The selective modulators act at the level of the estrogen receptor, but they appear to have either agonistic or antagonistic effects depending on the tissue. Because of the tissue-specific activity, they are a potentially versatile drug class that offers the prospect of individualized, targeted treatments. The authors wrote that the drugs "may ultimately provide women and their physicians with the ability to make safe and confident selections from a repertoire of medications that promise to expand life span and improve quality of life for women after menopause."

The observed risk of breast cancer with hormone replacement therapy has long alarmed patients and physicians and dissuaded many from using or prescribing the therapy. With new data from the Women's Health Initiative trial about the increased risk of coronary artery disease and strokes, many women have stopped using replacement therapy altogether. This has left scientists searching for a safer alternative.

In the current study, researchers reviewed the literature to investigate the risks and benefits of hormone replacement therapy and therapy with selective estrogen receptor modulators. The authors also examined their respective clinical and cellular effects on breast tissue to assess the potential of selective modulation of estrogen receptors to treat postmenopausal women.

The proven efficacy of hormone replacement therapy to prevent osteoporosis, osteoporotic fractures, and specific cancers, as well as to alleviate the vasomotor and central nervous system disturbances of menopause is its greatest benefit. However, recent studies have also proven substantial risk. Meta-analyses of clinical data to date have demonstrated that there is a significant increased risk of breast cancer by 2.3 percent per year of use. The Women’s Health Initiative demonstrated a more substantial 26 percent increased risk of breast cancer after five years of replacement therapy. Other studies have demonstrated that progesterone in combined replacement therapy probably increases the risk of breast cancer even further. In contrast, the selective modulators are actually protective against breast cancer.

In contrast, tamoxifene exhibits antiestrogenic effects in the breast, inhibiting growth of estrogen-receptor positive breast tumor cells. In the uterus tamoxifene is estrogenic and stimulatory, increasing the risk of endometrial cancer. Raloxifene has been shown to increase bone mineral density in postmenopausal women, but it shows antiestrogenic effects on both breast tissue and endometrial tissue.

Both tamoxifene and raloxifene have estrogenic effects on serum lipoproteins and coagulation. Raloxifene has been recently shown to reduce cardiovascular events but increase the incidence of thromboembolic events such as strokes. Selective estrogen receptor modulators increase vasomotor instability such as hot flashes but have unknown effects on the central nervous system.

"The demonstration that selective estrogen receptor modulators act in an estrogen agonistic or antagonistic manner, depending on the target tissue, suggests that this class of drugs may be invaluable in the prevention and/or treatment of menopausal morbidities," wrote the authors.

The value in their versatility is that there is now potential "to create an arsenal of modulators with individual combinations of tissue specificities, because this may enable the individualization of patient treatment according to a particular woman's risk factor and/or disease profile for each menopause-associated morbidity."

The authors concluded, "a major goal of pharmacologic research is the discovery of novel selective estrogen receptor modulators that can retain estrogenic effects on bones, lipids, and the central nervous system while acting as antiestrogens at the breast and endometrium."