Postmenopausal Hormone Therapy and the Risks of Coronary Heart Disease, Breast Cancer, and Stroke

The principal findings are briefly reviewed from the Women's Health Initiative trials of the most commonly used postmenopausal hormone regimens in the United States-conjugated equine estrogens and these same estrogens plus medroxyprogesterone acetate. A more detailed review is presented for three major clinical outcomes: coronary heart disease (CHD), the primary trial outcome for which a major benefit was hypothesized; invasive breast cancer, the primary safety outcome for which some adverse effect was expected; and stroke which surfaced as an important adverse effect with both regimens, and one that is influential in decisions concerning the continued use of postmenopausal estrogens alone. The review for these outcomes includes an update on interactions of treatment effects with study subject characteristics and exposures and with prerandomization biomarker levels. It also includes a focus on timing issues that are important to the understanding of treatment effects. Specifically, with combined estrogen plus progestin, CHD risk was elevated early with the elevation dissipating after a few years of treatment, whereas breast cancer elevations increased during the treatment period, and climbed to about a threefold increase following 5 years of adherence. Importantly, breast cancer risk elevations appear to be higher among women who initiate treatment at the menopause, or soon thereafter, compared with women having a longer gap time. Stroke effects, on the contrary, did not seem to vary appreciably with these timing issues. The adverse effect was evidently localized to ischemic strokes, for which there was an approximate 50% increase with either regimen. The rather limited knowledge concerning the biomarkers and biological pathways that mediate the hormone therapy effects on these diseases is also briefly reviewed.