{"paper_id":"f23fbcb8-58c3-4f59-814a-7c740fb8a6cb","body_text":"Objectives\nThis is a protocol for a Cochrane Review (intervention). The objectives are as follows:\nTo assess the effectiveness and safety of gonadotrophin‐releasing hormone analogues (GnRHas) in the treatment of endometriosis.\nBackground\nDescription of the condition\nEndometriosis is a common gynaecological condition. It is characterised as a fibrotic condition in which endometrial stroma and epithelium can be identified, predominantly found in the pelvic peritoneum, ovaries and rectovaginal septum (Burney 2012; Vigano 2018). Endometriosis is associated with symptoms such as dysmenorrhoea, dyspareunia, abdominal pain and infertility (Vercellini 2014). It affects 6% to 11% of women of reproductive age, but the prevalence increases in women with infertility or pelvic pain (Darwish 2006; Eskenazi 1997; Mahmood 1991; Meuleman 2009; Wheeler 1989).\nThe precise pathogenesis of endometriosis remains unclear, however there are some hypotheses that have widely been accepted. Possible theorised mechanisms of the pathogenesis of endometriosis include induction, in situ development and retrograde menstruation or implantation (Levander 1955; Van der Linden 1997; Viganò 2004). The 'induction theory', introduced by Levander and Normann in 1955, is based on the assumption that specific substances released during the degeneration of the endometrium induce endometriosis from omnipotent blastema, present in connective tissues (Levander 1955). The ‘in‐situ development theory’ stated that endometriosis develops from either the Wolffian duct or knob, or from Müllerian tissue (Van der Linden 1997). The most common hypothesis is based on retrograde menstruation; this theory proposes that endometriosis arises by the dissemination of endometrial tissue to ectopic sites where implantation, hypertrophy and invasion of pelvic structures occurs (Vercellini 2014). This ectopic growth provokes an inflammatory response, resulting in the symptoms mentioned above (Guidice 2010).\nEndometriosis is generally believed to be an oestrogen‐dependent disorder (Guidice 2010). Local oestradiol stimulates the activation of pain fibres and promotes sprouting of nociceptors that contribute to persistent inflammatory pain, that often worsens over time (Guidice 2010).\nTo treat chronic pelvic pain associated with endometriosis, repeated courses of medical therapy or surgical therapy (or both) are often required. Hormonal treatment, such as gonadotrophin‐releasing hormone analogues (GnRHas), suppress ovarian function and alter the endometrium, which in turn often results in amenorrhoea and relief of symptoms (Stratton 2011).\nDescription of the intervention\nThe 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, or by subcutaneous or intramuscular injection. Buserelin, goserelin, leuprorelin, nafarelin and triptorelin are some of the most common GnRHas. Hypo‐oestrogenic side‐effects (relating to low levels of oestrogen), such as hot flushes, mood swings and sleep disturbances, are common when prescribing GnRHas. To prevent bone loss and hypo‐oestrogenic symptoms it is therefore recommended to prescribe hormonal add‐back therapy concomitantly.\nOther common treatments for endometriosis‐associated symptoms (including infertility and pain), are analgesics, danazol and progestogens (Brown 2012), including intra‐uterine systems, combined oral contraceptive pills (Brown 2018) and surgical therapies (Bafort 2020). A combination of surgery with hormonal treatment (pre‐surgical, post‐surgical or pre‐ and post‐surgical hormonal therapy), is also used as a treatment option for people with endometriosis. Only post‐surgical medical therapy provides a reduction in pain symptoms, reduced rate of recurrence and increased chance of pregnancy (Chen 2020)\nThe European Society of Human Reproduction and Embryology (ESHRE) recommends the use of GnRHas (nafarelin, leuprorelin, buserelin, goserelin or triptorelin) as one of the options for reducing endometriosis‐associated pain, however evidence is limited regarding dosage or duration of treatment Dunselman 2014. In addition, clinicians are recommended to prescribe hormonal add‐back therapy to coincide with the start of GnRH agonist therapy, to prevent bone loss and hypo‐oestrogenic symptoms during treatment. It is recommended to give careful consideration to the use of GnRHas in young women and adolescents, since these individuals may not have reached maximum bone density (Dunselman 2014).\nHow the intervention might work\nNon‐analgesic medical treatment of endometriosis aims to suppress the ectopic endometrium deposits in premenopausal women by inducing atrophy within the hormonally dependent ectopic endometrium, making the endometrial tissue inactive. The observation that endometriosis is rarely diagnosed in hypo‐oestrogenic post‐menopausal women led to the concept of medical treatment of endometriosis by induction of a pseudo‐menopause.\nGonadotrophin‐releasing hormone analogues are a potent synthetic analogue of the hypothalamic hormone gonadorelin. This stimulates the pituitary gland to produce luteinizing hormone (LH) and follicle‐stimulating hormone (FSH). However, with continued use, suppression occurs due to exhaustion and desensitivity of the gonadotrophic pituitary cells. This suppresses ovarian function and therefore reduces oestrogen and progesterone levels, introducing a hypogonadotropic hypogonadal state.\nIn endometriosis, this treatment leads to a reduction in the endometriosis implants and induces atrophy within them (Chen 2020). By reducing the endometriosis implants, GnRHas can provide a reduction in pain and other endometriosis‐related complaints.\nWhy it is important to do this review\nEndometriosis occurs in approximately one in every 10 women within the reproductive, general population (Macer 2012). It is a chronic disease with severe pain that impacts negatively on physical, mental and social well‐being (Klein 2014). In addition, the cost of endometriosis is high in both economic and psychosocial terms (Matthias 1996, Simoens 2012).\nTreatment availability 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. One of the available treatment options is treatment with GnRHas. While GnRHas are not free of side effects, it is important to know how well they perform in comparison to other medical treatments and placebo.\nThis review will evaluate the effect of GnRHas specifically on the relief of pain and on bone mineral density in symptomatic women with endometriosis. This review is a combination of two previously published Cochrane Reviews on GnRHas for bone mineral density (Farmer 2003) and for pain associated with endometriosis (Brown 2010). It was decided to merge both reviews, in order to provide the best overview of the use of GnRHas in women with endometriosis.\nObjectives\nTo assess the effectiveness and safety of gonadotrophin‐releasing hormone analogues (GnRHas) in the treatment of endometriosis.\nMethods\nCriteria for considering studies for this review\nTypes of studies\nAll randomised controlled trials (RCTs) comparing the use of GnRHas in the treatment of symptomatic endometriosis will be eligible for inclusion. Cross‐over trials will be included in the review providing that data from before and after cross‐over are available and only the first‐arm data are used for analysis. We will exclude trials that used self‐reporting of endometriosis, as well as quasi‐randomised and non‐randomised studies (case control studies, cohort studies).\nTypes of participants\nPre‐menopausal women with symptoms ascribed to endometriosis will be eligible for inclusion. For a trial to be included, the clinical diagnosis of endometriosis must have been made by direct visualisation (laparoscopy or laparotomy) or from ultrasonographic imaging or magnetic resonance imaging (MRI). We will exclude women with asymptomatic disease or infertility as the only presenting complaint.\nTypes of interventions\nWe will include RCTs reporting the following comparisons for relieving painful symptoms associated with endometriosis and its related adverse effects.\nGnRHas versus no treatment.\nGnRHas versus placebo.\nGnRHas versus analgesics.\nGnRHas versus danazol.\nGnRHas versus intra‐uterine progestogen.\nGnRHas versus oral or injectable progestogens.\nGnRHas versus gestrinone.\nWe will also include RCTs comparing the following for relieving painful symptoms associated with endometriosis and its related adverse effects.\nDifferent doses of GnRHas.\nDifferent treatment lengths of GnRHas.\nDifferent routes of administration of GnRHas.\nDifferent treatment regimens of GnRHas.\nGnRHas versus GnRHas in conjunction with add‐back therapy (hormonal or non‐hormonal).\nGnRHas versus GnRHas in conjunction with calcium‐regulating agents.\nShould we identify trials that mention the effect of GnRHas on bone mineral density (BMD), we will consider them for inclusion providing the treatment period exceeded six months. The reason for this decision is that shorter treatment periods do not seem to treat the disease effectively (Audebert 1998).\nThe following trials will be excluded from this review.\nTrials comparing GnRHas with surgical therapies, the combined oral contraceptive pill, progesterone receptor modulators or selective oestrogen receptor modulators (SERMs), as these are included in separate Cochrane Reviews (Bafort 2020; Brown 2018; Fu 2017; van Hoesel 2021, respectively).\nTrials comparing GnRHas with GnRHas, as this is a registered title of a Cochrane Review to be conducted by Cochrane Gynaecology and Fertility (Houda 2014).\nTrials comparing GnRHas with alternative and complementary medicine such as Chinese herbs or acupuncture, as these are addressed by published Cochrane Reviews (Flower 2012 and Zhu 2011, respectively).\nTrials where GnRHas are administered in post‐surgical participants as adjuvant therapy.\nTypes of outcome measures\nThe choice of outcome measures is based on the core outcome set (COS) determined for endometriosis research (Duffy 2020). This COS was developed by conducting a systematic review and a widely supported Delphi study, in which it was determined which outcome measures in endometriosis research should definitely be requested during endometriosis trials. With this COS, a more uniform way of performing and reporting endometriosis research must be conducted.\nPrimary outcomes\nOverall pain, defined by using both quantitative measures such as visual analogue scales or categorical outcomes, at the end of treatment and at three, six, nine, twelve, eighteen and twenty‐four months' follow‐up, where possible\nThe objective measurement of bone mineral density (BMD), including dual‐energy photon absorptiometry (DPA), dual‐energy X‐ray absorptiometry (DEXA), single‐energy photon absorptiometry (SPA), single‐energy X‐ray absorptiometry (SXA) and quantitative computed tomography (QCT). Measurements taken at the lumbar spine and femoral head will be considered, whilst those at the distal forearm will be excluded because these measurements are of cortical bone which is less affected by GnRHa therapy (Whitehouse 1990; Ylikorkala 1990). Bone density measurements at the end of treatment and in the follow‐up period will be included. Measurements will be grouped according to the anatomical location of measurements and the timing of measurements.\nSecondary outcomes\nAdverse 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)\nQuality of life and factors affecting quality of life (by quality‐of‐life scores)\nImprovement in the most troublesome symptoms\nPatients' satisfaction with treatment\nCost‐effectiveness and pregnancy rate are not outcomes of this review.\nSearch methods for identification of studies\nThe search strategy of Cochrane Gynaecology and Fertility will be utilised to identify all publications that describe or might describe randomised trials of GnRHas in the treatment of symptomatic endometriosis.\nElectronic searches\nThere will be no language or date restrictions in the searches. The following electronic databases, trial registers and websites will be searched:\nCochrane Gynaecology and Fertility Group's specialised register of controlled trials; to be searched from inception to present, ProCite platform (Appendix 1);\nCENTRAL, via the Cochrane Register of Studies Online (CRSO); (now containing output from two trials registers and CINAHL), to be searched from inception to present, web platform (Appendix 2);\nMEDLINE, to be searched from 1946 to present, Ovid platform (Appendix 3);\nEmbase, to be searched from 1980 to present, Ovid platform (Appendix 4);\nPsycINFO, searched from 1806 to present, Ovid platform (Appendix 5).\nThe MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). The Embase search will be combined with the trial filter developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/what-we-do/methodology/search-filters/).\nOther web based electronic sources of trials to be searched are as follows:\nISI Web of Science, for conference abstracts;\nLILACS database, as a source of trials from the Portuguese and Spanish regions;\nClinical Study Results, for clinical trial results of marketed pharmaceuticals;\nOpenSIGLE database, for grey literature;\nGoogle, for grey literature and for trials that are not yet indexed in the major databases.\nSearching other resources\nAny relevant journals and conference abstracts that are not covered in the Cochrane Gynaecology and Fertility specialised register will be handsearched in liaison with the Group's Information Specialist, Marian Showell.\nThe reference lists of relevant articles retrieved by the search will also be handsearched, and we will personally communicate with experts in the field to obtain any additional trials. In addition, we will approach all distributors of GnRHas for details of unpublished trials of GnRHas known to, or undertaken by, them or their parent companies.\nData collection and analysis\nSelection of studies\nTwo review authors (VV and MK) will independently scan the search results for relevant titles and abstracts and will remove those that are clearly irrelevant. The full text of all potentially eligible studies will be retrieved. Two review authors (VV and MK) will independently examine the full‐text articles for compliance with the inclusion criteria. Authors will correspond with study investigators to clarify study eligibility. Communication with study authors will be documented in the appendices. Where required, disagreements regarding study eligibility will be resolved by consensus or by the assessment of a third review author (JM).\nData extraction and management\nData extraction will be conducted independently by two review authors (VV and MK). Data extraction forms will be developed and pilot‐tested by the authors. Where studies have multiple publications, the main trial report will be used as the reference and additional details supplemented from secondary papers. Authors will correspond with study investigators in order to resolve any data queries as required. When disagreements arise between the two review authors, a third review author will be contacted to resolve the dispute.\nAssessment of risk of bias in included studies\nAssessment of the risk of bias in the included studies will be undertaken by two of the review authors, using the Cochrane 'Risk of Bias' tool (Higgins 2011). The assessment will be based on allocation (random sequence generation and allocation concealment), blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other bias. Should uncertainty arise, or discrepancy between the two review authors (VV and MK), a third review author will be contacted to make further assessment. When a study protocol is available, we will assess whether there are differences between the study protocol and published results.\nIf necessary, additional information will be sought from the principal investigator of the original trial. All judgements will be fully described and the conclusions presented in the 'Risk of bias' table.\nMeasures of treatment effect\nFor continuous data like pain and BMD scores, mean differences (MDs) with 95% confidence intervals (CIs) will be reported using change‐from‐baseline scores. When similar outcomes are reported on different scales we intend to calculate standardised mean differences (SMDs). Ordinal data (e.g. quality‐of‐life scores) will be treated as continuous data. A summary statistic for each outcome will be calculated using a fixed‐effect model and a 95% CI. For dichotomous data, we will calculate for each study a Mantel‐Haenszel risk ratio (RR) with corresponding 95% CI.\nUnit of analysis issues\nData will be presented according to each woman randomised. In cross‐over trials only the first‐arm data will be used for analysis where data are available, and in case data are not available the primary author will be contacted.\nDealing with missing data\nThe data will be analysed on an intention‐to‐treat basis as far as possible, and attempts will be made to obtain missing data from the original investigators. If studies report sufficient detail to calculate MDs, but provide no information on associated standard deviation (SD), the outcome will be assumed to have SD equal to the highest SD from other studies within the same analysis. For other outcomes, only the available data will be analysed.\nAssessment of heterogeneity\nThe review authors will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta‐analysis to provide a meaningful summary. Statistical heterogeneity will be assessed using the I2 statistic (Higgins 2019). An I2 measurement greater than 50% indicates substantial heterogeneity; when this is detected, possible explanations will be explored in subgroup and sensitivity analyses where the quality of the studies is also taken into account.\nAssessment of reporting biases\nIn view of the difficulty of detecting and correcting for publication bias and other reporting biases, we will aim to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there are ten or more studies in an analysis, we will use a funnel plot to explore the possibility of small‐study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies)\nData synthesis\nWhen studies are sufficiently similar, the data from primary studies will be combined using the fixed‐effect model. The primary analysis will only include trials with low risk of selection bias.\nSubgroup analysis and investigation of heterogeneity\nData derived in all outcome measurements will be divided into subgroups by dosage (low or high, as defined by study); duration of treatment (three, six, nine, twelve, eighteen and twenty‐four months); route of administration (intranasal, intramuscular, subcuticular or depot injection); and drug regimens.\nSensitivity analysis\nSensitivity analyses will be conducted for the primary outcomes to determine whether the conclusions are robust to arbitrary decisions made regarding the eligibility and analysis. These analyses will include consideration of whether our conclusions would have differed in the following situations.\nIf all studies were included in the analysis.\nIf studies with outlying results were excluded.\nIf alternative imputation strategies were adopted.\nIf a random‐effects model was adopted.\nSummary of findings and assessment of the certainty of the evidence\nWe will prepare a 'Summary of findings' table using GRADEpro GDT software and Cochrane methods (Schünemann 2021). This table will evaluate the overall quality of the body of evidence for the main review outcomes, namely overall pain, the objective measurement of BMD, and adverse effects, for the following main comparisons.\nGnRHas versus no treatment.\nGnRHas versus placebo.\nGnRHas versus danazol.\nAdditional 'Summary of findings' tables will be also prepared for the main review outcomes for other important comparisons (GnRHas versus analgesics; and GnRHas versus intra‐uterine progestogen device). We will assess the quality of the evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate, low or very low) will be made by two review authors working independently, with disagreements resolved by discussion. Judgements will be justified, documented, and incorporated into reporting of results for each outcome. We plan to extract study data, format our comparisons in data tables and prepare a 'Summary of findings' table before writing the results and conclusions of our review.\nNotes\nThis review is a merge of two existing Cochrane Reviews (Farmer 2003 and Brown 2010).\nAcknowledgements\nWe thank everyone at Cochrane Gynaecology and Fertility, in particular Marian Showell, Information Specialist, who contributed to the search strategy. We would like to thank Julie Brown, Alice Pan, Roger Hart, Jessica E Farmer, Andrew Prentice, Andrew Breeze, Gaity Ahmad, Andrew Watson, and Andy Pick for contributing to the previous versions of the review.\nWe thank Rik van Eekelen, Edgardo Somigliana, Andy Watson, and Ankita Mukherjee (consumer) for their valuable peer review comments.\nAppendices\nAppendix 1. Cochrane Gynaecology and Fertility (CGF) specialist register search strategy\nProCite platform\nFrom inception to present\nKeywords CONTAINS \"endometriosis\" or \"The Endometriosis Health Profile\" or \"dyspareunia\" or \"pelvic pain\" or \"pain‐dyspareunia\" or \"pain‐endometriosis\" or \"pain‐pelvic\" or \"dyschezia\" or \"bone density\" or \"bone mineral density\" or \"bone turnover\" or \"bone turnover estimates\" or \"bone turnover markers\" or \"bone metabolism\" or \"bone metabolism indicators\" or Title CONTAINS \"endometriosis\" or \"The Endometriosis Health Profile\" or \"dyspareunia\" or \"pelvic pain\" or \"pain‐dyspareunia\" or \"pain‐endometriosis\" or \"pain‐pelvic\" or \"dyschezia\" or \"bone density\" or \"bone mineral density\" or \"bone turnover\" or \"bone turnover estimates\" or \"bone turnover markers\" or \"bone metabolism\" or \"bone metabolism indicators\"\nAND\nKeywords CONTAINS \"Gonadorelin\" or \"GnRh\" or \"GnRHa\" or \"GnRH agonist\" or \"GnRH agonists\" 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 \"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 \"triptorelin\" or \"Zoladex\" or \"Lupron\" or \"luprorelix\" or \"decapeptyl\" or \"decapeptyl\" or \"decapeptyl‐daily\" or \"decapeptyl‐depot\" or \"elagolix\" or \"Relugolix\" or linzagolix or Title CONTAINS \"GnRH agonist\" or \"GnRH agonists\" or \"Gonadorelin\" or \"GnRh\" or \"GnRHa\"\nAppendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO) search strategy\nWeb platform\nFrom inception to present\n#1 bone turnover:TI,AB,KY #2 bone loss:TI,AB,KY #3 bone adj2 densit*:TI,AB,KY #4 MESH DESCRIPTOR Bone Density EXPLODE ALL TREES #5 MESH DESCRIPTOR Endometriosis EXPLODE ALL TREES #6 Endometrio*:TI,AB,KY #7 dyspareunia:TI,AB,KY #8 (Dyschesia or Dyschezia):TI,AB,KY #9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 #10 MESH DESCRIPTOR Gonadotropin‐Releasing Hormone EXPLODE ALL TREES #11 gonadotropin‐releasing:TI,AB,KY #12 gonadotrophin‐releasing:TI,AB,KY #13 (luteini?ing hormone‐releasing hormone*):TI,AB,KY #14 (lhrh* or lhfshrh):TI,AB,KY #15 gonadorelin*:TI,AB,KY #16 (fsh releasing hormone*):TI,AB,KY #17 (lh rh*):TI,AB,KY #18 (buserelin or goserelin or leuprolide):TI,AB,KY #19 (triptorelin or nafarelin):TI,AB,KY #20 (leuprorelin or naferelin):TI,AB,KY #21 (GnRH* or Gn‐RH*):TI,AB,KY #22 (leuprorelin or naferelin):TI,AB,KY #23 (suprecur or suprefact):TI,AB,KY #24 (Zoladex or lupron):TI,AB,KY #25 (prostap or enantone):TI,AB,KY #26 (lucrin or trenantone*):TI,AB,KY #27 (synarel or synarella):TI,AB,KY #28 (decapeptyl or gonapeptyl):TI,AB,KY #29 (Elagolix or Relugolix):TI,AB,KY #30 (luliberin or cystorelin):TI,AB,KY #31 (dirigestran or factrel or gonadoliberin):TI,AB,KY #32 linzagolix or deslorelin #33 #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 OR #28 OR #29 OR #30 OR #31 OR #32 #34 #9 AND #33\nAppendix 3. MEDLINE search strategy\nOvid platform\nFrom 1946 to present\n1 exp Endometriosis/ 2 dyspareunia.tw. 3 (Dyschesia or Dyschezia).tw. 4 Endometrio*.tw. 5 ((cycl* or menstru*) adj2 pain*).tw. 6 Bone Density/ 7 (bone adj2 densit*).tw. 8 bone loss.tw. 9 bone turnover.tw. 10 or/1‐9 11 exp gonadotropin‐releasing hormone/ 12 (gonadotropin‐releasing or gonadotrophin‐releasing).tw. 13 (GnRH* or Gn‐RH*).tw. 14 luteini?ing hormone‐releasing hormone*.tw. 15 (lhrh* or lhfshrh).tw. 16 gonadorelin*.tw. 17 fsh releasing hormone*.tw. 18 lh rh*.tw. 19 (buserelin or goserelin or leuprolide).tw. 20 (triptorelin or nafarelin).tw. 21 (leuprorelin or naferelin).tw. 22 (suprecur or suprefact).tw. 23 (Zoladex or lupron).tw. 24 (prostap or enantone).tw. 25 (lucrin or trenantone$).tw. 26 (synarel or synarella).tw. 27 (decapeptyl or gonapeptyl).tw. 28 (Elagolix or Relugolix).tw. 29 (luliberin or cystorelin).tw. 30 (dirigestran or factrel or gonadoliberin).tw. 31 (linzagolix or deslorelin).tw. 32 or/11‐31 33 10 and 32 34 randomized controlled trial.pt. 35 controlled clinical trial.pt. 36 randomized.ab. 37 randomised.ab. 38 placebo.tw. 39 clinical trials as topic.sh. 40 randomly.ab. 41 trial.ti. 42 (crossover or cross‐over or cross over).tw. 43 or/34‐42 44 exp animals/ not humans.sh. 45 43 not 44 46 33 and 45\nAppendix 4. Embase search strategy\nOvid platform\nFrom 1980 to present\n1 exp endometriosis/ 2 Endometrio*.tw. 3 dyspareunia.tw. 4 (Dyschesia or Dyschezia).tw. 5 or/1‐4 6 exp gonadorelin/ 7 ((gonadotropin‐releasing or gonadotrophin‐releasing) adj2 (analog* or agonist* or antagonist*)).tw. 8 ((GnRH* or Gn‐RH*) adj2 (analog* or agonist* or antagonist*)).tw. 9 (GnRH a or GnRHa).tw. 10 luteini?ing hormone‐releasing hormone*.tw. 11 (lhrh* or lhfshrh).tw. 12 gonadorelin*.tw. 13 fsh releasing hormone*.tw. 14 lh rh*.tw. 15 (buserelin or goserelin or leuprolide).tw. 16 (triptorelin or nafarelin).tw. 17 (leuprorelin or naferelin).tw. 18 (suprecur or suprefact).tw. 19 (Zoladex or lupron).tw. 20 (prostap or enantone).tw. 21 (lucrin or trenantone*).tw. 22 (synarel or synarella).tw. 23 (decapeptyl or gonapeptyl).tw. 24 (Elagolix or Relugolix).tw. 25 (luliberin or cystorelin).tw. 26 (dirigestran or factrel or gonadoliberin).tw. 27 (linzagolix or deslorelin).tw. 28 or/6‐27 29 Clinical Trial/ 30 Randomized Controlled Trial/ 31 controlled clinical trial/ 32 multicenter study/ 33 Phase 3 clinical trial/ 34 Phase 4 clinical trial/ 35 exp randomization/ 36 Single Blind Procedure/ 37 Double Blind Procedure/ 38 Crossover Procedure/ 39 Placebo/ 40 Randomi?ed controlled trial$.tw. 41 Rct.tw. 42 (random$ adj2 allocat$).tw. 43 Single blind$.tw. 44 Double blind$.tw. 45 ((treble or triple) adj blind$).tw. 46 placebo$.tw. 47 prospective study/ 48 or/29‐47 49 case study/ 50 case report.tw. 51 abstract report/ or letter/ 52 Editorial.pt. 53 Letter.pt. 54 Note.pt. 55 or/49‐54 56 48 not 55 57 5 and 28 and 56\nAppendix 5. PsycINFO search strategy\nOvid platform\nFrom 1806 to present\n1 exp menstrual disorders/ 2 Endometrio*.tw. 3 1 and 2 4 Endometrio*.tw. 5 dyspareunia.tw. 6 (Dyschesia or Dyschezia).tw. 7 4 or 5 or 6 8 3 or 7 9 exp Gonadotropic Hormones/ 10 (gonadotropin‐releasing or gonadotrophin‐releasing).tw. 11 (GnRH* or Gn‐RH*).tw. 12 luteini?ing hormone‐releasing hormone*.tw. 13 (lhrh* or lhfshrh).tw. 14 gonadorelin*.tw. 15 fsh releasing hormone*.tw. 16 lh rh*.tw. 17 (buserelin or goserelin or leuprolide).tw. 18 (triptorelin or nafarelin).tw. 19 (leuprorelin or naferelin).tw. 20 (Zoladex or lupron).tw. 21 (prostap or enantone).tw. 22 (lucrin or trenantone*).tw. 23 (decapeptyl or gonapeptyl).tw. 24 (Elagolix or Relugolix).tw. 25 (luliberin or cystorelin).tw. 26 (dirigestran or factrel or gonadoliberin).tw. 27 (linzagolix or deslorelin).tw. 28 or/9‐27 29 8 and 28\nContributions of authors\nVeerle Veth took the lead in writing the protocol. They developed the objectives, selection criteria, methods, background.\nMajorie van de Kar contributed to the background, and search strategy.\nJames Duffy provided feedback on the protocol and reviewed the manuscript.\nMadelon van Wely provided feedback on the protocol and reviewed the manuscript.\nVelja Mijatovic provided feedback on the protocol and reviewed the manuscript.\nJacques Maas provided feedback on the protocol and reviewed the manuscript.\nSources of support\nInternal sources\nNo sources of support provided\nExternal sources\nNo sources of support provided\nDeclarations of interest\nVV: none known\nMvK: none known\nJD: none known\nJM: none known\nMvW: none known\nVM: none known\nNew\nReferences\nAdditional references\nAudebert 1998\n- Audebert A, Descamps P, Marret H, Ory-Lavollee L, Bailleul F, Hamamah S. Pre or post-operative medical treatment with nafarelin in stage III-IV endometriosis: a French multicenter study. 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