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Endometriosis: una revisión global de revisiones Cochrane

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Antecedentes

Esta revisión global informa sobre intervenciones para el alivio del dolor y la subfertilidad en mujeres premenopáusicas con diagnóstico clínico de endometriosis.

Objetivos

El objetivo fue resumir la evidencia de las revisiones sistemáticas Cochrane sobre las opciones de tratamiento para las mujeres con dolor o subfertilidad asociados con endometriosis.

Métodos

Para la inclusión en el resumen fueron elegibles las revisiones sistemáticas Cochrane publicadas que informaron sobre desenlaces de dolor o de fertilidad en mujeres con diagnóstico clínico de endometriosis. También se identificaron revisiones Cochrane en preparación (protocolos y títulos) para su inclusión futura. Las revisiones, los protocolos y los títulos se identificaron mediante búsquedas en la Base de Datos Cochrane de Revisiones Sistemáticas (Cochrane Database of Systematic Reviews) y en Archie (el sistema de gestión de información Cochrane), en marzo 2014.

Los desenlaces de la revisión global relacionados con el dolor fueron alivio del dolor, mejora o resolución clínica y recurrencia del dolor. Los desenlaces relacionados con la fertilidad fueron nacidos vivos, embarazo clínico, embarazo en curso, aborto espontáneo y eventos adversos.

La selección de las revisiones sistemáticas, la extracción de los datos y la evaluación de la calidad se realizaron por duplicado. La calidad de la revisión se evaluó mediante la herramienta AMSTAR. La calidad de la evidencia para cada desenlace se evaluó mediante los criterios GRADE. Los hallazgos de las revisiones se resumieron en el texto y los datos de cada desenlace se informaron en las "Tablas adicionales".

Resultados principales

Se incluyeron 17 revisiones sistemáticas publicadas en The Cochrane Library. Todas las revisiones fueron de calidad alta. La calidad de la evidencia para las comparaciones específicas varió de muy baja a moderada. Las limitaciones en la evidencia incluyeron riesgo de sesgo en los estudios primarios, inconsistencia entre los estudios e imprecisión en las estimaciones del efecto.

Alivio del dolor (14 revisiones)

Análogos de la hormona liberadora de gonadotrofina (GnRH)

Una revisión sistemática informó evidencia de calidad baja de un efecto beneficioso general de los análogos de la GnRH, en comparación con placebo o ningún tratamiento.

Supresión de la ovulación

Cinco revisiones sistemáticas informaron sobre el tratamiento médico mediante la supresión de ovulación. Hubo evidencia de calidad moderada de que el sistema intrauterino que libera levonorgestrel (DIU‐LNG) fue más efectivo que la conducta expectante, y evidencia de calidad muy baja de que el danazol fue más efectivo que placebo. No hubo evidencia consistentes de una diferencia en la efectividad entre los anticonceptivos orales y goserelina, estrógenos más progestágeno y placebo, o progestágenos y placebo, aunque en todos los casos la evidencia relevante fue de calidad baja o muy baja.

Fármacos antiinflamatorios no esteroideos (AINE)

Una revisión de los AINE informó de evidencia no concluyente de un efecto beneficioso sobre el alivio de los síntomas en comparación con placebo.

Intervenciones quirúrgicas

Hubo dos revisiones de intervenciones quirúrgicas. Una informó de evidencia de calidad moderada de un efecto beneficioso sobre el alivio del dolor después de la cirugía laparoscópica, en comparación con la laparoscopia de diagnóstico solamente. La otra informó de evidencia de calidad muy baja de que las tasas de recurrencia de los endometriomas fueron inferiores después de la cirugía para exéresis, en comparación con después de la cirugía ablativa.

Intervenciones médicas posquirúrgicas

Dos revisiones informaron sobre intervenciones médicas posquirúrgicas. Ninguna encontró evidencia de un efecto beneficioso sobre los desenlaces de dolor, aunque en ambos casos la evidencia fue de calidad baja o muy baja.

Medicina alternativa

Hubo dos revisiones sistemáticas de medicina alternativa. Una informó de evidencia de un efecto beneficioso de la acupuntura auricular comparada con las medicinas chinas a base de hierbas, y la otra no informó evidencia de una diferencia entre las medicinas chinas a base de hierbas y el danazol. En ambos casos la evidencia fue de calidad baja o muy baja.

Fármacos anti‐FNT‐α

Una revisión no encontró evidencia de una diferencia en la efectividad entre los fármacos anti‐FNT‐α y placebo. En general, la evidencia fue de calidad baja.

Revisiones que informan sobre desenlaces de fertilidad (ocho revisiones)

Intervenciones médicas

Cuatro revisiones informaron sobre intervenciones médicas para mejorar la fertilidad en mujeres con endometriosis. Una comparó tres meses de agonistas de GnRH con un control en mujeres a las que se les realizaron técnicas de reproducción asistida, y encontró evidencia de calidad muy baja de un aumento de los embarazos clínicos en el grupo de tratamiento. No hubo evidencia de una diferencia en la efectividad entre las intervenciones en las otras tres revisiones que compararon agonistas versus antagonistas de GnRH, supresión de la ovulación versus placebo o ningún tratamiento, y tratamiento médico prequirúrgico versus cirugía sola. En todos los casos la evidencia fue de calidad baja o muy baja.

Intervenciones quirúrgicas

Tres revisiones informaron sobre intervenciones quirúrgicas. Hubo evidencia de calidad moderada de que las tasas de nacidos vivos, de embarazo en curso y de embarazo clínico fueron mayores después de la cirugía laparoscópica que después de la laparoscopia de diagnóstico solamente. Hubo evidencia de calidad muy baja de ninguna diferencia en la efectividad entre la cirugía y la conducta expectante para el endometrioma. Una revisión encontró evidencia de calidad baja de que la cirugía para exéresis dio lugar a tasas mayores de embarazo clínico que el drenaje o la ablación del endometrioma.

Intervenciones posquirúrgicas

Dos revisiones informaron sobre intervenciones médicas posquirúrgicas. No encontraron evidencia de un efecto sobre las tasas de embarazo clínico. La evidencia fue de calidad baja o muy baja.

Medicina alternativa

Una revisión de medicinas chinas a base de hierbas en comparación con gestrinona no encontró evidencia de una diferencia entre los grupos en cuanto a las tasas de embarazo clínico. En general, la evidencia fue de calidad baja.

Eventos adversos

Las revisiones de los análogos de GnRH y el danazol informaron que las intervenciones se asociaron con tasas mayores de efectos adversos en comparación con placebo, y que los progestágenos de depósito se asociaron con tasas mayores de eventos adversos que otros tratamientos. Las medicinas chinas a base de hierbas se asociaron con menos efectos secundarios que la gestrinona o el danazol.

Tres revisiones informaron sobre el aborto espontáneo como resultado. No se encontraron diferencias entre la laparoscopia quirúrgica y de diagnóstico, entre los agonistas y los antagonistas de GnRH, ni entre la aspiración del endometrioma y la conducta expectante. Sin embargo, en todos los casos la calidad de la evidencia fue baja.

Conclusiones de los autores

En las mujeres con dolor y endometriosis, la supresión de los ciclos menstruales con análogos de la hormona liberadora de gonadotrofinas (GnRH), el sistema intrauterino que libera levonorgestrel (DIU‐LNG) y el danazol fueron intervenciones con efectos beneficiosos. El tratamiento laparoscópico de la endometriosis y la exéresis del endometrioma también se asociaron con mejoras en el dolor. La evidencia sobre los AINE no fue concluyente. No hubo evidencia de efectos beneficiosos con el tratamiento médico posquirúrgico.

En las mujeres con endometriosis a las que se les realizaron técnicas de reproducción asistida, el tratamiento con agonista de GnRH durante tres meses mejoró las tasas de embarazo. La cirugía para exéresis mejoró las tasas de embarazo espontáneo en los nueve a 12 meses posteriores a la cirugía, en comparación con la cirugía ablativa. La cirugía laparoscópica mejoró las tasas de nacidos vivos y de embarazo, en comparación con la laparoscopia de diagnóstico solamente. No hubo evidencia de que el tratamiento médico mejore las tasas de embarazo clínico.

La evidencia sobre los efectos perjudiciales no fue suficiente, pero los análogos de GnRH, el danazol y los progestágenos de depósito se asociaron con tasas mayores que otras intervenciones.

Endometriosis: una revisión global de revisiones Cochrane

Antecedentes

Los autores de la revisión Cochrane examinaron la evidencia sobre la endometriosis proveniente de revisiones sistemáticas Cochrane publicadas en The Cochrane Library. El objetivo fue resumir la evidencia sobre las opciones terapéuticas disponibles para las mujeres con dolor, subfertilidad, o ambos, asociados con diagnóstico clínico de endometriosis.

Características de los estudios

Se incluyeron 17 revisiones sistemáticas Cochrane. Catorce informaron de medidas de alivio del dolor y ocho informaron sobre desenlaces de fertilidad. Todas las revisiones fueron de calidad alta. La calidad de la evidencia para las comparaciones y los desenlaces específicos varió de muy baja a moderada debido a limitaciones en los estudios primarios, inconsistencia entre los estudios e imprecisión en los hallazgos.

Resultados clave

Varias intervenciones parecieron ser efectivas para el alivio del dolor en las mujeres con endometriosis. Dichas intervenciones fueron los análogos de la hormona liberadora de gonadotrofina (GnRH) comparados con placebo, el sistema intrauterino que libera levonorgestrel (DIU‐LNG) comparado con conducta expectante, el danazol comparado con placebo y los progestágenos y anti‐progestágenos comparados con placebo. Las intervenciones quirúrgicas laparoscópicas también mostraron ser efectivas para el dolor.

En las mujeres con endometriosis a las que se les realizaron técnicas de reproducción asistida, el tratamiento con agonista de GnRH durante tres meses mejoró las tasas de embarazo. La cirugía para exéresis mejoró las tasas de embarazo espontáneo en los nueve a 12 meses posteriores a la cirugía, en comparación con la cirugía ablativa. La cirugía laparoscópica mejoró las tasas de nacidos vivos y de embarazo, en comparación con la laparoscopia de diagnóstico solamente. No hubo evidencia de que el tratamiento médico mejore las tasas de embarazo clínico.

La evidencia sobre los efectos perjudiciales no fue suficiente, pero los análogos de GnRH y el danazol se asociaron con tasas mayores de efectos adversos a las de placebo, y los progestágenos de depósito se asociaron con tasas mayores en comparación con otros tratamientos.

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.

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.

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Table 1. Details of reviews

Review ID

Date assessed as up to date

Number of included trials

Number of participants

Intervention

Control or comparison intervention

Outcomes for which data assessed

Review limitations

GnRH agonist/antagonist

Sallam 2006

17/10/2008

3 RCTs

165 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 2010

27/09/2010

42 RCTs

4935 women

Any 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 2010

04/10/2010

4 RCTs

312 women

Surgical 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 2007

19/04/2009 (stable review no longer being updated)

25 RCTs

2600 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 2007

17/05/2007

1 RCT

57 women

Low 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 2013

13/6/2012

3 RCTs

135 women

LNG‐IUD

Expectant management

Pain

Satisfaction

Dropout rates

There was no evidence of blinding in two of the trials

Al‐Kadri 2009

10/07/2008

2 RCTs

193 women

Estrogen, with or without progesterone

Placebo

Tibolone

Pain

Disease recurrence

There was no evidence of blinding and the trials lacked precision

Farquhar 2007

15/06/2007 (stable review, no longer being updated)

5 RCTs

370 women

Danazol 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 2012

17/01/2011

13 RCTs

1511 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 2009

23/04/2008

2 RCTs

48 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 2010

04/10/2010

4 RCTs

312 women

Surgery (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 2014

31.7.13

10 RCTs

973 women

Laparoscopic surgery

Any 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 2008

31/08/2009

2 RCTs

Not detailed in review

Excision

Drainage 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 2004

20/09/2010

 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

Pregnancy

Live birth not reported

Lu 2012

20/03/2012

4 RCTs

334 women

Laparoscopic surgery + Pentoxifylline

Laparoscopic 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 2013

3/9/12

1 RCT

21 women

Anti‐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 2012

31/10/2011

2 RCTs

158 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 2011

27/7/2010

1 RCT

67 women

Acupuncture

Chinese herbal medicine

"cured" of pain

There was a lack of adequate explanation for randomisation and allocation concealment and there were no details on blinding

Furness 2004

20/09/2010

10 RCTs

1046 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, recurrence

Most of the included trials lacked adequate methodological detail and there was a lack of blinding

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Table 2. Description of populations in included reviews

Review author

Age (years)

Stage of disease

Abou‐Setta 2013

No 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 2009

Mean age 33 years

Eligible 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 2009

No details in review

Eligible 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 2010

Women 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 2010

All 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 2012

Women with age ranging from 18 to 49

Eligible participants were women of reproductive years with painful symptoms and a laparoscopic diagnosis of endometriosis.

Davis 2007

No details in review

Eligible 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 2014

No details in review

Eligible participants were women with endometriosis confirmed with a visual diagnosis at diagnostic or operative laparoscopy.

Farquhar 2007

Four 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 2012

No details in review

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

No further details in review

Furness 2004

Women 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 2008

No details in review

Eligible 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 2007

Range 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 2012

Mean 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 2013

Women 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 2006

No details in review

Eligible 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 2011

Age 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.

Open in table viewer
Table 3. AMSTAR assessment

Review no

First author

REVIEW TITLE

AMSTAR CRITERIA

Prespecified question and inclusion criteria

Duplicate study selection and data extraction

Comprehensive lit search

Grey lit included

Lists included and excluded studies

Describes characteristics of included studies

Study quality assessed

Studies combined using appropriate methods

Likelihood of publication bias considered/tested

Potential for conflict of interest addressed

AMAS1061

Abou‐Setta 2013

Levonorgestrel‐releasing intrauterine device (LNG‐IUD) for symptomatic endometriosis following surgery

MCA871

Allen 2009

Non‐steroidal anti‐inflammatory drugs for pain in women with endometriosis

x

HAK1181

Al‐Kadri 2009

Hormone therapy for endometriosis and surgical menopause

x

SG1241

Benschop 2010

Interventions for women with endometrioma prior to assisted reproductive technology

APO62

Brown 2010

Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

AP061

Brown 2012

Progestagens and anti‐progestagens for pain associated with endometriosis

SK141

Davis 2007

Oral contraceptives for pain associated with endometriosis

x

JD1830

Duffy 2014

Laparoscopic surgery for endometriosis.

VS081

Farquhar 2007

Danazol for pelvic pain associated with endometriosis

x

AF801

Flower 2012

Chinese herbal medicine for endometriosis

CY571

Furness 2004

Pre and post‐operative medical therapy for endometriosis surgery

x

RJH961

Hart 2008

Excisional surgery versus ablative surgery for ovarian endometriomata

EJ254

Hughes 2007

Ovulation suppression for endometriosis for women with subfertility

DL1540

Lu 2012

Pentoxifylline for endometriosis

DD1570

Lu 2013

Anti‐TNF‐α treatment for pelvic pain associated with endometriosis

HNS881

Sallam 2006

Long term pituitary down‐regulation before in vitro fertilisation (IVF) for women with endometriosis

x

KRF1291

Zhu 2011

Acupuncture for pain in endometriosis

x

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Table 4. Search date assessment

Review no

Review reference

REVIEW TITLE

<3 yrs since last search

(to March 6 2014)

AMAS1061

Abou‐Setta 2013

Levonorgestrel‐releasing intrauterine device (LNG‐IUD) for symptomatic endometriosis following surgery

MCA871

Allen 2009

Non‐steroidal anti‐inflammatory drugs for pain in women with endometriosis

HAK1181

Al‐Kadri 2009

Hormone therapy for endometriosis and surgical menopause

SG1241

Benschop 2010

Interventions for women with endometrioma prior to assisted reproductive technology

APO62

Brown 2010

Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

AP061

Brown 2012

Progestagens and anti‐progestagens for pain associated with endometriosis

SK141

Davis 2007

Oral contraceptives for pain associated with endometriosis

JD1830

Duffy 2014

Laparoscopic surgery for endometriosis

VS081

Farquhar 2007

Danazol for pelvic pain associated with endometriosis

Stable

AF801

Flower 2012

Chinese herbal medicine for endometriosis

CY571

Furness 2004

Pre and post‐operative medical therapy for endometriosis surgery

RJH961

Hart 2008

Excisional surgery versus ablative surgery for ovarian endometriomata

EJ254

Hughes 2007

Ovulation suppression for endometriosis for women with subfertility

Stable

DL1540

Lu 2012

Pentoxifylline for endometriosis

DD1570

Lu 2013

Anti‐TNF‐α treatment for pelvic pain associated with endometriosis

HNS881

Sallam 2006

Long term pituitary down‐regulation before in vitro fertilisation (IVF) for women with endometriosis

KRF1291

Zhu 2011

Acupuncture 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.

Open in table viewer
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 low

Lacked 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)

Low

Very 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)

Low

Very 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)

Low

Lacked 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)

Low

Evidence 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)

Low

Evidence 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)

Low

Evidence based on a single trial, quality of blinding very uncertain

Brown 2010 GnRHas versus no treatment

188/1000 achieved pain relief

737/1000 achieved pain relief

RR 3.93 (1.37 to 11.28)

35 (1 study)

Low

No blinding and evidence based on a single trial

Brown 2010 GnRHas versus danazol

825/1000 achieved pain relief

809/1000 achieved pain relief

RR 0.98 (0.92 to 1.04)

666 (7 studies)

Very low

Randomisation 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)

Moderate

Evidence was based on a single trial

Brown 2010 GnRHas (intranasal versus intramuscular depot)

828/1000 achieved pain relief

778/1000 achieved pain relief

RR 0.94 (0.82 to 1.08)

192 (1 study)

Low

Lack of adequate explanation of allocation concealment and evidence based on a single trial

Brown 2010 GnRHas (intranasal versus subcutaneous)

800/1000 achieved pain relief

976/1000 achieved pain relief

RR 1.22 (0.73 to 2.06)

10 (1 study)

Low

Open label trial with evidence based on a single trial

Furness 2004

Pre‐surgical medical therapy versus post‐surgical medical therapy

See Comment

See Comment

RR 0.0 (0 to 0)

53 (1 study)

Low

There 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 7.5

The mean dysmenorrhoea pain score in the intervention groups was 0.10 lower (1.28 lower to 1.08 higher)

50 (1 study)

Very low

There 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 2.3

The mean Biberoglu and Behrman score in the intervention groups was 0.2 higher (0.05 lower to 0.45 higher)

21 (1 study)

Low

Evidence 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 1.7

The mean Biberoglu and Behrman score in the intervention groups was 0.2 lower (0.68 lower to 0.28 higher)

21 (1 study)

Low

Evidence 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 0.05

The 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)

Moderate

Evidence 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 4.76

The 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)

Moderate

Evidence was based on a single trial

Brown 2012

Depot progestagen versus other treatment (6 months)

978/1000 achieved pain relief

895/1000 achieved pain relief

OR 0.19 (0.05 to 0.69)

274 (1 study)

Moderate

Evidence was based on a single trial

Brown 2012

Depot progestagen versus other treatment (12 months)

768/1000 achieved pain relief

676/1000 achieved pain relief

OR 0.63 (0.37 to 1.08)

274 (1 study)

Moderate

Evidence was based on a single trial

Brown 2012

Anti‐progestagen versus other treatment

667/1000 achieved pain relief

673/1000 achieved pain relief

OR 1.03 (0.55 to 1.93)

176 (2 studies)

Moderate

Trials 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)

Low

Allocation 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 3.63

The mean VAS score for painful symptoms in the intervention groups was 0.16 lower (2.02 to 1.7 higher)

40 (1 study)

Very low

No 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 1.85

The mean pelvic pain score in the intervention groups was 1.4 lower (1.33 to 0.77 lower)

35 (1 study)

Low

There 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 1.55

The mean pelvic pain score in the intervention groups was 1.1 lower (1.38 to 0.82 lower)

34 (1 study)

Low

There 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 months

226/1000 had moderate or severe pelvic pain at 6 months

OR 0.65 (0.2 to 2.05)

60 (1 study)

Low

There 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 1.45

The mean Biberoglu and Behrman score in the intervention groups was 0.15 lower (0.45 lower to 0.15 higher)

21 (1 study)

Low

Evidence 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 0.15

The mean Biberoglu and Behrman score in the intervention groups was 0.15 lower (0.51 lower to 0.21 higher)

21 (1 study)

Low

Evidence 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 41.8

The mean self‐reported pain in the intervention group was 1.6 lower (0.01 lower to 0.57 higher)

252 (1 study)

Low

Open 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 0.28

The mean use of analgesia in the intervention group was 0.1 (0.6 lower to 0.4 higher)

30 (1 study)

Low

Evidence 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

262/1000

128/1000

OR 0.41 (0.18 to 0.93)

164 (2 studies)

Very low

Included 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)

Low

No 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 low

Lacked 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)

Low

Lacked 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)

Low

There was a lack of adequate explanation for randomisation and allocation concealment and blinding

Brown 2010 GnRHas (400 mcg versus 800 mcg)

200/1000

82/1000

RR 0.41 (0.17 to 1.01)

143 (1 study)

Low

Lack 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)

Low

Open 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 low

Lacked 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

0/1000

0/1000

OR 2.53 (0.12 to 53.64)

172 (1 study)

Very low

There 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 0.2

The 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 low

Lacked 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 ‐4.5

The 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 low

Lacked 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 11.8

The mean AFS score in the intervention group was 1.4 higher (6.76 lower to 9.56 higher)

16 (1 study)

Very low

The 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 1.31

The mean AFS score in the intervention group was 0.34 higher (0.01 lower to 0.70 higher)

302 (1 study)

Moderate

There was an inadequate explanation of allocation concealment, randomisation and blinding

Brown 2012

Progestagen versus placebo

Mean AFS score in the control group was 1.76

Mean AFS score in the intervention group was 0.58 lower (1.41 lower to 0.25 higher)

33 (1 study)

Low

This single trial provided inadequate detail on allocation concealment and blinding

Resolution of pain

Zhu 2011 Acupuncture versus Chinese herbal medicine

267/1000

811/1000

RR 3.04 (1.65 to 5.62)

67 (1 study)

Very low

Lack of methodological detail. No blinding and evidence based on single study.

Brown 2010 GnRHas versus danazol

596/1000

655/1000

RR 1.1 (1.01 to 1.21)

1046 (9 studies)

Low

There 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)

Moderate

There was a lack of blinding and inadequate explanation of allocation concealment

Brown 2010 GnRHas (400mcg versus 800mcg)

356/1000

334/1000

RR 0.94 (0.53 to 1.66)

90 (1 study)

Moderate

Evidence based on a single trial

Davis 2007

Oral contraceptive versus goserelin

818/1000

774/1000

OR 0.76 (0.17 to 3.29)

44 (1 study)

Very low

There 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 months

756 per 1000 improved or better at 6 months (610 to 861)

OR 6.58 (3.31 to 13.10)

171 (3 studies)

Moderate

None 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 months

732 per 1000 improved or better at 12 months (467 to 895)

OR 10.00 (3.21 to 31.17)

69 (1 study)

Low

Only 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 months

530 per 1000 pain free at 12 months (191 to 843)

OR 5.63 (1.18 to 26.85

35 (1 study)

Low

Only 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

667/1000

673/1000

OR 1.03 (0.55 to 1.93)

176 (2 studies)

Low

Two 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

273/1000

207/1000

RR 0.76 (0.52 to 1.1)

332 (3 studies)

Low

Lacked sufficient evidence for allocation concealment or attrition and there was no blinding

Abou‐Setta 2013

LNG‐IUD versus expectant management

383/1000

84/1000

RR 0.22 (0.08 to 0.6)

95 (2 studies)

Moderate

Only one of the two studies had blinded outcome assessment

Al‐Kadri 2009

Estrogen with or without progesterone versus placebo

0/1000

0/1000

OR 4.64 (0.25 to 87.71)

172 (1 study)

Very low

There 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

91/1000

400/1000

OR 6.67 (0.6 to 74.51)

21 (1 study)

Very low

There was no blinding and there was a lack of adequate detail on allocation concealment. Evidence was based on a single trial

Open in table viewer
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)

270/1000

274/1000

OR 1.02 (0.69 to 1.5)

557 (11 studies)

Low

Included studies lacked adequate explanations for allocation concealment and blinding

Sallam 2006

Ultralong GnRHa agonist down‐regulation versus no agonist

325/1000

673/1000

OR 4.28 (2.0 to 9,15)

165 (3 studies)

Very low

Included studies lacked blinding and explanations for allocation concealment. There was some imprecision

Hart 2008 Excisional versus ablative surgery for endometriomata

170/1000

518/1000

OR 5.24 (1.92 to 14.27)

88 (2 studies)

Low

Included studies lacked blinding and there was some imprecision

Flower 2012 Chinese herbal medicine versus gestrinone

592/1000

699/1000

RR 1.18 (0.87 to 1.59)

45 (1 study)

Low

Evidence based on a single study

Furness 2004

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

500/1000

0/1000

RR 0.0 (0 to 0)

25 (1 study)

Very low

Included studies lacked adequate explanation of randomisation, allocation concealment and there was no blinding

Furness 2004

Post‐surgical medical therapy versus placebo/no treatment

246/1000

207/1000

RR 0.84 (0.59 to 1.18)

420 (8 studies)

Low

Included studies lack ed adequate explanation of randomisation and blinding

Lu 2012 Laparoscopic surgery plus pentoxifylline versus laparoscopic surgery plus placebo

196/1000

273/1000

OR 1.54 (0.89 to 2.66)

285 (3 studies)

Very low

Lacked methodological detail, and lack of precision. No trial reported on live birth

Benschop 2010 Aspiration of endometrioma versus expectant management

200/1000

244/1000

OR 1.29 (0.45 to 3.64)

81 (1 study)

Low

There was no blinding and evidence was based on a single trial

Benschop 2010 Cystectomy of endometrioma versus expectant management

317/1000

348/1000

OR 1.15 (0.52 to 2.55)

109 (1 study)

Low

There was no blinding and evidence was based on a single trial

Benschop 2010 GnRH agonist versus GnRH antagonist for endometrioma

242/1000

206/1000

OR 0.814 (0.26 to 2.54)

67 (1 study)

Low

Evidence based on a single trial

Duffy 2014 Laparoscopic ablation or excision versus diagnostic laparoscopy

186 per 1000

302 per 1000 (223 to 396)

OR 1.89 (1.25 to 2.86)

528 (3 studies)

Moderate

Two 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)

Moderate

One 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

190/1000

181/1000

OR 0.94 (0.35 to 2.54)

112 (2 studies)

Moderate

One 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 ART

30/1000

29/1000

OR 0.97 (0.06 to 15.85)

67 (1 study)

Low

Evidence based on a single trial and wide confidence intervals are indicative of some imprecision

Benschop 2010 Aspiration of endometrioma versus expectant management

100/1000

97/1000

OR 0.97 (0.23 to 4.15)

81 (1 study)

Low

There 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.

Table 1. Details of reviews

Review ID

Date assessed as up to date

Number of included trials

Number of participants

Intervention

Control or comparison intervention

Outcomes for which data assessed

Review limitations

GnRH agonist/antagonist

Sallam 2006

17/10/2008

3 RCTs

165 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 2010

27/09/2010

42 RCTs

4935 women

Any 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 2010

04/10/2010

4 RCTs

312 women

Surgical 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 2007

19/04/2009 (stable review no longer being updated)

25 RCTs

2600 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 2007

17/05/2007

1 RCT

57 women

Low 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 2013

13/6/2012

3 RCTs

135 women

LNG‐IUD

Expectant management

Pain

Satisfaction

Dropout rates

There was no evidence of blinding in two of the trials

Al‐Kadri 2009

10/07/2008

2 RCTs

193 women

Estrogen, with or without progesterone

Placebo

Tibolone

Pain

Disease recurrence

There was no evidence of blinding and the trials lacked precision

Farquhar 2007

15/06/2007 (stable review, no longer being updated)

5 RCTs

370 women

Danazol 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 2012

17/01/2011

13 RCTs

1511 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 2009

23/04/2008

2 RCTs

48 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 2010

04/10/2010

4 RCTs

312 women

Surgery (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 2014

31.7.13

10 RCTs

973 women

Laparoscopic surgery

Any 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 2008

31/08/2009

2 RCTs

Not detailed in review

Excision

Drainage 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 2004

20/09/2010

 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

Pregnancy

Live birth not reported

Lu 2012

20/03/2012

4 RCTs

334 women

Laparoscopic surgery + Pentoxifylline

Laparoscopic 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 2013

3/9/12

1 RCT

21 women

Anti‐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 2012

31/10/2011

2 RCTs

158 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 2011

27/7/2010

1 RCT

67 women

Acupuncture

Chinese herbal medicine

"cured" of pain

There was a lack of adequate explanation for randomisation and allocation concealment and there were no details on blinding

Furness 2004

20/09/2010

10 RCTs

1046 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, recurrence

Most of the included trials lacked adequate methodological detail and there was a lack of blinding

Figuras y tablas -
Table 1. Details of reviews
Table 2. Description of populations in included reviews

Review author

Age (years)

Stage of disease

Abou‐Setta 2013

No 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 2009

Mean age 33 years

Eligible 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 2009

No details in review

Eligible 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 2010

Women 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 2010

All 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 2012

Women with age ranging from 18 to 49

Eligible participants were women of reproductive years with painful symptoms and a laparoscopic diagnosis of endometriosis.

Davis 2007

No details in review

Eligible 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 2014

No details in review

Eligible participants were women with endometriosis confirmed with a visual diagnosis at diagnostic or operative laparoscopy.

Farquhar 2007

Four 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 2012

No details in review

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

No further details in review

Furness 2004

Women 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 2008

No details in review

Eligible 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 2007

Range 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 2012

Mean 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 2013

Women 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 2006

No details in review

Eligible 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 2011

Age 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

Figuras y tablas -
Table 2. Description of populations in included reviews
Table 3. AMSTAR assessment

Review no

First author

REVIEW TITLE

AMSTAR CRITERIA

Prespecified question and inclusion criteria

Duplicate study selection and data extraction

Comprehensive lit search

Grey lit included

Lists included and excluded studies

Describes characteristics of included studies

Study quality assessed

Studies combined using appropriate methods

Likelihood of publication bias considered/tested

Potential for conflict of interest addressed

AMAS1061

Abou‐Setta 2013

Levonorgestrel‐releasing intrauterine device (LNG‐IUD) for symptomatic endometriosis following surgery

MCA871

Allen 2009

Non‐steroidal anti‐inflammatory drugs for pain in women with endometriosis

x

HAK1181

Al‐Kadri 2009

Hormone therapy for endometriosis and surgical menopause

x

SG1241

Benschop 2010

Interventions for women with endometrioma prior to assisted reproductive technology

APO62

Brown 2010

Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

AP061

Brown 2012

Progestagens and anti‐progestagens for pain associated with endometriosis

SK141

Davis 2007

Oral contraceptives for pain associated with endometriosis

x

JD1830

Duffy 2014

Laparoscopic surgery for endometriosis.

VS081

Farquhar 2007

Danazol for pelvic pain associated with endometriosis

x

AF801

Flower 2012

Chinese herbal medicine for endometriosis

CY571

Furness 2004

Pre and post‐operative medical therapy for endometriosis surgery

x

RJH961

Hart 2008

Excisional surgery versus ablative surgery for ovarian endometriomata

EJ254

Hughes 2007

Ovulation suppression for endometriosis for women with subfertility

DL1540

Lu 2012

Pentoxifylline for endometriosis

DD1570

Lu 2013

Anti‐TNF‐α treatment for pelvic pain associated with endometriosis

HNS881

Sallam 2006

Long term pituitary down‐regulation before in vitro fertilisation (IVF) for women with endometriosis

x

KRF1291

Zhu 2011

Acupuncture for pain in endometriosis

x

Figuras y tablas -
Table 3. AMSTAR assessment
Table 4. Search date assessment

Review no

Review reference

REVIEW TITLE

<3 yrs since last search

(to March 6 2014)

AMAS1061

Abou‐Setta 2013

Levonorgestrel‐releasing intrauterine device (LNG‐IUD) for symptomatic endometriosis following surgery

MCA871

Allen 2009

Non‐steroidal anti‐inflammatory drugs for pain in women with endometriosis

HAK1181

Al‐Kadri 2009

Hormone therapy for endometriosis and surgical menopause

SG1241

Benschop 2010

Interventions for women with endometrioma prior to assisted reproductive technology

APO62

Brown 2010

Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

AP061

Brown 2012

Progestagens and anti‐progestagens for pain associated with endometriosis

SK141

Davis 2007

Oral contraceptives for pain associated with endometriosis

JD1830

Duffy 2014

Laparoscopic surgery for endometriosis

VS081

Farquhar 2007

Danazol for pelvic pain associated with endometriosis

Stable

AF801

Flower 2012

Chinese herbal medicine for endometriosis

CY571

Furness 2004

Pre and post‐operative medical therapy for endometriosis surgery

RJH961

Hart 2008

Excisional surgery versus ablative surgery for ovarian endometriomata

EJ254

Hughes 2007

Ovulation suppression for endometriosis for women with subfertility

Stable

DL1540

Lu 2012

Pentoxifylline for endometriosis

DD1570

Lu 2013

Anti‐TNF‐α treatment for pelvic pain associated with endometriosis

HNS881

Sallam 2006

Long term pituitary down‐regulation before in vitro fertilisation (IVF) for women with endometriosis

KRF1291

Zhu 2011

Acupuncture for pain in endometriosis

Figuras y tablas -
Table 4. Search date assessment
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 low

Lacked 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)

Low

Very 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)

Low

Very 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)

Low

Lacked 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)

Low

Evidence 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)

Low

Evidence 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)

Low

Evidence based on a single trial, quality of blinding very uncertain

Brown 2010 GnRHas versus no treatment

188/1000 achieved pain relief

737/1000 achieved pain relief

RR 3.93 (1.37 to 11.28)

35 (1 study)

Low

No blinding and evidence based on a single trial

Brown 2010 GnRHas versus danazol

825/1000 achieved pain relief

809/1000 achieved pain relief

RR 0.98 (0.92 to 1.04)

666 (7 studies)

Very low

Randomisation 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)

Moderate

Evidence was based on a single trial

Brown 2010 GnRHas (intranasal versus intramuscular depot)

828/1000 achieved pain relief

778/1000 achieved pain relief

RR 0.94 (0.82 to 1.08)

192 (1 study)

Low

Lack of adequate explanation of allocation concealment and evidence based on a single trial

Brown 2010 GnRHas (intranasal versus subcutaneous)

800/1000 achieved pain relief

976/1000 achieved pain relief

RR 1.22 (0.73 to 2.06)

10 (1 study)

Low

Open label trial with evidence based on a single trial

Furness 2004

Pre‐surgical medical therapy versus post‐surgical medical therapy

See Comment

See Comment

RR 0.0 (0 to 0)

53 (1 study)

Low

There 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 7.5

The mean dysmenorrhoea pain score in the intervention groups was 0.10 lower (1.28 lower to 1.08 higher)

50 (1 study)

Very low

There 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 2.3

The mean Biberoglu and Behrman score in the intervention groups was 0.2 higher (0.05 lower to 0.45 higher)

21 (1 study)

Low

Evidence 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 1.7

The mean Biberoglu and Behrman score in the intervention groups was 0.2 lower (0.68 lower to 0.28 higher)

21 (1 study)

Low

Evidence 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 0.05

The 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)

Moderate

Evidence 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 4.76

The 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)

Moderate

Evidence was based on a single trial

Brown 2012

Depot progestagen versus other treatment (6 months)

978/1000 achieved pain relief

895/1000 achieved pain relief

OR 0.19 (0.05 to 0.69)

274 (1 study)

Moderate

Evidence was based on a single trial

Brown 2012

Depot progestagen versus other treatment (12 months)

768/1000 achieved pain relief

676/1000 achieved pain relief

OR 0.63 (0.37 to 1.08)

274 (1 study)

Moderate

Evidence was based on a single trial

Brown 2012

Anti‐progestagen versus other treatment

667/1000 achieved pain relief

673/1000 achieved pain relief

OR 1.03 (0.55 to 1.93)

176 (2 studies)

Moderate

Trials 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)

Low

Allocation 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 3.63

The mean VAS score for painful symptoms in the intervention groups was 0.16 lower (2.02 to 1.7 higher)

40 (1 study)

Very low

No 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 1.85

The mean pelvic pain score in the intervention groups was 1.4 lower (1.33 to 0.77 lower)

35 (1 study)

Low

There 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 1.55

The mean pelvic pain score in the intervention groups was 1.1 lower (1.38 to 0.82 lower)

34 (1 study)

Low

There 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 months

226/1000 had moderate or severe pelvic pain at 6 months

OR 0.65 (0.2 to 2.05)

60 (1 study)

Low

There 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 1.45

The mean Biberoglu and Behrman score in the intervention groups was 0.15 lower (0.45 lower to 0.15 higher)

21 (1 study)

Low

Evidence 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 0.15

The mean Biberoglu and Behrman score in the intervention groups was 0.15 lower (0.51 lower to 0.21 higher)

21 (1 study)

Low

Evidence 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 41.8

The mean self‐reported pain in the intervention group was 1.6 lower (0.01 lower to 0.57 higher)

252 (1 study)

Low

Open 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 0.28

The mean use of analgesia in the intervention group was 0.1 (0.6 lower to 0.4 higher)

30 (1 study)

Low

Evidence 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

262/1000

128/1000

OR 0.41 (0.18 to 0.93)

164 (2 studies)

Very low

Included 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)

Low

No 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 low

Lacked 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)

Low

Lacked 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)

Low

There was a lack of adequate explanation for randomisation and allocation concealment and blinding

Brown 2010 GnRHas (400 mcg versus 800 mcg)

200/1000

82/1000

RR 0.41 (0.17 to 1.01)

143 (1 study)

Low

Lack 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)

Low

Open 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 low

Lacked 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

0/1000

0/1000

OR 2.53 (0.12 to 53.64)

172 (1 study)

Very low

There 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 0.2

The 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 low

Lacked 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 ‐4.5

The 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 low

Lacked 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 11.8

The mean AFS score in the intervention group was 1.4 higher (6.76 lower to 9.56 higher)

16 (1 study)

Very low

The 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 1.31

The mean AFS score in the intervention group was 0.34 higher (0.01 lower to 0.70 higher)

302 (1 study)

Moderate

There was an inadequate explanation of allocation concealment, randomisation and blinding

Brown 2012

Progestagen versus placebo

Mean AFS score in the control group was 1.76

Mean AFS score in the intervention group was 0.58 lower (1.41 lower to 0.25 higher)

33 (1 study)

Low

This single trial provided inadequate detail on allocation concealment and blinding

Resolution of pain

Zhu 2011 Acupuncture versus Chinese herbal medicine

267/1000

811/1000

RR 3.04 (1.65 to 5.62)

67 (1 study)

Very low

Lack of methodological detail. No blinding and evidence based on single study.

Brown 2010 GnRHas versus danazol

596/1000

655/1000

RR 1.1 (1.01 to 1.21)

1046 (9 studies)

Low

There 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)

Moderate

There was a lack of blinding and inadequate explanation of allocation concealment

Brown 2010 GnRHas (400mcg versus 800mcg)

356/1000

334/1000

RR 0.94 (0.53 to 1.66)

90 (1 study)

Moderate

Evidence based on a single trial

Davis 2007

Oral contraceptive versus goserelin

818/1000

774/1000

OR 0.76 (0.17 to 3.29)

44 (1 study)

Very low

There 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 months

756 per 1000 improved or better at 6 months (610 to 861)

OR 6.58 (3.31 to 13.10)

171 (3 studies)

Moderate

None 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 months

732 per 1000 improved or better at 12 months (467 to 895)

OR 10.00 (3.21 to 31.17)

69 (1 study)

Low

Only 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 months

530 per 1000 pain free at 12 months (191 to 843)

OR 5.63 (1.18 to 26.85

35 (1 study)

Low

Only 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

667/1000

673/1000

OR 1.03 (0.55 to 1.93)

176 (2 studies)

Low

Two 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

273/1000

207/1000

RR 0.76 (0.52 to 1.1)

332 (3 studies)

Low

Lacked sufficient evidence for allocation concealment or attrition and there was no blinding

Abou‐Setta 2013

LNG‐IUD versus expectant management

383/1000

84/1000

RR 0.22 (0.08 to 0.6)

95 (2 studies)

Moderate

Only one of the two studies had blinded outcome assessment

Al‐Kadri 2009

Estrogen with or without progesterone versus placebo

0/1000

0/1000

OR 4.64 (0.25 to 87.71)

172 (1 study)

Very low

There 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

91/1000

400/1000

OR 6.67 (0.6 to 74.51)

21 (1 study)

Very low

There was no blinding and there was a lack of adequate detail on allocation concealment. Evidence was based on a single trial

Figuras y tablas -
Table 5. Pain outcomes
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)

270/1000

274/1000

OR 1.02 (0.69 to 1.5)

557 (11 studies)

Low

Included studies lacked adequate explanations for allocation concealment and blinding

Sallam 2006

Ultralong GnRHa agonist down‐regulation versus no agonist

325/1000

673/1000

OR 4.28 (2.0 to 9,15)

165 (3 studies)

Very low

Included studies lacked blinding and explanations for allocation concealment. There was some imprecision

Hart 2008 Excisional versus ablative surgery for endometriomata

170/1000

518/1000

OR 5.24 (1.92 to 14.27)

88 (2 studies)

Low

Included studies lacked blinding and there was some imprecision

Flower 2012 Chinese herbal medicine versus gestrinone

592/1000

699/1000

RR 1.18 (0.87 to 1.59)

45 (1 study)

Low

Evidence based on a single study

Furness 2004

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

500/1000

0/1000

RR 0.0 (0 to 0)

25 (1 study)

Very low

Included studies lacked adequate explanation of randomisation, allocation concealment and there was no blinding

Furness 2004

Post‐surgical medical therapy versus placebo/no treatment

246/1000

207/1000

RR 0.84 (0.59 to 1.18)

420 (8 studies)

Low

Included studies lack ed adequate explanation of randomisation and blinding

Lu 2012 Laparoscopic surgery plus pentoxifylline versus laparoscopic surgery plus placebo

196/1000

273/1000

OR 1.54 (0.89 to 2.66)

285 (3 studies)

Very low

Lacked methodological detail, and lack of precision. No trial reported on live birth

Benschop 2010 Aspiration of endometrioma versus expectant management

200/1000

244/1000

OR 1.29 (0.45 to 3.64)

81 (1 study)

Low

There was no blinding and evidence was based on a single trial

Benschop 2010 Cystectomy of endometrioma versus expectant management

317/1000

348/1000

OR 1.15 (0.52 to 2.55)

109 (1 study)

Low

There was no blinding and evidence was based on a single trial

Benschop 2010 GnRH agonist versus GnRH antagonist for endometrioma

242/1000

206/1000

OR 0.814 (0.26 to 2.54)

67 (1 study)

Low

Evidence based on a single trial

Duffy 2014 Laparoscopic ablation or excision versus diagnostic laparoscopy

186 per 1000

302 per 1000 (223 to 396)

OR 1.89 (1.25 to 2.86)

528 (3 studies)

Moderate

Two 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)

Moderate

One 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

190/1000

181/1000

OR 0.94 (0.35 to 2.54)

112 (2 studies)

Moderate

One 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 ART

30/1000

29/1000

OR 0.97 (0.06 to 15.85)

67 (1 study)

Low

Evidence based on a single trial and wide confidence intervals are indicative of some imprecision

Benschop 2010 Aspiration of endometrioma versus expectant management

100/1000

97/1000

OR 0.97 (0.23 to 4.15)

81 (1 study)

Low

There was no blinding and the evidence is based on a single trial

Figuras y tablas -
Table 6. Fertility outcomes