GnRH-a联合治疗用于口服孕激素治疗失败的子宫内膜非典型增生及子宫内膜癌患者的探讨

GnRH-a combined fertility-sparing re-treatment in women with endometrial carcinoma or atypical endomertial hyperplasia who failed to oral progestin therapy

目的探讨以促性腺激素释放激素激动剂(GnRH-a)为基础的联合治疗方案对口服孕激素治疗失败的子宫内膜非典型增生(AEH)及子宫内膜癌(EC)患者的疗效、复发及妊娠结局。方法收集2012年1月至2020年12月中国医学科学院北京协和医学院北京协和医院收治的口服孕激素治疗失败后要求再次保留生育功能治疗,经评估仍符合保留生育功能治疗指征的患者共40例,其中AEH 7例、EC 33例,对其进行以GnRH-a为基础联合方案的再次保留生育功能治疗,具体方案包括GnRH-a联合左炔诺孕酮宫内缓释系统(GLI)方案(28例)和GnRH-a联合来曲唑(GAI)方案(12例),分析其疗效、复发及妊娠结局。结果(1)一般临床资料:40例AEH或EC患者的中位发病年龄为31岁(22~40岁),中位体质指数为24.7 kg/m2(18.9~39.5 kg/m2)。(2)再次保留生育功能治疗的疗效:40例AEH或EC患者中,37例(92%,37/40)达完全缓解(CR),其中AEH 6例(6/7)、EC 31例(94%,31/33);使用GLI和GAI方案患者的CR率分别为93%(26/28)和11/12;达CR的中位时间为5个月(3~12个月);1个疗程治疗后AEH、EC的CR率分别为5/7、42%(14/33),2个疗程后分别为6/7、82%(27/33)。(3)复发:37例获CR的患者均规律随访,中位随访时间为25个月(10~75个月);随访期内8例(22%,8/37)患者出现复发,包括AEH 1例(1/6)、EC 7例(23%,7/31),中位复发时间为18个月(9~26个月)。8例复发患者中,2例已完成生育者直接行子宫切除术;6例接受第3次保留生育功能治疗,其中5例(5/6)再次达CR。随访期内无死亡患者。(4)妊娠:37例获CR的患者中,33例近期有生育意愿,其中期待自然妊娠10例、接受辅助生殖技术治疗23例;共妊娠14例(42%,14/33),其中足月分娩9例(27%,9/33)、早期妊娠胚胎停止发育3例(9%,3/33)、中期妊娠流产2例(6%,2/33)。结论对于口服孕激素治疗失败的AEH或EC患者,给予以GnRH-a为基础的联合方案治疗仍有较好的疗效及妊娠结局,可以作为口服孕激素治疗的替代方案。

Objective To analyze the clinical efficacy and pregnancy outcomes of gonadotropin-releasing hormone agonist(GnRH-a)based fertility-sparing re-treatment in women with endometrial carcinoma(EC)and atypical endometrial hyperplasia(AEH)who failed with oral progestin therapy.Methods Forty cases with EC or AEH who failed to respond to oral progestin were included from January 2012 to December 2020 at Peking Union Medical College Hospital.Combination of GnRH-a with levonorgestrel-releasing intrauterine system(group GLI:a subcutaneous injection of GnRH-a every 4 weeks and LNG-IUS insertion constantly)or the combination of GnRH-a with aromatase inhibitor(group GAI:a subcutaneous injection of GnRH-a every 4 weeks and oral letrozole 2.5 mg,daily)were used for these patients.Histological evaluation were performed at the end of each course(every 3-4 months)by hysteroscopy and curettage.After the complete remission(CR),all patients were followed up regularly.Results(1)Clinical characteristics:among the 40 patients with EC or AEH,the median age at diagnosis was 31 years(range:22-40 years)and the median body mass index was 24.7 kg/m2(range:18.9-39.5 kg/m2).(2)Efficacy of fertility-sparing re-treatment:37(92%,37/40)patients achieved CR,6(6/7)in AEH and 31(94%,31/33)in EC patients.The CR rate was 93%(26/28)and 11/12 in group GLI and GAI,respectively.The median time to CR was 5 months(range:3-12 months).At the end of the first therapy course,the CR rates in AEH and EC were 5/7 and 42%(14/33),at the second course,the CR rates were 6/7 and 82%(27/33),respectively.(3)Recurrence:after 25 months of median follow-up duration(range:10-75 months),8(22%,8/37)women developed recurrence,1/6 in AEH and 7(23%,7/31)in EC patients,with the median recurrence time of 18 months(range:9-26 months).Among them,two cases who had completed childbirth chose to receive hysterectomy directly.Six patients met the criteria of fertility-preserving therapy and received conservative treatment again and 5(5/6)of them achieved CR.(4)Pregnancy:of the 37 patients with CR,33 desired to conceive.Ten women attempted to get pregnancy spontaneously and 23 cases with assisted reproductive technology.Fourteen(42%,14/33)patients became pregnant,including 9(27%,9/33)live births,3(9%,3/33)missed abortions,and 2(6%,2/33)miscarriages at the second trimester.Conclusions GnRH-a based fertility-sparing re-treatment in AEH or EC patients who failed with oral progestin therapy achieved good treatment effect and reproductive outcomes.It is an encouraging alternative regime for patients who failed with oral progestin therapy.