地诺孕素用于子宫内膜异位症保守术后维持治疗的Meta分析

doi:10.12280/gjfckx.20200539

摘要/Abstract

摘要：

目的:比较地诺孕素与其他治疗方法在预防腹腔镜下子宫内膜异位症（EMs）保守术后复发的有效性及安全性,从而为临床上药物的选择提供参考依据。方法:检索PubMed、Embase、Cochrane Library、Web of Science、ClinicalTrials.gov、中国知网、万方及维普数据库自建库至2020年4月的相关文献和试验,检索的文献由两名评价人员独立筛选、质量评价以及数据提取,最终纳入的数据使用Revman 5.3进行Meta分析。结果:最终纳入10篇文献,共1 740例患者。Meta分析结果显示,地诺孕素较期待治疗的病灶复发风险低（OR=0.11,95%CI:0.07~0.19,P<0.000 01）,并能缓解EMs相关疼痛;地诺孕素与促性腺激素释放激素激动剂（GnRHa）治疗相比,病灶复发风险（OR=0.49,95%CI:0.19~1.24,P=0.13）及疼痛缓解情况（P>0.05）差异无统计学意义,地诺孕素治疗后阴道出血（RR=13.11,95%CI:5.02~34.21,P<0.000 01）发生风险较高,潮热发生风险较低（RR=0.12,95%CI:0.06~0.26,P<0.000 01）,差异有统计学意义,头痛（RR=3.49,95%CI:0.99~12.25,P=0.05）发生风险较高,但差异无统计学意义;地诺孕素与左炔诺孕酮宫内缓释系统（LNG-IUS）治疗相比,病灶复发风险差异无统计学意义（OR=0.46,95%CI:0.50~1.04,P=0.06）,地诺孕素能有效缓解EMs相关疼痛（SMD=-0.46,95%CI:-0.70~-0.22,P=0.000 1）,地诺孕素治疗后发生阴道出血（OR=0.38,95%CI:0.18~0.81,P=0.01）、阴道分泌物增加（OR=0.03,95%CI:0.00~0.48,P=0.01）及同房不适（OR=0.04,95%CI:0.00~0.70,P=0.03）的风险相对较低;与米非司酮相比,地诺孕素能降低病灶复发风险（OR=0.41,95%CI:0.18~0.96,P=0.04）,且缓解疼痛的疗效相对较好（OR=21.00,95%CI:2.65~166.45,P=0.004）,地诺孕素发生潮热的风险较低（OR=0.11,95%CI:0.01~0.89,P=0.04）。结论:地诺孕素能有效预防EMs复发,效果优于期待治疗及米非司酮,与GnRHa及LNG-IUS相当;缓解疼痛的效果优于期待治疗、LNG-IUS及米非司酮,与GnRHa效果相当。尽管地诺孕素阴道出血和头痛发生风险相对较高,但其安全性和耐受性良好,值得临床上应用于EMs保守术后长期管理的治疗当中。

关键词: 子宫内膜异位症, 地诺孕素, 出血, 疼痛, 治疗结果, Meta分析

Abstract:

Objective: To compare the effectiveness and safety of dienogest and other treatment in preventing the recurrence of endometriosis (EMs) after laparoscopic excision, so as to provide a reference for clinical drug selection. Methods: Search PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, CNKI, Wanfang data and VIP related literature and trials before April 2020, the retrieved literature was independently screened, quality evaluated and data extracted by two reviewers. The final included data was Meta-analyzed using Revman 5.3. Results: A total of 1 011 articles were retrieved, and 10 articles were finally included, with a total of 1 740 patients. The dienogest group had a lower recurrence rate than the expectant treatment group (OR=0.11, 95%CI: 0.07~0.19, P<0.000 01), and could relieve EMs-related pain. Compared with the GnRHa group, there was no statistically significant difference in recurrence rate (OR=0.49, 95%CI: 0.19~1.24, P=0.13) and pain relief related to EMs (P>0.05), but has a higher rate of vaginal bleeding (RR=13.11, 95%CI: 5.02~34.21, P<0.000 01) and a lower hot flash rate (RR=0.12, 95%CI: 0.06~0.26, P<0.000 01), the difference is statistically significant. The risk of headache (RR=3.49, 95%CI: 0.99~12.25, P=0.05) is higher, but the difference is not statistically significant. Compared with LNG-IUS, there was no statistically significant difference in recurrence rate between these two group (OR=0.46, 95%CI: 0.50~1.04, P=0.06), but the difference in pain relief related to EMs was statistically significant (SMD=-0.46, 95%CI: -0.70~-0.22, P=0.000 1), the risk of vaginal bleeding (OR=0.38, 95%CI: 0.18~0.81, P=0.01), increased vaginal secretion (OR=0.03, 95%CI: 0.00~0.48, P=0.01), and coital discomfort (OR=0.04, 95%CI: 0.00~0.70, P=0.03) in the LNG-IUS group was relatively high, and the difference was statistically significant. Compared with the mifepristone group, the dienogest group can reduce the recurrence rate (OR=0.41, 95%CI: 0.18~0.96, P=0.04), and the pain relief effect is relatively good (OR=21.00, 95%CI: 2.65~166.45, P=0.004), dienogest also has a lower risk of hot flashes (OR=0.11, 95%CI: 0.01~0.89, P=0.04). Conclusions: Dienogest is effective in preventing the recurrence of EMs, and the effect is better than the expected treatment and mifepristone, which is equivalent to GnRHa and LNG-IUS. The pain relief effect is better than the expected treatment, LNG-IUS and mifepristone, equivalent to GnRHa. Although the risk of vaginal bleeding and headache is relatively high, dienogest is safe and well tolerated, and it is expected to become a new option for long-term treatment of EMs after conservative surgery.

Key words: Endometriosis, Dienogest, Hemorrhage, Pain, Treatment outcome, Meta-analysis

黄婷, 黄高廷, 杨国敏, 梁梦姗, 朱耀魁. 地诺孕素用于子宫内膜异位症保守术后维持治疗的Meta分析[J]. 国际妇产科学杂志, 2021, 48(1): 26-34.

HUANG Ting, HUANG Gao-ting, YANG Guo-min, LIANG Meng-shan, ZHU Yao-kui. Meta Analysis of Dienogest Used in Maintenance Treatment of Endometriosis after Conservative Surgery[J]. Journal of International Obstetrics and Gynecology, 2021, 48(1): 26-34.

图/表 15

参考文献 26

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文献	年份	国家	研究类型	样本量	年龄（岁）	干预措施	随访时间（个月）	结局指标
刘海绒^[2]	2016	中国	RCT	100	地诺孕素组:31.2±9.1;米非司酮组:30.4±8.5	地诺孕素,4 mg/d,3个月;米非司酮, 10 mg/d,3个月	12	缓解率;复发率;妊娠率;不良反应
Lee等^[3]	2018	韩国	回顾性队列研究	285	地诺孕素组:33.9±6.1;LNG-IUS组:43.7±7.3;期待治疗组:39.3±7.6	地诺孕素,2 mg/d;LNG-IUS;期待治疗	15~79	复发率;VAS评分;不良反应;停药率
Takaesu等^[4]	2016	日本	前瞻性队列研究	190	地诺孕素组:32.4±6.6;GnRHa组:35.9±6.2;期待治疗组:34.6±5.8	地诺孕素,2 mg/d,6个月;戈舍瑞林 1.8 mg,4周1次,6个月;期待治疗	24	复发率;VAS评分;不良反应
Yamanaka等^[5]	2017	日本	回顾性队列研究	126	地诺孕素组:35.0±6.8;期待治疗组:36.0±5.9	地诺孕素,2 mg/d,（31.0±17.6）个月; 期待治疗	32.0±16.3	病灶复发;疼痛复发
Dobrokhotova等^[6]	2017	俄罗斯	回顾性队列研究	53	地诺孕素组:31.0±2.5;期待治疗组:30.0±1.5	地诺孕素,2 mg/d,6个月;期待治疗	12	疼痛缓解情况;VAS评分;阴道出血程度
Ota等^[7]	2015	日本	回顾性队列研究	568	地诺孕素组:32.56±5.23;期待治疗组:33.23±6.01	地诺孕素,2 mg/d;期待治疗	60	复发率;不良反应
Adachi等^[8]	2016	日本	回顾性队列研究	81	地诺孕素组:35.4±1.0;期待治疗组:37.2±1.0	地诺孕素,2 mg/d;期待治疗	≥6	复发率;VAS评分
Morelli等^[9]	2013	意大利	回顾性队列研究	92	地诺孕素+雌二醇组:33.42±3.89;LNG-IUS组:32.36±3.25	地诺孕素+雌二醇;LNG-IUS	24	复发率;VAS评分;满意度
Ouchi等^[10]	2014	日本	回顾性队列研究	167	地诺孕素组:34.6±5.8;GnRHa组:31.0±5.5;连续OCP组:32.4±5.9;周期OCP组:30.2±2.3;期待治疗组:34.9±6.5	地诺孕素,2 mg/d,（13.28±4.85）个月; GnRHa,4周1次,6个月;连续或周期口服避孕药;期待治疗	38.3±29.0	复发率
Granese等^[11]	2015	意大利	RCT	78	地诺孕素+雌二醇组:31.2±2.6;GnRHa组:30.5±2.5	地诺孕素（前5 d 2 mg/d,后17 d 3 mg/d）+雌二醇（2 mg/d,22 d）,9个月;GnRHa,3.75 mg,30 d 1次,6个月	9	VAS评分;复发率;生活质量;不良反应

文献	年份	国家	研究类型	样本量	年龄（岁）	干预措施	随访时间（个月）	结局指标
刘海绒^[2]	2016	中国	RCT	100	地诺孕素组:31.2±9.1;米非司酮组:30.4±8.5	地诺孕素,4 mg/d,3个月;米非司酮, 10 mg/d,3个月	12	缓解率;复发率;妊娠率;不良反应
Lee等^[3]	2018	韩国	回顾性队列研究	285	地诺孕素组:33.9±6.1;LNG-IUS组:43.7±7.3;期待治疗组:39.3±7.6	地诺孕素,2 mg/d;LNG-IUS;期待治疗	15~79	复发率;VAS评分;不良反应;停药率
Takaesu等^[4]	2016	日本	前瞻性队列研究	190	地诺孕素组:32.4±6.6;GnRHa组:35.9±6.2;期待治疗组:34.6±5.8	地诺孕素,2 mg/d,6个月;戈舍瑞林 1.8 mg,4周1次,6个月;期待治疗	24	复发率;VAS评分;不良反应
Yamanaka等^[5]	2017	日本	回顾性队列研究	126	地诺孕素组:35.0±6.8;期待治疗组:36.0±5.9	地诺孕素,2 mg/d,（31.0±17.6）个月; 期待治疗	32.0±16.3	病灶复发;疼痛复发
Dobrokhotova等^[6]	2017	俄罗斯	回顾性队列研究	53	地诺孕素组:31.0±2.5;期待治疗组:30.0±1.5	地诺孕素,2 mg/d,6个月;期待治疗	12	疼痛缓解情况;VAS评分;阴道出血程度
Ota等^[7]	2015	日本	回顾性队列研究	568	地诺孕素组:32.56±5.23;期待治疗组:33.23±6.01	地诺孕素,2 mg/d;期待治疗	60	复发率;不良反应
Adachi等^[8]	2016	日本	回顾性队列研究	81	地诺孕素组:35.4±1.0;期待治疗组:37.2±1.0	地诺孕素,2 mg/d;期待治疗	≥6	复发率;VAS评分
Morelli等^[9]	2013	意大利	回顾性队列研究	92	地诺孕素+雌二醇组:33.42±3.89;LNG-IUS组:32.36±3.25	地诺孕素+雌二醇;LNG-IUS	24	复发率;VAS评分;满意度
Ouchi等^[10]	2014	日本	回顾性队列研究	167	地诺孕素组:34.6±5.8;GnRHa组:31.0±5.5;连续OCP组:32.4±5.9;周期OCP组:30.2±2.3;期待治疗组:34.9±6.5	地诺孕素,2 mg/d,（13.28±4.85）个月; GnRHa,4周1次,6个月;连续或周期口服避孕药;期待治疗	38.3±29.0	复发率
Granese等^[11]	2015	意大利	RCT	78	地诺孕素+雌二醇组:31.2±2.6;GnRHa组:30.5±2.5	地诺孕素（前5 d 2 mg/d,后17 d 3 mg/d）+雌二醇（2 mg/d,22 d）,9个月;GnRHa,3.75 mg,30 d 1次,6个月	9	VAS评分;复发率;生活质量;不良反应

文献	随机序列产生	分配隐藏	参与者和实施者施盲	结局评价者施盲	结果数据的完整性	选择性报告结果	其他偏倚
刘海绒^[2]	不清楚	不清楚	不清楚	不清楚	低风险	低风险	不清楚
Granese等^[11]	低风险	不清楚	不清楚	不清楚	低风险	低风险	不清楚

文献	随机序列产生	分配隐藏	参与者和实施者施盲	结局评价者施盲	结果数据的完整性	选择性报告结果	其他偏倚
刘海绒^[2]	不清楚	不清楚	不清楚	不清楚	低风险	低风险	不清楚
Granese等^[11]	低风险	不清楚	不清楚	不清楚	低风险	低风险	不清楚

文献	队列选择	组间可比性	结果	总分
Lee等^[3]	★★★	★	★★	★*6
Takaesu等^[4]	★★★★	★	★★★	★*8
Yamanaka等^[5]	★★★	★	★★★	★*7
Dobrokhotova等^[6]	★★	★	★★★	★*6
Ota等^[7]	★★★	★	★★★	★*7
Adachi等^[8]	★★	★	★★	★*5
Morelli等^[9]	★★	★★	★★★	★*7
Ouchi等^[10]	★★	★	★★★	★*6