Selective Estrogen Receptor Modulators Offer A Safer Alternative than Hormone Replacement Therapy to Postmenopausal Women

Selective Estrogen Receptor Modulators (SERMs) Eliminate Risk of Breast Cancer Associated with Hormone Replacement Therapy But Preserve Many Health Benefits of Estrogen

Tissue-Specific Estrogenic and Antiestrogenic Activity of SERMs Provide Opportunities for Individualized Treatment of Menopause-related Adverse Symptoms, Health Risks and Diseases

As scientific evidence mounts linking Hormone Replacement Therapy (HRT) to breast cancer and other illnesses, a class of drugs called Selective Estrogen Receptor Modulators (SERMs) is emerging as a safer and more versatile alternative to prevent and treat the symptoms and complications of menopause. Findings in a recent study to be published in the January 1, 2003 print issue of CANCER – and available online December 18, 2002 via Wiley InterScience – indicate that SERMs may be the preferred choice to HRT by mitigating the risk of breast cancer but maintaining many of the therapeutic benefits. SERMs act at the level of the estrogen receptor but appear to have either estrogenic or antiestrogenic effects depending on the tissue. Because of this tissue specific activity, SERMs are potentially a versatile drug class that offers the prospect of developing individualized, targeted treatments. SERMs, the authors declared, “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.”

For decades now HRT in estrogen-alone or combined estrogen-progesterone forms has been used by millions of women to alleviate the unwanted symptoms associated with menopause, such as flushing, mood swings, and night sweats. HRT also prevents such postmenopausal complications as urogenital atrophy, osteoporosis, and osteoporotic fractures; it prolongs life expectancy and protects women from colorectal cancer, neurocognitive dysfunction, and Alzheimer’s disease. However, HRT has been linked to a significant and growing number of adverse effects. The observed risk of breast cancer with HRT has long alarmed patients and physicians and dissuaded many from using or prescribing HRT. With new revelations from the Women’s Health Initiative (WHI) trial about the increased risk of coronary artery disease and strokes, many women have stopped using HRT altogether. This has left scientists searching for a safer alternative.

Diamanti-Kandarakis et al reviewed the literature to investigate the risks and benefits of HRT and SERMs. 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.

HRT’s proven efficacy to prevent osteoporosis, osteoporotic fractures, and specific cancers and alleviate the vasomotor and central nervous system disturbances of menopause are its greatest benefit. However, recent studies have also proven its substantial risks. Meta-analyses of clinical data to date have demonstrated that there is a significant increased risk of breast cancer by 2.3% per year of use. WHI demonstrated a more substantial 26% increased risk of breast cancer after 5 years of HRT. Other studies have demonstrated that progesterone in combined HRT forms likely increases the risk of breast cancer even further. In contrast SERMs are actually protective against breast cancer. Tamoxifene has long been used to treat estrogen-receptor positive breast cancer and shown to be protective in women at high risk for breast cancer. Raloxifene has also been shown to be protective against breast cancer.

SERMs’ potential as the next generation in menopausal treatment is that it exhibits different effects depending on the tissue; this is likely due to the way the SERM interacts with estrogen receptor(ER)a and ERb subtypes and the ER subtype distribution. Studies have found, for example, that the SERM Tamoxifene exhibits antiestrogenic effects in the breast thus inhibiting growth of breast tumor cells that have estrogen-receptors. In the uterus Tamoxifene is estrogenic and stimulatory, thereby increasing the risk of endometrial cancer. Raloxifene, another SERM, has been shown to increase bone mineral density in postmenopausal women but has antiestrogenic effects on both breast tissue and endometrial tissue. Both SERMs 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. SERMs exacerbate vasomotor instability such as hot flashes but have unknown effects on the central nervous system.

“The demonstration that SERMs 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 SERM versatility is that there is now potential “to create an arsenal of SERMs 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 conclude, “a major goal of pharmacologic research is the discovery of novel SERMs that can retain estrogenic effects on bones, lipids, and the central nervous system while acting as antiestrogens at the breast and endometrium.”