Efficacy and safety of ultra-low dose vaginal estriol in the therapy of genitourinary syndrome ofmenopause: a phase III multicenter randomized controlled trial

Background: Topical hormonal therapy with estriol is the treatment standard for women with genitourinary syndrome of menopause. The appropriate dosages of estriol to treat its symptoms and to minimize a risk to the patient continue to be debated. Objective: To compare the efficacy and safety of vaginal agents containing estriol 50 pg/g (gel) and 500pg/0.5 g (cream) in the treatment of postmenopausal atrophic vaginitis. Materials and methods: Design: this was an active controlled Phase III multicenter, open-label, prospective, randomized comparative parallel group clinical trial. It was conducted in 8 Russian research centers in 2016 to 2018. The trial included 120 postmenopausal patients with a history of vulvovaginal atrophy (VVA) lasting for at least one year, who were randomized to 2 groups; 1) 60 patients received vaginal estriol gel 50 pg and 2) 60 received vaginal estriol cream 500pg according to the regimens (the patients used the agents on their own at night every day once daily for 3 weeks; then maintenance therapy was performed, by reducing the dose twice a week for 9 weeks). The total therapy duration was 12 weeks. The main outcome criterion was an increase in the vaginal epithelium maturation value (VEMV). The relief or disappearance rate of VVA symptoms and clinical signs, vaginal pH value, and safety were also calculated. Results. The increase in VEMV relative to the baseline was 21.4 (SD 21.1) and 18.9 (SD 21.6) points in Groups 1 and 2, respectively; A=2.47(95% CI: -4.07; 9.01 points; p=0.27), which did not exceed the upper CI limit of 10% and suggested that there was no difference in VEMV between both drugs after 12 weeks of therapy. There was relief or disappearance of VVA symptoms and a vaginal pH decrease that was comparable between the groups. The drugs compared were well tolerated, there were a total of15 adverse events (AEs): 5 (33.3%) AEs in Group I and 10 (66.7%) in Group 2, no serious AEs were registered. The established AEs were consistent with the known safety information; the number of reported cases was comparable in both groups. Conclusion: The eff icacy of ultra-low dose (50pg/day) vaginal estriol gel in improving the symptoms and clinical signs of VVA is similar to that of standard dose vaginal cream (500pg/day). The safety of both agents is comparable.

menopause, genitourinary syndrome of menopause, vulvovaginal atrophy, non-hormonal agents, estriol, ultra-low doses, safety, adverse events, vaginal gel