A Review of the Relationships Between Endogenous Sex Steroids and Incident Ischemic Stroke and Coronary Heart Disease Events

For decades, it has been recognized that men have a higher age-adjusted risk of ischemic cardiovascular (CVD) events compared to women, thus generating hypotheses that sex steroids contribute to CVD risk. Potential mechanisms include genomic and non-genomic effects of sex steroids as well as mediation through classic CVD risk factors and obesity. However, results from randomized studies suggest that sex steroid supplementation in men and women do not result in improved CVD outcomes and may increase CVD risk. In contrast, prospective observations from endogenous sex steroid studies, i.e. among participants not using sex steroids, have suggested the opposite relationship. We reviewed the findings of prospective observational studies in men (17 studies) and women (8 studies) that examined endogenous sex steroids and CVD risk. These studies suggested a lack of association or that lower levels of testosterone or dihydrotestosterone are associated with higher CVD risk in both men and women. Higher, rather than lower, estradiol levels were associated with higher CVD risk in women. There were several significant gaps in the literature. First, it is unclear whether more sensitive measures of sex steroid levels might detect significant differences. Second, there are few prospective studies in women. Similarly, no studies report outcomes for high-risk groups such as African-Americans and Hispanics. Finally, few studies report upon ischemic coronary disease as opposed to ischemic stroke separately, although relationships between sex steroids and CVD may vary by vascular bed. Future investigations need to examine high risk groups and to distinguish between subtypes of CVD.