A protective role of genetically predicted sex hormone-binding globulin on stroke.

Introduction: The role of sex hormone-binding globulin (SHBG) on stroke has been investigated in several observational studies. To provide the causal estimates of SHBG on stroke and its subtypes, bi-directional and multivariable Mendelian randomization (MR) analyses are performed. Methods: The genetic instruments of SHBG were obtained from the UK Biobank. Outcome datasets for stroke and its subtypes were taken from the MEGASTROKE Consortium. The main analysis used in this study is the inverse variance weighting, complemented by other sensitivity approaches to verify the conformity of findings. Results: We found that the risk of stroke grew by 13% (odd ratio [OR] = 0.87, 95% confidence interval [CI] = 0.79-0.95, P = 0.0041) and the risk of ischemic stroke grew by 15% (OR = 0.85, 95%CI = 0.77-0.95, P = 0.0038) caused by genetically predicted SHBG. The causal association remains robust in the reverse MR and multivariable MR analyses for stroke (reverse MR: all P > 0.01 for the IVW method; MVMR: OR = 0.72, 95%CI = 0.59-0.87, P = 0.0011) and ischemic stroke (reverse MR: all P > 0.01 for IVW; MVMR: OR = 0.70, 95%CI = 0.56-0.86, P = 0.0007). Conclusion: Our MR study provides novel evidence that SHBG has an inverse association with stroke and ischemic stroke, exerting protective effects on stroke.

The Correlation between Sex Hormone-Binding Globulin and Clinical Characteristics According to Anti-Müllerian Hormone in Women with Regular Menstrual Cycles: A Prospective Study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) can be diagnosed when the anti-Müllerian hormone (AMH) levels are high, but in clinic, women who do not meet the diagnosis of PCOS but have elevated AMH levels are often seen. This study aimed to compare the differences in menstrual cycle patterns and hormone levels in women with regular menstrual cycles, but not PCOS, by dividing them into high and low AMH groups. MATERIAL AND METHODS: This multicenter prospective study included 68 healthy women. Participants with regular menstrual cycles were divided into two groups according to their AMH levels. The main outcome measures were menstrual cycle pattern, body mass index, and hormone levels (thyroid stimulating hormone, prolactin, testosterone, sex hormone-binding globulin, and free androgen index), which were compared between the groups according to AMH levels. The ovulation was assessed by performing pelvic ultrasound, and by assessing the hormone levels of the luteinizing hormone and progesterone. RESULTS: The criteria for determining normal and high AMH levels were based on previous literatures. The participants were divided into normal (39 people) and high (29 people) AMH group. No differences were found in age or BMI between the two groups, and no other differences were observed in TSH, prolactin, testosterone, or free androgen index. However, the high AMH group had significantly higher SHBG levels than the normal group (normal group: 65.46 ± 25.78 nmol/L; high group: 87.08 ± 45.05 nmol/L) (p = 0.025). CONCLUSIONS: This study is the first to analyze the association between SHBG and AMH levels in women with regular menstrual cycles. Elevated AMH levels are associated with increased levels of SHBG levels.

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.

The relationship between anthropometric and metabolic risk factors and testicular function in healthy young men.

OBJECTIVE: This study investigated the relationship of anthropometric and metabolic risk factors with seminal and sex steroidal hormone parameters in a screened population of healthy males. METHODS: The participants were healthy young men without chronic or congenital diseases. The body composition parameters that we investigated were measured weight, height, and waist circumference (WC), as well as bioelectrical impedance analysis. Semen samples were analyzed for semen volume, sperm concentration, sperm motility and morphology, seminal pH, and liquefaction time. Biochemistry analysis, including glucose and lipid metabolism parameters, was conducted on fasting blood samples. Testicular volume was calculated separately for each testis using ultrasonography. RESULTS: Body mass index exhibited an inverse association with total sperm count. WC showed negative correlations with numerous seminal parameters, including sperm concentration, total sperm count, sperm morphology, and follicle-stimulating hormone levels. The basal metabolic rate was associated with seminal pH, liquefaction time, and sperm motility. WC, fat mass percentage, and triglyceride levels exhibited negative correlations with sex hormone binding globulin. The measures of glucose metabolism were associated with a greater number of seminal parameters than the measures of cholesterol metabolism. C-reactive protein levels were inversely associated with sperm concentration and total sperm count. CONCLUSION: Anthropometric and metabolic risk factors were found to predict semen quality and alterations in sex steroidal hormone levels.

Low levels of sex hormone-binding globulin predict an increased breast cancer risk and its underlying molecular mechanisms.

Sex hormone-binding globulin (SHBG) is a serum glycoprotein exhibiting the unique feature of binding sex steroids with high affinity and specificity. Over the past few decades, there have been significant breakthroughs in our understanding of the function and regulation of SHBG. The biological role of SHBG has expanded from being considered a simple sex hormone transporter to being associated with several complex physiological and pathological changes in a variety of target tissues. Many factors can affect the plasma SHBG levels, with fluctuations in circulating levels affecting the development of various diseases, such as increasing the risk of developing breast cancer. This article reviews the clinical significance of changes in circulating SHBG levels in the development of breast cancer and the possible influence of these levels on endocrine drug resistance in hormone receptor-positive breast cancer. Higher levels of plasma SHBG significantly reduce the risk of estrogen receptor-positive breast cancer, especially in postmenopausal women. Moreover, the molecular mechanisms by which SHBG affects breast cancer risk are also summarized in detail. Finally, transcriptomics and proteomics data revealed that SHBG expression in breast tissue can effectively distinguish breast cancer from normal tissue. Additionally, the association between SHBG expression levels and various classical tumor-related pathways was investigated.

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.

Association of Testosterone and Sex Hormone-Binding Globulin With All-Cause and Cardiovascular Disease Mortality in Older Chinese Men.

BACKGROUND: The associations of high and low testosterone with all-cause and cardiovascular disease (CVD) mortality risk in men are conflicting. Our objective was to examine associations of total testosterone, free testosterone, bioavailable testosterone, and sex hormone-binding globulin (SHBG) with all-cause and CVD mortality in older Chinese men. METHODS: Total testosterone and SHBG were assayed, and free testosterone and bioavailable testosterone were calculated using Vermeulen formula. Cox proportional hazards regression was used to assess the associations with risks of all-cause and CVD mortality, giving hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Of 3 948 men aged 50+ years, 949 deaths (312 CVD) occurred during an average 10.5-year follow-up. After multivariable adjustments, the highest, versus the third, quartile of total testosterone and free testosterone were associated with higher all-cause mortality risk (1.17 [0.97-1.41] and 1.45 [1.20-1.74], respectively), whereas free testosterone was associated with higher CVD mortality risk (1.88 [1.33-2.66]). Similar positive associations were found for bioavailable testosterone and all-cause mortality risk (1.27 [1.05-1.54]). Lower SHBG (quartile 1 vs quartile 3) was associated with higher all-cause and CVD mortality risk (1.25 [1.04-1.52] and 1.28 [1.08-1.52], respectively). Consistent associations were observed in relatively healthy men and men excluded death during the first year. CONCLUSIONS: Higher total testosterone, free testosterone, and bioavailable testosterone were associated with higher all-cause mortality in older men, higher free testosterone was associated with higher CVD mortality whilst lower SHBG was associated with higher all-cause and CVD mortality. Clarification and confirmation of causality require further mechanistic studies.

Causal relationship between gut microbiome and sex hormone-binding globulin: A bidirectional two-sample Mendelian randomization study.

PROBLEM: Currently, there is a variety of evidence linking the gut microbiota to changes in sex hormones. In contrast, the causal relationship between SHBG, a carrier of sex hormones, and the gut microbiota is unclear. METHOD OF STUDY: Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between SHBG and the gut microbiome. Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and SHBG were obtained from public datasets. Inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger and simple mode methods were used to operate the MR analysis. F-statistics and sensitivity analyses performed to evaluate bias and reliability. RESULTS: When we set gut microbiome as exposure and SHBG as outcome, we identified nine causal relationships. In males, Coprobacter (PIVW = 2.01 × 10-6 ), Ruminococcus2 (PIVW = 3.40 × 10-5 ), Barnesiella (PIVW = 2.79 × 10-2 ), Actinobacteria (PIVW = 3.25 × 10-2 ) and Eubacterium fissicatena groups (PIVW = 3.64 × 10-2 ) were associated with lower SHBG levels; Alphaproteobacteria (PIVW = 1.61 × 10-2 ) is associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 9.75 × 10-3 ) and Defluviitaleaceae UCG011 (PIVW = 3.67 × 10-2 ) were associated with higher SHBG levels; Victivallaceae (PIVW = 2.23 × 10-2 ) was associated with lower SHBG levels. According to the results of reverse MR analysis, three significant causal effect of SHBG was found on gut microbiota. In males, Dorea (PIVW = 4.17 × 10-2 ) and Clostridiales (PIVW = 4.36 × 10-2 ) were associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 7.44 × 10-4 ) was associated with higherr SHBG levels. No signifcant heterogeneity of instrumental variables or horizontal pleiotropy was found in bidirectional two-sample MR analysis. CONCLUSIONS: This study may provide new insights into the causal relationship between the gut microbiome and sex hormone-binding protein levels, as well as new treatment and prevention strategies for diseases such as abnormal changes in sex hormones.

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-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.

Plasma SHBG Levels as an Early Predictor of Response to Bariatric Surgery.

BACKGROUND: Obesity is a growing global health problem, and currently, bariatric surgery (BS) is the best solution in terms of sustained total weight loss (TWL). However, a significant number of patients present weight regain (WR) in time. There is a lack of biomarkers predicting the response to BS and WR during the follow-up. Plasma SHBG levels, which are low in obesity, increase 1 month after BS but there is no data of plasma SHBG levels at long term. We performed the present study aimed at exploring the SHBG role in predicting TWL and WR after BS. METHODS: Prospective study including 62 patients with obesity undergoing BS. Anthropometric and biochemical variables, including SHBG were analyzed at baseline, 1, 6, 12, and 24 months; TWL ≥ 25% was considered as good BS response. RESULTS: Weight loss nadir was achieved at 12 months post-BS where maximum SHBG increase was reached. Greater than or equal to 25% TWL patients presented significantly higher SHBG increases at the first and sixth months of follow-up with respect to baseline (100% and 150% respectively, p = 0.025), than < 25% TWL patients (40% and 50% respectively, p = 0.03). Also, these presented 6.6% WR after 24 months. The first month SHBG increase predicted BS response at 24 months (OR = 2.71; 95%CI = [1.11-6.60]; p = 0.028) and TWL in the 12th month (r = 0.330, p = 0.012) and the WR in the 24th (r = - 0.301, p = 0.028). CONCLUSIONS: Our results showed for the first time that increase in plasma SHBG levels within the first month after BS is a good predictor of TWL and WR response after 2 years.

Androgenicity in Young Women and Development of Metabolic Syndrome Before Menopause: The CARDIA and CARDIA Women's Studies.

Context: There are no reported data from prospective long-term studies on the relation of androgen levels in young women with development of metabolic syndrome (MetS) before menopause. Objective: We investigated associations of androgens and SHBG with incident MetS during 23 years of follow-up. Methods: We included 366 White and 375 Black women ages 20 to 32 years participating in the CARDIA study and CARDIA Women's study, free of MetS at baseline examination (1987-1988), and premenopausal 23 years later. Androgens and SHBG were categorized into quartiles. MetS was defined according to the American Heart Association/National Heart, Lung, and Blood Institute 2009 Joint Scientific Statement. Cox proportional hazards models were used. Results: By year 23, 30% of women developed MetS. Adjusting for baseline age, race, and education, hazard ratios (95% CI) of developing MetS were 1.46 (1.02-2.10) and 2.22 (1.53-3.21) for women in the highest vs lowest total testosterone (T) and free T quartile, respectively. The hazards of developing MetS were 47%, 59%, and 53% lower for women with SHBG in the second, third, and fourth quartiles (vs lowest quartile), respectively. Associations were attenuated for total T with further adjustments for smoking, physical activity, menstrual status, oral contraceptive/hormone (OCHM) use, insulin level, oligomenorrhea, and age at menarche, but remained statistically significant for free T and SHBG. Associations were similar for both Blacks and Whites, and OCHM nonusers, but not for OCHM users. Conclusion: High androgenicity in young premenopausal women is associated with higher risk of future MetS, suggesting that early assessment of androgens may contribute to prevention.

Fructose intake from sugar-sweetened beverages is associated with a greater risk of hyperandrogenism in women: UK Biobank cohort study.

OBJECTIVE: To assess the association between fructose consumption and serum sex hormone-binding globulin (SHBG), (free) testosterone, and risk of hyperandrogenism in a population-based cohort. DESIGN: An observational and genetic association study in participants of the UK Biobank (n = 136 384 and n = 383 392, respectively). METHODS: We assessed the relationship of (1) the intake of different sources of fructose (ie, total, fruit, fruit juice, and sugar-sweetened beverages [SSBs]) and (2) rs2304681 (a missense variant in the gene encoding ketohexokinase, used as an instrument of impaired fructose metabolism), with SHBG, total and free testosterone levels, and risk of hyperandrogenism (free androgen index >4.5). RESULTS: The intake of total fructose and fructose from fruit was associated with higher serum SHBG and lower free testosterone in men and women and lower risk of hyperandrogenism in women. In contrast, fructose intake from SSB (≥10 g/day) was associated with lower SHBG in men and women and with higher free testosterone levels and risk of hyperandrogenism in women (odds ratio [OR]: 1.018; 95% confidence interval [CI]: 1.010; 1.026). Carriers of the rs2304681 A allele were characterized by higher circulating SHBG (both men and women), lower serum free testosterone (women), and a lower risk of biochemical hyperandrogenism (OR: 0.997, 95% CI: 0.955; 0.999; women) and acne vulgaris (OR: 0.975, 95% CI: 0.952; 0.999; men and women combined). CONCLUSIONS: The consumption of ≥10 g/day fructose from SSB, corresponding to ≥200 mL serving, is associated with a 2% higher risk of hyperandrogenism in women. These observational data are supported by our genetic data.

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.

Associations of Serum Testosterone and Sex Hormone-binding Globulin With Incident Arrhythmias in Men From UK Biobank.

CONTEXT: Sex hormones have been identified as cardiovascular risk factors, whereas the relationship between sex hormones and the risk of arrhythmias in men has not yet been well studied in the prospective cohort study. OBJECTIVE: To analyze associations of serum testosterone and SHBG concentrations and calculate free testosterone (cFT) with arrhythmias in men. METHODS: Sex hormones were measured at baseline from UK Biobank. Main outcomes were incidence of atrial fibrillation/flutter (AF), ventricular arrhythmia (VA), and bradyarrhythmia (BA). RESULTS: Of 173 498 men (aged 37-73 years, followed for 11 years), 11 368 had incident AF, 1646 had incident VA, and 4788 had incident BA. Compared with the third quartiles, the lowest category of serum testosterone was associated with increased risks of AF (hazard ratio [HR], 1.06; 95% CI, 1.00-1.12) and BA (HR, 1.11; 95% CI, 1.02-1.20) after multivariable adjustment, but no VA. Likewise, similar associations were found between cFT values and AF and BA events. Furthermore, higher levels of cFT were associated with increased risks of AF (HR, 1.07; 95% CI, 1.02-1.13) and VA (HR, 1.18; 95% CI, 1.01-1.37). Higher SHBG concentrations were associated with increased risks of AF (HR, 1.44; 95% CI, 1.34-1.54), VA (HR, 1.27; 95% CI, 1.07-1.52), and BA (HR, 1.17; 95% CI ,1.05-1.29). CONCLUSIONS: Lower levels of testosterone and cFT were associated with increased risk of AF and BA. Higher cFT levels were associated with increased risk of AF and VA. Higher SHBG levels were associated with increased risk of AF, VA, and BA.

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.

Exploring Causal Relationships between Leukocyte Telomere Length, Sex Hormone-Binding Globulin Levels, and Osteoporosis Using Univariable and Multivariable Mendelian Randomization.

OBJECTIVE: Recent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age-related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone-binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health. METHODS: Univariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse-variance weighted (IVW) model. RESULTS: Univariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73-0.99; p = 0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09-1.75; p < 0.01). We observed a negative causal effect for LTL on the occurrence of SHBG (OR: 0.96; 95% CI 0.94-0.98, p < 0.01). After adjustment of using multivariable MR, the causal effect of LTL on osteoporosis (OR: 0.92; 95% CI: 0.84-1.03; p = 0.14), and the effect of SHBG on osteoporosis (OR: 1.43; 95% CI: 1.16-1.75; p < 0.01) were observed. CONCLUSION: Longer LTL may confer a protective effect against osteoporosis. Additionally, the levels of SHBG appear to play a crucial role in mediating the relationship between LTL and osteoporosis. By understanding the interplay between these factors, we can gain valuable insights into the mechanisms underlying bone health and aging and potentially identify new avenues for prevention and intervention strategies.

Association Between 25-hydroxyvitamin D Levels and Testosterone in Healthy, Non-Obese, Young Adult, Filipino Men.

Objective: This study seeks to determine the association between vitamin D and testosterone in healthy, adult Filipino males. Methodology: This cross-sectional study included 110 healthy, non-obese, male volunteers aged 21-40. History and physical exam were taken, and blood was drawn for vitamin D, total testosterone (TT), sex hormone binding globulin (SHBG), albumin, insulin, fasting plasma glucose, and total cholesterol. Free testosterone (FT) was calculated. Vitamin D data were classified by status and TT, FT, and SHBG levels compared using the Kruskal-Wallis test. The associations of vitamin D levels with TT, FT, and SHBG were explored using multiple regression analysis. Results: Vitamin D levels were sufficient in 3 (2.7%), insufficient in 17 (15.45%), and deficient in 90 (81.8%) of the sample. There were no significant differences in the mean TT (p = 0.7981), FT (p = 0.8768), nor SHBG (p = 0.1838) across vitamin D status. Vitamin D was not associated with TT nor FT before or after adjustment for age and age plus body mass index (BMI). Vitamin D was associated with SHBG before and after the aforementioned adjustments, but this became insignificant on sensitivity analysis. Conclusion: There is no association between vitamin D and TT, FT nor SHBG in our cohort with deficient vitamin D levels.

Genetically predicted serum testosterone and risk of gynecological disorders: a Mendelian randomization study.

Background: Testosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies. Methods: We leveraged public genome-wide association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance-weighted (IVW), MR-Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane's Q value, and the horizontal pleiotropy test was performed on the data through MR-Egger intercept and MR-PRESSO methods. "mRnd" online analysis tool was used to evaluate the statistical power of MR estimates. Results: The results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031). Conclusion: Our analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.

Sex hormone-binding globulin exerts sex-related causal effects on lower extremity varicose veins: evidence from gender-stratified Mendelian randomization.

Background: The association between serum sex hormones and lower extremity varicose veins has been reported in observational studies. However, it is unclear whether the association reflects a causal relationship. Besides, serum sex hormone-binding globulin (SHBG) has been rarely studied in lower extremity varicose veins. Here, we aim to investigate the association between serum levels of SHBG, testosterone, and estradiol and the risk of lower extremity varicose veins using Mendelian randomization (MR). Methods: We obtained genome-wide association study summary statistics for serum SHBG levels with 369,002 European participants, serum testosterone levels with 424,907 European participants, serum estradiol levels with 361,194 European participants, and lower extremity varicose veins with 207,055 European participants. First, a univariable MR was performed to identify the causality from SHBG and sex hormone levels to lower extremity varicose veins with several sensitivity analyses being performed. Then, a multivariable MR (MVMR) was performed to further assess whether the causal effects were independent. Finally, we performed a gender-stratified MR to understand the role of genders on lower extremity varicose veins. Results: Genetically predicted higher serum SHBG levels significantly increased the risk of lower extremity varicose veins in the univariable MR analysis (OR=1.39; 95% CI: 1.13-1.70; P=1.58×10-3). Sensitivity analyses and MVMR (OR=1.50; 95% CI:1.13-1.99; P=5.61×10-3) verified the robustness of the causal relationships. Gender-stratified MR revealed that higher serum SHBG levels were associated with lower extremity varicose veins in both sexes. However, the OR of serum SHBG levels on lower extremity varicose veins risk in females (OR=1.51; 95% CI: 1.23-1.87; P=1.00×10-4) was greater than in males (OR=1.26; 95% CI: 1.04-1.54; P=1.86×10-2). Conclusions: Serum SHBG levels are positively related to lower extremity varicose veins risk in both sexes, especially in females. This may partly explain the higher prevalence of varicose vines among females.