Bu B Yeap1,2, Ross J Marriott3, Leen Antonio4, Yi X Chan1,2, Suchitra Raj2, Girish Dwivedi1,5, Christopher M Reid6, Bradley D Anawalt7, Shalender Bhasin8, Adrian S Dobs9, Graeme J Hankey1, Alvin M Matsumoto7,10, Paul E Norman1, Terence W O'Neill11, Claes Ohlsson12,13, Eric S Orwoll14, Dirk Vanderschueren4, Gary A Wittert15, Frederick C W Wu16, Kevin Murray3. 1. Medical School, University of Western Australia, Perth, Australia. 2. Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia. 3. School of Population and Global Health, University of Western Australia, Perth, Australia. 4. Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium. 5. Harry Perkins Institute of Medical Research and Fiona Stanley Hospital, Perth, Australia. 6. School of Public Health, Curtin University, Perth, Australia. 7. Department of Medicine, University of Washington School of Medicine, Seattle, Washington. 8. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 9. Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 10. Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington. 11. Manchester Institute for Collaborative Research on Ageing, University of Manchester, Manchester, UK. 12. Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 13. Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden. 14. Oregon Health and Science University, Portland, Oregon. 15. Freemasons Centre for Men's Health and Wellbeing, School of Medicine, University of Adelaide, Adelaide, Australia. 16. Division of Endocrinology, Diabetes and Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, UK.
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.
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.
Authors: Bu B Yeap; Ross J Marriott; Laurens Manning; Girish Dwivedi; Graeme J Hankey; Frederick C W Wu; Jeremy K Nicholson; Kevin Murray Journal: Eur J Endocrinol Date: 2022-06-01 Impact factor: 6.558
Authors: Jenny Pena Dias; Sabina A Haberlen; Adrian S Dobs; Jordan E Lake; Frank J Palella; Lawrence A Kingsley; Jennifer C Price; Shehzad Basaria; Ravi Varadhan; Joseph B Margolick; Chloe L Thio; Todd T Brown Journal: J Acquir Immune Defic Syndr Date: 2021-08-15 Impact factor: 3.771