Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men

Bu B Yeap¹, Ross J Marriott², Leen Antonio³, Suchitra Raj⁴, Girish Dwivedi⁵, Christopher M Reid⁶, Bradley D Anawalt⁷, Shalender Bhasin⁸, Adrian S Dobs⁹, David J Handelsman¹⁰, Graeme J Hankey¹¹, Robin Haring¹², Alvin M Matsumoto¹³, Paul E Norman¹¹, Terence W O'Neill¹⁴, Claes Ohlsson¹⁵, Eric S Orwoll¹⁶, Dirk Vanderschueren³, Gary A Wittert¹⁷, Frederick C W Wu¹⁸, 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 Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium (L.A., D.V.).
⁴ Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia (S.R.).
⁵ Medical School, University of Western Australia, Harry Perkins Institute of Medical Research, and Fiona Stanley Hospital, Perth, Western Australia, Australia (G.D.).
⁶ School of Population Health, Curtin University, Perth, Western Australia, Australia (C.M.R.).
⁷ Department of Medicine, University of Washington School of Medicine, Seattle, Washington (B.D.A.).
⁸ Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.B.).
⁹ Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland (A.S.D.).
¹⁰ Anzac Research Institute, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia (D.J.H.).
¹¹ Medical School, University of Western Australia, Perth, Western Australia, Australia (G.J.H., P.E.N.).
¹² School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia, and Faculty of Applied Public Health, European University of Applied Sciences, Rostock, Germany (R.H.).
¹³ Department of Medicine, University of Washington School of Medicine, and Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (A.M.M.).
¹⁴ Centre for Epidemiology Versus Arthritis, University of Manchester, and National Institute for Health Research Manchester Biomedical Research Centre, Manchester University National Health Service Foundation Trust, Manchester, United Kingdom (T.W.O.).
¹⁵ Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, and Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden (C.O.).
¹⁶ Oregon Health & Science University, Portland, Oregon (E.S.O.).
¹⁷ Freemasons Centre for Men's Health and Wellbeing, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia (G.A.W.).
¹⁸ Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, United Kingdom (F.C.W.).

PMID: 34958606
DOI: 10.7326/M21-0551

Observational Study

Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men

Bu B Yeap et al. Ann Intern Med. 2022 Feb.

. 2022 Feb;175(2):159-170.

doi: 10.7326/M21-0551. Epub 2021 Dec 28.

Authors

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 Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium (L.A., D.V.).
⁴ Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia (S.R.).
⁵ Medical School, University of Western Australia, Harry Perkins Institute of Medical Research, and Fiona Stanley Hospital, Perth, Western Australia, Australia (G.D.).
⁶ School of Population Health, Curtin University, Perth, Western Australia, Australia (C.M.R.).
⁷ Department of Medicine, University of Washington School of Medicine, Seattle, Washington (B.D.A.).
⁸ Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.B.).
⁹ Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland (A.S.D.).
¹⁰ Anzac Research Institute, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia (D.J.H.).
¹¹ Medical School, University of Western Australia, Perth, Western Australia, Australia (G.J.H., P.E.N.).
¹² School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia, and Faculty of Applied Public Health, European University of Applied Sciences, Rostock, Germany (R.H.).
¹³ Department of Medicine, University of Washington School of Medicine, and Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (A.M.M.).
¹⁴ Centre for Epidemiology Versus Arthritis, University of Manchester, and National Institute for Health Research Manchester Biomedical Research Centre, Manchester University National Health Service Foundation Trust, Manchester, United Kingdom (T.W.O.).
¹⁵ Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, and Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden (C.O.).
¹⁶ Oregon Health & Science University, Portland, Oregon (E.S.O.).
¹⁷ Freemasons Centre for Men's Health and Wellbeing, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia (G.A.W.).
¹⁸ Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, United Kingdom (F.C.W.).

PMID: 34958606
DOI: 10.7326/M21-0551

Abstract

Background: The 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.

Objective: To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men.

Design: Cohort study.

Setting: UK Biobank prospective cohort.

Participants: Community-dwelling men aged 40 to 69 years.

Measurements: Testosterone 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.

Results: Of 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]).

Limitation: Observational study; single baseline measurement of testosterone and SHBG.

Conclusion: Men 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 source: Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

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Comment in

Testosterone and Cardiovascular Disease in Men.
Zhao D, Guallar E. Zhao D, et al. Ann Intern Med. 2022 Feb;175(2):287-288. doi: 10.7326/M21-4777. Epub 2021 Dec 28. Ann Intern Med. 2022. PMID: 34958604 No abstract available.

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Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men

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Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men

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