Myocardial infarction during menses: lessons from trials and errors.

The history of changes in our beliefs about the effect of estrogen on the risk of coronary disease teaches several important clinical lessons. In the early 1960s, the simple facts that endogenous estrogen levels are higher in premenopausal women than in postmenopausal women or in men, and that premenopausal women rarely experience myocardial infarction, promoted the belief that treatment with estrogen might reduce the risk of coronary heart disease. About this time, it also became clear that estrogen treatment improves the lipoprotein profile, increasing high-density lipoprotein cholesterol and lowering low-density lipoprotein cholesterol levels. Based on this evidence, the National Institutes of Health conducted a large randomized trial of the effect of estrogen therapy on the risk of coronary events (1). About 8700 men with previous myocardial infarction were assigned randomly to five cholesterol-lowering drugs (including two doses of conjugated estrogen) or placebo. The estrogen arms were stopped prematurely because of an increase in the risk of venous thromboembolic events and substantial adverse effects. In the 1980s, there was renewed interest in estrogen for the prevention of coronary heart disease when several large observational studies suggested that the risk was lower in women who had used postmenopausal estrogen than in those who had not (2). Subsequently, multiple case-control and cohort studies reported a 30% to 50% lower risk among women taking postmenopausal estrogen or estrogen plus progestin compared with nonusers (3). Concurrently, small randomized trials also demonstrated that treatment with estrogen prolongs treadmill exercise time among women with coronary heart disease, prevents coronary vasoconstriction in women with atherosclerosis, and retards progression of coronary atherosclerosis in animals (4). Recently, however, large randomized controlled trials have found that postmenopausal estrogen either has no overall benefit (5,6) or increases the risk of cardiovascular events (7), raising questions about why the findings of the observational studies appear to have been wrong. It may have been that estrogen users, even before beginning treatment, are healthier and have lower cardiovascular risk than do nonusers (8). Although many of the observational studies attempted to adjust statistically for differences between women who used estrogen and those who did not, some important variables may not have been measured. For example, studies that adjusted for socioeconomic status, a major predictor of risk of coronary heart disease, did not find an association between estrogen use and lower risk (9). Were the findings of studies showing that estrogen improves lipoprotein levels, prevents vasoconstriction, and retards atherosclerosis also erroneous? These effects have been demonstrated in randomized trials, reducing the likelihood of baseline differences between estrogen users and nonusers (4). Some of the beneficial effects may occur only with acute treatment at pharmacologic doses. Perhaps estrogen does not reduce the risk of coronary heart disease because the effects of estrogen differ with chronic and acute treatment. In this issue of the Journal, Hamelin et al. (10) present data on 27 premenopausal women admitted with the diagnosis of myocardial infarction or unstable angina. The ischemic event occurred during the first 6 days of the menstrual cycle (menstrual phase) in 19 women and on days 7 to 14 (follicular phase) in 8 women. No events occurred in the last half (luteal phase) of the cycle (P 0.00001). Because endogenous estradiol levels decline from the highest at midcycle to the lowest during menses, the authors concluded that acute declines in estrogen level might increase the risk of ischemic events, perhaps by effects on local vasoactive substances such as endothelin-1 and endothelium-derived relaxing factor (nitric oxide). Although a small observational study, the findings are interesting because they suggest that acute changes in estrogen levels may be more important than stable absolute levels, and that women develop tolerance to coronary effects of estrogen over the course of a few days or that homeostatic systems somehow downregulate the effects of estrogen with chronic exposure. The development of tolerance to the vasodilatory effects of nitroglycerin is a classic example of how acute exposure to a drug can differ from chronic exposure. This is a particularly relevant example, because acute estrogen exposure results in local production and release of endotheliumderived relaxing factor, a potent arterial vasodilator that is chemically identical to nitric oxide (4). Thus, acute treatment might result in coronary vasodilation, and acute withdrawal might lead to vasoconstriction and coronary ischemia. Acute treatment with estrogen prolongs the length of time that women with coronary disease are Am J Med. 2003;114:611– 612. From the Women’s Health Clinical Research Center, University of California, San Francisco, and the San Francisco VA Medical Center, San Francisco, California Requests for reprints should be addressed to Deborah Grady, MD, MPH, Women’s Health Clinical Research Center, University of California, San Francisco, Box 0739, 1635 Divisadero Street, Suite 600, San Francisco, California 94115, or dgrady@itsa.ucsf.edu.