Estrogen Plus Progestin, Benefits and Risks: The “Women’s Health Initiative” Trials

The increase in coronary heart disease (CHD) in postmenopausal women continues unabated. Hormone replacement therapy given in an effort to contain this potentially fatal disease has had its successes and failures, but heretofore has not been fully evaluated. Hormone replacement therapy was first advocated in the 1940s for the treatment of menopausal symptoms. Subsequently several observational studies suggested cardiovascular benefits for women who were on hormone therapy. However no high risk clinical trials had been done until the early 1990s, when through the National Institutes of Health, 40 centers in the United States were recruited to enroll the largest number of postmenopausal women in a hormone study. The Women’s Health Initiative (WHI) was a large randomized placebo-controlled trial investigating the effects of estrogen plus progestin on specific potential long-term benefits versus risks. The Heart and Estrogen/progesterone Replacement Study (HERS), an “arm” of the WHI trial, was a randomly compared estrogen plus progestin trial given continuously to 16 000 women who were previously healthy and postmenopausal. A few women that were included in this “arm” had a history of coronary disease but had to have been asymptomatic for 6 months prior to enrollment. At the end of the study, there were no cardiovascular benefits and in fact, there was a significant increased risk in coronary events, primarily nonfatal myocardial infarctions, nearly 25% over 5+ years of follow-up. There was an increase in strokes, deep vein thrombosis, pulmonary emboli, and endometrial cancer. Breast cancer was a major risk after 4 years follow-up. An unusual finding was the increased requirement for gallbladder surgery. Two case presentations highlight key issues involved in hormone replacement therapy in women. Case 1