogen, oral glucose tolerance test, homoeostatic model assessment-insulin resistance index, fasting insulin, total cholesterol, triglycerides, lipoprotein(a), HDL, LDL, non-HDL-cholesterol, ferritin, iron, and 25-hydroxy-vitamin D. CONCLUSION: We identified 22 core biomarkers assessing the multisystemic impact of PCOS and inform its clinical management. Future research is required to establish validated healthcare pathways.

Sex hormone-binding globulin may explain sex differences for glucose homeostasis and incidence of type 2 diabetes: the KORA study.

Research has indicated that sex hormone-binding globulin (SHBG) is associated with glucose homeostasis and may play a role in the etiology of type 2 diabetes (T2D). While it is unclear whether SHBG may mediate sex differences in glucose control and subsequently, incidence of T2D. We used observational data from the German population-based KORA F4 study (n = 1937, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1387). T2D was initially assessed by self-report and validated by contacting the physicians and/ or reviewing the medical charts. Mediation analyses were performed to assess the role of SHBG in mediating the association between sex (women vs. men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis). After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower fasting glucose levels compared to men (ß = -4.94 (mg/dl), 95% CI: -5.77, -4.11). SHBG levels were significantly higher in women than in men (ß = 0.47 (nmol/l), 95% CI:0.42, 0.51). Serum SHBG may mediate the association between sex and fasting glucose levels with a proportion mediated (PM) of 30% (CI: 22-41%). Also, a potential mediatory role of SHBG was observed for sex differences in incidence of T2D (PM = 95% and 63% in models 1 and 2, respectively). Our novel findings suggest that SHBG may partially explain sex-differences in glucose control and T2D incidence.

Correlation between serum sex hormone-binding globulin levels and nutrition indicators and malnutrition exposure risk in men and postmenopausal women with type 2 diabetes.

BACKGROUND: This study sought to investigate the correlation between serum sex hormone-binding globulin (SHBG) levels and nutrition indicators and the malnutrition exposure risk in men and postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional analysis was conducted, involving patients diagnosed with T2DM at the Guangdong Provincial People's Hospital between May 2018 and December 2019. RESULTS: The study comprised 551 participants (363 men, mean age of 55.55 ± 11.57 years), among whom 167 (30.31%) were classified as with malnutrition exposure risk (GNRI ≤ 98). Multivariable logistic regression analysis revealed that SHBG (OR = 1.04, 95% CI: 1.02-1.05, P < 0.001), glycated hemoglobin (OR = 1.36, 95% CI: 1.22-1.51, P < 0.001), hemoglobin (OR = 0.96, 95% CI: 0.94-0.97, P < 0.001), and non-alcoholic fatty liver disease (OR = 0.41, 95% CI: 0.23-0.73, P < 0.003) were independently associated with the malnutrition exposure risk. SHBG was inversely correlated with body mass index (males: r = -0.34; postmenopausal females: r = -0.22), albumin (males: r = -0.30; postmenopausal females: r = -0.20), transferrin (males: r = -0.28; postmenopausal females: r = -0.19), and prealbumin (males: r = -0.35; postmenopausal females: r = -0.30) (all P < 0.05). CONCLUSIONS: Serum SHBG levels are correlated with nutritional indicators and the risk of malnutrition in men and postmenopausal women with T2DM. A multicenter prospective study is imperative to verify this result in the future.

Non-Linear Association of Serum Sex Hormone Binding Globulin Concentration with Female Infertility.

BACKGROUND: Accumulating proofs suggested that disturbance of serum sex hormone-binding globulin (SHBG) concentration can affect the reproductive system. However, the effect of serum SHBG on female infertility remains to be clarified. METHODS: Data from 1,787 adults from the National Health and Nutrition Examination Survey (NHANES) was applied to examine the correlation between serum SHBG and female infertility. Multivariate logistic regression was used to evaluate the independent association between serum SHBG and female infertility. Furthermore, generalized additive model (GAM) and two-piecewise linear regression model were applied to assess the underlying non-linear association in our participants. RESULTS: We observed a reverse association between serum SHBG and infertility based on a fully-adjusted model (OR = 0.99, 95% CI: 0.99-1, p = 0.002), and the results were stable in several sensitive analyses. Furthermore, we detected a non-linear link by GAM and two-piecewise linear regression model. A protective association was observed at < 58.84 nmol/L serum SHGB; in contrast, no statistical link was found at > 58.84 nmol/L serum SHGB. CONCLUSIONS: Our results provide evidence for a non-linear association with serum SHBG and female infertility. This finding needs to be further confirmed in future large-scale prospective cohort studies.

Is There a Relationship of Cortisol and Sex Steroid Hormones With Mental Health in Middle-Aged Adults? The FIT-AGEING Study.

OBJECTIVE: Mental health has emerged as a worldwide concern given the increasing incidence of anxiety and depression disorders in the last years. Cortisol and sex steroid hormones have been demonstrated to be important regulators of mental health processes in older adults. However, the evidence considering these integrated variables in apparently healthy middle-aged individuals has not been thoroughly addressed. The present study aimed to investigate the association of the plasma cortisol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS) levels with mental health in middle-aged adults. METHODS: This cross-sectional study included a cohort of 73 middle-aged adults aged 45 to 65 years (women, 53%). Plasma cortisol, testosterone, SHBG, and DHEAS were assessed using a competitive chemiluminescence immunoassay. Free testosterone was calculated from the total testosterone and SHBG. Self-reported depression severity, generic health-related quality of life, hope, satisfaction with life, and optimism-pessimism were evaluated using the Beck Depression Inventory-II (BDI-II), 36-Item Short-Form Health Survey, Adult Hope Scale, Satisfaction with Life Scale, and Life Orientation Test-Revised, respectively-with higher total scores of these scales indicating greater levels of these variables. RESULTS: The testosterone and free testosterone levels were inversely associated with the BDI-II values in men (all P ≤ .042). The cortisol levels were positively related with the Satisfaction with Life Scale scores, whereas the testosterone, free testosterone, SHBG, and DHEAS levels were negatively correlated with the BDI-II values in women (all P ≤ .045). CONCLUSION: In summary, these results suggest that the increased levels of steroid hormones-within the normal values-are associated with better mental health in middle-aged adults.

Evaluation of the Potential Clinical Utility of Maternal Serum Biomarkers for Risk Assessment in Gestational Diabetes.

BACKGROUND: The exact relationships of circulating fibronectin, SHBG, and ILGF-1 with T2DM and GDM remain inconsistent. Therefore, in this study we evaluate their associations in T2DM and GDM. Additionally, we evaluate their correlations with different biochemical parameters. METHODS: A total of 505 pregnant women (180 with T2DM, 160 GDM patients, and 165 controls) were enrolled in the current study. SHBG, ILGF-1, and fibronectin were estimated by using the ELISA technique. RESULTS: The GDM and T2DM groups had higher ILGF-1 and fibronectin levels than the control group, while having a lower SHGB level. The correlations of clinical characteristics with ILGF-1, SHBG, and fibronectin showed that ILGF-1 in GDM patients was positively associated with HbA1c% and insulin. T2DM was positively related to insulin and insulin resistance, as well. There was a positive association between SHBG and insulin among the T2DM groups. Furthermore, in T2DM individuals, fibronectin was positively related with HbA1c% and glucose. CONCLUSIONS: The study suggests that the circulating levels of fibronectin, SHBG, and ILGF-1 are linked to GDM and T2DM risk. Hence, the circulating concentrations of these biomarkers are potentially useful for predicting the risk of GDM as well as developing T2DM.

Sex hormones and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study.

BACKGROUND: Females are considered to have an increased susceptibility to neuromyelitis optica spectrum disorder (NMOSD) than males, especially aquaporin-4 (AQP4) antibody positive NMOSD, indicating that sex hormones may be involved in the NMOSD pathogenesis. However, the causality between sex hormones and NMOSD still remains unclear. METHODS: Based on the genome-wide association study (GWAS) data of three sex hormones (estradiol (E2), progesterone (PROG) and bioavailable testosterone (BAT)), sex hormone-binding globulin (SHBG), age of menarche, age of menopause, and NMOSD (total, AQP4 + and AQP4 -), we performed a two-sample bidirectional Mendelian randomization (MR) study. Sex-stratified GWAS data of E2, PROG, BAT, and SHBG was obtained for gender-specific MR analysis. Causal inferences were based on the inverse variance weighted method, MR-Egger regression, and weighted median method. The reverse MR analysis was also performed to assess the impact of NMOSD on hormone levels. RESULTS: PROG in females had aggravative effects on NMOSD (P < 0.001), especially AQP4 - NMOSD (P < 0.001). In the reverse MR analysis, total NMOSD was found to decrease the level of BAT (P < 0.001) and increase the level of SHBG (P = 0.001) in females. CONCLUSION: Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related pathogenesis of NMOSD.

The association between endometrial polyps and insulin resistance from the expression of PI3K and AKT proteins perspective.

BACKGROUND: Insulin resistance (IR) induces hyperinsulinemia, which activates downstream signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, ultimately leading to abnormal proliferation and apoptosis of endometrial cells. This is thought to be a key pathogenic mechanism underlying the development of endometrial polyps (EP). This study aims to investigate the relationship between IR and the development of EP, the expression levels of downstream signaling molecules, including PI3K and AKT, and related laboratory parameters were examined. METHODS: A total of 100 patients who visited the gynecology outpatient clinic of Zhongda Hospital affiliated with Southeast University from May 2021 to March 2023 and were diagnosed with abnormal endometrial echoes by vaginal ultrasound and underwent hysteroscopic diagnostic curettage were enrolled in this study. General data and relevant hematological indicators were compared, and intraoperative specimens were obtained for pathological examination. Possible factors influencing the development of endometrial polyps were analyzed using Pearson correlation analysis and logistic regression analysis. RESULTS: In terms of body mass index, waist circumference, fasting insulin, insulin resistance index, serum total testosterone, and free testosterone index, women of childbearing age in the endometrial polyp group had higher values than those in the non-polyp group, while sex hormone-binding globulin in the endometrial polyp group was lower than that in the non-polyp group, and the differences were statistically significant (P < 0.05). The expression scores and mRNA expression levels of PI3K and AKT proteins were higher in the EP group than in the non-EP group (p < 0.05). Pearson correlation analysis showed a positive correlation between HOMA-IR and the expression scores of PI3K and AKT proteins (p < 0.01). CONCLUSIONS: Insulin resistance and abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway may be potential pathogenic mechanisms for the development of endometrial polyps.

A more accurate relationship between serum androgen and metabolism among healthy, nonobese, reproductive-age women based on liquid chromatography-tandem mass spectrometry.

This study explored a more precise association between androgens and glycolipid metabolism in healthy women of different ages. Body mass index (BMI), waist circumference (WC), and waist-to-hip ratio were used as body fat indicators. High-density lipoprotein (HDL), low-density lipoprotein, triglycerides, and total cholesterol were used as lipid markers. Fasting blood glucose (FBG), fasting insulin, and the homeostatic model assessment of insulin resistance were used to assess insulin resistance and glucose metabolism. Liquid chromatography-tandem mass spectrometry was used to measure androgen indicators, including testosterone, sex hormone-binding globulin (SHBG), free testosterone (FT), dihydrotestosterone (DHT), androstenedione (A4), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). DHEAS levels varied across age groups. Correlation analyses with Spearman's coefficient showed that the free androgen index correlated positively with WC (p = 0.040), FT correlated positively with BMI (p = 0.033) and WC (p = 0.049), SHBG correlated positively with HDL (p = 0.013), and A4 correlated positively with FBG (p = 0.017). Multiple linear regression analysis showed that among healthful women aged 36-40 years, A4 increased with FBG, and SHBG increased with HDL. Even within healthy, nonobese women, lipid and glucose metabolism were robustly correlated with androgens. Yearly metabolic assessments are necessary, particularly for FBG and HDL, since these markers can predict the likelihood of hyperandrogenemia, enabling timely interventions.

Associations of glyphosate exposure and serum sex steroid hormones among 6-19-year-old children and adolescents.

Glyphosate, ranked as one of the most widely used herbicides in the world, has raised concerns about its potential disruptive effects on sex hormones. However, limited human evidence was available, especially for children and adolescents. The present study aimed to examine the associations between exposure to glyphosate and sex hormones among participants aged 6-19 years, utilizing data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Children and adolescents who had available data on urinary glyphosate, serum sex steroid hormones, including testosterone (TT), estradiol (E2) and sex hormone binding globulin (SHBG), and covariates were selected. Additionally, the ratio of TT to E2 (TT/E2) and the free androgen index (FAI), which was calculated using TT/SHBG, were also included as sex hormone indicators. Survey regression statistical modeling was used to examine the associations between urinary glyphosate concentration and sex hormone indicators by age and sex group. Among the 964 participants, 83.71% had been exposed to glyphosate (>lower limit of detection). The survey regression revealed a marginally negative association between urinary glyphosate and E2 in the overall population, while this association was more pronounced in adolescents with a significant trend. In further sex-stratified analyses among adolescents, a significant decrease in E2, FAI, and TT (p trend <0.05) was observed in female adolescents for the highest quartile of urinary glyphosate compared to the lowest quartile. However, no similar association was observed among male adolescents. Our findings suggest that exposure to glyphosate at the current level may decrease the levels of sex steroids in adolescents, particularly female adolescents. Considering the cross-sectional study design, further research is needed to confirm our findings.

Causal Relationship between Sex Hormones and Risk of Developing Common Neurodegenerative Diseases: A Mendelian Randomization Study.

BACKGROUND: Neurodegenerative diseases are a group of unexplained disorders of the central nervous system, and studies have shown that a large number of genetic and environmental factors are associated with these diseases. Since these diseases show significant gender differences in epidemiology, sex hormones are thought to be strongly associated with these diseases. In this study, we used Mendelian randomization to explore the causal relationship between sex hormones and the risk of developing neurodegenerative diseases. METHODS: We obtained genetic instrumental variables for sex hormones (sex hormone-binding globulin [SHBG], estradiol levels [EL], and bioavailable testosterone [BT]) separately through the Integrative Epidemiology Unit (IEU) database (https://gwas.mrcieu.ac.uk/). We analyzed the causal relationship of each with the risk of developing neurodegenerative diseases (Amyotrophic Lateral Sclerosis [ALS], Parkinson's disease [PD], and Alzheimer's disease [AD]) using inverse variance weighted (IVW) in Mendelian randomization. Data were then analyzed for sensitivity. RESULTS: BT was negatively associated with the risk of developing ALS (odds ratio [OR] = 0.794; 95% confidence interval [95% CI] = 0.672-0.938; p = 0.006). EL and SHBG were not associated with a risk for developing neurodegenerative diseases (ALS, PD, AD). CONCLUSIONS: Elevated BT is associated with a reduced risk of developing ALS. Further research is needed to investigate the underlying mechanisms of action for this correlation and how it can be used as a potential target of action to reduce the risk of developing ALS.

Nonlinear association of sex hormone-binding globulin levels and chronic kidney disease, an analysis based on the National Health and Nutrition Examination Survey (NHANES) 2013-2016.

Studies on the relationship between serum sex hormone-binding globulin (SHBG) levels and chronic kidney disease (CKD) remain limited and inconclusive. Therefore, this study aims to evaluate the effects of SHBG on CKD in a nationally representative population. We included a total of 7713 adults from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Multivariate logistic regression models were utilized to evaluate the association between SHBG levels and CKD, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Additionally, we employed a restricted cubic-spline regression model to explore potential dose-response associations. Among the participants, 4030 (52.2%) were women, and CKD was observed in 13.50% (1043/7713). After adjusting for various variables, SHBG levels were found to be associated with the risk of CKD (OR: 1.24; 95% CI: 1.11-1.38), indicating a 24% higher risk of CKD for SHBG levels (log2-transformed). A comparison between the highest quartile (Q4) and the lowest quartile (Q1) of SHBG levels revealed an OR of 1.51 (95% CI: 1.17-1.95) for CKD prevalence. Notably, while the association between SHBG and the risk of CKD disappeared when SHBG levels were <46.1 nmol/l, it existed when SHBG levels exceeded 46.1 nmol/l. Taken together, these findings indicate nonlinear correlations between serum SHBG levels and CKD, with the inflection point occurring at approximately 46.1 nmol/l, which suggest that SHBG levels could serve as a useful marker for assessing CKD risk, with potential applications in early detection and management strategies.

Sex-Hormone-Binding Globulin Gene Polymorphisms and Breast Cancer Risk in Caucasian Women of Russia.

In our work, the associations of GWAS (genome-wide associative studies) impact for sex-hormone-binding globulin (SHBG)-level SNPs with the risk of breast cancer (BC) in the cohort of Caucasian women of Russia were assessed. The work was performed on a sample of 1498 women (358 BC patients and 1140 control (non BC) subjects). SHBG correlated in previously GWAS nine polymorphisms such as rs780093 GCKR, rs17496332 PRMT6, rs3779195 BAIAP2L1, rs10454142 PPP1R21, rs7910927 JMJD1C, rs4149056 SLCO1B1, rs440837 ZBTB10, rs12150660 SHBG, and rs8023580 NR2F2 have been genotyped. BC risk effects of allelic and non-allelic SHBG-linked gene SNPs interactions were detected by regression analysis. The risk genetic factor for BC developing is an SHBG-lowering allele variant C rs10454142 PPP1R21 ([additive genetic model] OR = 1.31; 95%CI = 1.08-1.65; pperm = 0.024; power = 85.26%), which determines 0.32% of the cancer variance. Eight of the nine studied SHBG-related SNPs have been involved in cancer susceptibility as part of nine different non-allelic gene interaction models, the greatest contribution to which is made by rs10454142 PPP1R21 (included in all nine models, 100%) and four more SNPs-rs7910927 JMJD1C (five models, 55.56%), rs17496332 PRMT6 (four models, 44.44%), rs780093 GCKR (four models, 44.44%), and rs440837 ZBTB10 (four models, 44.44%). For SHBG-related loci, pronounced functionality in the organism (including breast, liver, fibroblasts, etc.) was predicted in silico, having a direct relationship through many pathways with cancer pathophysiology. In conclusion, our results demonstrated the involvement of SHBG-correlated genes polymorphisms in BC risk in Caucasian women in Russia.