Abstract

THE DISCOVERY THAT PHARMACOLOGIC AGENTS CAN BE estrogenic in some tissues while antiestrogenic in others has led to intense interest in better understanding the mechanism by which molecular structure interacts with cellular receptors to selectively affect DNA transcription in different organs. Appreciation for these selective estrogen receptor modulators (SERMs) has inevitably given way to the hope of developing one that could confer all of the benefits of estrogen without any of its risks. The first widely used SERM, tamoxifen citrate, has been found to have the antiestrogenic effect of reducing risk for breast cancer as well as beneficial estrogenic effects on serum lipids and bone density in women. However, tamoxifen also has the undesirable antiestrogenic effect of causing hot flashes and the undesirable estrogenic effects of increasing risk for endometrial cancer and venous thromboembolism in women. Because raloxifene hydrochloride, a secondgeneration SERM, has been shown to increase women’s bone density without increasing risk for endometrial cancer, results of clinical trials designed to study its protective effects against breast cancer have been eagerly awaited. In this issue of THE JOURNAL, Cummings and colleagues report results from a large, well-designed, randomized controlled trial (RCT), the Multiple Outcomes of Raloxifene Evaluation (MORE), which show that raloxifene significantly reduced the risk for estrogen receptor–positive breast cancer among postmenopausal women with osteoporosis. These findings, as well as the finding that raloxifene does not cause endometrial hyperplasia, provide a welcome confirmation of what was anticipated on the basis of prior human and animal studies. Although clinicians need to be cautious in generalizing from the findings of the MORE study, which lasted only 3 years and included only women with low bone density, the results do suggest that raloxifene may be a welcome alternative for women who are considering estrogen therapy for treatment or prevention of osteoporosis but who fear the increased risk for breast or endometrial cancer associated with estrogen. In addition to interest in SERMs as a way to treat osteoporosis and prevent breast cancer, there is avid interest in determining whether SERMs may someday prove superior to exogenous estrogen after menopause for the multitude of reasons for which estrogen is now prescribed. One of the greatest expected benefits of estrogen is the primary prevention of ischemic heart disease (IHD), the leading cause of death among women in the United States. Because the data suggesting a substantial reduction in risk for IHD among women who use estrogen emerged from observational studies rather than from RCTs, these effects have not been universally accepted. Although one RCT has clearly shown estrogen to have a beneficial effect on serum lipid levels, women in that study were not followed up long enough to measure the effects of estrogen on IHD risk. Of greater concern is a recent large and well-designed RCT of postmenopausal women with preexisting IHD that failed to show a protective effect of estrogen against subsequent ischemic events, despite affecting lipid levels in the same positive manner as shown in the previous trial. These disappointing findings have increased suspicion that some of the previously reported cardioprotective effects of estrogen may have been due to uncontrolled bias (eg, that women who chose to take estrogen were at lower risk for heart disease for other reasons or that women who became ill discontinued taking estrogen). Fortunately, several large RCTs designed to help clarify the role of estrogen in preventing IHD (including the Women’s Health Initiative in the United States) are currently under way. Evidence suggests that raloxifene, like tamoxifen, lowers women’s total and low-density lipoprotein cholesterol levels in a manner similar to estrogen but does not increase high-density lipoprotein cholesterol levels as estrogen does. Since the extent of cardioprotective effects of estrogen is currently in question, physicians should not assume that SERMs have cardioprotective effects solely because they have estrogenlike effects on lipid levels. Furthermore, the nonlipidrelated cardioprotective effects of estrogen have not been demonstrated for the SERMs. In fact, results of a study of raloxifene in menopausal monkeys showed no cardioprotective effect. The effect of estrogen and SERMs on cognitive function is yet another area of major interest. Although there is evidence

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