Clinical Review

SERMs: Protection without worry?

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The fear of breast cancer—and its link to estrogen use—causes many women to decline or discontinue estrogen replacement therapy. SERMs offer many of the same benefits with fewer risks, broadening the options for protecting long-term health.



Key points
  • Among ER-positive breast cancer patients treated with tamoxifen for 5 years, the annual recurrence rate is cut in half and the annual death rate is reduced by 28%.
  • Tamoxifen has been shown to reduce the incidence of breast cancer by 44%, 51%, and 55% in women aged 35 to 49, 50 to 59, and 60 and older, respectively.
  • Raloxifene mimics the effects of estrogen on the skeleton and lipids, but acts as a complete estrogen antagonist in the breast and uterus.
  • Recent data indicate that 4 years of raloxifene therapy reduces the risk of all ER-positive breast cancers by 72% compared with placebo.
  • The ideal candidate for raloxifene is a postmenopausal woman with osteopenia or osteoporosis, no increased risk of thromboembolism, and few or no vasomotor symptoms.

Although it was initially considered a female sex hormone, estrogen is now recognized as a systemic substance that affects every organ system and appears to be important for both men’s and women’s health.1-4 At puberty, elevated circulating estrogen levels transform girls into young women and shape their feminine fig-ures. In boys, estrogen is important in the closure of the epiphyseal plates to arrest postpubertal growth and support bone health throughout life. It also may have beneficial actions on the male cardiovascular system.2

As a systemic hormone, estrogen is important in women for the health of the skeleton, the heart, the integuments, and the brain.1,3 Women who suffer the loss of estrogen through surgery, illness, or early menopause often are advised to consider estrogen therapy to protect these organs from premature failure.

Unfortunately, estrogen replacement therapy (ERT) is a double-edged sword, with significant benefits in some organs and significant risks in others. ERT protects against vasomotor symptoms, urogenital atrophy, osteoporosis, cardiovascular disease, and perhaps Alzheimer’s disease.1,3 Unfortunately, it also increases the risk of venous thromboembolic events, recurrent myocardial infarction and cardiac death5 (in diseased hearts), and cancers of the uterus and breast.4

Of the many diseases that impact the lives of American women, none is more feared than breast cancer, the most common cancer in females and the second leading cause of female cancer mortality.6 The fear of this disease causes many women to decline or discontinue ERT, a decision that can profoundly affect their long-term health.7 Hence, the controversy regarding ERT centers on weighing the risk-benefit balance, i.e., trying to select patients who are more likely to benefit from the hormone and less likely to suffer from its adverse effects.

Physicians—particularly gynecologists who devote their care exclusively to women’s health—have longed for the ideal estrogen that will impart all of the benefits without the risks. This ideal estrogen would relieve women of vasomotor and urogenital symptoms and prevent the dire consequences of osteoporosis, accelerated atherosclerosis, neurogenic deficit, and collagen loss from the skin, without increasing the risk of cancer and thromboembolic phenomena. Some experts believe this ideal may be found in the new class of compounds referred to as selective estrogen receptor modulators (SERMs). Although several SERMs with desirable estrogenic properties are available, none is ideal. Nevertheless, this new class of estrogenic substances—with multiple beneficial effects and fewer risks—represents an important pharma-cotherapeutic advance in the care of postmenopausal women.


Tamoxifen citrate (Nolvadex; AstraZeneca, Wilmington, Del) has wide clinical applications in the treatment and prevention of breast cancer. In 1980, tamoxifen was approved by the FDA for postmenopausal women with node-positive breast cancer and for premenopausal women with estrogen-receptor (ER) positive advanced breast cancer. In 1990, the FDA extended the approval of tamoxifen to include pre- and postmenopausal women with node-negative, ER-positive breast cancer.

In patients with node-positive breast cancer, the 10-year-survival rate improves from 50% in control subjects to 61% in patients treated with tamoxifen for 5 years. Similar improvements in survival have been reported with tamoxifen therapy in node-negative breast cancer patients. After 5 years of tamoxifen therapy and a median follow-up of 10 years, the reduction of breast cancer recurrence and death with tamoxifen treatment compared with placebo are 47% and 26%, respectively.8

For women with ER-positive tumors (about 70% of all breast cancers), tamoxifen therapy of at least 1 year’s duration results in statistically significant recurrence and survival benefits. These results increase with the duration of treatment up to 5 years. Among ER-positive women treated with tamoxifen for 5 years—the optimal length of therapy—the annual recurrence rate is cut in half and the annual death rate is reduced by 28% (Figure 1).9 Treatment beyond 5 years does not accrue additional benefits and is associated with increased adverse events.10 Tamoxifen has little effect on animal tumors and ER-negative tumors in cell cultures and confers little or no benefit to women with ER-negative tumors.9