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Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men.
J Clin Endocrinol Metab. 2021 01 23; 106(2):e625-e637.JC

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.

Authors+Show Affiliations

Medical School, University of Western Australia, Perth, Australia. Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia.School of Population and Global Health, University of Western Australia, Perth, Australia.Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.Medical School, University of Western Australia, Perth, Australia. Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia.Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia.Medical School, University of Western Australia, Perth, Australia. Harry Perkins Institute of Medical Research and Fiona Stanley Hospital, Perth, Australia.School of Public Health, Curtin University, Perth, Australia.Department of Medicine, University of Washington School of Medicine, Seattle, Washington.Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland.Medical School, University of Western Australia, Perth, Australia.Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington.Medical School, University of Western Australia, Perth, Australia.Manchester Institute for Collaborative Research on Ageing, University of Manchester, Manchester, UK.Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden.Oregon Health and Science University, Portland, Oregon.Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.Freemasons Centre for Men's Health and Wellbeing, School of Medicine, University of Adelaide, Adelaide, Australia.Division of Endocrinology, Diabetes and Gastroenterology, School of Medical Sciences, University of Manchester, Manchester, UK.School of Population and Global Health, University of Western Australia, Perth, Australia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33059368

Citation

Yeap, Bu B., et al. "Serum Testosterone Is Inversely and Sex Hormone-binding Globulin Is Directly Associated With All-cause Mortality in Men." The Journal of Clinical Endocrinology and Metabolism, vol. 106, no. 2, 2021, pp. e625-e637.
Yeap BB, Marriott RJ, Antonio L, et al. Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men. J Clin Endocrinol Metab. 2021;106(2):e625-e637.
Yeap, B. B., Marriott, R. J., Antonio, L., Chan, Y. X., Raj, S., Dwivedi, G., Reid, C. M., Anawalt, B. D., Bhasin, S., Dobs, A. S., Hankey, G. J., Matsumoto, A. M., Norman, P. E., O'Neill, T. W., Ohlsson, C., Orwoll, E. S., Vanderschueren, D., Wittert, G. A., Wu, F. C. W., & Murray, K. (2021). Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men. The Journal of Clinical Endocrinology and Metabolism, 106(2), e625-e637. https://doi.org/10.1210/clinem/dgaa743
Yeap BB, et al. Serum Testosterone Is Inversely and Sex Hormone-binding Globulin Is Directly Associated With All-cause Mortality in Men. J Clin Endocrinol Metab. 2021 01 23;106(2):e625-e637. PubMed PMID: 33059368.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men. AU - Yeap,Bu B, AU - Marriott,Ross J, AU - Antonio,Leen, AU - Chan,Yi X, AU - Raj,Suchitra, AU - Dwivedi,Girish, AU - Reid,Christopher M, AU - Anawalt,Bradley D, AU - Bhasin,Shalender, AU - Dobs,Adrian S, AU - Hankey,Graeme J, AU - Matsumoto,Alvin M, AU - Norman,Paul E, AU - O'Neill,Terence W, AU - Ohlsson,Claes, AU - Orwoll,Eric S, AU - Vanderschueren,Dirk, AU - Wittert,Gary A, AU - Wu,Frederick C W, AU - Murray,Kevin, PY - 2020/08/27/received PY - 2020/10/16/pubmed PY - 2021/9/9/medline PY - 2020/10/15/entrez KW - cancer KW - cardiovascular disease KW - mortality KW - sex hormone-binding globulin KW - testosterone SP - e625 EP - e637 JF - The Journal of clinical endocrinology and metabolism JO - J Clin Endocrinol Metab VL - 106 IS - 2 N2 - 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. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/33059368/Serum_Testosterone_is_Inversely_and_Sex_Hormone_binding_Globulin_is_Directly_Associated_with_All_cause_Mortality_in_Men_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/clinem/dgaa743 DB - PRIME DP - Unbound Medicine ER -