Efficacy and safety of estetrol (15 mg)/drospirenone (3 mg) combination in a cyclic regimen for the treatment of primary and secondary dysmenorrhea: a multicenter, placebo-controlled, double-blind, randomized study

OBJECTIVE: To evaluate the efficacy and safety of the estetrol (E4) (15 mg)/drospirenone (DRSP) (3 mg) combination in a cyclic regimen in Japanese women with primary and secondary dysmenorrhea. DESIGN: A 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, followed by a 36-week, open-label, extension study. SUBJECTS: A total of 162 Japanese women with primary and secondary dysmenorrhea. INTERVENTION: Participants were randomly allocated to either the E4/DRSP group or the placebo group. In the E4/DRSP group, participants orally received one tablet containing E4 (15 mg) and DRSP (3 mg daily) for 24 days, followed by a placebo tablet for 4 days, constituting one cycle. The placebo group was given one placebo tablet daily for 28 days. After 16 weeks, participants in the placebo group were switched to receive E4/DRSP for 36 weeks. MAIN OUTCOME MEASURES: Absolute change in the most severe total dysmenorrhea score from baseline to the end of the 16-week double-blinded period. RESULTS: Estetrol/drospirenone reduced the most severe total dysmenorrhea score by 2.3 points from baseline at week 16. The between-group difference was significant (-1.4, two-sided 95% confidence interval, -1.8 to -1.0), showing superiority to placebo. The responder rate, the proportion of participants who achieved a ≥2.0-point reduction in the most severe total dysmenorrhea score from baseline, was 64.3% in the E4/DRSP group, significantly higher than in the placebo group, 28.4%. In the E4/DRSP group, visual analogue scale scores for pelvic pain and dysmenorrhea symptoms during the menstrual bleeding periods were decreased by 44.2 and 42.3 mm, respectively, from baseline at week 16, significantly more than in the placebo group. Objective gynecological examinations suggested amelioration of pelvic tenderness, uterine mobility, and cul-de sac induration in the E4/DRSP group. Estetrol/drospirenone improved the quality of life-related questionnaires (interference with daily activities and sleeping) and global impression scores. Intermenstrual bleeding was the primary treatment-emergent adverse event in the E4/DRSP group, similar to combined oral contraceptives. There were no cases of venous thromboembolism and less impact on hemostasis parameters in the E4/DRSP group. CONCLUSION: Estetrol/drospirenone is an effective treatment for dysmenorrhea, offering a safe, new treatment option with potentially reduced thromboembolic risk. CLINICAL TRIAL REGISTRATION NUMBER: jRCT2011210023.