C ardiovascular disease is the major cause of death among both men and women in developed countries. Coronary artery disease, the single most important component of cardiovascular disease, is responsible for about one quarter of all deaths. It is well recognized that, at all ages, women are relatively protected against cardiovascular disease in comparison with men, and many observational studies have suggested that estrogen treatment of postmenopausal women significantly reduces cardiovascular risk (1). Further, the Postmenopausal Estrogen/Progestin Intervention (PEPI) Study (2), which assessed the effect of hormonal therapy on cardiovascular risk factors over a 3-yr period, showed beneficial effects on lipoproteins in all treatment groups and concluded that the best regimen for women with an intact uterus was estrogen plus micronized progesterone, and the best regimen for women without a uterus was unopposed estrogen. However, the recently concluded Heart Estrogen/ progestin Replacement Study (HERS) found no significant evidence of a clinical benefit of hormonal therapy in women with established coronary artery disease (3). The question of whether such therapy is useful in women as primary prevention against cardiovascular disease is being addressed by the Women's Health Initiative, the results of which will not be known for several more years (4).Although in men estrogens are produced in significant quantities by local tissue aromatization of androgenic precursors from the testes and adrenal glands (5), there has been relatively limited study of the biological role of these hormones or their clinical implications. An investigation conducted 25 years ago into the cardiovascular effects of estrogen administration in men after myocardial infarction, the "Coronary Drug Project" showed an excess of deaths and recurrent infarction in the treatment group. This trial, which employed high doses of conjugated equine estrogens, was subsequently abandoned, and the subject has not been studied in detail since (6). Data gathered over the last quarter century on the epidemiology of cardiovascular disease, the mechanisms of actions of estrogens in women and men, and the biological role of endogenously produced estrogens in men, suggest that it might be time to re-open the Coronary Drug Project file, and re-assess the potential for estrogen therapy in men. Newer approaches to treatment and an ability to identify more precisely individuals at risk of coronary heart disease (CHD) may lead to new clinical applications for this group of hormones. Evidence of a role for endogenous estrogens in men Endogenous estrogens, lipoproteins, and glucose metabolism.There is now compelling evidence that endogenous production of estrogens in men plays an important role in cardiovascular health and disease. Physiological levels of estrogen have been reported to play a role in influencing plasma lipoprotein concentrations in men. When selective estrogen deficiency was induced in young men by administration of combined drug therapy with a GnRH ant...