Can women be identified that will derive considerable cardiovascular benefits from postmenopausal estrogen therapy

Few matters relating to the cardiovascular health of women at middle age and beyond have been more controversial than the question of whether estrogen therapy provides cardiovascular benefits. During the mid and late 1990s, animal model data and the results of observational studies contributed to the widely held belief that postmenopausal estrogen therapy provided major cardiovascular benefits. It was within that context of presumed understanding that three major randomized, prospective trials were planned and initiated. The first was the Heart and Estrogen/Progestin Replacement Study (1), which was followed in turn by the Estrogen Replacement Study (2) and the Women’s Health Initiative (WHI) (3). All three used oral conjugated equine estrogens (CEE), either alone or with medroxyprogesterone acetate (MPA). The Heart and Estrogen/Progestin Replacement Study enrolled older women (66.7 yr) that were symptomatic with coronary heart disease (CHD). The Estrogen Replacement Study evaluated the effect of CEE alone or in combination with MPA on women with angiographically documented CHD. Finally, the WHI enrolled women that were older than 67 yr. Taken together, those studies found no cardiovascular benefit of CEE or CEE plus MPA treatment. Each study, in fact, observed an increase in CHD events in the initial year of treatment. Unfortunately, many observers generalized those findings, which were based on older women or those with documented coronary disease, to all postmenopausal women irrespective of age or disease status. Over the past 5 yr, reassessment of the data from the WHI and other studies has led to an emerging appreciation that some groups of periand postmenopausal women may in fact derive cardiovascular benefits from hormone therapy. In this regard, much interest has focused on the timing hypothesis, which states that estrogens are atheroprotective if administered during the fatty streak to uncomplicated plaque stage of atherosclerosis progression but have null or deleterious effects if administered after plaques have become complicated by necrosis and inflammation (4). The timing hypothesis is supported in part by studies of monkey models and from recent reevaluation of data from the WHI. For example, in the CEE-only arm of the WHI, the hazard ratio for CHD among women aged 50–59 yr was 0.56 with a confidence interval of 0.30–1.03, whereas the hazard ratio for women aged 60–69 yr was 0.92 with a confidence interval of 0.69–1.23 (5). More recently, investigators assessed the effect of hormone treatment on coronary artery calcium scores among the 50to 59-yr-old women in the CEE-only arm of the WHI (6). Specifically, coronary artery calcium scores were determined for both the placeboand CEE-treated groups after 7.4 yr of treatment and 1.3 yr after the trial was completed. Presumably, the younger women on whom this study focused would have had minimal subclinical atherosclerosis when enrolled in the study. In fact, the coronary artery calcium scores (among the women that were at least 80% adherent to treatment) that were more than 0, 10 or more, and 100 or more had odds ratios of 0.64 (P 0.01), 0.55 (P 0.001), and 0.46 (P 0.001), respectively. Generally, this finding has been interpreted as indicating that CEE inhibited atherosclerosis progression among women in the 50to 59-yr age group. However, not all experts agree, because older age groups were not examined in the same analysis (e.g. Ref. 7). The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the impact of unopposed oral micronized estradiol on the progression of atherosclerosis in postmenopausal women. The investigators found that subclinical atherosclerosis progression [carotid artery intima media thickness (CIMT)] was significantly reduced in postmenopausal women randomized to receive oral micronized estradiol (8). The EPAT investigators subsequently reported additional findings that helped extend our understanding of the ways in which estrogen could affect the cardiovascular health of postmenopausal women. They reported, for example, that the proportion of oral micronized estradiol therapy’s atherosclerosis inhibitory effect was due to the changes in the lipid profile (9), concluding that