Do Androgens and Sex Hormone–Binding Globulin Mediate Sex Differences in the Risk of Stroke and Myocardial Infarction? The KORA Study

BACKGROUND: Sex differences in cardiovascular disease are well established, but the role of androgens and sex hormone-binding globulin (SHBG) remains unclear. We investigated whether these hormones and SHBG mediate sex differences in the risk of stroke and myocardial infarction (MI). METHODS: Observational data from the German population-based KORA (Cooperative Health Research in the Region of Augsburg) F4 study (n=1970; mean age, 54 years; 58% men) were used as baseline examination. Incident stroke and incident MI cases were identified through regular follow-ups until the end of 2016. Multivariable linear and Cox regression models were used to explore associations. Mediation analyses were performed to assess direct effects, indirect effects, and the mediating role of androgens (total testosterone, dihydrotestosterone, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate) and SHBG in the association between sex (women versus men) and risk of stroke/MI. RESULTS: During a median follow-up of 8.6 years, 71 stroke and 63 MI events occurred. An inconsistent mediatory role was observed for total testosterone and dihydrotestosterone on the association between sex and risk of stroke. The direct effects were 0.42 (95% CI, 0.18-0.86) and 0.40 (95% CI, 0.17-0.82) and indirect effects were 2.48 (95% CI, 1.27-6.17) and 2.90 (95% CI, 1.67-6.35) for total testosterone and dihydrotestosterone, respectively. No mediating role was observed for other androgens or SHBG in relation to stroke, and neither androgens nor SHBG mediated the risk of MI. CONCLUSIONS: Our findings suggest that both total testosterone and dihydrotestosterone may have dimorphic mediating role with stroke risk, and that these associations may vary between men and women.