Gender-Specific Associations Between Sex Hormones and Cardiovascular Disease: A Systematic Review and Meta-Analysis.

Background: Sex hormones play a critical role in the development of cardiovascular disease (CVD); however, the associations between specific circulating sex hormones and cardiovascular outcomes differ by sex, and the evidence remains inconclusive. Methods: A systematic review and meta-analysis of 23 prospective cohort studies was conducted to examine the associations between sex hormones and cardiovascular outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted, and random- or fixed-effects models were applied based on heterogeneity. Subgroup analyses were performed by hormone type, age, and sex. Results: In men, higher total testosterone (TT) levels were associated with a reduced risk of CVD. No consistent associations were found between sex hormone-binding globulin (SHBG), calculated free testosterone (cFT), and estradiol with CVD. In women, elevated TT and cFT were linked to increased CVD risk. Estradiol exhibited a modest and uncertain protective effect. An outcome-specific analysis revealed that higher dehydroepiandrosterone (DHEA) levels were linked to an increased risk of heart failure, while SHBG was associated with reduced cardiovascular mortality. Conversely, higher estradiol concentrations correlated with increased cardiovascular mortality. Conclusions: Sex hormones exert complex, sex-specific, and outcome-dependent effects on cardiovascular risk. In men, higher testosterone levels are associated with lower overall CVD risk, whereas in women, these levels are linked to higher CVD and heart failure risk. Estradiol demonstrated a protective trend against major adverse cardiovascular events (MACEs), yet was linked to increased cardiovascular mortality. Higher SHBG levels are associated with lower cardiovascular mortality, whereas higher DHEA levels correlate with increased heart failure risk. Together, these findings underscore the importance of integrating sex, age, and endocrine context into cardiovascular risk stratification and prevention strategies. The PROSPERO Registration: CRD42024551055, Registration Link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024551055.