Endometrial safety: a key hurdle for selective estrogen receptor modulators in development.

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.