Selective estrogen receptor modulators (
SERMs) have the ability to provide mixed functional
estrogen receptor (ER) agonist or antagonist activity, depending on the target tissue.
Tamoxifen, the first
SERM available for clinical use, is regarded as a highly effective agent for the prevention and treatment of
breast cancer. However,
tamoxifen exhibits ER agonist activity in the uterus and is associated with an increased risk of
endometrial hyperplasia and
malignancy. Endometrial safety has been an important consideration in the clinical development of
SERMs, with improved benefit-risk profiles.
Raloxifene, which is currently approved for the prevention and treatment of
postmenopausal osteoporosis and for the prevention of
breast cancer, seems to have neutral effects on the uterus. Promising results have been observed with the targeted development of newer and more tissue-specific
SERMs, many of which are under investigation for
postmenopausal osteoporosis. Of the newer
SERMs in development,
lasofoxifene has been shown to reduce fracture risk and decrease the incidence of
breast cancer but has been associated with an increased incidence of
vaginal bleeding, endometrial thickening, and endometrial
polyps.
Lasofoxifene and
ospemifene have shown beneficial effects on the vaginal epithelium. Phase 3 clinical data have shown that
bazedoxifene is effective in preventing and treating
postmenopausal osteoporosis, without adverse effects on the endometrium or breast.
Arzoxifene has been evaluated in phase 3 trials for
postmenopausal osteoporosis and has been studied for the treatment of uterine
malignancies but is no longer in clinical development. Further investigation of newer
SERMs is warranted to more clearly define the endometrial safety of these agents.