The search for the most optimal post-menopausal hormone replacement therapy (HRT) is rapidly becoming one of the most widely pursued ventures in modern medicine. A few basic goals should be considered. The optimal agent should prevent cardiovascular disease; it should prevent osteoporosis and encourage osteoblastic proliferation; it should not have an adverse effect on target tissue; and last, but not least, it should be effective in relieving the patient's symptoms.

A typical scenario is a woman who makes an office visit because she is experiencing perimenopausal symptoms such as vasomotor events or sleep dysfunction. She may already be knowledgeable about HRT and have formed strong opinions about whether she would be interested in receiving this therapy. Added to the dilemma is the fact that many women perceive HRT as “unnatural.”¹ Women may pursue health food supplements as an alternative to traditionally prescribed therapies, because these supplements are perceived as natural and thereby free of adverse effects. These women may already have purchased some of these products before visiting the family physician's office.

How do family physicians address this issue? First of all, how convinced are we that traditional HRT does what it is purported to do without adverse effects? Second, how convinced are we that nontraditional therapies are of unproved benefit or harmful to the patient? Third, have we done a careful review of the woman's risk of breast cancer, cardiovascular disease and osteoporosis?

The bottom line is that what really matters more than risk is the patient's perception of benefit or harm. Even if the woman has numerous risk factors that may affect her long-term health and longevity, she is not going to take HRT unless she believes it will do her no harm. Therein lies the dilemma. The fear of breast cancer, whether overestimated or not, is causing many women to decline HRT. Discussions that center on the fact that more women die of cardiovascular disease than breast cancer may not convince the patient that she only has a low risk of developing breast cancer while receiving HRT. Therefore, before a discussion of the pros and cons of HRT is initiated, the woman's fears and concerns have to be addressed rationally and compassionately. Because the patient may desire only relief of undesired symptoms, she may not view the entire portfolio of preventive health options that HRT affords.

The article by Scott and associates² reviews the unique properties of the selective estrogen receptor modulators (SERMs) that mimic the beneficial effects of estrogen on the cardiovascular and skeletal system while minimizing adverse effects on other tissue such as breast. SERMs are synthetic compounds that bind with high affinity to estrogen receptors and act as either estrogen agonists or antagonists. They are called “designer” drugs, because they are designed to target certain tissue receptors and avoid others.

The epithelium of the breast is stimulated by estrogen. Whether this stimulation induces abnormal epithelial growth is a subject of debate. A direct cause-and-effect relationship between estrogen and development of breast cancer has not been established. Tamoxifen (Nolvadex), classified as an estrogen antagonist on breast tissue, has been approved for the treatment of early and advanced breast cancer and for the prevention of breast cancer. Studies have demonstrated significant reductions in breast cancer recurrence and mortality in survivors who used adjuvant tamoxifen therapy.³ The downside of tamoxifen therapy is that it acts as a partial estrogen agonist in endometrial tissue, thus only partially blocking the stimulatory effect of estrogen on the endometrium.

Another SERM, raloxifene (Evista), is designed to mimic the effect of estrogen on the skeletal structure and serum lipids but, unlike tamoxifen, acts as a complete estrogen antagonist in the breast and endometrium. To date, there is no convincing evidence that raloxifene stimulates endometrial tissue or increases the risk of endometrial cancer.⁴ The Multiples Outcomes of Raloxifene Evaluation study⁵ compared the use of raloxifene with placebo in postmenopausal patients with documented osteoporosis. Compared with placebo, risk of vertebral fracture was reduced in two groups of women receiving different dosages of raloxifene. The reduction was seen both in women with prevalent fracture and in women without prevalent fracture. Risk of nonvertebral fractures did not differ significantly when raloxifene was compared with placebo. Raloxifene increased bone mineral density in the femoral neck and spine. The beneficial effects of raloxifene in reducing fracture incidence were in addition to the beneficial effects of supplemental calcium and cholecalciferol. However, clinical recommendations from these data must consider that, until more definitive comparisons are completed, estrogen or bisphosphonates remain the preferred therapy for postmenopausal women at high risk for nonspinal fractures.⁶

Does this all mean that raloxifene is the most optimal postmenopausal replacement drug? Although it is a synthetic compound and is somewhat less effective than estrogen as a preventive agent, will women more readily accept it if the breast cancer issue is resolved? The crucial question is still unanswered and will not be answered until the results of the National Cancer Institute's Study of Tamoxifen and Raloxifene (STAR) are known. It is impossible to make direct comparisons between the two SERMs at this point.

The controversial data on the link between breast cancer and HRT are primarily derived from reexamination of observational studies that suggest that a slightly increased risk of breast cancer has often but not always been seen with increasing duration of HRT use by postmenopausal women.⁷ The uneasiness about the postulated link between HRT and breast cancer is still unresolved, and the current data on raloxifene do not allow clinical recommendations to be made at this time. The search for the “perfect” postmenopausal replacement drug continues.