The pill and the pendulum.

Isaac Schiff, MD T article by Freeman et al1 in this issue of the Journal, “Symptoms Associated With Menopausal Transition and Reproductive Hormones in Midlife Women” (see p. 230), highlights perhaps the most prevalent menopausal accompaniment, namely, hot flushes. The most effective treatment that provides symptom relief is estrogen therapy. A brief history of the role estrogens have played in the health care of women will illuminate the controversy of whether or not to prescribe estrogens. The paper suggests also that some symptoms such as depressed mood will decrease as women progress past menopause. The modern medical romance with the hormone was probably signaled by Robert A. Wilson’s 1966 tome, Forever Feminine.2 Not only were estrogens touted early on to alleviate hot flushes, they were also seen as dispatching—forever! —the multiple maladies of aging. In short, estrogens became the long sought after, no longer legendary fountain of youth! Given the times, the medical audience for these thoughts comprised men predominantly. On top of that, the 1960s data lent themselves to the suggestion that if women suffered fewer heart attacks than men before age 50, but after that women began to catch up, the causality was “obviously” related to the lack of protection provided by ovarian estrogens. The follow-up logic called for prescribing estrogens for men. A further excursion using the same logic suggested that if a little bit were good, a lot of estrogens would be even better! Thus, the Coronary Drug Project3 was initiated wherein men who already had heart disease were given either a placebo, or conjugated estrogens, or some other regimen. The study was carefully designed and carried out. However, after 18 months, the code had to be broken because one group had gotten into trouble—the group given high-dose estrogens. What is truly sad is that women—for whom estrogens are the most widely prescribed drug (if one includes the birth control pill)—had to wait until 1998 for a comparable study.4 The gender discrimination defines an unforgivable moment in American medicine. Until the early 1970s, estrogens were being prescribed for women in an aggressive manner—until, that is, December of 1975,5,6 when two articles were published back to back in The New England Journal of Medicine showing an increased risk for endometrial cancer. It was soon demonstrated that if one added progestins to the estrogen recipe, the risk for endometrial cancer was eradicated. Nevertheless, a decline in estrogen prescriptions resulted, similar to what was found after the publication of the Women’s Health Initiative (WHI) in July of 2002.7 At about the same time, in the mid-1970s, one also started to see heart attacks in young women where they were never seen before. These occurred among women who were on the birth control pill and were smokers. It took a rather brave patient or a courageous health care provider for hormones to be prescribed by the late 1970s. With estrogens prescribed in lower doses, the 1980s and 1990s resurrected the promise of multiple hormone benefits. In the 1980s, through studies such as the Harvard Nurses’ Health Study,8 it was demonstrated that women who took estrogens gained significant protecSee related article on page 230.