Abstract 73: Sex Hormone Binding Globulin: A Novel Hormonal Biomarker for Ischemic Stroke Risk?

Introduction: Sex hormone binding globulin (SHBG) is a sex-steroid transporter previously linked to cardiometabolic outcomes such as diabetes (DM) and coronary heart disease and their risk factors. It remains uncertain whether SHBG also affects stroke risk, particularly in women. We investigated whether SHBG affects risk of incident ischemic stroke (IS) among women in the Women’s Health Initiative (WHI). Methods: The WHI includes randomized trials and an observational cohort of 161808 postmenopausal women enrolled at 40 sites across the U.S. from 1993 - 1998. We identified 13,192 participants free of prevalent stroke at baseline who were included in one of eleven ancillary studies with serum SHBG. Incident IS events through 2017 were identified via physician adjudication of medical records. We used Cox proportional hazards regression to assess IS risk across quartiles of SHBG levels (Q1 - Q4), first adjusted for demographics, body mass index (BMI), hypertension, alcohol use, and smoking status (Model 1). History of DM was added to remove indirect effects through DM (Model 2), followed by the addition of reproductive risk factors and physical activity (Model 3). Results: Of 13,192 participants (mean age 62.5 years, 67.4% non-Hispanic white, 18.5% black, 5.0% Asian, 7.6% Hispanic), 877 IS events were confirmed during follow-up. Compared to the highest SHBG quartile (referent), women in the lowest quartile had a higher risk of IS in all three models (Model 1: HR 1.51, 95%CI 1.23 - 1.86, Model 2: HR 1.46, 95%CI 1.18 - 1.80, Model 3: HR: 1.38, 95%CI 1.07 - 1.76, trend tests p <0.05 for all). Women in the middle quartiles (Q2, Q3) also had increased IS risk compared with those in the highest SHBG quartile (Table). Conclusions: In this prospective cohort of post-menopausal women, there was a statistically significant inverse association between SHBG levels and IS risk, which supports the notion that SHBG could be used as a risk stratification tool for predicting IS in women.

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Serum sex hormone-binding globulin and testosterone in relation to cardiovascular disease risk factors in young men: a population-based study

Acta Endocrinologica ◽

10.1530/eje-13-1046 ◽

2014 ◽

Vol 170 (6) ◽

pp. 863-872 ◽

Cited By ~ 19

Author(s):

D Canoy ◽

T M Barber ◽

A Pouta ◽

A L Hartikainen ◽

M I McCarthy ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Disease Risk ◽

Young Men ◽

Hdl Cholesterol ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Inverse Association ◽

Hormone Binding ◽

Cvd Risk

ObjectiveReduced sex hormone-binding globulin (SHBG) concentration predicts insulin resistance and type 2 diabetes, but its association with cardiovascular disease (CVD) risk is unclear. We examined the association between SHBG and cardiovascular risk factors, independently of total testosterone (TT), in young men.DesignObservational, cross-sectional study.SettingGeneral community.ParticipantsThe study included 2716 men aged 31 years in the Northern Finland Birth Cohort in 1996 with clinical examination data and fasting blood samples.Outcome variablesBlood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers.ResultsSHBG concentration was significantly and inversely related to systolic and diastolic BP, triglycerides and CRP, but positively to HDL cholesterol after adjusting for insulin, BMI, waist circumference, smoking, education and physical activity (allP<0.05). These linearly graded associations persisted with additional adjustment for TT. SHBG was significantly associated with total cholesterol only with adjustment for covariates and TT (P<0.05). The direction and magnitude of associations between TT and risk factors were variable, but further adjustment for insulin, adiposity and SHBG showed positive associations between TT and BP, total and LDL-cholesterol and triglycerides and an inverse association with CRP (allP<0.05), but its relation with HDL-cholesterol was no longer significant.ConclusionsIn this cohort of young adult men, higher SHBG concentration was associated with a more favourable CVD risk profile, independently of TT. SHBG concentration modified the associations of TT with CVD risk factors.

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Abstract P012: Association Between Testosterone And Sex Hormone Binding Globulin And Risk Of Ischemic Stroke: The Atherosclerosis Risk In Communities Study

Circulation ◽

10.1161/circ.143.suppl_1.p012 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Carin A Northuis ◽

Erin Michos ◽

Christie M Ballantyne ◽

Ron C Hoogeveen ◽

Pamela L Lutsey ◽

...

Keyword(s):

Ischemic Stroke ◽

Sex Hormones ◽

Stroke Risk ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Hormone Binding ◽

Atherosclerosis Risk In Communities ◽

Menopausal Women ◽

Atherosclerosis Risk ◽

Post Menopausal

Background: Sex hormones are associated with obesity, diabetes mellitus, and other stroke risk factors; however, studies on sex hormones and stroke risk report inconsistent results. We assessed the associations of testosterone and sex hormone binding globulin (SHBG) with risk of ischemic stroke among men and post-menopausal women in the Atherosclerosis Risk in Communities (ARIC) Study. Methods: A total of 4,349 men and 4,720 post-menopausal women who had SHBG and total testosterone measurements at visit 4 (1996-98) were followed through 2018 for the development of ischemic stroke. We examined log transformed SHBG and testosterone exposure as quartiles and as per 1 SD increment. We used Cox regression to estimate the hazard ratios (HR) for ischemic stroke, adjusting for demographic, behavioral and clinical variables. Analyses were stratified by sex and menopausal hormone therapy (HT) use. Results: Participants were aged 63±6 years at baseline, 52% were women (25% HT users), and 21% Black. There were 691 strokes over a median follow-up of 19.8 years. Mean log SHBG (nmol/L) and testosterone (nmol/L) were 4.3±0.7 and 3.1±0.5 for HT users, 3.6±0.7 and 3.2±0.5 for non-HT users, and 3.4±0.5 and 6.2±0.5 for men. Quartile 1 vs Q4 for SHBG and testosterone were ≤50.3 vs >121 and ≤16 vs >28 in HT users, ≤23.3 vs >55 and ≤17.9 vs >32.7 in non-HT users, and ≤23.3 vs >41.8 and ≤388 vs >657 in men. SHBG and testosterone were not significantly associated with stroke in any group (Figure). The HRs [95% confidence interval] for highest to lowest SHBG and testosterone quartiles were 1.04 [0.51-2.14] and 1.64 [0.85-3.17] in HT-users, 1.02 [0.70-1.48] and 1.16 [0.83-1.62] in HT non-users, and 0.96 [0.70-1.32] and 0.87 [0.63-1.21] in men, respectively. The HRs for stroke associated with 1 SD increase in SHBG and testosterone were 1.14 [0.88-1.46] and 1.19 [0.96-1.46] in HT users. Associations were also null among non-HT users and men. Conclusion: SHBG and testosterone were not associated with ischemic stroke risk in this cohort of older men and post-menopausal women.

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Gastrointestinal Disorders and Risk of First-Ever Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.030643 ◽

2020 ◽

Vol 51 (12) ◽

pp. 3577-3583

Author(s):

William H. Roth ◽

Anna Cai ◽

Cenai Zhang ◽

Monica L. Chen ◽

Alexander E. Merkler ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Gut Microbiome ◽

Stroke Risk ◽

Proportional Hazards ◽

Gastrointestinal Diseases ◽

Cox Proportional Hazards ◽

Gastrointestinal Disorders ◽

Stroke Risk Factors ◽

Increased Risk

Background and Purpose: Recent studies suggest that alteration of the normal gut microbiome contributes to atherosclerotic burden and cardiovascular disease. While many gastrointestinal diseases are known to cause disruption of the normal gut microbiome in humans, the clinical impact of gastrointestinal diseases on subsequent cerebrovascular disease remains unknown. We conducted an exploratory analysis evaluating the relationship between gastrointestinal diseases and ischemic stroke. Methods: We performed a retrospective cohort study using claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We included only beneficiaries ≥66 years of age. We used previously validated diagnosis codes to ascertain our primary outcome of ischemic stroke. In an exploratory manner, we categorized gastrointestinal disorders by anatomic location, disease chronicity, and disease mechanism. We used Cox proportional hazards models to examine associations of gastrointestinal disorder categories and ischemic stroke with adjustment for demographics and established vascular risk factors. Results: Among a mean of 1 725 246 beneficiaries in each analysis, several categories of gastrointestinal disorders were associated with an increased risk of ischemic stroke after adjustment for established stroke risk factors. The most notable positive associations included disorders of the stomach (hazard ratio, 1.17 [95% CI, 1.15–1.19]) and functional (1.16 [95% CI, 1.15–1.17]), inflammatory (1.13 [95% CI, 1.12–1.15]), and infectious gastrointestinal disorders (1.13 [95% CI, 1.12–1.15]). In contrast, we found no associations with stroke for diseases of the anus and rectum (0.97 [95% CI, 0.94–1.00]) or neoplastic gastrointestinal disorders (0.97 [95% CI, 0.94–1.00]). Conclusions: In exploratory analyses, several categories of gastrointestinal disorders were associated with an increased risk of future ischemic stroke after adjustment for demographics and established stroke risk factors.

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Abstract TP159: Risk of Ischemic Stroke in Patients with Atrial Flutter

Stroke ◽

10.1161/str.48.suppl_1.tp159 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Mais Al-Kawaz ◽

Setareh Salehi Omran ◽

Neal S Parikh ◽

Mitchell S Elkind ◽

Elsayed Z Soliman ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Lower Risk ◽

Stroke Risk ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Administrative Claims ◽

Primary Analysis ◽

Stroke Incidence ◽

The Difference

Introduction: Guidelines advise anticoagulation for patients with both atrial fibrillation (AF) and flutter (AFL). However, the risk of stroke associated with these two conditions has not been robustly compared. Methods: Using inpatient and outpatient Medicare administrative claims data from 2008-2014 for a 5% sample of all beneficiaries ≥66 years of age, we identified all patients diagnosed with AFL or AF. Patients with prior stroke were excluded. The primary outcome was ischemic stroke. Predictors and the outcome were ascertained by validated ICD-9-CM diagnosis codes. Patients were censored at the time of ischemic stroke, death, or last available follow-up. In the primary analysis, patients with AFL were censored upon diagnosis of AF. Survival statistics were used to compare stroke incidence in patients with AF versus AFL. We used Cox proportional hazards analysis to compare the associations of AFL and AF with ischemic stroke after adjustment for demographics and risk factors. In a secondary analysis, patients with AFL were not censored upon diagnosis of AF because the natural history of AFL frequently features the development of AF. Results: We identified 16,441 patients with AFL and 338,726 with AF. Patients with AFL were less often female (42.4% versus 53.0%), but other baseline characteristics, including mean CHA 2 DS 2 -VASc scores (3.9), were similar between groups. Over 2.4 (±2.0) years, 16,451 ischemic strokes were identified. The annual incidence of ischemic stroke in patients with AFL was 0.60% (95% confidence interval [CI], 0.48-0.75%), whereas it was 2.00% (95% CI, 1.96-2.02%) in patients with AF. After adjustment for demographics and vascular risk factors, AFL was associated with a lower risk of ischemic stroke than AF (hazard ratio [HR], 0.30; 95% CI, 0.24-0.37). Within 1 year, 64.9% (95% CI, 64.1-65.6%) of patients with AFL received a diagnosis of AF. The difference between stroke risk in AFL compared to AF was attenuated (HR, 0.85; 95% CI, 0.79-0.92) when patients with AFL were not censored upon diagnosis of AF. Conclusions: Patients with AFL may face a lower risk of ischemic stroke than patients with AF. However, AF often develops in those with AFL, and taking this into account, the difference in stroke risk between the two conditions grows smaller.

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Abstract 11900: Influence of Competing Risks on the Association Between Warfarin and Ischemic Stroke in Atrial Fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study

Circulation ◽

10.1161/circ.132.suppl_3.11900 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Jeffrey M Ashburner ◽

Alan S Go ◽

Yuchiao Chang ◽

Margaret C Fang ◽

Lisa Fredman ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Competing Risks ◽

Stroke Risk ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Subdistribution Hazard ◽

Risk Of Death

Introduction: Studies examining the association between warfarin therapy and incidence of ischemic stroke in adults with atrial fibrillation (AF) have not accounted for patients who die of non-stroke causes. Hypothesis: Accounting for the competing risk of death may provide greater understanding of the “real world” impact of warfarin on stroke risk during multiyear follow-up in a large, diverse cohort of AF patients. Methods: We assessed this association in the ATRIA community-based cohort of AF patients (n=13,559; study years 1996-2003), with thromboembolic (>90% ischemic stroke) events (TEE) being clinician-adjudicated. Extended Cox proportional hazards regression with time-varying warfarin exposure estimated the cause-specific hazard ratio (HR) for TEE while adjusting for stroke risk factors. Fine and Gray subdistribution regression was used to estimate this association while also accounting for competing death events. Results: Patients using warfarin were younger, more likely to have had a prior stroke, and to have known diabetes, coronary disease, and heart failure, and also had higher mean CHA2DS2VASc scores (3.68 vs. 3.22). The death rate was much higher in the non-warfarin group (8.1 deaths/100 person-years; 2637 deaths vs. 5.5 deaths/100 person-years; 1777 deaths on warfarin). The cause-specific HR indicated a large reduction in TE with warfarin use (adjusted HR: 0.57, 95% CI: 0.50-0.65). In subdistribution hazard models accounting for competing death events over the full follow-up of 6 years, this association was substantially attenuated (adjusted HR: 0.87, 95% CI: 0.77-0.99). In analyses limited to 1-year follow-up with only 648 competing death events, the results without accounting for competing risks (adjusted cause-specific HR: 0.55, 95% CI: 0.43-0.71) were similar to the results that did account for competing risks (adjusted subdistribution HR: 0.59, 95% CI: 0.46-0.75). Conclusions: By accounting for competing death events, our results reflect a more realistic estimate of the multi-year stroke prevention benefits of warfarin for patients with AF. Many old/frail individuals with AF will not live long enough to gain substantial benefit from warfarin.

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Abstract TP196: New Zealand Workforce Stroke Incidence: Urban and Rural Risk Factor Evaluation

Stroke ◽

10.1161/str.44.suppl_1.atp196 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Hope E Buell ◽

Patricia Metcalf ◽

Daniel Exeter

Keyword(s):

Risk Factors ◽

New Zealand ◽

Stroke Risk ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Smoking Status ◽

Prior History ◽

Stroke Incidence ◽

Stroke Outcomes ◽

The Impact

This analysis aims to assess the impact of urban and rural risk factors on a model of stroke incidence in a New Zealand workforce population. The New Zealand study consisted of 4,926 subjects prospectively enrolled at 46 worksites. The subjects were aged 40-78 years at baseline and had no prior history of stroke. This prospective study defines stroke events experienced by the study subjects during follow-up between 1988 and 2012 based on hospital admission coding. Proportional hazards regression models were fit using baseline characteristics. The difference in stroke outcomes for urban and rural worksites was also evaluated. Results demonstrate that baseline demographic, physical exam, and behavioural measures impact stroke outcomes. While the baseline distribution of stroke risk factors such as Pacific Island ethnicity, smoking status, and increased blood pressure indicates a potentially higher risk of stroke in the rural population, the proportional hazards model does not identify increased stroke risk for rural workers. Additional analysis of the diet, exercise and Quality of Life measures for these subjects may provide further information into the stroke risk profiles of individuals working in different locales.

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Abstract TMP58: Determinants of White Matter Hyperintensity in Acute Ischemic Stroke Patients: The MRI-GENIE Study

Stroke ◽

10.1161/str.48.suppl_1.tmp58 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Anne-Katrin Giese ◽

Markus D Schirmer ◽

Adrian V Dalca ◽

Ramesh Sridharan ◽

Lisa Cloonan ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Ischemic Stroke ◽

White Matter ◽

Stroke Risk ◽

Smoking Status ◽

Vascular Risk Factors ◽

White Matter Hyperintensity ◽

Vascular Risk ◽

Prior Stroke

Introduction: White matter hyperintensity (WMH) is a highly heritable trait and a significant contributor to stroke risk and severity. Vascular risk factors contribute to WMH severity; however, knowledge of the determinants of WMH in acute ischemic stroke (AIS) is still limited. Hypothesis: WMH volume (WMHv) varies across AIS subtypes and is modified by vascular risk factors. Methods: We extracted WMHv from the clinical MRI scans of 2683 AIS subjects from the MRI-Genetics Interface Exploration (MRI-GENIE) study using a novel fully-automated, volumetric analysis pipeline. Demographic data, stroke risk factors and stroke subtyping for the Causative Classification of Stroke (CCS) were performed at each of the 12 international study sites. WMHv was natural log-transformed for linear regression analyses. Results: Median WMHv was 5.7cm 3 (interquartile range (IQR): 2.2-12.8cm 3 ). In univariable analysis, age (63.1 ± 14.7 years, β=0.04, SE=0.002), prior stroke (10.2%, β=0.66, SE=0.08), hypertension (65.4%, β=0.75, SE=0.05), diabetes mellitus (23.1%, β=0.35, SE=0.06), coronary artery disease (17.6%, β=0.04, SE=0.002), and atrial fibrillation (14.6%, β=0.48, SE=0.07) were significant predictors of WMHv (all p<0.0001), as well as smoking status (52.2%, β=0.15, SE=0.05, p=0.005), race (16.5% Non-Caucasian, β=0.25, SE=0.07) and ethnicity (8.2% Hispanic, β=0.30, SE=0.11) (all p<0.01). In multivariable analysis, age (β=0.04, SE=0.002), prior stroke (β=0.56, SE=0.08), hypertension (β=0.33, SE=0.05), smoking status (β=0.16, SE=0.05), race (β=0.42, SE=0.06), and ethnicity (β=0.34, SE=0.09) were independent predictors of WMHv (all p<0.0001), as well as diabetes mellitus (β=0.13, SE=0.06, p=0.02). WMHv differed significantly (p<0.0001, unadjusted) across CCS stroke subtypes: cardioembolic stroke (8.0cm 3 , IQR: 4.2-15.4cm 3 ), large-artery stroke (6.9cm 3 , IQR: 3.1-14.7cm 3 ), small-vessel stroke (5.8cm 3 , IQR: 2.5-13.5cm 3 ), stroke of undetermined (4.7cm 3 , IQR: 1.6-11.0cm 3 ) or other (2.55cm 3 , IQR: 0.9-8.8cm 3 ) causes. Conclusion: In this largest-to-date, multicenter hospital-based cohort of AIS patients with automated WMHv analysis, common vascular risk factors contribute significantly to WMH burden and WMHv varies by CCS subtype.

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Concentrations of sex-hormone binding globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women.

Clinical Chemistry ◽

10.1093/clinchem/32.1.146 ◽

1986 ◽

Vol 32 (1) ◽

pp. 146-152 ◽

Cited By ~ 80

Author(s):

L Lapidus ◽

G Lindstedt ◽

P A Lundberg ◽

C Bengtsson ◽

T Gredmark

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Body Mass Index ◽

Body Mass ◽

Significant Risk ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Hormone Binding ◽

Corticosteroid Binding Globulin ◽

Overall Mortality

Abstract We determined sex-hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) by radioimmunoassay of serum samples from a group of 253 women, who were 54 or 60 years old when first studied in 1968-69. The SHBG concentration was highly significantly and inversely related to body mass, body mass index, waist-to-hip circumference ratio, and serum triglyceride concentration; CBG concentration was inversely related to body mass and body mass index. The concentration of neither protein was related to whether or not the subject smoked. Decrease in the concentration of SHBG, but not of CBG, was a significant risk factor for 12-year overall mortality. The plot of the 12-year incidence of myocardial infarction vs SHBG concentration was U-shaped. We recommend that SHBG be included when serum androgens or estrogens are being evaluated as risk factors for cardiovascular disease and death.

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Baseline Serum Bilirubin and Risk of First Stroke in Hypertensive Patients

Journal of the American Heart Association ◽

10.1161/jaha.119.015799 ◽

2020 ◽

Vol 9 (12) ◽

Author(s):

Jiancheng Wang ◽

Xianglin Zhang ◽

Zhuxian Zhang ◽

Yuanyuan Zhang ◽

Jingping Zhang ◽

...

Keyword(s):

Ischemic Stroke ◽

Proportional Hazards ◽

Total Bilirubin ◽

Serum Bilirubin ◽

Cox Proportional Hazards ◽

Direct Bilirubin ◽

Serum Total Bilirubin ◽

Inverse Association ◽

Baseline Serum ◽

Hypertensive Patients

Background Data on the association between serum bilirubin and the risk of stroke are limited and inconclusive. We aimed to evaluate the association between serum bilirubin and the risk of first stroke and to examine any possible effect modifiers in hypertensive patients. Methods and Results Our study was a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). A total of 19 906 hypertensive patients were included in the final analysis. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for the risk of first stroke associated with serum bilirubin levels. The median follow‐up period was 4.5 years. When serum total bilirubin was assessed as tertiles, the adjusted HR of first ischemic stroke for participants in tertile 3 (12.9–34.1 μmol/L) was 0.75 (95% CI, 0.59–0.96), compared with participants in tertile 1 (<9.3 μmol/L). When direct bilirubin was assessed as tertiles, a significantly lower risk of first ischemic stroke was also found in participants in tertile 3 (2.5–24.8 μmol/L) (adjusted HR, 0.77; 95% CI, 0.60–0.98), compared with those in tertile 1 (<1.6 μmol/L). However, there was no significant association between serum total bilirubin (tertile 3 versus 1: adjusted HR, 1.45; 95% CI, 0.89–2.35) or direct bilirubin (tertile 3 versus 1: adjusted HR, 1.27; 95% CI, 0.76–2.11) and first hemorrhagic stroke. Conclusions In this sample of Chinese hypertensive patients, there was a significant inverse association between serum total bilirubin or direct bilirubin and the risk of first ischemic stroke.

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Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa743 ◽

2020 ◽

Author(s):

Bu B Yeap ◽

Ross J Marriott ◽

Leen Antonio ◽

Yi X Chan ◽

Suchitra Raj ◽

...

Keyword(s):

Mortality Rate ◽

Serum Testosterone ◽

Cox Proportional Hazards ◽

Community Dwelling ◽

Sex Hormone ◽

Sex Hormone Binding Globulin ◽

Atherosclerotic Cardiovascular Disease ◽

Hormone Binding ◽

Baseline Serum ◽

Related Mortality

Abstract Context Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. Objective To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men. Design, Setting, and Participants The UK Biobank prospective cohort study of community-dwelling men aged 40–69 years old, followed for 11 years. Main Outcome Measures All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa. Results In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06–1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09–1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63–0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59–0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72–0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results. Conclusions Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.

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