Serum Testosterone is Inversely and Sex Hormone-binding Globulin is 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

Research output: Contribution to journalArticlepeer-review

Abstract

Context: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. Objective: To analyze 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 aged 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 a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate 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 a lower mortality rate 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, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 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 (US)
Pages (from-to)E625-E637
JournalJournal of Clinical Endocrinology and Metabolism
Volume106
Issue number2
DOIs
StatePublished - Feb 1 2021

Keywords

  • cancer
  • cardiovascular disease
  • mortality
  • sex hormone-binding globulin
  • testosterone

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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