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Atherosclerosis, hormone therapy, and outcomes in younger postmenopausal women: waiting for more answers.

C ardiologists are generally apprehensive about hormone therapy (HT) use in postmenopausal women. The 2011 update of the Guidelines on Prevention of Cardiovascular Disease (CVD) in Women classified HT as a class III intervention (Bnot useful/effective and may be harmful[) for primary or secondary preventionVin the same category as antioxidant supplements and folic acid. This across-the-board recommendation is based on early findings from the Heart and Estrogen/Progestin Replacement Study (secondary prevention) and Women’s Health Initiative (primary prevention) clinical trials, demonstrating a lack of efficacy and an increased incidence of coronary heart disease (CHD) events in older postmenopausal women treated with HT versus placebo. To many, it now seems that HT use for CVD prevention is a medical curiosity whose time has passed. Regardless, recently published data focused specifically on HT use in younger postmenopausal women challenge this thinking. In this edition ofMenopause, Shufelt et al present the results of a cross-sectional study within the Women’s Ischemia Syndrome Evaluation cohort, investigating the relationship between HT use, type of menopause (natural vs surgical), and coronary atherosclerosis as assessed by quantitative coronary angiography (computerized assessment of coronary angiographic images). This technique, which is not generally used in routine clinical practice, is reliable and reproducible, particularly in the setting of a core laboratory as used in this study. The investigators found that among women with natural menopause, those who initiated HT at a younger age had significantly lower coronary artery disease (CAD) severity as compared with HT never users (mean [SE] age-adjustedA,j6.23 [1.50]; P G 0.0001), whereas women who initiated HT at an older age demonstrated the same burden of CAD as never users. Of note, the most commonly used form of HT among these women (68% of the population) was unopposed estrogen. The investigators additionally found an association between HT use and fewer CVD events in the natural menopause subset (unadjusted hazard ratio [HR], 0.60; 95% CI, 0.41-0.88; P = 0.009), which became nonsignificant after adjusting for CAD burden. This suggests that HT use by younger postmenopausal women may have been protective against CVD events by mediating CAD burden. Among women with surgical menopause, no differences in CAD severity were noted among groups. However, this could be due to the relatively small size of the subgroup of HT never users, which had only 29 women (22% of the surgical menopause cohort). The small sample size of this subset makes interpretation of the data difficult. Although cross-sectional studies are not ideal for investigating epidemiological cause-and-effect relationships, the suggestion that HT use, and specifically unopposed estrogen use, in younger postmenopausal women may result in lower atherosclerotic burden and improved outcomes resonates in contemporary literature. In the recently published estrogen-alone component of the Women’s Health Initiative clinical trial, a subgroup analysis showed that after an average of 10.7 years, younger women (aged 50-59 y) with prior hysterectomy initially treated with conjugated equine estrogens versus placebo had a statistically significant lower risk of CHD (HR, 0.59; 95%CI, 0.38-0.90) andmyocardial infarction (HR, 0.54; 95% CI, 0.34-0.86), with a similar trend in all-cause mortality (HR, 0.73; 95% CI, 0.53-1.00). The findings of this subgroup analysis are consistent with the results published by Shufelt et al and set the stage for ongoing randomized clinical trials of HT use and atherosclerosis in younger postmenopausal women. Two such trials, Kronos Early Estrogen Prevention Study (KEEPS) and Early Versus Late Intervention Trial With Estradiol (ELITE), are ongoing: