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

Abstract

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.

Testosterone Concentrations and Cardiovascular Autonomic Neuropathy in Men with Type 1 Diabetes in the Epidemiology of Diabetes Interventions and Complications Study (EDIC)

“…However, consistent associations were not observed between testosterone and R-R variation or between testosterone and CAN. Although previous studies have reported associations between exogenous testosterone administration and CVD risk [26] and between low endogenous testosterone concentrations and CVD risk [27], testosterone is unlikely to influence CVD outcomes through CAN. The peripheral nervous system expresses both classic and non-classic steroid receptors, and rat studies suggest that androgens can affect neuron proliferation and myelin protein expression [28].…”

“…However, consistent associations were not observed between testosterone and R–R variation or between testosterone and CAN. Although previous studies have reported associations between exogenous testosterone administration and CVD risk [26] and between low endogenous testosterone concentrations and CVD risk [27], testosterone is unlikely to influence CVD outcomes through CAN.…”

Testosterone and cardiac mass and function in men with type 1 diabetes in the Epidemiology of Diabetes Interventions and Complications Study (EDIC)

“…Separate multivariable linear regression models were built to estimate the associations between testosterone concentrations (independent variable) at EDIC year 10 and continuous CMR measures (dependent variable) at EDIC year 14/15. Due to previous reports modelling a nonlinear relationship between testosterone and CVD events, we used quantile regression to determine whether the effect of testosterone was homogeneous among quantiles of CMR; the effects were similar in the top and bottom quantile for each CMR measure. We did not assess whether testosterone concentrations consistent with hypogonadism were associated with CMR measures as only 26 participants had total testosterone concentrations <10·4 nmol/l, a cutpoint commonly used to define hypogonadism .…”

Associations of sex hormones with components of insulin-glucose homeostasis

“…(2015) при изучении восьми проспективных обсервационных исследований у женщин резюмировали, что у женщин высокий эстрадиол чаще, чем низкий, был ассоциирован с сердечно-сосудистым риском. Авторы считают, что механизм действия половых гормонов, в частности эстрадиола, может быть опосредован геномными, негеномными эффектами, воздействием на общепринятые и другие, менее изученные факторы риска [30]. Предполагается, что действие эстрогенов на сосуды, по крайней мере отчасти, зависит от выраженности атеросклероза.…”