The search for an even safer alternative to hormone replacement therapy has led to the evaluation of several compounds, previously referred to as ‘antiestrogens’. Initially, these compounds were used for the treatment of hormonally responsive cancers, such as breast cancer. Therefore, they were termed ‘antiestrogens’. One such compound is tamoxifen. However, after the realization that postmenopausal women with breast cancer treated with tamoxifen had lower cholesterol and increased spinal bone density compared with untreated controls, it became evident that the term ‘antiestrogen’ did not fully describe these compounds. The term selective estrogen receptor modulators (SERMs) has been suggested in order to define more precisely these substances, which are capable of binding to and activating ERs, but which have effects on target tissues that are different from those of estradiol. Newer SERMs are raloxifene, droloxifene and toremifene. The estrogen agonist/antagonist properties of selective estrogen receptor modulators are not fully understood and are difficult to explain. One major mechanism appears to be a change in the conformation of the ER; another mechanism lies in differences in recruitment of co-activators and co-repressors; and a third mechanism is by activation/deactivation of different classes of ERs. For example, raloxifene seems to activate predominantly ERb and only to a lesser extend ERa which accounts for the lack of stimulation of the breast or uterus. For a more detailed discussion of ERs the reader is referred to site. The fundamental concept behind SERMs is to try and maintain the beneficial effects of hormone replacement therapy while avoiding its drawbacks, especially with regard to endometrial stimulation, breast cancer and prothrombotic changes.
The one selective estrogen receptor modulator that has been particularly well studied in radomized clinical trials in menopausal women and that is licensed for use is raloxifene. It, like estrogen, reduces bone remodeling in estrogen-deficient early postmenopausal women and induces a positive calcium balance shift. At 60 mg/day, raloxifene leads to an increase of bone mineral density in the spine and the hip and a reduction in vertebral fracture rates. Raloxifene decreases LDL, Lp(a) and fibrinogen, increases HDL-2, but not total HDL, and has no effect on triglycerides or PAI-1. During a median of 40 months of treating postmenopausal women for osteoporosis, there was a 76% reduction in newly diagnosed invasive breast cancers. Raloxifene does not cause endometrial stimulation or breast tenderness, but does cause DVT at a rate similar to that of hormone replacement therapy. The effects of raloxifene on CHD and stroke was studied in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a randomized controlled trial of menopausal women with osteoporosis. It recruited 7705 patients who were followed for 4 years. There was no difference in the rates of coronary events or stroke between the treatment and placebo groups. A subgroup analysis found that women with a high risk of CHD or stroke may even benefit from the treatment. Reassuringly, raloxifene does not seem to affect cognitive function. Overall raloxifene is well tolerated with discontinuation rates in clinical studies similar to placebo, but it may slightly worsen hot flashes and it can cause leg cramps in a small percentage of women. It is very likely that in future new selective estrogen receptor modulators will be developed and their indications will broaden to include relief of estrogen deficiency symptoms, prevention of breast cancer, treatment for fibroids, endometriosis, uterine cancer, etc.