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.

The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization.

This study aimed to examine the association between sex hormone-binding globulin (SHBG) and osteoporosis through a cross-sectional study and a two-sample bidirectional Mendelian randomization (MR). We used the National Health and Nutrition Examination Survey (NHANES) 2013-2014 and 2015-2016 data, with exposure as serum SHBG and outcome as osteoporosis and performed multivariate logistic regression to test the correlation between SHBG and osteoporosis. To determine the causal relationship between SHBG and osteoporosis, a two-sample bidirectional MR was employed. The genome-wide association study (GWAS) dataset for SHBG (n = 189,473) was obtained from the IEU database, and the GWAS dataset for osteoporosis (n = 212,778) was obtained from the FinnGen bioBank. The principal MR technique was inverse-variance weighting (IVW). In MR analyses, the MR-Egger intercept and Cochran Q test were used to detect multiple validity and horizontal heterogeneity. 1249 older adult participants (age ≥ 60) were involved in the cross-sectional study, including 113 osteoporosis cases. We identified a significant relationship between circulating SHBG concentration and osteoporosis risk [OR 3.963, 95% CI (2.095-7.495), P < 0.05]. Subgroup analysis indicated that SHBG was closely linked to the risk of osteoporosis in the female population [OR 1.008, 95% CI (1.002-1.013), P = 0.005] but not in males (P = 0.065). In addition, The IVW approach suggested a causal connection between SHBG and increased osteoporosis risk [OR 1.479, 95% CI (1.144-1.912), P = 0.003], and the MR-Egger intercept and the Cochran Q test validated the consistency of the MR results. Finally, the reverse MR analysis declined to identify a causal relation between SHBG and osteoporosis. Our research demonstrates a significant causal connection between circulating SHBG levels and increased osteoporosis risk. These results indicate that high SHBG may be associated with the risk of osteoporosis in postmenopausal women, but more research is needed.

A genome-wide cross-trait analysis identifies genomic correlation, pleiotropic loci, and causal relationship between sex hormone-binding globulin and rheumatoid arthritis.

BACKGROUND: Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings. METHODS: Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBGadjBMI; Noverall = 368,929; Nmen = 180,094; Nwomen = 188,908), crude SHBG (Noverall = 370,125; Nmen = 180,726; Nwomen = 189,473), and RA (Ncase = 22,350; Ncontrol = 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship. RESULTS: Among the overall population, a significant global genetic correlation was observed for SHBGadjBMI and RA ([Formula: see text] = 0.11, P = 1.0 × 10-4) which was further supported by local signal (1q25.2). A total of 18 independent pleiotropic SNPs were identified, of which three were highly likely causal variants and four were found to have effects on both traits through gene expression mediation. A putative causal association of SHBGadjBMI on RA was demonstrated (OR = 1.20, 95% CI = 1.01-1.43) without evidence of reverse causality (OR = 0.999, 95% CI = 0.997-1.000). Sex-specific analyses revealed distinct shared genetic regions (men: 1q32.1-q32.2 and 5p13.1; women: 1q25.2 and 22q11.21-q11.22) and diverse pleiotropic SNPs (16 in men and 18 in women, nearly half were sex-specific) underlying SHBGadjBMI and RA, demonstrating biological disparities between sexes. Replacing SHBGadjBMI with crude SHBG, a largely similar yet less significant pattern of results was observed. CONCLUSION: Our cross-trait analysis suggests an intrinsic, as well as a sex-specific, link underlying SHBG and RA, providing novel insights into disease etiology.

Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study.

INTRODUCTION: The association of serum sex hormone-binding globulin (SHBG) concentrations with dementia risk remains uncertain in middle-aged to older women. We examined associations of serum SHBG levels with incidence of all-cause dementia and its subtypes in middle-aged to older women from the large population-based UK Biobank cohort study. METHODS: Serum total SHBG levels were measured by immunoassay. The incidence of all-cause dementia and its subtypes was recorded. Cox proportional hazards models were used to calculate hazard ratios (HR) for main outcomes. RESULTS: Among 171,482 community-dwelling women (mean [SD] age was 59.9 [5.4] years, median follow-up of 11.8 years), 2,368 developed dementia, including 1,088 from Alzheimer's disease (AD), 451 from vascular dementia (VAD), and 1,609 from other dementia. After multivariable adjustments, higher serum SHBG levels were significantly associated with higher risks of all-cause dementia, AD, and other dementia (all p < 0.05). Compared to those in the lowest quartile of SHBG levels, participants in the highest quartile of SHBG levels had a higher risk of all-cause dementia (HR: 1.34; 95% confidence interval [CI]: 1.16-1.53), AD (HR: 1.32; 95% CI: 1.07-1.62), and other dementia (HR: 1.44; 95% CI: 1.21-1.70). However, this relationship was not significant for VAD (HR: 1.16; 95% CI: 0.86-1.56). CONCLUSION: These findings indicated that higher serum SHBG concentrations were independently associated with higher risks of incident all-cause dementia, as well as AD and other dementia among middle-aged to older women. No association was found for VAD.

Association of sex hormones with non-alcoholic fatty liver disease: An observational and Mendelian randomization study.

BACKGROUND AND AIMS: Sex-specific associations of sex hormone-binding globulin (SHBG) and bioavailable testosterone (BAT) with NAFLD remain indeterminate. We aimed to explore observational and genetically determined relationships between each hormone and NAFLD. METHODS: We included 187 395 men and 170 193 women from the UK Biobank. Linear and nonlinear Cox regression models and Mendelian randomization (MR) analysis were used to test the associations. RESULTS: During 12.49 years of follow-up, 2209 male and 1886 female NAFLD cases were documented. Elevated SHBG levels were linearly associated with a lower risk of NAFLD in women (HR (95% CI), .71 (.63, .79)), but not in men (a "U" shape, pnon-linear < .001). Higher BAT levels were associated with a lower NAFLD risk in men (HR (95% CI), .81 (.71, .93)) but a higher risk in women (HR (95% CI): 1.25 (1.15, 1.36)). Genetically determined SHBG and BAT levels were linearly associated with NAFLD risk in women (OR (95% CI): .57 (.38, .87) and 2.21 (1.41, 3.26) respectively); in men, an "L-shaped" MR association between SHBG levels and NAFLD risk was found (pnon-linear = .016). The bidirectional MR analysis further revealed the effect of NAFLD on SHBG and BAT levels in both sexes. CONCLUSIONS: Consistently, linear associations of lower SHBG and higher BAT levels with increased NAFLD risk were both conventionally and genetically found in women, while in men, SHBG acts in a nonlinear manner. In addition, NAFLD may affect SHBG and BAT levels.

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.

Genetically predicted high sex hormone binding globulin was associated with decreased risk of polycystic ovary syndrome.

BACKGROUND: Previous observational studies have indicated an inverse correlation between circulating sex hormone binding globulin (SHBG) levels and the incidence of polycystic ovary syndrome (PCOS). Nevertheless, conventional observational studies may be susceptible to bias. Consequently, we conducted a two-sample Mendelian randomization (MR) investigation to delve deeper into the connection between SHBG levels and the risk of PCOS. METHODS: We employed single-nucleotide polymorphisms (SNPs) linked to serum SHBG levels as instrumental variables (IVs). Genetic associations with PCOS were derived from a meta-analysis of GWAS data. Our primary analytical approach relied on the inverse-variance weighted (IVW) method, complemented by alternative MR techniques, including simple-median, weighted-median, MR-Egger regression, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) testing. Additionally, sensitivity analyses were conducted to assess the robustness of the association. RESULTS: We utilized 289 SNPs associated with serum SHBG levels, achieving genome-wide significance, as instrumental variables (IVs). Our MR analyses revealed that genetically predicted elevated circulating SHBG concentrations were linked to a reduced risk of PCOS (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.39-0.78, P = 8.30 × 10-4) using the IVW method. MR-Egger regression did not detect any directional pleiotropic effects (P intercept = 0.626). Sensitivity analyses, employing alternative MR methods and IV sets, consistently reaffirmed our results, underscoring the robustness of our findings. CONCLUSIONS: Through a genetic epidemiological approach, we have substantiated prior observational literature, indicating a potential causal inverse relationship between serum SHBG concentrations and PCOS risk. Nevertheless, further research is needed to elucidate the underlying mechanism of SHBG in the development of PCOS.

Effects of depot medroxyprogesterone acetate, the copper IUD and the levonorgestrel implant on testosterone, sex hormone binding globulin and free testosterone levels: ancillary study of the ECHO randomized clinical trial.

BACKGROUND: Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice and development of new methods. METHODS: In this ancillary study at the East London, South Africa site of the ECHO multicentre randomized trial, we compared effects of three contraceptive methods on serum androgen levels among contraceptive users aged 18 to 35 years. Participants were allocated by centrally-managed randomization to open label depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD) or levonorgestrel implant. The primary outcome was free testosterone at 6 months. RESULTS: We analysed stored baseline and 6-month serum samples in 398/615 participants (DMPA-IM 131/205, IUD 135/205 and implant 132/205). Median testosterone levels at baseline were DMPA-IM 0.82, IUD 0.9 and implant 0.87 nmol/L; at 6 months, DMPA 0.68 (lower than IUD, mean percentage difference 28.35, (p <  0.001), IUD 0.86 (unchanged) and implant 0.66, lower than IUD, mean percentage difference - 22.98, p <  0.001). Median SHBG levels at baseline were DMPA 52.4, IUD 50.5 and implant 55.75 nmol/L; at 6 months, DMPA 40.65, lower than IUD (mean percentage difference 21.19, p = 0.005), IUD 49.1 (unchanged), and implant 23.35 nmol/L, lower than IUD (mean percentage difference - 50.04, p <  0.001 and than DMPA (mean percentage difference - 39.45, p <  0.001). Free testosterone levels at baseline were DMPA 10, IUD 12 and implant 11 pmol/L; at 6 months, DMPA 11, less than IUD (mean percentage difference 13.53, p = 0.047), IUD 12 and implant 14, higher than IUD (mean percentage difference 14.15, p = 0.038) and than DMPA, (mean percentage difference 29.60, p < 0.001). CONCLUSIONS: This is the first randomized trial to show lower SHBG and higher free testosterone with the levonorgestrel implant than with DMPA, and contrasts with reports of increased SHBG with combined oral ethinyl estradiol/levonorgestrel use, and reduced androgens (and impaired sexual function) reported with the etonorgestrel implant. The higher free testosterone with the LNG implant might improve sexual function, mood and bone health as well as increasing side-effects such as acne and hirsutism, and is consistent with the greater sexual activity (with respect to multiple sex partners, new sex partner and unprotected sex) with the implant compared with DMPA documented in the ECHO study. ECHO TRIAL REGISTRATION: ClinicalTrials.gov , number NCT02550067 15/09/2015. Contraception, or family planning, is central to the role of women in societies. It is most important to have accurate information on the relative side-effects of various contraceptive options in order to empower women to make informed choices regarding their preferred method. Hormonal contraceptives contain various forms of the female sex hormones, estrogens and/or progestogens. These hormones have direct effects on the users, as well as modifying the levels of the users' own circulating sex hormones, both the 'female' and the 'male' sex hormones (androgens). In this study, consenting participants requesting contraception, were allocated randomly to receive either depot medroxyprogesterone acetate (DMPA-IM) a 3-monthly progestogen injection, the copper intrauterine device (IUD), a non-hormonal contraceptive inserted within the womb, or the levonorgestrel implant, a device placed under the skin which releases a progestogen for 5 years. We measured the participants' androgen levels after 6 months, and found for the first time that the active form of testosterone (free testosterone) was 29% higher with the implant than with DMPA-IM. The level with the IUD was intermediate, and significantly different from the other two methods. This finding is relevant to the effects experienced by users of these methods, because free testosterone has effects on sexual function, bone health and mood, as well as on conditions such as acne and hair distribution patterns.

Genetically predicted high serum sex hormone-binding globulin levels are associated with lower ischemic stroke risk: A sex-stratified Mendelian randomization study.

OBJECTIVE: Cross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke. METHODS: Single-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders. RESULTS: Inverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003). CONCLUSION: Our findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.

Bone turnover markers and muscle decay indicator in patients with proximal femur fracture - a case-control study.

Introduction: Fracture of the proximal femur is common in elderly patients, in fact threatening their lives. Age-related sarcopenia may be involved in the imbalance resulting in the injury. Handy and readily accessible biochemical tests would be useful to assess the musculoskeletal system condition in daily practice. The aim of the study was to determine whether there is any relation between muscle decay and fracture of the proximal femur and to assess bone quality in elderly patients. Material and methods: In the study 22 patients who represented the treatment group were hospitalized due to proximal femur fracture. Eighteen patients from the control group with no fracture in their history were admitted to the Internal Medicine Department. Anyone treated for osteoporosis, immune disease affecting protein balance, neoplasm, mental illness, heart failure, or myocardial infarction was excluded from the study. In every case a blood sample from an elbow vein was drawn, collected in EDTA-K2 tubes, and then centrifuged to separate plasma from the whole blood. Subsequently, the concentrations of C-terminal cross-linked telopeptide of type I collagen (CTX-I), sex hormone binding globulin (SHBG) and creatine kinase (CK) in plasma were determined using commercial enzyme-linked immunosorbent assays. Results: The CK plasma concentration differed between the patient groups (p = 0.011). The SHBG plasma concentration was significantly higher in the treatment group (p = 0.006), whereas a slight difference in CTX-I plasma concentration between the groups was found (p = 0.038). No significant correlations between plasma CK, SHBG or CTX-I were found (p > 0.05). Conclusions: Creatine kinase is actually not an appropriate marker for the clinical assessment of muscle tissue quality in patients with or at risk of proximal femur fracture. Analyzing the quality of bone tissue, we can conclude it was poorer in patients with proximal femur fracture than in the control group.

Serum sex hormone-binding globulin is a mediator of the association between intrahepatic lipid content and type 2 diabetes: the Maastricht Study.

AIMS/HYPOTHESIS: Serum sex hormone-binding globulin (SHBG) has been proposed to act as a hepatokine that contributes to the extrahepatic complications observed in non-alcoholic fatty liver disease (NAFLD). However, it remains uncertain whether serum SHBG mediates the association between intrahepatic lipids (IHL) and type 2 diabetes. Therefore, we studied whether, and to what extent, serum SHBG mediates the association between IHL content and type 2 diabetes. METHODS: We used cross-sectional data from the Maastricht Study (n=1554), a population-based cohort study with oversampling of individuals with type 2 diabetes. Type 2 diabetes status was assessed by oral glucose tolerance test, and IHL content was measured using 3T Dixon MRI. Mediation analyses were performed to assess the role of serum SHBG in mediating the association between IHL content and type 2 diabetes. RESULTS: IHL content was significantly associated with type 2 diabetes in women and men (OR 1.08 [95% CI 1.04, 1.14] and OR 1.12 [95% CI 1.08, 1.17], respectively). Serum SHBG significantly mediated the association between IHL content and type 2 diabetes. The contribution of serum SHBG was higher in women (OR 1.04 [95% CI 1.02, 1.07]; proportion mediated 50.9% [95% CI 26.7, 81.3]) than in men (OR 1.02 [95% CI 1.01, 1.03]; proportion mediated 17.2% [95% CI 9.6, 27.6]). Repeat analyses with proxies of type 2 diabetes and adjustment for covariates did not substantially affect the results. CONCLUSIONS/INTERPRETATION: In this large-scale population-based cohort study, serum SHBG was found to be a mediator of the association between IHL content and type 2 diabetes. These findings extend our understanding of the potential mechanisms by which NAFLD is a risk factor for type 2 diabetes, and further elaborate on the role of SHBG as a hepatokine.

The Association between Inflammation, Testosterone and SHBG in men: A cross-sectional Multi-Ethnic Study of Atherosclerosis.

CONTEXT: Earlier studies have investigated the role of obesity-related inflammation and endogenous sex hormones in men. The role of interleukin-6 (IL-6) and C-reactive protein (CRP) with testosterone and sex hormone binding globulin (SHBG) levels in men is still debated. OBJECTIVE: To investigate the independent association between levels of high sensitivity CRP (hsCRP) and IL-6 with endogenous sex hormones in men. DESIGN: Cross-sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. PATIENTS OR OTHER PARTICIPANTS: A community-based sample of 3212 men aged 45-84 years was included. After exclusions, 3041 men remained for the analyses. MAIN OUTCOME MEASURE(S): Serum concentrations of testosterone, SHBG, hsCRP, IL-6, and sTNFR were measured from the baseline exam. Multivariable linear regressions were used to examine the association of inflammatory markers with sex hormones. RESULTS: An inverse association was found between levels of hsCRP and levels of testosterone and SHBG, even after adjustment for confounders and IL-6 (Total Testosterone; B = -0.14, Bioavailable Testosterone; B = -0.06, and SHBG; B = -0.66). Similar results were found for IL-6, although a positive association was found for SHBG (B = 0.95). Notably, an inverse association was found for IL-6 with bioavailable testosterone in African Americans and Hispanic Americans aged 45-54 years. No associations were found for sTNFR and endogenous sex hormones. CONCLUSION: Our results indicate that inflammatory markers have independent associations with levels of testosterone (total and bioavailable) and furthermore, appear to associate differently with SHBG levels.

Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity.

AIMS: We studied whether androgen excess and low sex hormone-binding globulin (SHBG) measured in early pregnancy are independently associated with fasting and post-prandial hyperglycaemia, gestational diabetes (GDM), and its severity. MATERIALS AND METHODS: This nationwide case-control study included 1045 women with GDM and 963 non-diabetic pregnant controls. We measured testosterone (T) and SHBG from biobanked serum samples (mean 10.7 gestational weeks) and calculated the free androgen index (FAI). We first studied their associations with GDM and secondly with the type of hyperglycaemia (fasting, 1 and 2 h glucose concentrations during the oral glucose tolerance test), early-onset GDM (<20 gestational weeks) and the need for anti-diabetic medication. RESULTS: After adjustments for gestational weeks at sampling, pre-pregnancy BMI, and age, women with GDM had 3.7% (95% CI 0.1%-7.3%) lower SHBG levels, 3.1% (95% CI 0.1%-6.2%) higher T levels, and 4.6% (95% CI 1.9%-7.3%) higher FAI levels than controls. SHBG was inversely associated with fasting glucose, whereas higher FAI and T were associated with higher post-prandial glucose concentrations. Women with early-onset GDM had 6.7% (95% CI 0.7%-12.7%) lower SHBG levels and women who needed insulin for fasting hyperglycaemia 8.7% (95% CI 1.8%-14.8%) lower SHBG levels than other women with GDM. CONCLUSIONS: Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion.

Mendelian randomization identifies age at menarche as an independent causal effect factor for gestational diabetes mellitus.

AIMS: The relationship between age at menarche (AAM) and gestational diabetes mellitus (GDM) risk is still inconclusive. This Mendelian randomization (MR) analysis was used to assess systematically the causal relationship between AAM and GDM risk in human beings. MATERIALS AND METHODS: Single-nucleotide polymorphisms associated with AAM, oestradiol levels, sex hormone-binding globulin (SHBG) levels and bioavailable testosterone (BioT) levels were screened via the genome-wide association study enrolling individuals of European descent. Summary-level data for GDM (123 579 individuals) were extracted from the UK Biobank. An inverse-variance-weighted method was used for the primary MR analysis. Sensitivity analyses were examined via MR-Egger regression, heterogeneity tests, pleiotropy tests and leave-one-out tests. The directionality that exposure causes the outcome was verified using the MR-Steiger test. RESULTS: Genetically predicted early AAM was found to have a causal positive association with a higher risk of GDM (odds ratio = 0.798, 95% confidence interval = 0.649-0.980, p = .031). In the multivariable MR analysis adjusted for oestradiol, SHBG and BioT levels, the causal association between AAM and GDM risk remained (odds ratio = 0.651, 95% confidence interval = 0.481-0.881, p = .006). A 1-SD increase in SHBG or BioT levels was significantly associated with a 41.4% decrease or 20.8% increase in the overall GDM risk (p = 3.71E-05 and .040), respectively. However, after controlling for AAM, oestradiol levels and BioT levels by multivariable MR analysis, there was no direct causal effect of SHBG levels on GDM risk (p = .084). Similarly, after adjusting for AAM, oestradiol levels and SHBG levels by multivariable MR analysis, there was no direct causal effect of BioT levels on the risk of GDM (p = .533). In addition, no direct causal association was identified between oestradiol levels and GDM risk in univariable MR analysis or multivariable MR analysis. CONCLUSION: Genetic variants predisposing individuals to early AAM were independently associated with higher GDM risk. Further research is required to understand the mechanisms underlying this putative causative association. In addition, AAM may be helpful in clinical practice to identify women at risk for GDM; pregnant women who are young for menarche may need to take precautions before GDM develops.

Causal relationship between sex hormone-binding globulin and major depression: A Mendelian randomization study.

OBJECTIVE: This study aimed to explore the causal relationship between sex hormone-binding globulin (SHBG) and major depression using two-sample Mendelian randomization (MR) studies. METHODS: Based on the genome-wide association study (GWAS) summary data of SHBG and major depression in the European population, which included 214,989 female SHBG samples, 185,221 male SHBG samples, and 500,199 major depression samples, we used genetic factors as instrumental variables to conduct two-sample MR analyses. We used methods including inverse variance weighted (IVW), weighted median, weighted mode, and MR Egger to evaluate the bidirectional causal relationship between SHBG and major depression. RESULTS: The results showed that there was a causal relationship between female SHBG and major depression, which was positively correlated. The ORs were 1.056 (95% CI: 1.005-1.109, p = 0.031) for the weighted median and 1.067 (95% CI: 1.012-1.126, p = 0.021) for the weighted mode. There was no significant effect of male SHBG on major depression (p > 0.05), and there was no significant effect of major depression on female SHBG (p > 0.05). Major depression was negatively correlated with male SHBG, indicating that major depression could lead to a decrease in male SHBG. The OR was 0.954 (95% CI: 0.916-0.993, p = 0.023) for IVW. CONCLUSION: Female SHBG was positively correlated with the risk of major depression, however, major depression was found to be negatively correlated with serum SHBG levels in men, indicating that SHBG plays distinct roles in patients with major depression of different genders.

Do testosterone and sex hormone-binding globulin affect cancer risk? A Mendelian randomization and bioinformatics study.

Using Mendelian Randomization (MR) and large-scale Genome-Wide Association Study (GWAS) data, this study aimed to investigate the potential causative relationship between testosterone and sex hormone-binding globulin (SHBG) levels and the onset of several cancers, including pathway enrichment analyses of single nucleotide polymorphisms (SNPs) associated with cancer allowed for a comprehensive bioinformatics approach, which offered a deeper biological understanding of these relationships. The results indicated that increased testosterone levels in women were associated with a higher risk of breast and cervical cancers but a lower risk of ovarian cancer. Conversely, increased testosterone was linked to lower stomach cancer risk for men, whereas high SHBG levels were related to decreased risks of breast and prostate cancers. The corresponding genes of the identified SNPs, as revealed by pathway enrichment analysis, were involved in significant metabolic and proliferative pathways. These findings emphasize the need for further research into the biological mechanisms behind these associations, paving the way for potential targeted interventions in preventing and treating these cancers.

An antibody-free LC-MS/MS method for the quantification of sex hormone binding globulin in human serum and plasma.

OBJECTIVES: Sex hormone binding globulin (SHBG) is a hormone binding protein which plays an important role in regulating the transport and availability of biologically active androgens and estradiol to target cells and used to calculate free testosterone concentrations. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed, featuring an albumin removal step followed by a tryptic digestion. After a reduction step with dithiothreitol and alkylation with iodoacetamide three signature peptides were used for the quantification of SHBG. RESULTS: The method enables the quantification of serum and plasma SHBG over the clinically relevant range of 200-20,000 ng/mL and was validated according to the most recent guidelines. The LC-MS/MS method correlates well with the Abbott Alinity immunoassay (R2>0.95), but the LC-MS/MS results are on average 16-17% lower than the immunoassay results, which is consistent for all three signature peptides. CONCLUSIONS: The LC-MS/MS method which includes an albumin depletion step allows quantification of SHBG in serum and plasma without an immunocapture step at clinically relevant SHBG levels, thus contributing to better lab-to-lab consistency of results.

Causal inference of sex hormone-binding globulin on venous thromboembolism: evidence from Mendelian randomisation.

BACKGROUND: Previous cohort studies have shown that exogenous sex hormone use, such as testosterone replacement therapy and oestrogen-containing contraceptives, can increase the risk of venous thromboembolism (VTE). However, the relationship between endogenous sex hormone levels and VTE remains unclear. The goal of the present study was to explore the causal roles of endogenous sex hormones, including hormone-binding globulin (SHBG), bioactive testosterone (BT), and total testosterone (TT), in VTE and its two subgroups, deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: We used a genome-wide association study of sex hormones as exposure data and Finnish VTE data as the outcome. Inverse variance weighting, MR-Egger, and weighted median were used for two-sample Mendelian randomisation (MR). Sensitivity analyses included MR-Egger, MR-PRESSO, Cochrane Q test, MR Steiger, leave-one-out analysis, and funnel plot, combined with multivariate MR and replicated MR analyses using larger VTE data from the global biobank meta-analysis initiative. Linkage disequilibrium score regression (LDSC) was used to determine genetic associations and estimate sample overlap. RESULTS: Our findings genetically predicted that an increase in serum SHBG levels by one standard deviation (SD) caused 25% higher odds for VTE (OR: 1.25, 95% CI: 1.01-1.55) and 58% higher odds for PE (OR: 1.58, 95% CI: 1.20-2.08). LDSC supported the genetic correlation between these two traits and replicated analyses confirm SHBG's genetic effect on VTE in both sexes (OR: 1.46, 95% CI: 1.20-1.78) and in females (OR: 1.49, 95% CI: 1.17-1.91). In addition, an increase in serum TT levels by one SD caused 32% higher odds for VTE (OR: 1.32, 95% CI: 1.08-1.62) and 31% higher odds for DVT (OR: 1.31, 95% CI: 1.01-1.69); however, LDSC and replicated analyses did not find a genetic correlation between TT and VTE or its subtypes. No significant correlation was observed between BT and all three outcome traits. CONCLUSION: Our study provides evidence that elevated serum SHBG levels, as predicted by genetics, increase VTE risk. However, the causal effect of testosterone levels on VTE requires further investigation.

Estrone, sex hormone binding globulin and lipid profiles in older women: an observational study.

OBJECTIVE: We investigated whether estrone and sex hormone binding globulin (SHBG) concentrations are associated with lipid concentrations in older postmenopausal women. METHODS: This was a cross-sectional study of 6358 Australian women, aged 70-95 years, recruited between 2010 and 2014. Associations between estrone and SHBG and lipid concentrations were examined in participants not using medications that influence estrogen concentrations or lipid-lowering therapy. Linear regression models included age, body mass index, smoking, alcohol consumption, renal function and diabetes, with the lowest quartile (Q1) as the reference for estrone and SHBG. RESULTS: The study included 3231 participants with median age of 74.0 (interquartile range 71.7-77.9) years. Estrone concentration Q3 and Q4 were positively associated with high-density lipoprotein cholesterol (HDL-C) (p = 0.017 and p = 0.046, respectively). Inverse associations were seen for estrone Q4 with total cholesterol (p = 0.018), Q2 and Q4 with non-HDL-C (p = 0.045 and p = 0.002, respectively) and Q3 and Q4 with triglycerides (p = 0.030 and p = 0.001, respectively). For SHBG, Q2, Q3 and Q4 were positively associated with HDL-C (all p < 0.001), and inversely with non-HDL-C (all p = 0.001) and triglycerides (all p < 0.001). CONCLUSIONS: Estrone and SHBG are associated with lipid concentrations in older women. SHBG, but not estrone, may provide additional clinical predictive utility for the assessment of cardiometabolic disease risk in older women.