Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses

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; Frederick C W Wu; Kevin Murray

doi:10.7326/M23-2781

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses

Ann Intern Med. 2024 May 14. doi: 10.7326/M23-2781. Online ahead of print.

Authors

Bu B Yeap¹, Ross J Marriott², Girish Dwivedi³, Robert J Adams⁴, Leen Antonio⁵, Christie M Ballantyne⁶, Douglas C Bauer⁷, Shalender Bhasin⁸, Mary L Biggs⁹, Peggy M Cawthon¹⁰, David J Couper¹¹, Adrian S Dobs¹², Leon Flicker¹³, David J Handelsman¹⁴, Graeme J Hankey¹⁵, Anke Hannemann¹⁶, Robin Haring¹⁷, Benjumin Hsu¹⁸, Sean A Martin¹⁹, Alvin M Matsumoto²⁰, Dan Mellström²¹, Claes Ohlsson²¹, Terence W O'Neill²², Eric S Orwoll²³, Matteo Quartagno²⁴, Molly M Shores²⁵, Antje Steveling²⁶, Åsa Tivesten²⁷, Thomas G Travison²⁸, Dirk Vanderschueren⁵, Gary A Wittert²⁹, Frederick C W Wu³⁰, Kevin Murray²

Affiliations

¹ Medical School, University of Western Australia, and Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia (B.B.Y.).
² School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia (R.J.M., K.M.).
³ Medical School, University of Western Australia; Harry Perkins Institute of Medical Research; and Department of Cardiology, Fiona Stanley Hospital, Perth, Western Australia, Australia (G.D.).
⁴ Adelaide Institute for Sleep Health, Flinders University, Bedford Park, South Australia, Australia (R.J.A.).
⁵ Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium (L.A., D.V.).
⁶ Internal Medicine, Baylor College of Medicine, Houston, Texas (C.M.B.).
⁷ General Internal Medicine, University of California, San Francisco, San Francisco, California (D.C.B.).
⁸ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (S.B.).
⁹ Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington (M.L.B.).
¹⁰ San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, California (P.M.C.).
¹¹ Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (D.J.C.).
¹² School of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University, Baltimore, Maryland (A.S.D.).
¹³ Medical School, University of Western Australia, and Western Australian Centre for Healthy Ageing, University of Western Australia, Perth, Western Australia, Australia (L.F.).
¹⁴ ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (D.J.H.).
¹⁵ Medical School, University of Western Australia, and Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia (G.J.H.).
¹⁶ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, and German Centre for Cardiovascular Research, Partner Site Greifswald, Greifswald, Germany (A.H.).
¹⁷ School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia, and European University of Applied Sciences, Faculty of Applied Public Health, Rostock, Germany (R.H.).
¹⁸ Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales, Australia (B.H.).
¹⁹ Australian Institute of Family Studies, Southbank, Victoria, Australia (S.A.M.).
²⁰ Department of Medicine, University of Washington School of Medicine, and Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington (A.M.M.).
²¹ Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden (D.M., C.O.).
²² Centre for Epidemiology Versus Arthritis, University of Manchester, and NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, United Kingdom (T.W.O.).
²³ Oregon Health & Science University, Portland, Oregon (E.S.O.).
²⁴ MRC Clinical Trials Unit, University College London, London, United Kingdom (M.Q.).
²⁵ School of Medicine, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington (M.M.S.).
²⁶ Department of Internal Medicine, University Medicine Greifswald, Greifswald, Germany (A.S.).
²⁷ Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, and Department of Endocrinology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden (Å.T.).
²⁸ Brigham and Women's Hospital, Harvard Medical School, and Institute for Aging Research, Hebrew Senior Life, Beth Israel Deaconess Medical Center, Boston, Massachusetts (T.G.T.).
²⁹ Freemasons Centre for Men's Health and Wellbeing, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia (G.A.W.).
³⁰ Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, United Kingdom (F.C.W.W.).

PMID: 38739921
DOI: 10.7326/M23-2781

Abstract

Background: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial.

Purpose: To clarify associations of sex hormones with these outcomes.

Data sources: Systematic literature review to July 2019, with bridge searches to March 2024.

Study selection: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up.

Data extraction: Independent 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 synthesis: Nine 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.

Limitations: Observational study design, heterogeneity among studies, and imputation of missing data.

Conclusion: Men 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 source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Publication types

Review