• Bu B Yeap, Ross J Marriott, Girish Dwivedi, Robert J Adams, Leen Antonio, Christie M Ballantyne, Douglas C Bauer, Shalender Bhasin, Mary L Biggs, Peggy M Cawthon, David J Couper, Adrian S Dobs, Leon Flicker, David J Handelsman, Graeme J Hankey, Anke Hannemann, Robin Haring, Benjumin Hsu, Sean A Martin, Alvin M Matsumoto, Dan Mellström, Claes Ohlsson, Terence W O'Neill, Eric S Orwoll, Matteo Quartagno, Molly M Shores, Antje Steveling, Åsa Tivesten, Thomas G Travison, Dirk Vanderschueren, Gary A Wittert, WuFrederick C WFCW0000-0002-7005-4798Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, United Kingdom (F.C.W.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. 2024 Jun 1; 177 (6): 768781768-781.

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

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