促性腺激素释放激素激动剂联合反向添加疗法治疗子宫内膜异位症的效果及安全性

Effects and safety of gonadotrophin-releasing hormone agonist combined with estradiol patch and oral medroxyprogesterone acetate on endometriosis

目的探讨促性腺激素释放激素激动剂（GnRH-a）联合反向添加疗法（经皮雌激素及口服醋酸甲羟孕酮）治疗子宫内膜异位症（内异症）的疗效及安全性。方法选择2007年1月1日-7月31日于复旦大学附属妇产科医院住院接受治疗、经腹腔镜或开腹手术确诊的内异症患者28例，随机分为A、B两组，每组各14例。A组患者于月经周期第2天起给予戈舍瑞林3．6mg皮下注射，每4周注射1次，共12周；B组患者在A组治疗方案基础L同时加用半水合雌二醇贴剂，每周1／2片贴于腹部皮肤，并每晚口服醋酸甲羟孕酮6mg，共12周。比较两组患者治疗前、治疗后（疗程第12周内）及月经恢复后的血清激素及骨钙素水平、阴道脱落细胞百分比、疼痛症状视觉模拟评分（VAS）、腰椎骨密度及骨量丢失率、绝经症状严重程度（以Kupperman评分表示）等。结果（1）两组患者治疗后的血清卵泡刺激素（FSH）及雌二醇水平，A组分别为（5．0±2．6）U／L和（29±17）pmol／L，B组分别为（3．0±1．5）U／L和（87±53）pmol／L，均分别低于治疗前水平[A组分别为（17．0±12．2）U／L和（184±194）pmol／L，B组分别为（15．3±13．6）U／L和（281±242）pmol／L]，差异均有统计学意义（P〈0．01）；治疗后B组的雌二醇水平高于A组，FSH水平低于A组，差异也均有统计学意义（P〈0．01）。（2）治疗后的阴道脱落细胞中，A组的底层细胞百分比[（66．2±29．0）％]高于B组[（11．8±28．0）％]，中层细胞[（29．1±23．1）％]、表层细胞[（4．0±5．5）％]和伊红染色细胞百分比[（2．3±2．6）％]则分别低于B组[分别为（73．0±25．2）％、（15．2±10．9）％、（10．8±7．9）％]，差异均有统计学意义（P〈0．01）。（3）两组患者治疗前的疼痛症状总分及盆腔痛、痛经、性交痛评分，A组分别为（7．43±3．20）、（2．35-4-1．82）、（4．93±1．98）和（0．14±0．53）分，B组分别为（7．71±2．02）、（2．57±1．60）、（4．86±1．56）和（0．29±1．07）分；治疗后，两组患者的VAS总分及各项评分[A组分别为（0．14±0．36）、（0．07±0．27）、（0．07±0．27）和0分，B组分别为（0．36±0．50）、（0．29±0．47）、（0．07±0．27）和0分]均低于治疗前，差异均有统计学意义（P〈0．01）；月经恢复后，两组的总分及各项评分[A组分别为（0．21±0．43）、（0．07±0．27）、（0．14±0．36）和0分，B组分别为（0．50±0．65）、（0．29±0．47）、（0．21±0．43）和0分]也均低于治疗前，差异也均有统计学意义（P〈0．01）；两组之间各项评分比较，差异均无统计学意义（P〉0．05）。（4）治疗前A、B两组的骨密度分别为（0．99±0．06）g／cm^2和（0．99±0．10）g/cm^2，治疗后A组的骨密度为（0．96±0．06）g／cm^2，低于治疗前水平，差异有统计学意义（P〈0．01），B组的骨密度为（0．98±0．09）g／cm^2，也低于治疗前水平，但差异无统计学意义（P=0．201）；治疗前、后两组间骨密度分别比较，差异均无统计学意义（P〉0．05）。A、B两组的骨量丢失率分别为（-2．77±1．97）％和（-0．93±2．86）％，两组之间比较，差异无统计学意义（P=0．058）。治疗前A、B两组外周血骨钙素水平分别为（13±3）μg,／L和（13±6）μg／L，治疗后A组外周血骨钙素水平为（17±6）μg/L，高于治疗前水平，差异有统计学意义（P〈0．01），B组为（16±6）μg/L，也高于治疗前水平，但差异无统计学意义（P=0．053）；治疗前、后两组问骨钙素水平分别比较，差异均无统计学意义（P〉0．05）。（5）A、B两组患者治疗后的改良Kuppennan评分总分分别为（15±7）分和（11±6）分，两组间比较，差异无统计学意义（P〉0．05）。A、B两组患者中潮热出汗的发生率分别为93％（13／14）和57％（8／14），两组间比较，差异有统计学意义（P〈0．01）。结论经皮雌激素加口服醋酸甲羟孕酮治疗内异症是一种安全有效的反向添加疗法。

Objective To evaluate effects and safety of gonadotrophin-releasing hormone agonist （GnRH-a） combined with transdermal estradiol and medroxyprogesterone acetate in the treatment of endometriosis. Methods From January 1 st, 2007 to July 31 st, 2007, 28 endometriosis patients underwent laparoscopic or transabdominal surgery in Obstetrics and Gynecology Hospital affiliated to Fudan University were randomly divided into group A and group B. 14 patients in group A received 3.6 mg goserelin once every 4 weeks, 12 weeks in all. 14 patients in group B received goserelin and added 1/2 piece of halfhydrate estradiol every week and 6 mg oral medroxyprogesterone acetate per day, 12 weeks in all. Serum estradiol （ E2 ）, follicle stimulating hormone （FSH） , bone gla protein levels, visual analogue scale （VAS） of pain, bone mineral density of lumbar spine, vaginal exfoliate cell spurs and the form of Kupperman were compared in patients before and after treatment. Results （ 1 ） After treatment, the level of FSH and E2 levels were （5.0±2. 6）U/L and（29 ± 17） pmol/L in group A and （3.0 ± 1.5）U/L, and（87 ±53）pmol/L in group B, which were significantly lower than those before treatment [ FSH （ 17.0 -＋ 12. 2） U/L, and E2 （ 184 ± 194） pmoL/L in group A and FSH ： （ 15.3 ± 13.6） U/L and E2 ： （ 281± 242） pmol/L in group B, P 〈 0. 01 ]. On the seventh day after three-month GnRH-a treatment, it was observed that the level of E2 was higher and FSH was lower in group B than the level of E2 and FSH of group A （P〈0. 01）. （2） After treatment, the basal vaginal exfoliate cell proportion in group A [ （66. 2 ±29.0 ） % ] was significantly lower than that in group B [ （11.8 ± 28. 0）% , P 〈 0. 01 ] ; while patients in group A owned a lower proportion of the middle [（29.1 ±23.1）%], superficial layers [（4.0 -＋5.5）% ] and esinophilic cells[（2.3 ± 2. 6）% ]than oatients group B [ middle laver： （73.0 ± 25.2）% ： superficial laver, （ 15.2 ±10. 9）% ：esinophilic cells ： （ 10. 8± 7.9） % ; P 〈 0. 01 ]. （3） Before the treatment, patients＇ VAS scores of total, pelvic pain, dysmenorrheal and dyspareunia were 7. 43 ±3.20,2. 35 ±1.82, 4. 93± 1.98 and 0. 14 ±0. 53 in group A and were 7.71±2. 02, 2. 57 ± 1.60, 4. 86 ± 1.56 and 0. 29 ± 1. 07 in group B; after treatment, the scores above were changed to 0. 14 ±0. 36,0. 07±0. 27,0. 07±0. 27and 0 in group A and 0. 36±0. 50, 0. 29±0. 47, 0. 07± 0. 27 and 0 in group B, which were all significantly lower than those before treatment separately （ P 〈 0. 01 ）. When menstruation recovered, the scores were 0. 21 ± 0. 43, 0. 07 ± 0. 27, 0. 14 ±0.36, and0 in group A and 0.50 ±0.65, 0.29 ±0.47, 0.21±0.43 and 0 in group B, which were also significantly lower than those before treatment（ P 〈 0. 01 ）, however, no statistical difference was found between groups at any time spot（P 〉0. 05）. （4） In group A, the bone density after treatment [ （0. 96 ± 0. 06） g/cm^2 ] was lower than that before treatment [ （ 0. 99 ± 0. 06 ） g/cm^2, P 〈 0. 01 ） ]. In group B, the index was （0. 98 ±0.09）g/cm^2, which was lower than that before treatment[ （0. 99± 0. 10）g/cm^3. P =0. 201 ]. No statistical difference was found between groups（P 〉 0. 05 ）. The bone loss rate were （ -2. 77±1.97）% in group A and （ -0.93 ±2.86）% in group B（P=0.058）. Before treatment, the bone gla protein was （13±3）μg/L in group A and （13±6）μg/L in group B. After treatment, the bone gla protein levels was （ 17±6） μg/L in group A, which was higher than that before treatment （P 〈0. 01 ）, the level was （ 16 ±6） μg/L in group B, which was higher than that before treatment, however showed no statistical difference（P =0. 053）. No difference was found in bone gla protein before and after treatment between two groups （ P 〉 0. 05 ）. （5） The form of Kupperman after treatment were 15 ± 7 in group A and 11 ± 6 in group B, which did not show significant difference （ P 〉 0. 05 ） . The incidence of flash and sweat were 93% （13/14） in grouo A. which was significantly higher than that 57% （8/14） in group B （P 〈 0. 01 ）.