Estrogen replacement therapy and cardioprotection: mechanisms and controversies

Abstract

Epidemiological and case-controlled studies suggest that estrogen replacement therapy might be beneficial in terms of primary prevention of coronary heart disease (CHD). This beneficial effect of estrogens was initially considered to be due to the reduction of low density lipoproteins (LDL) and to increases in high density lipoproteins (HDL). Recent studies have shown that estrogens protect against oxidative stress and decrease LDL oxidation. Estrogens have direct effects on the arterial tissue and modulate vascular reactivity through nitric oxide and prostaglandin synthesis. While many of the effects of estrogen on vascular tissue are believed to be mediated by estrogen receptors a and ß, there is evidence for immediate non-genomic effects. The role of HDL in interacting with 17ß-estradiol including its esterification and transfer of esterified estrogens to LDL is beginning to be elucidated. Despite the suggested positive effects of estrogens, two recent placebo-controlled clinical trials in women with CHD did not detect any beneficial effects on overall coronary events with estrogen therapy. In fact, there was an increase in CHD events in some women. Mutations in thrombogenic genes (factor V Leiden, prothrombin mutation, etc.) in a subset of women may play a role in this unexpected finding. Thus, the cardioprotective effect of estrogens appears to be more complicated than originally thought and requires more research.

Biochemical Marker Reference Values across Pediatric, Adult, and Geriatric Ages: Establishment of Robust Pediatric and Adult Reference Intervals on the Basis of the Canadian Health Measures Survey

“…On the other hand, HDL declined with age in males but actually increased in females. These results support the role of estrogen in modulating HDL, a mechanism thought to explain, in part, the protection against cardiovascular disease in premenopausal women (26 ).…”

Menopause, Estrogens, and Endothelial Dysfunction: Current Concepts

“…7 More recently, studies have also demonstrated an antioxidant effect by estrogen, reducing LDL oxidation in vivo and in vitro. 43 The direct effects of estrogen on the vascular system and which modulate the vascular tonus comprise 1) acute vasodilatation, increasing the synthesis and bioactivity of nitric oxide; 44,45 2) long-term modulation of vascular tonus, regulating the production of prostaglandins and expression of eNOS and the endothelin gene 46 ; 3) inhibition of endothelin-induced vasoconstriction 47 ; and 4) inhibition of sympathetic activity. 27 In addition to these actions on the vascular tonus, estrogen exerts an antiproliferative action on the vascular smooth layer.…”

Genistein Induces Estrogen-Like Effects in Ovariectomized Rats but Fails to Increase Cardiac GLUT4 and Oxidative Stress

“…1 Genistein, a phytoestrogen, binds to estrogen receptors, thereby exerting estrogenic effects, and has therefore been proposed as a natural alternative to estrogen replacement. 2 Evidence suggests that genistein exhibits a potency similar to that of 17b-estradiol (each administered at 100 mg=kg i.v.)…”