• Bu B Yeap, Ross J Marriott, Leen Antonio, Suchitra Raj, Girish Dwivedi, Christopher M Reid, Bradley D Anawalt, Shalender Bhasin, Adrian S Dobs, David J Handelsman, Graeme J Hankey, Robin Haring, Alvin M Matsumoto, Paul E Norman, Terence W O'Neill, Claes Ohlsson, Eric S Orwoll, Dirk Vanderschueren, Gary A Wittert, WuFrederick C WFCWDivision of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, United Kingdom (F.C.W.)., and Kevin Murray.
• Medical School, University of Western Australia, and Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia (B.B.Y.).
• Ann. Intern. Med. 2022 Feb 1; 175 (2): 159-170.

BackgroundThe influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria.ObjectiveTo analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men.DesignCohort study.SettingUK Biobank prospective cohort.ParticipantsCommunity-dwelling men aged 40 to 69 years.MeasurementsTestosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors.ResultsOf 210 700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]).LimitationObservational study; single baseline measurement of testosterone and SHBG.ConclusionMen with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined.Primary Funding SourceWestern Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

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