Serum testosterone is inversely, and sex hormone-binding globulin directly, associated with all-cause mortality in men

Bu B Yeap, Ross J Marriott, Leen Antonio, Yi X Chan, Suchitra Raj, Girish Dwivedi, Christopher M Reid, Bradley D Anawalt, Shalender Bhasin, Adrian S Dobs, Graeme J Hankey, Alvin M Matsumoto, Paul E Norman, Terence W O'Neill, Claes Ohlsson, Eric S Orwoll, Dirk Vanderschueren, Gary A Wittert, Frederick C W Wu, Kevin Murray

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CONTEXT: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase.

OBJECTIVE: To analyse 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 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 complete case analysis of 149,436 men with 10,053 deaths (1,925 CVD and 4,927 cancer-related), men with lower testosterone had higher mortality 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 lower mortality 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, 3,128 CVD and 7,468 cancer-related) and analysis excluding deaths within first two years (9,261, 1,734 and 4,534 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.

Original languageEnglish
Pages (from-to)e625-e637
JournalThe Journal of clinical endocrinology and metabolism
Issue number2
Early online date16 Oct 2020
Publication statusPublished - 1 Feb 2021


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