The WHI Estrogen-Alone Trial—Do Things Look Any Better? (2004)

OVER THE PAST HALF-CENTURY, A GROWING BElief among women and their physicians held that “replacing” the estrogen lost at menopause would prevent many of the manifestations of aging, including coronary heart disease (CHD), osteoporotic fractures, and a decline in cognitive and sexual function. This attractive and plausible view led to widespread use of hormone therapy after menopause in the era before randomized trials with disease end points were required for proving the effects of new drugs. Clinicians were drawn in by other accumulating lines of evidence for CHD benefit that were consistently favorable: observational studies showed less heart disease among women taking estrogen, pathophysiologic mechanisms provided biological plausibility, and clinical trials revealed improvements in blood lipid levels and other surrogate measures. A fateful bump in the road in the 1980s was the recognition that postmenopausal estrogen treatment was causing endometrial cancer. Although uncommon and usually curable, this cancer could be prevented by antagonizing the estrogen with a progestin, and several estrogen plus progestin combinations were explored in the search for one that preserved the benefits of estrogen. In the 1990s, after it was demonstrated that lipid effects remained largely favorable when conjugated estrogens were combined with medroxyprogesterone acetate (MPA), this particular estrogen plus progestin regimen became the most widely used in the United States for postmenopausal women with a uterus. In 1998, the Heart and Estrogen/progestin Replacement Study (HERS), the first major trial with disease event outcomes, surprised everyone by finding an increase in CHD events during the first year, and no overall cardiovascular benefit with longer follow-up, when estrogen plus progestin treatment was compared with placebo in 2763 women with prior coronary disease. This trial also found that estrogen plus progestin caused venous thromboembolism. Four years later, the Women’s Health Initiative (WHI) estrogen plus progestin trial was stopped early due to net harm. Among 16608 healthy postmenopausal women with a uterus, estrogen plus progestin caused an increased risk of coronary events, stroke, breast cancer, and pulmonary embolism. A “global index” found these harmful outcomes to outweigh the decreased risk of hip fracture and colon cancer (TABLE). The net harm was markedly accentuated by a subsequent report of a significant 2-fold increase in dementia among WHI women older than 65 years. The findings of these 2 large trials led the US Food and Drug Administration to require a boxed warning of harm and to recommend that estrogen preparations not be used to prevent CHD or considered first-line therapy for prevention of osteoporosis. Medical organizations altered their guidelines to recommend that hormone therapy not be used for preventing disease, and when used for treating symptoms that it be at the lowest dose and for the shortest time possible. Many women using postmenopausal hormone therapy attempted to stop taking these agents, and sales of Premarin (which had been the most-prescribed drug in the United States) dropped precipitously. In this issue of THE JOURNAL, the WHI investigators report findings from the eagerly awaited WHI estrogenalone trial in 10739 healthy women with hysterectomy who were randomly assigned to receive unopposed conjugated estrogen or placebo. Now that these important results are available, do things look any better? As in the HERS and WHI estrogen plus progestin trials, the main hypothesis of the WHI estrogen-alone trial was that hormone therapy would reduce the risk of CHD. Once again this did not happen, although early CHD harm, which may be a consequence of progestin, appeared less pronounced. Given the absence of evidence in all 3 trials that these hormone regimens prevent CHD in these populations (Table), it is now clear that the previously available evidence was misleading. Observational studies were probably confounded by the tendency of healthier women to seek and comply with hormone treatment, and surrogate end point trials probably addressed the wrong mechanisms. This is an excellent illustration of the evidence-based medicine premise that disease end point trials are indispensable for examining the benefits and harms of treatments.