The role of estrogens in cardiovascular disease in the aftermath of clinical trials.

The effects of estrogens on reproductive tissues and climacteric symptoms are unambiguous. However, their effects on other tissues and, in particular, the cardiovascular system remain controversial. In general, premenopausal women are protected from coronary heart disease (CHD) compared with aged-matched men but this ;female protection' appears to be lost after menopause, suggesting beneficial effects of female sex hormones on the cardiovascular system. This view has been supported by observational studies showing that estrogen replacement therapy (ERT) is associated with a 30% to 50% decrease in CHD risk in postmenopausal women. Nevertheless, randomized clinical trials in postmenopausal women, with or without pre-existing CHD, have found no benefits to combined hormone replacement therapy (HRT). A possible explanation for these apparently contradictory findings may relate to the divergent effects of estrogens depending on the state of the vascular endothelium. It has been suggested that estrogens may prevent the development and early progression of atherosclerosis by contributing to the maintenance of endothelial health but may have a neutral or negative effect on a dysfunctional endothelium or on advanced atheromatous lesions. Furthermore, it is possible that estrogens have adverse effects on other cardiovascular risk factors such as thrombosis and inflammation. It is also conceivable that a decline in vascular estrogen receptor expression with advancing age, through methylation of the estrogen receptor promoter, prevents postmenopausal women from deriving the beneficial cardiovascular effects of estrogens. In conclusion, estrogens possibly prevent the development of atherosclerosis through favourable effects on an intact endothelium, but once the vascular endothelium is damaged, the prothrombotic and possibly proinflammatory effects of estrogens are likely to predominate and prove harmful.