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This study aims to confirm the local effects of intravaginal prasterone on moderate to severe dyspareunia, a symptom of vulvovaginal atrophy (VVA) associated with menopause.In a prospective, randomized, double-blind, placebo-controlled phase III clinical trial, we examined the effects of daily intravaginal prasterone (6.5 mg) on four co–primary objectives, namely, percentage of vaginal parabasal cells, percentage of vaginal superficial cells, vaginal pH, and moderate to severe dyspareunia identified by women as the most bothersome VVA symptom.After daily intravaginal prasterone administration for 12 weeks, the percentage of parabasal cells decreased by 45.8% compared with placebo (P < 0.0001), the percentage of superficial cells increased by 4.7% over placebo (P < 0.0001), and vaginal pH decreased by 0.83 pH units compared with placebo (P < 0.0001). The severity of most bothersome dyspareunia decreased by 46% over placebo (P = 0.013) at 12 weeks, whereas moderate to severe vaginal dryness decreased by 0.43 severity score units (or 42%) compared with placebo (P = 0.013). On gynecologic evaluation, a 14.4% to 21.1% improvement in vaginal secretions, epithelial integrity, epithelial surface thickness, and color over placebo (P = 0.0002 to P < 0.0001) was observed. Serum steroids, in agreement with the physiology of intracrinology and menopause, remained well within reference postmenopausal concentrations. All endometrial biopsies at 12 weeks have shown atrophy.Daily intravaginal prasterone (0.50%; 6.5 mg) treatment has clinically and statistically significant beneficial effects on the four co–primary objectives of VVA, according to US Food and Drug Administration guidelines. No significant drug-related adverse effect in line with the strictly local action of treatment has been reported, thus providing a high benefit-to-risk ratio for intravaginal prasterone.