Pre and post‐operative medical therapy for endometriosis surgery

Susan Furness; Christine Yap; Cindy Farquhar; Ying C Cheong

doi:10.1002/14651858.CD003678.pub2

. 2004 Jul 19;2004(3):CD003678. doi: 10.1002/14651858.CD003678.pub2

Pre and post‐operative medical therapy for endometriosis surgery

Susan Furness ^1,^✉, Christine Yap ^#, Cindy Farquhar ³, Ying C Cheong ⁴

Editor: Cochrane Gynaecology and Fertility Group

PMCID: PMC6984629 PMID: 15266496

Abstract

Background

Endometriosis is a common gynaecological condition affecting approximately 10% of women of reproductive age (Ozkan 2008). Common symptoms are dysmenorrhoea, pelvic pain, infertility or a pelvic mass. Diagnosis by laparoscopy or laparotomy enables identification of the location, extent and severity of the disease. Surgery may include removal (excision) or destruction (ablation) of endometriotic tissue, division of adhesions and removal of endometriotic cysts. Laparoscopic excision or ablation of endometriosis has been shown to be effective in the management of pain in mild to moderate endometriosis. Adjunctive medical treatment pre or post‐operatively may prolong the symptom‐free interval.

Objectives

To determine the effectiveness of medical therapies for hormonal suppression before or after surgery for endometriosis for improving painful symptoms, reducing disease recurrence and increasing pregnancy rates.

Search methods

We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched Sept 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Sept 2010), MEDLINE (January 1966 to September 2010), EMBASE (January 1985 to September 2010) and reference lists of articles.

Selection criteria

Trials were included if they were randomised controlled trials comparing medical therapies for hormonal suppression before or after or before and after, surgery for endometriosis.

Data collection and analysis

Data extraction and assessment of risk of bias were performed independently by two authors. Where possible, data were combined using relative risk (RR), standardised mean difference or mean difference and 95% confidence intervals (CI).

Main results

Sixteen trials were included. Two trials of pre‐surgical medical therapy showed no evidence of benefit compared to surgery alone. There was no evidence of benefit for post‐surgical hormonal suppression of endometriosis compared to surgery alone for the outcomes of pain, disease recurrence or pregnancy rates (RR 0.84, 95% CI 0.59 to 1.18). There were no trials identified in the search that compared hormonal suppression of endometriosis before and after surgery with surgery alone. One trial found no evidence that pre‐surgical hormonal suppression was different from post‐surgical hormonal suppression for the outcome of pain. Another single trial comparing post‐surgical medical therapy with both pre and post‐surgery found no difference in the outcomes of American Fertility Society (AFS) scores and pregnancy rate.

Authors' conclusions

There is no evidence of benefit associated with post surgical medical therapy and insufficient evidence to determine whether there is a benefit from pre‐surgical medical therapy with regard to the outcomes evaluated.

Plain language summary

There is no evidence that hormonal suppression either before or after surgery for endometriosis is associated with a benefit

Endometriosis is caused by the lining of the uterus (endometrium) spreading outside the uterus. It can cause pelvic pain, painful periods and infertility. Common treatments are hormonal suppression with medical therapy to reduce the size of endometrial implants or laparoscopic surgery (where small incisions are made in the abdomen) to remove visible areas of endometriosis. There is no evidence that hormonal suppression either before or after surgery is associated with a benefit compared with surgery alone.

(Synopsis prepared by Cochrane Menstrual Disorders and Subfertility Group)

Summary of findings

Background

Description of the condition

Endometriosis is a common gynaecological condition which affects women during their reproductive years. Endometriosis occurs when endometrial tissue, which usually grows in the uterus (normal), is found in other parts of the body, for example the ovaries, fallopian tubes and pelvis. A range of symptoms are evident and women most commonly present with dysmenorrhoea (painful periods), pelvic pain, infertility or a pelvic mass. Endometriosis also responds to hormonal changes associated with the menstrual cycle and cyclical growth of endometriotic implants or cysts is thought to be associated with pelvic pain and the development of adhesions (scar tissue). Estimates of the prevalence of endometriosis amongst women vary but a recent article (Ozkan 2008) reported a prevalence of 0.5% to 5% in fertile women and 25% to 40% in a subfertile population, with the peak incidence between 30 and 45 years of age (Guzick 1989). Endometriosis may be asymptomatic (no symptoms) or associated with chronic pelvic pain and subfertility (Cook 1991).

The 'gold standard' for the diagnosis of endometriosis is visualisation of endometriosis lesions or cysts during a surgical procedure, either laparoscopy or laparotomy. The extent of the disease can be graded according to a scale developed by the American Fertility Society (AFS 1985), although there is no direct correlation between the severity of the disease and the severity of the symptoms experienced (Vercellini 1996). Concern over the reproducibility of the scoring system resulted in the publication of a new scoring system in 1997 by the American Society of Reproductive Medicine (ASRM 1997).

Description of the intervention

Current treatments that are available for endometriosis include both surgery and medical therapy. Surgical therapy can be performed concurrently with diagnostic surgery and may involve the destruction of endometriotic tissue (ablation), division of adhesions (scar tissue) or removal of endometriotic cysts. In advanced endometriosis (AFS stage III or IV), laparoscopic surgery to remove (excise) visible endometrial implants, divide adhesions (scar tissue) or surgically interrupt neural pathways is the treatment of choice (Muzii 1996; Proctor 1999; Rana 1996). This is because large (> 3 cm) lesions respond poorly to medical therapy and hormonal suppression does not influence the extent of the adhesions which are often associated with large lesions (Shaw 1992).

Medical therapies for systemic hormonal suppression of endometriosis include danazol (a synthetic testosterone hormone derivative), gonadotrophin releasing hormone analogues (GnRHas), progestogens, gestrinone and the oral contraceptive pill. These therapies may be effective for relief of pain associated with endometriosis but they also decrease fertility. Both danazol and GnRHas are associated with side effects related to hyperandrogenism (increased hair growth and a deepening of the voice) and hypoestrogenism (such as hot flushes and vaginitis), respectively, and should only be used for periods of up to six months. Recurrence of endometriosis symptoms and disease is common after the cessation of medical therapy (Barbieri 1990).

How the intervention might work

Over recent years there has been interest in combining medical and surgical therapy in an attempt to reduce recurrence of endometriosis. The pre‐operative use of GnRHas may decrease the extent of endometriosis and the size of endometriomas (ovarian endometriosis) making complete removal of endometriosis easier during laparoscopic surgery and increasing subsequent pregnancy rates (Hemmings 1998; Donnez 1987). However possible disadvantages of pre‐operative medical therapy, especially with danazol or GnRHas, are the adverse effects associated with these medications (for example hot flushes or vaginal dryness), which may influence women's willingness to use the therapy and result only in a delay of surgery. Post‐operative medical therapy appears be an effective treatment of microscopic endometriosis which may not have been evident to the surgeon. It induces suppression of lesions that can not be surgically removed and reduces the risk of recurrence of endometriosis as a result of surgery (Kettel 1989; Thomas 1992).

Why it is important to do this review

Although the combination of surgery and medical therapy would appear to be beneficial, it is necessary to evaluate the benefits and consider the harms prior to this strategy being recommended. This review aims to evaluate the use of medical therapy before or after, or before and after, surgery for endometriosis.

Objectives

To determine the effectiveness of medical therapies for hormonal suppression before or after or before and after surgery for endometriosis for improving painful symptoms, reducing disease recurrence and increasing pregnancy rates.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials of the use of medical hormonal suppression therapies used:

pre‐surgery for endometriosis compared with surgery alone or placebo prior to surgery for the treatment of endometriosis;
post‐surgery for endometriosis compared with surgery alone or surgery and placebo;
pre and post‐surgery for endometriosis compared with surgery alone or surgery and placebo;
pre‐surgery for endometriosis compared with medical therapies used post‐surgery for endometriosis.

Types of participants

The study population included 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.   Studies in the hospital care setting were considered.

Types of interventions

All systemic medical treatments for the hormonal suppression of endometriosis including GnRHas, danazol, progestogens, gestrinone or the oral contraceptive pill (or combinations of these) administered before surgery, after surgery or before and after surgery for endometriosis compared to medical treatment after surgery, before surgery, no medical treatment, or placebo were studied. The use of medical therapy was considered at any dosage and for a period of at least three months duration before or after surgery. Only agents used with the aim of hormonal suppression were included. Medical treatment with analgesics, anti‐inflammatory drugs or antibiotics were excluded. Alternative, dietary or complementary therapeutic strategies were also excluded. Modulation of the immune system via pentoxifylline treatment is considered in a separate systematic review (Lv 2009). All surgical procedures for the treatment of endometriosis that conserve the pelvic organs (such as ovarian cystectomy, drainage of endometriosis, excision or ablation of endometriosis) were included.

Types of outcome measures

The effectiveness of the use and timing of medical therapy as an adjunct to surgery for endometriosis was compared to surgery alone (no medical treatment or placebo) and was assessed by the following outcome measures where the data were available.

Primary outcomes

Painful symptoms of endometriosis as measured by a visual analogue scale (VAS) of pain, other validated scales or dichotomous outcomes
Recurrence of disease as evidenced by rAFS (revised American Fertility Society) or rASRM scores at second look laparoscopy
Pregnancy rate per woman (measured by either urinary human chorionic gonadotrophin (HCG) levels or foetal heart detected by ultrasound)

Secondary outcomes

Ease of surgery, duration of surgery, post‐operative complications
Levels of satisfaction of women participants
Adverse effects (proportion of women with one or more reported adverse effects associated with medical treatment)

Search methods for identification of studies

Reports that described or might have described randomised controlled trials of hormonal suppression in the treatment of endometriosis before or after surgery were obtained using the following search strategy.

Electronic searches

(1) We searched the Menstrual Disorders and Subfertility Group Specialised Register of controlled trials (10 September 2003) for any trials of hormonal suppression in the treatment of endometriosis before or after surgery. The Cochrane Menstrual Disorders and Subfertility Group Specialised Register is based on regular searches of CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO, the handsearching of 20 relevant journals and conference proceedings, and searches of several key grey literature sources. A full description is given in the Group's module on The Cochrane Library.

(2) The following electronic databases were searched using Ovid software: MEDLINE (1966 to September 2010) (Appendix 1); EMBASE (1980 to September 2010) (Appendix 3); CINAHL (1982 to September 2010); Biological Abstracts (1980 to September 2010); PsycINFO (1872 to September 2010).

The search strategy was developed for MEDLINE Ovid and adapted for use on the other Ovid databases listed above.

(3) We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (20 September 2010) in all fields using the search terms listed in Appendix 2.

(4) We searched controlled trials.com for ongoing and recently completed trials.

Searching other resources

(5) We searched the reference lists and bibliographies of all relevant articles to identify additional trials for inclusion in this review.

(6) We sent letters to experts within the field, pharmaceutical companies producing the products being reviewed and authors of unpublished abstracts to identify unpublished trials of medical therapy before or after surgery for endometriosis.

Data collection and analysis

Selection of studies

The selection of trials for inclusion in the latest update of the review was performed by the two review authors (YC and SF) after employing the search strategy previously described. The titles and abstracts were screened and studies that were clearly ineligible were discarded but we aimed to be overly inclusive rather than risk losing relevant studies. Copies of the full articles were obtained. Both review authors then independently assessed whether the studies met the inclusion criteria. Disagreements were resolved by discussion. Further information was sought from the authors where papers contained insufficient information to make a decision about eligibility.

Data extraction and management

Included trials were analysed for the following methodological details.

(1) Duration, timing and location of the study.   (2) Inclusion and exclusion criteria for the trial.   (3) Number of patients randomised, excluded or lost to follow up.

(4) Whether a power calculation was done.

(5) Source of funding for the trial.

This information is presented in the Characteristics of included studies table, which describes the included studies and provides a context for discussing the reliability of results.

Characteristics of the study participants

(1) Method of diagnosis of endometriosis   (2) Severity of endometriosis (rAFS scores)   (3) Severity of painful symptoms associated with endometriosis (pain scales)   (4) Age and parity of study participants   (5) General demographic characteristics of study participants

Interventions used

(1) Type of medical treatment used, dosage, duration of treatment, mode of administration   (2) Type of control or placebo used   (3) Timing of medical treatment (before or after surgery, or before and after surgery)

Outcomes

(1) Methods used to measure recurrence of disease (rAFS or rASRM scores at second look laparoscopy)   (2) Methods used to measure pain relief achieved by treatment (e.g. VAS pain scores, other validated pain scores, dichotomous outcomes)   (3) Pregnancy rate per woman during follow up   (4) Methods used to measure adverse effects (including post‐operative complications) and types of adverse effects reported   (5) Methods used to measure ease of surgery, duration of surgery   (6) Length of follow up and timing of outcome measurement relative to timing of treatment   (7) Methods used to measure levels of satisfaction of the women participants

Assessment of risk of bias in included studies

For the studies included in this review, assessment of risk of bias was conducted by two review authors using the Cochrane risk of bias assessment tool (Higgins 2009). We assessed six domains for each included study: sequence generation, allocation concealment, blinding of outcome assessor, completeness of outcome data, risk of selective outcome reporting and risk of other potential sources of bias .

For this systematic review we assessed risk of bias according to the following criteria.

Adequate sequence generation: use of a random number table, use of a computerised system, central randomisation by statistical coordinating centre, randomisation by an independent service using minimisation technique, permuted block allocation or Zelan technique were considered adequate. If the paper merely stated 'randomised' or 'randomly allocated' with no further information this was assessed as being unclear.

Allocation concealment: centralised allocation including access by telephone call or fax, or pharmacy controlled randomisation, using sequentially numbered, sealed opaque envelopes were considered adequate. Where there was no mention of allocation concealment methods, this domain was assessed as unclear.
Blinding: for these treatments, even when blinding of patients and clinicians to treatment allocation was part of the trial protocol, the adverse effects of medical therapies make it difficult for blinding to be maintained. Therefore we have focused on whether the outcome assessment was blinded. Unless the trial was specifically described as double blind, or there was a statement about blinding in the methods section of the paper, it was assumed that blinding of patients, clinical staff and outcome assessors did not occur.
Outcome data: outcome data were considered complete if all patients randomised were included in the analysis of the outcome(s).
Selective outcome reporting: a trial was assessed as being at low risk of bias due to selective outcome reporting if the outcomes of interest described in the methods section were systematically reported in the results section. Where reported outcomes did not include those outcomes specified or expected in trials of treatments for endometriosis, this domain was assessed as unclear.
Other bias: imbalance in potentially important prognostic factors between the treatment groups at baseline, or the use of a co‐intervention in only one group (for example analgesics) were examples of potential sources of bias that were noted.

Additional information on trial methodology or original trial data was sought from the principal authors of trials which appeared to meet the eligibility criteria but were unclear in aspects of methodology or outcomes, or where the data were in a form unsuitable for meta‐analysis.

Measures of treatment effect

This review used both positive and negative outcome measures. This was taken into account when the meta‐analysis was interpreted. For example with regard to the outcome of pain, a positive treatment effect was associated with a reduction in pain scores indicated by a WMD less than zero. However with regard to pregnancy rates, which was a desirable outcome in the treatment of subfertility, a positive treatment effect was associated with an increase in pregnancy rate indicated by a relative risk (RR) greater than one. The data were entered so that in positive outcomes (for example pregnancy) points to the left of the 'line of no effect' favoured the control, and in the negative outcomes (for example pain) points to the left of the 'line of no effect' favoured treatment.

When neither continuous nor dichotomous data suitable for the calculation of mean difference, standardised mean difference or relative risk could be extracted from a trial, any available data were reported descriptively in additional data Table 11. It is expected that the data for outcomes of pain are skewed rather than normally distributed. Any skew ness was described in the results section.

1. Descriptive data for trials not included in the meta‐analysis.

Study ID	Comparison	Outcome	n	Conclusion
Donnez 1994	pre‐surgical GNRHa (goserelin) versus no medical therapy	mean endometrioma size	40/40	favouring goserelin mean difference ‐1.81cm (95% CI ‐2.05 to 1.57)
Shaw 2001	pre‐surgical GNRHa (goserelin) versus no medical treatment	change in endometrioma size	21/27	favouring goserelin adj mean difference ‐1.25 cm (95% CI ‐2.42 to ‐0.08)
Shaw 2001		complete excision of cyst	21/27	no difference 13/21 (72%) and 16/27 (73%) had cysts completely excised at surgery
Shaw 2001		recurrence of residual cysts at 6 months	21/27	favours goserelin 2/21 (10%) and 4/27 (15%) had recurrence of residual cysts
Shaw 2001		mean rAFS scores	21/27	no difference 41.7, 42.5 (no SD given)
Telimaa 1987	MPA versus placebo	pain	17/8	pain scores after 12 months assessed with 4 point scales; MPA 1.8; Placebo 4.4 "significant difference"
Telimaa 1987	danazol versus placebo	pain	18/8	pain scores after 12 months assessed with 4 point scales; danazol 2.5; placebo 4.4, "significant difference"
Telimaa 1987	MPA versus placebo	patient satisfaction	17/8	patient satisfaction achieved in MPA 84% vs placebo 24%
Telimaa 1987	danazol versus placebo	patient satisfaction	18/8	patient satisfaction achieved in danazol 84% vs placebo 24%
Tsai 2004	post‐surgical leuprolide/danazol versus no treatment	cumulative pregnancy rate at 12 months after clomiphene stimulation in both groups	15/30	no difference 56.7% and 54.5%
Yang 2006	post‐surgical gestrinone versus no medical treatment	disease recurrence at 6‐30 months	19/13	favours medical treatment 1/19 and 4/13 (p<0.05)
Audebert 1998	pre‐surgical versus post‐surgical GnRHa (nafarelin)	AFS scores	25/28	total AFS score after 6 months was 0 and 6 in pre and post groups respectively (p= 0.007); no SD or SE given and not calculable.
Audebert 1998		AFS scores	25/28	adhesion AFS score after 6 months was 0 and 2 in pre and post groups respectively (p= 0.007), no SD or SE given and not calculable.
Audebert 1998		AFS scores	25/28	implant AFS score after 6 months was 0 and 4 in pre and post groups respectively (p= 0.05), no SD or SE given and not calculable.
Audebert 1998		ease of surgery	25/28	surgery was easy in 56% of patients with GnRHa treatment pre‐surgery (Grp II) compared to 35.7% in the post‐surgery group (Grp I)

Post surgical medical therapies compared to No treatment or placebo for infertility associated with endometriosis
Patient or population: patients with infertility associated with endometriosis   Intervention: Post surgical medical therapies   Comparison: No treatment or placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	No treatment or placebo	Post surgical medical therapies
Pregnancy	246 per 1000	207 per 1000   (145 to 290)	RR 0.84   (0.59 to 1.18)	420   (8 studies)	⊕⊕⊝⊝   low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Pre and post operative medical therapies versus placebo for endometriosis
Patient or population: patients with infertility associated with endometriosis   Intervention: Post surgical medical therapies   Comparison: Pre and post‐surgical medical therapy with GnRHa
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Pre and post‐surgical medical therapy with GnRHa	Post surgical medical therapies
Pregnancy Rate	500 per 1000	0 per 1000   (0 to 0)	RR 0   (0 to 0)	25   (1 study)	⊕⊕⊝⊝   low¹
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Pre‐surgical medical therapy compared to no medical therapy for endometriosis surgery
Patient or population: patients with endometriosis surgery   Intervention: Pre‐surgical medical therapy   Comparison: no medical therapy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	no medical therapy	Pre‐surgical medical therapy
Recurrence ‐ AFS Score ‐ Total AFS		The mean Recurrence ‐ AFS Score ‐ Total AFS in the intervention groups was   9.6 lower   (11.42 to 7.78 lower)		80   (1 study)	⊕⊕⊝⊝   low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Post‐surgical medical therapy compared to placebo or no treatment for endometriosis
Patient or population: patients with endometriosis   Intervention: Post‐surgical medical therapy   Comparison: placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo or no treatment	Post‐surgical medical therapy
Pain (VAS) ‐ Dysmenorrhoea at 12 months		The mean Pain (VAS) ‐ Dysmenorrhoea at 12 months in the intervention groups was   0.58 standard deviations lower   (0.87 to 0.28 lower)		187   (1 study)	⊕⊕⊝⊝   low^1,2	SMD ‐0.58 (‐0.87 to ‐0.28)
Pain (dichotomous) ‐ Pain recurrence </= 12 months	273 per 1000	207 per 1000   (142 to 300)	RR 0.76   (0.52 to 1.1)	332   (3 studies)	⊕⊕⊝⊝   low³
Pain (dichotomous) ‐ pain persistence/recurrence 5 years	480 per 1000	446 per 1000   (254 to 797)	RR 0.93   (0.53 to 1.66)	54   (1 study)	⊕⊝⊝⊝   very low^2,4
Recurrence ‐ AFS Score ‐ Total AFS score (12 months)		The mean Recurrence ‐ AFS Score ‐ Total AFS score (12 months) in the intervention groups was   2.29 lower   (4.69 lower to 0.11 higher)		43   (1 study)	⊕⊕⊝⊝   low^2,5
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Pre‐surgical compared to Post‐surgical medical therapy for endometriosis surgery
Patient or population: patients with endometriosis surgery   Intervention: Pre‐surgical   Comparison: Post‐surgical medical therapy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Post‐surgical medical therapy	Pre‐surgical
Pain (Dichotomous) ‐ Dysmenorrhoea	See comment	See comment	Not estimable	53   (1 study)	⊕⊕⊝⊝   low^1,2	There were no events reported in either the intervention or the control group
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.

Trial ID	Adverse Drug Effects	Withdrawals‐ADE
Audebert 1998	Side effects were reported with equal frequency in both groups and were consistent with those published by other investigators	2 withdrawals after randomisation from hot flushes and headaches
Batioglu 1997	Not described	None
Bianchi 1999	Hyperandrogenism 16.7%, weight gain ≥3kg 8.3%	None
Busacca 2001	Most experienced menopausal symptoms, all became amenorrhoeic	1 withdrawal from unacceptable side effects
Donnez 1994	Not described	None
Hornstein 1997	Not described	Not due to ADE
Loverro 2001	Not described	None
Loverro 2008	Not described	None
Muzii 2000	Not described	Not due to ADE
Parazzini 1994	Amenorrhoea in all actively treated, none in placebo group	None
Sesti 2007	Menopausal symptoms, spotting, bloating, weight gain and headache reported but "well tolerated"	4 withdrew from hormonal suppression group due to AE
Shaw 2001	Hot flushes (62%), headaches (29%), dysmenorrhoea (14%) in goserelin group and 33% had dysmenorrhoea in no treatment group	4 withdrew from goserelin gp due to serious AE (1 treated to treatment)
Telimaa 1987‐Danazol and Telimaa 1987‐MPA	Weight increase MPA 1.9±1.3kg, danazol 3.4±2.3kg, placebo 0.4±2.6kg; breakthrough bleeding at 6/12: MPA 65%, danazol 56%, placebo 6%; acne at 6/12: danazol 56%, placebo 6%	Not due to ADE
Tsai 2004	Not described	Reasons for withdrawals not given
Vercellini 1999	Not described	None
Yang 2006	Not described	None

Date	Event	Description
20 September 2010	New search has been performed	Substantive update September 2010 ‐ 5 new trials included. Risk of bias assessment on all included studies. Minor changes to the objectives ‐ hypotheses deleted
7 November 2008	Amended	Converted to new review format.
26 May 2004	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Recurrence ‐ AFS Score	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1 Total AFS	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Implant AFS	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Adhesion AFS	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain (VAS)	3		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 Pelvic pain at 12 months	2	240	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.96 [‐1.23, ‐0.68]
1.2 Dysmenorrhoea at 12 months	1	187	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.58 [‐0.87, ‐0.28]
1.3 Deep Dyspareunia at 12 months	1	187	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐0.62, ‐0.03]
1.4 Change in pelvic pain score at 12 months	1	93	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.56, 0.26]
2 Pain (dichotomous)	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 Pain recurrence </= 12 months	3	332	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.52, 1.10]
2.2 Pain recurrence 13‐24 months	3	312	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.47, 1.03]
2.3 pain persistence/recurrence 5 years	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.53, 1.66]
3 Recurrence ‐ AFS Score	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 Total AFS score (12 months)	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Disease/symptom recurrence	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 Disease/symptoms recurrence at 12 months	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.30, 1.90]
4.2 Disease/symptoms recurrence at 24 months	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.01, 3.75]
5 Pregnancy	8	420	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.59, 1.18]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Pain (Dichotomous)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.1 Dysmenorrhoea	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Dyspareunia	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Pelvic pain	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Pelvic tenderness	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.5 Pelvic induration	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Methods	Location: France   No. of centres: multi centre Recruitment period: December 1990 to March 1993
Participants	Inclusion criteria: < 40 years, stage III‐IV endometriosis, pelvic pain, dysmenorrhoea or dyspareunia   Exclusion criteria: > 40 years, hormonal treatment for endometriosis within 3/12 (including OCP, progestins), significant medical illness e.g. liver, heart, renal disease, abnormal PAP smear, pregnancy, surgery for endometriosis within 6/12   No. randomised: 55   No. analysed: 53
Interventions	Gr A (n=28) Pre‐surgery medical treatment with nafarelin nasal 400 uG daily x 6/12   Gr B (n=25) Post‐surgery medical treatment with nafarelin nasal 400 uG daily x 6/12
Outcomes	Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, pelvic induration   AFS scores: global, adhesions, endometriosis   Ease of surgery
Notes	Power calculation: NS   Funding: Syntex Pharmaceuticals International for supply of Nafarelin, grant for trial
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomised" no details of method of sequence generation provided
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	Low risk	double blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	all randomised patients included in analysis
Selective reporting (reporting bias)	Low risk	important outcomes ‐ AFS scores, recurrence, surgical difficulty reported
Other bias	Low risk	groups appear comparable at baseline

Methods	Location: University of Milan, Italy No. of centres: 1 Recruitment period: July 1997 to December 1999
Participants	Inclusion criteria: < 40 yrs, laparoscopic diagnosis of endometriosis stage III‐IV   Exclusion criteria: previous medical or surgical therapy for endometriosis, other diseases that might affect fertility or cause pelvic pain; liver, endocrine or neoplastic disease   No. randomised: 89   No. analysed: 89
Interventions	Post‐surgical medical therapy   Gr A (n=44): leuprolide acetate SC 3.5 mg 4 weekly x 3 doses   Gr B (n=45): no treatment
Outcomes	Pain: pelvic pain recurrence at 18/12   AFS scores: objective disease recurrence   Cumulative pregnancy rates at 18/12
Notes	Power calculation: yes   Funding: NS
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomization was performed according to a computer generated list unknown to the physicians"
Allocation concealment (selection bias)	Unclear risk	not described
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo
Incomplete outcome data (attrition bias)   All outcomes	Low risk	all randomised patients included in the analysis
Selective reporting (reporting bias)	Low risk	important outcomes of pregnancy and recurrence of endometriosis and pain reported
Other bias	Low risk	groups appear comparable at baseline

Methods	No. of centres: 1   Location: Catholic University of Louvain, Belgium Recruitment period: January 1990 to December 1990
Participants	Inclusion criteria: age < 35 yrs, infertility, laparoscopic confirmed ovarian endometriotic cysts (AFS moderate n = 41, AFS severe n = 39)   Exclusion criteria: none   No. randomised: 80   No. analysed: 80
Interventions	Medical therapy pre‐surgery   1. Goserelin S/C 4 weekly x 4 (n = 40)   2. No therapy (n = 40)
Outcomes	AFS scores: total, implants, adhesions, moderate, severe scores   Ovarian cyst diameter   Degree of active endometriosis as determined histologically from ovarian cyst wall biopsy
Notes	Power calculation: NS   Funding: Fonds de la Recherche Scientifique
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomised according to official randomisation tables"
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo used
Incomplete outcome data (attrition bias)   All outcomes	Low risk	all randomised patients included in outcome assessment
Selective reporting (reporting bias)	Unclear risk	AFS scores at second look laparoscopy ‐ no pregnancy data reported
Other bias	Low risk	groups appear comparable at baseline

Methods	No. of centres: 13   Location: 13 clinics (North America) Recruitment period: not stated
Participants	Inclusion criteria: age 18‐47, normal menstrual cycles of 24‐36 days, clinical pelvic pain, dysmenorrhoea, dyspareunia   Exclusion criteria: received medical therapy for endometriosis within 3 months, abnormal bone density, significant medical illness, laboratory abnormalities, pregnancy and lactation   No. randomised: 109   No. analysed: 93   7 in nafarelin group and 8 in placebo group withdrew after 90 days of therapy   1 in placebo group excluded because missed 5 days of medication
Interventions	Post‐surgery medical therapy   1. Nafarelin nasal 400 uG daily x 6/12 (n = 49)   2. Placebo (n = 44)
Outcomes	Pain   Physician scores for tenderness and induration on physical examination at end of treatment and 6/12 after treatment
Notes	Power calculation: NS   Funding: Syntex laboratory, California
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"multicenter, prospective, randomized, double‐blind study" method of sequence generation not described
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	Low risk	"double blind" but authors acknowledge difficulty of maintaining blinding with this treatment
Incomplete outcome data (attrition bias)   All outcomes	Low risk	7 and 8 patients were excluded from analyses of treatment and placebo groups because they withdrew before completing 90 days of therapy. Remaining 93 patients included in analysis even though 39 and 43 patients from treatment and placebo groups terminated the study early
Selective reporting (reporting bias)	Low risk	primary outcome was time to requiring alternative treatment; pain & recurrence also reported
Other bias	Low risk	groups appear comparable at baseline

Methods	Location: Ankara Turkey   No. of Centres: 1 Recruitment period: NS
Participants	Inclusion criteria: ovarian endometriomas >3cm unilateral/bilateral No. randomised: 25   No. analysed: 25
Interventions	Post‐surgery medical treatment with triptorelin 3.75 mg IM x 4 weekly for 6 months (n = 13)   versus   Pre‐surgery and post‐surgery treatment with triptorelin 3.75 mg IM x 4 weekly for 6 months (n = 12)
Outcomes	AFS scores at 6 months   Pregnancy rate at 1 year follow up
Notes	Power calculation: NS   Funding: NS
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	"randomly allocated into one of the treatment groups, odd numbers in the first group and even numbers in the second
Allocation concealment (selection bias)	High risk	no allocation concealment
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo
Incomplete outcome data (attrition bias)   All outcomes	Low risk	pregnancy rate reported for all randomised patients
Selective reporting (reporting bias)	Unclear risk	mean AFS scores reported per endometrioma not per patient, pregnancy rate
Other bias	Unclear risk	there were differences between the groups at baseline with regard to mean adhesion scores

Methods	No. of centres: 1   Location: University of Milan, Italy Recruitment period: July 1994 to October 1996
Participants	Inclusion criteria: < 40 yrs   Exclusion criteria: medical or surgical treatment for endometriosis, concurrent disease that might affect fertility or cause pelvic pain, women without pain symptoms, women not seeking pregnancy, liver or endocrine disease   No. randomised: 77   No. analysed: 77
Interventions	Post‐surgical medical therapy   1. Danazol oral 600 mg daily x 3/12 (n = 36)   2. No treatment (n = 41)
Outcomes	Pain recurrence   AFS scores   Pregnancy rates   Adverse events of medication
Notes	Power calculation: NS   Funding: NS
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was done according to a computer generated list"
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo
Incomplete outcome data (attrition bias)   All outcomes	Low risk	all randomised patients included in analysis
Selective reporting (reporting bias)	Low risk	important outcomes ‐ pregnancy rate and recurrence of endometriosis pain, adverse effects reported
Other bias	Low risk	groups appear comparable at baseline

Methods	No. of centres: 1   Location: Bari, Italy Recruitment period: January 1996 to January 1997
Participants	Inclusion criteria: AFS score III‐IV   Exclusion criteria: NS   No. randomised: 62   No. analysed: 62?
Interventions	Post‐surgery medical therapy   1. Triptorelin SC 3.75 mg every 4 weeks x 3 months (n = 33)   2. No treatment (n = 29)
Outcomes	Pain   Pregnancy rates
Notes	Power calculation: NS   Funding: NS   Pregnancy outcomes and pain recurrence were only expressed as percentages in each group so numbers calculated were rounded up to the nearest whole number
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"prospective and randomized" ‐ no details of method of sequence generation
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo used
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	not stated how many women are included in the outcomes ‐ only percentages reported.
Selective reporting (reporting bias)	Low risk	important outcomes ‐ time to relapse (pelvic pain) and pregnancy reported
Other bias	Unclear risk	no information on comparability of groups at baseline given

Methods	Location: Italy   No. of centres: one Recruitment period: January 1998 to January 1999
Participants	Inclusion criteria: women of reproductive age with stage III ‐ IV endometriosis, associated with chronic pelvic pain,adnexial mass or infertility, who had undergone complete laparoscopic excision, had rAFS score > 15 and no previous hormonal treatment   Exclusion criteria:   No. randomised: 60   No. analysed: 54
Interventions	Post‐operative triptorelin versus placebo   Gr A (n=29): triptorelin 3.75 mg depot monthly on day 20 of cycle for 3 months   Gr B (n=25): placebo monthly on day 20 of cycle for 3 months
Outcomes	Pain persistence, pregnancy
Notes	Power calculation: NS Funding: NS Email sent to contact author Feb 2010 requesting further information ‐ no reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"using a computer generated randomization table"
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	Low risk	patients were blinded to treatment allocation. placebo injections used
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	1 and 5 patients lost to follow up from triptorelin and no treatment groups respectively. Possibility of bias
Selective reporting (reporting bias)	Low risk	pain, relapse and pregnancy reported (for those who desired pregnancy)
Other bias	Low risk	groups appear similar at baseline

Methods	Location: University departments, Rome, Italy   No. of centres: 2 Recruitment period: January 1994 to June 1997
Participants	Inclusion criteria: 20‐35 yrs, moderate to severe dysmenorrhoea and/or chronic pelvic pain, not desiring fertility   Exclusion criteria: treatment for endometriosis in previous 6 months   No. randomised: 70   No. analysed: 68
Interventions	Post‐surgical medical therapy   Gr A (n=35): cyclic monophasic oral contraceptive pill (ethinyl estradiol 0.03 mg, gestodene 0.075 mg) for 21 days with 7 pill free days x 6/12   Gr B (n=35): no treatment
Outcomes	Recurrence of pain and time to recurrence   Recurrence of cysts
Notes	Power calculation: yes   Funding: NS. Drugs supplied by Population Council
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomly allocated to one of two management arms on the basis of a computer generated sequence"
Allocation concealment (selection bias)	Unclear risk	not described
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo
Incomplete outcome data (attrition bias)   All outcomes	Low risk	two post‐randomisation withdrawals. Unlikely to have introduced a bias
Selective reporting (reporting bias)	Low risk	important outcomes reported ‐ recurrence of endometriosis, pain, AFS scores. Patients not desiring pregnancy
Other bias	Unclear risk	no information of the baseline characteristics of the groups reported

Methods	Location: University centres in Italy   No. of centres: 6 Recruitment period: January 1990 to July 1991
Participants	Inclusion criteria: age < 38 yrs, normal medical examination, unexplained infertility for at least 1 year, with/without chronic pelvic pain, endometriosis stage III‐IV, partners with normal sperm analysis and post‐coital tests   Exclusion criteria: previous laparoscopic/clinical diagnosis of endometriosis, other diseases that might cause infertility or pelvic pain, previous treatment for endometriosis or infertility   No. randomised: 75   No. analysed: 75 (pregnancy rates), 68 (pain scores)
Interventions	Post‐surgical medical therapy   Gr A (n=36): nafarelin nasal 400 μg daily x 3/12   Gr B (n=39): placebo
Outcomes	Pain (multidimensional and 10‐point linear scale) score at 12 months   Pregnancy rates   Adverse drug outcome (amenorrhoea)
Notes	Power calculation: yes (post‐hoc?)   Funding: Recordati Milan provided nafarelin
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer generated randomization list"
Allocation concealment (selection bias)	Low risk	assigned by telephone call 7 days from surgery
Blinding (performance bias and detection bias)   All outcomes	Low risk	double blind but authors acknowledge that adverse effects of treatment make maintaining blinding difficult
Incomplete outcome data (attrition bias)   All outcomes	Low risk	no losses to follow up, all randomised patients included in analyses
Selective reporting (reporting bias)	Low risk	pregnancy rate and pelvic pain reported
Other bias	Low risk	groups appear comparable at baseline

Methods	Location: Rome, Italy   No. of centres: one Recruitment period: January 1999 to May 2005
Participants	Inclusion criteria: women of reproductive age <40, with endometriosis related symptoms (dysmenorrhoea, pelvic pain, deep dyspareunia), laparoscopic diagnosis of St III ‐IV endometriosis, desiring pregnancy, nulliparous   Exclusion criteria: concurrent disease, such as cancer or pelvic inflammatory disease, previous surgery for endometriosis, contraindications to estrogens/progestins   No. randomised: 234   No. analysed: 222
Interventions	Gr A (n=115 ): placebo for 6 months   Gr B (n=119 ): post‐operative medical or dietary therapy patients in group B received either triptorelin or leuprorelin 3.75 mg depot monthly for 6 months (n=42) continuous low dose monophasic oral contraceptives for 6 months, (ethinlyestradiol 0.03 mg + gestoden 0.75 mg) (n=40) dietary therapy for 6 months (vitamins, mineral salts, lactic ferments and omega 3 and omega 6 fatty acids together with individually tailored diet) (n=37)
Outcomes	Pelvic pain
Notes	Power calculation: yes   Funding: NS
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomized according to a computer generated randomization sequence"
Allocation concealment (selection bias)	Low risk	allocated by serially numbered opaque sealed envelopes
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	"neither the surgeons not the patients were aware of the regimen prescribed during the study period". Hoever placebo not described and it seems unlikely that blinding of patients could be maintained when treatments are either SC, oral medication or diet plus supplements
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	5 and 3 lost to follow up from placebo and GNRHa groups and reasons given. 2 lost to follow up from each of OCP and diet groups but reasons not given. 222 evaluated
Selective reporting (reporting bias)	Unclear risk	pain and health related quality of life reported. No pregnancy outcome in a group of women desiring pregnancy
Other bias	Low risk	groups appear comparable at baseline

Methods	Location: UK and Republic of Ireland   No. of centres: 7 Recruitment period: not stated
Participants	Inclusion criteria: 18‐50 year old women referred for symptom management or infertility   Exclusion criteria: cervical intraepithelial neoplasia (CIN)   No. randomised: 48   No. analysed: 40
Interventions	Pre‐operative goserelin versus no treatment   Gr A (n=21 ): goserelin 3.6 mg SC monthly for 3 months pre‐operatively   Gr B (n=27 ): no medical therapy
Outcomes	Change in endometrioma size, recurrence, pregnancy
Notes	Power calculation: yes   Funding: Astra Zeneca, Macclesfield, UK
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	participants were stratified by endometrioma size and "randomly allocated using computer generated randomization lists"
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	33%(7) and 41% (11) of patients in Gr A & B withdrew from trial before surgery. Reasons given but are different in each group. 4 withdrawals from goserelin group pre surgery due to serious AE ‐ migraine/headache/hot flushes, groin pain, muscle cramps, pain iliac fossa/sciatica. However all patients are included in outcome evaluation provided there is >1 post baseline measurement of endometrioma, but these numbers are not stated
Selective reporting (reporting bias)	Low risk	primary outcome is change in size of endometrioma, range of other outcomes including ease of surgery and pregnancy reported
Other bias	Unclear risk	some differences between the groups at baseline in mean endometrioma size. Difficulty in recruiting patients made trial underpowered, with different numbers in each group

Methods	Location: University of Oulu, Finland   No. of centres: 1 Recruitment period: not stated
Participants	Inclusion criteria: advanced endometriosis   Exclusion criteria: NS   No. randomised: 60   No. analysed: 51 (pain), 59 (pregnancy)
Interventions	Post‐surgical medical therapy   Gr A (n = 20): danazol oral 600 mg daily x 180 days   Gr B (n = 20): MPA 100 mg daily x 180 days   Gr C (n=20): placebo
Outcomes	Pain scores   AFS scores   Pregnancy rates   Patient satisfaction   Adverse drug reactions: weight gain, breakthrough bleeding, acne
Notes	Power calculation: NS   Funding: Research and Science Foundation Farmos Ltd, Turku; Cultural Foundation of Keski‐Pohjanmaa, Finland; Farmos Group, Turku, Finland supplied drugs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomized" no information on method of sequence generation
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	Low risk	double blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Numbers and reasons for post randomisation exclusions similar in each group. 3,2,3 excluded in groups A,B & C due to pregnancy. 1 adverse event in placebo group
Selective reporting (reporting bias)	Low risk	important outcomes of pregnancy recurrence and pain reported
Other bias	Low risk	groups appear comparable at baseline and authors state that" no other medication was used during the trial"

Methods	Location: Taiwan   No. of centres: one Recruitment period: June 1988 to December 2001
Participants	Inclusion criteria: women of reproductive age with infertility and stage III or IV endometriosis planning to undergo controlled ovarian hyperstimulation and intrauterine insemination or in vitro fertilisation and embryo transfer. All had surgery for endometriosis ‐ either laparotomy or laparoscopy for cystectomy, adhesiolysis, ablation of endometriosis   Exclusion criteria: NS   No. randomised: 45   No. analysed: 41
Interventions	Post‐operative medical therapy (either danazol or GNRH analogue)   Gr A (n=15 ): either 3 months 400 mg danazol orally, twice daily for 3 months or 3.75 mg leuprolide acetate depot SC every 28 days for 3 months   Gr B (n= 30): no post‐operative medical treatment
Outcomes	Pregnancy rate, recurrence
Notes	Power calculation: NS   Funding: NS
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"simple randomisation with a computer generated list unknown to physicians"
Allocation concealment (selection bias)	Low risk	list "unknown to physicians"
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo
Incomplete outcome data (attrition bias)   All outcomes	High risk	4 lost to follow up from Gr A (27%)
Selective reporting (reporting bias)	Low risk	pregnancy and recurrence reported
Other bias	Unclear risk	13 years of recruitment ‐ ? associated changes in surgical techniques over this time

PERMALINK

Pre and post‐operative medical therapy for endometriosis surgery

Susan Furness

Christine Yap

Cindy Farquhar

Ying C Cheong

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Characteristics of the study participants

Interventions used

Outcomes

Assessment of risk of bias in included studies

Measures of treatment effect

1. Descriptive data for trials not included in the meta‐analysis.

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

Pre‐surgical medical therapy

Post‐surgical medical therapy versus placebo or no treatment

Post‐surgical medical therapy compared with pre and post‐surgical medical therapy

Risk of bias in included studies

1.

Allocation

Blinding

Incomplete outcome data

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Post surgical medical therapies compared to No treatment or placebo for infertility associated with endometriosis.

Summary of findings 2. Pre and post operative medical therapies versus placebo for endometriosis.

Summary of findings 3. Pre‐surgical medical therapy compared to no medical therapy for endometriosis surgery.

Summary of findings 4. Post‐surgical medical therapy compared to placebo or no treatment for endometriosis.

Summary of findings 5. Pre‐surgical compared to Post‐surgical medical therapy for endometriosis surgery.

Summary of findings 6. Post‐surgical medical therapy compared to Pre and post‐surgical medical therapy with GnRHa for endometriosis surgery.

Pre‐surgical medical therapy

1.1. Analysis.

Disease recurrence

Post‐surgical medical therapy versus placebo or no treatment

Pain

2.1. Analysis.

2.2. Analysis.

Disease recurrence

2.3. Analysis.

2.4. Analysis.

Pregnancy

2.5. Analysis.

Methods	Location: Italy No. of centres: 19 Recruitment period: February 1992 to June 1994
Participants	Inclusion criteria: pre‐menopausal, endometriosis score >/= 4 points, chronic pelvic pain   Exclusion criteria: NS   No. randomised: 269   No. analysed: 210
Interventions	Post‐surgical medical therapy   Gr A (n= 133): goserelin SC 3.6 mg every 4 weeks x 6 months   Gr B (n=134): no treatment
Outcomes	Pain recurrence   Pregnancy rates
Notes	Power calculation: Yes   Funding: Zeneca Pharmaceuticals provided drugs and financial support
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomised in a proportion of 1:1 ... in accordance with a computer‐generated randomisation sequence"
Allocation concealment (selection bias)	Low risk	centralised randomisation, allocation obtained by phone call
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	269 patients randomised, 2 excluded because case record forms not completed, 26 & 31patients (22%) withdrew from treatment and control groups respectively for reasons other than symptom recurrence or were excluded due to major protocol violations. Reasons for exclusion similar in each group‐ may have introduced bias
Selective reporting (reporting bias)	Low risk	important outcomes of recurrence, dysmenorrhoea and pregnancy reported
Other bias	Low risk	groups appear comparable at baseline

Methods	Location: Harbin, China   No. of centres: one Recruitment period:March 2002 to March 2004
Participants	Inclusion criteria: women with stage 3 endometriosis who had undergone conservative or semi‐conservative surgery, with normal renal function and blood count, aged 23 to 42   Exclusion criteria: history of hypertension, heart disease, diabetes mellitis, had undergone hormone therapy in 6 months prior to surgery   No. randomised: 52   No. analysed: unclear
Interventions	Post‐operative   Gr A (n=20): yiweining (YWN) 200 ml orally twice daily, for 3 months, starting on 7th post‐operative day   Gr B (n=19): gestrinone 2.5 mg twice weekly, SC? for 3‐6 months, starting on 7th post‐operative day Gr C (n=13): control ‐ no treatment
Outcomes	Pregnancy, recurrence of endometriosis, adverse effects
Notes	Power calculation: not stated   Funding: Fund of National Science of Heilongjiang Province Email sent to corresponding author requesting additional information April 2010 ‐ mailbox not found
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly divided" ‐ no details of method of sequence generation given
Allocation concealment (selection bias)	Unclear risk	not mentioned
Blinding (performance bias and detection bias)   All outcomes	High risk	not mentioned, no placebo used
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	not clear how many of the randomised patients are included in the outcomes (% only given)
Selective reporting (reporting bias)	Unclear risk	pregnancy and recurrence reported ‐ no details as criteria for measuring these
Other bias	Low risk	groups are similar in age and type of surgery at baseline

Study	Reason for exclusion
Morgante 1999	This trial was excluded because all the patient received triptorelin for 6 months post‐surgery before randomisation to danazol or no treatment.
Schindler 1998	This is a prospective multi centre phase three study published in German. Preliminary translation suggests however that treatment was not randomly assigned.
Vercellini 2003	This is a pilot study using the levonorgestrel‐releasing intrauterine system for treatment of endometriosis post‐surgery. This is a locally effective hormonal suppressive therapy and has low systemic effects.
Ylanen 2003	This is a dose finding study with no comparison of treatment modality with placebo or no treatment.

Methods	Location: Egypt Recruitment: February 1999 to March 2000
Participants	68 women with stage I or II endometriosis, subfertility, failed clomiphene citrate stimulation, known tubal patency and partner with fertile semen analysis
Interventions	Post‐operative goserelin 3.6 mg injection every 28 days for 6 months versus no medical therapy, followed by 3 months of no treatment. If no pregnancy occurs then 2 cycles of clomiphene citrate stimulation follow
Outcomes	Pregnancy rate (spontaneous or following stimulation)
Notes	Published abstract only. Outcomes expressed as percentage only, no details of randomisation, allocation concealment, withdrawals, duration of follow up. Emailed author requesting more information (February and March 2010). No reply received