Atherosclerosis and estrogen replacement therapy

Abstract

Cardiovascular morbidity and mortality increase after menopause. There has been reluctance to use estrogen replacement therapy (ERT) for treating women with a high risk of cardiovascular disease because of adverse experience in two areas: (1) The Coronary Drug Project administered high doses of estrogen to male survivors of MI, which was associated with excess coronary and thromboembolic events. (2) Studies of OC use revealed an increased incidence of heart attacks among women over the age of 35 years who smoke. Eight case- control studies have examined the effect of estrogen replacement therapy on cardiovascular events; five have shown a protective effect. Eleven of 19 reports have found a protective effect. Ten of 11 cohort studies have found a protective effect. One randomized study (by Nachtigall et al) found a beneficial effect. Angiographic studies at the University of Tennessee/Baptist Memorial Hospital, Memphis have examined the relative risk for coronary artery disease for postmenopausal women relative to estrogen use. Cases with significant coronary stenosis were compared to controls. Estrogen use was reported by significantly fewer women with positive coronary angiograms. Logistic regression analysis showed that estrogen use had a statistically significant independent protective effect against coronary atherosclerosis. These observations have been confirmed by three subsequent studies. The same study group also examined the effect of estrogen replacement on survival of patients who underwent coronary arteriography at baseline. Of 23,190 patients undergoing arteriography, 2,268 women were eligible for long-term study. While patients who were initially free of coronary artery lesions did not have a significant reduction of mortality when given estrogen replacement, a significant reduction of all-cause mortality was observed in those groups with coronary artery disease who received estrogens. The cardiovascular protective effect of ERT has been attributed to an effect on serum lipoproteins. After menopause, serum HDL levels fall as LDL levels rise. Estrogen replacement therapy reverses this patter. The Lipid Research Clinics Trial initially suggested that the effect of estrogen replacement on cardiovascular events was associated solely with the effect on HDL cholesterol. Recent analyses of long-term followup data suggested that changes in HDL cholesterol accounted for no more than 33% of the reductions in CV events and that the relative reduction was greatest for women with pre-existing cardiovascular disease. To reduce the risk of endometrial cancer, most physicians prescribe progestins along with estrogens (HRT); this has the result of reducing the potentially favorable effect on HDL cholesterol. Few published studies have examined the effect of combination therapy on cardiovascular events. Two large observational studies have observed little difference in HDL levels between ERT- and HRT-treated groups over time. One small randomized study found fewer myocardial infarctions in women receiving HRT, and a recent observational study noted similar reduction of cardiovascular events regardless of whether ERT or HRT was used. In studies of surgically menopausal non-human primates, investigators have reported that both ERT and HRT retard the development of atherosclerosis and inhibit the uptake of LDL cholesterol by blood vessels. Evidence is growing that estrogens directly affect blood vessel walls by mechanisms not involving lipids. These include occupying specific estrogen receptors, increasing production of prostacyclin, inhibiting platelet function, and maintaining production of endothelial-derived relaxing factor, thus preventing coronary vasospasm.