Association of Testosterone-to-Estradiol Ratio and Coronary Heart Disease: A NHANES-Based Study with the Weight-Adjusted Waist Index as a Potential Mediator

Objectives Sex differences in coronary heart disease (CHD) are well known, but the impact of sex hormone balance on cardiovascular risk is still unclear. We studied how the testosterone-to-estradiol ratio (TT/E2) relates to CHD and investigated whether abdominal fatness mediates this relationship across different sexes and menopausal states. Methods We included 9,558 adults aged ≥ 30 years from the 2013–2016 National Health and Nutrition Examination Survey (NHANES). Serum total testosterone and estradiol levels were measured using isotope-dilution liquid chromatography–tandem mass spectrometry. The TT/E2 ratio was log-transformed and standardized. CHD was defined as a self-reported physician diagnosis. Survey-weighted logistic regression models with multiple imputation estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for demographic and cardiometabolic variables. Interaction terms evaluated effect modification by sex and menopausal status. Restricted cubic splines assessed dose–response relationships. A counterfactual mediation analysis was used to examine the mediating effect of the weight-adjusted waist index (WWI). Results In fully adjusted models, a higher log(TT/E2) was associated with a lower odds of CHD in men (OR per 1-SD increase: 0.81; 95% CI 0.70–0.94), but this association was not observed in women overall. There were significant interactions with sex ( p _interaction = 0.017) and menopausal status ( p _interaction = 0.009). Stratified analysis revealed an inverse relationship in premenopausal women (OR 0.73; 95% CI 0.56–0.95), but not in postmenopausal women. Spline analyses showed a mainly linear inverse association in men. WWI partially mediated the link in men (indirect effect p  = 0.019), but not in premenopausal women. Conclusions A higher TT/E2 ratio was inversely associated with CHD in men and premenopausal women, with partial mediation by abdominal adiposity in men. These findings underscore the context-dependent role of sex hormone balance in cardiovascular risk.