Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause.

Ospemifene is a unique tissue-selective estrogen agonist/antagonist (also known as a selective estrogen receptor modulator [SERM]) with demonstrated efficacy in Phase 3 studies of postmenopausal women with vulvar and vaginal atrophy (VVA). This report describes preclinical studies on the effects of ospemifene in the ovariectomized (OVX) rat model of menopause. Ospemifene (10mg/kg/day) and the SERM comparator, raloxifene (10mg/kg/day) were administered for 2 weeks and both increased vaginal weight; ospemifene was more effective than raloxifene. In addition, ospemifene had a greater effect on increasing vaginal epithelial height compared with raloxifene. The effect on uterine weight was less pronounced for both ospemifene and raloxifene. The ED50 of ospemifene on vaginal epithelial height was 0.39mg/kg/day and the magnitude was nearly the same as was seen with the positive control, 17α-ethinyl estradiol (EE2). In a histological analysis of ospemifene-treated rat vaginas, basal cells were overlaid by 2 to 3 cell layers of thickened goblet-like mucified cells apically; however, the cornification observed with EE2 was absent. Estrogenic activity of ospemifene was confirmed by upregulation of progesterone receptors in vaginal epithelium and stroma. Ospemifene showed similar affinity for estrogen receptor (ER)-α and ER-β, but an overall lower affinity than estradiol. Ospemifene antagonized estrogen response element (ERE)-mediated transactivation on MCF-7 cells, confirming its anti-estrogenic activity in breast cancer cells. The dose response for ospemifene in the rat is consistent with that observed in clinical studies of ospemifene 30 and 60mg, showing that the OVX rat is a highly predictive model of SERM activity in postmenopausal VVA.