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, multi-center, randomized, double-blind, placebo-controlled, parallel-group study, followed by a 36-week, open-label, extension study. SUBJECTS 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 E4/DRSP 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 (p<0.001). 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%, (p<0.05). In the E4/DRSP group, visual analog scale scores for pelvic pain and dysmenorrhea symptoms during the menstrual bleeding periods were decreased by 44.2 mm and 42.3 mm, respectively, from baseline at week 16, significantly more than in the placebo group (p<0.001). Objective gynecological examinations suggested amelioration of pelvic tenderness, uterine mobility, and cul-de sac induration in the E4/DRSP group. E4/DRSP 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 E4/DRSP is an effective treatment for dysmenorrhea, offering a safe, new treatment option with potentially reduced thromboembolic risk.

中文翻译：

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雌酯醇 （E4） 15 mg/屈螺酮 （DRSP） 3 mg 联合治疗原发性和继发性痛经的疗效和安全性：一项多中心、安慰剂对照、双盲、随机研究。


目的 评价雌激素 （E4） 15 mg/屈螺酮 （DRSP） 3 mg 联合治疗日本原发性和继发性痛经女性的周期性方案的疗效和安全性。设计 一项为期 16 周、多中心、随机、双盲、安慰剂对照、平行组研究，然后是一项为期 36 周、开放标签、扩展研究。对象 162 名患有原发性和继发性痛经的日本女性。干预 参与者被随机分配到 E4/DRSP 组或安慰剂组。在 E4/DRSP 组中，参与者每天口服一片含有 E4 15 mg 和 DRSP 3 mg的片剂，持续 24 天，然后口服安慰剂片剂 4 天，构成一个周期。安慰剂组每天服用 1 片安慰剂片剂，持续 28 天。16 周后，安慰剂组的参与者转为接受 E4/DRSP，持续 36 周。主要结局指标 从基线到 16 周双盲期结束最严重痛经总评分的绝对变化。结果 E4/DRSP 在第 16 周时，最严重的痛经总评分较基线降低了 2.3 分。组间差异显著 （-1.4，双侧 95% 置信区间： -1.8 至 -1.0），显示优于安慰剂 （p<0.001）。E4/DRSP 组的反应率，即最严重痛经总评分较基线降低 ≥2.0 分的参与者比例）为 64.3%，显著高于安慰剂组的 28.4%，（p<0.05）。在 E4/DRSP 组中，月经出血期间盆腔疼痛和痛经症状的视觉模拟量表评分在第 16 周时较基线分别降低了 44.2 mm 和 42.3 mm，显著高于安慰剂组 （p<0.001）。 客观的妇科检查表明 E4/DRSP 组盆腔压痛、子宫活动度和死胡同硬结得到改善。E4/DRSP 提高了生活质量相关问卷 （对日常活动和睡眠的干扰） 和总体印象评分。月经间期出血是 E4/DRSP 组的主要治疗中出现的不良事件，类似于复方口服避孕药。E4/DRSP 组无静脉血栓栓塞病例，对止血参数的影响较小。结论 E4/DRSP 是一种治疗痛经的有效方法，提供了一种安全的新治疗选择，可能降低血栓栓塞风险。