Gonadotrophin-releasing hormone analogues for pain associated with endometriosis

Background Endometriosis is a common gynaecological condition, characterised by the presence of endometrial tissue in sites other than the uterine cavity (excluding adenomyosis) that frequently presents with pain. The gonadotrophin‐releasing hormone analogues (GnRHas) comprise one intervention that has been offered for pain relief in pre‐menopausal women. GnRHas can be administered intranasally, by subcutaneous, or intramuscular injection. They are thought to result in down regulation of the pituitary and induce a hypogonadotrophic hypogonadal state.

To determine the effectiveness and safety of GnRHas in the treatment of the painful symptoms associated with endometriosis. Search methods Electronic searches of the Cochrane Menstrual Disorders and Subfertility Group specialist register, CENTRAL, MEDLINE, EMBASE, PSYCInfo and CINAHL were conducted in April 2010 to identify relevant randomised controlled trials (RCTs). Selection criteria RCTs of GnRHas as treatment for pain associated with endometriosis versus no treatment, placebo, danazol, intra‐uterine progestagens, or other GnRHas were included. Trials using add‐back therapy, oral contraceptives, surgical intervention, GnRH antagonists or complementary therapies were excluded. Data collection and analysis Quality assessment and data extraction were performed independently by two reviewers. The primary outcome was pain relief. Relative risk was used as the measure of effect for dichotomous data. For continuous data, mean differences or standardised mean differences were used. Main results Forty one trials (n=4935 women) were included. The evidence was inconsistent as to whether GnRHas were more effective at symptom relief than no treatment/placebo (low quality evidence) (see SoFs 1 and 2). The evidence was also inconsistent as to whether GnRHas were more effective than Danazol (low or very low quality evidence) (see SoF 3) More adverse events were reported in the GnRHa group,There was no statistically significant difference in overall pain relief between GnRHas and levonorgestrel intrauterine system (LNG IUS) SMD ‐0.25 (95%CI ‐0.60 to 0.10, P=0.46, moderate quality evidence). Evidence was limited on optimal dosage,duration and route of administration for treatment for GnRHas. Authors' conclusions It is unclear whether GnRHas is more effective at relieving pain associated with endometriosis than no treatment/placebo. There was no consistent evidence of a difference in pain relief between GnRHas and danazol although more adverse events were reported in the GnRHa groups. There was also no evidence of a difference in pain relief between GnRHas and LNG IUS. No studies compared GnRHas with analgesics.

Female, Humans, Danazol, Danazol/therapeutic use, Drug Administration Routes, Dysmenorrhea, Dysmenorrhea/drug therapy, Dyspareunia, Dyspareunia/drug therapy, Endometriosis, Endometriosis/drug therapy, Estrogen Antagonists, Estrogen Antagonists/therapeutic use, Gonadotropin-Releasing Hormone, Gonadotropin-Releasing Hormone/analogs & derivatives, Levonorgestrel, Levonorgestrel/therapeutic use, Pain, Pain/drug therapy, Pelvic Pain, Pelvic Pain/drug therapy, Randomized Controlled Trials as Topic Plain language summary Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis Endometriosis is a common condition affecting women of child‐bearing age, and is usually due to the presence of endometrial tissue in places other than the uterus. Common symptoms include pain and infertility. GnRHas are a group of drugs often used to treat endometriosis by decreasing hormone levels. This review f it unclear whether treatment with a GnRHa improved symptom relief compared with no treatment or placebo. There was also no evidence of a statistically significant difference when compared with danazol or LNG IUS. However, there more side effects in the GnRHa group compared with the danazol group. The quality of the evidence ranged from very low to moderate, Summary of findings Summary of findings 1. GnRHas compared to No treatment for pain associated with endometriosis. | GnRHas compared to no treatment for pain associated with endometriosis | |||||| | Population: women with pain associated with endometriosis Settings: Gynaecology clinics Intervention: GnRHas Comparison: 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 | ||||| | No treatment | GnRHas | ||||| | Relief of painful symptoms ‐ Dysmenorrhoea | 188 per 1000 | 737 per 1000 (257 to 1000) | RR 3.93 (1.37 to 11.28) | 35 (1 study) | ⊕⊕⊝⊝ low1,2 | | | *The basis for the assumed risk is the median control group risk across studies. 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. | 1 No blinding 2 Evidence based on a single trial which did not describe methods of sequence generation or allocation concealment Summary of findings 2. GnRHas compared to Placebo for pain associated with endometriosis. | GnRHas compared to Placebo for pain associated with endometriosis | |||||| | Population: women with pain associated with endometriosis Settings: gynaecology clinic Intervention: GnRHas Comparison: 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 | ||||| | Placebo | GnRHas | ||||| | Relief of painful symptoms ‐ pelvic tenderness | 160 per 1000 | 667 per 1000 (259 to 1709) | RR 4.17 (1.62 to 10.68) | 49 (1 study) | ⊕⊕⊝⊝ low1 | | | Pain score ‐ Overall at 4 weeks | The mean overall pain score at 4 weeks was 2.9 points higher in the intervention group (2.11 to 3.69 higher) on a 0‐12 scale | 120 (1 study) | ⊕⊕⊝⊝ low1 | Endometriosis Symptom Severity Score (ESSS), range 0‐12 points | || | *The basis for the assumed risk is the median control group risk across studies. 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. | 1 Evidence based on a single trial, with inadequate explanation of allocation concealment and blinding Summary of findings 3. GnRHas compared to Danazol for women with pain due to endometriosis. | GnRHas compared to Danazol for women with pain due to endometriosis | |||||| | Population: women with pain due to endometriosis Settings: gynaecological clinics Intervention: GnRHas Comparison: Danazol | |||||| | Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | | | Assumed risk | Corresponding risk | ||||| | Danazol | GnRHas | ||||| | Relief of painful symptoms ‐ Dysmenorrhoea | 825 per 1000 | 809 per 1000 (759 to 858) | RR 0.98 (0.92 to 1.04) | 666 (7 studies) | ⊕⊝⊝⊝ very low1,2 | | | Overall resolution ‐ Overall resolution/improvement | 596 per 1000 | 655 per 1000 (602 to 721) | RR 1.1 (1.01 to 1.21) | 1046 (9 studies) | ⊕⊕⊝⊝ low3 | | | *The basis for the assumed risk is the median control group risk across studies. 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. | 1 Randomisation was inadequately reported in five of the seven trials. Four of the trials failed to described allocation concealment adequately. There was no blinding in two trials and blinding was unclear in two trials. 2 I square was 44% which indicated issues of heterogeneity 3 There was a lack of adequate reporting of allocation concealment and/ or randomisation in most of the trials. Three of the nine trials did not give sufficient details for blinding and two trials were open label. Summary of findings 4. GnRHas compared to intra‐ uterine progestogen device for pain associated with endometriosis. | GnRHas compared to intra‐ uterine progestogen device for pain associated with endometriosis | |||||| | Population: women with pain associated with endometriosis Settings: gynaecological clnics Intervention: GnRHas Comparison: LNG IUS intra‐uterine device | |||||| | Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | | | Assumed risk | Corresponding risk | ||||| | Intra‐ uterine progestagen device | GnRHas | ||||| | Relief of painful symptoms ‐ Overall | The mean relief of painful symptoms ‐ overall in the intervention groups was 0.25 standard deviations lower (0.6 lower to 0.1 higher) | 129 (3 studies) | ⊕⊕⊕⊝ moderate1 | Standardised mean difference ‐0.25 (‐0.6 to 0.1), indicating no clinically meaningful difference in pain score between the groups | || | *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. | 1 Two of the three trials were open label and one trial did not provide adequate explanation of allocation concealment

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 woman in their reproductive years as it is generally believed to be an oestrogen 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 oestrogen therapy (Bruner‐Tran 2002). 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 on or following sexual intercourse), pelvic or abdominal pain. The patient may also present with cyclical symptoms related to endometriosis at extra‐pelvic sites. The precise pathogenesis (mode of development) of endometriosis remains unclear but it is evident that endometriosis arises by 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 intervention The gonadotrophin‐releasing hormone analogues (GnRHas) are a family of compounds that differ from natural gonadotrophin‐releasing hormone (GnRH), a ten amino acid hormone (decapeptide), by modifications in the decapeptide at positions six and ten (Shaw 1991). They may be administered intranasally (IN), by subcutaneous (SC) or intramuscular (IM) injection. Buserelin, goserelin, leuprorelin, leuprolide, nafarelin and triptorelin are some of the most common GnRHas. Other common treatments for endometriosis include analgesics, danazol, progestogens (Prentice 2000) including intra‐uterine systems, combined oral contraceptive pills (Davis 2007), surgical therapies (Jacobson 2009). How the intervention might work Non‐analgesic medical treatment of endometriosis aims to suppress the ectopic endometrium deposits by inducing atrophy within the hormonally dependent ectopic endometrium (making the endometrial tissue inactive).The observation that endometriosis is rarely seen in the hypo‐oestrogenic (low levels of oestrogen) post‐menopausal woman led to the concept of medical treatment of endometriosis by induction of a pseudo‐menopause. When GnRHas are administered in a non‐pulsatile manner (the pituitary is normally stimulated by pulses of natural GnRH and all analogues act on the pituitary at a constant level) their use results in down regulation (switching off) of the pituitary and through the induction of a hypogonadotrophic hypogonadal state (low levels of female hormones due to non stimulation of the ovary). Why it is important to do this review The prevalence of endometriosis in the general population is not known but it has been estimated to affect about 7% of women of reproductive age (Haney 1991). The cost of endometriosis is high in both economic and psychosocial terms (Mathias 1996). The annual economic burden of endometriosis in the USA is estimated to be approximately $22 billion which is considerably higher than those of Crohn's disease ($865 million) or migraine ($13‐17 billion) (Simoens, 2007). In addition the symptoms associated with endometriosis have a negative impact on physical, mental and social well‐being (Kennedy 2005). Treatment available is dependent upon available resources but also upon the preferences of the individual woman and the gynaecologist. This particularly relates to their decisions concerning the conservation of fertility or requirements for contraception. Other factors include age, degree of symptoms and personal preferences. This review will evaluate the role of GnRHas in the relief of pain in symptomatic women with endometriosis.

To determine the effectiveness and safety of GnRHas in the treatment of the painful symptoms associated with endometriosis.

Criteria for considering studies for this review Types of studies Only randomised controlled trials (RCTs) comparing the use of GnRHas in the treatment of symptomatic endometriosis were eligible for inclusion. Crossover trials were included in the review providing that pre and post crossover data were available and only the first arm data were used for analysis. Types of participants Pre‐menopausal women with symptoms ascribed to endometriosis were eligible for inclusion. The clinical diagnosis of endometriosis had to be made by direct visualisation (laparoscopy). Studies were included irrespective of the duration of symptoms. The symptoms considered were: cyclical pain associated with menstruation (dysmenorrhoea) or not associated with menstruation; deep dyspareunia (pain on or following sexual intercourse); lower abdominal or pelvic pain of a non cyclical nature; pain on defecation, and any other painful symptoms ascribed to endometriosis studied in any trial. Studies were considered in any care setting (primary or secondary). Exclusions: Women with asymptomatic disease or infertility as the only presenting complaint Self‐reporting of endometriosis Trials where GnRHa is administered in post‐surgical participants as adjuvant therapy Types of interventions Randomised trials reporting the following comparisons were included: Trials comparing GnRHas versus no treatment for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing GnRHas versus placebo for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing GnRHas versus analgesics for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing GnRHas versus danazol for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing GnRHas versus intra‐uterine progestogen for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing different doses of GnRHas for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing different treatment length of GnRHas for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing different route of administration of GnRHas for relieving painful symptoms associated with endometriosis and its related adverse effects Trials comparing different GnRHas treatment regimens for relieving painful symptoms associated with endometriosis and its related adverse effects Exclusions: Trials comparing GnRHas versus GnRHas in conjunction with add‐back therapy as a separate review will be conducted on the subject Trials comparing GnRHas with combined oral contraceptive pill (Davis 2007), oral or injectable progestogens (Prentice 2000) or surgical therapies (Jacobson 2009) as they exist under separate reviews. Trials comparing GnRHas with GnRH antagonists as that is a registered title of a review to be conducted by the Menstrual Disorders and Subfertility Group of Cochrane Collaboration. Trials comparing GnRHas with alternative and complementary medicine Types of outcome measures Primary outcomes Pain relief defined by using both quantitative measures such as visual analogue scales or categorical outcomes at the end of treatment and when possible at three, six, nine, twelve and twenty‐four months follow‐up. Secondary outcomes Adverse effects ( e.g. hot flushes, insomnia, reduced libido, vaginal dryness and headaches) both short term during therapy and long term extending beyond the treatment period Resolution of endometriosis defined by a change in revised American Fertility Society (rAFS) score assessed at second laparoscopy (high score equates to greater severity) Quality of life and factors affecting quality of life Additional use of analgesics Cost effectiveness was not an outcome of this review. Search methods for identification of studies The search strategy of the Menstrual Disorders and Subfertility Group was utilised to identify all publications that describe or might describe randomised trials of GnRHas in the treatment of symptomatic endometriosis. The search terms used to search the Menstrual Disorders and Subfertility Group specialist register can be referred to in Appendix 1 . The search was conducted in September 2010. Electronic searches There were no language restrictions in the searches. In addition to the Specialist Register, the following electronic databases, trial registers and web sites were searched: Ovid The Cochrane Central Register of Controlled Trials (CENTRAL) Appendix 2 Ovid MEDLINE Appendix 3 - Ovid EMBASE Appendix 4 EMBASE will only be searched one year back as the United Kingdom Central Council for Nursing, Midwifery and Health Visiting (UKCC) has hand searched EMBASE to this point and these trials are already in CENTRAL. Ovid PSYCInfo Appendix 5 CINAHL database Appendix 6 The MEDLINE search was combined with the Cochrane highly sensitive search strategy for identifying randomised trials which appears in the Cochrane Handbook of Systematic Reviews of Interventions (Version 5.0.1 chapter 6, 6.4.11) (Higgins 2008) The EMBASE and CINAHL searches were combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN). Other electronic sources of trials included: Trial registers for ongoing and registered trials ‐ 'Current Controlled Trials', "ClinicalTrials.gov' a service of the US national Institutes of Health and 'The World Health Organisation International Trials Registry Platform search portal' Citation indexes Conference abstracts in the ISI Web of Knowledge LILACS database, as a source of trials from the Portugese and Spanish speaking regions of the world Clinical Study Results for clinical trial results of marketed pharmaceuticals OpenSIGLE database and Google for grey literature Searching other resources All distributors of GnRHas were approached for details of unpublished trials of GnRHas known to or undertaken by them or their parent companies. The reference lists of articles retrieved by the search were hand‐searched. Any relevant journals and conference abstracts that are not covered in the MDSG register were hand‐searched in liaison with the Menstrual Disorders and Subfertility Group Trial Search Co‐ordinator, Marian Showell. Personal communication was made with experts in the field to obtain any additional relevant information. Data collection and analysis Selection of studies One review author scanned the retrieved searches for relevant titles and abstracts of articles retrieved by the search and removed those that were clearly irrelevant. The full text of all potentially eligible studies were retrieved. Two review authors (JB and AP) independently examined the full text articles for compliance with the inclusion criteria. Authors corresponded with study investigators to clarify study eligibility. Where required disagreements as to study eligibility were resolved by consensus or by the assessment of a third author. Data extraction and management Data extraction was conducted independently by two review authors (JB and AP) . Data extraction forms were developed and pilot‐tested by the authors. Where studies have multiple publications, the main trial report was used as the reference and additional details supplemented from secondary papers. Authors corresponded with study investigators in order to resolve any data queries as required. When disagreements arose between the two review authors, a third review author was contacted to resolve the dispute. Assessment of risk of bias in included studies The assessment of the quality of trials identified by the search strategy was undertaken by two of the reviewers. When uncertainty arose regarding suitability for inclusion or when discrepancy arose between the two reviewers (JB and AP), a third reviewer was contacted to make further assessment. The trials were assessed using the Cochrane risk of bias assessment tool to assess: sequence generation (low risk: investigators using random number table; computer random number generator; shuffling cards etc., unclear risk ‐ method of sequence generation not described [have deleted as these studies will not have got through selection process] allocation concealment (low risk: central allocation; sequentially numbered sealed opaque envelopes etc. whilst high risk: open random allocation schedule; alternation or rotation etc.) blinding (low risk: blinding of participants and/or key study personnel; blinding with placebo etc. whilst high risk: incomplete blinding; comparison group with no treatment etc.) attrition bias (low risk: no missing outcome data etc. whilst high risk: if attrition is equal or greater than 20% etc.) selective outcome reporting and other potential sources of bias (low risk: study protocol is available etc. whilst high risk: not all primary outcomes were reported; outcomes reported were not pre‐specified etc.) If necessary, additional information was sought from the principal investigator of the original trial. All judgments were fully described and the conclusions were presented in the Risk of Bias table. Measures of treatment effect Relative risk (RR) was used as the measure of effect for dichotomous data. For continuous data, mean differences (MD) were used whenever outcomes were measured in a standard way across studies. However, as many different methods exist for assessing pain, standardised mean differences(SMD) were calculated when comparing multiple methods. Ordinal data (E.g. quality of life scores) were treated as continuous data. A summary statistic for each outcome was calculated using a fixed effect model and a 95% confidence interval was used. Unit of analysis issues Data were presented as per woman randomised. In cross‐over trials only the first arm data were used for analysis where data were available, and in case where data were unavailable the primary author was contacted. Dealing with missing data The data were analysed on an intention‐to‐treat basis as far as possible and attempts were made to obtain missing data from the original investigators. If studies reported sufficient detail to calculate mean differences but no information on associated standard deviation (SD), the outcome was assumed to have standard deviation equal to the highest SD from other studies within the same analysis (Note this method was not required in the update). For other outcomes, only the available data were analysed. Assessment of heterogeneity The review authors considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a meaningful summary. Statistical heterogeneity was assessed by the measure of the I2 statistic (Higgins 2008). An I2 measurement greater than 50% indicates substantial heterogeneity and when substantial heterogeneity was detected, possible explanations were explored in subgroup and sensitivity analyses where the quality of study was also taken into account. Assessment of reporting biases In view of the difficulty in detecting and correcting for publication bias and other reporting biases, the authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. Care was also taken to search for within study reporting bias such as trials failing to report obvious outcomes, or reporting them in insufficient detail to allow inclusion. A funnel plot was undertaken if there were ten or more studies in an analysis. Data synthesis The data from primary studies were combined using fixed effect models in the following comparisons: GnRHas versus no treatment GnRHas versus placebo GnRHas versus analgesics GnRHas versus danazol GnRHas versus 'intra‐uterine progestogen' - GnRHas stratified by dosage (as defined by study) high low - GnRHas stratified by length of treatment 3 months 6 months - GnRHas stratified by mode of administration intranasal intramuscular subcutaneous GnRHas stratified by different regimes Subgroup analysis and investigation of heterogeneity Data were divided into subgroups by dosage (low or high as defined by study), duration of treatment (three, six, nine, twelve and twenty‐four months), route of administration (intranasal, intramuscular, subcuticular or depot injection) and drug regimes Sensitivity analysis Sensitivity analyses were conducted for the primary outcomes to determine whether the conclusions were robust to arbitrary decisions made regarding the eligibility and analysis. These analyses included consideration of whether conclusions would have differed if: Eligibility was restricted to studies without high risk of bias (e.g. unclear allocation concealment; attrition rate equal or greater than 20%; incomplete outcome data etc.) Studies with outlying results had been excluded; Alternative imputation strategies had been adopted; A random effect model had been adopted.

Description of studies See: Characteristics of included studies; Characteristics of excluded studies;Characteristics of studies awaiting classification

of the search 762 records were identified using the search strategy. After initial screening 124 full‐text records were retrieved for more in‐depth analysis. 43 randomised controlled trials were included in the meta‐analysis, 82 studies were excluded. Two studies (Chan 1993; Chen 2009) are currently awaiting classification. These studies are not included in the meta‐analysis. Included studies Forty‐two randomised controlled trials met our eligibility criteria and were included in this review (Adamson 1994; Agarwal 1997; AN Zoladex 1996; Audebert 1997; Bergqvist 1997; Bergqvist 1998; Burry 1992; Chang 1996; Cheng 2005; Cirkel 1995; Claesson 1989; Dawood 1990; Dlugi 1990; Dmowski 1989a; Fedele 1989; Fedele 1993;Ferreira 2010; Fraser 1991; Gomes 2007; Henzl 1988; Henzl 1990a; Hornstein 1995; Jelley 1986; Lemay 1988; Matta 1988; Miller 1990; Miller 2000; Minaguchi 1986; Moghissi 1987; NEET 1992; Odukoya 1995; Palagiano 1994; Petta 2005; Rock 1993; Rolland 1990; Shaw 1986; Shaw 1990; Shaw 1992; Skrzypulec 2004; Tummon 1989; Wheeler 1992; ). See Characteristics of included studies for description. Five trials were included in two comparisons. Adamson 1994, Henzl 1988 and Moghissi 1987 compared varying dosage of GnRHa in addition to a comparison with danazol, while Dawood 1990 and Dmowski 1989a compared varying route of administration of GnRHa in addition to its comparison with danazol. Excluded studies Of the 83 studies that were excluded, 22 studies did not have relief of pain as an outcome (Acien 1989a; Bergquist 1990a;Burry 1989a; Calvo 2000a; de Sa Rosa e Silva 2006a; Donnez 1989a; el‐Roeiy 1988a; Fedele 1993b; Franssen 1992a; Maouris 1989; Maouris 1991a; Matalliotakis 2000a; Matalliotakis 2004a;Ochs 1993;Rotondi 2002a; Roux 1995; Surrey 1993; Tapanainen 1993; Valimaki 1989a; Vieira 2007a; Wright 1995a; Yee 1986), 19 studies did not make comparisons with GnRHas that fitted our 'Types of Interventions' protocol, see Types of interventions for detail. Choktanasiri 2001a; Cooke 1989;Crosignani 1996a; Dmowski 1989; Donnez 2004; Franke 2000; Kiesel 1989; Kiilholma 1995; Luciano 2004; Magini 1993; Newton 1996; Surrey 1995; Surrey 2002; Tahara 2000; Taskin 1997; Toomey 2003; Vercellini 1994; Warnock 1998; Zupi 2005), five studies looked at the outcome in post‐surgical participants (Adiyono 2006; Harada 2000; Ling 1999; Vercellini 2009; Ylikorkala 1995), endometriosis was not the main condition discussed in four studies (Fraser 1996; Shaw 2001; Sorensen 1997; Sowter 1997) Risk of bias in included studies Details on the quality of each individual study are described in the table 'Characteristics of included studies' where the individual quality criteria were rated for each study. Authors have been contacted for more information when required. See Figure 1 for 'risk of bias' table and Figure 2 for 'risk of bias' graph. Allocation In nine trials method of allocation concealment was adequately described (Audebert 1997; Cheng 2005; Gomes 2007; Hornstein 1995; Jelley 1986; Odukoya 1995; Petta 2005; Shaw 1992; Skrzypulec 2004). Blinding Twenty trials had adequate blinding where the participants and investigators were blinded by the use of an identical placebo (Adamson 1994; Agarwal 1997; Bergqvist 1997; Bergqvist 1998;Chang 1996; Cheng 2005; Dlugi 1990; Fraser 1991; Henzl 1988; Hornstein 1995;Lemay 1988;Miller 1990; Moghissi 1987; NEET 1992; Petta 2005; Rolland 1990; Shaw 1990; Skrzypulec 2004; Wheeler 1992; Wheeler 1993). 11 trials were open‐trials where there were no blinding (Audebert 1997; Dawood 1990; Dmowski 1989a; Fedele 1993;Ferreira 2010; Gomes 2007; Jelley 1986; Matta 1988; Palagiano 1994; Rock 1993; Shaw 1992). The remaining trials had unclear information or no details on blinding. Incomplete outcome data Only one trial did not have adequate reporting of attrition (Chang 1996). No trials lost more than 20% of the original sample during follow up. Selective reporting All of the included trials (n=42) reported on their stated primary outcomes and had no additional outcomes that were not stated in their methods section. Other potential sources of bias All studies reported baseline equality between groups with respect to age and stage of endometriosis. Effects of interventions See: Table 1; Table 2; Table 3; Table 4 1. GnRHas versus no treatment There was only one study which compared GnRHas with no treatment (Fedele 1993) for the outcome of relief of painful symptoms (dysmenorrhoea) . The evidence suggested a statistically significant benefit for GnRHa compared with no treatment for the relief of the pain of dysmenorrhoea associated with endometriosis RR 3.93 (95% CI 1.37 to 11.28, P=0.01). No data were reported on adverse effects. 2. GnRHas versus placebo Five studies were identified which compared GnRHas with placebo (Bergqvist 1998, Dlugi 1990, Miller 1990, Miller 2000, Skrzypulec 2004). Only Bergqvist 1998 and Miller 2000 provided usable data. Bergqvist 1998 demonstrated that there was a statistically significant benefit in favour of GnRHas for the relief of pelvic tenderness RR 4.17 (95% CI 1.62 to 10.68, P=0.003) but no statistically significant differences between groups for dyspareunia (RR 1.16; 95%CI 0.57 to 2.34) or defecation pressure (RR 11.44; 95%CI 0.67 to 196.30). GnRHas appeared to be associated with greater incidence of sleep disturbances (20/24) compared with placebo (9/25), RR 2.31 (95% CI 1.33 to 4.02, P=0.003). Miller 2000 evaluated pain, using the Endometriosis Symptom Severity Score (ESSS) during the stimulatory phase of GnRHa therapy and found evidence which suggested a significant increase in ESSS with GnRHa therapy compared to placebo with a MD 2.90 (95% CI 2.11 to 3.69, P<0.001). 3. GnRHas versus analgesics No studies comparing GnRHas and analgesics were identified 4. GnRHas versus danazol Twenty seven studies compared a GnRHa with danazol (Adamson 1994, AN Zoladex 1996, Audebert 1997, Burry 1992, Chang 1996, Cheng 2005, Cirkel 1995, Claesson 1989, Dawood 1990, Dmowski 1989a, Fedele 1989, Fraser 1991, Henzl 1988, Henzl 1990a, Jelley 1986, Matta 1988, Moghissi 1987, NEET 1992, Odukoya 1995, Palagiano 1994, Rock 1993, Rolland 1990, Shaw 1990, Shaw 1992, Tummon 1989, Wheeler 1992, Wheeler 1993). Dichotomous data indicated no evidence of a statistically significant difference between groups for the effectiveness of pain relief in dysmenorrhoea (Adamson 1994;Cirkel 1995; Fedele 1989;Matta 1988;NEET 1992; Palagiano 1994; Wheeler 1992) RR 0.98 (95% CI 0.92 to 1.04, P=0.53); dyspareunia (Adamson 1994; Cirkel 1995; Fedele 1989; Jelley 1986; Matta 1988; NEET 1992; Palagiano 1994) RR 1.02 (95% CI 0.93 to 1.12, P=0.69); pelvic pain (Adamson 1994; Cirkel 1995; Fedele 1989; Matta 1988; NEET 1992; Palagiano 1994; Wheeler 1992) RR 0.96 (95% CI 0.86 to 1.07, P=0.47); induration (Cirkel 1995; NEET 1992) RR 1.10 (95% CI 0.94 to 1.29, P=0.23) and pelvic tenderness (Cheng 2005; NEET 1992; Wheeler 1992) RR 0.98 (95% CI 0.88 to 1.09, P=0.70). Refer to Figure 3. Continuous data from four studies (Cheng 2005; Dmowski 1989a; Tummon 1989; Fraser 1991) also indicated no statistically significant differences between GnRHas and danazol. Refer to Figure 4 Overall resolution was reported in nine studies ( AN Zoladex 1996; Audebert 1997; Burry 1992; Claesson 1989; Henzl 1988; NEET 1992; Palagiano 1994; Rolland 1990; Shaw 1990) the evidence suggested a benefit in resolution in those groups receiving GnRHas RR1.10 (95% CI 1.01 to 1.21, P=0.03). Refer to Figure 5. The outcome of improved Retrospective American Fertility Society (rAFS) score was compared by four studies (Burry 1992, Henzl 1988, Matta 1988, Rock 1993). This score measures the incidence, extent and severity of endometriosis. There was no evidence to suggest any statistically significant differences between GnRHas (248/488) compared with danazol (109/244), RR 1.14 (95% CI 0.98 to 1.32, P=0.08). The rAFS score at approximately 24 weeks follow up was recorded by ten studies [Cheng 2005, Cirkel 1995, Claesson 1989, Dmowski 1989a, Fedele 1989, Fraser 1991, Henzl 1990a, NEET 1992, Shaw 1992, Tummon 1989]. They found no evidence of a statistically significant difference between groups, SMD ‐0.01 (95% CI ‐0.12 to 0.15, P=0.85). There were 39 different side effects reported by 19 studies (AN Zoladex 1996, Audebert 1997, Burry 1992, Chang 1996, Cheng 2005, Cirkel 1995, Dawood 1990, Dmowski 1989a, Fedele 1989, Fraser 1991, Henzl 1988, Jelley 1986, Matta 1988, NEET 1992, Palagiano 1994, Rock 1993, Rolland 1990, Shaw 1992, Wheeler 1993). Five of the most commonly reported side effects were vaginal dryness, hot flushes, headaches, weight gain and acne. Side effects were more frequently reported in groups receiving GnRHas than those receiving danazol. Vaginal dryness was compared in 16 studies, the evidence suggested a significant between GnRHas (444/1266) and danazol (146/802), RR 1.96 (95% CI 1.68 to 2.30, P<0.00001). Nineteen studies looked at hot flushes and found a significant difference between GnRHas (1410/1646) and danazol (537/991), RR 1.55 (95% CI 1.47 to 1.65, P<0.00001), however heterogeneity is high at I²=73%. Headaches were compared in 16 studies and a statistically significant benefit was found in favour of GnRHas (380/1303) compared to danazol (173/799), RR 1.40 (95% CI 1.22 to 1.61, P<0.00001). Weight gain was reported in 12 studies that found evidence to suggest a statistically significant increase in danazol (206/675) compared to GnRHas (60/1088) RR 0.20 (95% CI 0.16 to 0.26, P<0.00001), heterogeneity was high at I²= 78%. Acne was reported by 13 studies and evidence suggested a statistically significant increase in danazol (202/747) compared to GnRHas (198/1218) RR 0.55 (95% CI 0.47 to 0.65), heterogeneity high at I²=75%. Refer to Figure 6. 5. GnRHas versus intra‐uterine progestogen (LNG‐IUS) Three studies were included that compared GnRHas with LNG IUS(Ferreira 2010; Gomes 2007, Petta 2005). There was no evidence of a statistically significant difference in overall pain score between GnRHas and LNG IUS SMD ‐0.25 favouring GnRHas (95% CI ‐0.60 to 0.10, P=0.46). One study (Gomes 2007) also looked at the rAFS score and appeared to have found no statistically significant difference between GnRHas and LNG IUS SMD 9.50 favouring LNG IUS (95% CI ‐10.77 to 29.7, P=0.36). 6. GnRHa versus GnRHa (varying dosage) Six studies were identified that compared varying doses of GnRHas: Bergqvist 1997 compared 200mcg vs 400mcg nafarelin daily. Adamson 1994, Henzl 1988 and Moghissi 1987 compared 400mcg vs 800mcg nafarelin daily. Minaguchi 1986 compared 300mcg vs 600mcg daily, 300mcg vs 900mcg buserelin daily as well as 600mcg vs 900mcg daily which Shaw 1986 also compared. Three studies (Adamson 1994, Henzl 1988, Minaguchi 1986) compared the relief of painful symptoms.The evidence suggested there was no statistically significant differences between the two groups for any outcome (Refer to Figure 7). One study (Henzl 1988) reported on improvement in rAFS score during a 6 months follow up after treatment and found evidence of a significant difference between low (6/73) and high (14/70) groups, RR 0.41 (95% CI 0.17 to 1.01, P=0.05). Refer to Figure 8 One study Bergqvist 1997) looked at the side effects (hot flushes, sleep disturbances, rhinitis and upper respiratory tract infections) between 200 micrograms daily of GnRHa compared with 400 micrograms daily. The study did not find any evidence to suggest there was any significance in any of the side effects: hot flushes 7/12 for both groups, RR 1.0 (95% CI 0.51 to 1.97); sleep disturbances 9/12 for both groups, RR 1.0 (95% CI 0.63 to 1.59); rhinitis 2/12 200mcg/d versus 5/12 400mcg/d, RR 0.40 (95% CI 0.10 to 1.67) and URTI 1/12 200mcg/d versus 5/12 400mcgd, RR 0.20 (95% CI 0.03 to 1.47). 7. GnRHa versus GnRHa (varying length of treatment) Hornstein 1995 was the only study to look at relief of painful symptoms for varying length of treatment of GnRHas. The author examined the effect of relief of dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and pelvic induration. Refer to Figure 9. The only outcome to show a statistically significant difference was dyspareunia MD ‐0.98 (95%CI ‐1.29 to ‐0.66; P<0.00001) in favour of a shorter duration. 8. GnRHa versus GnRHa (varying routes of administration) Four studies were included that compared varying routes of administration of GnRHa. Agarwal 1997 compared intra‐nasal (IN) vs intramuscular (IM) depot while Dawood 1990, Dmowski 1989a and Lemay 1988 all compared IN vs subcutaneous (SC) daily. There was no evidence of a statistically significant difference between IN and IM depot for the relief of painful symptoms associated with endometriosis. The same study had no evidence to suggest there was a statistically significant difference between the episodes of hot flushes experienced in the IN (95/98) or IM depot (93/93) group RR 0.97 (95% CI 0.93 to 1.01, P=0.14). In the comparison between IN and SC for the relief of painful symptoms associated with endometriosis, there was no evidence to suggest a statistically significant difference for the effectiveness of pain relief between the groups (Lemay 1988) for pelvic pain (RR 1.0; 95%CI 0.53 to 1.87), dyspareunia (RR 1.0; 95%CI 0.57 to 1.75), dysmenorrhoea (RR 1.22; 95%CI 0.75 to 2.06), pelvic tenderness (RR 1.55, 95%CI 0.69 to 3.27), pelvic induration (RR 0.86, 95%CI 0.47 to 1.55). There was also no evidence for a statistically significant difference in the rAFS score between groups MD 9.00 (95% CI ‐5.93 to 23.93, P=0.24). There was no evidence to suggest any statistically significant differences in adverse effects experienced between the two groups. Hot flushes were encountered in 5/7 IN and 5/6 SC, RR 0.86 (95% CI 0.48 to 1.55, P=0.62); vaginal dryness in 2/7 IN and 2/6 SC, RR 0.86 (95% CI 0.17 to 4.37, P=0.85); headaches in 2/7 IN and 1/6 SC, RR 1.71 (95% CI 0.20 to 14.55, P=0.62) and decreased libido in 1/7 IN and 1/6 SC, RR 0.86 (95% CI 0.07 to 10.96, P=0.91).

Summary of main results It is unclear whether GnRHas are more effective at relieving pain associated with endometriosis (pelvic tenderness and ESSS) than either no treatment or placebo. There was also no consistent evidence of a difference in pain relief between GnRHas and Danazol (dysmenorrhoea, dyspareunia, pelvic pain, pelvic induration, pelvic tenderness) although there were more adverse events reported in the GnRHa groups. There was no evidence of a difference in overall pain relief between GnRHas and LNG IUS and no studies compared GnRHas with analgesics. It is of note that the cost of danazol is generally less than that of GnRHas but anecdotally the use of danazol has decreased over time due to the irreversible side effect of voice change with this drug (Matabese 2009). There is limited evidence to draw conclusions regarding the benefit of varying doses, or length of treatment. The route of administration does not appear to be an important factor in attaining benefit. Overall completeness and applicability of evidence Although attempts were made to contact authors regarding missing data, there are still some missing data which cannot be included in the analysis. The review authors have attempted to obtain all the relevant published and unpublished material with regards to the objectives of the review. One issue of concern is the methods of reporting pain in the trials. Some trials report overall pain whilst others provide details of specific endometriosis associated pain which includes dysmenorrhoea, dyspareunia, pelvic pain, pelvic induration, pelvic tenderness. There may be some scepticism when generalising overall pain relief and concern when trials do not report on all subcategories of pain. Quality of the evidence This was a systematic review of forty one trials including 4742 women. The overall quality of the evidence ranged from very low to moderate. The older studies lacked clarity on randomisation and allocation concealment and these authors were often difficult to contact. Potential biases in the review process Obtaining additional data from authors has proved difficult due to the age of some of the studies. Raw data were often misplaced or no longer available. One source of bias was an inconsistency in the reporting of adverse events. Agreements and disagreements with other studies or reviews The use of add‐back therapy to alleviate symptoms is the subject of another registered Cochrane review and the risk of bone demineralisation with GnRHas is discussed in the review by Sagsveen 2003. Authors' conclusions Implications for practice. This comprehensive review of the literature demonstrates that it is unclear whether GnRHAs are of benefit for pain relief for women with endometriosis, compared to no treatment, placebo or danazol. the siWith respect to danazol, the side‐effect profile of these two drugs were different, with significantly more women experiencing vaginal dryness and hot flushes when treated with GNRH analogues, whereas significantly more women experienced weight gain and acne when treated with danazol. There was also no evidence of a benefit of use of GnRHas compared tothe LNG IUS. Furthermore there is limited evidence available to determine the optimal dose, route or duration of treatment to alleviate symptoms, although it is generally recommended that treatment should not continue for more than six months, due to the risks associated with bone demineralisation. Not all aspects of pain relief are discussed in all of the trials and generalisabilty about the relief of specific aspects of pain may be difficult. Implications for research. More studies of the use of tGnRH analogues versus other interventions would help to determine the place of these treatments in the management of a woman with endometriosis. The impact of the results on the clinical impact is somewhat diluted by the decline in the use of danazol to treat the symptoms of endometriosis. More consistent use of pain outcomes when reporting this measure would be of use in determining which categories are specifically improved by treatment. What's new | Date | Event | Description | |---|---|---| | 14 November 2023 | Amended | This review has been replaced in 2023 by a review entitled 'Gonadotropin‐releasing hormone analogues for endometriosis'. | History Protocol first published: Issue 4, 2010 Review first published: Issue 12, 2010 | Date | Event | Description | |---|---|---| | 27 September 2010 | New search has been performed | Two additional studies added to review | | 8 April 2010 | Amended | Authorship amendment made | | 17 March 2010 | Amended | This protocol is a new version of a previously published review which required a major methodological restructure Prentice 1999 | | 17 March 2010 | New citation required and major changes | Substantive amendment. Type of intervention has been limited to GnRHas versus placebo or no treatment; GnRHas versus danazol; analgesics; and levonorgestrel. |

Everyone at the Cochrane Gynaecology and Fertility Group, in particular Marian Showell, information specialist, who contributed to the search strategy and its updates; Jane Clarke, Managing Editor, and Dr. Cindy Farquhar who has been consulted as an expert in the field. We would like to thank Julie Brown, Tineke Crawford and Alice Pan for contributing to previous versions of the review. Appendices Appendix 1. Cochrane Gynaecology and Fertility Group (CGFG) Specialist register search terms

CONTAINS "*Endometriosis" or "dysmenorrhea" or "dysmenorrhoea" or "dyspareunia" or "pelvic pain" or "pain‐dysmenorrhea" or "pain‐dyspareunia" or "pain‐endometriosis" or "pain‐pelvic" or "menstrual pain" or "dyschezia" or "abdominal pain" or Title CONTAINS" *Endometriosis" or "dysmenorrhea" or "dysmenorrhoea" or "dyspareunia" or "pelvic pain" or "pain‐dysmenorrhea" or "pain‐dyspareunia" or "pain‐endometriosis" or "pain‐pelvic" or "menstrual pain" or "dyschezia" or "abdominal pain" AND

CONTAINS "Gonadorelin" or "GnRh" or "GnRHa" or "GnRHa‐gonadotropin" or "Gonadotrophin releasing agonist" or "Gonadotrophin releasing hormones" or "gonadotrophins" or "gonadotropin" or "gonadotropin releasing hormone agonist" or "goserelin acetate" or "Gosereline " or "Luteinising hormone releasing hormone" or "Lutenising hormone releasing hormone" or "LHRH" or "LHRH agonists" or "LHRH antagonists" or "leuprorelin" or "leuprorelin acetate" or "leuprolin" or "leuprolide depot" or "Leuprolide" or "leuprolide acetate" or "buserelin" or "Buserelin Acetate" or "buserelin naferelin" or "busereline" or "Nafarelin" or "Nafarelin Study Group" or "triptoielin" or "triptorelin" or "triptoreline" or "triptorelyn" or "triptrolein" or "Zoladex" or "Lupron" or "luprorelix" or "decapeptyl" or "decapeptyl" or "decapeptyl‐daily" or "decapeptyl‐depot" (150 hits) Appendix 2. CENTRAL CRSO search strategy Database: CENTRAL CRSO01 January 2009 to 02 November 2016 Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 MESH DESCRIPTOR Endometriosis EXPLODE ALL TREES (511) 2 Endometrios*:TI,AB,KY (1134) 3 dyspareunia:TI,AB,KY (482) 4 (Dyschesia or Dyschezia):TI,AB,KY (23) 5 1 OR 2 OR 3 OR 4 (1525) 6 MESH DESCRIPTOR Gonadotropin‐Releasing Hormone EXPLODE ALL TREES (1996) 7 (gonadotropin‐releasing or gonadotrophin‐releasing):TI,AB,KY (1898) 8 GnRH*:TI,AB,KY (2223) 9 (luteini?ing hormone‐releasing hormone):TI,AB,KY (341) 10 lhrh*:TI,AB,KY (453) 11 (fsh‐releasing hormone*):TI,AB,KY (1) 12 gonadorelin:TI,AB,KY (762) 13 (lh rh*):TI,AB,KY (151) 14 (buserelin or goserelin or leuprolide):TI,AB,KY (1702) 15 (triptorelin or nafarelin):TI,AB,KY (640) 16 (leuprorelin or naferelin):TI,AB,KY (359) 17 (suprecur or suprefact):TI,AB,KY (9) 18 (Zoladex or lupron):TI,AB,KY (271) 19 (prostap or enantone):TI,AB,KY (13) 20 (lucrin or trenantone):TI,AB,KY (4) 21 (synarel or synarella):TI,AB,KY (3) 22 (decapeptyl or gonapeptyl):TI,AB,KY (62) 23 Elagolix:TI,AB,KY (14) 24 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 (4541) 25 5 AND 24 (438) 26 2009 TO 2016:YR (343851) 27 25 AND 26 (138) Appendix 3. MEDLINE search strategy Database: Ovid MEDLINE(R) Epub Ahead of Print, In Process & Other Non‐Indexed Citations, Ovid MEDLINE (R) Daily, and Ovid MEDLINE (R) 1946‐2 November 2016 Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 exp Endometriosis/ (18955) 2 exp Dysmenorrhea/ (3483) 3 dysmenorrh$.tw. (4828) 4 (pain$ adj5 menstrua$).tw. (1439) 5 dyspareunia.tw. (3086) 6 (pelvi$ adj2 pain$).tw. (7885) 7 (pain$ adj3 defecat$).tw. (473) 8 (Dyschesia or Dyschezia).tw. (253) 9 Endometrios$.tw. (18998) 10 or/1‐9 (37118) 11 exp gonadotropin‐releasing hormone/ or exp buserelin/ or exp goserelin/ or exp leuprolide/ or exp nafarelin/ or exp triptorelin/ (30312) 12 (gonadotropin‐releasing or gonadotrophin‐releasing).tw. (15263) 13 GnRH$.tw. (20333) 14 luteinizing hormone‐releasing hormone$.tw. (5329) 15 lhrh$.tw. (6264) 16 fsh‐releasing hormone$.tw. (54) 17 gonadorelin$.tw. (195) 18 lh fsh releasing hormone$.tw. (27) 19 lh rh$.tw. (3379) 20 (buserelin or goserelin or leuprolide).tw. (3765) 21 (triptorelin or nafarelin).tw. (892) 22 (leuprorelin or naferelin).tw. (405) 23 (suprecur or suprefact).tw. (31) 24 (Zoladex or lupron).tw. (532) 25 (prostap or enantone).tw. (27) 26 (lucrin or trenantone$).tw. (12) 27 (synarel or synarella).tw. (12) 28 (decapeptyl or gonapeptyl).tw. (215) 29 Elagolix.tw. (12) 30 or/11‐29 (42878) 31 randomized controlled trial.pt. (434446) 32 controlled clinical trial.pt. (91874) 33 randomized.ab. (375224) 34 placebo.tw. (185604) 35 clinical trials as topic.sh. (180550) 36 randomly.ab. (266388) 37 trial.ti. (164264) 38 (crossover or cross‐over or cross over).tw. (71773) 39 or/31‐38 (1103073) 40 (animals not (humans and animals)).sh. (4302705) 41 39 not 40 (1015791) 42 10 and 30 and 41 (395) 43 (2009$ or 2010$ or 2011$ or 2012$ or 2013$ or 2014$ or 2015$ or 2016$).ed. (7845311) 44 (2009$ or 2010$ or 2011$ or 2012$ or 2013$ or 2014$ or 2015$ or 2016$).dp. (7881129) 45 43 or 44 (8821265) 46 42 and 45 (117) Appendix 4. EMBASE search strategy Database: Embase Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 exp Endometriosis/ (30662) 2 exp Dysmenorrhea/ (9744) 3 dysmenorrh$.tw. (6165) 4 (pain$ adj5 menstrua$).tw. (1924) 5 dyspareunia.tw. (5425) 6 (pelvi$ adj2 pain$).tw. (12011) 7 (pain$ adj3 defecat$).tw. (800) 8 (Dyschesia or Dyschezia).tw. (492) 9 (abdom$ adj2 pain$).tw. (75118) 10 Endometrio$.tw. (34299) 11 or/1‐10 (134357) 12 (gonadotropin‐releasing or gonadotrophin‐releasing).tw. (16752) 13 GnRHa$.tw. (1955) 14 luteinizing hormone‐releasing hormone$.tw. (5673) 15 lhrh$.tw. (7559) 16 fsh‐releasing hormone$.tw. (56) 17 gonadorelin$.tw. (317) 18 lh fsh releasing hormone$.tw. (26) 19 lh rh$.tw. (3914) 20 (buserelin or goserelin or leuprolide).tw. (5000) 21 (nafarelin or triptorelin).tw. (1297) 22 (leuprorelin or naferelin).tw. (588) 23 (suprecur or suprefact).tw. (1231) 24 (Zoladex or lupron).tw. (3462) 25 (prostap or enantone).tw. (395) 26 (lucrin or trenantone$).tw. (369) 27 (synarel or synarella).tw. (328) 28 (decapeptyl or gonapeptyl).tw. (1773) 29 Elagolix.tw. (35) 30 exp gonadorelin/ or exp gonadorelin agonist/ or exp goserelin/ or exp histrelin/ or exp leuprorelin/ or exp lutrelin/ or exp nafarelin/ or exp nafarelin acetate/ or exp ovurelin/ or exp triptorelin/ (57894) 31 or/12‐30 (65198) 32 Clinical Trial/ (985874) 33 Randomized Controlled Trial/ (458122) 34 exp randomization/ (83367) 35 Single Blind Procedure/ (26668) 36 Double Blind Procedure/ (136356) 37 Crossover Procedure/ (53582) 38 Placebo/ (320740) 39 Randomi?ed controlled trial$.tw. (148173) 40 Rct.tw. (22153) 41 random allocation.tw. (1618) 42 randomly allocated.tw. (26455) 43 allocated randomly.tw. (2203) 44 (allocated adj2 random).tw. (843) 45 Single blind$.tw. (18562) 46 Double blind$.tw. (172305) 47 ((treble or triple) adj blind$).tw. (636) 48 placebo$.tw. (246520) 49 prospective study/ (383281) 50 or/32‐49 (1761961) 51 case study/ (92253) 52 case report.tw. (321646) 53 abstract report/ or letter/ (983480) 54 or/51‐53 (1388297) 55 50 not 54 (1711983) 56 11 and 31 and 55 (1138) 57 2016$.em. or 2016$.dp. (1935287) 58 2016$.dd. or 2016$.dc. (1513569) 59 57 or 58 (1938578) 60 56 and 59 (75) Appendix 5. PSYCInfo search strategy Database: PsycINFO Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 exp Dysmenorrhea/ (193) 2 dysmenorrh$.tw. (359) 3 (pain$ adj5 menstrua$).tw. (238) 4 dyspareunia.tw. (528) 5 (pelvi$ adj2 pain$).tw. (524) 6 (pain$ adj3 defecat$).tw. (20) 7 (Dyschesia or Dyschezia).tw. (7) 8 Endometrios$.tw. (208) 9 or/1‐8 (1659) 10 (gonadotropin‐releasing hormone$ or gonadotrophin‐releasing hormone$).tw. (891) 11 GnRH$.tw. (883) 12 luteinizing hormone‐releasing hormone$.tw. (224) 13 lhrh$.tw. (207) 14 fsh‐releasing hormone$.tw. (1) 15 gonadorelin$.tw. (4) 16 lh fsh releasing hormone$.tw. (1) 17 lh rh$.tw. (42) 18 (buserelin or goserelin or leuprolide).tw. (106) 19 (nafarelin or triptorelin).tw. (27) 20 (leuprorelin or naferelin).tw. (11) 21 (suprecur or suprefact).tw. (0) 22 (Zoladex or lupron).tw. (20) 23 (prostap or enantone).tw. (1) 24 (lucrin or trenantone$).tw. (1) 25 (synarel or synarella).tw. (0) 26 (decapeptyl or gonapeptyl).tw. (3) 27 Elagolix.tw. (0) 28 exp gonadotropic hormones/ or exp hormones/ or exp follicle stimulating hormone/ or exp luteinizing hormone/ (57521) 29 or/10‐28 (57842) 30 9 and 29 (103) 31 random*.ti,ab,hw,id. (159760) 32 trial*.ti,ab,hw,id. (148526) 33 controlled stud*.ti,ab,hw,id. (10504) 34 placebo*.ti,ab,hw,id. (35478) 35 ((singl* or doubl* or trebl* or tripl*) and (blind* or mask*)).ti,ab,hw,id. (25208) 36 (cross over or crossover or factorial* or latin square).ti,ab,hw,id. (25143) 37 (assign* or allocat* or volunteer*).ti,ab,hw,id. (137782) 38 treatment effectiveness evaluation/ (20532) 39 mental health program evaluation/ (1970) 40 exp experimental design/ (52109) 41 "2000".md. (0) 42 or/31‐41 (435791) 43 30 and 42 (14) 44 limit 43 to yr="2009 ‐Current" (9) Appendix 6. CINAHL search strategy Database: CINAHL Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 (MM "Endometriosis") (1703) 2 (MM "Dyspareunia") (255) 3 TX dyspareunia (917) 4 TX Dyschesia or TX Dyschezia (20) 5 TX Endometrio* (3228) 6 1 OR 2 OR 3 OR 4 OR 5 (4066) 7 (MM "Gonadorelin+") (659) 8 TX gonadotrop?in‐releasing hormone* (87) 9 TX Gonadorelin (921) 10 TX buserelin (11) 11 (MM "Goserelin") (101) 12 TX goserelin (263) 13 (MM "Leuprolide") (132) 14 TX leuprolide (302) 15 (MM "Nafarelin") (6) 16 TX nafarelin (16) 17 TX triptorelin (43) 18 TX GnRH* (450) 19 TX luteini?ing hormone‐releasing hormone* (144) 20 TX lhrh (88) 21 TX lh rh (83) 22 TX Zoladex or TX lupron (39) 23 TX suprecur or TX suprefact (1) 24 TX prostap or TX enantone (1) 25 TX lucrin or TX trenantone (3) 26 TX synarel or TX synarella (2) 27 TX decapeptyl or TX gonapeptyl (3) 28 TX Elagolix (0) 29 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 1761) 30 6 AND 29 (140) 31 (MH "Clinical Trials+") (203615) 32 PT Clinical trial (79710) 33 TX clinic* n1 trial* (190184) 34 TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) (858841) 35 TX randomi* control* trial* (111103) 36 (MH "Random Assignment") (41777) 37 TX random* allocat* (5293) 38 TX placebo* (39720) 39 (MH "Placebos") (9848) 40 (MH "Quantitative Studies") (14946) 41 TX allocat* random* (5293) 42 31 OR 32 OR 33 OR 34 OR 35 OR 36 OR 37 OR 38 OR 39 OR 40 OR 41 (1083518) 43 30 AND 42 (54) Data and analyses Comparison 1. GnRHas versus no treatment. | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 1.1 Relief of painful symptoms | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 1.1.1 Dysmenorrhoea | 1 | 35 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.93 [1.37, 11.28] | Comparison 2. GnRHas versus placebo. | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 2.1 Relief of painful symptoms | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 2.1.1 pelvic tenderness | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.17 [1.62, 10.68] | | 2.1.2 Dyspareunia | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.57, 2.34] | | 2.1.3 Defecation pain/pressure | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 11.44 [0.67, 196.30] | | 2.2 Side effects | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 2.2.1 Hot flushes/flashes | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.62 [0.87, 3.02] | | 2.2.2 Sleep disturbances | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.31 [1.33, 4.02] | | 2.3 Pain score | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | | | 2.3.1 Overall at 4 weeks | 1 | 120 | Mean Difference (IV, Fixed, 95% CI) | 2.90 [2.11, 3.69] | Comparison 3. GnRHas versus danazol. | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 3.1 Relief of painful symptoms | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 3.1.1 Dysmenorrhoea | 7 | 666 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.92, 1.04] | | 3.1.2 Dyspareunia | 7 | 431 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.93, 1.12] | | 3.1.3 Pelvic pain | 7 | 647 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.86, 1.07] | | 3.1.4 Induration | 2 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.94, 1.29] | | 3.1.5 Pelvic tenderness | 3 | 404 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.88, 1.09] | | 3.2 Overall resolution | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 3.2.1 Overall resolution/improvement | 9 | 1046 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [1.01, 1.21] | | 3.3 Relief of painful symptoms | 4 | Std. Mean Difference (IV, Fixed, 95% CI) | Subtotals only | | | 3.3.1 Overall 90 days | 1 | 59 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.13 [‐0.64, 0.38] | | 3.3.2 Overall 180 days | 3 | 103 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.30, 0.50] | | 3.3.3 Dsypareunia | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.19 [‐0.41, 0.79] | | 3.3.4 Pelvic pain | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.60, 0.60] | | 3.3.5 Pelvic tenderness | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.19 [‐0.79, 0.41] | | 3.3.6 Pelvic induration | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.60, 0.60] | | 3.4 rAFS | 10 | 1012 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.01 [‐0.13, 0.12] | | 3.4.1 change at 180 days | 1 | 59 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐0.81, 0.21] | | 3.4.2 24 weeks | 9 | 953 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.12, 0.15] | | 3.5 Improved rAFS score | 4 | 732 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.98, 1.32] | | 3.6 Side effects | 18 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 3.6.1 vaginal dryness/vaginitis | 15 | 1798 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.04 [1.72, 2.42] | | 3.6.2 Hot flushes/flashes | 18 | 2367 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.55 [1.46, 1.65] | | 3.6.3 Headaches | 15 | 1832 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [1.21, 1.64] | | 3.6.4 Infections and flu like symptoms | 1 | 71 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.60 [1.31, 9.88] | | 3.6.5 Muscle cramps/myalgia | 10 | 1537 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.06, 0.18] | | 3.6.6 Sleep disturbance | 6 | 679 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.87 [1.46, 2.39] | | 3.6.7 Skin rash | 3 | 324 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.02, 0.51] | | 3.6.8 Gastrointestinal | 4 | 363 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.26, 1.05] | | 3.6.9 Weight gain | 11 | 1493 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.11, 0.21] | | 3.6.10 Acne | 12 | 1695 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.42, 0.58] | | 3.6.11 Breast atrophy/changes | 7 | 1035 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.47, 0.76] | | 3.6.12 Emotional lability/altered mood | 3 | 534 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.60, 1.61] | | 3.6.13 Oedema/fluid retention | 5 | 626 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.05, 0.20] | | 3.6.14 Asthenia | 5 | 781 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.23, 0.58] | | 3.6.15 Bleeding | 3 | 161 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.12, 0.48] | | 3.6.16 Depression | 5 | 513 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.38, 0.99] | | 3.6.17 Leukorrhoea | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.23, 4.71] | | 3.6.18 chest pain | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.23 [0.39, 134.16] | | 3.6.19 Generalised spasm | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.08 [0.00, 1.35] | | 3.6.20 pharyngitis | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.74] | | 3.6.21 Voice alteration | 2 | 114 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.02, 1.27] | | 3.6.22 vulvovaginal disorder | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.74] | | 3.6.23 Hirsutism | 6 | 866 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.11, 0.39] | | 3.6.24 Seborrhoea | 6 | 835 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.33, 0.53] | | 3.6.25 Alopecia | 2 | 365 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.02, 0.53] | | 3.6.26 Altered libido | 9 | 1620 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.88, 1.24] | | 3.6.27 Sweating | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.28 [0.03, 2.51] | | 3.6.28 Breast tenderness | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.04, 4.33] | | 3.6.29 Fatigue | 2 | 84 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.40, 1.26] | | 3.6.30 Arthralgia | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 17.61 [1.08, 286.40] | | 3.6.31 Hunger | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.05 [0.00, 0.81] | | 3.6.32 Nervousness | 2 | 504 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.20, 1.02] | | 3.6.33 Irritability | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.74 [1.67, 13.45] | | 3.6.34 Clitoromegaly | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.14 [0.01, 2.59] | | 3.6.35 Appetite increase | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.09 [0.01, 1.54] | | 3.6.36 Fatigue/malaise | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.06, 0.61] | | 3.6.37 Dizziness | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.03, 2.06] | | 3.6.38 Nausea | 2 | 374 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.31, 0.80] | | 3.6.39 Breast pain | 1 | 307 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.05 [0.66, 38.91] | Comparison 4. GnRHas versus intra‐ uterine progestagen device. | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 4.1 Relief of painful symptoms | 3 | Std. Mean Difference (IV, Fixed, 95% CI) | Subtotals only | | | 4.1.1 Overall | 3 | 129 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.25 [‐0.60, 0.10] | | 4.2 rAFS/ASRM score | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | 9.50 [‐10.77, 29.77] | Comparison 5. GnRHa versus GnRHa (Varying Dosage). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 5.1 Side effects | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 5.1.1 Sleep disturbance Nafareline 200mcg versus 400mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.63, 1.59] | | 5.1.2 Rhinitis Nafareline 200mcg versus 400 mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.10, 1.67] | | 5.1.3 Upper respiratory tract infection Nafareline 200mcg versus 400 mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.03, 1.47] | | 5.1.4 Hot flushes/flashes Nafareline 200mcg versus 400 mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.51, 1.97] | | 5.2 rAFS score (400mcg vs 800mcg) | 1 | 143 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.17, 1.01] | | 5.3 relief of painful symptoms | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 5.3.1 Dsymenorrhoea Nafarelin 400mcg versus 800mcg | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.53, 1.66] | | 5.3.2 Dyspareunia | 1 | 57 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.79, 1.68] | | 5.3.3 Pelvic pain | 1 | 77 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.67, 1.74] | | 5.3.4 Overall Nafarelin 400mcg versus 800mcg | 1 | 143 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.78, 1.14] | | 5.3.5 Overall buserelin 300mcg vs 900 mcg | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.94, 2.35] | Comparison 6. GnRHa versus GnRHa (Length of Treatment). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 6.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up | 1 | Std. Mean Difference (IV, Fixed, 95% CI) | Subtotals only | | | 6.1.1 Dysmenorrhoea | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.02 [‐0.31, 0.27] | | 6.1.2 Dyspareunia | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.98 [‐1.29, ‐0.66] | | 6.1.3 Pelvic pain | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.15, 0.44] | | 6.1.4 Pelvic tenderness | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.14 [‐0.43, 0.15] | | 6.1.5 Pelvic induration | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.11 [‐0.40, 0.18] | Comparison 7. GnRHa versus GnRHa (Route of Administration). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 7.1 Side effects (IN vs SC) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 7.1.1 Hot flushes/flashes | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.48, 1.55] | | 7.1.2 Vaginal dryness | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.17, 4.37] | | 7.1.3 Decreased libido | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.07, 10.96] | | 7.1.4 Headaches | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.71 [0.20, 14.55] | | 7.2 rAFS score (IN vs SC) | 1 | 19 | Mean Difference (IV, Fixed, 95% CI) | 9.00 [‐5.93, 23.93] | | 7.3 Relief of painful symptoms (IN versus IMdepot) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 7.3.1 Dysmenorrhea | 1 | 192 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.82, 1.08] | | 7.3.2 Dyspareunia | 1 | 166 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.85, 1.43] | | 7.3.3 Pelvic pain | 1 | 192 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.78, 1.40] | | 7.3.4 Tenderness | 1 | 192 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.67, 1.09] | | 7.3.5 Induration | 1 | 190 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.78, 1.06] | | 7.4 Side effects (IN versus IMdepot) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 7.4.1 Hot flushes/flashes | 1 | 191 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.93, 1.01] | | 7.5 Improvement in symptoms (IN versus IMdepot) | 1 | 100 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.58, 3.30] | | 7.6 Relief of painful symptoms (IN versus SC) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | | | 7.6.1 Pelvic pain | 1 | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.53, 1.87] | | 7.6.2 Dyspareunia | 1 | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.57, 1.75] | | 7.6.3 Dysmenorrhoea | 1 | 10 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.73, 2.06] | | 7.6.4 Pelvic tenderness | 1 | 10 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.69, 3.27] | | 7.6.5 Pelvic induration | 1 | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.47, 1.55] | Characteristics of studies Characteristics of included studies [ordered by study ID] Acien 1989. | Study characteristics | || | Methods | Trial design: Randomised, multiple arm trial. | | | Participants | Participants: 54 randomised Inclusion criteria: aged 22 to 43 years, with laparoscopically confirmed endometriosis, 14 reguarly menstruating women and 11 post‐menopausal women no on HRT and with no history of post‐menopausal bleeding, endometrial or ovarian carcinoma were comparisons. Exclusion critieria: Setting: UK and Spain Timing: | | | Interventions | Danazol 600 mg per day for six months (n=20) versus Buserelin 400 mcg 8 hourly intranasally for six months (n=15) versus Zoladex depot 3.6 mg intramuscularly monthly for six months (n=19) | | | Outcomes | This trial did not report on any outcomes of interest for this review. Serum CA 125 levels | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "Randomised" no further details | | Allocation concealment (selection bias) | Unclear risk | No details on methods used to conceal allocation to study groups. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details of blinding of study personnel or participants | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 43/54 participants had 3 and 6 month blood samples. | | Selective reporting (reporting bias) | High risk | This paper states that all patients were part of randomised studies assessing the efficacy of Danazol, Buserelin, and Zoladex in the treatement of endometriosis but does not reference these trials. | Adamson 1994. | Study characteristics | || | Methods | Trial design: Prospective randomised double blind controlled study | | | Participants | Participants: 213 patients. 124 patients were randomised who reported pain symptoms Mean age: Inclusion: aged 18 to 48 years with laparoscopically confirmed pelvic endometriosis and dysmenorrhoea, dyspareunia or pelvic pain. Exclusion: no surgical procedures were performed during the diagnostic laparoscopy, no patient who had received hormonal treatment during the previous 6 months. Setting: Timing: | | | Interventions | Nafarelin acetate 400mcg bid IN + placebo PO or 6 months (n=45) versus Nafarelin acetate 200mcg bid IN + placebo PO for 6 months (n=45) versus Danazol 400mg bid PO + placebo IN for 6 months (n=34) | | | Outcomes | Pain: dysmenorrhoea, dyspareunia, pelvic pain. | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors responded to methods query | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Computerised randomisation | | Allocation concealment (selection bias) | Low risk | Centralised randomisation, sequentially numbered, sealed opaque envelopes | | Blinding (performance bias and detection bias) All outcomes | Low risk | All patients received placebo so patients and investigators were blinded | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All women randomised were analysed with intention to treat for main outcome | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Agarwal 1997. | Study characteristics | || | Methods | Trial design: "Multicentre, randomised, double‐blind, double‐placebo study" | | | Participants | Participants: 208 women were randomised, 192 were analysed Mean age: Nafarelin = 29.8 ± 0.6 and LA = 31.7 ± 0.6 (SEM) Inclusion criteria: Laparoscopically diagnosed endometriosis within 18 months prior to study19‐44 years old Patients demonstrating clinical symptoms and signs Bone mineral density within normal age range Exclusion criteria: Conditions or drug therapies that may interfere with the study Pregnant or lactating women Danazol use within 6 months prior to study GnRHa use within 12 months prior to study OCP within 30 days prior to study treatment Thyroid disease Setting: United States of America Timing: | | | Interventions | Nafarelin 200mcg BD IN + placebo every 4 weeks IM for 6 months (n=105) versus LA Depot 3.75mg every 4 weeks IM + placebo BD IN for 6 months (n=103) | | | Outcomes | Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | 'Randomisation using permuted blocks of random numbers' | | Allocation concealment (selection bias) | Unclear risk | No details were provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo nasal spray and injection, "Subjects remained blind regarding the study medication and assignment, and the study coordinator and investigator remained blind as to subject treatment status by having injections prepared and administered by a third party" | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Details for attrition: 24 women withdrew due to:ineffectiveness 3 (Naf) and 3 (LA), adverse effects 4 (Naf) and 8 (LA), lost to follow up 5 (LA), administrative reasons 1 (LA) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | AN Zoladex 1996. | Study characteristics | || | Methods | Trial design: 'Multicentre, open, randomised study' | | | Participants | Participants: 71 women were randomised, 48 were analysed Mean age: Goserelin = 29.5 and Danazol = 29.85 Stage: I to IV Inclusion criteria: Laparoscopically diagnosed endometriosis within 2 months prior to study 18‐40 years old rAFS score of equal or greater to 2 Normal menstrual cycle (21 ‐ 42 days) Normal cervical smear for previous 12 months Exclusion criteria: Pregnant or lactating women Other medical illnesses Hormone use within 2 months prior to study Danazol or GnRHa use within 12 months prior to study Hypersensitivity to trial drugs Showing signs of virilization Taking anticoagulant therapy Surgical treatment Setting: Australia and New Zealand Timing: Not stated | | | Interventions | Goserelin acetate 3.6mg every 4 weeks SC for 24 weeks (n=35) versus Danazol 200mg TDS PO for 24 weeks (n=36) | | | Outcomes | Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration rAFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "Patients were randomised in a 1 to 1 ratio". No further details of method used to generate the randomisation sequence are provided. | | Allocation concealment (selection bias) | Unclear risk | No details were provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | Open label trial as blinding of study personnel and participants would not have been possible due to nature of intervention. No details provided of blinding of outcome assessors. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | "Analysis was performed on both an 'intention to treat' basis and also on a 'patient treated' basis details given for attrition: 19 in Danazol and 4 in Goserelin group withdrew due to: Adverse effect 9 (Dan), Unwilling to continue 8 (Dan) and 4 (Gos), Withdrawn by investigator 1 (Dan), Other 1 (Dan) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Audebert 1997. | Study characteristics | || | Methods | Trial design: Open, multi‐centre, central randomised study | | | Participants | Participants: 120 eligible women; 71 were randomised; 55 were analysed Mean age: 31 ± 5.9 years Stage: I ‐ IV Inclusion criteria: Laparoscopically diagnosed endometriosis Symptomatic Recurrence of endometriosis after surgery Over 18 years old No other hormone therapy except insulin Exclusion criteria: Amenorrhoea Patient having had hysterectomy Pregnant women Serious illness e.g. liver disease Setting: France Timing: | | | Interventions | Leuprorelin 3.75mg SC depot every 28 days for 24 weeks (n=33) versus Danazol 600‐800mg PO daily for 24 weeks (n=22) | | | Outcomes | Pain: dysmenorrhoea, dyspareunia, pelvic pain, induration and pelvic tenderness rAFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Cannot use data unless mean and SD specified; author contacted. Author replied that study was sponsored by a pharmaceutical company who hold the raw data. He is attempting to locate a contact for further information. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Central randomisation" | | Allocation concealment (selection bias) | Low risk | "Central randomisation" | | Blinding (performance bias and detection bias) All outcomes | High risk | Open study as blinding would not have been possible due to nature of intervention. No mention of blinding of outcome assessors. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Sufficient reporting of attrition:Refuse 2nd laparoscopy n=1 (L) Lost to follow up n=2 (L) n=9 (D) Progression of disease n=2 (D) Not meeting protocol n=1 (D) Other n=1 (D) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Bergquist 1990. | Study characteristics | || | Methods | Trial design: | | | Participants | Participants: Mean age: Inclusion criteria: Exclusion criteria: Setting: Timing: | | | Interventions | Intervention: Comparison: | | | Outcomes | || | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: | Bergqvist 1997. | Study characteristics | || | Methods | Trial design: "Double‐blind randomised study" | | | Participants | Participants: 49 eligible women; 49 were randomised and 47 were analysed Mean age: mean age not stated, median age 30 years (range 21‐46years) Inclusion criteria: Laparoscopically diagnosed endometriosis Not to use any hormonal preparations during study No hormone treatment in previous 3 months No GnRHas for previous 12 months No steroid therapy for previous 12 months Exclusion criteria: Setting: Europe Timing: not stated | | | Interventions | Nafarelin 200mcg daily IN + placebo PO for 6 months (n=12) versus Nafarelin 400mcg daily IN + placebo PO for 6 months (n=12) versus Nafarelin 200mcg daily IN + norethisterone 1.2mg daily PO for 6 months (n=25) | | | Outcomes | Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration Adverse effects AFS score | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Need raw data for symptom scores. Authors contacted regarding methods and data. No response to date. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | 1:1:2 Naf200:Naf400:Naf200+Norethisterone "randomisation was carried out on a block basis" | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Participants and study personnel were blinded to treatment through the use of a placebo | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Two participants from the Naf+Norethisterone group withdrew from the trial due to mood swings (1 participant) and pregnancy (1 participant), | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Bergqvist 1998. | Study characteristics | || | Methods | Trial design: "Prospective, randomised, placebo‐controlled, double‐blind, parallel study" | | | Participants | Participants: 49 women eligible; 49 were randomised and 46 were analysed Age: mean of 31 years (19‐44years) Stage: most mild to moderate (IV n=1) Inclusion criteria: Menstruating regularly 3 months before study Clinical symptoms of endometriosis Not taken oral contraceptive or oral steroid therapy for 3 months Not taken long acting depot gestagens or GnRHas within past 6 months Not pregnant in prior 3 months Not breastfeeding No history of osteoporosis or coagulation disorders Exclusion criteria: Intraperitoneal adhesions making visual inspection and careful evaluation of the extension of endometriotic lesions difficult or impossible Setting: Sweden Timing: | | | Interventions | Triptorelin 3.75mg IM depot every 4 weeks for 24 weeks (n=24) versus Placebo IM every 4 weeks for 24 weeks (n=25) | | | Outcomes | Pain Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Needs raw score for pain. Authors contacted and awaiting response. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details were provided of method used to generate the randomisation sequence. | | Allocation concealment (selection bias) | Unclear risk | No details were provided of method used to conceal treatment group allocation. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Participants and researchers were blinded through the use of identical kits for injections. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Three participants withdrew from the study. Two from the placebo group (1 prior to the first injection due to pregnancy, and one after 4 months due to lack of effect), and one from the Triptorelin group due to hypoestrogenic side effects and depression. | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Burry 1989. | Study characteristics | || | Methods | Trial design: | | | Participants | Participants: Mean age: Inclusion criteria: Exclusion criteria: Setting: Timing: | | | Interventions | Intervention: Comparison: | | | Outcomes | || | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: | Burry 1992. | Study characteristics | || | Methods | Trial design: "Multi‐centre, double‐blind study" | | | Participants | Participants: 169 women eligible; 169 were randomised and 147 analysed for efficacy Mean age: Inclusion criteria: Laparoscopically diagnosed endometriosis Exclusion criteria: Setting: USA Timing: | | | Interventions | Nafarelin 400mcg daily IN for 6 months (n=111) versus Danazol 600mg daily PO for 6 months (n=58) | | | Outcomes | Symptoms Change in laparoscopic scores Adverse effects Quality of life score | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Need more info on randomisation and participants and raw data for quality of life. Authors contacted, awaiting response. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | 2:1 Nafarelin: Danazol | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | "double‐blind" | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Sufficient details for attrition:Side effects n=6 (N) n=3 (D) Elevated liver enzyme n=1 (D) Administrative reasons n=12 | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Calvo 2000. | Study characteristics | || | Methods | Trial design: Randomised, no further detail. | | | Participants | Participants: 15 participants with laparoscopically diagnosed endometriosis Mean age: Inclusion criteria: Exclusions criteria: Setting: Mexico Timing: | | | Interventions | Goserelin acetate 3.6 mg every 21 days (n=8) average age 29 years Nafarelin acetate 200 or 400 mcg 12 hourly for six months (n=7) average age 30.4 years | | | Outcomes | Serum levels of follicle stimulating hormone, luteinising hormone, estradiol and prolactin. | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Article in Spanish. Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details provided of method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment group | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details provided of blinding of participants or personnel. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No losses to follow up. | | Selective reporting (reporting bias) | Unclear risk | Insufficient information to enable a judgement of low risk of bias. | Chang 1996. | Study characteristics | || | Methods | Trial design: "Randomised comparative study" | | | Participants | Participants: 45 women eligible; 45 were randomised and 33 were analysed Mean age: 33 years (LA) Stage: I to IV Inclusion criteria: Laparoscopic diagnosis of endometriosis Pain symptoms Exclusion criteria: Setting: Taiwan Timing: | | | Interventions | Leuprorelin acetate 3.75mg SC depot every 28days for 20 weeks (n=30) versus Danazol 200mg QID (800mg/day) PO for 20 weeks (n=15) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain Change in AFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Need raw data for pain. Authors contacted, and additional methodological data provided, no raw data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Randomisation was in the ratio two LA to one danazol with this study having its randomisation list" | | Allocation concealment (selection bias) | Unclear risk | "sequentially numbered, identical containers of identical drugs" | | Blinding (performance bias and detection bias) All outcomes | Low risk | Outcome assessors were blinded to treatment group | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No details were provided on attrition | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Cheng 2005. | Study characteristics | || | Methods | Trial design: "Randomised, parallel, comparative study" | | | Participants | Participants: 59 women eligible; 59 were randomised and 41 were analysed for efficacy Mean age: 34.8 ± 6.6 (N) and 32.4± 7.2 (D) Inclusion criteria: Laparoscopically diagnosed within 3 months prior to study Age 18‐48 years Barrier contraception Exclusion criteria: Pregnancy Breastfeeding Menopause or post‐menopausal Use of oestrogen, progesterone or contraceptive steroids in previous 3 months Impaired hepatic or renal function Cardiovascular disease AIDS or other sexually transmitted diseases Setting: Taiwan Timing: | | | Interventions | Nafarelin acetate 200mcg BD (400mcg/day) IN for 180 days (n=29) versus Danazol 200mg TID (600mg/day) PO for 180 days (n=30) | | | Outcomes | Total symptom severity score and physician assessed pelvic tenderness Change in laparoscopic score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors provided additional data on methods | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Randomisation done by a pharmacy | | Allocation concealment (selection bias) | Low risk | Sealed, opaque, sequentially numbered, identical envelopes | | Blinding (performance bias and detection bias) All outcomes | Low risk | Investigators, outcome assessors and clinicians were blinded according to author | | Incomplete outcome data (attrition bias) All outcomes | Low risk | "All 59 patients were considered as the intent‐to‐treat population"4 withdrawals due to: Three patients (3/4) underwent Herb drug treatment, withdrawals All patients (4/4) were anxious with side effects, including significant weight gain, acne vagaries, and severe menopausal syndrome. One patient went abroad after randomisation | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Choktanasiri 2001. | Study characteristics | || | Methods | Trial design: Parallel arm, randomised controllled trial | | | Participants | Participants: 14 women eligible Age: Group 1 29.3 ±6.1, Group 2 28.9 ±1.7 Inclusion: Women with laparoscopically confirmed endometriosis Severe dysmenorrhea with or without deep dysparunia and pelvic pain Exclusion: Prior hormonal treatment Planning to conceive in the next one to two years Setting: Thailand Timing: | | | Interventions | Buserelin acetate 6.6 mg implants injected subcutaneously in the lateral region of the anterior abdominal wall: Group 1: every 8 weeks for 3 doses (n=7) Group 2: every 12 weeks for 2 doses (n=7) | | | Outcomes | Serum estradiol, bone mineral density | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Insufficient information provided to enable a judgement of low risk. | | Allocation concealment (selection bias) | Unclear risk | Insufficient information provided to enable a judegment of low risk. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details provided of blinding of participants or personnel. | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No losses to follow up. | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes are reported on. | Cirkel 1995. | Study characteristics | || | Methods | Trial design: "controlled comparative clinical study" | | | Participants | Participants: 60 women eligible; 60 were randomised and 55 were analysed Mean age: 30± 0.5 (T) and 30± 0.8 (D) Stage: II to IV Inclusion criteria: Laparoscopically diagnosed endometriosis No medication affecting pituitary or ovarian function in preceding 6 months Exclusion criteria: Stage I endometriosis Setting: Germany Timing: | | | Interventions | Triptorelin 3.75mg IM depot every 28 days for 24 weeks (n=30) versus Danazol 200mg TDS (600mg/day) PO for 24 weeks (n=25) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration Adverse effects Change in AFS score | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted and awaiting response regarding methods. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Computer generated randomisation list | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Sufficient detail for attrition:Refused to fulfil protocol n=3 (D) Pregnancy n=2 (D) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Claesson 1989. | Study characteristics | || | Methods | Trial design: "Ongoing, Phase III, multi‐centre, double‐blind, double‐dummy study" | | | Participants | Participants: 24 women were randomised, 23 were analysed Mean age: 33.9 (N) and 32.6 (D) Inclusion criteria: Exclusion criteria: Setting: Sweden Timing | | | Interventions | Nafarelin 400mcg daily IN for 6 months (n=16) versus Danazol 600mg daily PO for 6 months (n=8) | | | Outcomes | Pain, dysmenorrhoea, dyspareunia Changes in AFS score | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted with regards to methods and raw data. Awaiting response. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details, "double blind, double dummy" | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Sufficient data on attrition:Intercurrent lower back pain n=1 (N) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Crosignani 1996. | Study characteristics | || | Methods | Trial design: Parallel arm, randomised controlled trial | | | Participants | Participants: 30 women randomised (Group 1 ‐ three monthly leuprolide n = 15, Grou p2 ‐ monthly leuprolide n = 15) 27 women analysed (Group 1 ‐ three monthly leuprolide n = 14, Group 2 ‐ monthly leuprolde n = 13) Mean age: Group 1: 28.6 ± 6.0, Group 2: 31.0 ± 5.2 Inclusion: Premenopausal women (FSH < 30 mIU/ml), aged 18‐38, symptomatic endometriosis at stage I ‐ IV of the revised American Fertility Society (rAFS) classification, diagnosed at laparoscopy. Exclusion: any major disease Setting: Univeristy clinics in Milan, Genoa, Rome, Italy. Timing: timing of recruitment not stated. | | | Interventions | Intervention: Leuprolide acetate 11.25 mg intramuscularly every 84 days (group 1) for 6 months Comparison: Leuprolide acetate 3.75 mg every 28 days (group 2) for 6 months. | | | Outcomes | Pain symptoms according to Biberoglu and Behrman varbal rating scale, rAFS score, bone mineral density, acceptability of treatment schedule. | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Was previously excluded for pain not being an outcome but ????should be included as pain score is an outcome | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Eligible subjects were randomised according to a computer generated sequence | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | "open label trial" | | Incomplete outcome data (attrition bias) All outcomes | Low risk | One woman from group 1 (three monthly) withdrew from study as she did not want to undergo repeated venipunctures and laparoscopy. Two women in group 2 (monthly) stopped treatment due to a desire to conceive. | | Selective reporting (reporting bias) | Low risk | All prespecified outcome are reported on. | Dawood 1990. | Study characteristics | || | Methods | Trial design: Multi‐centre, open, randomised study | | | Participants | Participants: 355 women eligible and 310 were analysed Mean age: Inclusion criteria: Age 20‐40 years old Laparascopically diagnosed endometriosis within 6 weeks of study entry Exclusion criteria: Danazol treatment in last 6 months Oral contraceptives in last 2 months Drugs releasing IUD in last 3 months Any other investigational drug in 4 weeks Conditions for which danazol is contraindicated Setting: USA Timing: Not stated | | | Interventions | Buserelin 400mcg TDS (1200mcg/day) IN for 6 months (n=149) versus Buserelin 200mcg daily SC for 6 months (n=60) versus Danazol 400‐800mg daily PO for 6 months (n=101) | | | Outcomes | Intermenstrual pelvic pain, dyspareunia, pelvic tenderness and induration Changes in rAFS score Adversse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and raw data for pain. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "assigned to... treatment groups according to a randomisation schedule" 2:1 Buserelin: Danazol. No other details are provided of method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | High risk | Open study | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No details on attrition | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Dlugi 1990. | Study characteristics | || | Methods | Trial design: "Phase III, randomised, double‐blind, multi‐centre study" | | | Participants | Participants: 63 women eligible; 63 were randomised and 52 were analysed Mean age: 30 years Stage: I to IV Inclusion criteria: Laparoscopically diagnosed endometriosis within 3 months of study entry Pain secondary to endometriosis Over 18 years old No previous treatment with leuprolide acetate or other GnRHas At least one ovary intact Non pregnant Non lactating No treatment for endometriosis within 3 months of study entry Exclusion criteria: Setting: USA Timing: Not stated. | | | Interventions | Leuprolide acetate 3.75mg IM depot every 4 weeks for 20 weeks (n=32) versus Placebo (diluent) 2ml IM every 4 weeks for 20 weeks (n=31) | | | Outcomes | Dysmenorrhoea, pelvic pain, dyspareunia, pelvic tenderness, induration | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted for details on allocation concealment and SEMs. Letter returned to sender, author moved with no forwarding address. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "Patients were assigned a 3 digit patient number in sequential order from those numbers allocated to each investigator. The patient number encoded the random assignment to a treatment group" | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Patients and investigators were blinded | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Sufficient details for attrition: 7 withdrawn as subsequently determined they had failed to meet entry requirements, 4 excluded because they had received less than 3 injections of the study drug. There were partial exclusions for efficacy data due to non‐compliance with intended study procedures and dosing regimens for 15 patients (7=Leuprolide and 8=placebo). 27 placebo (24 terminated because of worsened symptoms, 1 because of salpingitis, 1 became pregnant and 1 was non‐compliant) and 3 (2 because of intolerable pain and 1 because of an adverse event) leuprolide patients prematurely terminated study. | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Dmowski 1989a. | Study characteristics | || | Methods | Trial design: "Open‐label, randomised, prospective study" | | | Participants | Participants: 36 women eligible, 36 were randomised and 29 were analysed Mean age: 30.8 ± 0.6 (SE) Inclusion Criteria: Laparoscopically diagnosed endometriosis, no hormonal treatment 8 months prior to study entry Exclusion criteria: not stated Setting: USA Timing: Not stated. | | | Interventions | Buserelin 400mcg TDS (1200mcg/day) IN for 6 months (n=10) versus Buserelin 200mcg daily SC for 6 months (n=9) versus Danazol 200mg QDS (800mg/day) PO for 6 months (n=10) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain Change in rAFS scores Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding allocation concealment | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details were provided of the method used to generate the randomisation sequence. 2:1 Buserelin: Danazol "Those who were randomised into Buserelin were given an option of SC injections or IN sprays of the drug" | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal the allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | High risk | "open label" | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Detail for attrition: 3 in SC Buserelin, 2 in IN Buserelin and 2 in Danazol group. 2 withdrew for family reasons, 3 were non‐compliant, 1 had sever emotional side effects on IN Buserelin and 1 was allergic to Danazol. | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Donnez 1989. | Study characteristics | || | Methods | Trial design: Prospective, parallel, randomised controlled trial. | | | Participants | Participants: 100 women randomised (50 per group). All women randomised appear to have been analysed, Mean age: Group 1: 27.3 ± 4.4, Group 2: 28.2 ± 5.2 Inclusion: Exclusion: Setting: Belgium Timing: January 1985 ‐ December 1987 | | | Interventions | Intervention: Intranasal Buserelin spray 300 μg three times a day for 6 months (n = 50). Comparison: Biodegradable implant containing 6.6 mg Buserelin injected subsutaneously at 0, 6 and 12 weeks (n = 50). | | | Outcomes | Change in AFS scores between start and end of treatment. | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | States "randomized" with no further information of method used to generate the randomisation sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | Blinding of participants and personnel was not possible due to nature of intervention and comparison. Pre and post treatment assessment was carried out by the same observer, however no details are provided as to whether the observer was blinded to treatment group. | el‐Roeiy 1988. | Study characteristics | || | Methods | Trial design: Prospective, open label randomised controlled trial. | | | Participants | Participants: 20 women were randomised and analysed (10 per treatment group. There was also a control group of 250 'normal' women) Mean age: GnRA Group: 31.0 ± 1.1. Danazol Group: 30.7 ± 1.5, Control Group: 31.0 ± 1.0 Inclusion: Laparoscopically diagnosed and staged endometriosis. Exclusion: History and/or symptoms of autoimmune disease, acute or chronic infection, malignancy, or drug abuse, Setting: Chicago, IL, USA Timing: Not stated | | | Interventions | Intervention: GnRA Group (n=10): Four participants received Buserelin intranasally 0.4 mg three times a day, four received Buserelin subcutaneously 0.2 mg daily, and two received Leuprolide intranasally 1.6 mg daily for 6 months. Danazol Group (n=10): Danazol 200 mg four times a day | | | Outcomes | Autoantibody production, clinical outcome | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "Patient assignment was at random". No further details provided of method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | Method used to conceal allocation to treatment groups not provided. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | Open label trial. All serum collections were coded and stored at a laboratory until tested simultaneously after all data had been reported. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No losses to follow up reported. | | Selective reporting (reporting bias) | Low risk | Prespecified outcomes are reported on. | Fedele 1989. | Study characteristics | || | Methods | Trial design: Randomised controlled study | | | Participants | Participants: 62 women were randomised and analysed Mean age: Buserelin = 29.8 ± 3.3 and Danazol 31.3 ± 4.3 Inclusion criteria: Laparoscopically diagnosed endometriosis within 3 months prior to study No therapeutic intervention Exclusion criteria: Bilateral tube occlusion or partner with severe dyspermia Danazol or other sex hormone use within 6 months prior to study Systemic or endocrine disease Setting: Italy Timing: | | | Interventions | Buserelin 400mcg TDS IN for 6 months (n=30) versus Danazol 200mg TDS PO for 6 months (n=32) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain rAFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted for information on raw data for pain scores, and methods. No response to date | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Detail for attrition:1 subject from Buserelin group withdrew due to severe pelvic pain | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Fedele 1993. | Study characteristics | || | Methods | Trial design: Multicentre, randomised controlled study | | | Participants | Participants: 35 women eligible, 35 were randomised, 35 were analysed Mean age: not stated Inclusion criteria: Laparoscopically diagnosed stage I or II endometriosis One or more of dysmenorrhoea, pelvic pain and deep dyspareunia Exclusion criteria: Setting: Italy Timing: not stated. | | | Interventions | Buserelin acetate 1200 mcg daily IN for 6 months (n=19) versus Expectant management (n=16) Treatment group followed up for 18 months and expectant management group for 12 months | | | Outcomes | Dysmenorrhoea, pelvic pain and deep dyspareunia Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methodology and data. Still awaiting response. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details provided of method used to generate randomisation sequence., | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | High risk | Blinding was not possible due to the nature of the intervention (Buserelin acetate versus expectant management (no treatment) ) | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All women who were randomised were analysed | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Ferreira 2010. | Study characteristics | || | Methods | Trial design: Randomised, prospective open labelled study | | | Participants | Participants: 44 women with endometriosis (confirmed laparoscopically/histologically), consecutively selected at the pain and endoscopy out‐patient clinic. Mean age: 28.8 ±4.9 years for LNG‐IUS and 41.4±5.8 years for GnRHa Inclusion criteria: 18‐40 years of age chronic pelvic pain. No use of oral hormone contraceptives for at least 3 months or with depot progestogens or GnRHa for at least 6 months prior to randomisation. Exclusion: obese patients (BMI >30kg/m2), smokers, diabetics, alcohol or drug users, patients wishing to conceive, those with chronic disease, acute and/or chronic inflammatory and/or infectious processes, family history of thromboembolic events, taking medications known to interfere with inflammation markers for a period of less than 15 days before the study. Setting: Brazil Timing: not stated. | | | Interventions | LNG‐IUS (n=22) versus GnRHa (n=22) 3.75mg leuprolide i.m. monthly treatment for 6 months | | | Outcomes | BMI, SAP, DAP, HR, pain score (VAS), inflammatory markers | | | Notes | No ITT analysis Intention‐to‐treat analysis: Sample size calculation: Funding: | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | 'Randomised by computer programme' | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | High risk | Open labelled. Blinding not possible due to nature of invtervention and comparison. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | GnRHa (1 pregnancy before drug administered and 3 moved and lost to follow‐up) | | Selective reporting (reporting bias) | Low risk | All a priori outcomes discussed | Franssen 1992. | Study characteristics | || | Methods | Trial design: | | | Participants | Participants: Mean age: Inclusion criteria: Exclusion critieria: Setting: Timing: | | | Interventions | Intervention: Comparison | | | Outcomes | || | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: This manscript appears to be a secondary analysis of two trials cited in it ??? to check Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | Fraser 1991. | Study characteristics | || | Methods | Trial design: "Double‐blind, double‐dummy, randomised, parallel study" | | | Participants | Participants: 49 women were randomised and 45 were analysed Mean age: Stage: I to III Inclusion criteria: Laparoscopically diagnosed endometriosis Symptomatic Regular menstrual cycle 24‐36 days Not pregnant Negative pap smear Barrier contraception Exclusion criteria: Concurrent disease which may interfere with drug Surgical therapy within 6 months prior to study entry Steroid therapy within 3 months prior to study entry Setting: Australia / New Zealand Timing: not stated. | | | Interventions | Nafarelin 200mcg BDS (400mcg/d) IN + placebo PO for 6 months (n=33) versus Danazol 200mg TDS (600mg/d) PO + placebo IN for 6 months (n=16) | | | Outcomes | Dyspareunia, pelvic pain, pelvic tenderness, induration Change in rAFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted with regards to allocation concealment. Author replied that the data was difficult to find but would try | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Computer generated list of random numbers" | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo pill + placebo nasal spray so patient and investigators blinded | | Incomplete outcome data (attrition bias) All outcomes | Low risk | 3 participants "dropped out" of intranasal nafarelin group, no "drop outs" from Danazol group. | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Gomes 2007. | Study characteristics | || | Methods | Trial design: "randomised, controlled clinical study" | | | Participants | Participants: 22 women were randomised, 18 were analysed Mean age: LNG‐IUS = 29.2 +/‐ 5.5 and Lupron = 32.6 +/‐ 5.3 Inclusion criteria: Laparoscopically diagnosed endometriosis made 3 months before enrolment in the study Chronic pelvic pain that was cyclic VAS of 3 or more Regular menstrual cycle (25‐35 days) for 3 months or more before study entry Had not used any hormonal therapy for at least 3 months before study entry Had not taken long acting progestins or GnRHas within the preceding 9 months Not pregnant or breastfeeding during the 3 months preceding study No osteoporosis, coagulation disorders or contraindications to LNG‐IUS Exclusion criteria: Use of medication outside study Setting: Brazil Timing: | | | Interventions | LNG‐IUS IU for 6 months (n=11) versus Lupron Depot 3.75mg IM every 4 weeks for 6 months (n=11) | | | Outcomes | Pain as defined by VAS Change in laparoscopic outcome as defined by ASRM | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Computer generated system" | | Allocation concealment (selection bias) | Low risk | "Sealed envelopes" | | Blinding (performance bias and detection bias) All outcomes | High risk | Different route of administration of intervention | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Detail given for attrition:4 withdrawals due to refusal of second laparoscopy | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Henzl 1988. | Study characteristics | || | Methods | Trial design: "parallel, randomised, double‐placebo design" | | | Participants | Participants: 236 women were randomised, 213 analysed Age: most 30‐40 Stage: 45% had III and IV Inclusion criteria: 18‐45 years old. Laparoscopically diagnosed endometriosis within 3 months prior to study enrolment. No hormonal treatment for endometriosis 6 months prior to study. Exclusion critieria: Setting: USA, Canada, Sweden Timing: not stated | | | Interventions | Nafarelin IN 200mcg BD + placebo PO for 6 months (n=77) versus Nafarelin IN 400mcg BD + placebo PO for 6 months (n=79) versus Danazol PO 400mg BD + placebo IN for 6 months (n=80) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration AFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding randomisation and allocation concealment | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details provided of method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo nasal sprays and tablets to blind patients and researchers, "both the patients and the investigators were thus blinded regarding the medication" | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Detail given for attrition: 9 for reasons not related to the study drugs 7 in 800mcg Nafarelin and 4 in Danazol due to hot flushes 2 in Danazol due to rapid rise in serum enzymes 1 in Danazol because of a lack of efficacy | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Henzl 1990a. | Study characteristics | || | Methods | Trial design: Randomised study | | | Participants | Participants: 194 women were randomised, 167 were analysed Mean age: Stage: 41% had stage III or IV Inclusion criteria: Laparoscopically diagnosed endometriosis Exclusion criteria: Setting: Europe (not further defined) Timing: not stated | | | Interventions | Nafarelin 200mcg BD IN (n=104) for 6 months versus Danazol 200mgs TDS PO (n=63) for 6 months | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration rAFS score | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted with regards to methodology and raw scores for pain. No response to date | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No details | | Selective reporting (reporting bias) | Low risk | A priori outcomes presented | Hornstein 1995. | Study characteristics | || | Methods | Trial design: "double‐blind, prospective, multi centre, randomised clinical trial" | | | Participants | Participants: 179 women were randomised and analysed Mean age: 3 monthgroup = 31.0 +/‐ 6.1 and 6 month group = 31.3 +/‐ 5.7 (SEM) Stage: I to IV Inclusion criteria: 18‐46 years old Laparoscopically diagnosed endometriosis within 24 months prior to study enrolment 24‐36 day menstrual cycle Symptomatic endometriosis Exclusion criteria: Hormone treatment 3 months prior to study Significant illness or lab test abnormality Prior treatment with Nafarelin Pregnant or lactating women Setting: USA Timing: not stated. | | | Interventions | Nafarelin 200mcg BD IN for 3 months + placebo IN for 3 months after (n=91) versus Nafarelin 200mcg BD IN for 6 months (n=88) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted and replied | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details provided of method used to generate random sequence. | | Allocation concealment (selection bias) | Low risk | 'randomisation was done by a pharmacy' | | Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo nasal spray to blind participants; participants, investigators, outcome assessors and clinicians were blinded | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants who were randomised were analysed | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Jelley 1986. | Study characteristics | || | Methods | Trial design: "Open, prospective, randomised, parallel study", multi centre | | | Participants | Participants: 80 women were randomised, 68 were analysed Median age: Buserelin = 28 and Danazol = 30 (? range) Inclusion criteria: Laparoscopically diagnosed endometriosis 18 ‐ 40 years old Symptomatic disease Active menstrual cycle Exclusion criteria: Previous use of danazol or hormone treatment without success Use of danazol within 6 months prior to study Serious endocrine disease or use of other drugs which may interfere with therapy Setting: UK Timing: | | | Interventions | Buserelin 300mcg TDS IN for 7 months (n=34) versus Danazol 600mg OD PO for 7 months (n=34) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration rAFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Preliminary findings for the first 68 women treated only Attempted to contact author regarding data. Author not contactable | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "The code was derived from random number tables" | | Allocation concealment (selection bias) | Low risk | "A sealed envelope was provided for each patient, and opened only after the patient's name had been entered on it" | | Blinding (performance bias and detection bias) All outcomes | High risk | Open study | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Detail for attrition:1 randomised patient failed to start treatment as her symptoms improved So far 4 have withdrawn from study due to adverse effects: 3 (Dan) and 1 (Bus) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Lemay 1988. | Study characteristics | || | Methods | Trial design: Randomised study | | | Participants | Participants: 13 women were randomised and analysed Age: 24 ‐ 37 Inclusion criteria: Laparoscopially diagnosed endometriosis within 6 weeks of study Not received medical treatment in the previous 6 months Exclusion criteria: Surgery alone or hormonal treatment and surgery were indicated Concurrent serious endocrine or systemic disease History of alcohol or substance abuse Use of an oral contraceptive within the past 2 months Drug‐releasing intrauterine device within the past 3 month Setting: Canada Timing: | | | Interventions | Buserelin 400mcg TDS IN for 6 ‐ 9 months (n=7) versus Buserelin 200mcg OD SC injection for 6 ‐ 9 months (n=6) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration AFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Author contacted regarding methods and replied | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Computerised allocation | | Allocation concealment (selection bias) | Low risk | Sealed, opaque, sequentially numbered, identical envelopes | | Blinding (performance bias and detection bias) All outcomes | High risk | Only outcome assessors were blinded | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants who were randomised were analysed | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Maouris 1991. | Study characteristics | || | Methods | Trial design: randomised controlled trial | | | Participants | Participants: 30 women randomised, Mean age: 31 years Inclusion criteria: laparoscopically diagnosed endometriosis Exclusion criteria: not stated Setting: London, UK Timing: not stated | | | Interventions | Intervention: Danazol 200 mg orally three times a day (total dose of 600 mg daily) for six months. Comparison: Goserelin 3.6 mg monthly subcutaneously for six months. | | | Outcomes | Serum hormone concentrations | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details provided of the method used to generate the random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of the method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details of blinding, but unlikely due to nature of intervention and comparison. | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No details are provided on attrition. All women randomised appear to have been analysed. | | Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes are reported on. | Matalliotakis 2000. | Study characteristics | || | Methods | Trial design: double blind randomised controlled trial | | | Participants | Participants: 20 women with endometriosis were randomised, 10 women without endometriosis were controls. Mean age: women with endometriosis 28.6 ± 5.4 years, women without endometriosis 28.1 ± 5.1 years. Stage I ‐ 7 participants, Stage II ‐ 4 participants, Stage III ‐ 5 participants, Stage IV ‐ 4 participants. Inclusion criteria: Laparoscopically diagnosed endometriosis. Exclusion criteria: Setting: Greece Timing: 1993 ‐ 1998 | | | Interventions | Intervention: Danazol 200 mg orally three times a day (total dose of 600 mg daily) for six months (n=10). Comparison: Leuprolide acetate depot IM 3.75 mg every 28 days for six months (n=10). | | | Outcomes | Serum soluble CD23 concentrations. | | | Notes | Intention‐to‐treat analysis: Sample size calculation: The sample size of 10 per group was chosen arbitrarily Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Computerized random‐number generator" used to generate randomisation sequence. | | Allocation concealment (selection bias) | Low risk | Concealment of allocation to treatment group was achieved by the use of "sealed, numbered, opaque envelopes" | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | States this trial is double masked, but no details are provided of who was blinded and how. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants randomised were analysed. | | Selective reporting (reporting bias) | Low risk | The prespecificed outcome of serum soluble CD23 concentrations was reported on. | Matta 1988. | Study characteristics | || | Methods | Trial design: Randomised, open label, comparative study | | | Participants | Participants: 61 women were randomised, 56 were analysed Age: 21‐40 Stage: "varying degrees" Inclusion criteria: Laparoscopically diagnosed endometriosis within 6 weeks prior to study Exclusion criteria: Use of Danazol within past 6 months Use of other sex steroid within past 3 months Primary surgery indicated Serious systemic disease Setting: UK Timing: not stated | | | Interventions | Buserelin 400mcg TDS IN for 6 months (n=41) versus Danazol 400‐800mg OD PO for 6 months (n=20) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain AFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Study funded by research grant from Hoechst‐Roussel US Authors contacted regarding methods, and replied This manuscript presents provisional data on an incomplete study. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | 2:1 Buserelin: Danazol, "Recruited patients were randomised by an open‐label method" | | Allocation concealment (selection bias) | Low risk | "centralised randomisation process" "sealed opaque sequentially numbered envelopes | | Blinding (performance bias and detection bias) All outcomes | High risk | Open label | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Details given for attrition:4 excluded due to failure to attend follow up 1 declined a second look laparoscopy | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Miller 1990. | Study characteristics | || | Methods | Trial design: "randomised, double‐blind" study | | | Participants | Participants: No details of numbers of participants Inclusion criteria: Laparoscopically diagnosed endometriosis Experiences significant pain No treatment of endometriosis within 3 months prior to study Exclusion criteria: Setting: USA Timing: | | | Interventions | Lupron depot 3.75mg IM every 4 weeks for 24 weeks versus Placebo IM every 4 weeks for 24 weeks | | | Outcomes | Pain Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Study mentioned in paper referring to two studies Authors contacted regarding methods and data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details provided of method used to generate the random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | Low risk | "double‐blind", placebo injection used to blind participant | | Incomplete outcome data (attrition bias) All outcomes | High risk | No details are provided of number of participants. | | Selective reporting (reporting bias) | Low risk | Prespecified outcomes discussed | Miller 2000. | Study characteristics | || | Methods | Trial design: "prospective, randomised, double‐blind, parallel, placebo‐controlled study" | | | Participants | Participants: 120 women were randomised, 120 were analysed Age: 18‐40 Inclusion criteria: Laparoscopically diagnosed endometriosis within 24 months prior to study Elected to have leuprolide acetate as a treatment option Sexually active Not pregnant or breastfeeding Intact uterus and at least one ovary in good health Not received treatment for endometriosis within previous 3 months Not received medroxyprogesterone acetate within previous 6 months No history of use of a GnRHa Exclusion criteria: coexisting conditions that might interfere with the conduct or analysis of study concomitant disease that might cause pain contraindication to leuprolide Unable to complete questionnaires suspected history of alcohol or drug abuse Setting: USA Timing: not stated | | | Interventions | Leuprolide acetate 3.75mg single IM for 4 weeks (n=60) versus Placebo for 4 weeks (n=60) | | | Outcomes | Pain as defined by VAS and ESSS Quality of Life SF36 | | | Notes | Intention‐to‐treat analysis: All participants recruited are analysed. Sample size calculation: not stated. Funding: not stated. Authors contacted regarding methods and raw data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "assigned to groups in the order in which they were enrolled according to a computer generated schedule prepared before the start of the study" | | Allocation concealment (selection bias) | Unclear risk | No details were provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | States double‐blind. A placebo injection was used to blind participants, but no other details of blinding of trial personnel or outcome assessors is provided. . | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants completed the trial with no attrition. | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Minaguchi 1986. | Study characteristics | || | Methods | Trial design: Multicentre study | | | Participants | Participants: 191 women were randomised and analysed Stage: II to IV Mean age: Inclusion criteria: Laparoscopically diagnosed endometriosis Over 18 years old Patients who have received hormonal therapy Patients with persistent diagnosed endometriosis post‐operatively Exclusion criteria: Patients receiving conservative surgery Setting: Japan Timing: | | | Interventions | Buserelin 300mcg OD IN for 6 months (n=69) versus Buserelin 300mcg BD IN for 6 months (n=59) versus Buserelin 300mcg TDS IN for 6 months (n=63) | | | Outcomes | Intermenstrual abdominal pain, lumbago, dyspareunia, pain on defecation, pelvic tenderness, flexibility of the uterus, nodules in the posterior cul‐de‐sac, endometrial cyst Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | "envelope" | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All women who were randomised were analysed | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | NEET 1992. | Study characteristics | || | Methods | Trial design: Multicentre, parallel, randomised, double‐blind, double‐dummy study | | | Participants | Participants: 315 women were randomised, 307 were analysed for safety and 263 were analysed for efficacy Mean age:not stated Inclusion criteria: Laparoscopically diagnosed endometriosis 18‐45 years old Not pregnant Pap smear negative for malignancy Normal menstrual cycle 21‐36 days for previous 4 months Weight between 45‐110 kg Exclusion criteria: Amenorrhoea Concurrent disease which may interfere with endometriosis or contraindicate the use of androgenic therapy Surgical treatment at baseline or within 6 months prior to study Use of danazol, androgenic hormones, eostrogens, or progestogens within 3 months prior to study Setting: Multiple sites within Europe Timing: not stated | | | Interventions | Nafarelin 200mcg BD IN + placebo PO for 6 months (n=206) versus Danazol 200mg TDS PO + placebo IN for 6 months (n=101) Note: 8 participants who were randomised never took the study medication | | | Outcomes | Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration AFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: No Sample size calculation: not stated Funding: Supported in part by Syntex Research, Palo Alto, California, US Authors contacted regarding methods, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "patients were randomised so that 2 were assigned to receive nafarelin for every 1 assigned to receive danazol". No further information was provided on method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo tablets and spray were used to blind participants. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Detail for attrition:"307 were included in the safety analyses, of whom 263 also qualified for the efficacy analyses (171 nafarelin and 92 danazol recipients)" 25 had been treated 150 days but refused or otherwise missed the post‐treatment laparoscopy 12 violated the study protocol 14 discontinued due to adverse events 4 for intercurrent illness 4 for personal reasons 1 due to ineffective treatment 2 lost to follow up | | Selective reporting (reporting bias) | Low risk | All pre‐specified primary outcomes were reported on. | Odukoya 1995. | Study characteristics | || | Methods | Trial design: Randomised study | | | Participants | Participants: 21 women were randomised and analysed Mean age: 33 +/‐ 5 (SD) Inclusion criteria: Laparoscopically diagnosed endometriosis Pelvic pain Exclusion criteria: not stated Setting: UK Timing: not stated | | | Interventions | Leuprolide acetate 3.75 SC monthly for 3 months (n=10) versus Danazol 400mg daily PO for 3 months (n=11) | | | Outcomes | Pain (Biberoglu + Behrman scale) | | | Notes | Intention‐to‐treat analysis: Yes Sample size calculation: not stated Funding: not stated Authors contacted regarding methods (blinding) and SD data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Randomisation was "computer generated". | | Allocation concealment (selection bias) | Low risk | "concealed in an envelope only opened at commencement of treatment" | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details provided of blinding of participants or trial personnel, | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All women who were randomised were analysed | | Selective reporting (reporting bias) | Low risk | All prespecified primary outcomes were reported on, however data is presented as | Palagiano 1994. | Study characteristics | || | Methods | Trial design: Randomised, open study | | | Participants | Participants: 50 women were randomised, 47 were analysed Age: 20‐40 Inclusion criteria: Laparoscopically diagnosed endometriosis No treatment for endometriosis within previous 12 months Exclusion criteria: Setting: Italy Timing: | | | Interventions | Leuprolide acetate 3.75mg IM monthly for 6 months (n=30) versus Danazol 600mg OD PO for 6 months (n=20) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and replied | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "randomly allocated" | | Allocation concealment (selection bias) | Low risk | Randomisation done by a pharmacy | | Blinding (performance bias and detection bias) All outcomes | High risk | Open study | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Withdrawals after randomisation <10% "drop out patients without M.D. consultation" | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Petta 2005. | Study characteristics | || | Methods | Trial design: Randomised controlled trial | | | Participants | Participants: 83 women were randomised, 71 were analysed Mean age: LNG‐IUS = 29.4 +/‐ 4.8 and Lupron = 30.5 +/‐ 6.4 (SD) Stage: I to IV Inclusion criteria: Laparoscopically and histologically confirmed endometriosis within 3 to 24 months prior to study enrolment 18‐40 years old Complaints of cyclic chronic pelvic pain with or without dysmenorrhoea VAS pain score of greater or equal to 3 during the pretreatment cycle Regular menstrual cycle of 25‐35 days for at least 3 months prior to study Exclusion criteria: Hormone treatment within 3 months of entering study Long acting progestins or GnRHa within 9 months prior to study Pregnant or breastfeeding within 3 months prior to study Osteoporosis, coagulation disorders or contra‐indications to LNG‐IUS Setting: Brazil Timing: February 2002 to May 2004 | | | Interventions | LNG‐IUS (Mirena) 20mcg/day 5 years IU for 6 months (n=40) versus Lupron 3.75mg every 28 days IM for 6 months (n=43) | | | Outcomes | Pain as defined by VAS score Psychological general well being index | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Randomisation was by "computer generated system". | | Allocation concealment (selection bias) | Low risk | "sealed envelopes" were used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Low risk | Blinding of participants would not have been possible due to nature of the intervention. Outcome assessors were blinded according to author. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | "data analysis did not follow intention‐to‐treat principles" but details given for attrition:6 each from both groups withdrew 1 pregnant and 5 did not complete pain diary (LNG‐IUS) 6 did not complete pain diary (Lupron) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Rock 1993. | Study characteristics | || | Methods | Trial design: "multi‐centre, open, parallel study" | | | Participants | Participants: 315 women were randomised and analysed Mean age: Goserelin = 30.4 and Danazol = 29.7 Stage: I to IV Inclusion criteria: laparoscopically confirmed endometriosis AFS score of greater or equal to 2 Symptomatic (total pelvic score of equal or greater than 3) or asymptomatic disease, with or without infertility Exclusion criteria: Stage IV disease Setting: USA Timing: not stated | | | Interventions | Goserelin 3.6mg every 28 days SC for 24 weeks (n=208) versus Danazol 400mg BD PO for 24 weeks (n=107) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration rAFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Randomised 2:1 Goserelin: Danazol. No other details are provided of method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | High risk | Open study | | Incomplete outcome data (attrition bias) All outcomes | Low risk | "All randomised subjects were included in the overall analysis of treatment outcome" details given for attrition: 15 in Goserelin and 18 in Danazol group withdrew 6 in Goserelin and 13 in Danazol group withdrew due to adverse events | | Selective reporting (reporting bias) | Low risk | All pre specified primary outcomes were reported on | Rolland 1990. | Study characteristics | || | Methods | Trial design: Randomised, parallel study | | | Participants | Participants: 194 women were randomised, 170 were analysed Mean age: Inclusion criteria: Laparoscopically confirmed endometriosis 18 ‐ 45 years old Body weight of 45 ‐ 110kg Menstrual cycle of 24 ‐ 36 days Symptomatic Not pregnant Negative pap smear test Exclusion criteria: Prescence of amenorrhoea Interferring concurrent disease Surgical treatment at baseline laparoscopy or within 6 months prior to study Gonadal hormone or danazol use within 3 months prior to study Simultaneous participation in other studies Setting: The Netherlands Timing: | | | Interventions | Nafarelin 200mcg BD IN + placebo PO for 6 months (n=127) versus Danazol 200mg BD PO + placebo IN for 6 months (n=67) | | | Outcomes | Pain defined by symptoms severity score AFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and data. Letter returned with author unknown at Department | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | randomised 2:1 Nafarelin: Danazol. No other details provided of method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | no details provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | Low risk | double placebo, double blind | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Details for attrition:20 in Nafarelin and 4 in Danazol group withdrew due to: adverse effects 7 (Naf) vs 2 (Dan) intercurrent illness 1 (Naf) vs 2 (Dan) personal reasons 3 (Naf) lost to follow up 3 (Naf) lack of drug efficacy 1 (Naf) other 5 (Naf) | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Rotondi 2002. | Study characteristics | || | Methods | Trial design: | | | Participants | Participants: 81 women were randomised in a 2:1 ratio to leuprolide n=54, or danazol n=27 Mean age: mean age not provided, median age was 32 years (range 19‐41). Inclusion criteria: Laparoscopically confirmed endometriosis Exclusion criteria: not stated Setting: Italy Timing: 1992 to 1999 | | | Interventions | Intervention: Leuprolide acetate 3.75 mg subcutaneously every 28 days, for 6 months. Comparison: Danazol 200 mg orally three times a day for 6 months. | | | Outcomes | rAFS scores Subjective symptom scores using a numerical scale Adverse events | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "randomly allocated", no further details provided about method used to generate the random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment group. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details provided of blinding, but unlikely due to nature of routes of administration. | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 3 women from leuprolide group (n = 54) and 5 from danazol group (n = 27) withdrew due to "adverse findings" | | Selective reporting (reporting bias) | Unclear risk | Prespecified outcomes are reported. | Shaw 1986. | Study characteristics | || | Methods | Trial design: Randomised study | | | Participants | Participants: 20 women were randomised, 19 analysed Mean age: 30.4 +/‐ 3.8 (SEM?) Inclusion criteria: Laparoscopically diagnosed disease No treatment within 4 months prior to study Exclusion criteria: not stated Setting: UK Timing: not stated | | | Interventions | Buserelin 200mcg TDS IN for 6 months (n=10) versus Buserelin 300mcg TDS IN for 6 months (n=10 with one withdrawal due to adverse effects) | | | Outcomes | Symptomatic changes rAFS score Adverse effects | | | Notes | Authors contacted but unable to provide further details as trial was almost 20 years old Intention‐to‐treat analysis: No Sample size calculation: not stated Funding: Hoechst UK supplied the Buserelin used in this study. No further details provided. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "randomly allocated". No further details of method used to generate random sequence. | | Allocation concealment (selection bias) | Unclear risk | No details provided of method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | "this paper reports an open study" with no further details. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Detail for attrition:1 from Buserelin 300mcg TDS group withdrew after 3 months due to adverse effects | | Selective reporting (reporting bias) | Unclear risk | No comparisons between groups for symptomatic changes | Shaw 1990. | Study characteristics | || | Methods | Trial design: Multi‐centre, randomised trial | | | Participants | 82 women were randomised, 74 were analysed Mean age: Inclusion criteria: Exclusion critiera: Setting: UK Timing: | | | Interventions | Nafarelin 200mcg BD IN + placebo PO for 6 months (n=55) versus Danazol 200mg TDS PO + placebo IN for 6 months (n=26) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration | | | Notes | Authors contacted but unable to provide further details as trial was almost 20 years old | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding (performance bias and detection bias) All outcomes | Low risk | Patients were blinded and received placebo nasal spray or tablets | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Details for attrition given:8 withdrew: Nafarelin = 3 due to side effects, 1 left country, 1 poor compliance Danazol = 2 due to side effects, 1 poor compliance | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Shaw 1992. | Study characteristics | || | Methods | Trial design: "open, randomised comparative study" multicentre | | | Participants | Participants: 307 women were randomised, 286 were analysed Age: 18‐40 Stage: I to IV Inclusion criteria: laparoscopically confirmed endometriosis within 12 weeks prior to study enrolment Exclusion criteria: No hormonal agents within 8 weeks prior to study No GnRHas or Danazol within 24 weeks prior to study No anticoagulants Setting: Europe Timing: not stated | | | Interventions | Goserelin acetate 3.6mg every 28 days SC for 24 weeks (n=204) versus Danazol 200mg TDS PO for 24 weeks (n=103) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration rAFS score Adverse effects | | | Notes | Intention‐to‐treat analysis: Sample size calculation: Funding: | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Randomisation was in the ratio two goserelin: one danazol with each centre having its randomisation list", "The randomised trial of Zoladex and Danazol was a multi centre trial with randomisation envelopes provided by the sponsors ICI to each of the centres as plain sealed envelopes and computerised randomisation lists for each centre" (author's reply) | | Allocation concealment (selection bias) | Low risk | "plain, sealed envelopes" | | Blinding (performance bias and detection bias) All outcomes | High risk | Open study | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Details given for attrition:81 in Goserelin and 54 in Danazol group withdrew due to lack of effect, adverse effects, pregnancy and administrative reasons | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Skrzypulec 2004. | Study characteristics | || | Methods | Trial design: Placebo, randomised, parallel study | | | Participants | 34 women were randomised and analysed Mean age: GnRHa = 31.02 ± 2.5 and Placebo = 32.13 ±1.5 (SD) Inclusion criteria: Laparoscopically diagnosed endometriosis Symptomatic Surgically or pharmacologically treated in 6 months prior Regular menstrual cycle in prior 3 months Not pregnant Exclusion criteria: Cardiovascular burden Hormone dependent neoplasms Osteoporosis Bilateral oophorecystectomy Abnormal liver and renal tests Setting: Poland Timing: | | | Interventions | GnRHa 50mg OD PO for 12 weeks (n=16) versus Placebo PO for 12 weeks (n=18) | | | Outcomes | Dysmenorrhoea, dyspareunia, pain in pelvic minor | | | Notes | Author provided additional details on methods | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Centralised randomisation process, computerised allocation according to author | | Allocation concealment (selection bias) | Low risk | Sealed, opaque, sequentially numbered, identical envelopes and sequentially numbered, identical containers of identical drugs | | Blinding (performance bias and detection bias) All outcomes | Low risk | Participants, investigators, outcome assessors and clinicians were all blinded according to author | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All women who were randomised were analysed | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Tummon 1989. | Study characteristics | || | Methods | Trial design: Prospective, randomised study | | | Participants | Participants: 15 women were randomised and analysed Mean age: 32.1 +/‐ 0.9 (SE) Inclusion criteria: Laparoscopically diagnosed endometriosis within 3 months prior to study Infertile women Regular menstrual cycles Exclusion criteria: not stated. Setting: USA Timing: not stated | | | Interventions | Leuprolide 400mcg QDS IN for 26 weeks (n=10) versus Danazol 200mg QDS PO for 26 weeks (n=5) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain rAFS score | | | Notes | Authors contacted regarding methods and data, awaiting response Intention‐to‐treat analysis: Sample size calculation: Funding: | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Randomised 2:1 ratio Leuprolide: Danazol. Method used to generate the random sequence is not provided. | | Allocation concealment (selection bias) | Unclear risk | No details are provided of the method used to conceal allocation to treatment groups. | | Blinding (performance bias and detection bias) All outcomes | Unclear risk | No details are provided of blinding of participants or trial personnel. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All randomised participants were analysed | | Selective reporting (reporting bias) | Low risk | All prespecified primary outcomes were reported on | Valimaki 1989. | Study characteristics | || | Methods | Trial design: "Parallel, randomized, double placebo design" | | | Participants | 18 women randomised and analysed. Mean age: Nafarelin = 34.1±1.8 and Danazol = 32.6±1.9 Inclusion criteria: Women with laparoscopically confirmed pelvic endometriosis Exclusion criteria: not stated Setting: Timing: | | | Interventions | Intranasal nafarelin 200 mcg twice daily with placebo tablets (n=12) vs Danazol tablets 200 mg three times daily with placebo nasal spray (n=6) | | | Outcomes | Serum lipids and lipoproteins AFS endometriosis score | | | Notes | Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data. | Wheeler 1992. | Study characteristics | || | Methods | Trial design: "double‐blind, multi‐centre, randomised trial" | | | Participants | 270 women were randomised and 253 were analysed Age: Leuprolide = 31.0 and Danazol = 29.8 Inclusion criteria: Laparoscopically diagnosed endometriosis within 4 months prior to study Over 18 years of age No surgical treatment at time of laparoscopy Premenopausal Not pregnant or lactating Never previously taken GnRHa Any other treatment completed at least 3 months prior to study Setting: USA Timing: | | | Interventions | Leuprolide 3.75mg monthly IM + placebo OD PO for 24 weeks (n=134) versus Danazol 800mg OD PO + placebo monthly IM for 24 weeks (n=136) | | | Outcomes | Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness rAFS score Analgesic use | | | Notes | Authors contacted regarding methods and data, awaiting response | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No details | | Allocation concealment (selection bias) | Unclear risk | No details | | Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo injection and tablets to blind participants and investigators | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Details given for attrition:17 patients were excluded due to: failure to meet inclusion criteria 2 (Leu) and 1 (Dan) non‐compliance 3 (Leu) and 10 (Dan) inadvertent dosing with another patient's designated leuprolide 1 | | Selective reporting (reporting bias) | Low risk | All primary outcomes stated were reported on | Wright 1995. | Study characteristics | || | Methods | Trial design: Prospective randomined controlled trial | | | Participants | 40 randomised, 30 analysed Ages of participants not stated. Inclusion criteria: Women with mild, moderatate or severe endometriosis, confirmed by laparoscopy Exclusion criteria: moderate to severe pelvic adhesive disease, bilateral tubal obstruction, positive pregnancy test Setting: USA Timing: | | | Interventions | Leuprolide acetate 0.1 mg SC daily for three months (n=15) vs Danazol 400 mg orally daily for three months (n=15) | | | Outcomes | AFS score size of ovarian endometrioma | | | Notes | Characteristics of excluded studies [ordered by study ID] | Study | Reason for exclusion | |---|---| | Adiyono 2006 | Wrong participants: post‐surgical treatment | | Cooke 1989 | Wrong comparisons: gestrinone (not a GnRH agonist) vs placebo only | | Dmowski 1989 | Wrong comparisons: focuses on Danazol | | Donnez 2004 | Wrong comparisons: comparison not stated in our protocol | | Franke 2000 | Wrong comparisons: add‐back therapy | | Fraser 1996 | Ineligible condition: not about endometriosis but rather menorrhagia | | Harada 2000 | Ineligible participants: not laparoscopically diagnosed endometriosis | | Kiilholma 1995 | Ineligible comparisons: add‐back therapy | | Ling 1999 | Ineligible participants: not laparoscopically diagnosed endometriosis | | Luciano 2004 | Ineligible comparisons: Leuprolide acetate vs DMPA | | Magini 1993 | Ineligible comparisons | | Matalliotakis 2004 | Ineligible participants: GnRH used as a post surgical treatment | | Newton 1996 | Ineligible comparisons: Leuprolide vs Nafarelin | | Roux 1995 | Ineligible outcomes: investigates effect of nasal calcium supplement on bone mineral loss during GnRH treatment in participants with endometriosis. | | Shaw 2001 | Ineligible condition and comparison: not about endometriosis but rather ovarian endometriomas. GnRH is used in combination with surgery. | | Sorensen 1997 | Ineligible condition: not about endometriosis | | Sowter 1997 | Ineligible condition: not about endometriosis but rather menorrhagia | | Surrey 1993 | Ineligible outcomes: effect of calcium and progesterone supplementation on bone density loss in women with endometriosis on long term GnRH therapy | | Surrey 1995 | Ineligible comparisons: add back therapy | | Surrey 2002 | Ineligible comparisons: add‐back therapy | | Tahara 2000 | Ineligible comparisons: comparison not stated in our protocol | | Tapanainen 1993 | Ineligible outcomes: investigates the role of GnRH in IVF outcomes. | | Taskin 1997 | Ineligible comparisons: add‐back therapy | | Toomey 2003 | Ineligible comparison: complementary medicine | | Vercellini 1994 | Ineligible comparisons: focuses on Danazol | | Vercellini 2009 | Ineligible participants: post‐surgical treatment | | Warnock 1998 | Ineligible comparisons: focuses on antidepressants in addition to GnRHas | | Yee 1986 | Ineligible outcomes: pain not an outcome | | Ylikorkala 1995 | Ineligible participants: not laparoscopically diagnosed endometriosis | | Zupi 2005 | Ineligible comparisons: add‐back therapy | Characteristics of studies awaiting classification [ordered by study ID] Chan 1993. | Methods | "Comparative Study" | | Participants | Singapore study 149 woman were randomised Inclusion criteria: laparoscopically diagnosed endometriosis | | Interventions | Gestrinone for 6 months (n= 44) versus Danazol PO for 6 months (n=57) versus Triptorelin IM for 4 injections (n=48) | | Outcomes | Symptoms of endometriosis, side effects of medication, blood for CA125, vertebral bone scan for bone loss | | Notes | Will email author for the full study | Chen 2009. | Methods | Randomised, blind parallel trial | | Participants | 149 women with endometriosis | | Interventions | Leuprolide acetate vs Enaltone | | Outcomes | Ovarian mass volume, hormone levels, pelvic pain, subjective symptoms | | Notes | Awaiting translation from Chinese | Differences between protocol and review Significant changes have been made since this review was first published in 1999 by Andrew Prentice. However the main objective has remained the same: to determine the effectiveness and safety of GnRHas in the treatment of the painful symptoms associated with endometriosis. The review published in 1999 stated under 'Type of Participants' that "the diagnosis of endometriosis was made by direct visualisation (laparoscopy). Trials where the diagnosis had been made by history alone or by some other imaging technique would have been considered...". This was modified so that "the clinical diagnosis of endometriosis had to be made by direct visualisation (laparoscopy)" only. Trials where the diagnosis was made by techniques other than direct visualisation were excluded. Trials where GnRHa is administered in post‐surgical participants as adjuvant therapy was also specifically stated to be excluded in this current review. Numerous modifications have been made under 'Type of Interventions'. The review published in 1999 compared GnRHa, any dosage or route of administration, with no treatment, placebo, danazol, gestrinone, progestogens, combined oral contraceptive pill, surgical ablation of endometriotic deposits, surgical treatments that purport to interrupt neural pathways (e.g. LUNA), combination of GnRHas and hormone replacement therapy, and another GnRHa. Treatments designed only to achieve relief of symptoms such as treatment with non‐steroidal anti‐inflammatory drugs or other analgesics were not considered. The current review has removed GnRHas comparisons with gestrinone, progestogens (Prentice 2000), combined oral contraceptive pill (Davis 2007), and combination of GnRHas and hormone replacement therapy as they are described under separate reviews. The current review limited comparisons of GnRHas with other medical therapies only and excluded comparisons with any surgical intervention (Jacobson 2009). Since the main objective of the review was to look at the effectiveness and safety of GnRHas in treatment of endometriosis‐associated painful symptoms, trials that compared GnRHas with other analgesics would have been considered but no trials were identified. The current review also considered trials which compared GnRHas with the relatively new LNG IUS but excluded trials that compared GnRHas with GnRH antagonists as that is a registered title of a review to be conducted by the Menstrual Disorders and Subfertility Group of Cochrane Collaboration.Trials that compared one type of GnRHa with another were excluded as that would not have contributed towards the objective, instead trials which compared different dosages, length of treatment, routes of administration, and treatment regimes of GnRHas were considered. Outcomes of pain relief, adverse effects and resolution of endometriotic implants were considered in both reviews. Quality of life and the additional use of analgesics were additional outcomes that were considered in the current review. Cost‐effectiveness was specifically stated as an outcome not considered in the current review. Risk of bias. Funnel plot to be conducted if eight or more studies included has been altered to 10 or more studies. Contributions of authors In the update of this review Julie Brown and Alice Pan were responsible for identification of studies and data extraction and entry and the writing of the review drafts. Roger Hart was responsible for providing comments and clinical input. The original authors of the review were: Andrew Prentice, Department of Obstetrics and Gynaecology, Rosie Maternity Hospital, Cambridge, UK Alison Deary, Clinical Pharmacology, Addenbrooke's Hospital, Cambridge, UK Sandra Goldbeck‐Wood, Obstetrics and Gynaecology/Psychosexual Medicine, Ipswich Hospital, Cambridge, UK Cindy Farquhar, Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand Stephen Smith, Faculty of Medicine, Imperial College, London, UK Sources of support Internal sources - Uiniversity of Auckland, New Zealand Lead author AP (who is an undergraduate medical student) has been funded to complete the review. External sources No sources of support provided Declarations of interest None Edited (no change to conclusions)

References to studies included in this review Acien 1989 {published data only} Adamson 1994 {published data only} - Adamson GD, Kwei L, Edgren RA. Pain of endometriosis: effects of nafarelin and danazol therapy. International Journal of Fertility & Menopausal Studies 1994;39(4):215-7. [PubMed] Agarwal 1997 {published data only} - Agarwal SK, Hamrang C, Henzl MR, Judd HL. Nafarelin vs. leuprolide acetate depot for endometriosis. Changes in bone mineral density and vasomotor symptoms. Nafarelin Study Group. Journal of Reproductive Medicine 1997;42(7):413-23. [PubMed] AN Zoladex 1996 {published data only} Audebert 1997 {published data only} - Audebert A, Lucas C, Joubert-Collin M. Efficacy and safety of slow-release leuprorelin 3,75 mg compared to Danazol treatment. EFFICACITE ET TOLERANCE DE LA LEUPRORELINE 3,75 MG A LIBERATION PROLONGEE DANS LE TRAITEMENT DE 1'ENDOMETRIOSE EN COMPARAISON AU DANAZOL. References En Gynecologie Obstetrique 1997;5(1):49-57. Bergquist 1990 {published data only} Bergqvist 1997 {published data only} Bergqvist 1998 {published data only} Burry 1989 {published data only} Burry 1992 {published data only} - Burry K. Nafarelin in the management of endometriosis: Quality of life assessment. American Journal of Obstetrics & Gynecology 1992;166:735-9. [DOI] [PubMed] - Burry KA, Buttram V, Moghissi K, M F. Quality of life during and after treatment of endometriosis with Nafarelin or Danazol (ABSTRACT). Fertility & Sterility 1990;54(pp.s13):0-029. Calvo 2000 {published data only} - Calvo Lugo GE, Sauceda Gonzalez LF, Jimenez Perea ML, Diaz Arias FJ. [Treatment of pelvic endometriosis with goserelin acetate or nafarelin acetate. Comparative study]. Ginecologia y Obstetricia de Mexico 2000;68:7-14. [PubMed] Chang 1996 {published data only} - Chang SP, Ng HT. A randomized comparative study of the effect of leuprorelin acetate depot and danazol in the treatment of endometriosis. Chung Hua i Hsueh Tsa Chih - Chinese Medical Journal 1996;57(6):431-7. [PubMed] Cheng 2005 {published data only} Choktanasiri 2001 {published data only} - Choktanasiri W, Rojanasakul A. Buserelin acetate implants in the treatment of pain in endometriosis. Journal of The Medical Association of Thailand 2001;84(5):656-60. [PubMed] Cirkel 1995 {published data only} - Cirkel U, Ochs H, Schneider HP. A randomized, comparative trial of triptorelin depot (D-Trp6-LHRH) and danazol in the treatment of endometriosis. European Journal of Obstetrics, Gynecology, & Reproductive Biology 1995;59(1):61-9. [DOI] [PubMed] - Cirkel U, Ochs H, Schneider HPG. GNRH Analogue Depot (Triptorelin) Versus Danazol in the Treatment of Endometriosis. Gynecological Endocrinology 3rd International Symposium 1993;7(Supp 2):43. - Ochs H, Cirkel U, Schneider HP. Correlation between extent of ovarian suppression and regression of endometriosis: decapeptyl vs danazol. Gynecological Endocrinology 3rd International Symposium 1993;7(Supp 2):43. Claesson 1989 {published data only} - Claesson B, Bergquist C. Clinical experience treating endometriosis with nafarelin. Journal of Reproductive Medicine 1989;34(12 Suppl):1025-8. [PubMed] Crosignani 1996 {published data only} Dawood 1990 {published data only} - Dawood MY. A comparison of the efficacy and safety of buserelin vs danazol in the treatment of endometriosis. Current Concepts in Endometriosis 1990:253-67. [PubMed] Dlugi 1990 {published data only} Dmowski 1989a {published data only} Donnez 1989 {published data only} el‐Roeiy 1988 {published data only} Fedele 1989 {published data only} - Fedele L, Bianchi S, Arcaini L, Vercellini P, Candiani GB. Buserelin versus danazol in the treatment of endometriosis-associated infertility. American Journal of Obstetrics & Gynecology 1989;161(4):871-6. [DOI] [PubMed] - Fedele L, Marchini M, Bianchi S, Baglioni A, Zanotti F. Vaginal patterns during danazol and buserelin acetate therapy for endometriosis: structural and ultrastructural study. Fertility & Sterility 1993;59(6):1191-5. [DOI] [PubMed] Fedele 1993 {published data only} Ferreira 2010 {published data only} - Ferreira, RA Vieira, C Rosa-e-Silava, J Rosa-e-Silva, A Nogueira, A Ferriani, R. Effects of the levonorgestrel-releasing intrauterine system on cardiovascular risk markers in patients with endometriosis: a comparative study with the GnRH analogue. Contraception 2010;81:117-122. [DOI] [PubMed] [Google Scholar] Franssen 1992 {published data only} Fraser 1991 {published data only} Gomes 2007 {published data only} Henzl 1988 {published data only} - Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, Jacobson J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. New England Journal of Medicine 1988;318(8):485-9. [DOI] [PubMed] - Henzl MR. Role of nafarelin in the management of endometriosis. Journal of Reproductive Medicine 1989;34(12 Suppl):1021-4. [PubMed] - Jacobs L, Field C, Thie J, Coulam C. Treatment of endometriosis with the GnRH agonist naferelin acetate. International Journal of Fertility 1991;36:30-5. [PubMed] [Google Scholar] - Moghissi KS, Corson SL, Buttram V, Henzl MR. Evaluation of a GnRH Agonist (Nafarelin) versus Danazol for Treatment of Endometriosis. Contributions to Gynecology & Obstetrics 1987;16:266. Henzl 1990a {published data only} - Henzl MR, Monroe SE. Nafarelin: a new medical therapy for endometriosis. Progress in Clinical & Biological Research 1990;323:343-55. [PubMed] Hornstein 1995 {published data only} - Hornstein M, Yuzpe A, Burry K, Heinrichs L, Orwoll E. A prospective randomised double-blind trial of 3 versus 6 months nafarelin therapy for symptoms of endometriosis. Fertility and Sterility 1992;58:S84. [PubMed] - Hornstein MD, Yuzpe AA, Burry KA, Heinrichs LR, Buttram VL Jr, et al. Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertility & Sterility 1995;63(5):955-62. [PubMed] Jelley 1986 {published data only} - Jelley RY, Magill PJ. The effect of LHRH agonist therapy in the treatment of endometriosis (English experience). Progress in Clinical & Biological Research 1986;225:227-38. [PubMed] - Jelley RY. Multicentre Open Comparative Study of Buserelin and Danazol in the Treatment of Endometriosis. British Journal of Clinical Practice 1986;48(Suppl):64-8. Lemay 1988 {published data only} - Lemay A, Maheux R, Huot C, Blanchet J, Faure N. Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment of endometriosis. American Journal of Obstetrics & Gynecology 1988;158(2):233-6. [DOI] [PubMed] - Lemay A, Maheux R, Quesnel G, Bureau M, Faure N, Merat P. LH-RH agonist treatment of endometriosis. Contributions to Gynecology and Obstetrics 1987;16:247-53. [PubMed] Maouris 1991 {published data only} - Maouris P, Dowsett M, Rose G, D E. Comparison of the endocrine effects of danazol and the LHRH agonist goserelin (Zoladex) in the treament of endometriosis. Silver Jubilee British Congress of Obstetrics and Gynaecology 1989:61. - Maouris P. Pseudomenopause Treatment for Endometriosis: The Endocrine Effects of Danazol Compared with the use of the LH-RH Agonist Goserelin. Journal of Obstetrics & Gynaecology 1991;11:123-7. Matalliotakis 2000 {published data only} Matta 1988 {published data only} - Matta W, Shaw R. A comparative study between buserelin and danazol in the treatment of endometriosis. The British Journal of Clinical Practice 1988;40(4):69-72. Miller 1990 {published data only} - Miller JD. Leuprolide acetate for the treatment of endometriosis. Progress in Clinical & Biological Research 1990;323:337-41. [PubMed] Miller 2000 {published data only} Minaguchi 1986 {published data only} - Minaguchi H, Uemura T, Shirasu K. Clinical study on finding optimal dose of a potent LHRH agonist (buserelin) for the treatment of endometriosis--multicenter trial in Japan. Progress in Clinical & Biological Research 1986;225:211-25. [PubMed] NEET 1992 {published data only} - Kennedy SH, Williams IA, Brodribb J, Barlow DH, Shaw RW. A comparison of nafarelin acetate and danazol in the treatment of endometriosis. Fertility & Sterility 1990;53(6):998-1003. [DOI] [PubMed] - NEET. Nafarelin for endometriosis: a large-scale, danazol-controlled trial of efficacy and safety, with 1-year follow-up The Nafarelin European Endometriosis Trial Group (NEET) [see comments]. Fertility & Sterility 1992;57(3):514-22. [PubMed] Odukoya 1995 {published data only} Palagiano 1994 {published data only} - Palagiano A, Capuano V. [Medical treatment of endometriosis: comparative study of leuprolide acetate and danazol]. Minerva Ginecologica 1994;46(4):173-7. [PubMed] Petta 2005 {published data only} - Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa ESJC, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Human Reproduction 2005;20(7):1993-8. [DOI] [PubMed] - Vieira CS, Ferreira RA, Rosa e Silva JC, Rosa e Silva ACJS, Gomes MK, Ferriani RA. Comparative study of the influence of the levonorgestrel intra-uterine system and the GnRH analogues on cardiovascular risk markers in patients with endometriosis. Fertility & Sterility 2007;88(Suppl 1):211. - Sa Rosa e Silva AC, Rosa e Silva JC, Nogueira AA, Petta CA, Abrao MS, Ferriani RA. The levonorgestrel-releasing intrauterine device reduces CA-125 serum levels in patients with endometriosis. Fertility & Sterility 2006;86(3):742-4. [DOI] [PubMed] Rock 1993 {published data only} - Allen TW. Zoladex versus danazol in endometriosis therapy. Journal of the American Osteopathic Association 1993;93(10):1013. - Rock JA, Truglia JA, Caplan RJ. Zoladex (goserelin acetate implant) in the treatment of endometriosis: a randomized comparison with danazol. The Zoladex Endometriosis Study Group. Obstetrics & Gynecology 1993;82(2):198-205. [PubMed] - Rock JA. A multicenter comparison of GnRH agonist (Zoladex) and danazol in the treatment of endometriosis Abstract. Fertility & Sterility 1991;56(pp.s49). Rolland 1990 {published data only} Rotondi 2002 {published data only} - Rotondi M, Labriola D, Ammaturo FP, Amato G, Carella C, Izzo A, et al. Depot leuprorelin acetate versus danazol in the treatment of infertile women with symptomatic endometriosis. European Journal of Gynaecological Oncology 2002;23(6):523-6. [PubMed] Shaw 1986 {published data only} - Shaw RW, Matta W. Reversible pituitary ovarian suppression induced by an LHRH agonist in the treatment of endometriosis - comparison of two dose regimens. Clinical Reproduction and Fertility 1986;4(5):329-36. [PubMed] Shaw 1990 {published data only} Shaw 1992 {published data only} - Shaw RW. A Randomised Comparative Study of the Effects of Goserelin and Danazol for the Treatment of Endometriosis. Gynecological Endocrinology 1990;4(70 Suppl 2):45. - Shaw RW. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Zoladex Endometriosis Study Team. Fertility & Sterility 1992;58(2):265-72. [DOI] [PubMed] - Shaw RW. [Goserelin depot: an analog of LHRH for the treatment of endometriosis] [Italian]. Drugs Under Experimental & Clinical Research 1990;16(Suppl):69-75. [PubMed] Skrzypulec 2004 {published data only} - Skrzypulec V, Walaszek A, Drosdzol A, Nowosielski K, Piela B, Rozmus-Warcholinska W. [Influence of GnRH analogue on the intensification of endometriosis symptoms and infertility treatment]. Wiadomosci Lekarskie 2004;57 Suppl 1:301-4. [PubMed] Tummon 1989 {published data only} Valimaki 1989 {published data only} Wheeler 1992 {published data only} - Wheeler JM, Knittle JD, Miller JD. Depot leuprolide acetate versus danazol in the treatment of women with symptomatic endometriosis: a multicenter, double-blind randomized clinical trial. II. Assessment of safety. The Lupron Endometriosis Study Group. American Journal of Obstetrics & Gynecology 1993;169(1):26-33. [DOI] [PubMed] - Wheeler JM, Knittle JD, Miller JD. Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results. American Journal of Obstetrics & Gynecology 1992;167(5):1367-71. [DOI] [PubMed] Wright 1995 {published data only} - Wright S, Valdes CT, Dunn RC, Franklin RR. Short-term Lupron or danazol therapy for pelvic endometriosis. Fertility & Sterility 1995;63(3):504-7. [PubMed]

to studies excluded from this review Adiyono 2006 {published data only} - Adiyono W, Adisusianto I. The impact of combination laparoscopic surgery and GNRH analog on quality of life endometriosis patients. In: XVIII FIGO World Congress of Gynecology and Obstetrics. Vol. 2. 5-10 November Kuala Lumpur, Malaysia, 2006:143. Cooke 1989 {published data only} - Cooke ID, Thomas EJ. The medical treatment of mild endometriosis. Acta Obstetricia et Gynecologica Scandinavica - Supplement 1989;150:27-30. [PubMed] Dmowski 1989 {published data only} - Dmowski WP. Comparitive Study of Buserelin Versus Danazol in the Management of Endometriosis. Gynecological Endocrinology 1989;3(Suppl 2):21-31. Donnez 2004 {published data only} Franke 2000 {published data only} Fraser 1996 {published data only} Harada 2000 {published data only} - Harada T. Empirical leuprolide treatment of women with suspected endometriosis was effective in reducing chronic pain. Evidence-based Obstetrics and Gynecology 2000;2:45. Kiilholma 1995 {published data only} Ling 1999 {published data only} Luciano 2004 {published data only} - Luciano AA. Leuprolide Acetate in the Management of Endometriosis-Associated Pain: A Multicenter, Evaluator-Blind, Comparative Clinical Trial. Global congress of Gynecologic Endoscopy 33rd Annual Meeting of the AAGL "Advancing Minimally Invasive Gynecology Worldwide" 2004;11(Suppl 3):s5. Magini 1993 {published data only} Matalliotakis 2004 {published data only} - Matalliotakis IM, Arici A, Goumenou AG, Katassos T, Karkavitsas N, Koumantakis EE. Comparison of the effects of leuprorelin acetate and danazol treatments on serum CA-125 levels in women with endometriosis. International Journal of Fertility & Womens Medicine 2004;49(2):75-8. [PubMed] Newton 1996 {published data only} Roux 1995 {published data only} Shaw 2001 {published data only} - Shaw R, Garry R, McMillan L, Sutton C, Wood S, Harrison R, et al. A prospective randomized open study comparing goserelin (Zoladex) plus surgery and surgery alone in the management of ovarian endometriomas. Gynaecological Endoscopy 2001;10(3):151-7. Sorensen 1997 {published data only} Sowter 1997 {published data only} - Sowter MC, Bidgood K, Richardson JA. A prospective randomized trial of the effect of preoperative endometrial inhibition on the long-term outcome of transcervical endometrial resection. Gynaecological Endoscopy 1997;6(1):33-7. Surrey 1993 {published data only} - Surrey ES, Fournet N, Voigt B, Judd HL. Effects of sodium etidronate in combination with low-dose norethindrone in patients administered a long-acting GnRH agonist: a preliminary report. Obstetrics & Gynecology 1993;81(4):581-6. [PubMed] Surrey 1995 {published data only} - Surrey ES, Voigt B, Fournet N, Judd HL. Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic endometriosis: the role of cyclic sodium etidronate and low-dose norethindrone "add-back" therapy. Fertility and sterility 1995;63(4):747-55. [PubMed] Surrey 2002 {published data only} Tahara 2000 {published data only} Tapanainen 1993 {published data only} Taskin 1997 {published data only} Toomey 2003 {published data only} - Toomey C, Krauss B, Hammerschlag R, Burry K. Endometriosis: traditional medicine vs hormone therapy. National Centre for Complementary and Alternative Medicine 2003. Vercellini 1994 {published data only} - Vercellini P, Trespidi L, Panazza S, Bramante T, Mauro F, Crosignani PG. Very low dose danazol for relief of endometriosis-associated pelvic pain: a pilot study. Fertility & Sterility 1994;62(6):1136-42. [PubMed] Vercellini 2009 {published data only} Warnock 1998 {published data only} Yee 1986 {published data only} - Yee B. A preliminary report on the comparative use of buserelin (Hoe 766) and danazol in the treatment of endometriosis: the University of Southern California experience. Progress in Clinical & Biological Research 1986;225:175-88. [PubMed] Ylikorkala 1995 {published data only} - Ylikorkala O, Tiitinen A, Hulkko S, Kivinen S, Nummi S. Decrease in symptoms, blood loss and uterine size with nafarelin acetate before abdominal hysterectomy: a placebo-controlled, double-blind study. Human Reproduction 1995;10(6):1470-4. [PubMed] Zupi 2005 {published data only} - Zupi E, Sbracia M, Marconi D, Sorrenti G, Zullo F, Palomba S. Role of medical therapy in the treatment of endometriosis associated pelvic pain: a randomized controlled study. Journal of Minimally Invasive Gynecology 2005;12(5):S6.

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