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 (E2), dehydroepiandrosterone, and dehydroepiandrosterone-sulphate 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 interested were included. The risk of bias was assessed using the ROBINS-E tool. The certainty of evidence was evaluated using GRADE framework. Pooled hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using a random effects model for the top versus bottom tertile of sex hormones and risk of mortality. Results 53 publications with 359,047 participants were included in the systematic review. A significant association was observed between higher level of TT and risk of all-cause mortality (HR (95%CI): 0.89 (0.83 to 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 level of SHBG was significantly associated with higher risk of all-cause mortality in women (1.25 (1.13 to 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 to 0.91), n=6) and no association was observed in women. Conclusions 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. Source of Funding None. PROSPERO registration code CRD42022329605