子宮內(nèi)膜異位癥 診斷及治療的進(jìn)展

北大醫(yī)院

周應(yīng)芳
大體病理
郎景和教授將內(nèi)異癥分為四個(gè)類型：
腹膜型
卵巢型
陰道直腸型
特殊部位型或盆腔外型
   
 但對(duì)內(nèi)異癥的診段尚無統(tǒng)一的、規(guī)范性的標(biāo)準(zhǔn)出臺(tái)
大體病理
日本產(chǎn)科婦人科學(xué)會(huì)所分的類型：

1．無色素異位病灶

2．含色素異位病灶

3．繼發(fā)性病變
無色素異位病灶

1. 小水泡

2. 漿液性囊泡

3. 表面隆起

含色素異位病灶
1 .紫藍(lán)色結(jié)節(jié) 
2. 血性囊泡 
3. 散在燒灼樣灶 
4. 含鐵血黃素著色 
5. 點(diǎn)狀出血斑
6. 漿膜下出血 
7. 子宮內(nèi)膜異位囊腫

子宮內(nèi)膜異位癥繼發(fā)性病變

1. 粘連及腹膜袋形成

2. 攣縮狀瘢痕

異位癥的治療
郎景和教授總結(jié)近年來國內(nèi)外多數(shù)學(xué)者達(dá)成的共識(shí)子宮內(nèi)膜異位癥的治療有5個(gè)“最好方法”：
腹腔鏡手術(shù)是最好的治療
卵巢抑制是最好的治療
手術(shù)?藥物治療?再次腹腔鏡手術(shù)的3階段治療(three phase therapy）是最好的治療
妊娠是最好的治療
助孕技術(shù)是最好的治療
腹腔鏡手術(shù)
 1.腹腔鏡手術(shù)優(yōu)于開腹手術(shù)

 2.巨大內(nèi)膜囊腫、估計(jì)有廣泛腸粘連、需行腸切除術(shù)或判定為很復(fù)雜的手術(shù)以開腹手術(shù)為宜
  
  腹腔鏡下行腸切除術(shù)治療腸道子宮內(nèi)膜異位癥（Surg Laparosc Endosc Percutan Tech 2001）
Feasibility of robotic laparoscopic surgery: 146 cases(Belgium)
 The first robot-assisted procedure in humans was performed in March 1997. 
Gynecological surgeries:
tubal reanastomoses  28
hysterectomies   2
endometriosis cure  1
neosalpingostomy   1

World J Surg  2001 Nov;25(11):1467-77
保守性手術(shù) （手段）
二氧化碳激光
治療內(nèi)異癥經(jīng)循征醫(yī)學(xué)證實(shí)療效肯定，安全性高，但因設(shè)備昂貴、手術(shù)速度慢和止血效果差等近年來臨床報(bào)道明顯減少
單極和雙極電凝
微波
超聲刀
 這些新技術(shù)能否徹底破壞異位病灶及其安全性均有待于進(jìn)一步積累資料。

手術(shù)方法　　
1．分離粘連　　

2．清除子宮內(nèi)膜異位結(jié)節(jié)　

3．去除卵巢子宮內(nèi)膜異位病灶
卵巢子宮內(nèi)膜異位囊腫分型

Nezhat等對(duì)216個(gè)出血性囊腫（子宮內(nèi)膜異位囊腫）進(jìn)行了仔細(xì)的病理研究后，將卵巢子宮內(nèi)膜異位囊腫分為兩型。
Ⅰ型子宮內(nèi)膜異位囊腫（原發(fā)性）
Ⅱ型子宮內(nèi)膜異位囊腫（繼發(fā)性） 
ⅡA
ⅡB
ⅡC

囊腫部分切除術(shù) 不可取！
手術(shù)要點(diǎn)
充分分離粘連----防止損傷

徹底剝除囊腫----減少復(fù)發(fā)

認(rèn)真止血----防止血腫及粘連

多保留正常卵巢----利于日后妊娠
硬化療法
腹腔鏡下或超聲監(jiān)測(cè)下囊腫穿刺抽液注入無水乙醇或重組白介素-2（最近），認(rèn)為創(chuàng)傷小、恢復(fù)快，囊腫復(fù)發(fā)率減少。

Noma 和Yoshida（J Gynaecol Obstet 2001）83例：
隨訪半年以上者有74例，復(fù)發(fā)11例（14.9% ）；
同期30例腹腔鏡下剝除術(shù)的復(fù)發(fā)率3.8%（P>0.05);
乙醇留置時(shí)間小于10min及多發(fā)囊腫的復(fù)發(fā)率明顯高 。
Epithelial abnormalities in cystic ovarian endometriosis (Italy)
339 cases:
metaplasia    12.1 %
hyperplasia    9.4%
atypia     5.9%
endometrioid carcinoma arising in endometriosis   4.1%

 Gynecol Oncol  2002 Feb;84(2):280-4
子宮神經(jīng)去除術(shù)或 骶前神經(jīng)切除術(shù)

緩解盆腔中央疼痛

我們近年來開展了子宮神經(jīng)去除術(shù) (laparoscopy uterine nerve  ablation，LUNA)，初步看來，對(duì)痛經(jīng)有一定效果

循證醫(yī)學(xué)證據(jù)
國外循證醫(yī)學(xué)證據(jù)：
對(duì)下腹中央疼痛者行骶前神經(jīng)切除術(shù)（PSN）療效明顯
近年來許多醫(yī)生提倡用腹腔鏡子宮神經(jīng)去除術(shù)(laparoscopy uterine nerve  ablation，LUNA)替代PSN，手術(shù)簡(jiǎn)單易行，安全性高，近期療效同骶前神經(jīng)切除術(shù)，痛經(jīng)緩解率可達(dá)75%
但也有學(xué)者研究發(fā)現(xiàn)LUNA緩解疼痛的效果并不明顯，此外，LUNA的遠(yuǎn)期療效也不如PSN

國內(nèi)循證醫(yī)學(xué)研究：尚缺乏資料

藥物治療

 1. 適用于病情較輕、無明確子宮內(nèi)膜異位囊  腫者，療程一般6～9個(gè)月
 
 2. 若作為手術(shù)前后的輔助治療，療程可縮短      為3～6個(gè)月
 
  3. 對(duì)有疼痛癥狀者,療程有延長趨勢(shì)
EBM data
腹腔鏡保守性手術(shù)后用藥療程以6個(gè)月為宜，3個(gè)月的療程不能降低疼痛復(fù)發(fā)率

重度內(nèi)異癥有生育要求者，術(shù)后是否有必要行藥物治療仍有爭(zhēng)議，雖然藥物治療推遲了患者的妊娠時(shí)機(jī)，但也有報(bào)道認(rèn)為積極助孕治療后妊娠機(jī)會(huì)還會(huì)增加

Danazol
國外已少用

RCT（ Morgante 等，Hum Reprod 1999）：腹腔鏡手術(shù)+ GnRH-a治療6個(gè)月后每天100mg小劑量達(dá)那唑再用藥6個(gè)月：
能減少中重度子宮內(nèi)膜異位癥患者的盆腔疼痛復(fù)發(fā)，并且?guī)缀鯖]有副作用

國內(nèi)許多醫(yī)生更傾向于使用孕三烯酮或內(nèi)美通
Danazol-loaded IUD
A danazol-loaded IUD

Containing 300-400 mg of danazol

Inserted for 6 months (n = 18) (median age 36.6 years) referred for recurrent pelvic pain.

Dysmenorrhea, dyspareunia, and pelvic pain significantly decreased after the first month, with a persistent effect during the 6 months of IUD insertion.

 Cobellis L.Fertility & Sterility 2004

GnRH-a治療
是發(fā)達(dá)國家最常使用的藥物緩解疼痛效果明顯（90%以上）
保守性手術(shù)后使用可以推遲疼痛復(fù)發(fā)（Br J Obstet Gynaecol 1999）
價(jià)格昂貴
低雌激素效應(yīng)
對(duì)不孕患者能提高受孕力?（Curr Opin Obstet Gynecol 2000）

GnRHa 對(duì) 骨密度（BMD）的影響

反向添加療法 ( add-back therapy)
定義：使用GnRH-a類的同時(shí)補(bǔ)充小劑量雌激素和   孕激素
作用：即可防止骨質(zhì)丟失，又減少了低雌激素的  副反應(yīng)，同時(shí)并不降低對(duì)子宮內(nèi)膜異位癥  的治療效果 
添加方案：
  1．倍美力  0.3mg～0.625mg/d 和安宮黃體       酮  2mg～5mg/天
  2．利維愛  1.25mg ～ 2.5mg/d
GnRH-a減量治療 （draw-back therapy）
目前使用的劑量偏大？
buserelin減量治療的報(bào)道（J Obstet Gynaecol Res 1999）；
減量治療：先用全量nafarelin，4周后將藥量減半維持，療效同全量，低雌激素癥狀減輕，骨質(zhì)丟失減少（Fertil Steril 2000 ）；
triptorelin作用時(shí)間較長，可每6周注射1次（Hong Kong Med J 2000）；
避孕藥
假孕療法(pseudopregnancy therapy)
已少用

短效避孕藥
1～2片/d，以閉經(jīng)為準(zhǔn)，連服6～9個(gè)月
療效和假孕療法相似
副作用輕
 
Mifepristone

國外有學(xué)者用米非司酮治療子宮內(nèi)膜異位癥，國內(nèi)近年來報(bào)道明顯增多
結(jié)果認(rèn)為閉經(jīng)率高，副反應(yīng)輕，控制疼痛效果滿意
米非司酮價(jià)格便宜，使用前景好
國內(nèi)正在做臨床驗(yàn)證

Others
芳香化酶抑制劑(aromatase inhibitor) 瑞寧得（anastrozole，阿那曲唑）
環(huán)氧合酶抑制劑
LNG-IUS (Mirena)
SERM: raloxifene (USA)
含藥物陰道環(huán)?
GnRH拮抗劑
芳香化酶抑制劑(Ais)
In premenopausal women, the ovary can overcome the estrogen blockade by reflex increments of LH and FSH, so AIs must be combined with a gonadotropin releasing hormone (GnRH) agonist to prevent the reflex LH and FSH increments.

AIs have been used in infertility and can increase ovulation rate.

A pilot trials showed that aromatase inhibitors could decrease pelvic pain associated with endometriosis.

芳香化酶抑制劑-臨床研究
Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study.
 10 patients with endometriosis
letrozole (2.5 mg, po) and norethindrone acetate (2.5 mg) for 6 months
Second-look laparoscopy
 marked reduction of laparoscopically visible and histologically confirmed endometriosis in all 10 patients and significant pain relief in nine out of 10 patients
 Ailawadi,-R-K,et al. Fertil-Steril. 2004 Feb; 81(2): 290-6

環(huán)氧合酶抑制劑 COX-2 specific inhibitor
Animal researchs
Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib.
Dogan E, Fertility & Sterility. 82 Suppl 3, 2004  Turkey
Cyclooxygenase-2 selective inhibitor prevents implantation of eutopic endometrium to ectopic sites in rats.
Matsuzaki S. Fertility & Sterility. 2004 France

環(huán)氧合酶抑制劑-臨床應(yīng)用
STUDY DESIGN
pelvic pain after conservative surgery for symptomatic endometriosis (Stage I and II) (n = 28) . 
a COX-2 specific inhibitors (rofecoxib, 25mg per day) (n = 16) or placebo (n = 12) was given for 6 months.
RESULTS
A significant improvement of both pelvic pain and dyspareunia was observed after a 6 months persisting since the end of the treatment (P < 0.0001).
The efficacy of rofecoxib was higher than placebo and no recurrence occurred, while in the placebo-treatment a 16% (2/12) occurred.
No significant side effects have been found with the use of rofecoxib.
CONCLUSIONS
rofecoxib was effective, safe and low cost therapy in the management of pelvic pain associated to endometriosis and might be also proposed in early stage of endometriosis.
Cobellis L,European Journal of Obstetrics, Gynecology, & Reproductive Biology. 116(1):100-2, 2004 Italy

Successful treatment of severe endometriosis in two premenopausal women with an aromatase inhibitor
Methods
anastrozole with the addition of 200-mg oral progesterone (P) capsules once daily, hs, and calcitriol 0.5 microg oral capsules twice daily. All three medications were given daily for 21 days followed by 7 days off, for a 28-day treatment cycle. rofecoxib 12.5 mg was administered once a day continuously for the 28-day cycle.
RESULT(S):
Treatment resulted in a rapid, progressive reduction in symptms over 3 months with the maintenance of remission of symptoms for over 24 months after treatment in both cases. There was confirmation of absence of disease in one case by follow-up laparoscopy 15 months after treatment. Pregnancy was achieved in both cases after 24 months.
Shippen ER, Fertility & Sterility, 2004 USA.

含藥物宮內(nèi)節(jié)育器 （LNG-IUS）
Vercellini 等（Fertil Steril 1999 ）治療20例行保守性手術(shù)后痛經(jīng)復(fù)發(fā)患者，12個(gè)月后隨訪效果：
很滿意 4例
滿意  11例
一般          2例
不滿意 3例
 
Fedele等（Fertil Steril 2001）治療11例直腸陰道膈子宮內(nèi)膜異位癥，患者痛經(jīng)、性交痛和盆腔痛癥狀明顯改善，異位結(jié)節(jié)縮小

新近報(bào)道：對(duì)中重度內(nèi)異癥行腹腔鏡保守性手術(shù)后即刻放置LNG-IUS可明顯降低疼痛的復(fù)發(fā)率
GnRH拮抗劑-臨床報(bào)道（Germany）
GnRH antagonist cetrorelix (Cetrotide) subcutaneous injection in a 3 mg dosage once weekly over 8 weeks
All the 15 patients  reported asymptom-free period during GnRH antagonist treatment,
Serum oestradiol oscillated around a mean concentration of 50 pg/ml during therapy.
Second look Lap： regression occurred in 60% of cases (9/15)， a mean stage III of disease. declined to stage II.
  
 Kupker W, et al. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online 2002Jul-Aug;5(1):12-6

新的治療探索
內(nèi)異癥的基礎(chǔ)研究將會(huì)繼續(xù)地推動(dòng)臨床治療，甚至?xí)淖內(nèi)藗冎委焹?nèi)異癥的傳統(tǒng)思路
抗黏附
抗侵襲
抗血管生成藥物可能會(huì)逐步用于臨床
細(xì)胞因子調(diào)控
受體干預(yù)
基因治療

動(dòng)物實(shí)驗(yàn)
抗腫瘤壞死因子
Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons（狒狒）.
 Etanercept (n = 8) or sterile water (n = 4) administered subcutaneously three times weekly.
A statistically significant decrease in red lesion surface area in the treatment group

Barrier,-B-F，et al. Fertil-Steril. 2004 Mar; 81 Suppl 1: 775-9

動(dòng)物實(shí)驗(yàn)
Antiangiogenesis therapy for endometriosis  in the nude mouse （裸鼠）model.
antihuman vascular endothelial growth factor
TNP-470
Endostatin
 anginex
The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions
Nap,-A-W,et al.J-Clin-Endocrinol-Metab. 2004 Mar; 89(3): 1089-95

人體研究
血管生成抑制劑（腫瘤治療方面）
進(jìn)入臨床研究的有20種
抗體有3中
抗VEGF抗體（endostatin，內(nèi)皮抑素）
Ⅲ期臨床
抗VEGF-R2抗體
Ⅰ期臨床
抗av?3抗體
Ⅱ期臨床
新的治療探索
郎景和教授創(chuàng)立的內(nèi)異癥發(fā)病的“在位內(nèi)膜決定論” ：
加強(qiáng)對(duì)在位子宮內(nèi)膜進(jìn)行調(diào)控、干預(yù)和治療的研究，以改變其生物學(xué)特質(zhì)和行為
這種 “源頭治療”即可治療異位病灶又有利于防治出現(xiàn)新的異位病灶，可望收到“標(biāo)本兼治”的理想效果
給內(nèi)異癥的治療開辟了一個(gè)嶄新的天地