Objective: To compare the effects and safety of dydrogesterone (DG) and medroxyprogesterone acetate (MPA) on the treatment in patients with endometrial hyperplasia without atypia (EH). Methods: This was a single-center, open-label, prospective non-inferior randomized controlled phase Ⅲ trial. From February 2019 to November 2021, patients with EH admitted to the Obstetrics and Gynecology Hospital of Fudan University were recruited. Enrolled patients were stratified according to the pathological types of simple hyperplasia (SH) or complex hyperplasia (CH), and were randomised to receive MPA or DG. Untill May 14, 2022, the median follow-up time after complete response (CR) was 9.3 months (1.1-17.2 months). The primary endpoint was the 6-month CR rate (6m-CR rate). The secondary endpoints included the 3-month CR rate (3m-CR rate), adverse events rate, recurrence rate, and pregnancy rate in one year after CR. Results: (1) A total of 292 patients with EH were enrolled in the study with the median age of 39 years (31-45 years). A total of 135 SH patients were randomly assigned to MPA group (n=67) and DG group (n=68), and 157 CH patients were randomly assigned to MPA group (n=79) and DG group (n=78). (2) Among 292 patients, 205 patients enrolled into the primary endpoint analysis, including 92 SH patients and 113 CH patients, with 100 patients in MPA group and 105 in DG group, respectively. The 6m-CR rate of MPA group and DG group were 90.0% (90/100) and 88.6% (93/105) respectively, and there were no statistical significance (χ2=0.11, P=0.741), with the rate difference (RD) was -1.4% (95%CI:-9.9%-7.0%). Stratified by the pathology types, the 6m-CR rate of SH patients was 93.5% (86/92), and MPA group and DG group were respectively 91.1% (41/45) and 95.7% (45/47); and the 6m-CR rate of CH patients was 85.8% (97/113), and MPA group and DG group were 89.1% (49/55) and 82.8% (48/58) respectively. The 6m-CR rates of the two treatments had no statistical significance either (all P>0.05). A total of 194 EH patients enrolled into the secondary endpoint analysis, including 88 SH patients and 106 CH patients, and 96 patients in MPA group and 98 in DG group, respectively. The 3m-CR rate of SH patients were 87.5% (77/88), while the 3m-CR rates of MPA group and DG group were 90.7% (39/43) and 84.4% (38/45), respectively; the 3m-CR rate of CH patients was 66.0% (70/106), and MPA group and DG group had the same 3m-CR rate of 66.0% (35/53). No statistical significance was found between the two treatments both in SH and CH patients (all P>0.05). (3) The incidence of adverse events between MPA group and DG group had no statistical significance (P>0.05). (4) A total of 93 SH patients achieved CR, and the cumulative recurrence rate in one year after CR were 5.9% and 0 in MPA group and DG group, respectively. While 112 CH patients achieved CR, and the cumulative recurrence rate in one year after CR were 8.8% and 6.5% in MPA group and DG group, respectively. There were no statistical significance between two treatment groups (all P>0.05). Among the 93 SH patients, 10 patients had family planning but no pregnancy happened during the follow-up period. Among the 112 CH patients, 21 were actively preparing for pregnancy, and the pregnancy rate and live-birth rate in one year after CR in MPA group were 7/9 and 2/7, while in DG group were respectively 4/12 and 2/4, and there were no statistical significance in pregnancy rate and live-birth rate between the two treatment groups (all P>0.05). Conclusions: Compared with MPA, DG is of good efficacy and safety in treating EH. DG is a favorable alternative treatment for EH patients.
目的： 比较地屈孕酮（DG）与醋酸甲羟孕酮（MPA）治疗子宫内膜增生不伴非典型性（EH）的疗效及安全性。 方法： 本研究为单中心、开放标签、非劣效、前瞻性随机对照Ⅲ期临床试验。招募自2019年2月至2021年11月就诊于复旦大学附属妇产科医院门诊的EH患者，入组EH患者根据病理类型即子宫内膜单纯性增生（SH）和子宫内膜复杂性增生（CH）分层后再按1∶1随机（随机序列由SPSS软件的随机数字生成器产生）分配至MPA组或DG组。随访截至2022年5月14日，完全缓解（CR）后中位随访时间为9.3个月（1.1~17.2个月）。主要研究终点为治疗6个月的CR率（6m-CR率），次要终点为治疗3个月的CR率（3m-CR率）、副反应发生率、CR后1年累积复发率和CR后1年妊娠率。 结果： （1）本研究共入组292例EH患者，中位初诊年龄为39岁（31~45岁）。其中，SH患者135例，随机分配至MPA组67例、DG组68例；CH患者157例，随机分配至MPA组79例、DG组78例。（2）292例EH患者中，205例患者纳入主要终点分析，包括92例SH和113例CH，MPA组、DG组分别为100、105例。MPA组和DG组的总体6m-CR率分别为90.0%（90/100）和88.6%（93/105），两组比较，差异无统计学意义［χ2=0.11，P=0.741；率差（RD）=-1.4%，95%CI为-9.9%~7.0%］。按照病理类型分层，SH患者的总体6m-CR率为93.5%（86/92），其中MPA组和DG组的6m-CR率分别为91.1%（41/45）和95.7%（45/47）；CH患者的总体6m-CR率为85.8%（97/113），其中MPA组和DG组的6m-CR率分别为89.1%（49/55）和82.8%（48/58），两组分别比较，差异均无统计学意义（P均>0.05）。194例患者纳入次要终点分析，包括88例SH和106例CH，MPA组、DG组分别为96、98例。SH患者的总体3m-CR率为87.5%（77/88），其中MPA组和DG组的3m-CR率分别为90.7%（39/43）和84.4%（38/45）；CH患者的总体3m-CR率为66.0%（70/106），其中MPA组和DG组的3m-CR率均为66.0%（35/53），两组分别比较，差异均无统计学意义（P均>0.05）。（3）EH患者的常见副反应包括月经过多（27.1%，79/292）、乳房胀痛（26.4%，77/292）、月经周期或经期改变（20.5%，60/292），MPA与DG组各副反应发生率分别比较，差异均无统计学意义（P均>0.05）。（4）93例SH患者达到CR，CR后1年累积复发率MPA组和DG组分别为5.9%和0；112例CH患者达到CR，CR后1年累积复发率MPA组和DG组分别为8.8%和6.5%，两组分别比较，差异均无统计学意义（P均>0.05）。93例达到CR的SH患者中10例有生育计划，暂无妊娠者；112例达到CR的CH患者中有生育计划者21例，MPA组CR后1年妊娠率及活产率分别为7/9和2/7，DG组分别为4/12和2/4，两组分别比较，差异均无统计学意义（P均>0.05）。 结论： 与MPA比较，DG治疗EH同样具有较好的有效性和安全性，是一种可以选择的替代方案。.