Endogenous Sex Steroid Hormones, Sex Hormone-Binding Globulin, and Risk of All-Cause and Cause-Specific Mortality: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies

Abstract

Background While abundant research suggests a sex-specific role of endogenous sex steroid hormones in chronic diseases, research on mortality remains inconclusive. We quantified the sex-specific associations of endogenous sex steroid hormones, including total testosterone (TT), free testosterone, bioavailable testosterone, estradiol, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS), and sex hormone-binding globulin (SHBG) with risk of all-cause and cause-specific mortality in the general population. Methods Embase, Medline, Web of Science, and Cochrane Central were searched and population-based cohort studies investigating the association of interest were included. The risk of bias was assessed using the ROBINS-E tool. The certainty of evidence was evaluated using the GRADE framework. Pooled hazard ratios (HRs) and 95% CI were calculated using a random effects model for the top vs bottom tertile of sex hormones and risk of mortality. Results The systematic review included 53 publications with 359 047 participants. A significant association was observed between higher level of TT and risk of all-cause mortality (HR [95% CI]: 0.89 [0.83-0.97], n = 19 studies) in men, while no association was found in women. Dose-response analysis suggested a significant U-shaped association between TT and all-cause mortality in men and a J-shaped association in women. Higher SHBG level was significantly associated with higher risk of all-cause mortality in women (1.25 [1.13-1.39], n = 3) and no association was observed in men. Additionally, higher DHEAS levels were associated with lower risk of all-cause mortality in men (0.72 [0.57-0.91], n = 6) and no association was observed in women. Conclusion This meta-analysis reveals a dose-response link between endogenous sex steroid hormones and mortality, highlighting the need for sex-specific studies on hormone modulation's impact on mortality and longevity.