Endometriosis: an overview of Cochrane Reviews

  • Review
  • Overview

Authors


Abstract

Background

This overview reports on interventions for pain relief and for subfertility in pre-menopausal women with clinically diagnosed endometriosis.

Objectives

The objective of this overview was to summarise the evidence from Cochrane systematic reviews on treatment options for women with pain or subfertility associated with endometriosis.

Methods

Published Cochrane systematic reviews reporting pain or fertility outcomes in women with clinically diagnosed endometriosis were eligible for inclusion in the overview. We also identified Cochrane reviews in preparation (protocols and titles) for future inclusion. The reviews, protocols and titles were identified by searching the Cochrane Database of Systematic Reviews and Archie (the Cochrane information management system) in March 2014.

Pain-related outcomes of the overview were pain relief, clinical improvement or resolution and pain recurrence. Fertility-related outcomes were live birth, clinical pregnancy, ongoing pregnancy, miscarriage and adverse events.

Selection of systematic reviews, data extraction and quality assessment were undertaken in duplicate. Review quality was assessed using the AMSTAR tool. The quality of the evidence for each outcome was assessed using GRADE methods. Review findings were summarised in the text and the data for each outcome were reported in 'Additional tables'.

Main results

Seventeen systematic reviews published in The Cochrane Library were included. All the reviews were high quality. The quality of the evidence for specific comparisons ranged from very low to moderate. Limitations in the evidence included risk of bias in the primary studies, inconsistency between the studies, and imprecision in effect estimates.

Pain relief (14 reviews)

Gonadotrophin-releasing hormone (GnRH) analogues

One systematic review reported low quality evidence of an overall benefit for GnRH analogues compared with placebo or no treatment.

Ovulation suppression

Five systematic reviews reported on medical treatment using ovulation suppression. There was moderate quality evidence that the levonorgestrel-releasing intrauterine system (LNG-IUD) was more effective than expectant management, and very low quality evidence that danazol was more effective than placebo. There was no consistent evidence of a difference in effectiveness between oral contraceptives and goserelin, estrogen plus progestogen and placebo, or progestogens and placebo, though in all cases the relevant evidence was of low or very low quality.

Non-steroidal anti-inflammatory drugs (NSAIDS)

A review of NSAIDs reported inconclusive evidence of a benefit in symptom relief compared with placebo.

Surgical interventions

There were two reviews of surgical interventions. One reported moderate quality evidence of a benefit in pain relief following laparoscopic surgery compared to diagnostic laparoscopy only. The other reported very low quality evidence that recurrence rates of endometriomata were lower after excisional surgery than after ablative surgery.

Post-surgical medical interventions

Two reviews reported on post-surgical medical interventions. Neither found evidence of an effect on pain outcomes, though in both cases the evidence was of low or very low quality.

Alternative medicine

There were two systematic reviews of alternative medicine. One reported evidence of a benefit from auricular acupuncture compared to Chinese herbal medicine, and the other reported no evidence of a difference between Chinese herbal medicine and danazol. In both cases the evidence was of low or very low quality.

Anti-TNF-α drugs

One review found no evidence of a difference in effectiveness between anti-TNF-α drugs and placebo. However, the evidence was of low quality.

Reviews reporting fertility outcomes (8 reviews)

Medical interventions

Four reviews reported on medical interventions for improving fertility in women with endometriosis. One compared three months of GnRH agonists with a control in women undergoing assisted reproduction and found very low quality evidence of an increase in clinical pregnancies in the treatment group. There was no evidence of a difference in effectiveness between the interventions in the other three reviews, which compared GnRH agonists versus antagonists, ovulation suppression versus placebo or no treatment, and pre-surgical medical therapy versus surgery alone. In all cases the evidence was of low or very low quality.

Surgical interventions

Three reviews reported on surgical interventions. There was moderate quality evidence that both live births or ongoing pregnancy rates and clinical pregnancy rates were higher after laparoscopic surgery than after diagnostic laparoscopy alone. There was low quality evidence of no difference in effectiveness between surgery and expectant management for endometrioma. One review found low quality evidence that excisional surgery resulted in higher clinical pregnancy rates than drainage or ablation of endometriomata.

Post-surgical interventions

Two reviews reported on post-surgical medical interventions. They found no evidence of an effect on clinical pregnancy rates. The evidence was of low or very low quality.

Alternative medicine

A review of Chinese herbal medicine in comparison with gestrinone found no evidence of a difference between the groups in clinical pregnancy rates. However, the evidence was of low quality.

Adverse events

Reviews of GnRH analogues and of danazol reported that the interventions were associated with higher rates of adverse effects than placebo; and depot progestagens were associated with higher rates of adverse events than other treatments. Chinese herbal medicine was associated with fewer side effects than gestrinone or danazol.

Three reviews reported miscarriage as an outcome. No difference was found between surgical and diagnostic laparoscopy, between GnRH agonists and antagonists, or between aspiration of endometrioma and expectant management. However, in all cases the quality of the evidence was of low quality.

Authors' conclusions

For women with pain and endometriosis, suppression of menstrual cycles with gonadotrophin-releasing hormone (GnRH) analogues, the levonorgestrel-releasing intrauterine system (LNG-IUD) and danazol were beneficial interventions. Laparoscopic treatment of endometriosis and excision of endometriomata were also associated with improvements in pain. The evidence on NSAIDs was inconclusive. There was no evidence of benefit with post-surgical medical treatment.

In women with endometriosis undergoing assisted reproduction, three months of treatment with GnRH agonist improved pregnancy rates. Excisional surgery improved spontaneous pregnancy rates in the nine to 12 months after surgery compared to ablative surgery. Laparoscopic surgery improved live birth and pregnancy rates compared to diagnostic laparoscopy alone. There was no evidence that medical treatment improved clinical pregnancy rates.

Evidence on harms was scanty, but GnRH analogues, danazol and depot progestagens were associated with higher rates than other interventions.

摘要

子宮內膜異位症:縱觀考科藍文獻回顧

背景

本次文獻回顧針對臨床診斷為子宮內膜異位症 (endometriosis) 的停經前女性,探究緩解疼痛及治療低生育力 (subfertility) 的相關介入。

目的

本次文獻回顧的目的旨在概述來自考科藍系統性文獻回顧的證據,探討子宮內膜異位症女性患者的疼痛或低生育力治療選擇。

方法

本次文獻回顧納入已發表的考科藍系統性文獻回顧,探討臨床診斷為子宮內膜異位症的女性患者,其疼痛或生育力結果。我們也找尋籌備中的考科藍文獻回顧 (試驗計畫書與標題),以備未來將其納入文獻回顧。我們於2014年3月搜尋考科藍系統性回顧暨檔案檢索系統 (Cochrane Database of Systematic Reviews and Archie) (考科藍資訊管理系統),找尋文獻回顧、試驗計畫書和標題。

文獻回顧的疼痛相關結果為疼痛緩解、臨床改善或治癒,以及疼痛復發。生育力相關結果則為活產、臨床懷孕 (clinical pregnancy)、持續懷孕 (ongoing pregnancy)、流產和不良事件。

以一式兩份的方式選擇系統性文獻回顧、萃取資料和評估品質。利用AMSTAR工具評估文獻回顧的品質,並採用GRADE方法評估各項結果的證據品質。回顧結果匯整摘述於內文,並以「附表」的方式呈現各項結果的數據。

主要結果

我們納入17篇發表於考科藍圖書館的系統性文獻回顧,所有文獻回顧均具有高品質。具體比較的證據品質範圍介於極低至中等之間,證據的限制包括原始試驗的偏差風險、各試驗之間的不一致性,以及效果估計不夠精確。

緩解疼痛 (14篇文獻回顧)

促性腺激素釋放素 (Gonadotrophin-releasing hormone, GnRH) 類似物

有1篇系統性文獻回顧指出,相對於安慰劑或無治療組,GnRH 的整體效益證據品質偏低。

抑制排卵

有5篇系統性文獻回顧探討抑制排卵作用的內科治療。「levonorgestrel 子宮內投藥系統 (levonorgestrel-releasing intrauterine system, LNG-IUD) 療效優於預期處置 (expectant management)」的證據品質中等;「danazol優於安慰劑」的證據品質極低。關於口服避孕藥和goserelin、雌激素 (estrogen) 加黃體素 (progestonge) 和安慰劑,或黃體素和安慰劑的療效差異比較,所得到的證據並不一致,雖然所有相關證據的品質均偏低或極低。

非類固醇類消炎劑 (Non-steroidal anti-inflammatory drug, NSAID)

關於NSAID的文獻回顧指出,相對於安慰劑,並無明確證據顯示NSAID可有效緩解症狀。

外科手術介入

有2篇關於外科手術介入的文獻回顧,其中1篇文獻回顧指出,相較於僅進行診斷性腹腔鏡檢查 (laparoscopy),「腹腔鏡外科手術後可緩解疼痛」的證據品質中等;另1篇文獻回顧指出相較於分離手術 (ablative surgery),切除手術 (excisional surgery) 後子宮內膜異位瘤 (endometriomata) 的復發率較低,但證據品質極低。

手術後內科介入

有2篇文獻回顧提出關於手術後內科介入的報告,並未發現對疼痛結果具有影響,雖然2篇文獻回顧所收集的證據品質偏低或極低。

另類醫學

有2篇關於另類醫學的系統性文獻回顧,其中1篇提出耳針 (auricular acupuncture) 的療效優於中草藥 (Chinese herbal medicine) 的證據,另1篇則指出並無證據顯示中草藥和danazol的療效具有差異。2篇文獻回顧所收集的證據品質偏低或極低。

抗α腫瘤壞死因子藥物 (Anti-TNF-α drug)

有1篇文獻回顧發現,並無證據顯示抗α腫瘤壞死因子藥物的療效,與安慰劑不同。不過此篇文獻回顧所收集的證據品質偏低。

生育力結果的文獻回顧 (8篇文獻回顧)

內科介入

有4篇文獻回顧提出以內科介入,改善子宮內膜異位症患者生育力的相關報告。有1篇文獻回顧針對接受人工協助生殖 (assisted reproduction) 的女性,比較3個月的GnRH促效劑組和對照組,結果發現治療組的臨床懷孕率增加,但證據品質極低。其他3篇文獻回顧,並未發現這些介入具有療效差異,上述文獻回顧比較GnRH促效劑和拮抗劑、排卵抑制和安慰劑或無治療介入,以及手術前內科治療與單獨使用外科手術等介入方式。所有文獻回顧收集的證據品質均偏低或極低。

外科手術介入

有3篇文獻回顧提出關於外科介入的報告。相較於單獨使用診斷性腹腔鏡檢查,進行腹腔鏡手術後患者的活產或持續懷孕率與臨床懷孕率均較高,此項證據品質中等。外科手術和預期處置對子宮內膜異位瘤的療效並無差異,此項證據品質偏低。有1篇文獻回顧發現,相較於子宮內膜異位瘤引流或分離手術,切除手術後的臨床懷孕率較高,此項證據品質低。

手術後介入

有2篇文獻回顧報告外科手術後的內科介入。研究者並未發現對臨床懷孕率有影響的證據,此項證據品質偏低或極低。

另類醫學

有1篇文獻回顧比較中草藥與gestrinone,並未發現2個治療組的臨床懷孕率有差異,不過此項證據品質偏低。

不良作用

GnRH類似物和danazol的文獻回顧指出,這些介入的不良作用發生率高於安慰劑;持續型黃體素 (depot progestagen) 的不良事件發生率高於其他治療。中草藥的副作用比gestrinone或danazol少。

有3篇文獻回顧以流產為結果。外科手術和診斷性腹腔鏡檢查、GnRH促效劑和拮抗劑,或子宮內膜瘤抽吸術和預期處置的流產發生率,並無組間差異。不過所有的證據品質皆偏低。

作者結論

對於有經痛和子宮內膜異位症的女性患者,使用促性腺激素釋放素 (Gonadotrophin-releasing hormone, GnRH) 類似物、levonorgestrel 子宮內投藥系統 (levonorgestrel-releasing intrauterine system, LNG-IUD)和danazol抑制月經週期,可能是有效的治療方法。以腹腔鏡手術治療子宮內膜異位症並切除子宮內膜瘤,也可以改善疼痛症狀。NSAID的證據比較不明確,並無證據顯示手術後的內科治療具有療效。

對於進行人工協助生殖的子宮內膜異位症女性患者,接受3個月的GnRH促效劑治療可以提高懷孕率。相對於分離手術,切除手術將可提高手術後9至12個月內的自然懷孕率。相較於僅使用診斷性內視鏡檢查,內視鏡手術可提高活產和懷孕率。並無證據顯示內科治療能提高臨床懷孕率。

雖然極為欠缺傷害的相關證據,但GnRH類似物、danazol和持續型黃體素的不良作用發生率,高於其他介入。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

アブストラクト

子宮内膜症:コクランレビューの概要

背景

この概要では、臨床的に子宮内膜症と診断された閉経前の女性の疼痛緩和および低妊孕性に対する介入について報告する。

目的

この概要の目的は、子宮内膜症に起因する疼痛を有する女性または低妊孕性の女性に対する治療の選択肢について、コクランシステマティックレビューから得られたエビデンスを要約することであった。

方法

発表されたコクランシステマティックレビューは、臨床的に子宮内膜症と診断された女性における疼痛アウトカムまたは妊孕性能アウトカムを報告しており、この概要に含めるのに適格であった。今後の選択に備えて準備中(プロトコルとタイトル)のコクランレビューを確認した。そのレビュー、プロトコル、タイトルは2014年3月にCochrane Database of Systematic Reviews and Archie (the Cochrane information management system)を検索する事によって確認された。

この概要の疼痛関連アウトカムは疼痛緩和、臨床的改善または症状消失、そして痛みの再発であった。妊孕性関連アウトカムは生児出生、臨床的に確認された妊娠、妊娠の継続、流産、そして有害事象であった。

システマティックレビューの選択、データの抽出と質的評価は繰り返して試みた。レビューの質はAMSTAR ツールを使って評価した。個々のアウトカムに対するエビデンスの質はGRADE 法を用いて評価した。。レビューの結果は、本文中に要約され、個々のアウトカムについてのデータは’Additional tables’の中で報告された。

主な結果

The Cochrane Libraryで公表された17件のシステマティックレビューを含めたを含めた。すべてのレビューは質が高かった。個々の比較に関するエビデンスの質は非常に低いから中等度までの範囲であった。エビデンスの限界には、予備試験におけるバイアスのリスク、研究間の不一致、および効果の推定値における不正確さが含まれた。

疼痛緩和(14件のレビュー)

ゴナドトロピン放出ホルモン(GnRH)アナログ

プラセボまたは無治療と比較して、GnRHアナログの全体的有益性に関する質の低いエビデンスが1件のシステマティックレビューによって報告された。

排卵抑制

5件のシステマティックレビューは、排卵抑制剤を使用した内科的治療について報告した。レボノルゲストレル放出子宮内システム(LNG-IUD)は待機的管理に比較してより有効であるという中等度の質のエビデンスが存在し、ダナゾールはプラセボに比較してよりも有効であるという非常に質の低いエビデンスが認められた。経口避妊薬とゴセレリン、エストロゲン+プロゲストーゲンとプラセボ、またはプロゲストーゲンとプラセボとの間の有効性の差について一貫したエビデンスは存在しない。とはいえ、すべての症例で関連のあるエビデンスは質が低いか非常に質が低かった。

非ステロイド抗炎症薬(NSAIDs)

NSAIDsについてのレビューでは プラセボと比較して症状緩和の有益性について結論に到達しないエビデンスが報告された。

外科的介入

外科的介入に関する2件のレビューが存在した。1件のレビューでは、診断的腹腔鏡検査単独と比較した腹腔鏡下手術後の疼痛緩和の有益性の中等度の質のエビデンスが報告された。もう1件では、切除術後の子宮内膜腫の再発率がアブレーション後より低いという非常に質の低いエビデンスが報告された。

手術後の内科的介入

2件のレビューでは、手術後の内科的介入について報告された。2件の症例ともエビデンスは質が低いか非常に質が低かったが、どちらも疼痛アウトカムに対する効果を示すエビデンスは認められなかった。

代替医療

代替医療の2件のシステマティックレビューが存在した。1件のレビューでは漢方薬と比較して耳介の鍼治療からの有益性を示すエビデンスが、もう1件では漢方薬とダナゾールとの間の差を示すエビデンスは無いと報告された。2件の症例においてエビデンスは質が低いか非常に質が低かった。

抗TNF-α薬

1件のレビューでは、抗TNF-α薬とプラセボとの間の有効性における差についてのエビデンスは認められなかった。しかしながらそのエビデンスは質が低かった。

妊孕性能アウトカムについて報告しているレビュー(8件のレビュー)

内科的介入

4件のレビューでは、子宮内膜症の女性の妊孕性能の改善に関する内科的介入に関して報告された。1件のレビューでは、生殖補助医療を受けている女性においてGnRHアゴニストを3カ月間対照と比較し、治療群における臨床妊娠の増加の非常に質の低いエビデンスが認められた。その他の3件のレビューにおける介入の有効性の差を示すエビデンスが存在しなかった。その3件の介入とは、GnRHアゴニストとアンタゴニスト、排卵抑制とプラセボまたは無治療、術前の内科的療法と手術単独の比較であったすべてのケースにおいてエビデンスの質は低いか非常に質が低かった。

外科的介入

3件のレビューでは、外科的介入に関する報告があった。生児出生率または継続妊娠率および臨床妊娠率は共に診断的腹腔鏡検査単独後よりも腹腔鏡下手術の後の方がより高いという中程度の質のエビデンスがあった。子宮内膜症に関して手術と待機的管理との間には有効性に差が無いという質の低いエビデンスが存在した。1件のレビューでは、切除術は結果的にドレナージまたは子宮内膜腫のアブレーションより高い臨床妊娠率になるという質の低いエビデンスが認められた。

術後介入

2件のレビューでは、手術後の内科的介入について報告された。それらのレビューでは、臨床妊娠率に対する効果を示すエビデンスは認められなかった。そのエビデンスの質は低いか非常に低かった。

代替医療

ゲストリノンと比較した漢方薬の1件のレビューでは、臨床妊娠率におけるグループ間の差を示すエビデンスが認められなかったしかしながらそのエビデンスは質が低かった。

有害事象

GnRHアナログのレビューとダナゾールのレビューでは、その介入によってプラセボに比較して有害事象がより高率になり;プロゲステロン徐放性製剤では他の治療法に比較して有害事象がより高率になることが報告された。漢方薬はゲストリノンやダナゾールに比較してより副作用が少なかった。

3件のレビューではアウトカムとして流産が報告された。手術と診断的腹腔鏡検査との間、GnRHアゴニストとアンタゴニストとの間、または子宮内膜腫の吸引と待機的管理との間の差は認められなかった。しかしながらすべての症例でエビデンスの質は低かった。

著者の結論

疼痛および子宮内膜症を有する女性にとってゴナドトロピン放出ホルモン(GnRH)アナログ、レボノルゲストレル放出子宮内システム(LNG-IUD)、およびダナゾールによる月経周期の抑制は有益な介入であった。子宮内膜症の腹腔鏡検査治療と子宮内膜腫切除術によっても疼痛が改善する。NSAIDsのエビデンスは決定的なものではなかった。手術後の内科的有益性を示すエビデンスは認められなかった。

生殖補助医療を受けている子宮内膜症の女性において、GnRHアゴニストを用いた3カ月の治療によって妊娠率が改善された。切除術はアブレーションと比較して、術後9カ月から1カ月の自然妊娠率を改善した。腹腔鏡下手術は診断的腹腔鏡術のみの場合と比較して、生児出生率および妊娠率を改善した。内科的治療が臨床的妊娠率を改善したというエビデンスは存在しなかった。

有害性のエビデンスはわずかだが、GnRHアナログ、ダナゾール、プロゲステロン徐放剤は他の介入に比較してより高い割合になった。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.8.9]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Endometriosis: an overview of Cochrane Reviews

Background

Cochrane review authors examined the evidence on endometriosis from Cochrane systematic reviews published in The Cochrane Library. We aimed to summarise the evidence on treatment options that are available to women with pain or subfertility, or both, associated with clinically diagnosed endometriosis.

Study characteristics

We included 17 Cochrane systematic reviews. Fourteen reported measures of pain relief and eight reported fertility outcomes. All the reviews were high quality. The quality of the evidence for specific comparisons and outcomes ranged from very low to moderate, due to limitations in the primary studies, inconsistency between the studies and imprecision in the findings.

Key results

A number of interventions appeared effective in alleviating pain in women with endometriosis. These were gonadotrophin-releasing hormone (GnRH) analogues when compared with placebo, the levonorgestrel-releasing intrauterine system (LNG-IUD) compared with expectant management, danazol compared with placebo, and progestagens and anti-progestagens compared with placebo. Laparoscopic surgical interventions also appeared to be effective for pain.

In women with endometriosis undergoing assisted reproduction, three months of treatment with GnRH agonist improved pregnancy rates. Excisional surgery improved spontaneous pregnancy rates in the nine to 12 months after surgery compared to ablative surgery. Laparoscopic surgery improved live birth and pregnancy rates compared to diagnostic laparoscopy alone. There was no evidence that medical treatment improved clinical pregnancy rates.

Evidence on harms was scanty but GnRH analogues and danazol were associated with higher rates of adverse effects than placebo, and depot progestagens were associated with higher rates than other treatments.

淺顯易懂的口語結論

子宮內膜異位症:縱觀考科藍文獻回顧

背景

考科藍文獻回顧作者依據考科藍圖書館所發表的考科藍系統性文獻回顧,檢視子宮內膜異位症的證據。我們的目的在於摘述經臨床診斷患有子宮內膜異位症,並因此出現經痛或低生育力或兩者的女性可利用的治療選擇。

試驗特色

我們納入17篇考科藍系統性文獻回顧,其中有14篇文獻回顧提及疼痛緩解的狀況,有8篇文獻回顧報告生育力的結果。所有的文獻回顧品質皆高,但受限於原始試驗、各試驗間的不一致性,以及結果不夠精確,具體比較和結果的證據品質,則介於極低至中等之間。

重要結果

某些介入顯然可有效緩和子宮內膜異位症女性患者的疼痛症狀,包括促性腺激素釋放素 (Gonadotrophin-releasing hormone, GnRH) 類似物 (相對於安慰劑)、levonorgestrel 子宮內投藥系統 (levonorgestrel-releasing intrauterine system, LNG-IUD) (相對於預期處置 [expectant management])、danazol (相對於安慰劑),以及黃體素和抗黃體素 (相對於安慰劑)。內視鏡手術介入顯然也可有效緩解經痛。

對於進行人工協助生殖的子宮內膜異位症女性患者,接受3個月的GnRH促效劑治療可以提高懷孕率。相對於分離手術,切除手術將可提高手術後9至12個月內的自然懷孕率。相較於僅使用診斷性內視鏡檢查,內視鏡手術可提高活產和懷孕率。並無證據顯示內科治療能提高臨床懷孕率。

雖然非常欠缺關於傷害的證據,但GnRH類似物和danazol的不良作用發生率高於安慰劑;而持續型黃體素的不良作用發生率,則高於其他介入。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

平易な要約

子宮内膜症:コクランレビューの概要

背景

コクランレビューアーらは、The Cochrane Libraryで公表したコクランシステマティックレビューから得られた子宮内膜症のエビデンスについて検討した。我々は、臨床的に診断された子宮内膜症に関連して疼痛か低妊孕性、またはその両方を有する女性に利用出来る治療の選択肢のエビデンスを要約することを目的とした。

研究の特性

17件のコクランシステマティックレビューを含めた。14件のレビューは疼痛緩和の指標を、8件のレビューは妊孕性能アウトカムを報告した。すべてのレビューは質が高かった。予備試験の限界、その研究間の不一致、そして結果の不正確さによって、個々の比較とアウトカムに関するエビデンスの質は非常に低いから中等度までの範囲であった。

主な結果

多くの介入は、子宮内膜症の女性の疼痛緩和に有効であると考えられた。それらは、プラセボと比較した場合のゴナドトロピン放出ホルモン(GnRH)アナログ、待機的管理と比較したレボノルゲストレル放出子宮内システム(LNG-IUD)、プラセボと比較したダナゾール、そしてプラセボと比較したプロゲストーゲンと抗プロゲストーゲンであった。腹腔鏡下手術の介入も疼痛に有効であると考えられた。

生殖補助医療を受けている子宮内膜症の女性において、GnRHアゴニストを用いた3カ月の治療によって妊娠率が改善された。切除術はアブレーションと比較して、術後9カ月から1カ月の自然妊娠率を改善した。切除術はアブレーションと比較して、術後9カ月から1カ月の自然妊娠率を改善した。内科的治療が臨床的妊娠率を改善したというエビデンスは存在しなかった。

有害性を示すエビデンスはわずかであるが、GnRHアナログ、ダナゾールではプラセボと比較して有害作用の割合がより高く、プロゲステロン徐放剤では他の治療に比較してより有害作用の割合が高くなった。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.8.9]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Background

This overview examines the interventions available for pain relief and for subfertility in pre-menopausal women with clinically diagnosed endometriosis.

Description of the condition

Endometriosis is characterised by the presence of endometrial tissue in sites other than the uterine cavity. It is a common gynaecological condition affecting women in their reproductive years and is generally believed to be an estrogen-dependent disorder. The many observations that support this view include amelioration of pre-existing endometriosis after surgical or natural menopause (Kitawaki 2002) and the growth of endometrial tissue in animals on estrogen therapy (Bruner-Tran 2002).

Estimates of prevalence in the general population are up to 10% (Ozkan 2008). For women with subfertility the prevalence rate ranges from 25% to 40% (Ozkan 2008). These values are potentially underestimates as visualisation of the disease is required for a diagnosis. 

Whilst endometriosis is associated with infertility (occasionally as the cause) (Prentice 1996), it frequently presents with the symptom of pain (Barlow 1993). This pain may take the form of dysmenorrhoea (cyclical pain associated with menstruation), dyspareunia (pain with or following sexual intercourse) and pelvic or abdominal pain. The woman may also present with cyclical symptoms related to endometriosis at extra-pelvic sites.

A major challenge for women with endometriosis is the risk of recurrence. Symptomatic recurrence rates of endometriosis have been reported to range from 21.5% at two years to 50% at five years after treatment (Guo 2009).

The precise pathogenesis (mode of development) of endometriosis remains unclear but it is evident that endometriosis arises from the dissemination of endometrium to ectopic sites and the subsequent establishment of deposits of ectopic endometrium (Haney 1991; McLaren 1996). It has been postulated that the presence of these ectopic deposits gives rise to the symptoms associated with the condition.

Description of the interventions

There are a number of potential interventions for endometriosis, dependent on whether the primary problem is pain or subfertility. The primary aims of the interventions are the reduction or removal of ectopic endometrial implants, restoration of normal anatomy, reduction of disease progression and symptom relief (Ozkan 2008).

Pain

In the case of pain the treatments include the following.

1. Medical therapy
  • Combined oral contraceptive pill (COCP)

  • Non-steroidal anti-inflammatory drugs (NSAIDS)

  • Gonadotrophin releasing hormone analogues (GnRHa)

  • Progestins, including oral and intrauterine

  • Androgens (danazol)

  • Aromatase inhibitors

  • Estrogen ± progesterone

  • Anti-TNF (tumour necrosis factor)

  • Selective estrogen receptor modulators (SERMS)

  • Other treatments such as Chinese herbal medicine and oral supplements

Medical therapy could be independently administered or be used pre or post-surgery.

2. Surgical intervention
  • Laparoscopic surgery

  • Surgical interruption of the nerve pathways

  • Excisional versus ablative surgery

  • Post-surgical barrier agents to prevent adhesions

  • Laparoscopic helium plasma coagulation

Subfertility

1. Medical therapy prior to assisted reproductive technologies (ART)
  • GnRHa

  • Controlled ovarian hyperstimulation

2. Medical therapy
  • Ovulation suppression

  • Other treatments such as Chinese herbal medicine and oral supplements

3. Pre or post-operative medical therapy
  • GnRHa

  • COCP

  • Androgens

4. Surgical intervention
  • Laparoscopic surgery

  • Excisional versus ablative surgery for endometriomata

How the intervention might work

Surgical removal of endometrial deposits or medical suppression of hormones may decrease endometrial deposits, which may assist in the relief of pain. Removal of endometrial deposits and medical therapy to shrink the size of deposits may increase the chances of conception.

Why it is important to do this overview

There are now numerous intervention reviews available for the medical and surgical treatment of endometriosis for pain relief and for subfertility. For the first time, this overview brings these together into one coherent document that can be used by clinicians and policy makers in making decisions about optimal treatment based on the available evidence on benefits and harms. It also provides a useful resource to guide consumers and clinicians to the original reviews for further information.

Objectives

The objective of this overview was to summarise the evidence from Cochrane systematic reviews on treatment options for women with pain or subfertility associated with endometriosis.

Methods

Criteria for considering reviews for inclusion

Only Cochrane reviews were considered for inclusion in this overview. Cochrane protocols and titles were identified for future inclusion.

Participants

Eligible participants were pre-menopausal women with a clinical diagnosis of endometriosis who had sought medical attention for pain or subfertility, or both. Women with endometriomata who had sought medical attention for pain or subfertility, or both, were also included.

Interventions

Interventions for pain relief

Medical treatments, complementary therapies or surgical interventions (including excisional and ablative surgery for endometriomata) were considered. Medical and complementary therapies could be used as single interventions or administered pre or post-operatively, or both.

Interventions for subfertility

Medical treatments, complementary therapies or surgical interventions (including excisional and ablative surgery for endometriomata) were considered. Medical and complementary therapies could be used as a single intervention or administered pre or post-operatively, or both.

Outcomes of interest

Outcomes for pain relief

Primary outcome measure: self reported pain relief for dysmenorrhoea

Secondary outcome measures: clinical improvement or resolution of endometriosis-related pain; pain recurrence, adverse events

Outcomes for subfertility

Primary outcome measures: live birth, clinical pregnancy, ongoing pregnancy, miscarriage, adverse events

Search methods for identification of reviews

The Cochrane Database of Systematic Reviews and Archie (the Cochrane information management system) were searched on 6th March 2014 using the keyword 'endometriosis'. The term was restricted to title, abstract, or keywords. No other databases were searched.

Data collection and analysis

Selection of reviews

Reviews addressing treatment of pain associated with endometriosis and reviews addressing treatment of subfertility associated with endometriosis were identified by one overview author and confirmed for inclusion by the second overview author. Any disagreement was resolved by discussion with a third party.

Data extraction and management

Data were extracted independently by the two overview authors (CF, JB) using an Excel spreadsheet. Disagreements were resolved by discussion. Where data were missing, the original review authors were contacted for assistance. Information was extracted on the following.

  • The population demographics: a summary of the participant characteristics was made.

  • Review characteristics: the number of included trials, the number of participants in each review, the date that the review was assessed as up to date, interventions and comparisons, all outcomes, and limitations of the review.

  • Statistical summary: the summary effects from relevant comparisons and outcomes.

Assessment of methodological quality of included reviews

Quality of included reviews

The quality of the included reviews was assessed using the AMSTAR tool (Shea 2007). We also noted in each case whether the literature search had been conducted or updated within the past three years (to March 2014).

Quality of evidence from primary studies in included reviews

We used the GRADEPro 'Summary of findings' tables from each review (or if necessary we constructed such a table) to indicate the quality of the evidence for the main comparisons. The following criteria were taken into account: study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias.

Data synthesis

We combined the reviews in a narrative summary, organised by outcomes.

Results

Seventeen systematic reviews published in The Cochrane Library were included in this overview. See Table 1 for a summary of the characteristics of these reviews (review ID, when the review was last assessed as up to date, how many randomised controlled trials and participants were included, the interventions, comparisons, outcomes, and main limitations of each review). See Table 2 for a description of the populations in the included reviews.

Table 1. Details of reviews
Review IDDate assessed as up to dateNumber of included trialsNumber of participantsInterventionControl or comparison interventionOutcomes for which data assessedReview limitations
GnRH agonist/antagonist
Sallam 200617/10/20083 RCTs165 women

Leuprolide acetate 3.75mg

 

Triptorelin 3.75mg

No treatment

 

Leuprolide acetate 0.5 to 1.0mg

 

GnRH agonist 3.75mg

Clinical pregnancy

 

Dose of FSH/HMG

 

Duration of FSH

 

Number of oocytes retrieved

 

Only 3 trials

 

Trials lacked details of  allocation concealment

 

No blinding

Brown 201027/09/201042 RCTs4935 womenAny GnRHa

No treatment

Placebo

Danazol

Intrauterine progesterone devices

Another GnRHa

Pain relief

Adverse effects

Resolution of endometriosis

Quality of life

Additional use of analgesia

The trials were limited by lack of adequate information on randomisation, allocation concealment and blinding
Benschop 201004/10/20104 RCTs312 womenSurgical or medical therapy prior to treatment

Placebo

No treatment

Other surgical or medical therapy

Clinical pregnancy rate

Live birth

Adverse events

Quality of life

Pain

Recurrence

Estrodial levels

Number of mature oocytes

No live birth reported in the included trials. Overall trials well conducted but two of the trials did not conduct any blinding
Ovarian suppression
Hughes 200719/04/2009 (stable review no longer being updated)25 RCTs2600 women

Dienogest

 

Triptorelin

 

MPA

 

Leuprolide acetate

 

Nafarelin

 

Provera

 

Goserelin

 

Danazol

 

Mestronol

 

Gestrinone

 

Buserelin

 

Triptorelin

 

Expectant management

 

Placebo

 

No treatment

 

Nafarelin

 

Danazol

Live birth

 

Clinical pregnancy

Only 2 trials reported live birth

 

The majority of the trials included in the review lacked details on randomisation and allocation concealment and there was limited blinding of allocation

Davis 200717/05/20071 RCT57 womenLow dose oral contraceptive (0.02mg ethinyl estradiol with 0.15mg desogestrel taken cyclically)Monthly goserelin 3.6mg subcutaneous

Pain

Satisfaction

Withdrawal

Side effects

Economic evaluation

The trial included in the review lacked details on randomisation and allocation concealment, there was no blinding and evidence was based on a single trial
Abou-Setta 201313/6/20123 RCTs135 womenLNG-IUDExpectant management

Pain

Satisfaction

Dropout rates

There was no evidence of blinding in two of the trials
Al-Kadri 200910/07/20082 RCTs193 womenEstrogen, with or without progesterone

Placebo

Tibolone

Pain

Disease recurrence

There was no evidence of blinding and the trials lacked precision
Farquhar 200715/06/2007 (stable review, no longer being updated)5 RCTs370 womenDanazol 600 mg daily

MPA 100mg

Placebo

No treatment

Pain

AFS score

Pregnancy

Side effects

Symptoms

Hormone level

Biochemical markers

There was a lack of evidence for randomisation and allocation concealment in many of the included trials and four of the trials were open label
Brown 201217/01/201113 RCTs1511 women

Medroxyprogesterone PO/depot/sc

Gestrinone 2.5mg

Dienogest 2mg

Dydrogesterone 40/60 mg

Cyproterone acetate 12.5mg

Nafarelin 200 ug IN

Danazol 400mg/ 600mg

Leuprolide 3.75mg/ 11.25mg IM

Buserelin 300ug IN

Oral contraceptive

Placebo

Pain scores

rAFS

Side effects

Fertility

Bone mineral density

Lipid profiles

Biochemical measures

Quality of life

 
Analgesics
Allen 200923/04/20082 RCTs48 women

Indomethecin 25mg

Acetylsalictyic acid 500mg

Tolfenamic acid 200mg

Naproxen 275mg

Placebo

Pain

Side effects

Effects on activities of daily living

Additional medication use

Trials lacked detail on allocation concealment and randomisation methods and one of the trials lacked details on blinding
Surgical
Benschop 201004/10/20104 RCTs312 womenSurgery (aspiration or cystectomy)Expectant management

Clinical pregnancy rate

Live birth

Adverse events

Quality of life

Pain

Recurrence

Estrodial levels

Number of mature oocytes

No live birth reported in the included trials. Overall trials well conducted but two of the trials did not conduct any blinding
Duffy 201431.7.1310 RCTs973 womenLaparoscopic surgeryAny other laparoscopic or robotic intervention, holistic or medical treatment or diagnostic laparoscopy only

Overall pain

Live birth

Specific types of pain

Clinical pregnancy

Adverse events

Common limitations in the primary studies included lack of clearly-described blinding, failure to fully describe methods of randomisation and allocation concealment, and risk of attrition bias
Hart 200831/08/20092 RCTsNot detailed in reviewExcisionDrainage and ablation

Pelvic pain

 

Spontaneous conception

Recurrence of endometrioma

 

Requirements for further surgery

 

Conversion to laparotomy

 

Pregnancy rate

 

Ovarian response to stimulation

 

 

 

 

 

No reporting of live birth

 

Studies lacked details on blinding but otherwise methodologically sound

Pre or post-surgical medical therapy
Furness 200420/09/2010 9 RCTS 769 women

Post-surgical triptorelin 3.75mg 

Danazol 600mg

Leuprolide acetate 3.5mg

Triptorelin 3.75mg

Nafarelin 400 µg

MPA 100mg

Goserelin 3.6mg

Gestrinone 2.5 mg

Pre and post-surgical triptorelin

No treatment/placebo

PregnancyLive birth not reported
Lu 201220/03/20124 RCTs334 womenLaparoscopic surgery + PentoxifyllineLaparoscopic surgery alone or + Placebo

Reduction in pain

 

Clinical pregnancy

 

Recurrence rates

Live birth not reported

 

Only two trials adequately reported allocation concealment.  Only one trial reported blinding. All of the trials lacked adequate information on addressing incomplete outcome data

Other
Lu 20133/9/121 RCT21 womenAnti-TNF-α

Placebo

No treatment

Medical treatment

Surgical treatment

Biberoglu and Behrman score

Visual analogue pain score

Use of analgesics

Did not conduct ITT analysis
Flower 201231/10/20112 RCTs158 women Chinese herbal medicine 

Gestrinone or

Danazol or

other Chinese herbal medicine 

Pregnancy rate

Symptomatic relief

Dysmenorrhoea score

Rectal irritation relief

Tenderness of vaginal nodes

Adnexal masses, tenderness or shrinkage

No live birth reported. Evidence is based on single trials. 
Zhu 201127/7/20101 RCT67 womenAcupunctureChinese herbal medicine"cured" of painThere was a lack of adequate explanation for randomisation and allocation concealment and there were no details on blinding
Furness 200420/09/201010 RCTs1046 women

Post-surgical triptorelin 3.75mg 

Danazol 600mg

Leuprolide acetate 3.5mg

Triptorelin 3.75mg

Nafarelin 400 µg

MPA 100mg

Goserelin 3.6mg

Gestrinone 2.5 mg

Pre and post-surgical triptorelin

No treatment/placebo

Pain, recurrenceMost of the included trials lacked adequate methodological detail and there was a lack of blinding
Table 2. Description of populations in included reviews
Review authorAge (years)Stage of disease
Abou-Setta 2013No details in review

Eligible participants were women with any stage of endometriosis who had undergone any type of surgical treatment for endometriosis that preserved their uterus, with surgery no more than three months prior to randomisation.

One trial included women with moderate to severe endometriosis and one trial included only women with severe endometriosis. The third trial included women with moderate to severe endometriosis-related pain who were scheduled for laparoscopic surgery.

Allen 2009Mean age 33 yearsEligible participants were women with any stage or severity of endometriosis. Endometriosis was diagnosed by visualisation (for example laparoscopy or laparotomy) or was a suspected diagnosis based on the history and pelvic examination and other tests such as ultrasound, MRI, and the CA-125 blood test.
Al-Kadri 2009No details in reviewEligible participants were women with ectopic endometrial tissue that potentially could lead to distressing and debilitating symptoms regardless of the size and site of the deposits.
Benschop 2010Women with age ranging from 25 to 36 years

Eligible participants were women with endometriomata who underwent surgical, medical or combination treatment or expectant management prior to ART. The endometriomata were diagnosed by laparoscopy or imaging tests such as ultrasound and magnetic resonance imaging (MRI).

The women in the included studies had endometriomata ranging in size from ≥ 1.28cm to < 6 cm.

Brown 2010All participants were pre-menopausal

Eligible participants were pre-menopausal women with symptoms ascribed to endometriosis. The clinical diagnosis of endometriosis had to be made by direct visualisation (laparoscopy). Studies were included irrespective of the duration of symptoms.

There were no details on stage of disease for 26 trials. Twelve trials reported including stages I to IV.

Brown 2012Women with age ranging from 18 to 49Eligible participants were women of reproductive years with painful symptoms and a laparoscopic diagnosis of endometriosis.
Davis 2007No details in reviewEligible participants were women of reproductive age who complained of symptoms ascribed to the diagnosis of endometriosis. The diagnosis must have been established during a surgical procedure performed prior to the start of treatment.
Duffy 2014No details in reviewEligible participants were women with endometriosis confirmed with a visual diagnosis at diagnostic or operative laparoscopy.
Farquhar 2007Four trials reported mean ages which ranged from 28.2 to 32.5 years, one trial reported women were aged <41 years

Eligible participants were women of reproductive age with the diagnosis of endometriosis made by direct visualisation (laparoscopy or laparotomy). This included women who were asymptomatic and where endometriosis was an incidental finding.

Four trials recruited women who mainly had a diagnosis of stage I to II disease, one trial recruited women with moderate to severe disease. Two trials appeared to have recruited women post-surgically

Flower 2012No details in review

Eligible participants were women of reproductive age with a laparoscopically confirmed diagnosis of endometriosis.

No further details in review

Furness 2004Women of reproductive age or <40 years were included

Eligible participants were women of reproductive age who were undergoing surgery for endometriosis. The diagnosis of endometriosis could have been made provisionally by clinical examination and confirmed during the surgery, or could have been confirmed endometriosis where women were undergoing second or subsequent surgery. They would have further medical treatment either before or after surgery.

Two trials did not report on inclusion criteria for stage of disease but the remaining trials included women with AFS III to IV

Hart 2008No details in reviewEligible participants were women with ovarian endometriomata who were undergoing surgery for the indication of pain or infertility. Endometriomata were defined as cysts of endometriosis within the ovary.
Hughes 2007Range 18 to 45

Eligible participants were women with visually diagnosed endometriosis, either by laparoscopy or laparotomy, who had failed to conceive after 12 or more months of unprotected intercourse. Trials where medical treatment was administered after surgical treatment for endometriosis were included.

The majority of included trials reported laparoscopically diagnosed endometriosis. Five trials reported including women with any stage of disease and eight trials reported including women with Stage III to IV endometriosis. Three trials included women with mild to moderate disease and the remaining trials did not report on this measure.

Lu 2012Mean ages in the intervention group ranged from 29.7±8.1 to 33.1±3.6; for the control group mean age ranged from 28.31±4.19 to 32.9±6.5 years

Eligible participants were premenopausal, subfertile women with visually diagnosed endometriosis, either by laparoscopy or on the basis of international guidelines used to diagnose endometriosis. Trials where medical treatment was administered after surgical treatment for endometriosis were included.

Three of the included studies recruited women with AFS I-II and one trial recruited women with Stage I-IV disease

Lu 2013Women aged 20 to 45 years

Eligible participants were pre-menopausal, subfertile women with visually diagnosed endometriosis, either by laparoscopy or on the basis of international guidelines used to diagnose endometriosis. Trials where medical treatment was administered after surgical treatment for endometriosis were included.

Women in the included study had deep endometriosis nodule of at least 1 cm in diameter and severe pain

Sallam 2006No details in reviewEligible participants were infertile women diagnosed with endometriosis and treated with IVF or ICSI. The diagnosis of endometriosis must have been based on laparoscopy or laparotomy
Zhu 2011Age range of participants 22 to 47 years

Eligible participants were women of reproductive age with a diagnosis of endometriosis confirmed laparoscopically. Participant exclusion criteria included primary dysmenorrhoea (the absence of an identifiable pathological condition) or asymptomatic endometriosis.

Women in the included study had all stages of disease from mild to severe

An additional protocol and two titles were identified, which will be added to the overview when they are published as full reviews and the overview is updated. For details see Appendix 1.

Description of included reviews

Pain

Fourteen reviews were identified that reported on pain outcomes in pre-menopausal women with a diagnosis of endometriosis (Abou-Setta 2013; Al-Kadri 2009; Allen 2009; Brown 2010; Brown 2012; Davis 2007; Duffy 2014; Farquhar 2007; Flower 2012; Furness 2004; Hart 2008; Lu 2012; Lu 2013; Zhu 2011).

Subfertility

Eight systematic reviews were identified that reported on fertility outcomes in pre-menopausal women with a diagnosis of endometriosis (Benschop 2010; Duffy 2014; Flower 2012; Furness 2004; Hart 2008; Hughes 2007; Lu 2012; Sallam 2006). Sallam 2006 and Benschop 2010 reported ART-related outcomes whilst the other reviews reported spontaneous pregnancy.

Methodological quality of included reviews

1. Quality of systematic reviews

The quality of the 17 included reviews was rated using the AMSTAR tool (Shea 2007).

  • All reviews pre-specified their clinical question and inclusion criteria.

  • All reviews conducted study selection and data extraction in duplicate.

  • All reviews conducted a comprehensive literature search.

  • All reviews included searches of grey literature.

  • All reviews listed included and excluded studies.

  • All reviews described the characteristics of the included studies.

  • All reviews assessed study quality.

  • All reviews combined the studies using appropriate methods.

  • Eleven of the 17 reviews formally addressed the risk of reporting bias, using a statistical test where appropriate.

  • All reviews addressed the potential for conflict of interest.

Eight of the 17 reviews had conducted a literature search within the past three years (to March 2014), or have been deemed stable (meaning that they will not be updated with a full literature search unless new evidence emerges).

See Table 3 and Table 4 for details.

Table 3. AMSTAR assessment
Review noFirst authorREVIEW TITLEAMSTAR CRITERIA
   Prespecified question and inclusion criteriaDuplicate study selection and data extractionComprehensive lit searchGrey lit includedLists included and excluded studiesDescribes characteristics of included studiesStudy quality assessedStudies combined using appropriate methodsLikelihood of publication bias considered/testedPotential for conflict of interest addressed
AMAS1061 Abou-Setta 2013Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery
MCA871 Allen 2009Non-steroidal anti-inflammatory drugs for pain in women with endometriosisx
HAK1181 Al-Kadri 2009Hormone therapy for endometriosis and surgical menopausex
SG1241 Benschop 2010Interventions for women with endometrioma prior to assisted reproductive technology
APO62 Brown 2010Gonadotrophin-releasing hormone analogues for pain associated with endometriosis
AP061 Brown 2012Progestagens and anti-progestagens for pain associated with endometriosis
SK141 Davis 2007Oral contraceptives for pain associated with endometriosisx
JD1830 Duffy 2014Laparoscopic surgery for endometriosis.
VS081 Farquhar 2007Danazol for pelvic pain associated with endometriosisx
AF801 Flower 2012Chinese herbal medicine for endometriosis
CY571 Furness 2004Pre and post-operative medical therapy for endometriosis surgeryx
RJH961 Hart 2008Excisional surgery versus ablative surgery for ovarian endometriomata
EJ254 Hughes 2007Ovulation suppression for endometriosis for women with subfertility
DL1540 Lu 2012Pentoxifylline for endometriosis
DD1570 Lu 2013Anti-TNF-α treatment for pelvic pain associated with endometriosis
HNS881 Sallam 2006Long term pituitary down-regulation before in vitro fertilisation (IVF) for women with endometriosisx
KRF1291 Zhu 2011Acupuncture for pain in endometriosisx
Table 4. Search date assessment
Review noReview referenceREVIEW TITLE

<3 yrs since last search

(to March 6 2014)

AMAS1061 Abou-Setta 2013Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery
MCA871 Allen 2009Non-steroidal anti-inflammatory drugs for pain in women with endometriosis
HAK1181 Al-Kadri 2009Hormone therapy for endometriosis and surgical menopause
SG1241 Benschop 2010Interventions for women with endometrioma prior to assisted reproductive technology
APO62 Brown 2010Gonadotrophin-releasing hormone analogues for pain associated with endometriosis
AP061 Brown 2012Progestagens and anti-progestagens for pain associated with endometriosis
SK141 Davis 2007Oral contraceptives for pain associated with endometriosis
JD1830 Duffy 2014Laparoscopic surgery for endometriosis
VS081 Farquhar 2007Danazol for pelvic pain associated with endometriosisStable
AF801 Flower 2012Chinese herbal medicine for endometriosis
CY571 Furness 2004Pre and post-operative medical therapy for endometriosis surgery
RJH961 Hart 2008Excisional surgery versus ablative surgery for ovarian endometriomata
EJ254 Hughes 2007Ovulation suppression for endometriosis for women with subfertilityStable
DL1540 Lu 2012Pentoxifylline for endometriosis
DD1570 Lu 2013Anti-TNF-α treatment for pelvic pain associated with endometriosis
HNS881 Sallam 2006Long term pituitary down-regulation before in vitro fertilisation (IVF) for women with endometriosis
KRF1291 Zhu 2011Acupuncture for pain in endometriosis

2. Quality of evidence from primary studies in included reviews

The quality of the evidence reported by the primary studies in the included reviews was rated using GRADE methods and ranged from very low to moderate for individual comparisons. The main reasons for reviews being downgraded for quality were inadequate reporting of allocation concealment and randomisation methods, lack of blinding and imprecision. The evidence frequently comprised a single small trial.

Details of the quality of the evidence for each outcome are reported in Table 5 and Table 6.

Table 5. Pain outcomes

Outcome

Intervention and comparison intervention

 Illustrative comparative risks (95% CI)

Relative effect

(95% CI)

Number of participants

(studies)

Quality of the evidence

(GRADE)

Comments
  

Assumed risk

with comparator

Corresponding risk

with intervention

    
Reduction in pain at 3 months
Lu 2012 Laparoscopic surgery plus pentoxifylline versus laparoscopic surgery plus placebo The mean reduction in pain at 3 months in the laparoscopic surgery plus placebo groups was 5.53 (VAS score)The mean reduction in pain at 3 months in the laparoscopic surgery plus pentoxifylline groups was 1.6 lower (3.32 lower to 0.12 higher) (VAS score)-34 ( 1 study)Very lowLacked methodological detail, and lack of precision. Evidence based on a single study
Dysmenorrhoea

Duffy 2014

Laparoscopic excision versus diagnostic laparoscopy

  At 6 months, the mean dysmenorrhoea pain score in the excision group was 2.4 higher than in the diagnostic laparoscopy group (6.18 lower to 10.98 higher) on a VAS 0-100 scale 39 (1 study)LowVery serious imprecision - single small study, wide confidence intervals

Duffy 2014

Laparoscopic excision versus diagnostic laparoscopy

  At 12 months, the mean dysmenorrhoea pain score in the excision group was 9.5 lower than in the diagnostic laparoscopy group (20.58 lower to 1.58 higher) on a VAS 0-100 scale 39 (1 study)LowVery serious imprecision - single small study, wide confidence intervals

Furness 2004

Post-surgical medical therapy versus placebo

 -The mean pain score (VAS) in the intervention group was 0.58 standard deviations lower than in the placebo group (0.87 to 0.28 lower)-187 (1 study)LowLacked sufficient details on allocation concealment and blinding
Flower 2012 Chinese herbal medicine Nei Yi pills versus danazol -The mean dysmenorrhoea score in the Chinese herbal medicine Nei Yi pills group was 1.01 lower (3.11 lower to 1.09 higher) than in the danazol group-34 ( 1 study)LowEvidence based on a single trial, quality of blinding very uncertain
Flower 2012 Chinese herbal medicine Nei Yi pills + Nei Yi enema versus danazol -The mean dysmenorrhoea score in the Chinese herbal medicine Nei Yi pills group was 2.9 lower (4.55 lower to 1.25 higher) than in the danazol group 42 (1 study)LowEvidence based on a single trial, quality of blinding very uncertain
Flower 2012 Chinese herbal medicine Nei Yi pills + Nei Yi enema versus Nei Yi pills  The mean dysmenorrhoea score in the Chinese herbal medicine Nei Yi pills + enema group was 1.89 lower (3.89 lower to 0.11 higher) than in the Nei Yi pills alone group-40 (1 study)LowEvidence based on a single trial, quality of blinding very uncertain
Brown 2010 GnRHas versus no treatment 188/1000 achieved pain relief737/1000 achieved pain reliefRR 3.93 (1.37 to 11.28)35 (1 study)LowNo blinding and evidence based on a single trial
Brown 2010 GnRHas versus danazol 825/1000 achieved pain relief809/1000 achieved pain reliefRR 0.98 (0.92 to 1.04)666 (7 studies)Very lowRandomisation and allocation concealment was inadequately reported in most of the trials. Blinding was unclear in two trials and there was no blinding in two trials. I2 was 44% which suggests some heterogeneity
Brown 2010 GnRHas (3 month versus 6 month) -The mean dysmenorrhoea score in the three month group was 0.02 standard deviations lower (0.31 lower to 0.27 higher) than in the six month group-179 (1 study)ModerateEvidence was based on a single trial
Brown 2010 GnRHas (intranasal versus intramuscular depot) 828/1000 achieved pain relief778/1000 achieved pain reliefRR 0.94 (0.82 to 1.08)192 (1 study)LowLack of adequate explanation of allocation concealment and evidence based on a single trial
Brown 2010 GnRHas (intranasal versus subcutaneous) 800/1000 achieved pain relief976/1000 achieved pain reliefRR 1.22 (0.73 to 2.06)10 (1 study)LowOpen label trial with evidence based on a single trial

Furness 2004

Pre-surgical medical therapy versus post-surgical medical therapy

 See CommentSee CommentRR 0.0 (0 to 0)53 (1 study)LowThere were no events reported in either the intervention or the control group. There were insufficient methodological details for allocation concealment or randomisation

Davis 2007

Oral contraceptive versus goserelin

 The mean dysmenorrhoea pain score in the control groups was 7.5The mean dysmenorrhoea pain score in the intervention groups was 0.10 lower (1.28 lower to 1.08 higher)-50 (1 study)Very lowThere was a lack of adequate explanation for allocation concealment, and randomisation. There was no blinding. The evidence was based on a single trial.

Lu 2013

Anti-TNF-α plus surgery versus placebo plus surgery - clinician score

 The mean dysmenorrhoea Biberoglu and Behrman score in the control groups was 2.3The mean Biberoglu and Behrman score in the intervention groups was 0.2 higher (0.05 lower to 0.45 higher)-21 (1 study)LowEvidence based on a single trial and not ITT conducted.

Lu 2013

Anti-TNF-α plus surgery versus placebo plus surgery - patient score

 The mean Biberoglu and Behrman score in the control groups was 1.7The mean Biberoglu and Behrman score in the intervention groups was 0.2 lower (0.68 lower to 0.28 higher)-21 (1 study)LowEvidence based on a single trial and not ITT conducted.

Brown 2012

Anti-progestagen versus other treatment (end of treatment)

 The mean patient assessed efficacy at end of treatment in the control groups was 0.05The mean patient assessed efficacy at end of treatment in the intervention groups was 0.82 higher (0.15 to 1.49 higher)-55 (1 study)ModerateEvidence was based on a single trial

Brown 2012

Anti-progestagen versus other treatment (12 months)

 The mean patient assessed efficacy at 12 months follow-up in the control groups was 4.76The mean patient assessed efficacy at 12 months follow-up in the intervention groups was 3 lower (4.79 to 1.21 lower)-55 (1 study)ModerateEvidence was based on a single trial

Brown 2012

Depot progestagen versus other treatment (6 months)

 978/1000 achieved pain relief895/1000 achieved pain reliefOR 0.19 (0.05 to 0.69)274 (1 study)ModerateEvidence was based on a single trial

Brown 2012

Depot progestagen versus other treatment (12 months)

 768/1000 achieved pain relief676/1000 achieved pain reliefOR 0.63 (0.37 to 1.08)274 (1 study)ModerateEvidence was based on a single trial

Brown 2012

Anti-progestagen versus other treatment

 667/1000 achieved pain relief673/1000 achieved pain reliefOR 1.03 (0.55 to 1.93)176 (2 studies)ModerateTrials lacked details on randomisation. One trial appeared to have inadequate allocation concealment and no blinding
Pain score 

Brown 2010

GnRHas versus placebo

 -The mean overall pain score at 4 weeks in the intervention group was 2.9 higher (2.11 to 3.69 higher) than in the placebo group-120 (1 study)LowAllocation concealment and blinding were inadequately explained and the evidence was based on a single trial

Abou-Setta 2013

LNG-IUD versus GnRHa

 The mean VAS score for painful symptoms in the control groups was 3.63The mean VAS score for painful symptoms in the intervention groups was 0.16 lower (2.02 to 1.7 higher)-40 (1 study)Very lowNo evidence of blinding in the included trial and evidence was based on a single trial. There was also imprecision in the summary statistic

Farquhar 2007

Danazol versus placebo (no surgery)

 The mean pelvic pain score in the control groups was 1.85The mean pelvic pain score in the intervention groups was 1.4 lower (1.33 to 0.77 lower) 35 (1 study)LowThere was a lack of adequate explanation for allocation concealment and randomisation and evidence was based on a single trial

Farquhar 2007

Danazol versus placebo (post-surgery) - pelvic pain 6 months

 The mean pelvic pain score in the control groups was 1.55The mean pelvic pain score in the intervention groups was 1.1 lower (1.38 to 0.82 lower) 34 (1 study)LowThere was a lack of adequate explanation for allocation concealment and randomisation and evidence was based on a single trial

Farquhar 2007

Danazol versus placebo (post-surgery) - pelvic pain 6 months

 310/1000 had moderate or severe pelvic pain at 6 months226/1000 had moderate or severe pelvic pain at 6 monthsOR 0.65 (0.2 to 2.05)60 (1 study)LowThere was a lack of adequate explanation for allocation concealment and randomisation and evidence was based on a single trial

Lu 2013

Anti-TNF-α plus surgery versus placebo plus surgery - clinician score

 The mean Biberoglu and Behrman score in the control groups was 1.45The mean Biberoglu and Behrman score in the intervention groups was 0.15 lower (0.45 lower to 0.15 higher)-21 (1 study)LowEvidence was based on a single trial. No ITT analysis conducted

Lu 2013

Anti-TNF-α plus surgery versus placebo plus surgery - patient score

 The mean Biberoglu and Behrman score in the control groups was 0.15The mean Biberoglu and Behrman score in the intervention groups was 0.15 lower (0.51 lower to 0.21 higher)-21 (1 study)LowEvidence was based on a single trial. No ITT analysis conducted

Brown 2012

Oral progestagens versus other treatment (6 months)

 The mean self-reported pain in the control group was 41.8The mean self-reported pain in the intervention group was 1.6 lower (0.01 lower to 0.57 higher)-252 (1 study)LowOpen label study with evidence based on a single trial
Supplementary analgesia use

Lu 2013

Anti-TNF-α plus surgery versus placebo plus surgery

 The mean use of analgesia in the control group was 0.28The mean use of analgesia in the intervention group was 0.1 (0.6 lower to 0.4 higher)-30 (1 study)LowEvidence was based on a single trial. No ITT analysis conducted

Allen 2009

NSAIDS versus placebo

 --OR (inverse variance) 0.12 (0.01 to 12.9)20 (1 study)Unable to conduct GRADE analysis as inverse variance used (no raw data)There was a lack of adequate explanation for allocation concealment, and randomisation. The evidence was based on a single trial
Disease recurrence/rAFS       

Hart 2008

Excisional versus ablative surgery for endometriomata

 262/1000128/1000OR 0.41 (0.18 to 0.93)164 (2 studies)Very lowIncluded studies lacked blinding

Furness 2004

Pre-surgical medical therapy versus no medical therapy

 -The mean recurrence (AFS) score was 9.6 lower (11.42 to 7.78 lower) in the intervention group-80 (1 study)LowNo blinding and trial lacked details on allocation concealment

Furness 2004

Post-surgical medical therapy versus pre and post-surgical medical therapy with GnRHa

 -The mean recurrence (AFS) score was 3.49 higher (5.1 to 12.08 higher) in the intervention group-

25

(1 study)

Very lowLacked sufficient detail on randomisation and allocation concealment and there was a lack of precision

Furness 2004

Post-surgical medical therapy versus placebo

 -The mean recurrence (AFS) score was 2.29 lower (4.69 lower to 0.11 higher) in the intervention group-43 (1 study)LowLacked sufficient detail on randomisation and allocation concealment

Brown 2010

GnRHas versus danazol

 -The mean rAFS in the intervention groups was 0.01 standard deviations lower (0.13 to 0.12)-1012 (10 studies)LowThere was a lack of adequate explanation for randomisation and allocation concealment and blinding
Brown 2010 GnRHas (400 mcg versus 800 mcg) 200/100082/1000RR 0.41 (0.17 to 1.01)143 (1 study)LowLack of adequate explanation for randomisation, allocation concealment and blinding. Evidence was based on a single trial
Brown 2010 GnRHas versus intrauterine progestagen device -The mean rAFS score in the intervention groups was 9.5 higher (10.77 lower to 29.77 higher)-18 (1 study)LowOpen label study with no blinding and evidence based on a single trial
Brown 2010 GnRHas (intranasal versus subcutaneous) -The mean rAFS score in the intervention groups was 9 higher (5.93 lower to 23.93 higher)-19 (1 study)Very lowLacked an adequate explanation of allocation concealment and randomisation and blinding. Evidence based on a single trial

Al-Kadri 2009

Estrogen, with or without progesterone versus placebo

 0/10000/1000OR 2.53 (0.12 to 53.64)172 (1 study)Very lowThere was no evidence of blinding , there was imprecision and the evidence was based on a single trial
Farquhar 2007 Danazol versus placebo (no surgery) The mean change in total AFS scores in the control group was 0.2The mean change in total AFS scores in the intervention group was 1.9 lower (4.16 lower to 0.36 higher)-31 (1 study)Very lowLacked an adequate explanation of randomisation and allocation concealment and the evidence was based on a single trial
Farquhar 2007 Danazol versus placebo (post-surgery) The mean change in total AFS scores in the control group was -4.5The mean change in total AFS scores in the intervention group was 0.9 lower (3.02 lower to 1.22 higher)-27 (1 study)Very lowLacked an adequate explanation of randomisation and allocation concealment and the evidence was based on a single trial

Brown 2012

Anti-progestagen versus other treatment

 The mean AFS score in the control group was 11.8The mean AFS score in the intervention group was 1.4 higher (6.76 lower to 9.56 higher)-16 (1 study)Very lowThe single trial was open label and appeared to have inadequate allocation concealment

Brown 2012

Oral progestagens versus other treatment

 The mean change in AFS scores in the control group was 1.31The mean AFS score in the intervention group was 0.34 higher (0.01 lower to 0.70 higher)-302 (1 study)ModerateThere was an inadequate explanation of allocation concealment, randomisation and blinding

Brown 2012

Progestagen versus placebo

 Mean AFS score in the control group was 1.76Mean AFS score in the intervention group was 0.58 lower (1.41 lower to 0.25 higher)-33 (1 study)LowThis single trial provided inadequate detail on allocation concealment and blinding
Resolution of pain       
Zhu 2011 Acupuncture versus Chinese herbal medicine 267/1000811/1000RR 3.04 (1.65 to 5.62)67 (1 study)Very lowLack of methodological detail. No blinding and evidence based on single study.
Brown 2010 GnRHas versus danazol 596/1000655/1000RR 1.1 (1.01 to 1.21)1046 (9 studies)LowThere was a lack of adequate detail for randomisation and allocation concealment and blinding. Two trials had no blinding
Brown 2010 GnRHas versus intrauterine progestagen device (LNG-IUD) -The mean relief of painful symptoms in the intervention group was 0.25 standard deviations lower (0.6 lower to 0.1 higher)-129 (3 studies)ModerateThere was a lack of blinding and inadequate explanation of allocation concealment
Brown 2010 GnRHas (400mcg versus 800mcg) 356/1000334/1000RR 0.94 (0.53 to 1.66)90 (1 study)ModerateEvidence based on a single trial

Davis 2007

Oral contraceptive versus goserelin

 818/1000774/1000OR 0.76 (0.17 to 3.29)44 (1 study)Very lowThere was a lack of adequate explanation for allocation concealment, and randomisation. There was no blinding. The evidence was based on a single trial

Duffy 2014

Laparoscopic ablation or excision

 321 per 1000 improved or better at 6 months756 per 1000 improved or better at 6 months (610 to 861)OR 6.58 (3.31 to 13.10)171 (3 studies)ModerateNone of studies blinded participants, only one fully described methods of randomisation and allocation concealment

Duffy 2014

Laparoscopic ablation or excision

 214 per 1000 improved or better at 12 months732 per 1000 improved or better at 12 months (467 to 895)OR 10.00 (3.21 to 31.17)69 (1 study)LowOnly conference abstract available: randomisation methods not fully described, high risk of attrition bias, unclear whether blinded; single small study

Duffy 2014

Laparoscopic surgery versus laparoscopic surgery plus medical therapy

 167 per 1000 pain free at 12 months530 per 1000 pain free at 12 months (191 to 843)OR 5.63 (1.18 to 26.8535 (1 study)LowOnly conference abstract available: randomisation methods not fully described, unclear whether blinded; single small study

Allen 2009

NSAID versus placebo

 --

OR (inverse variance)

0.327 (0.61 to 17.69)

20 (1 study)Unable to conduct GRADE analysis as inverse variance used (no raw data)There was a lack of adequate explanation for allocation concealment, and randomisation. The evidence was based on a single trial

Brown 2012

Anti-progestagen versus other treatment

 667/1000673/1000OR 1.03 (0.55 to 1.93)176 (2 studies)LowTwo trials lacked details on randomisation. One of the trials appeared to have inadequate allocation concealment and no blinding
Pain recurrence up to 1 year       

Furness 2004

Post-surgical medical therapy versus placebo

 273/1000207/1000RR 0.76 (0.52 to 1.1)332 (3 studies)LowLacked sufficient evidence for allocation concealment or attrition and there was no blinding

Abou-Setta 2013

LNG-IUD versus expectant management

 383/100084/1000RR 0.22 (0.08 to 0.6)95 (2 studies)ModerateOnly one of the two studies had blinded outcome assessment

Al-Kadri 2009

Estrogen with or without progesterone versus placebo

 0/10000/1000OR 4.64 (0.25 to 87.71)172 (1 study)Very lowThere was no evidence of blinding , there was imprecision and the evidence was based on a single trial

Al-Kadri 2009

Estrogen with or without progesterone versus tibolone

 91/1000400/1000OR 6.67 (0.6 to 74.51)21 (1 study)Very lowThere was no blinding and there was a lack of adequate detail on allocation concealment. Evidence was based on a single trial
Table 6. Fertility outcomes

Outcome

Intervention and comparison intervention

Illustrative comparative risks (95% CI)

Relative effect

(95% CI)

Number of participants

(studies)

Quality of the evidence

(GRADE)

Comments
 

Assumed risk

with comparator

Corresponding risk

with intervention

    
Clinical pregnancy

Hughes 2007

Ovulation suppression versus placebo (for subfertile couples)

270/1000274/1000OR 1.02 (0.69 to 1.5)557 (11 studies)LowIncluded studies lacked adequate explanations for allocation concealment and blinding

Sallam 2006

Ultralong GnRHa agonist down-regulation versus no agonist

325/1000673/1000OR 4.28 (2.0 to 9,15)165 (3 studies)Very lowIncluded studies lacked blinding and explanations for allocation concealment. There was some imprecision
Hart 2008 Excisional versus ablative surgery for endometriomata170/1000518/1000OR 5.24 (1.92 to 14.27)88 (2 studies)LowIncluded studies lacked blinding and there was some imprecision
Flower 2012 Chinese herbal medicine versus gestrinone592/1000699/1000RR 1.18 (0.87 to 1.59)45 (1 study)LowEvidence based on a single study

Furness 2004

Post-surgical medical therapy versus pre and post-surgical medical therapy with GnRHa

500/10000/1000RR 0.0 (0 to 0)25 (1 study)Very lowIncluded studies lacked adequate explanation of randomisation, allocation concealment and there was no blinding

Furness 2004

Post-surgical medical therapy versus placebo/no treatment

246/1000207/1000RR 0.84 (0.59 to 1.18)420 (8 studies)LowIncluded studies lack ed adequate explanation of randomisation and blinding
Lu 2012 Laparoscopic surgery plus pentoxifylline versus laparoscopic surgery plus placebo196/1000273/1000OR 1.54 (0.89 to 2.66)285 (3 studies)Very lowLacked methodological detail, and lack of precision. No trial reported on live birth
Benschop 2010 Aspiration of endometrioma versus expectant management200/1000244/1000OR 1.29 (0.45 to 3.64)81 (1 study)LowThere was no blinding and evidence was based on a single trial
Benschop 2010 Cystectomy of endometrioma versus expectant management317/1000348/1000OR 1.15 (0.52 to 2.55)109 (1 study)LowThere was no blinding and evidence was based on a single trial
Benschop 2010 GnRH agonist versus GnRH antagonist for endometrioma242/1000206/1000OR 0.814 (0.26 to 2.54)67 (1 study)LowEvidence based on a single trial
Duffy 2014 Laparoscopic ablation or excision versus diagnostic laparoscopy186 per 1000302 per 1000 (223 to 396)OR 1.89 (1.25 to 2.86)528 (3 studies)ModerateTwo studies didnot adequately describe randomisation methods; one study was at high risk of attrition bias
Ongoing pregnancy (20 weeks) or live birth

Duffy 2014

Laparoscopic ablation or excision versus diagnostic laparoscopy

179 per 1000

297 per 1000

(207 to 408)

OR 1.94 (1.20 to 3.16)382 (2 studies)ModerateOne study did not describe methods in detail, as it is only published as an abstract. Most of the data apply to ongoing pregnancy: of 92 events in this comparison, only 12 were live birth
Fetal loss or miscarriage

Duffy 2014

Laparoscopic surgery versus diagnostic laparoscopy

190/1000181/1000OR 0.94 (0.35 to 2.54)112 (2 studies)ModerateOne study did not describe methods in detail, as was only available as an abstract. The larger study (n=100 pregnancies) did not include fetal losses after 20 weeks
Benschop 2010 GnRH agonist versus GnRH antagonist for endometrioma prior to ART30/100029/1000OR 0.97 (0.06 to 15.85)67 (1 study)LowEvidence based on a single trial and wide confidence intervals are indicative of some imprecision
Benschop 2010 Aspiration of endometrioma versus expectant management100/100097/1000OR 0.97 (0.23 to 4.15)81 (1 study)LowThere was no blinding and the evidence is based on a single trial

Effect of interventions

1. Pain outcomes

See Table 5

1.1 Gonadotrophin-releasing hormone agonist or antagonist (GnRHa)

Brown 2010 concluded that women receiving GnRHas were more likely to achieve symptom relief than those having no treatment (risk ratio (RR) 3.93, 95% confidence interval (CI) 1.37 to 11.28). There was no statistically significant difference between GnRHas and danazol for the rate of relief of dysmenorrhoea (RR 0.98, 95% CI 0.92 to 1.04). More adverse events were reported in the GnRHa group. There was a benefit in overall pain resolution for GnRHas (RR 1.10, 95% CI 1.01 to 1.21) compared with danazol. There was no statistically significant difference in overall pain scores between the GnRHas and levonorgestrel groups (standardised mean difference (SMD) -0.25, 95% CI -0.60 to 0.10). Evidence was limited on optimal dosage or duration of treatment for GnRHas. No one route of administration appeared superior to another.

1.2 Ovulation suppression

Davis 2007 provided evidence from a single trial of 57 women that found no difference between the oral contraceptive pill and goserelin (a GnRH analogue) for relieving pain associated with endometriosis (odds ratio (OR) 0.76, 95% CI 0.17 to 3.29, 44 participants, 1 trial).

Farquhar 2007 found that treatment with danazol (including its use as an adjunct to surgery) was effective in relieving pain associated with endometriosis when compared with placebo (mean difference (MD) -3.4, 95% CI -4.8 to -1.8, 60 participants, 1 trial). There was also an improvement in laparoscopic scores, although women who received danazol as treatment were more likely to experience side effects than women receiving placebo.

Al-Kadri 2009 found no difference between the groups in pain or recurrence of disease in a randomised trial comparing sequential administration of estrogen and progesterone with placebo. There was also no difference between the groups in pain in a trial comparing non-stop transdermal 17β estradiol combined with cyclic medroxyprogesterone acetate compared with tibolone (OR 6.67, 95% CI 0.6 to 74.51, 21 participants, 1 trial).

Abou-Setta 2013 reported on a review of three randomised trials. There was evidence of a significant decrease in recurrence of painful menstruation in the levonorgestrel hormone-releasing intrauterine device (LNG-IUD) group compared with the expectant management group (RR 0.22, 95% CI 0.08 to 0.60, two trials, 95 women). In the third trial (n = 40) there was no evidence of a significant difference in visual analogue scale (VAS) pain scores between the LNG-IUD group and women who received GnRHas.

Brown 2012 conducted a review of progestagens and anti-progestagens for pain associated with endometriosis.There was no evidence of a difference in the American Fertility Society (AFS) scores between the prostagens (medroxyprogesterone) group and the placebo group (mean difference (MD) 0.58, 95% CI -1.41 to 0.25). Progestagens were associated with more adverse events (acne and oedema) than placebo. There was no evidence of a benefit for subjective or objective outcomes for dydrogesterone compared with placebo. When depot progestagens were compared with other treatments, symptoms were improved in the depot group. However there were also more adverse events in the depot group. There was no evidence of a difference in pain outcomes when oral progestagens were compared with other treatments. The evidence for anti-progestagens was mixed, with one study indicating a benefit for anti-progestagens compared to other treatment at 12 months follow-up, and another study finding no evidence of a difference between groups.

1.3 Analgesics
Non-steroidal anti-inflammatory drugs (NSAIDS)

Allen 2009 reported inconclusive evidence on the effectiveness of NSAIDS (naproxen) when compared with placebo based on the management of pain associated with endometriosis (OR inverse variance 0.33, 95% CI 0.61 to 17.69, 20 participants, 1 trial).

1.4 Surgical interventions

Hart 2008 reported that laparoscopic excision of the cyst wall of the endometrioma was associated with a reduced recurrence rate of the symptoms of dysmenorrhoea compared to laparoscopic ablation.

Duffy 2014 reported that there was no significant difference between laparoscopic surgery and diagnostic laparoscopy for relief of dysmenorrhoea at 6 or 12 months. However, only one small study reported this outcome and there was very serious imprecision in the result (MD on VAS 0 to 100 scale 2.40, 95% CI -6.18 to 10.98; MD -9.50, 95% CI -20.58 to 1.58, respectively). Laparoscopic surgery was associated with decreased overall pain (measured as ‘pain better or improved’) compared with diagnostic laparoscopy, both at 6 months (OR 6.58, 95% CI 3.31 to 13.10) and at 12 months (OR 10.00, 95% CI 3.21 to 31.17). When laparoscopic ablation was compared with diagnostic laparoscopy plus medical therapy (GNRHa with add back therapy), more women in the ablation group were pain free at 12 months (OR 5.63, 95% CI 1.18 to 26.85). The difference between laparoscopic ablation and laparoscopic excision in the proportion of women reporting overall pain relief at 12 months on a VAS 0 to 10 pain scale was 0 (95% CI to 1.22 to 1.22). There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.

1.5 Post-surgical interventions

Lu 2012 found no evidence of a benefit from pentoxifylline when compared with no treatment on the reduction of pain associated with endometriosis after laparoscopic surgery in one randomised trial; and neither was there evidence of a difference between pentoxifylline and placebo after surgery on recurrence of disease, as reported in the single randomised trial. The mean reduction in pain at three months was 5.53 in the control group. In the intervention group the mean pain reduction was 1.6 lower (range 3.32 lower to 0.12 higher, 34 participants, 1 trial).

Furness 2004 found no evidence of a benefit from pre-surgical medical therapy compared to surgery alone for the symptomatic relief of endometriosis, or for post-surgical hormone suppression compared with surgery alone for the pain and disease recurrence outcomes. There was also no evidence that pre-surgical hormone suppression was different to post-surgical hormone suppression for the outcome of pain, and there were no differences in AFS scores in a comparison of post-surgical medical therapy and pre and post-surgery therapy.

1.6 Other medical intervention
Anti-tumour necrosis factor-α (anti-TNF-α)

Lu 2013 found no evidence to support the use of anti-TNF-α drugs for the alleviation of pain associated with endometriosis. The evidence was based on a single trial. The patient Biberoglu and Behrman score was a mean of 1.7 in the control group and 0.2 lower in the intervention group (range 0.68 lower to 0.28 higher).

1.7 Other interventions

Zhu 2011 reported on one trial of 67 women. The trial found that auricular acupuncture was significantly more effective at reducing pain associated with endometriosis than Chinese herbal medicine (RR 3.04, 95% CI 1.65 to 5.62, 67 participants, 1 trial).

Flower 2012 reported on two post-surgical interventions using Chinese herbal medicine. The authors concluded that Chinese herbal medicine may have comparable benefits to conventional medicine (gestrinone and danazol) but with fewer side effects. Chinese herbal medicine appeared to have some superiority over danazol in the relief of symptoms. The review was based on only two randomised trials.

2. Fertility outcomes

2.1 GnRH agonist

Sallam 2006 reported evidence of significantly more pregnancies among women undergoing ART who received ultra-long GnRH agonist down-regulation than among those who did not receive the agonist (OR 4.28, 95% CI 2.0 to 9.15, 165 participants, 3 trials).

Benschop 2010 found no evidence of a difference in clinical pregnancy rates between GnRH agonists and GnRH antagonists administered for endometrioma prior to ART (OR 0.81, 95% CI 0.26 to 2.54, 67 participants, 1 trial).

2.2 Ovulation suppression

Hughes 2007 reported that there was no difference in clinical pregnancy rates between a group receiving ovulation suppression and a group receiving placebo or no treatment (OR 1.02, 95% CI 0.70 to 1.52, 557 participants,11 trials) despite the use of a variety of suppression agents. The review concluded that there was no evidence of a benefit in the use of ovulation suppression in subfertile women with endometriosis who wished to conceive.

2.3 Pre-surgical interventions

Furness 2004 reported insufficient evidence to determine whether there was a difference in clinical pregnancy rates when pre-surgical medical therapy was compared with surgery alone (RR 0.46, 95% CI 0.15 to 1.45, 25 participants, 1 trial).

2.4 Surgical interventions

Duffy 2014 reported that laparoscopic surgery was associated with a higher live birth or ongoing pregnancy rate than diagnostic laparoscopy (OR 1.94, 95% CI 1.20 to 3.16). The clinical pregnancy rate was also higher (OR 1.89, 95% CI 1.25 to 2.86). There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.

Hart 2008 reported that two randomised controlled trials suggested a benefit of excisional surgery over drainage or ablation of endometriomata for achieving pregnancy in previously subfertile women (OR 5.24, 95% CI 1.92 to 14.27, 88 participants, 2 trials).

Benschop 2010 found no evidence of a difference in clinical pregnancy rates between surgery (aspiration or cystectomy) for endometrioma prior to ART and expectant management (aspiration OR 1.29, 95% CI 0.45 to 3.64. 81 participants, 1 trial; cystectomy OR 1.15, 95% CI 0.52 to 2.55, 109, 1 trial).

2.5 Post-surgical interventions

Lu 2012 reported no evidence of a significant difference in clinical pregnancy rates between the group receiving pentoxifylline and the placebo group in three randomised trials (OR 1.54, 95% CI 0.89 to 266, 285 participants). There was insufficient evidence to recommend the use of pentoxifylline in the management of pre-menopausal women with endometriosis-associated subfertility.

Furness 2004 found no evidence to support the use of post-surgical medical therapy for increasing pregnancy rates (RR 0.84, 95% CI 0.59 to 1.18, 420 participants, 8 studies).

2.6 Other interventions

Flower 2012 found no significant difference between the pregnancy rates in the Chinese herbal medicine group and the gestrinone group in a single randomised trial (RR 1.18, 95% CI 0.87 to 1.59, 45 participants, 1 trial).

Discussion

Summary of main results

Pain relief (14 reviews)

Gonadotrophin-releasing hormone (GnRH) analogues

One systematic review reported low quality evidence of an overall benefit for GnRH analogues compared with placebo or no treatment (Brown 2010).

Ovulation suppression

Five systematic reviews reported on medical treatment using ovulation suppression. There was moderate quality evidence that the levonorgestrel-releasing intrauterine system (LNG-IUD) was more effective than expectant management (Abou-Setta 2013), and very low quality evidence that danazol was more effective than placebo (Farquhar 2007). There was no consistent evidence of a difference in effectiveness between oral contraceptives and goserelin (Davis 2007), estrogen plus progestogen (Al-Kadri 2009) and placebo, or progestogens and placebo (Brown 2012), though the relevant evidence was of low or very low quality.

Non-steroidal anti-inflammatory drugs (NSAIDS)

A review of NSAIDs reported inconclusive evidence on a benefit in symptom relief compared with placebo (Allen 2009).

Surgical interventions

There were two reviews of surgical interventions. One reported moderate quality evidence of a benefit in pain relief following laparoscopic surgery compared to diagnostic laparoscopy. The other review reported very low quality evidence that recurrence rates of endometriomata were lower after excisional surgery than after ablative surgery (Hart 2008; Duffy 2014).

Post-surgical medical interventions

Two reviews reported on post-surgical medical interventions. Neither found evidence of an effect on pain outcomes (Furness 2004; Lu 2012); the evidence was of low or very low quality.

Alternative medicine

There were two systematic reviews of alternative medicine. One reported evidence of a benefit of auricular acupuncture compared to Chinese herbal medicine (Zhu 2011). The other review reported no evidence of a difference between Chinese herbal medicine and danazol (Flower 2012). In both cases the evidence was of low or very low quality.

Anti-TNF-α drugs

One review (Lu 2013) found low quality evidence that anti-TNF-α drugs were no more effective than placebo.

Fertility outcomes (eight reviews)

Medical interventions

Four reviews reported on medical interventions for improving fertility in women with endometriosis (Benschop 2010; Furness 2004; Hughes 2007; Sallam 2006). One compared three months of GnRH agonists with a control intervention in women undergoing ART and found very low quality evidence of an increase in clinical pregnancies in the treatment group (Sallam 2006). There was no evidence of a difference in effectiveness between the interventions in the other three reviews, which compared GnRH agonists versus antagonists (Benschop 2010), ovulation suppression versus placebo or no treatment (Hughes 2007), and pre-surgical medical therapy versus surgery alone (Furness 2004). In all cases the evidence was of low or very low quality.

Surgical interventions

Three reviews reported on surgical interventions. There was moderate quality evidence of a benefit from laparoscopic surgery compared to diagnostic laparoscopy, with higher live birth or ongoing pregnancy rates and also higher clinical pregnancy rates (Duffy 2014). There was no evidence of a difference in effectiveness between surgery and expectant management for endometrioma (Benschop 2010). One review (Hart 2008) found that excisional surgery resulted in higher clinical pregnancy rates than drainage or ablation of endometrioma. In the latter two cases the evidence was of low quality. However, there are concerns about reducing ovarian reserve in women who have ovarian surgery that should be considered in further studies.

Post-surgical interventions

Two reviews reported on post-surgical medical interventions. They found no evidence of an effect on the clinical pregnancy rate (Furness 2004; Lu 2012). The evidence was of low or very low quality.

Alternative medicine

A review of Chinese herbal medicine in comparison with gestrinone found no evidence of a difference between the groups in clinical pregnancy rates (Flower 2012). However, the evidence was of low quality.

Other outcomes

Reviews of GnRH analogues and of danazol reported that the interventions were associated with higher rates of adverse effects than placebo, and depot progestagens were associated with higher rates of adverse events than other treatments. Chinese herbal medicine was associated with fewer side effects than gestrinone or danazol.

Two reviews reported miscarriage as an outcome. For this outcome no difference was found between surgical and diagnostic laparoscopy (Duffy 2014), between GnRH agonists and antagonists (Benschop 2010), or between aspiration of endometrioma and expectant management (Benschop 2010). The quality of the evidence was moderate (Duffy 2014) or low (Benschop 2010).

Overall completeness and applicability of evidence

All women in the included reviews had confirmed endometriosis.

For many interventions there were too few data to reach a firm conclusion.

Nearly all the studies in the reviews of treatment for subfertility associated with endometriosis failed to report live birth rates.

Quality of the evidence

The included systematic reviews were prepared according to the guidelines of The Cochrane Collaboration and were of high quality in most respects, though only eight of the 17 had had a literature search within the past three years.

The quality of the evidence reported by the primary studies in the included reviews was rated using GRADE methods and ranged from very low to moderate. The main reasons for the quality of the evidence being downgraded were bias in the primary studies (inadequate reporting of allocation concealment and randomisation methods, lack of blinding) and imprecision. The evidence was frequently restricted to a single small trial.

Potential biases in the overview process

No biases were identified during the overview process.

Agreements and disagreements with other studies or reviews

No other overviews were identified.

Authors' conclusions

Implications for practice

For women with pain and endometriosis, suppression of menstrual cycles with GnRH analogues, LNG-IUD and danazol was beneficial. Laparoscopic treatment of endometriosis and excision of endometriomata were associated with pain improvements and therefore surgical approaches can be considered.

There are no medical treatments that are recommended to improve natural fertility in women with endometriosis. Women who are undergoing ART and who have known endometriosis could be treated with three months of a GnRH agonist, as this may improve pregnancy outcomes. Laparoscopic surgery improved fertility outcomes compared to diagnostic laparoscopy. There is insufficient evidence about the surgical treatment of endometriosis in women undergoing ART interventions.

Implications for research

Head to head trials of medical and surgical treatments for women with painful symptoms of endometriosis may be useful.

Further trials are required considering the role of surgery in women undergoing ART cycles. In addition, there are concerns about reducing ovarian reserve in women who have ovarian surgery.

Acknowledgements

The authors wish to acknowledge the support of the Cochrane Menstrual Disorders and Subfertility Group and the advice received from Sofia Dias (statistician). We also acknowledge the contribution of Jane Marjoribanks in providing editorial oversight and approved the final version.

Appendices

Appendix 1. Protocols and titles for future inclusion in this review

Protocols and titles for future inclusion in this overview

Protocols

Bignardi 2011: Excisional versus ablative surgery for peritoneal endometriosis

Fu 2012: Progesterone receptor antagonists and progesterone receptor modulators for endometriosis

Titles

Houda unpublished 2013: Gonadotrophin antagonists for endometriosis

Chen unpublished 2013: Selective estrogen receptor modulators (SERMs) for endometriosis

What's new

DateEventDescription
16 June 2014AmendedMinor typographical errors corrected

Contributions of authors

Julie Brown and Cindy Farquhar were responsible for the writing of the protocol and overview.

Declarations of interest

None

Sources of support

Internal sources

  • Department of Obstetrics and Gynaecology, University of Auckland, New Zealand.

External sources

  • Auckland District Health Board Charitable Trust, New Zealand.