Endometrial Safety of Ospemifene and the Ability of Transvaginal Ultrasonography to Detect Small Changes in Endometrial Thickness

Abstract

INTRODUCTION: Ospemifene is a nonestrogen with tissue selective agonist and antagonist effects recently approved for treatment of moderate to severe dyspareunia, a symptom of vulvovaginal atrophy resulting from menopause. The known increase in endometrial hyperplasia and carcinoma associated with unopposed systemic estrogen therapies warranted vigilance with regard to endometrial safety. Discussed here are the modalities to best establish endometrial safety in the context of the randomized controlled clinical trials of oral ospemifene at 60 mg per day compared with placebo in postmenopausal women exposed up to 52 weeks. METHODS: Six phase 2 and 3 clinical trials compared ospemifene at 60 mg per day with placebo. RESULTS: Endometrial safety was evaluated in 851 women exposed to ospemifene at 60 mg per day. Endometrial biopsies, vaginal bleeding, and transvaginal ultrasound scans for thickness and lesions were used. Change in endometrial thickness was significantly greater than placebo at 12 months (0.8±1.5 mm; P<.001); however, endometrial thickening of greater than 5 mm at the last visit demonstrated no statistically significant increase. Small endometrial thickness increases or decreases were not reproducible at different time points. Vaginal bleeding or spotting was reported in 1.2% of women with a uterus receiving ospemifene compared with 0.9% on placebo. There were no carcinomas, one case of simple hyperplasia without atypia (0.3%), and less than 1.0% active proliferation. CONCLUSION: The ospemifene endometrial profile, including histology and ultrasonography results for a maximum of 1 year of daily oral treatment, appears more consistent with the selective estrogen receptor modulator raloxifene than with steroidal estrogen. Histology, transvaginal ultrasonography greater than 5 mm, and symptoms of vaginal bleeding were helpful in discerning endometrial safety.