{"paper_id":"95d49230-c3cf-48b4-b578-011cf276ccb0","body_text":"Cochrane\nLibrary\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis\n(Review)\n/uni00A0\n/uni00A0Veth VB, van de Kar MMA, Duﬀy JMN, van Wely M, Mijatovic V, Maas JWM /uni00A0\n/uni00A0 Veth/uni00A0VB, van/uni00A0de Kar/uni00A0MMA, Duﬀy/uni00A0JMN, van/uni00A0Wely/uni00A0M, Mijatovic/uni00A0V, Maas/uni00A0JWM. \nGonadotropin-releasing hormone analogues for endometriosis. \nCochrane Database of Systematic Reviews 2023, Issue 6. Art. No.: CD014788. \nDOI: 10.1002/14651858.CD014788.pub2.\n/uni00A0\n/uni00A0 www.cochranelibrary.com /uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)/uni00A0\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nT A B L E /uni00A0 O F /uni00A0 C O N T E N T S\nABSTRACT..................................................................................................................................................................................................... 1\nPLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2\nSUMMARY OF FINDINGS .............................................................................................................................................................................. 5\nBACKGROUND.............................................................................................................................................................................................. 11\nOBJECTIVES.................................................................................................................................................................................................. 12\nMETHODS..................................................................................................................................................................................................... 12\nRESULTS........................................................................................................................................................................................................ 14\nFigure 1.................................................................................................................................................................................................. 16\nFigure 2.................................................................................................................................................................................................. 18\nFigure 3.................................................................................................................................................................................................. 19\nDISCUSSION.................................................................................................................................................................................................. 32\nAUTHORS' CONCLUSIONS........................................................................................................................................................................... 33\nACKNOWLEDGEMENTS................................................................................................................................................................................ 34\nREFERENCES................................................................................................................................................................................................ 35\nCHARACTERISTICS OF STUDIES.................................................................................................................................................................. 45\nDATA AND ANALYSES.................................................................................................................................................................................... 149\nAnalysis 1.1. Comparison 1: GnRHas versus placebo, Outcome 1: Relief of overall pain - dichotomous - decrease of pain........... 150\nAnalysis 1.2. Comparison 1: GnRHas versus placebo, Outcome 2: Adverse eﬀects - dichotomous................................................. 151\nAnalysis 2.1. Comparison 2: GnRHas versus placebo - all studies included, Outcome 1: Relief of overall pain - dichotomous....... 153\nAnalysis 2.2. Comparison 2: GnRHas versus placebo - all studies included, Outcome 2: Relief of overall pain - dichotomous -\ndecrease of pain....................................................................................................................................................................................\n154\nAnalysis 2.3. Comparison 2: GnRHas versus placebo - all studies included, Outcome 3: Relief of overall pain - continuous.......... 155\nAnalysis 2.4. Comparison 2: GnRHas versus placebo - all studies included, Outcome 4: Adverse eﬀects - dichotomous............... 156\nAnalysis 2.5. Comparison 2: GnRHas versus placebo - all studies included, Outcome 5: Quality of life - continuous..................... 157\nAnalysis 3.1. Comparison 3: GnRHas versus danazol, Outcome 1: Relief of overall pain - dichotomous......................................... 159\nAnalysis 3.2. Comparison 3: GnRHas versus danazol, Outcome 2: Relief of overall pain - continuous............................................ 160\nAnalysis 3.3. Comparison 3: GnRHas versus danazol, Outcome 3: Adverse eﬀects - dichotomous.................................................. 162\nAnalysis 4.1. Comparison 4: GnRHas versus danazol - all studies included, Outcome 1: Relief of overall pain - dichotomous....... 167\nAnalysis 4.2. Comparison 4: GnRHas versus danazol - all studies included, Outcome 2: Relief of overall pain - continuous.......... 169\nAnalysis 4.3. Comparison 4: GnRHas versus danazol - all studies included, Outcome 3: Bone mineral density of spinal bone mass\n- continuous...........................................................................................................................................................................................\n170\nAnalysis 4.4. Comparison 4: GnRHas versus danazol - all studies included, Outcome 4: Adverse eﬀects - dichotomous............... 171\nAnalysis 4.5. Comparison 4: GnRHas versus danazol - all studies included, Outcome 5: Improvement of most troublesome\nsymptoms - dichotomous.....................................................................................................................................................................\n177\nAnalysis 5.1. Comparison 5: GnRHas versus intra-uterine progestagen device - all studies included, Outcome 1: Relief of overall\npain - continuous..................................................................................................................................................................................\n178\nAnalysis 5.2. Comparison 5: GnRHas versus intra-uterine progestagen device - all studies included, Outcome 2: Quality of life\n- continuous...........................................................................................................................................................................................\n179\nAnalysis 6.1. Comparison 6: GnRHas versus oral or injectable progestogens, Outcome 1: Relief of overall pain - continuous....... 180\nAnalysis 6.2. Comparison 6: GnRHas versus oral or injectable progestogens, Outcome 2: Adverse eﬀects - dichotomous............ 181\nAnalysis 7.1. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 1: Relief of overall\npain - dichotomous...............................................................................................................................................................................\n186\nAnalysis 7.2. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 2: Relief of overall\npain - continuous..................................................................................................................................................................................\n187\nAnalysis 7.3. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 3: Bone mineral\ndensity of spinal bone mass - continuous..........................................................................................................................................\n189\nAnalysis 7.4. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 4: Adverse eﬀects\n- dichotomous.......................................................................................................................................................................................\n190\nAnalysis 7.5. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 5: Adverse eﬀects\n- continuous...........................................................................................................................................................................................\n192\nAnalysis 7.6. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 6: Quality of life -\ncontinuous.............................................................................................................................................................................................\n193\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\ni\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 7.7. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 7: Improvement of\nmost troublesome symptoms - dichotomous.....................................................................................................................................\n194\nAnalysis 7.8. Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 8: Improvement of\nmost troublesome symptoms - continuous........................................................................................................................................\n195\nAnalysis 8.1. Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 1: Relief of overall pain - continuous....... 198\nAnalysis 8.2. Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 2: Bone mineral density of spinal bone\nmass - continuous.................................................................................................................................................................................\n199\nAnalysis 8.3. Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 3: Adverse eﬀects - dichotomous........... 200\nAnalysis 9.1. Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 1: Relief of overall pain -\n200 /uni03BCg versus 400 /uni03BCg nafarelin - continuous......................................................................................................................................\n204\nAnalysis 9.2. Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 2: Relief of overall pain -\n400 /uni03BCg versus 800 /uni03BCg nafarelin - dichotomous...................................................................................................................................\n205\nAnalysis 9.3. Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 3: Adverse eﬀects - 200\n/uni03BCg versus 400 /uni03BCg nafarelin - dichotomous..........................................................................................................................................\n206\nAnalysis 9.4. Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 4: Adverse eﬀects - 3.75\nmg versus 1.88 mg leuprolide acetate - continuous...........................................................................................................................\n207\nAnalysis 9.5. Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 5: Improvement of most\ntroublesome symptoms - 400 /uni03BCg versus 800 /uni03BCg nafarelin - dichotomous........................................................................................\n207\nAnalysis 10.1. Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies included, Outcome 1: Relief of overall\npain - 3 months vs 6 months - continuous.........................................................................................................................................\n209\nAnalysis 10.2. Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies included, Outcome 2: Bone mineral\ndensity of spinal bone mass - 3 months vs 6 months - continuous..................................................................................................\n209\nAnalysis 10.3. Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies included, Outcome 3: Bone mineral\ndensity of proximal femoral bone - 3 months vs 6 months - continuous.........................................................................................\n210\nAnalysis 11.1. Comparison 11: GnRHas versus GnRHas (route of administration), Outcome 1: Relief of overall pain - IN versus\nSC - dichotomous..................................................................................................................................................................................\n211\nAnalysis 11.2. Comparison 11: GnRHas versus GnRHas (route of administration), Outcome 2: Adverse eﬀects - IN vs SC -\ndichotomous..........................................................................................................................................................................................\n212\nAnalysis 12.1. Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 1: Relief of\noverall pain - IN versus SC - dichotomous..........................................................................................................................................\n214\nAnalysis 12.2. Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 2: Relief of\noverall pain - IN versus IM - dichotomous...........................................................................................................................................\n215\nAnalysis 12.3. Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 3: Adverse\neﬀects - IN vs SC - dichotomous..........................................................................................................................................................\n216\nAnalysis 12.4. Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 4: Adverse\neﬀects - IN versus IM depot - dichotomous........................................................................................................................................\n217\nAnalysis 12.5. Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 5: Bone mineral\ndensity of spinal bone mass - IN vs IM depot - continuous...............................................................................................................\n218\nAnalysis 13.1. Comparison 13: GnRHas versus GnRHas (diﬀerent treatment regimens) - all studies included, Outcome 1: Relief\nof overall pain - monthly versus 3-monthly depot leuprolide acetate - continuous........................................................................\n220\nAnalysis 13.2. Comparison 13: GnRHas versus GnRHas (diﬀerent treatment regimens) - all studies included, Outcome 2: Adverse\neﬀects - monthly versus 3-monthly depot leuprolide acetate - dichotomous..................................................................................\n221\nAnalysis 14.1. Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome 1:\nRelief of overall pain - dichotomous...................................................................................................................................................\n224\nAnalysis 14.2. Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome 2:\nRelief of overall pain - continuous.......................................................................................................................................................\n225\nAnalysis 14.3. Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome 3:\nBone mineral density of spinal bone mass - continuous...................................................................................................................\n226\nAnalysis 14.4. Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome\n4: Adverse eﬀects - dichotomous.........................................................................................................................................................\n227\nAnalysis 14.5. Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome\n5: Quality of life - continuous...............................................................................................................................................................\n229\nAnalysis 14.6. Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome 6:\nImprovement of most troublesome symptoms - continuous/uni00A0...........................................................................................................\n229\nAnalysis 15.1. Comparison 15: GnRHas versus GnRHas in conjunction with calcium-regulating agents, Outcome 1: Bone mineral\ndensity of spinal bone mass - continuous..........................................................................................................................................\n230\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\nii\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 15.2. Comparison 15: GnRHas versus GnRHas in conjunction with calcium-regulating agents, Outcome 2: Improvement\nof most troublesome symptoms - dichotomous................................................................................................................................\n231\nAnalysis 16.1. Comparison 16: GnRHas versus GnRHas in conjunction with calcium-regulating agents - all studies included,\nOutcome 1: Bone mineral density of spinal bone mass - continuous...............................................................................................\n232\nAnalysis 16.2. Comparison 16: GnRHas versus GnRHas in conjunction with calcium-regulating agents - all studies included,\nOutcome 2: Improvement of most troublesome symptoms - dichotomous.....................................................................................\n232\nAPPENDICES................................................................................................................................................................................................. 232\nHISTORY........................................................................................................................................................................................................ 236\nCONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 236\nDECLARATIONS OF INTEREST..................................................................................................................................................................... 237\nSOURCES OF SUPPORT............................................................................................................................................................................... 237\nDIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 237\nNOTES........................................................................................................................................................................................................... 237\nINDEX TERMS............................................................................................................................................................................................... 237\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\niii\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n[Intervention Review]\nGonadotropin-releasing hormone analogues for endometriosis\nVeerle B Veth1, Majorie MA van de Kar2, James MN Duﬀy3, Madelon van Wely4, Velja Mijatovic5, Jacques WM Maas6\n1Department of Obstetrics & Gynecology, Maastricht University Medical Center (MUMC+), Maastricht, Netherlands. 2Emergency\nDepartment, Laurentius Ziekenhuis, Roermond, Netherlands. 3King's Fertility, The Fetal Medicine Research Institute, London, UK.\n4Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands. 5Academic Endometriosis\nCenter, Department of Reproductive Medicine, Amsterdam UMC, Amsterdam, Netherlands. 6Department of Obstetrics & Gynaecology,\nMaastricht University Medical Center (MUMC+), Maastricht, Netherlands\nContact: Veerle B Veth, veerle.veth@mumc.nl.\nEditorial group: Cochrane Gynaecology and Fertility Group.\nPublication status and date: New, published in Issue 6, 2023.\nCitation: Veth/uni00A0VB, van/uni00A0de Kar/uni00A0MMA, Duﬀy/uni00A0JMN, van/uni00A0Wely/uni00A0M, Mijatovic/uni00A0V, Maas/uni00A0JWM. Gonadotropin-releasing hormone analogues for\nendometriosis. Cochrane Database of Systematic Reviews 2023, Issue 6. Art. No.: CD014788. DOI: 10.1002/14651858.CD014788.pub2.\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\nA B S T R A C T\nBackground\nEndometriosis is a common gynaecological condition aﬀecting 6 to 11% of reproductive-age women and may cause dyspareunia,\ndysmenorrhoea, and infertility. One treatment strategy is medical therapy with gonadotrophin-releasing hormone analogues (GnRHas) to\nreduce pain due to endometriosis. One of the adverse eﬀects of GnRHas is a decreased bone mineral density. In addition to assessing the\neﬀect on pain, quality of life, most troublesome symptom and patients' satisfaction, the current review also evaluated the eﬀect on bone\nmineral density and risk of adverse eﬀects in women with endometriosis who use GnRHas versus other treatment options.\nObjectives\nTo assess the eﬀectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis\nand to determine the eﬀects of GnRHas on bone mineral density of women with endometriosis.\nSearch methods\nWe searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and the trial\nregistries in May 2022 together with reference checking and contact with study authors and experts in the field to identify additional studies.\nSelection criteria\nWe included randomised controlled trials (RCTs) which compared GnRHas with other hormonal treatment options, including analgesics,\ndanazol, intra-uterine progestogens, oral or injectable progestogens, gestrinone and also GnRHas compared with no treatment or placebo.\nTrials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) or calcium-regulation agents\nwere also included in this review.\nData collection and analysis\nWe used standard methodology as recommended by Cochrane. Primary outcomes are relief of overall pain and the objective measurement\nof bone mineral density. Secondary outcomes include adverse eﬀects, quality of life, improvement in the most troublesome symptoms\nand patient satisfaction.\nDue to high risk of bias associated with some of the studies, primary analyses of all review outcomes were restricted to studies at low risk\nof selection bias. Sensitivity analysis including all studies was then performed.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n1\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMain results\nSeventy-two studies involving 7355 patients were included. The evidence was very low to low quality: the main limitations of all studies\nwere serious risk of bias due to poor reporting of study methods, and serious imprecision.\nTrials comparing GnRHas versus no treatment\nWe did not identify any studies.\nTrials comparing GnRHas versus placebo\nThere may be a decrease in overall pain, reported as pelvic pain scores (RR 2.14; 95% CI 1.41 to 3.24, 1 RCT, n = 87, low-certainty evidence),\ndysmenorrhoea scores (RR 2.25; 95% CI 1.59 to 3.16, 1 RCT, n = 85, low-certainty evidence), dyspareunia scores (RR 2.21; 95% CI 1.39 to 3.54,\n1 RCT, n = 59, low-certainty evidence), and pelvic tenderness scores (RR 2.28; 95% CI 1.48 to 3.50, 1 RCT, n = 85, low-certainty evidence) a/f_ter\nthree months of treatment. We are uncertain of the eﬀect for pelvic induration, based on the results found a/f_ter three months of treatment\n(RR 1.07; 95% CI 0.64 to 1.79, 1 RCT, n = 81, low-certainty evidence). Besides, treatment with GnRHas may be associated with a greater\nincidence of hot flushes at three months of treatment (RR 3.08; 95% CI 1.89 to 5.01, 1 RCT, n = 100, low-certainty evidence).\nTrials comparing GnRHas versus danazol\nFor overall pain, for women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved\nand completely resolved. We are uncertain about the eﬀect on relief of overall pain, when a subdivision was made for overall pain (MD\n-0.30; 95% CI -1.66 to 1.06, 1 RCT, n = 41, very low-certainty evidence), pelvic pain (MD 0.20; 95% CI -0.26 to 0.66, 1 RCT, n = 41, very low-\ncertainty evidence), dysmenorrhoea (MD 0.10; 95% CI -0.49 to 0.69, 1 RCT, n = 41, very low-certainty evidence), dyspareunia (MD -0.20;\n95% CI -0.77 to 0.37, 1 RCT, n = 41, very low-certainty evidence), pelvic induration (MD -0.10; 95% CI -0.59 to 0.39, 1 RCT, n = 41, very low-\ncertainty evidence), and pelvic tenderness (MD -0.20; 95% CI -0.78 to 0.38, 1 RCT, n = 41, very low-certainty evidence) a/f_ter three months\nof treatment. For pelvic pain (MD 0.50; 95% CI 0.10 to 0.90, 1 RCT, n = 41, very low-certainty evidence) and pelvic induration (MD 0.70; 95%\nCI 0.21 to 1.19, 1 RCT, n = 41, very low-certainty evidence), the complaints may decrease slightly a/f_ter treatment with GnRHas, compared\nto danazol, for six months of treatment.\nTrials comparing GnRHas versus analgesics\nWe did not identify any studies.\nTrials comparing GnRHas versus intra-uterine progestogens\nWe did not identify any low risk of bias studies.\nTrials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents\nThere may be a slight decrease in bone mineral density (BMD) a/f_ter 12 months treatment with GnRHas, compared to GnRHas in conjunction\nwith calcium-regulating agents for anterior-posterior spine (MD -7.00; 95% CI -7.53 to -6.47, 1 RCT, n = 41, very low-certainty evidence) and\nlateral spine (MD -12.40; 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low-certainty evidence).\nAuthors' conclusions\nFor relief of overall pain, there may be a slight decrease in favour of treatment with GnRHas compared to placebo or oral or injectable\nprogestogens. We are uncertain about the eﬀect when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. For BMD,\nthere may be a slight decrease when women are treated with GnRHas, compared to gestrinone. There was a bigger decrease of BMD in\nfavour of GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. However, there may be a slight increase in adverse\neﬀects when women are treated with GnRHas, compared to placebo or gestrinone.\nDue to a very low to low certainty of the evidence, a wide range of outcome measures and a wide range of outcome measurement\ninstruments, the results should be interpreted with caution.\nP L A I N /uni00A0 L A N G U A G E /uni00A0 S U M M A R Y\nGonadotrophin-releasing hormone analogues for pain associated with endometriosis\nWhat are the benefits and risks of gonadotrophin-releasing hormone analogues (GnRHas) for pain associated with endometriosis?\nKey messages\nGnRHas oﬀer more pain reduction compared to placebo or progestogens. However, the largest decrease in bone mineral density (BMD)\nwas found when using GnRHas, compared to a diﬀerent hormone called gestrinone and GnRHas together with calcium-regulating agents\n(acting on bone).\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n2\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMost adverse eﬀects were hot flushes for patients treated with GnRHas or gestrinone (hormone) and weight gain when treated with danazol\n(hormone).\nFurther, well-designed research is needed to provide better understanding of the benefits and risks of using GnRHas and other hormonal\ntreatment options for pain associated with endometriosis.\nWhat is endometriosis?\nEndometriosis is a common condition, aﬀecting women of childbearing age, and is usually due to the presence of endometrial-like tissue\nin places other than the uterus. The most reported symptoms are pain and infertility.\nWhat are GnRHas?\nGnRHas are a group of drugs o/f_ten used to treat endometriosis. GnRHas are a synthetic form of the hormone gonadorelin, released\nby the hypothalamus in the brain. They stimulate the pituitary gland in the brain to produce luteinising hormone (LH) and follicle-\nstimulating hormone (FSH), both reproductive hormones. These reproductive hormones further stimulate the production of progesterone\nand oestrogen in the ovaries, the hormones that control your menstrual cycle.\nHowever, continued use of GnRHas results in a suppression of ovarian function and therefore reduces oestrogen and progesterone levels.\nThis will in turn result in a decrease of endometrial tissue and therefore reduce complaints of endometriosis.\nBecause GnRHas temporarily stop the production of reproductive hormones, they mimic symptoms of menopause, including a decrease\nin bone mineral density (the amount of calcium and other minerals present in your bones).\nWhat did we want to find out?\nIn the current review, we looked at women with endometriosis, who were treated with GnRHas, and compared this treatment with other\nforms of hormonal treatment.\nWe wanted to find out if GnRHas were better than any other hormonal treatment to improve pain and to see their eﬀect on bone mineral\ndensity.\nAdditionally, we wanted to find out if GnRHas were associated with an improved quality of life and also unveil any unwanted eﬀects.\nWhat did we do?\nThe review involved searching for studies that investigated the eﬀect of GnRHas compared with placebo (dummy treatment) and other\nhormonal treatment in women with endometriosis. We compared and summarised the results of the studies and rated our confidence in\nthe evidence, based on factors such as study methods and sizes.\nWhat did we find?\nWe found 72 trials that involved 7355 women with endometriosis.\n- A diﬀerence in overall pain, reported as pain reduction was seen in favour of GnRHas compared to placebo. We also saw that women\ntreated with GnRHas had less pelvic pain reduction and an increase in endometriotic lesions a/f_ter six months of treatment, compared to\ndanazol.\n- A/f_ter six months of treatment, there was a greater decrease of pain for women treated with GnRHas compared to gestrinone.\n- No diﬀerence was seen in pain scores between women treated with GnRHas compared to other hormonal treatment options.\n- Most adverse eﬀects were seen in women treated with GnRHas compared to placebo (hot flushes), with danazol (weight gain) and\ngestrinone (hot flushes).\n- A greater decrease in bone mineral density was found in GnRHas compared to gestrinone and GnRHas in conjunction with calcium-\nregulating agents.\n- For the other comparisons examined in the current review, we are uncertain of the eﬀect between the examined groups. It should be\nnoted, however, that the evidence was o/f_ten of (very) low quality in the analyses undertaken for the other comparisons.\nWhat are the limitations of the evidence?\nThe included studies were of low quality mainly due to poor reporting of study methods and the inaccuracy with which the results were\nreported.\nHow up-to-date is this evidence?\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n3\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nThe evidence is up-to-date to May 2022.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n4\n\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n5\nS U M M A R Y /uni00A0 O F /uni00A0 F I N D I N G S\n/uni00A0\nSummary of findings 1. /uni00A0 GnRHas compared to no treatment for relief of overall pain associated with endometriosis and its related adverse eﬀects\nGnRHas compared to no treatment for relief of overall pain associated with endometriosis\nPopulation: Women with endometriosis\nSettings: Gynaecology clinics\nIntervention: GnRHas\nComparison: No treatment\nIllustrative comparative risks* (95% CI)\nAssumed risk Corresponding risk\nOutcomes\nNo treatment GnRHas\nRelative effect\n(95% CI)\nNo of Partici-\npants\n(studies)\nQuality of the evi-\ndence\n(GRADE)\nComments\nNo studies included for\nany outcomes\n/uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0\nGRADE Working Group grades of evidence\nHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.\nModerate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.\nLow 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.\nVery low quality: We are very uncertain about the estimate.\n/uni00A0\n/uni00A0\nSummary of findings 2. /uni00A0 GnRHas compared to placebo for relief of overall pain associated with endometriosis and its related adverse eﬀects\nGnRHas compared to placebo for relief of overall pain associated with endometriosis\nPopulation: Women with endometriosis\nSettings: Gynaecology clinic\nIntervention: GnRHas\nComparison: Placebo\nIllustrative comparative risks* (95% CI)\nAssumed risk Corresponding risk\nOutcomes\nPlacebo GnRHas\nRelative effect\n(95% CI)\nNo of Partici-\npants\n(studies)\nQuality of the\nevidence\n(GRADE)\nComments\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n6\nRelief of overall pain - reported as pelvic\npain - 3 months\n372 per 1000 796 per 1000\n(525 to 1205)\nRR 2.14\n(1.41 to 3.24)\n87\n(1 study)\n⊕⊕⊝⊝\nlow1\n/uni00A0\nRelief of overall pain - reported as dysmen-\norrhoea - 3 months\n439 per 1000 988 per 1000\n(698 to 1387)\nRR 2.25\n(1.59 to 3.16)\n87\n(1 study)\n⊕⊕⊝⊝\nlow1\n/uni00A0\nRelief of overall pain - reported as dyspare-\nunia - 3 months\n387 per 1000 855 per 1000\n(538 to 1370)\nRR 2.21\n(1.39 to 3.54)\n87\n(1 study)\n⊕⊕⊝⊝\nlow1\n/uni00A0\nRelief of overall pain - reported as pelvic\ntenderness scores- 3 months\n357 per 1000 814 per 1000\n(529 to 1250)\nRR 2.28\n(1.48 to 3.50)\n87\n(1 study)\n⊕⊕⊝⊝\nlow1\n/uni00A0\nRelief of overall pain - reported as pelvic\ninduration scores - 3 months\n405 per 1000 434 per 1000\n(259 to 726)\nRR 1.07\n(0.64 to 1.79)\n87\n(1 study)\n⊕⊕⊝⊝\nlow1\n/uni00A0\n*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\nthe comparison group and the relative effect of the intervention (and its 95% CI).\nCI: Confidence interval;\nGRADE Working Group grades of evidence\nHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.\nModerate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.\nLow 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.\nVery low quality: We are very uncertain about the estimate.\n1 Evidence based on a single trial\n/uni00A0\n/uni00A0\nSummary of findings 3. /uni00A0 GnRHas compared to analgesics for relief of overall pain associated with endometriosis and its related adverse eﬀects\nGnRHas compared to analgesics for relief of overall pain associated with endometriosis\nPopulation: Women with pain due to endometriosis\nSettings: Gynaecological clinics\nIntervention: GnRHas\nComparison: Analgesics\nOutcomes Illustrative comparative risks* (95% CI) Relative effect\n(95% CI)\nNo of Partici-\npants (studies)\nQuality of the evi-\ndence (GRADE)\nComments\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n7\nAssumed risk Corresponding risk\nAnalgesics GnRHas\nNo studies included for\nany outcomes\n/uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0\n*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\nthe comparison group and the relative effect of the intervention (and its 95% CI).\nCI: Confidence interval; RR: Risk ratio;\nGRADE Working Group grades of evidence\nHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.\nModerate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.\nLow 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.\nVery low quality: We are very uncertain about the estimate.\n/uni00A0\n/uni00A0\nSummary of findings 4. /uni00A0 GnRHas compared to danazol for relief of overall pain associated with endometriosis and its related adverse eﬀects\nGnRHas compared to danazol for relief of overall pain associated with endometriosis\nPopulation: Women with pain due to endometriosis\nSettings: Gynaecological clinics\nIntervention: GnRHas\nComparison: Danazol\nIllustrative comparative risks* (95% CI)\nAssumed risk Corresponding risk\nOutcomes\nDanazol GnRHas\nRelative effect\n(95% CI)\nNo of Partici-\npants\n(studies)\nQuality of the\nevidence\n(GRADE)\nComments\nRelief of overall pain - re-\nported as pelvic tender-\nness, partly resolved - 6\nmonths\n316 per 1000 363 per 1000\n(155 to 862)\nRR 1.15\n(0.49 to 2.73)\n41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nRelief of overall pain - re-\nported as pelvic tender-\nness, complete resolved -\n6 months\n579 per 1000 637 per 1000\n(388 to 1048)\nRR 1.10/uni00A0\n(0.67 to 1.81)\n41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n8\nRelief of overall pain - 6\nmonths\nThe mean relief of over-\nall pain in the control\ngroups was -4.6\nThe mean relief of overall pain in\nthe intervention group was 0.4\nhigher\n(-0.86 to 1.66)\n- 41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nRelief of overall pain - re-\nported as pelvic pain - 6\nmonths\nThe mean relief of pelvic\npain in the control\ngroups was -0.5\nThe mean relief of pelvic pain in\nthe intervention group was 0.5\nhigher\n(0.10 to 0.90)\n- 41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nRelief of overall pain - re-\nported as dysmenorrhoea\n- 6 months\nThe mean relief of dys-\nmenorrhoea in the con-\ntrol groups was -2.4\nThe mean relief of dysmenorrhoea\nin the intervention group was 0.4\nhigher\n(-0.12 to 0.92)\n- 41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nRelief of overall pain - re-\nported as pelvic indura-\ntion - 6 months\nThe mean relief of pelvic\ninduration in the control\ngroups was -0.7\nThe mean relief of pelvic indura-\ntion in the intervention group was\n0.7 higher\n(0.21 to 1.19)\n- 41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nRelief of overall pain - re-\nported as pelvic tender-\nness - 6 months\nThe mean relief of pelvic\ntenderness in the con-\ntrol groups was -0.7\nThe mean relief of pelvic tender-\nness in the intervention group was\n0.2 lower\n(-0.75 to 0.35)\n- 41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\n*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\nthe comparison group and the relative effect of the intervention (and its 95% CI).\nCI: Confidence interval; RR: Risk ratio;\nGRADE Working Group grades of evidence\nHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.\nModerate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.\nLow 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.\nVery low quality: We are very uncertain about the estimate.\n1 Evidence based on a single trial\n2 Small number of events\n/uni00A0\n/uni00A0\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n9\nSummary of findings 5. /uni00A0 GnRHas compared to intra-uterine progestogens device for relief of overall pain associated with endometriosis and its\nrelated adverse eﬀects\nGnRHas compared to intra-uterine progestogens device for relief of overall pain associated with endometriosis\nPopulation: Women with pain due to endometriosis\nSettings: Gynaecological clinics\nIntervention: GnRHas\nComparison: Intra-uterine progestogens device\nIllustrative comparative risks* (95% CI)\nAssumed risk Corresponding risk\nOutcomes\nIntra-uterine progestogens device GnRHas\nRelative effect\n(95% CI)\nNo of Partici-\npants (studies)\nQuality of\nthe evidence\n(GRADE)\nComments\nNo studies included with\nonly low risk of bias\n/uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0\n*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\nthe comparison group and the relative effect of the intervention (and its 95% CI).\nCI: Confidence interval; RR: Risk ratio;\nGRADE Working Group grades of evidence\nHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.\nModerate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.\nLow 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.\nVery low quality: We are very uncertain about the estimate.\n/uni00A0\n/uni00A0\nSummary of findings 6. /uni00A0 Eﬀect of GnRHas versus other hormonal treatment on bone mineral density\nEffect of GnRHas versus other hormonal treatment on bone mineral density\nPopulation: Women with endometriosis, treated with GnRHas with effect on bone mineral density\nSettings: Gynaecological clinics/uni00A0\nIntervention: GnRHas\nComparison: Other hormonal treatment\nOutcomes Illustrative comparative risks* 95% CI Relative effect\n/uni00A0\nNo of partici-\npants\nQuality of the\nevidence\nComments\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n10\nAssumed risk Corresponding risk\nOther hormonal treat-\nment\nGnRHas\n(95% CI) (studies) (GRADE)\nGnRHas vs gestrinone\nPercentage change values\n- 6 months\nThe mean percentage\nchange in BMD in the con-\ntrol groups was 0.88\nThe mean percentage change in\nBMD in the intervention group\nwas 1.96 lower\n(3.62 to 0.30)\n- 41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nGnRHas vs gestrinone\nPercentage change values\n- 12 months\nThe mean percentage\nchange in BMD in the con-\ntrol groups was 2.06\nThe mean percentage change in\nBMD in the intervention group\nwas 5.10 lower\n(7.39 to 2.81)\n- 41\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nGnRHas vs GnRHas in con-\njunction with calcium-reg-\nulating agents\nAnterior-posterior spine -\n12 months\nThe mean change in BMD\nin the control groups was\n2.1\nThe mean change in BMD in the\nintervention group was 7.00 low-\ner\n(7.53 to 6.47)\n- 43\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\nGnRHas vs GnRHas in con-\njunction with calcium-reg-\nulating agents\nLateral spine - 12 months\nThe mean change in BMD\nin the control groups was\n7.5\nThe mean relief of pelvic pain\nin the intervention group was\n12.40lower\n(13.31 to 11.49)\n- 43\n(1 study)\n⊕⊝⊝⊝\nvery low1,2\n/uni00A0\n*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\nthe comparison group and the relative effect of the intervention (and its 95% CI).\nCI: Confidence interval; RR: Risk ratio;\nGRADE Working Group grades of evidence\nHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.\nModerate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.\nLow 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.\nVery low quality: We are very uncertain about the estimate.\n1 Evidence based on a single trial\n2 Small number of events\n/uni00A0\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nB A C K G R O U N D\nDescription of the condition\nEndometriosis is a common gynaecological condition.\nEndometriosis is characterised as an inflammatory condition\nleading to fibrotic tissue formation, predominantly found in the\npelvic peritoneum, ovaries and rectovaginal septum (Burney 2012;\nVigano 2018). Endometriosis is associated with symptoms such\nas dysmenorrhoea, dyspareunia, abdominal pain and infertility\n(Vercellini 2014). It aﬀects 6% to 11% of women of reproductive age,\nbut the prevalence increases in women with infertility or pelvic pain\n(Darwish 2006; Eskenazi/uni00A01997; Mahmood 1991 ; Meuleman 2009 ;\nWheeler 1989).\nThe precise pathogenesis of endometriosis remains unclear,\nhowever there are some hypotheses that have widely been\naccepted. Possible theorised mechanisms of the pathogenesis\nof endometriosis include induction, in situ development and\nretrograde menstruation or implantation/uni00A0(Levander 1955; Sampson\n1940; Van der Linden 1997). The 'induction theory', introduced\nby Levander and Normann in 1955, is based on the assumption\nthat specific substances released during the degeneration of the\nendometrium induce endometriosis from omnipotent blastema,\npresent in connective tissues (Bontis 1997; Levander 1955). The ‘in-\nsitu development theory’ states that endometriosis develops from\neither the Wolﬀian duct or knob, or from Müllerian tissue (Batt 2007;\nVan der Linden 1997). The most common hypothesis is based on\nretrograde menstruation; this theory proposes that endometriosis\narises by the dissemination of endometrial-like tissue to ectopic\nsites where implantation, hypertrophy and invasion of pelvic\nstructures occurs (Burney 2012; Robboy 2010; Sampson 1940 ;\nViganò 2004). This ectopic growth provokes an inflammatory\nresponse, resulting in the symptoms mentioned above (Guidice\n2010). Endometriosis is generally believed to be an oestrogen-\ndependent disorder (Zondervan 2020). Local oestradiol stimulates\nthe activation of pain fibres and promotes sprouting of nociceptors\nthat contribute to persistent inflammatory pain, that o/f_ten worsens\nover time (Guidice 2010).\nTo treat chronic pelvic pain associated with endometriosis,\nrepeated courses of medical therapy or surgical therapy (or both)\nare o/f_ten required. Hormonal treatment, such as gonadotrophin-\nreleasing hormone analogues (GnRHas), suppress ovarian function\nand alter the endometrium as well as the endometriosis tissue,\nwhich in turn o/f_ten results in amenorrhoea and relief of\nendometriosis-related pain symptoms (Stratton 2011). In the\ncurrent review, only the GnRH agonists are included, not the GnRH\nantagonists.\nDescription of the intervention\nThe GnRHas are a family of compounds that diﬀer from\nnatural gonadotrophin-releasing hormone (GnRH), a ten-amino-\nacid hormone (decapeptide), by modifications in the decapeptide\nat positions six and ten (Shaw 1991 ). They may be administered\nintranasally, or by subcutaneous or intramuscular injection.\nBuserelin, goserelin, leuprorelin, nafarelin and triptorelin are some\nof the most common GnRHas. Hypo-oestrogenic side eﬀects\n(relating to low levels of oestrogen), such as hot flushes, mood\nswings, sleep disturbances and bone mass loss are common when\nprescribing GnRHas. This is considered significant as it could\nincrease the risk of women developing osteoporosis and place\nthem at risk of osteoporotic fractures. To prevent bone loss and\nother hypo-oestrogenic symptoms, it is therefore recommended to\nprescribe hormonal add-back therapy concomitantly.\nOther common treatments for endometriosis-associated\nsymptoms (including infertility and pain),/uni00A0are analgesics, danazol\nand progestogens (Brown 2012), including intra-uterine systems,\ncombined oral contraceptive pills (Brown 2018) and surgical\ntherapies (Bafort 2020)./uni00A0A combination of surgery with hormonal\ntreatment (pre-surgical, post-surgical or pre- and post-surgical\nhormonal therapy), is also used as a treatment option for people\nwith endometriosis. Only post-surgical medical therapy provides\na reduction in pain symptoms, reduced rate of recurrence and\nincreased chance of pregnancy (Chen 2020)\nThe European Society of Human Reproduction and Embryology\n(ESHRE) recommends the use of GnRHas (nafarelin, leuprorelin,\nbuserelin, goserelin or triptorelin) as one of the options for\nreducing endometriosis-associated pain, however, evidence is\nlimited regarding dosage or duration of treatment/uni00A0(Becker 2022).\nIn addition, clinicians are recommended to prescribe hormonal\nadd-back therapy to coincide with the start of GnRH agonist\ntherapy, to prevent bone loss and hypo-oestrogenic symptoms\nduring treatment. It is recommended to give careful consideration\nto the use of GnRHas in young women and adolescents, since these\nindividuals may not have reached maximum bone density (Becker\n2022).\nHow the intervention might work\nNon-analgesic medical treatment of endometriosis aims to\nsuppress the ectopic endometrium deposits in premenopausal\nwomen by inducing atrophy within the hormonally dependent\nectopic endometrium, making the endometrial-like tissue inactive.\nThe observation that endometriosis is rarely diagnosed in hypo-\noestrogenic postmenopausal women led to the concept of medical\ntreatment of endometriosis by induction of a pseudo-menopause.\nGonadotrophin-releasing hormone analogues are a potent\nsynthetic analogue of the hypothalamic hormone gonadorelin. This\nstimulates the pituitary gland to produce luteinising hormone (LH)\nand follicle-stimulating hormone (FSH). However, with continued\nuse, suppression occurs due to exhaustion and/uni00A0desensitivity of the\ngonadotrophic pituitary cells. This suppresses ovarian function and\ntherefore reduces oestrogen and progesterone levels, introducing\na hypogonadotropic hypogonadal state.\nIn endometriosis, this treatment leads to a reduction in the\nendometriosis implants and induces atrophy within them/uni00A0(Chen\n2020). By reducing the endometriosis implants, GnRHas can\nprovide a reduction in pain and other endometriosis-related\ncomplaints.\nWhy it is important to do this review\nEndometriosis occurs in approximately one in every 10 women\nwithin the reproductive general population (Macer 2012). It is\na chronic disease with severe pain that impacts negatively on\nphysical, mental and social well-being (Klein 2014). In addition, the\ncost of endometriosis is high in both economic and psychosocial\nterms (Matthias 1996,/uni00A0Simoens 2012).\nTreatment availability is dependent upon available resources\nbut also upon the preferences of the individual woman and\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n11\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nthe gynaecologist. This particularly relates to their decisions\nconcerning the conservation of fertility or requirements for\ncontraception. One of the available treatment options is treatment\nwith GnRHas. While GnRHas are not free of side eﬀects, it is\nimportant to know how well they perform in comparison to other\nmedical/uni00A0treatments and placebo.\nThis review will evaluate the/uni00A0eﬀect of GnRHas specifically on\nthe relief of pain and on bone mineral density in symptomatic\nwomen with endometriosis. This review is a combination of\ntwo previously published Cochrane Reviews on GnRHas for bone\nmineral density/uni00A0(Farmer 2003) and for pain associated with\nendometriosis/uni00A0(Brown 2010). It was decided to merge both reviews,\nin order to provide the best overview of the use of GnRHas in\nwomen with endometriosis.\nO B J E C T I V E S\nTo assess the eﬀectiveness and safety of GnRH analogues\n(GnRHas) in the treatment of painful symptoms associated with\nendometriosis and to determine the eﬀects of GnRHas on bone\nmineral density of women with endometriosis.\nM E T H O D S\nCriteria for considering studies for this review\nTypes of studies\nAll randomised controlled trials (RCTs) comparing the use of\nGnRHas in the treatment of symptomatic endometriosis were\neligible for inclusion. Cross-over trials were included in the\nreview providing that data from before-and-a/f_ter cross-over were\navailable; only the first-arm data were used for analysis. We\nexcluded trials that used self-reporting of endometriosis, as well\nas quasi-randomised and non-randomised studies (case control\nstudies, cohort studies).\nTypes of participants\nPremenopausal women with symptoms ascribed to endometriosis\nwere eligible for inclusion. For a trial to be included, the clinical\ndiagnosis of endometriosis must have been made by direct\nvisualisation (laparoscopy or laparotomy) or from ultrasonographic\nimaging or magnetic resonance imaging (MRI). We excluded women\nwith asymptomatic disease or infertility as the only presenting\ncomplaint.\nTypes of interventions\nWe included RCTs reporting the following comparisons for relief of\npain associated with endometriosis and its related adverse eﬀects.\n• GnRHas versus no treatment.\n• GnRHas versus placebo.\n• GnRHas versus analgesics.\n• GnRHas versus danazol.\n• GnRHas versus intra-uterine progestogens.\n• GnRHas versus oral or injectable progestogens.\n• GnRHas versus gestrinone.\nWe also included RCTs comparing the following for relief of pain\nassociated with endometriosis and its related adverse eﬀects.\n• Diﬀerent doses of GnRHas.\n• Diﬀerent treatment duration of GnRHas.\n• Diﬀerent routes of administration of GnRHas.\n• Diﬀerent treatment regimens of GnRHas.\n• GnRHas versus GnRHas in conjunction with add-back therapy\n(hormonal or non-hormonal).\n• GnRHas versus GnRHas in conjunction with calcium-regulating\nagents.\nWhen we identified trials that assessed the eﬀect of GnRHas on\nbone mineral density (BMD), we considered them for inclusion\nproviding the treatment period exceeded six months. The reason\nfor this decision is that shorter treatment periods do not seem to\ntreat the disease eﬀectively (Audebert 1998).\nThe following trials were excluded from this review.\n• Trials comparing GnRHas with surgical therapies, the combined\noral contraceptive pill, progesterone receptor modulators/uni00A0or\nselective oestrogen receptor modulators (SERMs), as these are\nincluded in separate Cochrane Reviews (Bafort 2020; Brown\n2018; Fu 2017; Van Hoesel/uni00A02021, respectively).\n• Trials comparing GnRHas with gonadotrophin antagonists, as\nthis is a registered title of a Cochrane Review to be conducted by\nCochrane Gynaecology and Fertility (Houda 2014).\n• Trials comparing GnRHas with alternative and complementary\nmedicine such as Chinese herbs or acupuncture, as these are\naddressed by published Cochrane Reviews (Flower 2012; Zhu\n2011, respectively).\n• Trials where GnRHas were administered in post-surgical\nparticipants as adjuvant therapy.\nTypes of outcome measures\nThe choice of outcome measures is based on the core outcome\nset (COS) determined for endometriosis research (Duﬀy 2020). This\nCOS was developed by conducting a systematic review and a\nwidely-supported Delphi study, in which it was determined which\noutcome measures in endometriosis research should definitely be\nassessed in endometriosis trials. The COS is expected to provide\na more uniform way for conducting, performing and reporting\nendometriosis research.\nPrimary outcomes\n• Overall pain, defined by using both quantitative measures such\nas visual analogue scales or categorical outcomes, at the end of\ntreatment and at three, six, nine, 12, 18 and 24 months' follow-\nup, where possible\n• The objective measurement of bone mineral density (BMD),\nincluding dual-energy photon absorptiometry (DPA), dual-\nenergy X-ray absorptiometry (DEXA), single-energy photon\nabsorptiometry (SPA), single-energy X-ray absorptiometry (SXA)\nand quantitative computed tomography (QCT). Measurements\ntaken at the lumbar spine and femoral head will be considered,\nwhilst those at the distal forearm will be excluded because\nthese measurements are of cortical bone which is less aﬀected\nby GnRHa therapy (Whitehouse 1990; Ylikorkala 1990). Bone\ndensity measurements at the end of treatment and in the follow-\nup period will be included. Measurements will be grouped\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n12\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\naccording to the anatomical location of measurements and the\ntiming of measurements.\nFor overall pain, we applied the core outcome set (COS). Overall\npain is one of the outcome measures recommended with the COS.\nHowever, many studies still distinguish between diﬀerent sub-\nforms of pain, and do not use overall pain as an outcome measure.\nIn the current review, it was decided to include both overall pain\nand other sub-forms of pain, i.e. dysmenorrhoea, dyspareunia\nand pelvic pain. This is to provide as much useful information as\npossible for shared decision-making with patients.\nSecondary outcomes\n• Adverse eﬀects (e.g. hot flushes, insomnia, reduced libido,\nvaginal dryness and headaches), both short-term (during\ntherapy) and long-term (extending beyond the treatment\nperiod)\n• Quality of life and factors aﬀecting quality of life (by quality of\nlife scores)\n• Improvement in the most troublesome symptoms\n• Patients' satisfaction with treatment\nCost-eﬀectiveness and pregnancy rates are not outcomes of this\nreview.\nSearch methods for identification of studies\nThe search strategy of Cochrane Gynaecology and Fertility was\nutilised to identify all publications that describe or might describe\nrandomised trials of GnRHas in the treatment of symptomatic\nendometriosis.\nElectronic searches\nThere were no language or date restrictions in the searches. The\nfollowing electronic databases, trial registers and websites were\nsearched:\n• Cochrane Gynaecology and Fertility Group's specialised register\nof controlled trials; searched from inception to 26 May 2022,\nProCite platform (Appendix 1);\n• CENTRAL, via the Cochrane Register of Studies\nOnline (CRSO); now containing output from two trials\nregistries (clinicaltrials.gov https://clinicaltrials.gov/ and the\nInternational Clinical Trials Registry Platform (ICTRP) https://\nwww.who.int/clinical-trials-registry-platform) and CINAHL,\nsearched 26 May 2022, Web platform (Appendix 2);\n• MEDLINE, searched from 1946 to 26 May 2022, Ovid platform\n(Appendix 3);\n• Embase, searched from 1980 to 26 May 2022, Ovid platform\n(Appendix 4);\n• PsycINFO, searched from 1806 to 26 May 2022, Ovid platform\n(Appendix 5).\nThe MEDLINE search was/uni00A0combined with the Cochrane highly\nsensitive search strategy for identifying randomised trials,\nwhich appears in Chapter 6 of the Cochrane Handbook\nfor Systematic Reviews of Interventions ( Lefebvre 2011). The\nEmbase/uni00A0search/uni00A0was/uni00A0combined with the trial filter/uni00A0developed\nby the Scottish Intercollegiate Guidelines Network (SIGN)\n(www.sign.ac.uk/what-we-do/methodology/search-filters/).\nOther web-based electronic sources of trials searched were:\n• ISI Web of Science, for conference abstracts;\n• LILACS database, as a source of trials from the Portuguese and\nSpanish/uni00A0regions;\n• Clinical Study Results, for clinical trial results of marketed\npharmaceuticals;\n• OpenSIGLE database, for grey literature;\n• Google, for grey literature and for trials that were not yet indexed\nin the major databases.\nSearching other resources\nAny relevant journals and conference abstracts that were not\ncovered in the/uni00A0Cochrane Gynaecology and Fertility specialised\nregister were/uni00A0handsearched in liaison with the Group's Information\nSpecialist, Marian Showell.\nThe reference lists of relevant articles retrieved by the search\nwere/uni00A0handsearched, and we personally communicated with\nexperts in the field to obtain any additional trials. In addition, we\napproached all distributors of GnRHas for details of unpublished\ntrials of GnRHas known to, or undertaken by, them or their parent\ncompanies.\nData collection and analysis\nSelection of studies\nTwo review authors (VV and MK) independently scanned the\nsearch results for relevant titles and abstracts and removed\nthose that were clearly irrelevant. The full texts of all potentially\neligible studies were/uni00A0retrieved. Two review authors (VV and\nMK) independently examined the full-text articles for compliance\nwith the inclusion criteria. Authors corresponded with study\ninvestigators to clarify study eligibility. Communication with\nstudy authors was documented in the appendices. Where\nrequired, disagreements regarding study eligibility were/uni00A0resolved\nby consensus or by the assessment of a third review author (JM).\nData extraction and management\nData extraction was conducted independently by two review\nauthors (VV and MK). Data extraction forms were developed\nand pilot-tested by the authors. Where studies had multiple\npublications, the main trial report was/uni00A0used as the reference and\nadditional details supplemented from secondary papers. Authors\ncorresponded with study investigators in order to resolve any data\nqueries, as required. When disagreements arose/uni00A0between the two\nreview authors, a third review author was contacted to resolve the\ndispute (JM)./uni00A0\nAssessment of risk of bias in included studies\nAssessment of the risk of bias in the included studies was\nundertaken by two of the review authors, using the Cochrane risk\nof bias tool/uni00A0(Higgins 2011). The assessment is based on allocation\n(random sequence generation and allocation concealment),\nblinding of participants and personnel, blinding of outcome\nassessors, incomplete outcome data, selective reporting and other\nbias. Where uncertainty arose or there was a discrepancy between\nthe two review authors (VV and MK), a third review author was\ncontacted to make further assessment. When a study protocol was\navailable, we assessed whether there are diﬀerences between the\nstudy protocol and published results.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n13\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nIf necessary, additional information was sought from the principal\ninvestigator of the original trial. All judgements were fully described\nand the conclusions presented in the risk of bias table.\nMeasures of treatment eﬀect\nFor continuous data like pain and BMD (bone mineral density)\nscores, mean diﬀerences (MDs) with 95% confidence intervals\n(CIs) were reported using change-from-baseline scores./uni00A0 When\nsimilar outcomes were reported on diﬀerent scales we intended to\ncalculate standardised mean diﬀerences (SMDs). Ordinal data (e.g.\nquality of life scores) were treated as continuous data. A summary\nstatistic for each outcome was calculated using a fixed-eﬀect model\nand a 95% CI./uni00A0For dichotomous data, we/uni00A0calculated/uni00A0for each study\na/uni00A0Mantel-Haenszel risk ratio (RR) with/uni00A0corresponding/uni00A095% CI.\nUnit of analysis issues\nData were presented according to each woman randomised. In\ncross-over trials only the first-arm data were used for analysis\nwhere data were available, and where data were not available, we\nintended to contact the primary author.\nDealing with missing data\nThe data were analysed on an intention-to-treat basis as far as\npossible, and attempts were made to obtain missing data from\nthe original investigators. If studies reported suﬀicient detail to\ncalculate MDs, but provided no information on an associated\nstandard deviation (SD), the outcome was assumed to have an SD\nequal to the highest SD from other studies within the same analysis.\nFor other outcomes, only the available data were analysed.\nAssessment of heterogeneity\nThe review authors considered whether the clinical and\nmethodological characteristics of the included studies were\nsuﬀiciently similar for meta-analysis to provide a meaningful\nsummary. Statistical heterogeneity was assessed using the I2\nstatistic (Higgins 2019 ). An I 2 measurement greater than 50%\nindicates substantial heterogeneity. Sensitivity analyses including\nall studies were conducted where it was taken into account if the\nquality of the studies contributed to the heterogeneity.\nAssessment of reporting biases\nIn view of the diﬀiculty of detecting and correcting for publication\nbias and other reporting biases, we aimed to minimise their\npotential impact by ensuring a comprehensive search for eligible\nstudies and by being alert for duplication of data.\nData synthesis\nWhen studies were suﬀiciently similar, the data from primary\nstudies were combined using the fixed-eﬀect model./uni00A0The primary\nanalysis only included trials with a low risk of selection bias and no\nhigh risk of bias in other domains.\nSubgroup analysis and investigation of heterogeneity\nData derived in all outcome measurements/uni00A0were divided into\nsubgroups by dosage (low or high, as defined by study); duration\nof treatment (three, six, nine, 12, 18 and 24 months); route of\nadministration (intranasal, intramuscular, subcuticular or depot\ninjection); and drug regimens.\nSensitivity analysis\nSensitivity analyses were conducted for the primary outcomes\nto determine whether the conclusions were robust to arbitrary\ndecisions made regarding the eligibility and analysis. These\nanalyses included consideration of whether our conclusions\ndiﬀered in the following situations.\n• If all studies were included in the analysis (studies with unclear\nrisk of selection bias and high risk of bias in other domains).\n• If studies with outlying results were excluded.\n• If alternative imputation strategies were adopted.\n• If a random-eﬀects model was adopted.\nSummary of findings and assessment of the certainty of the\nevidence\nWe prepared a summary of findings table using GRADEpro GDT\nso/f_tware and Cochrane methods (Schünemann 2021 ). This table\nevaluated the overall quality of the body of evidence for the main\nreview outcomes, namely overall pain, the objective measurement\nof BMD, and adverse eﬀects, for the following main comparisons.\n• GnRHas versus no treatment.\n• GnRHas versus placebo.\n• GnRHas versus danazol.\nAdditional summary of findings tables were also prepared for\nthe main review outcomes for other important comparisons\n(GnRHas versus analgesics; and GnRHas versus intra-uterine\nprogestogen devices). We assessed the quality of the evidence\nusing GRADE criteria: risk of bias, consistency of eﬀect, imprecision,\nindirectness and publication bias. Judgements about evidence\nquality (high, moderate, low or very low) were made by two review\nauthors working independently, with disagreements resolved\nby discussion. Judgements were justified, documented, and\nincorporated into reporting of results for each outcome. We\nextracted study data, formatted our comparisons in data tables and\nprepared a summary of findings table before writing the results and\nconclusions of our review.\nR E S U L T S\nDescription of studies\nResults of the search\nThis is a combination of two previous reviews (Brown 2010;\nFarmer 2003). The inclusion and exclusion criteria, as well\nas the participants, diﬀer slightly from the two previous\nreviews./uni00A0Brown 2010/uni00A0only included women with a clinical\ndiagnosis of endometriosis, so the diagnosis had to be made\nby direct visualisation (laparoscopy). In this review, we also\ninclude women with a clinical diagnosis of endometriosis\nfrom ultrasonographic imaging or magnetic resonance imaging\n(MRI)./uni00A0Farmer 2003/uni00A0included premenopausal women suﬀering from\nendometriosis diagnosed visually by laparoscopy or laparotomy,\nor presumptively, from symptom history. Here, too, the inclusion\ncriteria diﬀer slightly from each other.\nA total of seventy-two studies were included. Two studies were still\nawaiting classification, however, as data were still not available\nat the current review, we also excluded these articles. A total\nof fi/f_ty-six studies were excluded, and five are still awaiting\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n14\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nclassification. See study tables: \"Characteristics of included\nstudies\", \"Characteristics of excluded studies\"; \"Characteristics of\nstudies awaiting classification\"./uni00A0Figure 1/uni00A0summarises the results of\nthe search.\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n15\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFigure 1. /uni00A0 Study flow diagram\n3980 records \nidentified through \ndatabase searching\n0 records \nidentified through \nother sources\n1969 records after \nduplicates removed\n1969 records \nscreened\n1698 records \nexcluded\n271 full-text \narticles assessed \nfor eligibility\n194 full-text \narticles excluded, \nwith reasons\n5 studies placed \nunder 'awaiting \nassessment'\n72 studies included \nin qualitative \nsynthesis\n58 studies included \nin quantitative \nsynthesis \n(meta-analysis)\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n16\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nIncluded studies\nSeventy-two randomised controlled trials met our eligibility criteria\nand were included in this review (Abdou 2018 ; Adamson 1994 ;\nAgarwal 1997; AN Zoladex 1996; Audebert 1997; Bergqvist 1997;\nBergqvist 1998; Bergqvist 2000; Burry 1989; Burry 1992; Chang\n1996; Cheng 2005; Cirkel 1995; Crosignani 1996; Crosignani 2006;\nDawood 1995; Dlugi 1990; Dmowski 1989a; Edmonds 1994; Fedele\n1989; Ferreira 2010; Finkelstein 1998; Finkelstein 1999; Franke 2000;\nFraser 1991; Freundl 1998; Fukushima 1993; Gnoth 1999; Gomes\n2007; Harada 2009; Henzl 1988 ; Hornstein 1995; Hornstein 1998;\nHowell 1995; Hurst 2000; Irahara 2001; Jelley 1986; Kennedy 1990;\nKiilholma 1995 ; Lemay 1988; Ling 1999 ; Mäkäräinen 1996; Miller\n2000; Minaguchi 1986 ; Moghissi 1998 ; NEET 1992 ; Odukoya 1995;\nOrwoll 1994; Ozaki 2020; Palagiano 1994; Petta 2005; Rock 1993;\nRolland 1990; Rotondi 2002; Roux 1995; Schlaﬀ 2006; Shaw 1986;\nShaw 1990; Sillem 1999; Skrzypulec 2004; Strowitzki 2012; Surrey\n1992; Surrey 2002; Tahara 2000; Tang 2017; Tummon 1988; Tummon\n1989; Vercellini 1994; Vercellini 1996; Wheeler 1992 ; Whitehouse\n1990; Zupi 2005). /uni00A0 See/uni00A0 Characteristics of included studies/uni00A0for\ndescription.\nAll the studies were randomised controlled trials and came from a\nvariety of diﬀerent countries:\nBrazil:/uni00A0Ferreira 2010; Gomes 2007; Petta 2005\nCanada:/uni00A0Lemay 1988\nEgypt:/uni00A0Abdou 2018\nFrance:/uni00A0Audebert 1997; Roux 1995\nFinland:/uni00A0Kiilholma 1995; Mäkäräinen 1996\nGermany:/uni00A0 Cirkel 1995; Freundl 1998; Gnoth 1999; Sillem 1999 ;\nStrowitzki 2012\nInternational (multi-centre):/uni00A0AN Zoladex 1996; Bergqvist 1997;\nBergqvist 2000; Crosignani 2006; Fraser 1991; Henzl 1988 ; NEET\n1992; /uni00A0Rolland 1990\nItaly:/uni00A0Crosignani 1996; Fedele 1989; Palagiano 1994; Rotondi 2002;\nVercellini 1994; Vercellini 1996; Zupi 2005\nJapan:/uni00A0Fukushima 1993; Harada 2009; Irahara 2001; Minaguchi\n1986; Ozaki 2020; Tahara 2000; Tang 2017\nNetherlands:/uni00A0Franke 2000\nPoland:/uni00A0Skrzypulec 2004\nSweden:/uni00A0Bergqvist 1998\nTaiwan:/uni00A0Chang 1996; Cheng 2005\nUnited Kingdom:/uni00A0Edmonds 1994; Howell 1995; Jelley 1986;\nKennedy 1990; Odukoya 1995; Shaw 1986; Shaw 1990; Whitehouse\n1990\nUnited States of America:/uni00A0Adamson 1994; Agarwal 1997; Burry 1989;\nBurry 1992; Dawood 1995; Dlugi 1990; Dmowski 1989a; Finkelstein\n1998; Finkelstein 1999; Hornstein 1995; Hornstein 1998; Hurst 2000;\nLing 1999 ; Miller 2000 ; Moghissi 1998 ; Orwoll 1994; Rock 1993;\nSchlaﬀ 2006 ; Surrey 1992; Surrey 2002; Tummon 1988; Tummon\n1989; Wheeler 1992\nThe included studies comprised 7355 women having complaints\nof endometriosis. Where reported, ages ranged from 18 to 48\nyears. All women with endometriosis had a clinical diagnosis\nof endometriosis made by direct visualisation (laparoscopy or\nlaparotomy) or from ultrasonographic imaging or magnetic\nresonance imaging (MRI).\nThe following interventions were tested in the included trials:\n• GnRHas versus placebo (five trials;/uni00A0Bergqvist 1998; Dlugi 1990;\nLing 1999; Miller 2000; Skrzypulec 2004)\n• GnRHas versus danazol (twenty-nine trials;/uni00A0Adamson 1994; AN\nZoladex 1996; Audebert 1997; Burry 1989; Burry 1992; Chang\n1996; Cheng 2005; Cirkel 1995; Dawood 1995; Dmowski 1989a;\nFedele 1989; Fraser 1991; Fukushima 1993; Gnoth 1999; Henzl\n1988; Jelley 1986; Kennedy 1990; NEET 1992 ; Odukoya 1995;\nPalagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002; Shaw\n1990; Tummon 1988; Tummon 1989; Vercellini 1994; Wheeler\n1992; Whitehouse 1990)\n• GnRHas versus intra-uterine progestogens (three trials;/uni00A0Ferreira\n2010; Gomes 2007; Petta 2005)\n• GnRHas versus /uni00A0oral or injectable progestogens (seven\ntrials;/uni00A0 Abdou 2018 ; Crosignani 2006; Harada 2009; Ozaki 2020;\nSchlaﬀ 2006; Strowitzki 2012; Zupi 2005)\n• GnRHas versus gestrinone (one trial;/uni00A0Vercellini 1996)\n• Trials comparing diﬀerent doses of GnRHas (eight\ntrials;/uni00A0 Adamson 1994 ; Bergqvist 1997; Burry 1989; Henzl 1988 ;\nMinaguchi 1986; Shaw 1986; Tahara 2000; Tang 2017)\n• Trials comparing diﬀerent treatment duration of GnRHas (two\ntrials;/uni00A0Hornstein 1995; Orwoll 1994)\n• Trials comparing diﬀerent route of administration of GnRHas\n(four trials;/uni00A0Agarwal 1997; Bergqvist 2000; Dmowski 1989a;\nLemay 1988)\n• Trials comparing diﬀerent GnRHas treatment regimens (one\ntrial;/uni00A0Crosignani 1996)\n• Trials comparing GnRHas versus GnRHas in conjunction with\nadd-back therapy (hormonal or non-hormonal) (seventeen\ntrials;/uni00A0Bergqvist 1997; Edmonds 1994; Franke 2000; Freundl 1998;\nGnoth 1999; Hornstein 1998; Howell 1995; Hurst 2000; Irahara\n2001; Kiilholma 1995 ; Mäkäräinen 1996; Moghissi 1998 ; Sillem\n1999; Surrey 1992; Surrey 2002; Vercellini 1994; Zupi 2005)\n• Trials comparing GnRHas versus GnRHas in conjunction\nwith calcium-regulating agents (three trials;/uni00A0Finkelstein 1998;\nFinkelstein 1999;/uni00A0/uni00A0Roux 1995)\n• Trials mentioning the eﬀect of GnRHas on BMD (thirty\ntrials;/uni00A0 Crosignani 1996; Crosignani 2006; Dawood 1995; Dlugi\n1990; Edmonds 1994; Finkelstein 1998; Finkelstein 1999; Franke\n2000; Freundl 1998; Fukushima 1993; Gnoth 1999; Harada 2009;\nHornstein 1998; Howell 1995; Irahara 2001; Moghissi 1998 ;\nOrwoll 1994; Rock 1993; Roux 1995; Schlaﬀ 2006; Sillem 1999;\nSurrey 1992; Surrey 2002; Tahara 2000; Tang 2017; Tummon\n1988; Vercellini 1996; Wheeler 1992 ; Whitehouse 1990; Zupi\n2005)\nNo trials comparing GnRHas versus no treatment or trials\ncomparing GnRH analogues versus analgesics were identified. \nSix trials were included in two diﬀerent comparisons, due to the\nfact that these trials included three diﬀerent treatment groups, and\ntherefore could be included in diﬀerent comparisons (Adamson\n1994; Bergqvist 1997; Burry 1989; Dmowski 1989a; Henzl 1988 ;\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n17\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nZupi 2005)./uni00A0Adamson 1994,/uni00A0Burry 1989,/uni00A0Dmowski 1989a, and/uni00A0Henzl\n1988/uni00A0compared varying dosage of GnRHas in addition to a\ncomparison with danazol,/uni00A0and/uni00A0Bergqvist 1997/uni00A0compared varying\ndosage of GnRHas in addition to a comparison with add-back\ntherapy (hormonal or non-hormonal)./uni00A0Zupi 2005/uni00A0compared GnRHas\nwith GnRHas in conjunction with add-back, and compared GnRHas\nwith oral or injectable progestogens. \nExcluded studies\nOf the fi/f_ty-six studies that were excluded, ten studies did not\nhave the stated outcome measures (Acien 1989; Calvo 2000;Donnez\n1989; el-Roeiy 1988; Maouris 1991; Matalliotakis 2000; Tapanainen\n1993; Valimaki 1989; Wright 1995 ; Yee 1986). Fi/f_teen studies\nreported wrong comparisons, see 'Types of Interventions' for\ndetails (Agarwal 2015; Cooke 1989; Dmowski 1989; Donnez 2004 ;\nFernandez 2004; Ferrero 2011; Imani 2009 ; Luciano 2004; Magini\n1993; Miller 1990 ; Newton 1996; Shaw 2001 ; Surrey 1993; Taskin\n1997; Toomey 2003; Warnock 1998). Four studies looked at the\noutcome in post-surgical participants (Adiyono 2006; Matalliotakis\n2004; Soysal 2004; Takaesu 2013); endometriosis was not the main\ncondition discussed in eleven studies (Al-Azemi 2009; Dodin 1991;\nEldred 1992; Fraser 1996; Lindsay 1996 ; Matta 1988; /uni00A0 Mukherjee\n1996; Ripps 2003 /uni00A0 Somekawa 1999; Sorensen 1997; Sowter 1997;\nSurrey 1995); and two studies had included a wrong population\n(Shaw 1992 ; Ylikorkala 1995). Nine studies were not randomised\ncontrolled trials (Bergqvist 1990; Choktanasiri 2001; Claesson 1989;\nDawood 1990; Fedele 1993; Franssen 1992; Harada 2000/uni00A0 Pierce\n2000; Vercellini 2009)./uni00A0 Chan 1993 /uni00A0 and/uni00A0 Chen 2009 /uni00A0were both still\nawaiting assessment, as they were in the original review (Brown\n2010) and therefore they were excluded.\nThe other five studies have been placed under 'awaiting\nclassification'. These are abstracts of articles that are not\navailable in full text and do not contain enough information\nto enable us to make a decision about inclusion or exclusion.\nTherefore, we decided to place these five studies under 'awaiting\nclassification' (Aisaka 2000; Archer 2004; Gregoriou 1997;/uni00A0 /uni00A0 Long\n2009; Vella 1995).\nRisk of bias in included studies\nDetails on the quality of each individual study are described in\nthe table/uni00A0Characteristics of included studies/uni00A0where the individual\nquality criteria were rated for each study. Authors have been\ncontacted for more information when required.\nOf the seventy-two articles included, only three were at overall\nlow risk of bias (Cheng 2005 ; Ling 1999 ; Vercellini 1996). Ten of\nthese seventy-two were indicated as having high risk of bias (AN\nZoladex 1996; Burry 1989; Cirkel 1995; Dlugi 1990; Edmonds 1994;\nFukushima 1993; Harada 2009; Howell 1995; Schlaﬀ 2006 ; Surrey\n2002). The other fi/f_ty-nine were assigned as having overall unclear\nrisk of bias.\nFor selection bias, six studies reported low risk of bias, without\nhigh risk of bias on the other domains, and were therefore included\nin the main analysis ( Abdou 2018 ; Cheng 2005 ; Finkelstein 1998;\nLemay 1988; Ling 1999; Odukoya 1995).\nSee/uni00A0Figure 2/uni00A0for the risk of bias graph and/uni00A0Figure 3/uni00A0for the risk of bias\nsummary.\n/uni00A0\nFigure 2. /uni00A0 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages\nacross all included studies.\nRandom sequence generation (selection bias)\nAllocation concealment (selection bias)\nBlinding of participants and personnel (performance bias): All outcomes\nBlinding of outcome assessment (detection bias): All outcomes\nIncomplete outcome data (attrition bias): All outcomes\nSelective reporting (reporting bias)\nOther bias\n0% 25% 50% 75% 100%\nLow risk of bias Unclear risk of bias High risk of bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n18\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFigure 3. /uni00A0 Risk of bias summary: review authors' judgements about each risk of bias item for each included study.\nRandom sequence generation (selection bias)\nAllocation concealment (selection bias)\nBlinding of participants and personnel (performance bias): All outcomes\nBlinding of outcome assessment (detection bias): All outcomes\nIncomplete outcome data (attrition bias): All outcomes\nSelective reporting (reporting bias)\nOther bias\nAbdou 2018+ + ? ? + + +\nAdamson 1994? + + + + + +\nAgarwal 1997? ? + + + + +\nAN Zoladex 1996? ? ? ? − + +\nAudebert 1997? ? ? ? + + +\nBergqvist 1997 ? ? + + + + +\nBergqvist 1998 ? ? + + + + +\nBergqvist 2000 ? ? ? ? + + +\nBurry 1989? ? + + + − +\nBurry 1992? ? + + + + +\nChang 1996? + ? + ? + +\nCheng 2005+ + + + + + +\nCirkel 1995+ ? ? ? − + +\nCrosignani 1996+ ? ? ? + + +\nCrosignani 2006? ? ? ? + + +\nDawood 1995? ? + + + + +\nDlugi 1990? + + + − + +\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n19\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFigure 3. /uni00A0 (Continued)\nDlugi 1990? + + + − + +\nDmowski 1989a? ? ? ? + + +\nEdmonds 1994? ? ? ? + − +\nFedele 1989? ? ? ? + + +\nFerreira 2010+ ? ? ? + + +\nFinkelstein 1998+ + ? + + + +\nFinkelstein 1999+ ? ? ? + + +\nFranke 2000? ? + + + + +\nFraser 1991+ ? + + + + +\nFreundl 1998? ? + + + + +\nFukushima 1993? ? ? + − + +\nGnoth 1999? ? + + + + +\nGomes 2007+ ? ? ? + + +\nHarada 2009+ + + + − + +\nHenzl 1988? ? + + + + +\nHornstein 1995? ? + + + + +\nHornstein 1998? ? + + + + +\nHowell 1995? ? ? ? − + +\nHurst 2000? ? + + + + +\nIrahara 2001? ? ? ? + + +\nJelley 1986? + ? ? + + +\nKennedy 1990? ? + + + + +\nKiilholma 1995? ? + + + + +\nLemay 1988+ + ? + + + +\nLing 1999+ + + + + + +\nMäkäräinen 1996? ? + + + + +\nMiller 2000+ ? + + + + +\nMinaguchi 1986? ? ? ? + + +\nMoghissi 1998? ? + + + + +\nNEET 1992 ? ? + + + + +\nOdukoya 1995+ + ? ? + + +\nOrwoll 1994? ? + + ? + +\nOzaki 2020+ ? ? ? + + +\nPalagiano 1994? ? ? ? + + +\nPetta 2005+ ? ? + + + +\nRock 1993? ? ? ? + + +\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n20\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFigure 3. /uni00A0 (Continued)\nPetta 2005+ ? ? + + + +\nRock 1993? ? ? ? + + +\nRolland 1990? ? + + + + +\nRotondi 2002? ? ? ? + + +\nRoux 1995? ? + + + + +\nSchlaff 2006 ? ? ? + − + +\nShaw 1986? ? ? ? + − +\nShaw 1990? ? + + + + +\nSillem 1999? ? + + ? + +\nSkrzypulec 2004+ ? + + + + +\nStrowitzki 2012? ? ? ? + + +\nSurrey 1992+ ? + + + + +\nSurrey 2002+ ? + + − + +\nTahara 2000 + ? ? ? + + +\nTang 2017 ? ? ? ? ? + +\nTummon 1988 ? ? ? ? ? + +\nTummon 1989 ? ? ? ? + + +\nVercellini 1994 + ? ? ? + + +\nVercellini 1996 ? + + + + + +\nWheeler 1992? ? + + + + +\nWhitehouse 1990? ? + + + + +\nZupi 2005+ ? ? + + + +\n/uni00A0\nAllocation\nTwenty-two trials were at low risk of selection bias related\nto random sequence generation, as they used computer\nrandomisation or random number tables (Abdou 2018 ; Cheng\n2005; Cirkel 1995; Crosignani 1996; Ferreira 2010; Finkelstein 1998;\nFinkelstein 1999; Fraser 1991; Gomes 2007 ; Harada 2009; Lemay\n1988; Ling 1999 ; Miller 2000 ; Odukoya 1995; Ozaki 2020; Petta\n2005; Skrzypulec 2004; Surrey 1992; Surrey 2002; Tahara 2000;\nVercellini 1994;/uni00A0 /uni00A0 Zupi 2005. The remaining trials were at unclear\nrisk of selection bias as they did not describe the method of\nrandomisation used.\nTwelve trials were at low risk of selection bias related to allocation\nconcealment (Abdou 2018 ; Adamson 1994 ; Chang 1996 ; /uni00A0 Cheng\n2005; Dlugi 1990; Finkelstein 1998; Harada 2009; Jelley 1986; Lemay\n1988; Ling 1999 ; Odukoya 1995;/uni00A0 /uni00A0 Vercellini 1996). The remaining\ntrials did not describe allocation concealment and were at unclear\nrisk of this bias.\nBlinding\nThirty-six studies described blinding of patients and personnel,\nand they were judged to be at low risk of performance bias\n(Adamson 1994 ; Agarwal 1997; Bergqvist 1997; Bergqvist 1998;\nBurry 1989; Burry 1992; Cheng 2005 ; Dawood 1995; Dlugi 1990 ;\nFranke 2000; Fraser 1991; Freundl 1998; Gnoth 1999; Harada 2009;\nHenzl 1988; Hornstein 1995; Hornstein 1998; Hurst 2000; Kennedy\n1990; Kiilholma 1995 ; Ling 1999 ; Mäkäräinen 1996; Miller 2000 ;\nMoghissi 1998; NEET 1992; Orwoll 1994; Rolland 1990; Roux 1995;\nShaw 1990; Sillem 1999; Skrzypulec 2004; Surrey 1992; Surrey 2002;\nVercellini 1996; Wheeler 1992 ; Whitehouse 1990). The remaining\ntrials were assigned as having unclear risk of bias.\nForty-two studies described blinding of outcome assessors, and\nthey were judged to be at low risk of detection bias (Adamson\n1994; Agarwal 1997; Bergqvist 1997; Bergqvist 1998; Burry 1989;\nBurry 1992; Chang 1996 ; Cheng 2005 ; Dawood 1995; Dlugi 1990 ;\nFranke 2000; Fraser 1991; Freundl 1998; Fukushima 1993; Gnoth\n1999; Harada 2009; Henzl 1988 ; Hornstein 1995; Hornstein 1998;\nHurst 2000; Kennedy 1990; Kiilholma 1995; Lemay 1988; Ling 1999;\nMäkäräinen 1996; Miller 2000 ; Moghissi 1998 ; NEET 1992 ; Orwoll\n1994; Petta 2005; Rolland 1990; Roux 1995; Schlaﬀ 2006; Shaw 1990;\nSillem 1999; Skrzypulec 2004; Surrey 1992; Surrey 2002; Vercellini\n1996; Wheeler 1992; Whitehouse 1990; Zupi 2005). The remaining\ntrials were assigned as having unclear risk of bias.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n21\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nIncomplete outcome data\nEight trials were considered to be at high risk of attrition bias due\nto high loss to follow-up (AN Zoladex 1996; Cirkel 1995; Dlugi 1990;\nFukushima 1993; Harada 2009; Howell 1995; Schlaﬀ 2006 ; Surrey\n2002). Five trials were considered to be at unclear risk of bias due to\ninsuﬀicient data (Chang 1996; Orwoll 1994; Sillem 1999; Tang 2017;\nTummon 1988) and the rest of the trials were assigned as having\nlow risk of bias.\nSelective reporting\nNone of the protocols from the original review were viewed but\nalmost all the published reports of all included articles included all\nexpected outcomes and were therefore judged to be at low risk of\nreporting bias. Only/uni00A0Burry 1989,/uni00A0Edmonds 1994/uni00A0and/uni00A0Shaw 1986/uni00A0did\nnot report any results of changes in symptoms, while this had been\nasked and reported during follow-up; they were assessed as being\nat high risk of reporting bias.\nOther potential sources of bias\nThere was no evidence of other potential sources of bias identified.\nEﬀects of interventions\nSee: Summary of findings 1 GnRHas compared to no treatment\nfor relief of overall pain associated with endometriosis and its\nrelated adverse eﬀects; Summary of findings 2 GnRHas compared\nto placebo for relief of overall pain associated with endometriosis\nand its related adverse eﬀects; Summary of findings 3 GnRHas\ncompared to analgesics for relief of overall pain associated\nwith endometriosis and its related adverse eﬀects; Summary\nof findings 4 GnRHas compared to danazol for relief of overall\npain associated with endometriosis and its related adverse\neﬀects; Summary of findings 5 GnRHas compared to intra-\nuterine progestogens device for relief of overall pain associated\nwith endometriosis and its related adverse eﬀects; Summary of\nfindings 6 Eﬀect of GnRHas versus other hormonal treatment on\nbone mineral density\nWe identified six studies at low risk of selection bias and not at\nhigh risk of any other bias (Abdou 2018 ; Cheng 2005 ; Finkelstein\n1998; Lemay 1988; Ling 1999; Odukoya 1995). The results of these\nstudies were included in the original reviews. We also performed\na sensitivity analysis, which included all studies. Results are stated\nbelow. \n1. GnRHas versus no treatment for relief of overall pain\nassociated with endometriosis and its related adverse eﬀects\nIn a previous version of this review, there was only one study\nwhich compared GnRHas with no treatment (Fedele 1993) for the\noutcome of overall pain, reported as relief of painful symptoms\n(dysmenorrhoea). We have excluded this study from the current\nreview because it was not possible to read this article in full text.\nNo further studies comparing GnRHas versus no treatment were\nidentified.\n2. GnRHas versus placebo for relief of overall pain associated\nwith endometriosis and its related adverse eﬀects\nFive studies were identified which compared GnRHas with placebo,\nall with a diﬀerent outcome measure (Bergqvist 1998; Dlugi 1990;\nLing 1999; Miller 2000; Skrzypulec 2004). Only/uni00A0Ling 1999/uni00A0was at low\nrisk of bias.\nFour were included in sensitivity analysis, however, these results\nshould be interpreted with caution./uni00A0Skrzypulec 2004/uni00A0did not\nprovide usable data.\n2.1 Relief of overall pain\nRelief of overall pain (reported as decrease in pain scores) was\nreported by three studies (Bergqvist 1998; Ling 1999; Miller 2000),\nbut only/uni00A0one study (Ling 1999) was included in the primary analysis.\n/uni00A0 GnRHas may improve pelvic pain compared to placebo (RR 2.14;\n95% CI 1.41 to 3.24, 1 RCT, n = 87), dysmenorrhoea (RR 2.25; 95%\nCI 1.59 to 3.16, 1 RCT, n = 87), dyspareunia (RR 2.21; 95% CI 1.39 to\n3.54, 1 RCT, n = 59) and pelvic tenderness (RR 2.28; 95% CI 1.48 to\n3.50,1 RCT, n = 85) a/f_ter three months of treatment. We are uncertain\nof the eﬀect of GnRHas compared to placebo for pelvic induration,\nbased on the results a/f_ter three months of treatment (RR 1.07; 95%\nCI 0.64 to 1.79, 1 RCT, n = 81). We graded all outcomes as having low-\ncertainty evidence;/uni00A0Analysis 1.1.\nThe sensitivity analysis including the studies with unclear or high\nrisk of bias/uni00A0suggested treatment with GnRHas compared to placebo\n(Analysis 2.1,/uni00A0Bergqvist 1998) at six months follow up may improve\nthe relief of dyspareunia (RR 0.28; 95% CI 0.09 to 0.89, 1 RCT, n =\n49) and pelvic tenderness (RR 0.22; 95% CI 0. 09 to 0.55, 1 RCT, n =\n49). We are uncertain of the eﬀect of GnRHas compared to placebo\nfor dyschezia (RR 0.26 95%CI 0.03 to 2.17, 1 RCT, n = 49). One/uni00A0study\n(Analysis 2.1 .;/uni00A0 Miller 2000 ) found pain, using the Endometriosis\nSymptom Severity Score (ESSS), may improve following GnRHa\ntherapy compared to placebo with an MD 2.90 (95% CI 2.80 to 3.00, 1\nRCT, n = 120,/uni00A0Analysis 2.3), as measured one month a/f_ter treatment.\n2.2 Bone mineral density\nNo studies at overall low risk of bias were included in this analysis.\nIn the sensitivity analysis including unclear or high risk of bias\nstudies,/uni00A0Dlugi 1990/uni00A0was the only study that reported eﬀects on BMD.\n\"Due to the variety of diﬀerent methodologies and anatomic sites\nused to assess changes in bone mineral density, sample sizes were\nsmall. In addition, very few placebo patients had data included in\nthe analysis. Consequently, between treatment group data could\nnot be adequately evaluated. Nevertheless, 15 patients treated\nwith leuprolide acetate, who had spinal bone mineral density\nassessed by dual photon absorptiometry demonstrated a mean\ndecrease of 3.6% (P = 0.001) from baseline to the end of treatment.\nEight patients treated with leuprolide acetate had spinal bone\nmineral density measured by quantitative computed tomography.\nThese patients had a mean decrease in their bone mineral density\nof 11.8% (P < 0.001)\".\n2.3 Adverse eﬀects\nAgain, only/uni00A0Ling 1999 /uni00A0was included in the primary analysis.\nTreatment with GnRHas may be associated with greater incidence\nof hot flushes at three months of treatment (RR 3.08; 95% CI 1.89 to\n5.01, 1 RCT, n = 100, low-certainty evidence)/uni00A0(Analysis 1.2).\nWe performed a sensitivity analysis including the studies with\nunclear or high risk of bias and found treatment with GnRHas may\nalso be associated with greater incidence of vasodilatation (RR 2.69;\n95% CI 1.51 to 4.81, 1 RCT, n = 63) and headache (RR 3.55; 95% CI\n1.09 to 11.53, 1 RCT, n = 63) at six months of treatment (Dlugi 1990)\nand sleep disturbances at 12 months treatment (RR 2.31; 95% CI\n1.33 to 4.02, 1 RCT, n = 49,/uni00A0Bergqvist 1998) compared to placebo. We\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n22\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nare uncertain of the eﬀect of GnRHas compared to placebo, for hot\nflushes at 12 months treatment (RR 1.62; 95% CI 0.87 to 3.02, 1 RCT,\nn = 49,/uni00A0 Bergqvist 1998)/uni00A0 (Analysis 2.4 ). Nevertheless, these results\nshould be interpreted with caution in view of the high risk of bias\nin these studies.\n2.4 Quality of life\nNo studies with overall low risk of bias were included in this\nanalysis.\nOne high risk of bias study reported on quality of life (Miller 2000).\n/uni00A0At one month of follow-up, GnRHas treatment resulted in lower\nphysical and mental health according to the Short Form (36) Health\nSurvey (SF-36) questionnaire (MD -0.46; 95% CI -0.48 - 0.44, 1 RCT,\nn = 120,/uni00A0Analysis 2.5).\n3. GnRHas versus analgesics for relief of overall pain\nassociated with endometriosis and its related adverse eﬀects\nNo studies comparing GnRHas and analgesics were identified.\n4. GnRHas versus danazol for relief of overall pain associated\nwith endometriosis and its related adverse eﬀects\nTwenty-nine studies were identified which compared GnRHas with\ndanazol (Adamson 1994 ; AN Zoladex 1996; Audebert 1997; Burry\n1989; Burry 1992; Chang 1996 ; Cheng 2005 ; Cirkel 1995; Dawood\n1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Fukushima 1993;\nGnoth 1999; Henzl 1988 ; Jelley 1986; Kennedy 1990; NEET 1992 ;\nOdukoya 1995; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi\n2002; Shaw 1990 ; Tummon 1988; Tummon 1989; Vercellini 1994;\nWheeler 1992; Whitehouse 1990).\nOf these twenty-nine studies, only two were low risk of selection\nbias ( Cheng 2005 ; Odukoya 1995). All twenty-nine studies were\nincluded in sensitivity analysis, nevertheless, these results should\nbe interpreted with caution.\n4.1 Relief of overall pain\nRelief of overall pain was reported by/uni00A0Cheng 2005 /uni00A0 and/uni00A0 Odukoya\n1995.\nDichotomous data suggested very low-certainty evidence of the\neﬀect of GnRHas versus danazol on relief of overall pain, reported as\npartly and completely resolved pelvic tenderness, a/f_ter six months\nof treatment ((RR 1.15, 95% CI 0.49 to 2.73, 1 RCT, n = 41) and\n(RR 1.10, 95% CI 0.67 to 1.81, 1 RCT, n = 41)), respectively (Cheng\n2005)./uni00A0/uni00A0One study reported that \"there was no diﬀerence between\nthe two drugs (aka leuprolide acetate versus danazol) in the relief\nof pain symptoms at the end of three months, but the mean score\nwas lower at the end of three months with leuprolide acetate\ninjections\" (Odukoya 1995).\nContinuous data suggested very low-certainty evidence of the\neﬀect of GnRHas versus danazol on relief of overall pain (MD -0.13,\n95% CI -0.74 to 0.49, 1 RCT, n = 41), pelvic pain (MD 0.26, 95% CI -0.35\nto 0.88, 1 RCT, n = 41), dysmenorrhoea (MD 0.10, 95% CI -0.51 to 0.72,\n1 RCT, n = 41), dyspareunia (MD -0.20, 95% CI -0.82 to 0.41, 1 RCT, n\n= 41), pelvic induration (MD -0.12, 95% CI -0.73 to 0.49, 1 RCT, n = 41\n(Cheng 2005)) and pelvic tenderness (MD -0.21, 95% CI -0.82 to 0.41,\n1 RCT, n = 41), all a/f_ter three months of treatment (Cheng 2005).\nSimilarly, a/f_ter six months of treatment, we found very low-\ncertainty evidence of the eﬀect of GnRHas versus danazol on relief\nof overall pain (MD 0.40, 95% CI -0.86 to 1.66, 1 RCT, n = 41), pelvic\npain (MD 0.50, 95% CI 0.10 to 0.90, 1 RCT, n = 41), dysmenorrhoea\n(MD 0.40, 95% CI -0.12 to 0.792, 1 RCT, n = 41), dyspareunia (MD -0.40,\n95% CI -0.90 to 0.10, 1 RCT, n = 41) and pelvic tenderness (MD -0.20,\n95% CI -0.75 to 0.35, 1 RCT, n = 41) (Cheng 2005).\nWe performed a sensitivity analysis including unclear or high risk\nof bias studies and found pain scores were reported by twenty-two\nstudies (Adamson 1994; Audebert 1997; Chang 1996; Cheng 2005;\nCirkel 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Fukushima\n1993; Henzl 1988; Jelley 1986; /uni00A0Kennedy 1990; NEET 1992; Odukoya\n1995; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002;\nTummon 1989; Vercellini 1994; Wheeler 1992 ; Whitehouse 1990),\nbut only thirteen of them could be included in meta-analyses\n(Adamson 1994 ; Audebert 1997; Chang 1996 ; Cheng 2005 ; Cirkel\n1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Jelley 1986; NEET\n1992; Palagiano 1994; Tummon 1989; Wheeler 1992). Dichotomous\ndata showed probably little or no diﬀerence in the eﬀect of GnRHas\nversus danazol on overall pain relief a/f_ter six months of treatment:\nreported as pelvic pain (RR 0.96, 95% CI 0.83 to 1.11, I2 = 0%,\n6 RCTs, n = 625, (Adamson 1994 ; Cirkel 1995; Fedele 1989; NEET\n1992; Palagiano 1994; Wheeler 1992 )), dysmenorrhoea (RR 1.01,\n95% CI 0.96 to 1.06, I2 = 0%, 6 RCTs, n = 644, (Adamson 1994 ;\nCirkel 1995; Fedele 1989; NEET 1992 ; Palagiano 1994; Wheeler\n1992)), dyspareunia (RR 1.10, 95% CI 0.90 to 1.34, I2 = 13%, 5 RCTs,\nn = 342, ( Adamson 1994 ; Cirkel 1995; Fedele 1989; NEET 1992 ;\nPalagiano 1994)), pelvic induration (RR 0.78, 95% CI 0.32 to 1.89, I2\n= 0%, 2 RCTs, n = 151, (Cirkel 1995; NEET 1992), pelvic tenderness\npartly resolved (RR 1.28, 95% CI 0.59 to 2.76, I2 = 0%, 2 RCTs, n\n= 96, ( Cheng 2005; Cirkel 1995) and pelvic tenderness completely\nresolved (RR 0.97, 95% CI 0.84 to 1.12, I2 = 0%, 2 RCTs, n = 194\n(Cheng 2005; Wheeler 1992))./uni00A0Also, we are uncertain of the eﬀect on\npain reduction when pelvic induration and pelvic tenderness were\ncombined (Kennedy 1990; Analysis 4.1).\nContinuous data suggested very low-certainty evidence of the\neﬀect of GnRHas versus danazol on relief of overall pain (SMD 0.00,\n95% CI -0.46 to 0.46, I2 = 81%, 3 RCTs, n = 85 (Cheng 2005; Dmowski\n1989a; Tummon 1989)), pelvic pain (SMD 0.35, 95% CI -0.08 to 0.79,\nI2 = 65%, 2 RCTs, n = 90 (Cheng 2005 ; Fraser 1991)), dyspareunia\n(SMD 0.25, 95% CI -0.19 to 0.69, I2 = 90%, 2 RCTs, n = 90 (Cheng\n2005; Fraser 1991)) and pelvic induration (SMD 0.40 95% CI -0.04\nto 0.83, I2 = 73%, 2 RCTs, n = 90 (Cheng 2005 ; Fraser 1991)), all\na/f_ter six months of treatment. Pelvic tenderness a/f_ter six months of\ntreatment with GnRHas compared to danazol may be decreased /uni00A0in\nfavour of GnRHas with SMD -0.59 (95% CI -1.03 to -0.15, I2 = 66%, 2\nRCTs, n = 90 (Cheng 2005; Fraser 1991))/uni00A0(Analysis 4.2). Two studies\nthat could not be included in the meta-analyses of continuous\npain outcomes reported similar results. One study reported \"The\ninvestigators' symptom severity scores also dropped a/f_ter 6 months\nfor both the nafarelin and danazol groups. There were no symptoms\nin 57% of the patients in the nafarelin group or 48% of patients in\nthe danazol group\" (Rolland 1990). This is comparable with/uni00A0Rotondi\n2002, who stated that \"Both treatments were associated with a\nsignificant reduction in mean total subjective scores but with no\ndiﬀerence between the treatments\", respectively. /uni00A0Nevertheless,\nas we included all types of risk of bias, these results should be\ninterpreted with caution.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n23\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nNo/uni00A0usable data could be extracted from/uni00A0Henzl 1988 ,/uni00A0 Rock\n1993/uni00A0and/uni00A0Vercellini 1994.\n4.2 Bone mineral density\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWhen we included all studies in the analysis, six studies reported\ndata on BMD (Dawood 1995; Fukushima 1993; Rock 1993; Tummon\n1988; Wheeler 1992; Whitehouse 1990). Two studies (Dawood 1995;\nWheeler 1992 ) reported the percentage change values of BMD at\nthe lumbar spine a/f_ter six months of treatment. /uni00A0Three studies\n(Fukushima 1993; Tummon 1988; Whitehouse 1990) reported\nabsolute values of BMD at the lumbar spine a/f_ter six months of\ntreatment. We are uncertain of the eﬀect of GnRHas or danazol\nbetween the two groups for absolute values of BMD (SMD 0.21 95%\nCI -0.31 to 0.73, I2 = 94%, 3 RCTs, n = 81)/uni00A0(Analysis 4.3).\nData reported by/uni00A0Rock 1993/uni00A0could not be used in a meta-analysis;\nit was reported that \"the mean percent loss following 12 and 24\nweeks of Zoladex therapy was 3.6% (n = 37; 95% CI -5.0 to -2.2)\nand 5.4% (n = 38; 95% CI -7.2 to -3.6), respectively. Danazol-treated\nwomen showed a mean percent loss in bone mineral density at\nweek 12 of 0.4% (n = 17; 95% CI -2.9 to +2.1) and a mean percent\nincrease in 1.0% (n = 17; 95% CI -1.4 to +3.4) at week 24\".\n4.3 Adverse eﬀects\nCheng 2005/uni00A0reported adverse eﬀects. We are uncertain about the\neﬀect of GnRHas compared to danazol on adverse eﬀects reported\nby patients treated for six months. The adverse eﬀects mentioned\nwere vaginal dryness (RR 1.45, 95% CI 0.52 to 4.05, 1 RCT, n =\n59), hot flushes (RR 15.50, 95% CI 0.93 to 259.61, 1 RCT, n = 59),\ngastrointestinal complaints (RR 0.15, 95% CI 0.01 to 2.74, 1 RCT, n\n= 59), weight gain (RR 0.26, 95% CI 0.08 to 0.82, 1 RCT, n = 59) acne\n(RR 0.08, 95% CI 0.00 to 1.35, 1 RCT, n = 59) and generalised spasm\n(RR 0.08, 95% CI 0.00 to 1.35, 1 RCT, n = 59), all very low-certainty\nevidence.\nWe performed a sensitivity analysis including /uni00A0unclear or high\nrisk of bias studies and found eighteen studies that reported on\nadverse eﬀects (AN Zoladex 1996; Audebert 1997; Burry 1989; Burry\n1992; Chang 1996; Cheng 2005; Cirkel 1995; Dmowski 1989a; Fedele\n1989; Fraser 1991; Henzl 1988 ; Jelley 1986; Kennedy 1990; NEET\n1992; Rock 1993; Rolland 1990; Rotondi 2002; Wheeler 1992 ). A\ntotal of forty diﬀerent types of adverse eﬀects were reported,\nof which a meta-analysis could be performed in twenty-three\nstudies. Eight of the most commonly reported adverse eﬀects were\nvaginal dryness, hot flushes, headaches, muscle cramps/myalgia,\nsleep disturbance/insomnia, altered libido, weight gain and acne.\nAdverse eﬀects were more frequently reported in groups receiving\nGnRHas than those receiving danazol. The evidence suggested\nthat, compared to danazol, GnRHas probably lead to more vaginal\ndryness (RR 1.82, 95% CI 1.53 to 2.18, I2 = 11%, 12 RCTs, n =\n1340 ( AN Zoladex 1996; Audebert 1997; Burry 1992; Cheng 2005 ;\nCirkel 1995; Dmowski 1989a; Fedele 1989; Jelley 1986; NEET 1992;\nPalagiano 1994; Rock 1993; Rolland 1990)), more hot flushes (RR\n1.50, 95% CI 1.42 to 1.60, I2 = 69%, 16 RCTs, n = 1998 (AN Zoladex\n1996; Audebert 1997; Burry 1992; Chang 1996; Cheng 2005; Cirkel\n1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Henzl 1988; Jelley\n1986; NEET 1992; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi\n2002; Wheeler 1992 )), more headaches (RR 1.43, 95% CI 1.21 to\n1.69, I2 = 0%, 12 RCTs, n = 1103 (AN Zoladex 1996; Audebert 1997;\nBurry 1992; Cirkel 1995; Dmowski 1989a; Fedele 1989; Fraser 1991;\nPalagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002)), more\nsleep disturbance/insomnia (RR 2.04, 95% CI 1.61 to 2.59, I2 = 45%, 7\nRCTs, n = 881,/uni00A0AN Zoladex 1996; Cirkel 1995; Dmowski 1989a; Jelley\n1986; NEET 1992; Rolland 1990; Wheeler 1992)), and more altered\nlibido (RR 1.58, 95% CI 1.30 to 1.92, I2 = 58%, 9 RCTs, n = 1286).\n/uni00A0On the other hand, compared to danazol, GnRHas probably lead\nto fewer muscle cramps/myalgia (RR 0.16, 95% CI 0.09 to 0.29, I2\n= 0%, 8 RCTs, n = 884 (AN Zoladex 1996; Burry 1992; Cirkel 1995;\nFedele 1989; Fraser 1991; Jelley 1986; NEET 1992; Rolland 1990)),\nless weight gain (RR 0.38 (95% CI 0.29 to 0.49, I2 = 65%, 9 RCTs, n =\n1081 (Audebert 1997; Burry 1992; Cheng 2005; Fedele 1989; Jelley\n1986; Palagiano 1994; Rock 1993; Rotondi 2002; Wheeler 1992)) and\nless acne (RR 0.59, 95% CI 0.47 to 0.73, I2 = 29%, 10 RCTs, n =\n1040 (Audebert 1997; Burry 1992; Cheng 2005; Cirkel 1995; Dmowski\n1989a; Fedele 1989; Jelley 1986; Rock 1993; Rolland 1990; Rotondi\n2002)). All adverse eﬀects reported in the previously mentioned\neighteen articles, are reported in/uni00A0Analysis 4.4.\nThe results, reported by/uni00A0Adamson 1994,/uni00A0Burry 1989/uni00A0and/uni00A0Kennedy\n1990, could not be extracted for current analyses.\n4.4 Quality of life\nNo studies with overall low risk of bias were identified for this\nanalysis.\nFor the sensitivity analysis, including all studies, only one study\nmentioned the eﬀect of GnRHas compared to danazol on quality\nof life (Burry 1992), but results could not be extracted for current\nanalyses. \"The quality of life measurements in the U.S. study were\nobtained by a questionnaire composed of 22 simple questions\nthat comprised the Psychological General Well-Being Index plus\na modification of Part II of the Nottingham Health Profile, which\nrequires only a patient's visual qualification of psychological\nstate rather than a numerical quantification. The results of these\nquestionnaires failed to reveal statistically significant diﬀerences\nbetween the entire treatment group.\"\n4.5 Improvement of most troublesome symptoms\nNo studies with overall low risk of bias were identified for this\nanalysis.\nIn the sensitivity analysis, including studies with unclear or high\nrisk of bias, six studies could be included that reported on\n\"improvement of most troublesome symptom\" (AN Zoladex 1996;\nBurry 1992; Henzl 1988; Kennedy 1990; Rolland 1990; Shaw 1990). A\ndistinction was made between overall improvement and complete\nresolution, both a/f_ter six months of treatment. We are uncertain of\nthe eﬀect between the two groups (RR 1.08, 95% CI 0.99 to 1.18,\nI2 = 39%, /uni00A0RCTs, n = 747 (AN Zoladex 1996; Burry 1992; Henzl 1988;\nKennedy 1990; Rolland 1990; Shaw 1990) and RR 1.14, 95% CI 0.99\nto 1.32, I2 = 43%, 5 RCTs, n = 534, (AN Zoladex 1996; Burry 1992;\nKennedy 1990; Rolland 1990; Shaw 1990 ), respectively)/uni00A0(Analysis\n4.5).\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n24\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n5. GnRHas versus intra-uterine progestogens for relief of\noverall pain associated with endometriosis and its related\nadverse eﬀects\nThree studies assessed outcome measures when GnRHas were\ncompared to intra-uterine progestogens (Ferreira 2010; Gomes\n2007; Petta 2005).\n5.1 Relief of overall pain\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including high risk of bias\nstudies and found very low-certainty evidence for an eﬀect on\nrelief of overall pain between groups for the eﬀectiveness of pain\nrelief, measured a/f_ter six months of treatment with GnRHas or intra-\nuterine progestogens (MD -0.76, 95% CI -1.62 to 0.10, I2 = 22%, 2\nRCTs, n = 58 (Ferreira 2010; Gomes 2007))/uni00A0(Analysis 5.1).\n5.2 Quality of life\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including high risk of bias\nstudies and found very low-certainty evidence for an eﬀect\non quality of life scores, measured by the psychological well-\nbeing questionnaire index (PGWBI) between both groups, a/f_ter six\nmonths of treatment (MD -2.00, 95% CI -10.26 to 6.26, 1 RCT, n =\n82,/uni00A0Petta 2005)/uni00A0(Analysis 5.2).\n6. GnRHas versus oral or injectable progestogens for relief\nof overall pain associated with endometriosis and its related\nadverse eﬀects\nSeven studies were identified which compared GnRHas with\noral or injectable progestogens (Abdou 2018 ; Crosignani 2006;\nHarada 2009; Ozaki 2020; Schlaﬀ 2006 ; Strowitzki 2012; Zupi\n2005)./uni00A0 Crosignani 2006/uni00A0did not provide usable data on relief of\noverall pain and changes in BMD. Data about adverse eﬀects\nwere provided, and included in meta-analysis./uni00A0Abdou 2018 /uni00A0was\nconsidered at low risk of selection bias, and was included in the\noriginal review.\n6.1 Relief of overall pain\nOnly one study reported relief of overall pain, a/f_ter three months of\ntreatment with either GnRHas or oral progestogens (Abdou 2018).\nThere may be an improvement in overall pain, reported as pelvic\npain (MD -2.50, 95% CI -3.55 to -1.45, 1 RCT, n = 261, low certainty of\nevidence) and dyspareunia (MD -2.10, 95% CI -2.83 to -1.37, 1 RCT,\nn = 261, low certainty of evidence) a/f_ter three months of treatment,\nin favour of oral progestogens. We are uncertain about the eﬀect on\nback pain of both GnRHas and oral progestogens (MD 0.50, 95% CI\n-0.40 to 1.40, 1 RCT, n = 261)/uni00A0(Analysis 6.1).\nWe performed a sensitivity analysis including all studies. Two\nstudies (Schlaﬀ 2006; Strowitzki 2012) reported relief of overall pain\nin dichotomous data, comparing GnRHas with oral or injectable\nprogestogens./uni00A0Schlaﬀ 2006 /uni00A0did not provide usable data on relief\nof overall pain, except for pelvic tenderness, but stated that,\n\"treatment with DMPA-SC 104 was statistically equivalent (P <\n0.02) to treatment with leuprolide at month 6 for the reduction\nof four of the five signs and symptoms, namely dysmenorrhoea,\ndyspareunia, pelvic pain, and pelvic tenderness\"./uni00A0Strowitzki\n2012/uni00A0reported results on diﬀerent outcome measurements, namely\npelvic pain, dysmenorrhoea, dyspareunia, pelvic induration and\npelvic tenderness. For both, all reported outcomes were a/f_ter six\nmonths of treatment. Therefore, a meta-analysis could only be\nperformed for pelvic tenderness; we are uncertain whether the two\ngroups diﬀer in eﬀects on pelvic tenderness (RR 1.11, 95% CI 0.95 to\n1.29, I2 = 0%, 2 RCTs, n = 419)/uni00A0(Analysis 7.1).\nContinuous outcome data were reported by four studies (Abdou\n2018; Harada 2009; Strowitzki 2012; Zupi 2005). However,\nthese studies had diﬀerent specific outcome measurements and\ntreatment periods. Consequently, meta-analysis could only be\nperformed for dyspareunia a/f_ter six months of treatment with\nGnRHas or oral or injectable progestogens. The results of/uni00A0Harada\n2009/uni00A0 and/uni00A0 Zupi 2005/uni00A0were combined, and we are uncertain about\nthe eﬀect of GnRHas or oral or injectable progestogens between\nboth groups (MD -0.10 95% CI -0.10 to 0.22, I2 = 0%, 2 RCTs, n =\n180)/uni00A0(Analysis 7.2).\nCrosignani 2006/uni00A0only mentioned the results of overall pain in\nfigures, but stated that \"6 months of treatment with subcutaneous\nformulation of depot medroxyprogesterone acetate 104 mg/0.65\nmL (DMPA-SC 104) resulted in statistically equivalent (P < 0.02)\nreductions of all five signs and symptoms of endometriosis\n(dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and\ninduration) compared with leuprolide treatment. Similarly, scores\nfor all three prespecified scales of the SF-36 (physical function, role\nphysical and social functioning) significantly improved at month 6\nrelative to pre-treatment in both treatment groups, (P ≤ 0.001)\".\n6.2 Bone mineral density\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including high risk of bias\nstudies. Four studies reported the eﬀect of GnRHas and oral versus\ninjectable progestogens on bone mineral density (Crosignani\n2006; Harada 2009; Schlaﬀ 2006 ; Zupi 2005). Again, however,\ndiﬀerent outcome measures have been used, namely percentage\nchange in BMD and absolute values a/f_ter six and 12 months\nof treatment. This means that a meta-analysis could not be\nundertaken. The diﬀerence in percentage change values a/f_ter six\nmonths of treatment may decrease according to one study (MD\n-1.60, 95% CI -2.57 to -0.63, 1 RCT, n = 87,/uni00A0Harada 2009). One study\nfound an uncertain diﬀerence (Zupi 2005)/uni00A0a/f_ter six months (MD -0.04\n95% CI -0.08 to 0.01, 1 RCT, n = 87), but BMD may decrease following\nGnRHas versus oral or injectable progestogens a/f_ter 12 months of\ntreatment (MD -0.05 95% CI -0.10 to -0.01, 1 RCT, n = 87)/uni00A0(Analysis\n7.3).\nCrosignani 2006/uni00A0could not be included in meta-analysis, but\n\"In the leuprolide group, significant (P < 0.001) reductions\nfrom pre-treatment in both total hip and lumbar spine BMD\n(median percentage changes of –2.10 and –4.00, respectively) were\nobserved at month 6. However, the DMPA-SC 104 group showed\nsignificant reduction from pre-treatment (P < 0.001) only in lumbar\nspine BMD (median percentage changes: total hip, –0.50; lumbar\nspine, –1.00). Compared with the leuprolide group, reductions in\nboth total hip and lumbar spine BMD were significantly smaller (P <\n0.001) in the DMPA-SC 104 group\".\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n25\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n\"The leuprolide group experienced significant (P < 0.001)\nreductions from baseline in both total hip and lumbar spine\nBMD at month 6 (median percentage changes of -1.65 and -3.95,\nrespectively). In comparison, the DMPA-SC 104 group showed a\nsignificant reduction from baseline in lumbar spine BMD only\n(median percentage changes were as follows: total hip BMD, -0.30\n[P = 0.063]; lumbar spine BMD, -1.10 [P < 0.001]). Compared with\nleuprolide, reductions in both total hip and lumbar spine BMD were\nsignificantly less (P < 0.001) for the DMPA-SC 104 group\" (Schlaﬀ\n2006).\n6.3 Adverse eﬀects\nOnly one study was included in the original analysis (Abdou 2018);\nit had with low-certainty evidence.\nThere may be a decrease of vaginal bleeding seen in women treated\nwith GnRHas, compared to oral progestogens (RR 0.33, 95% CI 0.23\nto 0.48, 1 RCT, n = 242). Also, there may be less weight gain in\nwomen treated with GnRHas instead of oral progestogens (RR 0.31,\n95% CI 0.10 to 0.92, 1 RCT, n = 242). We are uncertain about the\neﬀect of GnRHas compared to oral progestogens, for headache,\na/f_ter three months of treatment (RR 1.53, 95% CI 0.88 to 2.67, 1 RCT,\nn = 242)/uni00A0(Analysis 6.2).\nWe performed a sensitivity analysis including high risk of bias\nstudies. All the seven studies who were identified, mentioned\nadverse eﬀects when comparing GnRHas with oral or injectable\nprogestogens (Abdou 2018 ; Crosignani 2006; Harada 2009; Ozaki\n2020; Schlaﬀ 2006 ; Strowitzki 2012; Zupi 2005). A meta-analysis\ncould be performed for headache, intermenstrual bleeding and hot\nflushes a/f_ter six months of treatment.\nFor headache, an improvement was found between both groups\nin favour of GnRHas compared to oral or injectable progestogens\n(RR 1.46 95% CI 1.04 to 2.03, I2 = 0%, 3 RCTs, n = 110, (Crosignani\n2006; Harada 2009; Schlaﬀ 2006 )). Hot flushes may improve in\nwomen treated with GnRHas, compared to oral or injectable\nprogestogens (RR 2.11, 95% CI 1.70 to 2.62, I2 = 88%, 4 RCTs, n =\n902, ( Crosignani 2006; Harada 2009; Schlaﬀ 2006 ; Zupi 2005)). In\ncontrast, intermenstrual bleeding was decreased in women treated\nwith GnRHas, compared to oral or injectable progestogens (RR 0.58\n95% CI 0.50 to 0.67, I2 = 84%, 4 RCTs, n = 902, (Crosignani 2006;\nHarada 2009; Schlaﬀ 2006; Zupi 2005))/uni00A0(Analysis 7.4).\nThere may be an increase in the number of menopausal symptoms\nby the Kupperman Index (MD 6.80, 95% CI 2.37 to 11.23, 1 RCT, n\n= 70) and hot flushes (MD 1.10, 95% CI 0.71 to 1.49, 1 RCT, n = 70)\nin favour of GnRHas, and a decrease of breast pain (MD -0.20, 95%\nCI -0.39 to -0.01, 1 RCT, n = 70), and metrorrhagia (MD -0.90, 95%\nCI -1.31 to -0.49, 1 RCT, n = 70). We are uncertain about the eﬀect\nof GnRH compared to oral or injectable progestogens, when results\nare reported a/f_ter four months of treatment, when compared for\ndepression (MD 0.20, 95% CI -0.18 to 0.58, 1 RCT, n = 70), oedema\n(MD 0.20, 95% CI -0.14 to 0.54, 1 RCT, n = 70), and headache (MD 0.10,\n95% CI -0.32 to 0.52, 1 RCT, n = 70)/uni00A0(Analysis 7.5).\n6.4 Quality of life\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including high risk of bias\nstudies. Quality of life, measured by SF-36 was reported by\nfour studies (Harada 2009; Schlaﬀ 2006 ; Strowitzki 2012; Zupi\n2005)./uni00A0Harada 2009/uni00A0reported results a/f_ter six months of treatment\nand for all domains, but we are uncertain about the eﬀect\nfound between two groups. A/f_ter 12 months of treatment,/uni00A0Zupi\n2005/uni00A0also reported no significant diﬀerences in the results of the\nSF-36/uni00A0(Analysis 7.6).\nCrosignani 2006/uni00A0data were not usable for meta-analysis, but stated\nthat \"mean scores for all four prespecified Endometriosis Health\nProfile-30 (EHP-30) scales (pain, emotional well-being, self-image\nand intercourse) as well as the two remaining scales (social\nsupport, control and powerlessness), significantly improved in\nboth groups at month six compared with pretreatment. Similarly,\nscores for all three prespecified scales of the SF-36 (physical\nfunction, role physical and social functioning) significantly\nimproved at month six relative to pretreatment\". In addition,\n\"mean scores for all four prespecified EHP-30 scales (pain,\nemotional well-being, self-image, and intercourse) and two\nadditional EHP-30 scales (social support as well as control and\npowerlessness) significantly improved in both groups at month\nsix compared with the case of baseline (P < 0.05), and these\nimprovements were maintained at the 12-month post-treatment\nfollow-up. Similarly, scores for all three prespecified scales of\nthe SF-36 (physical function, role-physical, and social functioning)\nsignificantly improved at month six relative to baseline, with\nimprovements maintained through 12 months of follow-up, in\nboth groups (P < 0.05)\" (Schlaﬀ 2006 )./uni00A0 Strowitzki 2012/uni00A0stated\nthat \"at the end of treatment, QoL showed more pronounced\nabsolute improvements in the dienogest (DNG) group than in\nthe leuprolide acetate group, including both the physical health\n(DNG, 10.2 points; LA, 7.0 points) and the mental health (DNG, 3.3\npoints; LA, 1.9 points) summary scale scores. Compared with LA,\nDNG was also associated with greater relative improvements in\nspecific SF-36 scale categories. In particular, DNG produced greater\nimprovements in the categories 'physical functioning' (DNG, 18.0%;\nLA, 6.8%), 'role-physical' (DNG, 75.7%; LA, 33.6%), 'vitality' (DNG,\n28.3%; LA, 12.3%), and 'social functioning' (DNG, 21.4%; LA, 8.7%),\nwhich relate to everyday physical activity, productivity at work,\nenergy levels, and ability to interact in society, respectively\".\n6.5 Improvement of most troublesome symptom\nNo studies with overall low risk of bias were identified for this\nanalysis.\nFor the sensitivity analysis,/uni00A0Strowitzki 2012/uni00A0was the only study\nthat reported dichotomous results on improvement of the most\ntroublesome symptom. We are uncertain about the eﬀect between\nthe two groups a/f_ter six months of treatment (RR 1.00, 95% CI 0.79\nto 1.28, 1 RCT, n = 229)/uni00A0(Analysis 7.7).\nHarada 2009/uni00A0 and/uni00A0 Ozaki 2020/uni00A0both reported values for overall\nsymptoms./uni00A0Harada 2009/uni00A0reported no diﬀerence between two\ngroups, a/f_ter six months of treatment (MD -0.70, 95% CI -1.52 to\n0.12, 1 RCT, n = 253)./uni00A0Ozaki 2020/uni00A0reported results a/f_ter four months\nof treatment, and used a numerical rating scale (NRS) and a verbal\nrating scale (VRS). For GnRHas compared to oral or injectable\nprogestogens, there may be an improvement for NRS a/f_ter four\nmonths of treatment (MD 2.60, 95% CI 0.37 to 4.83, 1 RCT, n = 70) and\nalso for \"improvement of most troublesome symptom\" measured\nby VRS (MD 0.70, 95% CI 0.06 to 1.34, 1 RCT, n = 70)/uni00A0(Analysis 7.8). \nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n26\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n7. GnRHas versus gestrinone for relief of overall pain\nassociated with endometriosis and its related adverse eﬀects\nOnly one study compared GnRHas with gestrinone/uni00A0(Vercellini 1996),\nwith unclear and low risk for selection bias. This study was not\nincluded in the original review, but results below are from the\nsensitivity analyses.\n7.1 Relief of overall pain\nVercellini 1996/uni00A0reported relief of overall pain on a continuous scale,\na/f_ter three and six months of treatment with GnRHas or gestrinone.\nWe are uncertain about the eﬀect found for overall pain, reported\nas dysmenorrhoea, dyspareunia, and non-menstrual pelvic pain, all\nmeasured on a NRS and VRS scale/uni00A0(Analysis 8.1).\n7.2 Bone mineral density\nBMD was measured by/uni00A0Vercellini 1996, who reported the percentage\nof change a/f_ter six and 12 months of treatment with either GnRHas\nor gestrinone. A/f_ter both treatment periods, there may be a\ndecrease found in favour of GnRHas ((MD -1.96 95% CI -3.62 to -0.30,\n1 RCT, n = 41) and (MD -5.10 95% CI -7.39 to -2.81, 1 RCT, n = 41),\nrespectively)/uni00A0(Analysis 8.2).\n7.3 Adverse eﬀects\nA/f_ter six months of treatment, there may be an improvement for hot\nflushes a/f_ter treatment with GnRHas, compared to gestrinone (RR\n2.29 95% CI 1.21 to 4.32, 1 RCT, n = 55). For the remainder of all the\nreported adverse eﬀects, we are uncertain about the eﬀect on BMD\nbetween the two groups (Analysis 8.3).\n8. Trials comparing diﬀerent doses of GnRHas for relief of\noverall pain associated with endometriosis and its related\nadverse eﬀects\nA total of eight trials compared diﬀerent doses of GnRHas (Adamson\n1994; Bergqvist 1997; Burry 1989; Henzl 1988 ; Minaguchi 1986 ;\nShaw 1986 ; Tahara 2000; Tang 2017)./uni00A0 Tahara 2000/uni00A0 and/uni00A0 Bergqvist\n1997/uni00A0 both compared 200 /uni03BCg nafarelin with 400 /uni03BCg nafarelin\nfor a treatment period of six months./uni00A0Adamson 1994 ,/uni00A0 Burry\n1989/uni00A0 and/uni00A0 Henzl 1988 /uni00A0 all compared 400 /uni03BCg nafarelin with 800 /uni03BCg\nnafarelin for a treatment period of six months./uni00A0Tang 2017/uni00A0compared\n1.88 mg leuprorelin with 3.75 mg leuprorelin for a treatment period\nof six months. As this comparison only included studies with\nunclear or high risk of bias, results stated below are results of\nthe sensitivity analysis. Results from/uni00A0Minaguchi 1986 /uni00A0 and/uni00A0 Shaw\n1986/uni00A0could not be used for meta-analysis.\n8.1 Relief of overall pain\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies suited for\nmeta-analysis. We are uncertain about the eﬀect found for overall\npain, reported as pelvic pain a/f_ter two months (MD 0.20, 95% CI\n-1.07 to 1.47, 1 RCT, n = 15), four months (MD -0.10, 95% CI -1.07 to\n0.87, 1 RCT, n = 15) and six months (MD 0.30, 95% CI -0.61 to 1.21, 1\nRCT, n = 15) of treatment with 200 /uni03BCg nafarelin compared to 400 /uni03BCg\nnafarelin (Tahara 2000)/uni00A0(Analysis 9.1).\nBesides, we are also uncertain about the eﬀect found for overall\npain, reported as pelvic pain (RR 1.24, 95% CI 0.71 to 2.16, 1 RCT, n\n= 77), dysmenorrhoea (RR 3.00, 95% CI 0.13 to 71.74, 1 RCT, n = 90),\nand dyspareunia (RR 1.05, 95% CI 0.49 to 2.26, 1 RCT, n = 57) a/f_ter\nsix months of treatment with 400 /uni03BCg nafarelin compared to 800 /uni03BCg\nnafarelin (Adamson 1994)/uni00A0(Analysis 9.2).\nBergqvist 1997,/uni00A0Henzl 1988/uni00A0and/uni00A0Tang 2017/uni00A0did not provide suﬀicient\ndata to include them in the meta-analysis.\n8.2 Bone mineral density\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies suited\nfor meta-analysis. In one study, it was reported that \"bone\nmineral density of the lumbar spine at 24 weeks of treatment was\nsignificantly lower than before treatment in the control group, with\na mean bone loss of 5.56%. The decrease in bone mineral content\nwas less in the half-dose group, with a mean bone loss of 1.38%.\nIt has been reported that nafarelin at a dosage of 200 mg daily\ndoes not cause the significant reduction in bone density that is seen\nwith a dosage of 400 mg daily. Our data show that loss of BMD\nwas largely eliminated with half-dose nafarelin during 6 months of\nGnRH agonist therapy\" (Tahara 2000).\nTang 2017/uni00A0stated that \"the BMD was decreased in both groups at 20\nweeks a/f_ter treatment, and the degree of loss of BMD in the control\ngroup (= 3.75 mg leuprorelin) (5.6%) was higher than in the research\ngroup (= 1.88 mg leuprorelin)(1.2%; P < 0.05)\".\n8.3 Adverse eﬀects\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies suited\nfor meta-analysis. We are uncertain about the eﬀect found for\nvasomotor symptoms a/f_ter two months, four months and six\nmonths of treatment with 200 /uni03BCg nafarelin compared to 400 /uni03BCg\nnafarelin (Tahara 2000). In addition, rhinitis, upper respiratory\ninfections, and irregular bleeding were reported without any\nsignificant diﬀerence between either group (Bergqvist 1997)\n(Analysis 9.3).\nTang 2017/uni00A0compared 1.88 mg leuprorelin with 3.75 mg leuprorelin\nfor a treatment period of two, three, four and six months. A/f_ter\ntwo months, there was no diﬀerence in menopausal symptoms,\nmeasured by the Kupperman Index (MD 1.20, 95% CI -3.14 to 5.54, 1\nRCT, n = 50). However, a/f_ter three, four and six months, there may be\na diﬀerence in favour of 3.75 mg leuprorelin compared to 1.88 mg\nleuprorelin ((MD 5.70, 95% CI 2.12 to 9.28, 1 RCT, n = 50) (MD 9.50,\n95% CI 6.55 to 12.45, 1 RCT, n = 50) (MD 13.20, 95% CI 10.22 to 16.18,\n1 RCT, n = 50), respectively)/uni00A0(Analysis 9.4).\nBurry 1989/uni00A0reported the results of weight gain during treatment,\nbut it was not possible to extract data for meta-analysis.\n8.4 Improvement of most troublesome symptom\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies./uni00A0Henzl\n1988/uni00A0measured overall improvement, and we are uncertain about\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n27\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nthe eﬀect between 400 /uni03BCg nafarelin with 80 0/uni03BCg nafarelin for a\ntreatment period of six months (RR 0.94, 95% CI 0.78 to 1.14, 1 RCT,\nn = 143)/uni00A0(Analysis 9.5).\n9. Trials comparing diﬀerent treatment duration of GnRHas\nfor relief of overall pain associated with endometriosis and its\nrelated adverse eﬀects\nTwo trial mentioned the eﬀect of diﬀerent treatment duration\nof GnRHas (two trials;/uni00A0Hornstein 1995; Orwoll 1994). As this\ncomparison only included studies with unclear or high risk of bias,\nresults stated below are the results of the sensitivity analysis.\nHornstein 1995/uni00A0and/uni00A0Orwoll 1994/uni00A0both compared a total treatment\nperiod of three months with intranasal 200 /uni03BCg nafarelin twice\ndaily combined with three consecutive months of placebo use,\nwith a total treatment period of six months with intranasal 200 /uni03BCg\nnafarelin twice daily.\n9.1 Relief of overall pain\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies./uni00A0Hornstein\n1995/uni00A0measured relief of overall pain, with a comparison of a total\ntreatment period of three months with a total treatment period of\nsix months with intranasal 200 /uni03BCg nafarelin twice daily. There may\nbe an improvement /uni00A0for pelvic pain (MD 0.16, 95% CI 0.13 to 0.19, 1\nRCT, n = 179) and pelvic tenderness (MD 0.05, 95% CI 0.03 to 0.07, 1\nRCT, n = 179) a/f_ter six months of treatment, in favour of six months\ntreatment compared to three months of treatment (with intranasal\n200 /uni03BCg nafarelin twice daily and three months of placebo). For\noverall pain, reported as dysmenorrhoea (MD -0.09, 95% CI -0.11\nto -0.07, 1 RCT, n = 179) and dyspareunia (MD -0.14, 95% CI -0.17\nto -0.11, 1 RCT, n = 179), the opposite results were found. There\nmay be a slight decrease a/f_ter six months of treatment, in favour of\nthree months treatment, compared to six months of treatment with\nintranasal 200 /uni03BCg nafarelin twice daily. No significant diﬀerence was\nfound for pelvic induration between the two groups (MD -0.03, 95%\nCI -0.06 to 0.00, 1 RCT, n = 179)/uni00A0(Analysis 10.1).\n9.2 Bone mineral density\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies. For BMD,\na/f_ter a total treatment period of three months with intranasal 200\n/uni03BCg nafarelin twice daily combined with three consecutive months\nof placebo use, there might be a decrease in BMD, compared with\na total treatment period of six months with intranasal 200 /uni03BCg\nnafarelin twice daily. This applied to both spinal bone mass (MD\n1.60, 95% CI 1.51 to 1.69, 1 RCT, n = 183) and proximal femoral bone\n(MD 1.90, 95% CI 1.72 to 2.08, 1 RCT, n = 183) (Orwoll 1994)/uni00A0(Analysis\n10.2/uni00A0and/uni00A0Analysis 10.3).\n10. Trials comparing diﬀerent route of administration\nof GnRHas for relief of overall pain associated with\nendometriosis and its related adverse eﬀects\nFour trials comparing diﬀerent route of administration of GnRHas\nwere included in this comparison (Agarwal 1997; Bergqvist 2000;\nDmowski 1989a; Lemay 1988).\nBergqvist 2000/uni00A0compared subcutaneously administered goserelin\ndepot with intranasal nafarelin 200 /uni03BCg twice daily./uni00A0Dmowski\n1989a/uni00A0 and/uni00A0 Lemay 1988/uni00A0both compared subcutaneously\nadministered buserelin depot 200 /uni03BCg once daily with intranasal\nbuserelin 200 /uni03BCg thrice daily.\nThe results of/uni00A0Dmowski 1989a/uni00A0could not be used, because no\ndistinction was made in the article between subcutaneously\nadministered buserelin depot 200 /uni03BCg once daily and intranasal\nnafarelin 200 /uni03BCg buserelin thrice daily.\n10.1 Relief of overall pain\nLemay 1988/uni00A0compared subcutaneously administered buserelin\ndepot 200 /uni03BCg once daily with intranasal 400 /uni03BCg buserelin thrice\ndaily. We are uncertain about the eﬀect on pelvic pain (RR 1.00, 95%\nCI 0.53 to 1.87, 1 RCT, n = 5), dysmenorrhoea (RR 1.22, 95% CI 0.73 to\n2.06, 1 RCT, n = 9), dyspareunia (RR 1.00, 95% CI 0.57 to 1.75, 1 RCT,\nn = 7), pelvic induration (RR 0.86, 95% CI 0.47 to 1.55, 1 RCT, n = 8)\nand pelvic tenderness (RR 1.50, 95% CI 0.69 to 3.27, 1 RCT, n = 10)\nbetween either group, a/f_ter six months of treatment/uni00A0(Analysis 11.1).\nAs this comparison included only one low-risk study, a sensitivity\nanalysis reported comparable results.\nAgarwal 1997/uni00A0compared intramuscularly administered leuprolide\nacetate depot 3.75 mg once monthly with intranasal nafarelin 200\n/uni03BCg twice daily. We are uncertain about the eﬀect on overall pain,\nreported as pelvic pain (RR 0.96, 95% CI 0.73 to 1.26, 1 RCT, n =\n192), dysmenorrhoea (RR 1.29, 95% CI 0.72 to 2.30, 1 RCT, n = 192),\ndyspareunia (RR 0.88, 95% CI 0.62 to 1.25, 1 RCT, n = 166), pelvic\ninduration (RR 1.41, 95% CI 0.82 to 2.41, 1 RCT, n = 192) and pelvic\ntenderness (RR 1.23, 95% CI 0.88 to 1.73, 1 RCT, n = 192) between\neither group, a/f_ter six months of treatment/uni00A0(Analysis 12.1; Analysis\n12.2).\nBergqvist 2000/uni00A0reported that \"the total pain score, i.e. the three\nparameters dysmenorrhoea, dyspareunia and pelvic pain, was\nreduced in both groups, for goserelin by 45% and for nafarelin by\n43% 3 months a/f_ter the end of treatment\".\n10.2 Adverse eﬀects\nLemay 1988/uni00A0compared subcutaneously administered buserelin\ndepot 200 /uni03BCg once daily with intranasal 400 /uni03BCg buserelin thrice\ndaily. For hot flushes (RR 0.86, 95% CI 0.48 to 1.55, 1 RCT, n =\n13), vaginal dryness (RR 0.86, 95% CI 0.17 to 4.37, 1 RCT, n = 13),\ndecreased libido (RR 0.86, 95% CI 0.07 to 10.96, /uni00A01 RCT, n = 13) and\nheadaches (RR 1.71, 95% CI 0.20 to 14.55, 1 RCT, n = 13), we are\nuncertain about the eﬀects found between the two groups/uni00A0(Analysis\n11.2). As this comparison included only one low-risk study, a\nsensitivity analysis reported comparable results/uni00A0(Analysis 12.3).\nBergqvist 2000/uni00A0 and/uni00A0 Agarwal 1997/uni00A0reported adverse eﬀects a/f_ter\ncomparing intramuscular administered goserelin or leoprolide\nacetate depot with intranasal nafarelin 200 /uni03BCg twice daily. For hot\nflushes (RR 0.95, 95% CI 0.88 to 1.02, I2 = 38%, 2 RCTs, n = 404),\nheadaches (RR 0.83, 95% CI 0.63 to 1.10, 1 RCT, n = 213), sweating\n(RR 1.13, 95% CI 0.71 to 1.79, 1 RCT, n = 213), and vaginal dryness\n(RR 0.52, 95% CI 0.27 to 1.00, 1 RCT, n = 213), we are uncertain\nabout the eﬀect found between the two groups. This is in contrast\nwith the results of vaginal bleeding, because there may be an\nimprovement in favour of subcutaneously administered goserelin\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n28\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\ndepot compared to intranasal nafarelin 200 /uni03BCg twice daily (RR 19.19,\n95% CI 1.12 to 328.28, 1 RCT, n = 213) (Analysis 12.4).\n10.3 /uni00A0Bone mineral density\nAgarwal 1997/uni00A0stated the percentage of decrease of BMD when\nintranasal nafarelin was compared to intramuscular leuprolide\nacetate. A/f_ter six months of treatment, there may be a reduction in\nBMD in favour of nafarelin (MD -2.00, 95% CI -2.10 to -1.90, 1 RCT, n\n= 152).\n11. Trials comparing diﬀerent GnRHas treatment regimens\nfor relief of overall pain associated with endometriosis and its\nrelated adverse eﬀects\nThere was only one trial included, comparing diﬀerent GnRHa\ntreatment regimens (Crosignani 1996)./uni00A0Crosignani 1996/uni00A0compared\na monthly injection of leuprolide with a three-monthly injection\nof leuprolide. As this comparison only included one study with an\nunclear risk of bias, the results stated below are the results of the\nsensitivity analysis.\n11.1 Relief of overall pain\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies.\nOnly/uni00A0 Crosignani 1996/uni00A0was included in the comparison 'Trials\ncomparing diﬀerent GnRHa treatment regimens for revealing\npainful symptoms associated with endometriosis and its related\nadverse eﬀects'. We are uncertain about the eﬀect found for overall\npain, reported as pain symptom scores a/f_ter three and six months\nof treatment./uni00A0Results were subdivided into non-menstrual pelvic\npain (MD -0.20, 95% CI -0.52 to 0.12, 1 RCT, n = 30), dyspareunia\n(MD -0.10, 95% CI -0.51 to 0.31, 1 RCT, n = 30), pelvic induration (MD\n0.10, 95% CI -0.40 to 0.60, 1 RCT, n = 30) and pelvic tenderness (MD\n-0.30, 95% CI -0.71 to 0.11, 1 RCT, n = 30), during a treatment period\nof three months. For a treatment period of six months, the results\nwere similar for non-menstrual pelvic pain (MD 0.10, 95% CI -0.15 to\n0.35, 1 RCT, n = 30), dyspareunia (MD 0.00, 95% CI -0.50 to 0.50, 1 RCT,\nn = 30), and pelvic tenderness (MD 0.40, 95% CI -0.10 to 0.90, 1 RCT, n\n= 30). However, for pelvic induration a/f_ter six months of treatment,\nthere may be a diﬀerence between the two groups (MD 0.40, 95% CI\n0.10 to 0.70, 1 RCT, n = 30) (Analysis 13.1).\n11.2 Adverse eﬀects\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies. Adverse\neﬀects were reported by/uni00A0Crosignani 1996; we are uncertain about\nthe eﬀect on hot flushes (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n\n= 24), vaginal dryness (RR 0.67, 95% CI 0.13 to 3.44, 1 RCT, n =\n30), abdominal pain (RR 3.00, 95% CI 0.13 to 68.26, 1 RCT, n =\n30), arthralgia (RR 3.00, 95% CI 0.13 to 68.26, 1 RCT, n = 30) and\ndepression (RR 3.00, 95% CI 0.13 to 68.26, 1 RCT, n = 30), a/f_ter six\nmonths of treatment when a monthly injection of leuprolide was\ncompared with a three-monthly injection of leuprolide/uni00A0(Analysis\n13.2).\n11.3 Bone mineral density\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies./uni00A0Crosignani\n1996/uni00A0reported the results of monthly versus three-monthly doses\nof leuprolide acetate on BMD. The trial stated that there might be\na slight variation of lumbar spine bone mineral density observed\nat the end of GnRHa treatment in both study groups (P < 0.01), the\npercentage decrease over basal being 5.2% and 4.9%, respectively.\nBut the study did not provide suﬀicient data for comparison of\nthe groups; authors were contacted for the previous version of the\nreview, but have not replied to date.\n12. Trials comparing GnRHas versus GnRHas in conjunction\nwith add-back therapy (hormonal or non-hormonal) for relief\nof overall pain associated with endometriosis and its related\nadverse eﬀects\nSixteen trials compared GnRHas versus GnRHas in conjunction\nwith add-back therapy (hormonal or non-hormonal) (Bergqvist\n1997; Edmonds 1994; Franke 2000; Freundl 1998; Gnoth 1999;\nHornstein 1998; Howell 1995; Hurst 2000; Irahara 2001; Kiilholma\n1995; Mäkäräinen 1996; Moghissi 1998 ; Sillem 1999 ; Surrey 1992;\nSurrey 2002; Vercellini 1994; Zupi 2005). As this comparison only\nincluded studies with unclear or high risk of bias, the results stated\nbelow are the results of the sensitivity analysis.\n12.1 Relief of overall pain\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies. A total of\nten studies reported relief of overall pain as a primary or secondary\noutcome measure (Bergqvist 1997; Freundl 1998; Hornstein 1998;\nHowell 1995; Hurst 2000; Mäkäräinen 1996; Moghissi 1998; Surrey\n2002; Vercellini 1994; Zupi 2005).\nRelief of overall pain was presented both as a dichotomous and as\na continuous outcome measure./uni00A0Freundl 1998/uni00A0was the only study\nthat reported dichotomous outcomes; we are uncertain about the\neﬀect between GnRHas and GnRHas in conjunction with add-back\ntherapy (dysmenorrhoea, RR 0.63, 95% CI 0.58 to 159.04, 1 RCT, n\n= 28; dyspareunia, RR 6.07, 95% CI 0.86 to 43.04, 1 RCT, n = 28; and\nnon-menstrual pelvic pain, RR 1.30, 95% CI 0.26 to 6.62, 1 RCT, n\n= 28)/uni00A0(Analysis 14.1)./uni00A0Zupi 2005/uni00A0reported continuous outcomes; we\nare uncertain about the eﬀect found between groups for overall\npain, reported as dysmenorrhoea a/f_ter six months of treatment (not\nestimable), dyspareunia a/f_ter six months of treatment (MD -0.20,\n95% CI -0.40 to 0.80, 1 RCT, n = 90), and overall pain (MD -1.50, 95%\nCI -7.92 to 4.92, 1 RCT, n = 90); or dysmenorrhoea (not estimable)\nand dyspareunia (MD 0.20, 95% CI -0.03 to 0.43, 1 RCT, n = 90) both\na/f_ter 12 months of treatment. In contrast, values for pelvic pain may\nimprove slightly in favour of GnRHas in conjunction with add-back\ntherapy. This applied to both six months of treatment (MD -0.20,\n95% CI -0.39 to -0.01, 1 RCT, n = 90) and 12 months of treatment\n(MD -0.10, 95% CI -0.14 to -0.06, 1 RCT, n = 90)/uni00A0(Analysis 14.2). This\ncorresponds partly to the data extracted from/uni00A0Howell 1995, which\nstated that \"both groups showed similar improvement in pelvic\nsymptoms (dysmenorrhoea, dyspareunia, and other pelvic pain)\nand pelvic signs (tenderness and induration) during the course of\ntreatment with no significant diﬀerence between the two groups (P\n> 0.05)\".\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n29\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0 Hornstein 1998/uni00A0did not include data in the meta-analysis, but\nno significant diﬀerence was found between GnRHas alone (group\nA), compared with three diﬀerent add-back groups (group B\nreceived daily oral norethindrone acetate 5 mg with placebo for\noestrogen; group C received norethindrone 5 mg and conjugated\nequine oestrogens 0.625 mg; group D received norethindrone\n5 mg and conjugated equine oestrogens 1.25 mg), comparing\ndysmenorrhoea, non-menstrual pelvic pain, and pelvic tenderness.\n\"The mean decreases in group D were significantly less than those\nof group A at week 4, 8 (P < 0.05), 12 (P < 0.01), and 48 (P <\n0.05)\" ( Hornstein 1998). All participants in the study of/uni00A0Kiilholma\n1995/uni00A0showed subjective improvement on goserelin acetate therapy.\nThe authors reported that \"the response was equally good in\npatients with or without HRT (P = not significant [NS]). The pelvic\nsymptoms score decreased from 4.7 and 4.7 in goserelin acetate\nplus HRT and goserelin acetate plus placebo patients to 0.9 and 0.5\na/f_ter 6 months, respectively\".\nBergqvist 1997,/uni00A0 Hurst 2000,/uni00A0 Mäkäräinen 1996,/uni00A0 Moghissi\n1998/uni00A0and/uni00A0Vercellini 1994/uni00A0did not provide suﬀicient data to include\ntheir data in the meta-analysis.\nSurrey 2002/uni00A0compared four diﬀerent groups, all receiving GnRHas.\nGroup A received daily oral placebos for oestrogen and progestin\nadd-back. Patients included in group B received daily oral\nnorethindrone acetate 5 mg and placebo for oestrogen. Patients in\ngroup C received oral norethindrone acetate 5 mg and conjugated\nequine oestrogens 0.625 mg daily. Those in group D received oral\nnorethindrone acetate 5 mg and conjugated equine oestrogens\n1.25 mg daily. The authors reported that \"the median changes in\noverall pelvic pain, dysmenorrhoea, and dyspareunia scores from\npre-therapy baseline throughout the follow-up period for the four\ngroups are displayed in Figures 1–3, respectively. Decreases in\nsymptom scores from baseline remained statistically significant\nthrough month 12 of follow-up for all groups with the exceptions\nof dysmenorrhoea for groups A and D and deep dyspareunia for\ngroup D, which all remained suppressed through month 8 of follow-\nup. The only significant diﬀerence between groups regarding\nreturn to baseline scores occurred between groups A and D for\ndysmenorrhoea, where group D patients returned to baseline levels\nsooner\".\n12.2 Bone mineral density\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies. The eﬀect\nof add-back therapy on the GnRHas-induced loss of bone mineral\ndensity was reported by/uni00A0thirteen studies (Edmonds 1994,/uni00A0 Franke\n2000; Freundl 1998; Gnoth 1999; Hornstein 1998; Howell 1995;\nIrahara 2001; Moghissi 1998; Schlaﬀ 2006; Sillem 1999; Surrey 1992;\nSurrey 2002; Zupi 2005).\nA meta-analysis was undertaken for continuous outcome\nmeasures, and subdivided into percentage change values and\nabsolute values. The percentage change may improve when treated\nwith GnRHas compared with GnRHas in conjunction with add-\nback therapy (MD -3.88, 95% CI -4.27 to -3.49, I2 = 93%, 2 RCTs,\nn = 46,/uni00A0Freundl 1998; Surrey 1992)./uni00A0Gnoth 1999/uni00A0also mentioned a\nsignificant loss of BMD in the lumbar spine for the GnRHa + placebo\ngroup compared to that for the GnRHa + add-back group (6.5 vs.\n2.0%, respectively, P = 0.001). For absolute values, a/f_ter six months\nof treatment with either GnRHas or GnRHas in conjunction with\nadd-back therapy, there may be a diﬀerence in change in favour of\nGnRHas in conjunction with add-back therapy (MD 0.02, 95% CI 0.02\nto 0.02, I2 = 70%, 5 RCTs, n = 199,/uni00A0Gnoth 1999; Sillem 1999; Surrey\n1992; Zupi 2005). Only/uni00A0Zupi 2005/uni00A0reported results a/f_ter 12 months\nof treatment, without any changes between either group/uni00A0(Analysis\n14.3).\nBone mineral density loss is reduced by 50% to 2.5% overall by the\naddition of add-back therapy and there may be an improvement\nin the rate of return to normal of bone mineral density during\npost-treatment follow-up (Edmonds 1994)./uni00A0We are uncertain about\nthe eﬀect on BMD a/f_ter six months of treatment with GnRHas,\ncompared to GnRHas in conjunction with add-back therapy (Franke\n2000)./uni00A0Another study,/uni00A0Howell 1995, reported a \"reduction of bone\nmineral density at the lumbar spine in group 1 (= GnRHas) of\n-4.1% compared with -2.3% in group 2 (= GnRHas + add-back)\".\nThere was for both groups a reduction compared to baseline. /uni00A0A\ncomparison between the two groups has not been made./uni00A0Hornstein\n1998/uni00A0compared GnRHas alone (group A), and three diﬀerent add-\nback groups (group B: received daily oral norethindrone acetate 5\nmg with placebo for oestrogen; group C: received norethindrone 5\nmg and conjugated equine oestrogens 0.625 mg; group D: received\nnorethindrone 5 mg and conjugated equine oestrogens 1.25 mg).\n\"All three add-back groups had significantly less bone loss than the\nagonist-only group at 24- and 52-week measurements (P ≤ 0.001)\".\nThis corresponds to/uni00A0the results found by/uni00A0Irahara 2001/uni00A0and/uni00A0Sillem\n1999. \"The control group (= GnRHas alone) significantly (P <\n0.01) decreased BMD of the lumber spine (mean percentage\nchange: –6.3%) a/f_ter six months of treatment; however, add-back\ntherapy prevented this BMD reduction (mean percentage change:\n–0.8%)\" ( Irahara 2001) and \"both groups, a significant decrease\nin lumbar bone mineral density (LBMD) was observed a/f_ter six\nmonths of treatment. When compared to baseline values, the mean\nrelative bone loss was 4%, in both groups equally (P < 0.01, 0\nmonths vs. 6 months). Absolute values decreased from 1.28 ± 0.18\ng/cm2 (mean ± standard deviation) to 1.23 ± 0.16 g/cm2 in group\nA and from 1.19 ± 0.11 g/cm2 to 1.14 ± 0.1 g/cm2 in group B. No\nchange in bone mineral density was observed at the femoral neck\nor Ward's triangle\" (Sillem 1999)./uni00A0Moghissi 1998/uni00A0reported that the\nmean percentage loss was significantly higher in the group without\nadd-back therapy than in either group with once daily doses of\n0.3 mg of conjugated oestrogen and 5 mg of medroxyprogesterone\nacetate, or once daily doses of 0.625 mg of conjugated oestrogen\nand 5 mg of medroxyprogesterone acetate at week 12 (P < 0.001).\nData could not be included in meta-analyses.\n12.3 Adverse eﬀects\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies. Eleven\nstudies reported adverse eﬀects when comparing GnRHas with\nGnRHas in conjunction with add-back therapy (Bergqvist 1997;\nEdmonds 1994; Franke 2000; Freundl 1998; Hornstein 1998; Howell\n1995; Hurst 2000; Kiilholma 1995; Mäkäräinen 1996; Moghissi 1998;\nZupi 2005). Only six of them could be included in meta-analysis,\nnamely for assessment of hot flushes, loss of libido, vaginal\ndryness, headache and vaginal bleeding, all a/f_ter six months of\ntreatment. For hot flushes and vaginal dryness, there may be an\nimprovement in both groups, in favour of GnRHas (RR 1.59, 95%\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n30\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nCI 1.32 to 1.93, I2 = 92%, 4 RCTs, n = 215 (Edmonds 1994; Freundl\n1998; Howell 1995; Zupi 2005) and RR 1.40, 95% CI 1.11 to 1.76,\nI2 = 30%, 3 RCTs, n = 404 (Edmonds 1994; Howell 1995; Moghissi\n1998), respectively). \"Hot flushes were reported more frequently\nby the patients receiving goserelin acetate plus placebo than by\nthose receiving HRT. The diﬀerence was significant (P < 0.01) a/f_ter\n4 weeks of trial medication and highly significant at 6 months\n(P < 0.0001)\" ( Kiilholma 1995 ). In addition,/uni00A0 Hornstein 1998, who\ncompared the GnRHas alone (group A) with three diﬀerent add-\nback groups (group B: received daily oral norethindrone acetate 5\nmg with placebo for oestrogen; group C: received norethindrone 5\nmg and conjugated equine oestrogens 0.625 mg; group D: received\nnorethindrone 5 mg and conjugated equine oestrogens 1.25 mg)\nstated that \"the percentage of patients experiencing hot flashes\nwas dramatically less in the three add-back groups than in group\nA\", a/f_ter 52 weeks of treatment. We are uncertain of the eﬀect\nfound between GnRHas and GnRHas in conjunction with add-back\ntherapy for loss of libido (RR 1.07, 95% CI 0.58 to 1.97, I2 = 89%, 2\nRCTs, n = 96,/uni00A0Edmonds 1994; Howell 1995) and headache (RR 0.91,\n95% CI 0.67 to 1.24, I2 = 0%, 3 RCTs, n = 126,/uni00A0Edmonds 1994; Freundl\n1998; Howell 1995). Vaginal bleeding was seen more commonly in\nwomen treated with GnRH in conjunction with add-back therapy\n(RR 0.57, 95% CI 0.35 to 0.93, I2 = 70%, 3 RCTs, n = 185,/uni00A0Bergqvist\n1997; Howell 1995; Zupi 2005)/uni00A0(Analysis 14.4). This is comparable\nto the results of/uni00A0Mäkäräinen 1996, who stated: \"significantly fewer\npatients in the MPA group (=GnRHas + add-back) had hot flushes\nand sweating at 3 and 6 months than in the placebo group\n(=GnRHas alone). Other side eﬀects recorded occurred with similar\nfrequency in both groups\". The results mentioned above, are partly\nin contrast to/uni00A0Hurst 2000, who reported \"as expected, hot flush\nand headache mean scores during time period three are usually\nlower for the oestradiol group than for the placebo group, although\nthese diﬀerences were not statistically significant\". Besides these\noutcome measures, \"in the GnRH agonist plus placebo group, the\nKupperman index score decreased by 75% at 4 weeks, 129% at 12\nweeks, and 113% at 24 weeks (P = 0.0004). The diﬀerence between\ngroups at 24 weeks was statistically significant (P = 0.003)\" (Franke\n2000).\nThe results reported by/uni00A0Surrey 2002/uni00A0could not be extracted for\ncurrent analyses.\n12.4 Quality of life\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies. Quality\nof life, measured by SF-36, was reported by only one study (Zupi\n2005). A/f_ter 12 months of treatment,/uni00A0Zupi 2005/uni00A0reported that there\nmay be a slight diﬀerence in the results of the SF-36, in the domains\n'physical function' and 'vitality'. /uni00A0Both domains reported better\nquality of life in women treated with GnRHas in conjunction with\nadd-back therapy. /uni00A0For the other domains, we are uncertain of the\neﬀect a/f_ter 12 months of treatment/uni00A0(Analysis 14.5).\n12.5 Improvement of most troublesome symptom\nNo studies with overall low risk of bias were identified for this\nanalysis.\nWe performed a sensitivity analysis including all studies./uni00A0Surrey\n1992/uni00A0reported results of improvement of overall pain, a/f_ter four\nweeks of treatment with either GnRHas of GnRHas in conjunction\nwith add-back therapy. There may be a greater improvement in\nwomen treated with GnRHas, compared to GnRHas in conjunction\nwith add-back/uni00A0(Analysis 14.6).\nThis is in contrast to/uni00A0Edmonds 1994, which reported no diﬀerence\nin pain scores a/f_ter six months of treatment with GnRHas or with\nGnRHas in conjunction with add-back therapy.\n13. Trials comparing GnRHas versus GnRHas in conjunction\nwith calcium-regulating agents for relief of overall pain\nassociated with endometriosis and its related adverse eﬀects\nA total of three trials compared GnRHas versus GnRHas in\nconjunction with calcium-regulating agents (Finkelstein 1998;\nFinkelstein 1999; Roux 1995).\nSince/uni00A0Finkelstein 1998/uni00A0reported the same results for BMD\nas/uni00A0 Finkelstein 1999, only/uni00A0 Finkelstein 1998/uni00A0was included in the\nanalysis on BMD. As this comparison only included one study with\na low risk of bias, the results stated below are the results of the\nsensitivity analysis.\n13.1 Bone mineral density\nFinkelstein 1998/uni00A0reported that there may be a slight decrease in\nBMD a/f_ter 12 months treatment (MD -7.00 95% CI -7.53 to -6.47, 1\nRCT, n = 43) with GnRHas, compared to GnRHas in conjunction with\ncalcium-regulating agents (Analysis 15.1; Analysis 16.1).\nRoux 1995/uni00A0compared triptorelin alone (group 0) with triptorelin and\nsalmon calcitonin 100 IU daily (group 1) and triptorelin and salmon\ncalcitonin 200 IU daily (group 2). A/f_ter six months of treatment, the\nmean values (± SD) of BMD (g/cm2) of group 0 were 1.031 ± 0.091,\ncompared to 1.009 ± 0.152 in group 1 and 0.987 ± 0.143 in group 2.\n13.2 Adverse eﬀects\nFinkelstein 1998/uni00A0reported results about adverse eﬀects, but it was\nnot possible to report these outcomes in a meta-analysis. \"Mild\nnausea (P < 0.001) and arthralgias (P = 0.05) were reported more\ncommon in the women who received human parathyroid hormone,\nalthough only 1 woman reported that these symptoms aﬀected her\nroutine activities\".\nData of/uni00A0Roux 1995/uni00A0could not be used in the meta-analysis, but\n\"[t]here was no diﬀerence in side eﬀects in the three groups\n(GnRHas combined with placebo (group 0), salmon calcitonin 100\nIU daily (group 1) and salmon calcitonin 200 IU daily (group\n2)). Nasal symptoms were reported by 12 (31%) patients. Thirty\npatients (75%) experienced hot flushes, which were attributed\nto the menopausal status rather than the spray. However, 11 of\n40 patients (27.5%) experienced arthralgia, predominantly of the\nhand joints, including 3 patients with a clinical diagnosis of carpal\nsyndrome and 1 patient with spontaneous knee eﬀusion\".\n13.3 Improvement of most troublesome symptom\nWe are uncertain about the eﬀect mentioned by/uni00A0Finkelstein\n1998/uni00A0related to improvement of the most troublesome symptom,\nboth overall improvement (RR 0.96, 95% CI 0.84 to 1.08, 1 RCT,\nn = 43) and complete resolution (RR 0.95, 95% CI 0.64 to 1.41,\n1 RCT, n = 43), when GnRHas were compared to GnRHas in\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n31\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nconjunction with calcium-regulating agents for a treatment period\nof 12 months/uni00A0(Analysis 15.2; Analysis 16.2).\n14. Trials assessing the eﬀect of GnRHas on BMD\nThirty-one trials were included, across the 13 comparisons\n(Agarwal 1997; Crosignani 1996; Crosignani 2006; Dawood 1995;\nDlugi 1990 ; Edmonds 1994; Finkelstein 1998; Finkelstein 1999;\nFranke 2000; Freundl 1998; Fukushima 1993; Gnoth 1999; Harada\n2009; Hornstein 1998; Howell 1995; Irahara 2001; Moghissi 1998 ;\nOrwoll 1994; Rock 1993; Roux 1995; Schlaﬀ 2006 ; Sillem 1999 ;\nSurrey 1992; Surrey 2002; Tahara 2000; Tang 2017; Tummon 1988;\nVercellini 1996; Wheeler 1992 ; Whitehouse 1990; Zupi 2005). The\neﬀects on BMD are reported separately in the relevant comparisons\nand are also visible in/uni00A0Analysis 4.3 ; Analysis 7.3 ; Analysis 8.2 ;\nAnalysis 10.2 ; Analysis 10.3 ; Analysis 12.5 ; Analysis 14.3 ; Analysis\n15.1; Analysis 16.1.\nD I S C U S S I O N\nSummary of main results\nThere were no studies found comparing GnRHas with either no\ntreatment or analgesics.\nTrials comparing GnRHas versus placebo for relief of overall\npain associated with endometriosis and its related adverse\neﬀects\nThere may be a decrease in reported pelvic pain scores,\ndysmenorrhoea scores, dyspareunia scores, and pelvic tenderness\nscores a/f_ter three months of treatment. We are uncertain of the\neﬀect of GnRHas compared to placebo for pelvic induration, based\non the results found a/f_ter three months of treatment.\nAdditionally, treatment with GnRHas may be associated slightly\nwith a greater incidence of hot flushes at three months of\ntreatment.\nTrials comparing GnRHas versus danazol for relief of overall\npain associated with endometriosis and its related adverse\neﬀects\nFor pelvic pain in women treated with either GnRHas or danazol, a\nsubdivision was made between pelvic tenderness, partly resolved\nand completely resolved. These dichotomous data indicated the\nuncertainty of the eﬀect of GnRHas or danazol for the eﬀectiveness\nof pelvic tenderness a/f_ter six months of treatment with either\nGnRHas or danazol.\nWe are uncertain about the eﬀect of GnRHas compared to danazol\nfor relief of overall pain, when a subdivision was made for\noverall pain, pelvic pain, dysmenorrhoea, dyspareunia, pelvic\ninduration, and pelvic tenderness. For all results, this was a/f_ter\nthree months of treatment. A/f_ter six months of treatment, we are\nstill uncertain about the eﬀect of GnRHas or danazol on overall pain,\ndysmenorrhoea, dyspareunia, and pelvic tenderness. For pelvic\npain and pelvic induration, these complaints may decrease a/f_ter\ntreatment with GnRHas, compared to danazol, during six months\nof treatment.\nTrials comparing GnRHas versus intra-uterine progestogens\nfor relief of overall pain associated with endometriosis and its\nrelated adverse eﬀects\nWe are uncertain about the eﬀect on VAS scores between groups\na/f_ter six months of treatment. Besides, we are also uncertain about\nthe eﬀect of GnRHas compared to intra-uterine progestogens for\nrelief of overall pain a/f_ter six months of treatment.\nFor quality of life, we are uncertain about the eﬀects, measured by\nthe psychological well-being questionnaire index (PGWBI) between\ngroups, a/f_ter six months of treatment.\nTrials comparing GnRHas versus oral or injectable\nprogestogens for relief of overall pain associated with\nendometriosis and its related adverse eﬀects\nThere may be an improvement in pelvic pain and dyspareunia a/f_ter\nthree months of treatment, in favour of oral progestogens. We are\nuncertain about the eﬀects on back pain of both GnRHas and oral\nprogestogens a/f_ter three months of treatment.\nAdditionally, there may be a decrease of vaginal bleeding in women\ntreated with GnRHas, compared to oral progestogens. Also, there\nmay be slightly less weight gain in women treated with GnRHas\ninstead of oral progestogens. We are uncertain about the eﬀect of\nGnRHas compared to oral progestogens, for headache, a/f_ter three\nmonths of treatment.\nTrials comparing GnRHas versus gestrinone for relief of overall\npain associated with endometriosis and its related adverse\neﬀects\nWe are uncertain about the eﬀects found for dysmenorrhoea,\ndyspareunia, and non-menstrual pelvic pain, all measured on NRS\nand VRS scales.\nFor BMD, there may be a decrease found in favour of GnRHas a/f_ter\nsix and 12 months of treatment with either GnRHas or gestrinone.\nA/f_ter six months of treatment, there may be an improvement in hot\nflushes a/f_ter treatment with GnRHas compared to gestrinone.\nTrials comparing diﬀerent route of administration of GnRHas\nfor relief of overall pain associated with endometriosis and its\nrelated adverse eﬀects\nWe are uncertain about the eﬀect on pelvic pain, dysmenorrhoea,\ndyspareunia, pelvic induration and pelvic tenderness when\ncomparing buserelin depot 200 /uni03BCg once daily with intranasal\nbuserelin 200 /uni03BCg thrice daily, a/f_ter six months of treatment.\nWhen comparing subcutaneously administered buserelin depot\n200 /uni03BCg once daily with intranasal buserelin 200 /uni03BCg thrice daily, for\nhot flushes, vaginal dryness, decreased libido and headaches, we\nare uncertain about the eﬀects found between the two groups.\nTrials comparing GnRHas versus GnRHas in conjunction with\ncalcium-regulating agents for relief of overall pain associated\nwith endometriosis and its related adverse eﬀects\nThere may be a slightly bigger decrease in BMD a/f_ter 12 months\ntreatment with GnRHas, compared to GnRHas in conjunction with\ncalcium-regulating agents.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n32\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nWe are uncertain about the eﬀect related to improvement of\nthe most troublesome symptom, both overall improvement and\ncomplete resolution, when GnRHas were compared to GnRHas in\nconjunction with calcium-regulating agents for a treatment period\nof 12 months.\nOverall completeness and applicability of evidence\nUnfortunately, some data are still missing. Despite the attempts\nmade to contact the authors, the missing data could not be\nincluded in the review. Nevertheless, it is believed that, due to the\nlarge number of patients included (7355 in total), the evidence is\ncomprehensive and has covered a variety of treatment options and\noutcome measurements. In particular, the comparisons comparing\nGnRHas with danazol, including 23 studies, and GnRHas compared\nwith GnRHas in conjunction with add-back therapy, including 17\nstudies, cover a wide number of studies.\nOne issue of concern is the methods of reporting relief of overall\npain in the trials. Some trials report overall pain whilst others\nprovide details of specific endometriosis-associated pain such as\ndysmenorrhoea, dyspareunia, pelvic pain, pelvic induration, and\npelvic tenderness. In addition, these outcome measures were\nrequested at many diﬀerent follow-up periods. This means that a\nmeta-analysis was impossible at times. When it was possible, the\nanalysis contained only a limited amount of studies.\nIn addition, it should be noted that not all hormonal treatment\noptions (e.g. gestrinone and danazol) reported in this review are\nstill common treatment options for women with endometriosis.\nSince they are still treatment options that might be available, it has\nbeen decided to include these comparisons in the current review.\nQuality of the evidence\nThis was a systematic review of 72 trials including 7355 women.\nWe prepared Summary of findings tables using GRADEpro and\nCochrane methods. We judged the evidence for the comparisons\nincluded in the main analysis as low quality. This is primarily due\nto few studies with small sizes reporting each outcome. For the\nsensitivity analysis, due to poorly reported methods, the quality of\nevidence reviewed was either very low or low. Overall, the quality\nof the evidence was very mixed with only six of 72 trials reporting\nadequate details on all assessed categories, and so the evidence\nhas therefore been declared as having an overall low risk of bias.\nA total of nine studies were at low risk for selection bias, without\nhaving high risk of bias in other domains, and were therefore\nincluded in the original analysis. Ten of 72 studies reported high risk\nof bias on one category, and most of the studies reported unclear\nrisk of bias, due to missing data, mainly for 'selection bias'.\nA strength of this review is that all the included studies involved\npremenopausal women with symptoms of endometriosis. The\ndiagnosis of endometriosis was made by direct visualisation\n(laparoscopically or laparotomically diagnosed endometriosis) or\nfrom ultrasonographic imaging/MRI. In this way, an attempt was\nmade to include all women with complaints, with a clear diagnosis\nof endometriosis. Women without complaints, for example, women\nwith only infertility, were not included. This is especially important\nfor the outcome measures 'relief of overall pain', 'quality of\nlife', 'improvement of most troublesome symptom' and 'patient\nsatisfaction'. Weaknesses of this review are that the included\nstudies were small and many were at unclear of high risk of bias.\nIn addition to the above points, the form of reporting results\nby some included articles is debatable. Some included articles\nhave described the results for continuous outcome measures\n(such as pain complaints) as a dichotomous outcome measure\n(improvement, yes/no). This can cause the results to be interpreted\nincorrectly and the eﬀects to be underestimated or overestimated.\nWe would therefore recommend that continuous outcomes should\nnot be reported as dichotomous outcomes. /uni00A0This allows for a more\ncareful way of reporting results.\nPotential biases in the review process\nThe searches for this review included electronic searching by\nmultiple sources and is felt to be comprehensive. At least two\nreview authors independently extracted data and conducted the\nrisk of bias assessment. The publications included spanned over 34\nyears (from 1988 to 2022) during which time the methods and data\nreporting practices have changed significantly. Especially for older\npublications, attempts to contact authors were o/f_ten unsuccessful,\nresulting in poor scoring in risk of bias assessment due to\ninadequate information. Inaccessibility to useful information\navailable with these authors, but not included in papers, might\nhave also limited the meta-analysis and especially the Summary of\nfindings tables.\nAgreements and disagreements with other studies or\nreviews\nOther reviews concerning the use of GnRHas in treating\nendometriosis-associated pain agree with GnRHas being eﬀective\nin reducing overall pain (Jackson 2006 ; Kalaitzopoulos 2021;\nRafique 2017). There are several proposals within reviews and\nguidelines on the specific duration of treatment available, varying\nbetween six and 12 months. This does not completely correlate\nwith the findings of our review, as we as well have found that\nGnRHas could be eﬀective in reducing pelvic tenderness. However,\nour evidence is still of very low certainty.\nMost reviews describe danazol as an eﬀective orally used treatment\nin reducing endometriosis-associated pain. However, in the current\nESHRE, WES and SOGC guidelines, danazol is no longer described\nas a recommended treatment option because of a high risk of\nquality of life-reducing side eﬀects. ACOG is the only guideline that\nstill recommends danazol as a treatment option (Kalaitzopoulos\n2021).\nA U T H O R S ' /uni00A0 C O N C L U S I O N S\nImplications for practice\nWomen who have complaints of endometriosis can be treated in\ndiﬀerent ways. The current review suggests that, for relief of overall\npain, there may be a decrease in favour of treatment with GnRHas\ncompared to placebo or oral or injectable progestogens. We are\nuncertain about the eﬀects when comparing GnRHas with danazol,\nintra-uterine progestogens or gestrinone. Not all aspects of pain\nrelief are discussed in all the trials and generalisability about the\nrelief of specific aspects of pain may be diﬀicult.\nThis review showed that there may be a slight decrease in BMD\nwhen women were treated with GnRHas, compared to gestrinone.\nThere was also a greater decrease of BMD when women were\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n33\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\ntreated with GnRHas alone, compared to GnRHas in conjunction\nwith calcium-regulating agents. Thus, there may be an increase in\nadverse eﬀects when women are treated with GnRHas, compared\nto placebo or gestrinone. This must be taken into account\nin the decision-making process together with the patient, as\nendometriosis is a common disease, with many diﬀerent treatment\noptions that need to be individualised to the wishes and stage of\nlife of the individual patient.\nImplications for research\nDue to the limited number of low-risk studies and the high\nheterogeneity in the sensitivity analyses, we recommend further\nresearch into the eﬀects of GnRHas and other hormonal treatment\noptions on our stated outcome measures. We recommend\nconsidering a modern large study with low risk of bias to validate\nthe practice that has become common practice. In addition, it\nremains important to clearly describe the method in future articles,\nso that more articles can be labelled as low risk of bias in future\nreviews.\nA C K N O W L E D G E M E N T S\nWe thank everyone at Cochrane Gynaecology and Fertility, in\nparticular Marian Showell, Information Specialist, who contributed\nto the search strategy. We would like to thank Julie Brown,\nAlice Pan, Roger Hart, Jessica E. Farmer, Andrew Prentice,\nAndrew Breeze, Gaity Ahmad, Andrew Watson, and Andy Pick for\ncontributing to the previous versions of the review.\nWe would like to thank the following peer reviewers for their\nvaluable comments:\nDr Andrew Watson, Consultant Obstetrician and Gynaecologist.\nTameside Hospital, Greater Manchester, UK\nJack Wilkinson, Centre for Biostatistics, University of Manchester\nEdgardo Somigliana, Università degli Studi di Milano and\nFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan,\nItaly\nAngela Beros, Cochrane Gynaecology and Fertility Group.\nWe thank Anne Lethaby for copy-editing the review.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n34\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nREFERENCES\n/uni00A0\nReferences to studies included in this review\nAbdou 2018 {published data only}\n*/uni00A0 Abdou/uni00A0AM, Ammar/uni00A0IMM, Alenmr/uni00A0AAA, Abdelrhman/uni00A0AA.\nDienogest versus leuprolide acetate for recurrent pelvic pain\nfollowing laparoscopic treatment of endometriosis. Journal of\nObstetrics and Gynecology of India Aug 2018;4:306-13. [PMID:\nDOI: 10.1007/s13224-018-1119-3]\nAdamson 1994 {published data only}\n*/uni00A0 Adamson/uni00A0GD, Kwei/uni00A0L, Edgren/uni00A0RA. Pain of endometriosis:\neﬀects of nafarelin and danazol therapy. International Journal of\nFertility & Menopausal Studies 1994;39(4):215-7.\nAgarwal 1997 {published data only}\n*/uni00A0 Agarwal/uni00A0SK, Hamrang/uni00A0C, Henzl/uni00A0MR, Judd/uni00A0HL. Nafarelin vs.\nleuprolide acetate depot for endometriosis. Changes in bone\nmineral density and vasomotor symptoms. Nafarelin Study\nGroup. Journal of Reproductive Medicine 1997;42(7):413-23.\nAN Zoladex 1996 {published data only}\n*/uni00A0 AN Zoladex. Goserelin depot versus danazol in the treatment\nof endometriosis the Australian/New Zealand experience.\nAustralian & New Zealand Journal of Obstetrics & Gynaecology\n1996;36(1):55-60.\nAudebert 1997 {published data only}\n*/uni00A0 Audebert/uni00A0A, Lucas/uni00A0C, Joubert-Collin/uni00A0M. Eﬀicacy and safety\nof slow-release leuprorelin 3,75 mg compared to danazol\ntreatment./uni00A0 [Eﬀicacite et tolerance de la leuproreline 3,75 MG\na liberation prolongeedans le traitement de l'endometriose\nen comparaison au danazol]. References en Gynecologie\nObstetrique 1997;5(1):49-57.\nBergqvist 1997 {published data only}\n*/uni00A0 Bergqvist/uni00A0A, Jacobson/uni00A0J, Harris/uni00A0S. A double-blind randomized\nstudy of the treatment of endometriosis with nafarelin or\nnafarelin plus norethisterone. Gynecological Endocrinology\n1997;11(3):187-94. [DOI: 10.3109/09513599709152533]\nBergqvist 1998 {published data only}\n*/uni00A0 Bergqvist/uni00A0A, Bergh/uni00A0T, Hogstrom/uni00A0L, Mattsson/uni00A0S, Nordenskjold/uni00A0F,\nRasmussen/uni00A0C. Eﬀects of triptorelin versus placebo on\nthe symptoms of endometriosis. Fertility & Sterility\n1998;69(4):702-8.\nBergqvist 2000 {published data only}\n*/uni00A0 Bergqvist A and SCANDET group. A comparative\nstudy of the acceptability and eﬀect of goserelin\nand nafarelin on endometriosis. Gynecological\nEndocrinology Aug 2000;14:425-432. [DOI: https://\ndoi.org/10.3109/09513590009167714]\nBurry 1989 {published data only}\n*/uni00A0 Burry/uni00A0KA, Patton/uni00A0PE, Illingworth/uni00A0DR. Metabolic changes\nduring medical treatment of endometriosis: nafarelin acetate\nversus danazol.. American Journal of Obstetrics & Gynecology\n1989;160(6):1454-9; discussion 1459-61.\nBurry 1992 {published data only}\nBurry/uni00A0K. Nafarelin in the management of endometriosis: quality\nof life assessment. American Journal of Obstetrics & Gynecology\n1992;166:735-9.\n*/uni00A0 Burry/uni00A0KA, Buttram/uni00A0V, Moghissi/uni00A0KMF. Quality of life during and\na/f_ter treatment of endometriosis with Nafarelin or Danazol\n(abstract). Fertility & Sterility 1990;54(pp.s13):0-029.\nChang 1996 {published data only}\n*/uni00A0 Chang/uni00A0SP, Ng/uni00A0HT. A randomized comparative study of the\neﬀect of leuprorelin acetate depot and danazol in the treatment\nof endometriosis. Chung Hua i Hsueh Tsa Chih - Chinese Medical\nJournal 1996;57(6):431-7.\nCheng 2005 {published data only}\n*/uni00A0 Cheng/uni00A0MH, Yu/uni00A0BK, Chang/uni00A0SP, Wang/uni00A0PH. A randomized, parallel,\ncomparative study of the eﬀicacy and safety of nafarelin versus\ndanazol in the treatment of endometriosis in Taiwan. Journal of\nthe Chinese Medical Association 2005;68(7):307-14.\nCirkel 1995 {published data only}\n*/uni00A0 Cirkel/uni00A0U, Ochs/uni00A0H, Schneider/uni00A0HP. A randomized, comparative\ntrial of triptorelin depot (D-Trp6-LHRH) and danazol in the\ntreatment of endometriosis. European Journal of Obstetrics,\nGynecology, & Reproductive Biology 1995;59(1):61-9.\nCirkel/uni00A0U, Ochs/uni00A0H, Schneider/uni00A0HPG. GnRH analogue depot\n(triptorelin) versus danazol in the treatment of endometriosis.\nGynecological Endocrinology (3rd International Symposium)\n1993;7(Supp 2):43.\nOchs/uni00A0H, Cirkel/uni00A0U, Schneider/uni00A0HP. Correlation between extent\nof ovarian suppression and regression of endometriosis:\ndecapeptyl vs danazol. Gynecological Endocrinology (3rd\nInternational Symposium) 1993;7(Supp 2):43.\nCrosignani 1996 {published data only}\n*/uni00A0 Crosignani/uni00A0PG, De Cecco/uni00A0L, Gastaldi/uni00A0A, Venturini/uni00A0PL,\nOldani/uni00A0S, Vegetti/uni00A0W, et al. Leuprolide in a 3-monthly\nversus a monthly depot formulation for the treatment\nof symptomatic endometriosis: a pilot study. Human\nReproduction 1996;11(12):2732-5. [DOI: 10.1093/\noxfordjournals.humrep.a019199]\nCrosignani 2006 {published data only}\n*/uni00A0 Crosignani/uni00A0PG, Luciano/uni00A0A, Ray/uni00A0A, Bergqvist/uni00A0A. Subcutaneous\ndepot medroxyprogesterone acetate versus leuprolide acetate\nin the treatment of endometriosis-associated pain. Human\nReproduction Sep 2006;21:248-56. [DOI: 10.1093/humrep/\ndei290]\nDawood 1995 {published data only}\n*/uni00A0 Dawood/uni00A0MY, Ramos/uni00A0J, Khan-Dawood/uni00A0F. Depot leuprolide\nacetate versus danazol for treatment of pelvic endometriosis:\nchanges in vertebral bone mass and serum estradiol and\ncalcitonin. Fertility & Sterility 1995;63:1177-1183. [DOI: 10.1016/\ns0015-0282(16)57593-1]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n35\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nDlugi 1990 {published data only}\n*/uni00A0 Dlugi/uni00A0AM, Miller/uni00A0JD, Knittle/uni00A0J. Lupron depot (leuprolide acetate\nfor depot suspension) in the treatment of endometriosis: a\nrandomized, placebo-controlled, double-blind study. Lupron\nStudy Group. Fertility & Sterility 1990;54(3):419-27. [DOI:\n10.1016/s0015-0282(16)53755-8]\nDmowski 1989a {published data only}\n*/uni00A0 Dmowski/uni00A0WP, Radwanska/uni00A0E, Binor/uni00A0Z, Tummon/uni00A0I, Pepping/uni00A0P.\nOvarian suppression induced with Buserelin or danazol in the\nmanagement of endometriosis: a randomized, comparative\nstudy. Fertility & Sterility 1989;51(3):395-400. [DOI: 10.1016/\ns0015-0282(16)60543-5]\nEdmonds 1994 {published data only}\n*/uni00A0 Edmonds/uni00A0DK, Howell/uni00A0R. Can hormone replacement therapy\nbe used during medical therapy of endometriosis? British\nJournal of Obstetrics and Gynaecology May 1994;101:24-26.\n[DOI: 10.1111/j.1471-0528.1994.tb13681.x]\nFedele 1989 {published data only}\nFedele/uni00A0L, Bianchi/uni00A0S, Arcaini/uni00A0L, Vercellini/uni00A0P, Candiani/uni00A0GB.\nBuserelin versus danazol in the treatment of\nendometriosis-associated infertility. American Journal\nof Obstetrics & Gynecology 1989;161(4):871-6. [DOI:\n10.1016/0002-9378(89)90739-4]\n*/uni00A0 Fedele/uni00A0L, Marchini/uni00A0M, Bianchi/uni00A0S, Baglioni/uni00A0A, Zanotti/uni00A0F. Vaginal\npatterns during danazol and buserelin acetate therapy for\nendometriosis: structural and ultrastructural study. Fertility &\nSterility 1993;59(6):1191-5.\nFerreira 2010 {published data only}\n*/uni00A0 Ferreira/uni00A0RA, Vieira/uni00A0C, Rosa-e-Silava/uni00A0J, Rosa-e-Silva/uni00A0A,\nNogueira/uni00A0A, Ferriani/uni00A0R. Eﬀects of the levonorgestrel-releasing\nintrauterine system on cardiovascular risk markers in patients\nwith endometriosis: a comparative study with the GnRH\nanalogue. Contraception 2010;81:117-122. [DOI: 10.1016/\nj.contraception.2009.08.003]\nFinkelstein 1998 {published data only}\n*/uni00A0 Finkelstein/uni00A0JS, Klibanski/uni00A0A, Arnold/uni00A0AL, Toth/uni00A0TL, Hornstein/uni00A0MD,\nNeer/uni00A0RM. Prevention of estrogen deficiency–related bone\nloss with human parathyroid hormone–(1-34). Journal of\nthe American Medical Association 1998;280:1067-1073. [DOI:\n10.1001/jama.280.12.1067]\nFinkelstein 1999 {published data only}\n*/uni00A0 Finkelstein/uni00A0JS, Arnold AL/uni00A0. Increases in bone mineral density\na/f_ter discontinuation of daily human parathyroid hormone\nand gonadotropin-releasing hormone analog administration in\nwomen with endometriosis. Journal of Clinical Endocrinology &\nMetabolism 1999;84:1214-1219. [DOI: 10.1210/jcem.84.4.5643]\nFranke 2000 {published data only}\n*/uni00A0 Franke/uni00A0HR, Van der Weijer/uni00A0PHM, Pennings/uni00A0TMM, Van der\nMooren/uni00A0MJ. Gonadotropin-releasing hormone agonist plus\n“add-back” hormone replacement therapy for treatment of\nendometriosis: a prospective, randomized, placebo-controlled,\ndouble-blind trial. Fertility & Sterility Sept 2000;74:534-539.\n[DOI: 10.1016/s0015-0282(00)00690-7]\nFraser 1991 {published data only}\n*/uni00A0 Fraser/uni00A0IS, Shearman/uni00A0RP, Jansen/uni00A0RP, Sutherland/uni00A0PD. A\ncomparative treatment trial of endometriosis using the\ngonadotrophin-releasing hormone agonist, nafarelin, and the\nsynthetic steroid, danazol. Australian & New Zealand Journal\nof Obstetrics & Gynaecology 1991;31(2):158-63. [DOI: 10.1111/\nj.1479-828x.1991.tb01807.x]\nFreundl 1998 {published data only}\n*/uni00A0 Freundl/uni00A0G, Gödtke/uni00A0K, Gnotha/uni00A0C, Godehardt/uni00A0E, Kienle E.\nSteroidal ‘Add-Back’ Therapy in Patients Treated with GnRH\nAgonists. Gynecologic and Obstetric Investigation 1998;45:22-30.\n[DOI: 10.1159/000052848]\nFukushima 1993 {published data only}\nFukushima/uni00A0M, Shindo/uni00A0M, Sato/uni00A0K. Hormone treatment\nrelated bone mineral content changes in Japanese women\nwith endometriosis. Asia-Oceania Journal of Obstetrics\nand Gynaecology 1993;19(3):299-307. [DOI: 10.1111/\nj.1447-0756.1993.tb00389.x]\n*/uni00A0 Fukushima M/uni00A0. Changes in bone mineral content following\nhormone treatment for endometriosis./uni00A0. International\nJournal of Gynecology & Obstetrics 1995;50:S17-S21. [DOI:\n10.1016/0020-7292(95)02510-j]\nGnoth 1999 {published data only}\n*/uni00A0 Gnoth/uni00A0C, Gödtke/uni00A0K, Freundl/uni00A0G, Godehardt/uni00A0E, Kienle/uni00A0E. Eﬀects\nof add-back therapy on bone mineral density and pyridinium\ncrosslinks in patients with endometriosis treated with\ngonadotropin-releasing hormone agonists. Gynecologic and\nObstetric Investigation 1999;47:37-41. [DOI: 10.1159/000010059]\nGomes 2007 {published data only}\n*/uni00A0 Gomes/uni00A0MK, Ferriani/uni00A0RA, Rosa e Silva/uni00A0JC, Japur de Sa Rosa e\nSilva/uni00A0AC, Vieira/uni00A0CS, Candido dos Reis/uni00A0FJ. The levonorgestrel-\nreleasing intrauterine system and endometriosis staging.\nFertility & Sterility 2007;87(5):1231-4. [DOI: 10.1016/\nj.fertnstert.2006.11.044]\nHarada 2009 {published data only}\n*/uni00A0 Harada/uni00A0T, Momoeda/uni00A0M, Taketani/uni00A0Y, Aso/uni00A0T, Fukunaga/uni00A0M,\nHagino/uni00A0H, et al. Dienogest is as eﬀective as intranasal buserelin\nacetate for the relief of pain symptoms associated with\nendometriosis—a randomized, double-blind, multicenter,\ncontrolled trial. Fertility & Sterility 2009;91(3):675-681. [DOI:\n10.1016/j.fertnstert.2007.12.080]\nHenzl 1988 {published data only}\nHenzl/uni00A0MR, Corson/uni00A0SL, Moghissi/uni00A0K, Buttram/uni00A0VC, Berqvist/uni00A0C,\nJacobson/uni00A0J. Administration of nasal nafarelin as compared with\noral danazol for endometriosis. A multicenter double-blind\ncomparative clinical trial. New England Journal of Medicine\n1988;318(8):485-9.\nHenzl/uni00A0MR. Role of nafarelin in the management of\nendometriosis. Journal of Reproductive Medicine 1989;34(12\nSuppl):1021-4.\nJacobs/uni00A0L, Field/uni00A0C, Thie/uni00A0J, Coulam/uni00A0C. Treatment of endometriosis\nwith the GnRH agonist naferelin acetate. International Journal of\nFertility 1991;36:30-5.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n36\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n*/uni00A0 Moghissi/uni00A0KS, Corson/uni00A0SL, Buttram/uni00A0V, Henzl/uni00A0MR. Evaluation\nof a GnRH agonist (nafarelin) versus danazol for treatment\nof endometriosis. Contributions to Gynecology & Obstetrics\n1987;16:266.\nHornstein 1995 {published data only}\nHornstein/uni00A0M, Yuzpe/uni00A0A, Burry/uni00A0K, Heinrichs/uni00A0L, Orwoll/uni00A0E. A\nprospective randomised double-blind trial of 3 versus 6 months\nnafarelin therapy for symptoms of endometriosis. Fertility &\nSterility 1992;58:S84.\n*/uni00A0 Hornstein/uni00A0MD, Yuzpe/uni00A0AA, Burry/uni00A0KA, Heinrichs/uni00A0LR, Buttram VL\nJr, et al. Prospective randomized double-blind trial of 3 versus 6\nmonths of nafarelin therapy for endometriosis associated pelvic\npain. Fertility & Sterility 1995;63(5):955-62. [PMID: 7720940]\nHornstein 1998 {published data only}\n*/uni00A0 Hornstein/uni00A0MD, Surrey/uni00A0ES, Weisberg/uni00A0GW, Casino LA LUPRON\nadd-back study group. Leuprolide acetate depot and\nhormonal add-back in endometriosis: A 12- month study.\nObstetrics and Gynecology Jan 1998;1:16-24. [DOI: 10.1016/\ns0029-7844(97)00620-0]\nHowell 1995 {published data only}\n*/uni00A0 Howell/uni00A0R, Edmonds/uni00A0DK, Dowsett/uni00A0M, Crook/uni00A0D, Lees/uni00A0B,\nStevenson/uni00A0JC. Gonadotropin-releasing hormone analogue\n(goserelin) plus hormone replacement therapy for the\ntreatment of endometriosis: a randomized controlled\ntrial. Fertility & Sterility 1995;64(3):474-481. [DOI: 10.1016/\ns0015-0282(16)57779-6.]\nHurst 2000 {published data only}\n*/uni00A0 Hurst/uni00A0BS, Gardner/uni00A0SC, Tucker/uni00A0KE, Awoniyi/uni00A0CA, Schlaﬀ/uni00A0WD.\nDelayed oral estradiol combined with leuprolide increases\nendometriosis-related pain. Journal of the Society of\nLaparoendoscopic Surgeons 2000;4:97-101. [PMID: PMC3015370]\nIrahara 2001 {published data only}\n*/uni00A0 Irahara/uni00A0M, /uni00A0Uemura/uni00A0H, Yasui/uni00A0T, Kinoshita/uni00A0H, Yamada/uni00A0M,\nTezuka/uni00A0M, et al. Eﬀicacy of every-other-day administration\nof conjugated equine estrogen and medroxyprogesterone\nacetate on gonadotropin-releasing hormone agonists treatment\nin women with endometriosis. Gynecologic and Obstetric\nInvestigation 2001;52:217-222. [DOI: 10.1159/000052978]\nJelley 1986 {published data only}\nJelley/uni00A0RY, Magill/uni00A0PJ. The eﬀect of LHRH agonist therapy in the\ntreatment of endometriosis (English experience). Progress in\nClinical & Biological Research 1986;225:227-38.\n*/uni00A0 Jelley/uni00A0RY. Multicentre open comparative study of buserelin\nand danazol in the treatment of endometriosis. British Journal\nof Clinical Practice 1986;48(Suppl):64-8.\nKennedy 1990 {published data only}\n*/uni00A0 Kennedy/uni00A0SH, Williams/uni00A0IA, Brodribb/uni00A0J, Barlow/uni00A0DH, Shaw/uni00A0RW. A\ncomparison of nafarelin acetate and danazol in the treatment\nof endometriosis. Fertility & Sterility June 1990;53(6):998-1003.\n[DOI: 10.1016/s0015-0282(16)53574-2]\nKiilholma 1995 {published data only}\n*/uni00A0 Kiilholma/uni00A0P, Tuimala/uni00A0R, Kivinen/uni00A0S, Korhonen/uni00A0M, Hagman E.\nComparison of the gonadotropin-releasing hormone agonist\ngoserelin acetate alone versus goserelin combined with\nestrogen-progestogen add-back therapy in the treatment of\nendometriosis. Fertility & Sterility 1995;64(5):903-908. [DOI:\n10.1016/s0015-0282(16)57900-x]\nLemay 1988 {published data only}\nLemay/uni00A0A, Maheux/uni00A0R, Huot/uni00A0C, Blanchet/uni00A0J, Faure/uni00A0N. Eﬀicacy of\nintranasal or subcutaneous luteinizing hormone-releasing\nhormone agonist inhibition of ovarian function in the treatment\nof endometriosis. American Journal of Obstetrics & Gynecology\n1988;158(2):233-6. [DOI: 10.1016/0002-9378(88)90128-7]\n*/uni00A0 Lemay/uni00A0A, Maheux/uni00A0R, Quesnel/uni00A0G, Bureau M, Faure/uni00A0N, Merat/uni00A0P.\nLH-RH agonist treatment of endometriosis. Contributions to\nGynecology and Obstetrics 1987;16:247-53.\nLing 1999 {published data only}\n*/uni00A0 Ling/uni00A0FW. Randomized controlled trial of depot leuprolide\nin patients with chronic pelvic pain and clinically suspected\nendometriosis. Pelvic pain study group. Obstetrics & Gynecology\n1999;93(1):51-58. [DOI: 10.1016/s0029-7844(98)00341-x]\nMäkäräinen 1996 {published data only}\n*/uni00A0 Makarainen/uni00A0L, Rönnberg/uni00A0L, Kauppila/uni00A0A. Medroxyprogesterone\nacetate supplementation diminishes the hypoestrogenic side\neﬀects of gonadotropin-releasing hormone agonist without\nchanging its eﬀicacy in endometriosis. Fertility & Sterility\n1996;65(1):29-34. [DOI: 10.1016/s0015-0282(16)58023-6]\nMiller 2000 {published data only}\n*/uni00A0 Miller/uni00A0JD. Quantification of endometriosis-associated\npain and quality of life during the stimulatory phase of\ngonadotropin-releasing hormone agonist therapy: a double-\nblind, randomized, placebo-controlled trial. American Journal of\nObstetrics & Gynecology 2000;182(6):1483-1488. [DOI: 10.1067/\nmob.2000.106846]\nMinaguchi 1986 {published data only}\n*/uni00A0 Minaguchi/uni00A0H, Uemura/uni00A0T, Shirasu/uni00A0K. Clinical study on finding\noptimal dose of a potent LHRH agonist (buserelin) for the\ntreatment of endometriosis--multicenter trial in Japan. Progress\nin Clinical & Biological Research 1986;225:211-25. [PMID:\n3097667]\nMoghissi 1998 {published data only}\n*/uni00A0 Moghissi/uni00A0KS, Schlaﬀ/uni00A0WD, Olive/uni00A0DL, Skinner/uni00A0MA, Yin/uni00A0H.\nGoserelin acetate (Zoladex) with or without hormone\nreplacement. Therapy for the treatment of endometriosis.\nFertility & Sterility June 1998;69(6):1056-1062. [DOI: 10.1016/\ns0015-0282(98)00086-7]\nNEET 1992 {published data only}\nKennedy/uni00A0SH, Williams/uni00A0IA, Brodribb/uni00A0J, Barlow/uni00A0DH, Shaw/uni00A0RW. A\ncomparison of nafarelin acetate and danazol in the treatment of\nendometriosis. Fertility & Sterility 1990;53(6):998-1003.\n*/uni00A0 NEET. Nafarelin for endometriosis: a large-scale, danazol-\ncontrolled trial of eﬀicacy and safety, with 1-year follow-up The\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n37\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nNafarelin European Endometriosis Trial Group (NEET)/uni00A0. Fertility\n& Sterility 1992;57(3):514-22. [PMID: 1531464]\nOdukoya 1995 {published data only}\n*/uni00A0 Odukoya/uni00A0OA, Bansal/uni00A0A, Wilson/uni00A0AP, Weetman/uni00A0AP, Cooke/uni00A0ID.\nSerum-soluble CD23 in patients with endometriosis and the\neﬀect of treatment with danazol and leuprolide acetate depot\ninjection. Human Reproduction 1995;10(4):942-946. [DOI:\n10.1093/oxfordjournals.humrep.a136067]\nOrwoll 1994 {published data only}\n*/uni00A0 Orwoll/uni00A0ES, Yuzpe/uni00A0AA, Burry/uni00A0KA, Heinrichs/uni00A0L, Buttram/uni00A0VC,\n/uni00A0Hornstein/uni00A0MD. Nafarelin therapy in endometriosis: long-\nterm eﬀects on bone mineral density. American Journal of\nObstetrics and Gynecology Nov 1994;171(5):1221-1225. [DOI:\n10.1016/0002-9378(94)90136-8]\nOzaki 2020 {published data only}\n*/uni00A0 Ozaki/uni00A0R, /uni00A0Kumakiri/uni00A0J, Jinushi/uni00A0M, Ikuma/uni00A0S, Murakami/uni00A0K,\nKawasaki/uni00A0Y, et al. Comparison of eﬀect of preoperative\ndienogest and gonadotropin‑releasing hormone\nagonist administration on laparoscopic cystectomy for ovarian\nendometriomas. Archives of Gynecology and Obstetrics/uni00A0 July\n2020;302:969-976. [DOI: 10.1007/s00404-020-05691-3]\nPalagiano 1994 {published data only}\n*/uni00A0 Palagiano/uni00A0A, Capuano/uni00A0V. Medical treatment of endometriosis:\ncomparative study of leuprolide acetate and danazol. Minerva\nGinecologica 1994;46(4):173-7. [PMID: 8065590]\nPetta 2005 {published data only}\nPetta/uni00A0CA, Ferriani/uni00A0RA, Abrao/uni00A0MS, Hassan/uni00A0D, Rosa/uni00A0ESJC,\nPodgaec/uni00A0S, et al. Randomized clinical trial of a levonorgestrel-\nreleasing intrauterine system and a depot GnRH analogue\nfor the treatment of chronic pelvic pain in women with\nendometriosis. Human Reproduction 2005;20(7):1993-8. [DOI:\n10.1093/humrep/deh869]\nVieira/uni00A0CS, Ferreira/uni00A0RA, Rosa e Silva/uni00A0JC, Rosa e Silva/uni00A0ACJS,\nGomes/uni00A0MK, Ferriani/uni00A0RA. Comparative study of the influence\nof the levonorgestrel intra-uterine system and the GnRH\nanalogues on cardiovascular risk markers in patients with\nendometriosis. Fertility & Sterility 2007;88(Suppl 1):211.\n*/uni00A0 de/uni00A0Sa Rosa e Silva/uni00A0AC, Rosa e Silva/uni00A0JC, Nogueira/uni00A0AA,\nPetta/uni00A0CA, Abrao/uni00A0MS, Ferriani/uni00A0RA. The levonorgestrel-releasing\nintrauterine device reduces CA-125 serum levels in patients with\nendometriosis. Fertility & Sterility 2006;86(3):742-4.\nRock 1993 {published data only}\nAllen/uni00A0TW. Zoladex versus danazol in endometriosis\ntherapy. Journal of the American Osteopathic Association\n1993;93(10):1013.\nRock/uni00A0JA, Truglia/uni00A0JA, Caplan/uni00A0RJ. Zoladex (goserelin acetate\nimplant) in the treatment of endometriosis: a randomized\ncomparison with danazol. Obstetrics & Gynecology\n1993;82(2):198-205. [PMID: 8336864]\n*/uni00A0 Rock/uni00A0JA. A multicenter comparison of GnRH agonist (Zoladex)\nand danazol in the treatment of endometriosis/uni00A0. Fertility &\nSterility 1991;56(pp.s49).\nRolland 1990 {published data only}\n*/uni00A0 Rolland/uni00A0R, van der/uni00A0Heijden/uni00A0PF. Nafarelin versus danazol\nin the treatment of endometriosis. American Journal\nof Obstetrics & Gynecology 1990;162(2):586-8. [DOI:\n10.1016/0002-9378(90)90437-c]\nRotondi 2002 {published data only}\n*/uni00A0 Rotondi/uni00A0M, Labriola/uni00A0D, Ammaturo/uni00A0FP, Amato/uni00A0G, Carella/uni00A0C,\nIzzo/uni00A0A, et al. Depot leuprorelin acetate versus danazol\nin the treatment of infertile women with symptomatic\nendometriosis. European Journal of Gynaecological Oncology\n2002;23(6):523-526. [PMID: 12556096]\nRoux 1995 {published data only}\n*/uni00A0 Roux/uni00A0C, Pelissier/uni00A0C, Listrat/uni00A0V, Kolta/uni00A0S, Simonetta/uni00A0C, Guignard/uni00A0M,\net al. Bone loss during gonadotropin releasing hormone\nagonist treatment and use of nasal calcitonin. Osteoporosis\nInternational 1995;5:185-190. [DOI: 10.1007/BF02106098]\nSchlaﬀ 2006 {published data only}\n*/uni00A0 Schlaﬀ/uni00A0WD, Carson/uni00A0SA, Luciano/uni00A0A, Ross/uni00A0D, Bergqvist/uni00A0A.\nSubcutaneous injection of depot medroxyprogesterone\nacetate compared with leuprolide acetate in the treatment of\nendometriosis-associated pain. Fertility & Sterility February\n2006;85(2):314-325. [DOI: 10.1016/j.fertnstert.2005.07.1315.]\nShaw 1986 {published data only}\n*/uni00A0 Shaw/uni00A0RW, Matta/uni00A0W. Reversible pituitary ovarian suppression\ninduced by an LHRH agonist in the treatment of endometriosis\n- comparison of two dose regimens. Clinical Reproduction and\nFertility 1986;4(5):329-36. [PMID: 3100012]\nShaw 1990 {published data only}\n*/uni00A0 Shaw/uni00A0RW. Nafarelin in the treatment of pelvic pain caused\nby endometriosis. American Journal of Obstetrics & Gynecology\n1990;162(2):574-6. [DOI: 10.1016/0002-9378(90)90433-8]\nSillem 1999 {published data only}\n*/uni00A0 Sillem/uni00A0M, Parviz/uni00A0M, Woitge/uni00A0HW, Kiesel/uni00A0L, Ulrich/uni00A0U, von/uni00A0Holst/uni00A0T,\net al. Add-back medrogestone does not prevent bone loss in\npremenopausal women treated with goserelin. Experimental\nand Clinical Endocrinology & Diabetes 1999;107:379-385. [DOI:\n10.1055/s-0029-1212129]\nSkrzypulec 2004 {published data only}\n*/uni00A0 Skrzypulec/uni00A0V, Walaszek/uni00A0A, Drosdzol/uni00A0A, Nowosielski/uni00A0K, Piela/uni00A0B,\nRozmus-Warcholinska/uni00A0W. Influence of GnRH analogue on the\nintensification of endometriosis symptoms and infertility\ntreatment. Wiadomosci Lekarskie 2004;57 Suppl 1:301-4. [PMID:\n15884262]\nStrowitzki 2012 {published data only}\nStrowitzki/uni00A0T, Marr/uni00A0J, Gerlinger/uni00A0C, Faustmann/uni00A0T, Seitz/uni00A0C. Detailed\nanalysis of a randomized, multicenter, comparative trial\nof dienogest versus leuprolide acetate in endometriosis.\nInternational Journal of Gynecology and Obstetrics\n2012;117(3):228-233. [DOI: 10.1016/j.ijgo.2012.01.009]\n*/uni00A0 Strowitzki/uni00A0T, Marr/uni00A0J, Gerlinger/uni00A0C, Faustmann/uni00A0T, Seitz/uni00A0C.\nDienogest is as eﬀective as leuprolide acetate in treating the\npainful symptoms of endometriosis: a 24-week, randomized,\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n38\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nmulticentre, open-label trial. Human Reproduction January\n2010;25(3):633-641. [DOI: 10.1093/humrep/dep46]\nSurrey 1992 {published data only}\n*/uni00A0 Surrey/uni00A0ES, Judd/uni00A0HL. Reduction of vasomotor symptoms and\nbone mineral density loss with combined norethindrone and\nlong-acting gonadotropin-releasing hormone agonist therapy\nof symptomatic endometriosis: A prospective randomized\ntrial. Journal of Clinical Endocrinology and Metabolism\n1992;75(2):558-563. [DOI: 10.1210/jcem.75.2.1386374]\nSurrey 2002 {published data only}\n*/uni00A0 Surrey/uni00A0ES, Hornstein/uni00A0MD. Prolonged GnRH agonist and add-\nback therapy for symptomatic endometriosis: long-term follow-\nup. Obstetrics and Gynecology 2002;99(5 Pt 1):709-719. [DOI:\n10.1016/s0029-7844(02)01945-2]\nTahara 2000 {published data only}\n*/uni00A0 Tahara/uni00A0M, Matsuoka/uni00A0T, Yokoi/uni00A0T, Tasaka/uni00A0K, Kurachi/uni00A0H, Murata/uni00A0Y.\nTreatment of endometriosis with a decreasing dosage of\na gonadotropin-releasing hormone agonist (nafarelin): a\npilot study with low-dose agonist therapy (\"draw-back\"\ntherapy). Fertility & Sterility 2000;73(4):799-804. [DOI: 10.1016/\ns0015-0282(99)00636-6]\nTang 2017 {published data only}\n*/uni00A0 Tang/uni00A0H, Wu/uni00A0R, Li/uni00A0X, Zhou/uni00A0Y, Liu/uni00A0Z, Wang/uni00A0C, Chen/uni00A0Y, et al.\nCurative eﬀect of 1.88-mg and 3.75-mg gonadotrophin-releasing\nhormone agonist on stage III–IV endometriosis: Randomized\ncontrolled study. The Journal of Obstetrics and Gynaecology\nResearch October 2017;43(10):1550-1554. [DOI: 10.1111/\njog.13420]\nTummon 1988 {published data only}\n*/uni00A0 Tummon/uni00A0IS, Ali/uni00A0A, Pepping/uni00A0ME, Radwanska/uni00A0E, Binor/uni00A0Z,\nDmowski/uni00A0WP. Bone mineral density in women with\nendometriosis before and during ovarian suppression with\ngonadotropin-releasing hormone agonists or danazol. Fertility &\nSterility May 1988;49(5):792-796. [PMID: 3129312]\nTummon 1989 {published data only}\n*/uni00A0 Tummon/uni00A0IS, Pepping/uni00A0ME, Binor/uni00A0Z, Radwanska/uni00A0E, Dmowski/uni00A0WP.\nA randomized, prospective comparison of endocrine changes\ninduced with intranasal leuprolide or danazol for treatment\nof endometriosis. Fertility & Sterility 1989;51(3):390-4. [DOI:\n10.1016/s0015-0282(16)60542-3]\nVercellini 1994 {published data only}\n*/uni00A0 Vercellini/uni00A0P, Trespidi/uni00A0L, Panazza/uni00A0S, Bramante/uni00A0T, Mauro/uni00A0F,\nCrosignani/uni00A0PG. Very low dose danazol for relief of\nendometriosis-associated pelvic pain: a pilot study. Fertility &\nSterility 1994;62(6):1136-42. [PMID: 7525359]\nVercellini 1996 {published data only}\n*/uni00A0 Vercellini/uni00A0P, Soma/uni00A0M, Moro/uni00A0GL. Gestrinone versus a\ngonadotropin-releasing hormone agonist for the treatment\nof pelvic pain associated with endometriosis: A multicenter,\nrandomized, double-blind study. Fertility & Sterility\n196;66(6):911-919. [DOI: 10.1016/s0015-0282(16)58682-8]\nWheeler 1992 {published data only}\nWheeler/uni00A0JM, Knittle/uni00A0JD, Miller/uni00A0JD. Depot leuprolide acetate\nversus danazol in the treatment of women with symptomatic\nendometriosis: a multicenter, double-blind randomized clinical\ntrial. II. Assessment of safety. The Lupron Endometriosis\nStudy Group. American Journal of Obstetrics & Gynecology\n1993;169(1):26-33.\n*/uni00A0 Wheeler/uni00A0JM, Knittle/uni00A0JD, Miller/uni00A0JD. Depot leuprolide\nversus danazol in treatment of women with symptomatic\nendometriosis. American Journal of Obstetrics & Gynecology\n1992;167(5):1367-71. [DOI: 10.1016/0002-9378(93)90126-4.]\nWhitehouse 1990 {published data only}\n*/uni00A0 Whitehouse/uni00A0RW, Adams/uni00A0JE, Bancro/f_t/uni00A0K, Vaughan-Williams/uni00A0CA,\nElstein/uni00A0M. The eﬀects of nafarelin and danazol on vertebral\ntrabecular bone mass in patients with endometriosis.\nClinical Endocrinology 1990;33(3):365-373. [DOI: 10.1016/\ns0015-0282(16)58682-8]\nZupi 2005 {published data only}\n*/uni00A0 Zupi/uni00A0E, Sbracia/uni00A0M, Marconi/uni00A0D, Sorrenti/uni00A0G, Zullo/uni00A0F, Palomba/uni00A0S.\nRole of medical therapy in the treatment of endometriosis\nassociated pelvic pain: a randomized controlled study. Journal\nof Minimally Invasive Gynecology 2005;12(5):S6. [DOI: 10.3390/\njcm10051085]\n/uni00A0\nReferences to studies excluded from this review\nAcien 1989 {published data only}\n*/uni00A0 Acien/uni00A0P, Shaw/uni00A0RW, Irvine/uni00A0L, Burford/uni00A0GRG. CA 125 levels in\nendometriosis patients before, during and a/f_ter treatment with\ndanazol or LHRH agonists. European Journal of Gynaecological\nOncology 1989;32(1):241-6.\nAdiyono 2006 {published data only}\n*/uni00A0 Adiyono/uni00A0W, Adisusianto/uni00A0I. The impact of combination\nlaparoscopic surgery and GNRH analog on quality of life\nendometriosis patients. In: XVIII FIGO World Congress of\nGynecology and Obstetrics. Vol. 2. 5-10 November Kuala\nLumpur, Malaysia, 2006:143.\nAgarwal 2015 {published data only}\nAgarwal/uni00A0AK, Daniels/uni00A0A, Drosman/uni00A0SR, Udoﬀ/uni00A0L, Foster/uni00A0WG,\n/uni00A0Pike/uni00A0MC, /uni00A0et al. Treatment of endometriosis with the GnRHa\ndeslorelin and add-back estradiol and supplementary\ntestosterone. BioMed Research International 2015;2015:1-9.\n[PMID: 10.1155/2015/934164]\nAl-Azemi 2009 {published data only}\n*/uni00A0 Al-Azemi/uni00A0M, Jones/uni00A0G, Sirkeci/uni00A0F, Walters/uni00A0S, Houdmont/uni00A0M,\nLedger/uni00A0W. Immediate and delayed add-back hormonal\nreplacement therapy during ultra long GnRH agonist treatment\nof chronic cyclical pelvic pain. British Journal of Obstetrics\nand Gynaecology 2009;116:1646-1656. [DOI: 10.1111/\nj.1471-0528.2009.02319.x]\nBergqvist 1990 {published data only}\n*/uni00A0 Bergquist C. Eﬀects of nafarelin versus danazol on\nlipids and calcium metabolism. American Journal of\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n39\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nObstetrics and Gynecology 1990;162(2):589-591. [DOI:\n10.1016/0002-9378(90)90438-d]\nCalvo 2000 {published data only}\n*/uni00A0 Calvo Lugo/uni00A0GE, Sauceda Gonzalez/uni00A0LF, Jimenez Perea/uni00A0ML,\nDiaz Arias/uni00A0FJ. Treatment of pelvic endometriosis with goserelin\nacetate or nafarelin acetate. Comparative study. Ginecologia y\nObstetricia de Mexico 2000;68:7-14.\nChan 1993 {published data only}\n*/uni00A0 Chan/uni00A0CLK, Soon/uni00A0SB, Loh/uni00A0FH. Comparative study of gestrinone,\ndanazol and decapeptyl CR in the treatment of endometriosis.\n2nd International Scientific Meeting of the Royal College of\nObstetricians 1993:82.\nChen 2009 {published data only}\n*/uni00A0 Chen Q-Y, Bian M-L, Qiao/uni00A0J, Zhang Z-Y, Lin J-F, Zuo Y-W.\nRandomized blind, parallel-controlled and multiple centre\nclinical trial on the eﬀectiveness and safety of leuprolide\nacetate in the treatment of endometriosis. Chinese Journal of\nNew Drugs - Zhongguo 2009;18(9):797-801.\nChoktanasiri 2001 {published data only}\n*/uni00A0 Choktanasiri/uni00A0W, Rojanasakul/uni00A0A. Buserelin acetate implants in\nthe treatment of pain in endometriosis. Journal of the Medical\nAssociation of Thailand 2001;84(5):656-60.\nClaesson 1989 {published data only}\n*/uni00A0 Claesson/uni00A0B, Bergquist/uni00A0C. Clinical experience treating\nendometriosis with nafarelin. Journal of Reproductive Medicine\n1989;34(12 Suppl):1025-1028. [PMID: 2533617]\nCooke 1989 {published data only}\n*/uni00A0 Cooke/uni00A0ID, Thomas/uni00A0EJ. The medical treatment of mild\nendometriosis. Acta Obstetricia et Gynecologica Scandinavica -\nSupplement 1989;150:27-30.\nDawood 1990 {published data only}\n*/uni00A0 Dawood/uni00A0MY. A comparison of the eﬀicacy and safety of\nbuserelin vs danazol in the treatment of endometriosis. Current\nConcepts in Endometriosis 1990:253-67.\nDmowski 1989 {published data only}\n*/uni00A0 Dmowski/uni00A0WP. Comparitive study of buserelin versus\ndanazol in the management of endometriosis. Gynecological\nEndocrinology 1989;3(Suppl 2):21-31.\nDodin 1991 {published data only}\n*/uni00A0 Dodin/uni00A0S, Lemay/uni00A0A, Maheux/uni00A0R, Dumont/uni00A0M, Turcot-Lemay\nL. Bone mass in endometriosis patients treated with GnRH\nagonist implant or danazol. Obstetrics and Gynecology\n1991;77(3):410-415. [PMID: 1825135]\nDonnez 1989 {published data only}\n*/uni00A0 Donnez/uni00A0J, Nisolle-Pochet/uni00A0M, Clerckx-Braun/uni00A0F, Sandow/uni00A0J,\nCasanas-Roux/uni00A0F. Administration of nasal buserelin as compared\nwith subcutaneous buserelin implant for endometriosis.\nFertility & Sterility 1989;52(1):27-30.\nDonnez 2004 {published data only}\n*/uni00A0 Donnez/uni00A0J, Dewart/uni00A0PJ, Hedon/uni00A0B, Perino/uni00A0A, Schindler/uni00A0AE,\nBlumberg/uni00A0J, et al. Equivalence of the 3-month and 28-day\nformulations of triptorelin with regard to achievement\nand maintenance of medical castration in women with\nendometriosis. Fertility & Sterility 2004;81(2):297-304.\nEldred 1992 {published data only}\n*/uni00A0 Eldred/uni00A0JM, Haynes/uni00A0PJ, Thomas/uni00A0EJ. A randomized double blind\nplacebo controlled trial of the eﬀects on bone metabolism\nof the combination of nafarelin acetate and norethisterone.\nClinical Endocrinology 1992;37:354-359. [DOI: 10.1111/\nj.1365-2265.1992.tb02338.x]\nel-Roeiy 1988 {published data only}\n*/uni00A0 el-Roeiy/uni00A0A, Dmowski/uni00A0WP, Gleicher/uni00A0N, Radwanska/uni00A0E, Harlow/uni00A0L,\nBinor/uni00A0Z, et al. Danazol but not gonadotropin-releasing hormone\nagonists suppresses autoantibodies in endometriosis. Fertility &\nSterility 1988;50(6):864-71.\nFedele 1993 {published data only}\n*/uni00A0 Fedele/uni00A0L, Bianchi/uni00A0S, Bocciolone/uni00A0L, Di Nola/uni00A0G, Franchi/uni00A0D.\nBuserelin acetate in the treatment of pelvic pain associated\nwith minimal and mild endometriosis: a controlled study.\nFertility & Sterility 1993;59(3):516-21.\nFernandez 2004 {published data only}\n*/uni00A0 Fernandez H, Lucas/uni00A0C, Hédon B , Meyer JL, Mayenga JM and\nRoux C. One year comparison between two add-back therapies\nin patients treated with a GnRH agonist for symptomatic\nendometriosis: a randomized double-blind trial. Human\nReproduction April 2004;19:1465-1471. [DOI: 10.1093/humrep/\ndeh250]\nFerrero 2011 {published data only}\n*/uni00A0 Ferrero/uni00A0S, Venturini/uni00A0PL, Gillott/uni00A0DJ, Remorgida/uni00A0V. Letrozole\nand norethisterone acetate versus letrozole and triptorelin\nin the treatment of endometriosis related pain symptoms:\na randomized controlled trial. Reproductive Biology and\nEndocrinology 2011;9:1-7. [DOI: 10.1186/1477-7827-9-88]\nFranssen 1992 {published data only}\n*/uni00A0 Franssen/uni00A0AM, van der/uni00A0Heijden/uni00A0PF, Thomas/uni00A0CM, Doesburg/uni00A0WH,\nWillemsen/uni00A0WN, Rolland/uni00A0R. On the origin and significance of\nserum CA-125 concentrations in 97 patients with endometriosis\nbefore, during, and a/f_ter buserelin acetate, nafarelin, or\ndanazol. Fertility & Sterility 1992;57(5):974-9.\nFraser 1996 {published data only}\n*/uni00A0 Fraser/uni00A0IS, Healy/uni00A0DL, Torode/uni00A0H, Song/uni00A0JY, Mamers/uni00A0P, Wilde/uni00A0F.\nDepot goserelin and danazol pre-treatment before rollerball\nendometrial ablation for menorrhagia. Obstetrics & Gynecology\n1996;87(4):544-50.\nHarada 2000 {published data only}\n*/uni00A0 Harada/uni00A0T. Empirical leuprolide treatment of women with\nsuspected endometriosis was eﬀective in reducing chronic pain.\nEvidence-based Obstetrics and Gynecology 2000;2:45.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n40\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nHenzl 1990a {published data only}\n*/uni00A0 Henzl/uni00A0MR, Monroe/uni00A0SE. Nafarelin: a new medical therapy\nfor endometriosis. Progress in Clinical & Biological Research\n1990;323:343-55.\nImani 2009 {published data only}\n*/uni00A0 Imani/uni00A0R, Thai-Cuarto/uni00A0D, Jimenez/uni00A0R, Burke/uni00A0J, Kroll/uni00A0R, O'Brien/uni00A0C.\nPetal study: Safety, tolerability and eﬀectiveness of elagolix, an\noral GnRH antagonist for endometriosis. In: Fertility & Sterility.\nVol. 92. 2009:S111-S112. [DOI: 10.1016/j.fertnstert.2009.07.1100]\nLindsay 1996 {published data only}\n*/uni00A0 Lindsay/uni00A0PC, Shaw/uni00A0RW, Bennink/uni00A0HJC, Kicovic/uni00A0P. The eﬀect of\nadd-back treatment with tibolone (Livial) on patients treated\nwith the gonadotropin-releasing hormone agonist triptorelin\n(decapeptyl). Fertility & Sterility 1996;65(2):342-348. [DOI:\n10.1016/s0015-0282(16)58096-0]\nLuciano 2004 {published data only}\n*/uni00A0 Luciano/uni00A0AA. Leuprolide acetate in the management of\nendometriosis-associated pain: A multicenter, evaluator-\nblind, comparative clinical trial. Global Congress of Gynecologic\nEndoscopy 33rd Annual Meeting of the AAGL \"Advancing\nMinimally Invasive Gynecology Worldwide\" 2004;11(Suppl 3):s5.\nMagini 1993 {published data only}\n*/uni00A0 Magini/uni00A0A, Pellegrini/uni00A0S, Tavella/uni00A0K, Forti/uni00A0G, Massi/uni00A0GB, Serio/uni00A0M.\nEstrogenic suppression by diﬀerent administration schedules\nof goserelin depot for treatment of endometriosis. Journal of\nEndocrinological Investigation 1993;16(10):775-80.\nMaouris 1991 {published data only}\n*/uni00A0 Maouris/uni00A0P, Dowsett/uni00A0M, Nichols/uni00A0J, Rose/uni00A0G, Edmonds/uni00A0DK.\nPseudomenopause treatment for endometriosis: The endocrine\neﬀects of danazol compared with the use of the LH-RH agonist\ngoserelin. Journal of Obstetrics & Gynaecology 1991;11:123-127.\n[DOI: 10.1016/s0015-0282(16)58023-6]\nMaouris/uni00A0P, Dowsett/uni00A0M, Rose/uni00A0G, D E. Comparison of the endocrine\neﬀects of danazol and the LHRH agonist goserelin (Zoladex) in\nthe treament of endometriosis. Silver Jubilee British Congress of\nObstetrics and Gynaecology 1989:61.\nMatalliotakis 2000 {published data only}\n*/uni00A0 Matalliotakis/uni00A0IM, Neonaki/uni00A0MA, Koumantaki/uni00A0YG, Goumenou/uni00A0AG,\nKyriakou/uni00A0DS, Koumantakis/uni00A0EE. A randomized comparison of\ndanazol and leuprolide acetate suppression of serum-soluble\nCD23 levels in endometriosis. Obstetrics & Gynecology 2000;95(6\nPt 1):810-813. [DOI: 10.1016/s0029-7844(99)00635-3]\nMatalliotakis 2004 {published data only}\n*/uni00A0 Matalliotakis/uni00A0IM, Arici/uni00A0A, Goumenou/uni00A0AG, Katassos/uni00A0T,\nKarkavitsas/uni00A0N, Koumantakis/uni00A0EE. Comparison of the eﬀects of\nleuprorelin acetate and danazol treatments on serum CA-125\nlevels in women with endometriosis. International Journal of\nFertility & Womens Medicine 2004;49(2):75-8.\nMatta 1988 {published data only}\n*/uni00A0 Matta/uni00A0W, Shaw/uni00A0R. A comparative study between buserelin and\ndanazol in the treatment of endometriosis. The British Journal\nof Clinical Practice 1988;40(4):69-72.\nMiller 1990 {published data only}\n*/uni00A0 Miller/uni00A0JD. Leuprolide acetate for the treatment of\nendometriosis. Progress in Clinical & Biological Research\n1990;323:337-41.\nMukherjee 1996 {published data only}\n*/uni00A0 Mukherjee/uni00A0T, Barad/uni00A0D, Turk/uni00A0R, Reeman/uni00A0R. A randomized,\nplacebo-controlled study on the eﬀect of cyclic intermittent\netidronate therapy on the bone mineral density changes\nassociated with six months of gonadotropin-releasing\nhormone agonist treatment. American Journal of Obstetrics\nand Gynecology/uni00A0 1997;175(1):105-109. [DOI: 10.1016/\nS0002-9378(96)70258-2]\nNewton 1996 {published data only}\n*/uni00A0 Newton/uni00A0C, Slota/uni00A0D, Yuzpe/uni00A0AA, Tummon/uni00A0IS. Memory\ncomplaints associated with the use of gonadotropin-releasing\nhormone agonists: a preliminary study. Fertility & Sterility\n1996;65(6):1253-5.\nPierce 2000 {published data only}\n*/uni00A0 Pierce/uni00A0SJ, Gazvani/uni00A0RM, Farquharson/uni00A0RG. Long-term use\nof gonadotropin-releasing hormone analogs and hormone\nreplacement therapy in the management of endometriosis: a\nrandomized trial with a 6-year follow-up. Fertility & Sterility Nov\n2000;74(5):964-968. [DOI: 10.1016/s0015-0282(00)01537-5]\nRipps 2003 {published data only}\n*/uni00A0 Ripps/uni00A0BA, VanGilder/uni00A0K, Minhas/uni00A0B, Welford/uni00A0M, Mamish/uni00A0Z.\nAlendronate for the prevention of bone mineral loss during\ngonadotropin-releasing hormone agonist therapy. The Journal\nof Reproductive Medicine October 2003/uni00A0;48(10):761-766. [PMID:\n14619641]\nShaw 1992 {published data only}\nShaw/uni00A0RW. A randomised comparative study of the eﬀects of\ngoserelin and danazol for the treatment of endometriosis.\nGynecological Endocrinology 1990;4(70 Suppl 2):45.\nShaw/uni00A0RW. An open randomized comparative study of the\neﬀect of goserelin depot and danazol in the treatment\nof endometriosis. Zoladex Endometriosis Study Team.\nFertility & Sterility 1992;58(2):265-272. [DOI: 10.1016/\ns0015-0282(16)55205-4]\n*/uni00A0 Shaw/uni00A0RW. Goserelin depot: an analog of LHRH for the\ntreatment of endometriosis. Drugs Under Experimental & Clinical\nResearch 1990;16(Suppl):69-75.\nShaw 2001 {published data only}\n*/uni00A0 Shaw/uni00A0R, Garry/uni00A0R, McMillan/uni00A0L, Sutton/uni00A0C, Wood/uni00A0S, Harrison/uni00A0R,\net al. A prospective randomized open study comparing\ngoserelin (Zoladex) plus surgery and surgery alone in the\nmanagement of ovarian endometriomas. Gynaecological\nEndoscopy 2001;10(3):151-7.\nSomekawa 1999 {published data only}\n*/uni00A0 Somekawa/uni00A0Y, Chigughi/uni00A0M, Harada/uni00A0M, Ishibashi/uni00A0T. Use of\nvitamin K2 (Menatetrenone) and 1,25- dihydroxyvitamin\nD3 in the prevention of bone loss induced by leuprolide.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n41\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nThe Journal of Clinical Endocrinology & Metabolism Aug\n1999;84(8):2700-2704. [DOI: 10.1210/jcem.84.8.5920]\nSorensen 1997 {published data only}\n*/uni00A0 Sorensen/uni00A0SS, Colov/uni00A0NP, Vejerslev/uni00A0LO. Pre- and postoperative\ntherapy with GnRH agonist for endometrial resection. A\nprospective, randomized study. Acta Obstetricia et Gynecologica\nScandinavica 1997;76(4):340-4.\nSowter 1997 {published data only}\n*/uni00A0 Sowter/uni00A0MC, Bidgood/uni00A0K, Richardson/uni00A0JA. A prospective\nrandomized trial of the eﬀect of preoperative endometrial\ninhibition on the long-term outcome of transcervical\nendometrial resection. Gynaecological Endoscopy\n1997;6(1):33-7.\nSoysal 2004 {published data only}\n*/uni00A0 Soysal/uni00A0S, Soysal/uni00A0ME, Ozer/uni00A0S, Gul/uni00A0N, Gezgin/uni00A0T. The eﬀects of\npost-surgical administration of goserelin plus anastrozole\ncompared to goserelin alone in patients with severe\nendometriosis: a prospective randomized trial. Human\nReproduction 2004;19(1):160-167. [DOI: 10.1093/humrep/\ndeh035]\nSurrey 1993 {published data only}\n*/uni00A0 Surrey/uni00A0ES, Fournet/uni00A0N, Voigt/uni00A0B, Judd/uni00A0HL. Eﬀects of sodium\netidronate in combination with low-dose norethindrone\nin patients administered a long-acting GnRH agonist: a\npreliminary report. Obstetrics & Gynecology 1993;81(4):581-6.\nSurrey 1995 {published data only}\n*/uni00A0 Surrey/uni00A0ES, Voigt/uni00A0B, Fournet/uni00A0N, Judd/uni00A0HL. Prolonged\ngonadotropin-releasing hormone agonist treatment of\nsymptomatic endometriosis: the role of cyclic sodium\netidronate and low-dose norethindrone \"add-back\" therapy.\nFertility & Sterility 1995;63(4):747-55.\nTakaesu 2013 {published data only}\n*/uni00A0 Takaesu/uni00A0Y, Nishi/uni00A0H, Kojima/uni00A0J, Sasaki/uni00A0T, Nagamitsu/uni00A0Y, Kato/uni00A0R,\net al. Dienogest compared with gonadotropin-releasing\nhormone agonist a/f_ter conservative surgery for endometriosis.\nThe Journal of Obstetrics and Gynaecology Research Sept\n2016;42(9):1152-1158. [DOI: 10.1111/jog.13023]\nTapanainen 1993 {published data only}\n*/uni00A0 Tapanainen/uni00A0J, Hovatta/uni00A0O, Juntunen/uni00A0K, Martikainen/uni00A0H,\nRatsula/uni00A0K, Tuppala/uni00A0M, et al. Subcutaneous goserelin versus\nintranasal buserelin for pituitary down-regulation in patients\nundergoing IVF: a randomized comparative study. Human\nReproduction 1993;8(12):2052-5.\nTaskin 1997 {published data only}\n*/uni00A0 Taskin/uni00A0O, Yalcinoglu/uni00A0AI, Kucuk/uni00A0S, Uryan/uni00A0I, Buhur/uni00A0A, F B.\nEﬀectiveness of tibolone on hypoestrogenic symptoms induced\nby goserelin treatment in patients with endometriosis. Fertility\n& Sterility 1997;67(1):40-5.\nToomey 2003 {published data only}\n*/uni00A0 Toomey/uni00A0C, Krauss/uni00A0B, Hammerschlag/uni00A0R, Burry/uni00A0K.\nEndometriosis: traditional medicine vs hormone therapy.\nNational Centre for Complementary and Alternative Medicine\n2003.\nValimaki 1989 {published data only}\n*/uni00A0 Valimaki/uni00A0M, Nilsson/uni00A0CG, Roine/uni00A0R, Ylikorkala/uni00A0O. Comparison\nbetween the eﬀects of nafarelin and danazol on serum lipids\nand lipoproteins in patients with endometriosis. The Journal\nof Clinical Endocrinology and Metabolism 1989;69(6):1097-103.\n[DOI: 10.1210/jcem-69-6-1097]\nVercellini 2009 {published data only}\n*/uni00A0 Vercellini/uni00A0P, Somigliana/uni00A0E, Vigano/uni00A0P, Abbiati/uni00A0A, Barbara/uni00A0G,\nCrosignani/uni00A0PG. Endometriosis: current therapies and new\npharmacological developments. Drugs 2009;69(6):649-75.\nWarnock 1998 {published data only}\n*/uni00A0 Warnock/uni00A0JK, Bundren/uni00A0JC, Morris/uni00A0DW. Depressive symptoms\nassociated with gonadotropin-releasing hormone agonists.\nDepression and Anxiety 1998;7(4):171-7.\nWright 1995 {published data only}\n*/uni00A0 Wright/uni00A0S, Valdes/uni00A0CT, Dunn/uni00A0RC, Franklin/uni00A0RR. Short-term lupron\nor danazol therapy for pelvic endometriosis. Fertility & Sterility\n1995;63(3):504-7. [PMID: 7851578]\nYee 1986 {published data only}\n*/uni00A0 Yee/uni00A0B. A preliminary report on the comparative use\nof buserelin (Hoe 766) and danazol in the treatment of\nendometriosis: the university of Southern California experience.\nProgress in Clinical & Biological Research 1986;225:175-88.\nYlikorkala 1995 {published data only}\n*/uni00A0 Ylikorkala/uni00A0O, Tiitinen/uni00A0A, Hulkko/uni00A0S, Kivinen/uni00A0S, Nummi/uni00A0S.\nDecrease in symptoms, blood loss and uterine size with\nnafarelin acetate before abdominal hysterectomy: a placebo-\ncontrolled, double-blind study. Human Reproduction\n1995;10(6):1470-4.\n/uni00A0\nReferences to studies awaiting assessment\nAisaka 2000 {published data only}\n*/uni00A0 Aisaka/uni00A0K, Nakagawa/uni00A0K, Uesato/uni00A0T, Miwa/uni00A0A, Koshino/uni00A0T, Ooka/uni00A0F,\net al. Eﬀectiveness of long term GN-RH agonist administration\nfor treatment of endometriosis combined with estrogen-\nprogestogen add back therapy. In: XVI FIGO World Congress of O\n& G 2000. 2000. [DOI: doi.org/10.1016/S0020-7292(00)82576-X]\nArcher 2004 {published data only}\n*/uni00A0 Archer/uni00A0DF, Luciano/uni00A0A, Carson/uni00A0S, VilosG /uni00A0. New low dose\ndepot medroxyprogesterone acetate subcutaneous injection\nis equivalent to leuprolide acetate for endometriosis-\nassociated pain. In: Fertility & Sterility. Oct 2004. [DOI: https://\ndoi.org/10.1016/j.fertnstert.2004.07.182]\nGregoriou 1997 {published data only}\n*/uni00A0 Gregoriou/uni00A0O, Konidaris/uni00A0S, Vitoratos/uni00A0N, Papadias/uni00A0C, Papoulias/uni00A0I,\nChryssicopoulos/uni00A0A. Gonadotropin-releasing hormone analoque\n(leuprolide) plus hormone replacement therapy for the\ntreatment of endometriosis: a randomised controlled trial. Acta\nObstetricia et Gynecologica Scandinavica 1997;67:no pagination.\n[PMID: 9459084]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n42\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nLong 2009 {published data only}\n*/uni00A0 Long/uni00A0Q, Zhang S. A randomized clinical trial of GnRHa and\nadd-back therapy in the treatment of endometriosis. In:\nInternational Journal of Gynecology and Obstetrics/uni00A0. Vol. 107.\n2009:S247. [DOI: 10.1016/S0020-7292]\nVella 1995 {published data only}\n*/uni00A0 Vella/uni00A0A, Brincat/uni00A0M, Galea/uni00A0R, Muscat Baron/uni00A0Y. Skin thickness\nand bone density: eﬀect of add-back therapy in women on\nGnRh analogue. In: 27th British Congress of Obstetrics and\nGynaecology. Vol. 155. 1995.\n/uni00A0\nAdditional references\nAudebert 1998\nAudebert/uni00A0A, /uni00A0Descamps/uni00A0P, Marret/uni00A0H, /uni00A0Ory-Lavollee/uni00A0L, Bailleul/uni00A0F,\nHamamah/uni00A0S. Pre or post-operative medical treatment with\nnafarelin in stage III-IV endometriosis: a French multicenter\nstudy. European Journal of Obstetrics, Gynecology and\nReproductive Biology 1998;79(2):145-48. [DOI: 10.1016/\ns0301-2115(98)00028-1]\nBafort 2020\nBafort/uni00A0C, Beebeejaun/uni00A0Y, Tomassetti/uni00A0C, Bosteels/uni00A0J, Duﬀy/uni00A0JMN.\nLaparoscopic surgery for endometriosis. Cochrane Database\nof Systematic Reviews 2020, Issue 10. Art. No: CD011031. [DOI:\n10.1002/14651858.CD011031]\nBatt 2007\nBatt/uni00A0RE, Smith/uni00A0RA, Buck Louis/uni00A0GM, Martin/uni00A0DC, Chapron/uni00A0C,\nKoninckx/uni00A0PR, Yeh/uni00A0J. Müllerianosis. Histology & Histopathology\n22-10-2007;10:1161-6.\nBecker 2022\nBecker/uni00A0CM, Bokor/uni00A0A, Heikinheimo/uni00A0O, Horne/uni00A0A, Jansen/uni00A0F,\nKiesel/uni00A0L, King/uni00A0K, Kvaskoﬀ/uni00A0M, Nap/uni00A0A, /uni00A0Petersen/uni00A0K, Saridogan/uni00A0E,\nTomassetti/uni00A0C, van/uni00A0Hanegem/uni00A0N, Vulliemoz/uni00A0N, /uni00A0Vermeulen/uni00A0N,\nESHRE Endometriosis Guideline Group. ESHRE guideline:\nmanagement of women with endometriosis.. Human\nReproduction Open 2022;2:1-26. [DOI: 10.1093/hropen/hoac009]\nBontis 1997\nBontis/uni00A0JN, Vavilis/uni00A0DT. Etiopathology of endometriosis. Annals of\nthe New York Academy of Sciences 17-06-1997;816:305-9.\nBrown 2012\nBrown/uni00A0J, Kives/uni00A0S, Akhtar/uni00A0M. Progestagens and anti-progestagens\nfor pain associated with endometriosis. Cochrane Database\nof Systematic Reviews 2012, Issue 3. Art. No: CD002122. [DOI:\n10.1002/14651858.CD002122.pub2]\nBrown 2018\nBrown/uni00A0J, Crawford/uni00A0TJ, Datta/uni00A0S, Prentice/uni00A0A. Oral contraceptives\nfor pain associated with endometriosis. Cochrane Database\nof Systematic Reviews 2018, Issue 5. Art. No: CD001019. [DOI:\n10.1002/14651858.CD001019]\nBurney 2012\nBurney/uni00A0RO, /uni00A0Giudice/uni00A0LC. Pathogenesis and pathophysiology of\nendometriosis. Fertility and Sterility 2012;3:511-9. [DOI: 10.1016/\nj.fertnstert.2012.06.029]\nChen 2020\nChen/uni00A0I, Veth/uni00A0VB, Choudhry/uni00A0AJ, Murji/uni00A0A, Zakhari/uni00A0A, Black/uni00A0AY, et\nal. Pre- and postsurgical medical therapy for endometriosis\nsurgery. Cochrane Database of Systematic Reviews 2020, Issue\n11. Art. No: CD003678. [DOI: 10.1002/14651858.CD003678.pub3]\nDarwish 2006\nDarwish/uni00A0A, Hassanin/uni00A0MS, Abou Sekkin IA. Epidemiology and risk\nfactors associated with laparoscopicaly diagnosed typical and\natypical endometriosis among Egyptian women. Middle East\nFertility Society Journal 2006;11:196-201.\nDuﬀy 2020\nDuﬀy/uni00A0JMN, Hirsch/uni00A0M, /uni00A0/uni00A0Vercoe/uni00A0M, Abbott/uni00A0J, Barker/uni00A0C,\n/uni00A0Collura/uni00A0B, et al. A core outcome set for future endometriosis\nresearch: an international consensus development study\n[A core outcome set for future endometriosis research: an\ninternational consensus development study]. British Journal\nof Obstetrics and Gynaecology 2020;127(8):967-74. [DOI:\n10.1111/1471-0528.16157] [PMID: 32227676]\nEskenazi/uni00A01997\nEskenazi/uni00A0B, Warner/uni00A0ML. Epidemiology of endometriosis.\nObstetrics and Gynecology Clinics of North America\n1997;24:235-58. [DOI: 10.1016/s0889-8545(05)70302-8 Abstract]\n[PMID: 9163765]\nFlower 2012\nFlower/uni00A0A, Liu/uni00A0JP, Lewith/uni00A0G, Little/uni00A0P, Li/uni00A0Q. Chinese herbal\nmedicine for endometriosis. Cochrane Database of\nSystematic Reviews 2012, Issue 5. Art. No: CD006568. [DOI:\n10.1002/14651858.CD006568.pub3]\nFu 2017\nFu/uni00A0J, Song/uni00A0H, Zhou/uni00A0M, Zhu/uni00A0H, Wang/uni00A0Y, Chen/uni00A0H, Huang/uni00A0W.\nProgesterone receptor modulators for endometriosis.\nCochrane Database of Systematic Reviews 2017, Issue 7. Art. No:\nCD009881. [DOI: 10.1002/14651858.CD009881.pub2]\nGuidice 2010\nGiudice/uni00A0LC. Clinical practice: endometriosis. New England\nJournal of Medicine 2010;25:2389-98. [DOI: 10.1056/\nNEJMcp1000274]\nHiggins 2011\nHiggins/uni00A0JPT, Altman/uni00A0DG, Sterne JAC (editors). Chapter 8:\nAssessing risk of bias in included studies. In: Higgins JPT, Green\nS (editors)./uni00A0Cochrane Handbook for Systematic Reviews of\nInterventions/uni00A0Version 5.1.0 (updated March 2011). The Cochrane\nCollaboration, 2011. Available from training.cochrane.org/\nhandbook.\nHouda 2014\nHouda/uni00A0/uni00A0MR, Grant/uni00A0/uni00A0NH. Gonadotrophin antagonists for\npain associated with endometriosis. Cochrane Database of\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n43\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSystematic Reviews 2014, Issue 12. Art. No: CD011446. [DOI:\n10.1002/14651858.CD011446]\nJackson 2006\nJackson/uni00A0B, Telner/uni00A0DE. Managing the misplaced: approach to\nendometriosis. Canadian Family Physician/uni00A0 2006;11:1420-1424.\n[PMID: PMC1783710]\nKalaitzopoulos 2021\nKalaitzopoulos/uni00A0DR, Samartzis/uni00A0N, Kolovos/uni00A0GN, Mareti/uni00A0E,\nSamartzis/uni00A0EP, Eberhard/uni00A0M, Dinas/uni00A0K, Daniilidis/uni00A0A. Treatment of\nendometriosis: a review with comparison of 8 guidelines. BMC\nWomens Health 2021;1:397. [DOI: 10.1186/s12905-021-01545-5]\nKlein 2014\nKlein/uni00A0S, D'Hooghe/uni00A0T, /uni00A0Meuleman/uni00A0C, /uni00A0Dirksen/uni00A0C, /uni00A0Dunselman/uni00A0G,\n/uni00A0Simoens/uni00A0S. What is the societal burden of endometriosis-\nassociated symptoms? a prospective Belgian study.\nReproductive Biomedical Online 2013;28(1):116-224. [DOI:\n10.1016/j.rbmo.2013.09.020]\nLefebvre 2011\nLefebvre/uni00A0C, Manheimer/uni00A0E, Glanville/uni00A0J. Chapter 6: Searching for\nstudies. In: Higgins JP, Green S (editors). Cochrane Handbook\nfor Systematic Reviews of Interventions Version 5.1.0 (updated\nMarch 2011). The Cochrane Collaboration, 2011. /uni00A0Available from\ntraining.cochrane.org/handbook.\nLevander 1955\nLevander/uni00A0G, /uni00A0Normann/uni00A0P. The pathogenesis of\nendometriosis; an experimental study. Acta Obstetricia\net Gynecologica Scandinavica 1955;34(4):366-98. [DOI:\n10.3109/00016345509158287]\nMacer 2012\nMacer ML and Taylor/uni00A0HS. Endometriosis and Infertility: A review\nof the pathogenesis and treatment of endometriosis-associated\ninfertility. Obstetrics and Gynecology Clinics of North America\n2013;39(4):535-549. [DOI: 10.1016/j.ogc.2012.10.002]\nMahmood 1991\nMahmood/uni00A0TA, Templeton/uni00A0A. Prevalence and genesis of\nendometriosis. Human Reproduction 1991;6:544-9. [PMID:\n1918305]\nMatthias 1996\nMathias/uni00A0SD, Kuppermann/uni00A0M, /uni00A0Liberman/uni00A0RF, Lipschutz\nRC/uni00A0, /uni00A0Steege JF/uni00A0. Chronic pelvic pain: prevalence,\nhealth-related quality of life, and economic correlates.\nObstetrics and Gynecology 1996;87(3):321-7. [DOI:\n10.1016/0029-7844(95)00458-0]\nMeuleman 2009\nMeuleman/uni00A0C, Vandenabeele/uni00A0B, Fieuws/uni00A0S, Spiessend/uni00A0C,\nTimmermans/uni00A0D, D'Hooghe/uni00A0T. High prevalence of endometriosis\nin infertile women with normal ovulation and normospermic\npartners.. Fertility and Sterility 2009;92(1):68-74. [DOI: 10.1016/\nj.fertnstert.2008.04.056]\nRafique 2017\nRafique/uni00A0S, Decherney/uni00A0AH. Medical Management of\nEndometriosis. Clinical Obstetrics and Gynecology\n2017;3:485-496. [DOI: 10.1097/GRF.0000000000000292]\nRobboy 2010\nRobboy, S J, & Bean, S M. Pathogenesis of endometriosis.\nReproductive Biomedicine Online 01-07-2010;21(1):4-5.\nSampson 1940\nSampson/uni00A0JA. The development of the implantation theory for\nthe origin of peritoneal endometriosis. American Journal of\nObstetrics and Gynecology October 01, 1940;40(4):549-557. [DOI:\n10.1016/S0002-9378(40)91238-8]\nSchünemann 2021\nSchünemann/uni00A0HJ, Higgins/uni00A0JPT, Vist/uni00A0GE, Glasziou/uni00A0P, Akl/uni00A0EA,\nSkoetz/uni00A0N, Guyatt/uni00A0GH. Chapter 14: Completing ‘Summary of\nfindings’ tables and grading the certainty of the evidence. In:\nHiggins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ,\nWelch VA (editors). Cochrane Handbook for Systematic Reviews\nof Interventions version 6.2 (updated February/uni00A02021). Cochrane,\n2021. Available from www.training.cochrane.org/handbook\n2021.\nShaw 1991\nShaw/uni00A0RW. GnRH analogues in the treatment of endometriosis\n-rationale and eﬀicacy. London: Kluwer Academic Publishers,\n1991.\nSimoens 2012\nSimoens/uni00A0S, /uni00A0Dunselman/uni00A0G, /uni00A0Dirksen/uni00A0C, /uni00A0Hummelshoj/uni00A0L, /uni00A0Bokor/uni00A0A,\n/uni00A0Brandes/uni00A0I, /uni00A0et al. The burden of endometriosis: costs and quality\nof life of women with endometriosis and treated in referral\ncentres. Human Reproduction 2021;27(5):1292-9. [DOI: 10.1093/\nhumrep/des073]\nStratton 2011\nStratton/uni00A0P, /uni00A0Berkley/uni00A0KJ. Chronic pelvic pain and endometriosis:\ntranslational evidence of the relationship and implications.\nHuman Reproduction Update 2011;17(3):327–46. [PMID: https://\nwww.ncbi.nlm.nih.gov/pmc/articles/PMC3072022/]\nVan der Linden 1997\nvan der/uni00A0Linden/uni00A0PJ. Theories on the pathogenesis of\nendometriosis. Human Reproduction 1996;3:53-65. [DOI:\n10.1093/humrep/11.suppl_3.53.]\nVan Hoesel/uni00A02021\nVan Hoesel/uni00A0MH, Chen/uni00A0YL, Zheng/uni00A0A, Wan/uni00A0Q, Mourad/uni00A0SM. Selective\noestrogen receptor modulators (SERMs) for endometriosis.\nCochrane Database of Systematic Reviews 2021, Issue 5. Art. No:\nCD011169. [DOI: 10.1002/14651858.CD011169.pub2]\nVercellini 2014\nVercellini/uni00A0P, Viganò/uni00A0P, Somigliana/uni00A0E, Fedele/uni00A0L. Endometriosis:\npathogenesis and treatment. Nature Reviews, Endocrinology\n2014;5:261-75. [DOI: 10.1038/nrendo.2013.255]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n44\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nVigano 2018\nVigano/uni00A0P, /uni00A0Candiani/uni00A0M, /uni00A0Monno/uni00A0A, /uni00A0Giacomini/uni00A0E, /uni00A0Vercellini/uni00A0P,\nSomigliana/uni00A0E. Time to redefine endometriosis including its\npro-fibrotic nature. Human Reproduction 2018;1(33(3)):347-52.\n[PMID: https://pubmed.ncbi.nlm.nih.gov/29206943/]\nViganò 2004\nViganò/uni00A0P, Parazzini/uni00A0F, Somigliana/uni00A0E, Vercellini/uni00A0P, . Endometriosis:\nepidemiology and aetiological factors. Best Practice & Research\nClinical Obstetrics & Gynaecology 2004;18(2):177-200. [DOI:\n10.1016/j.bpobgyn.2004.01.007]\nWheeler 1989\nWheeler/uni00A0JM. Epidemiology of endometriosis-associated\ninfertility. Journal of Reproductive Medicine 1989;34:41-6. [PMID:\n2704007]\nWhitehouse 1990\nWhitehouse/uni00A0RW, Adams/uni00A0JE, Bancro/f_t/uni00A0K, Vaughan-Williams/uni00A0CA,\nElstein/uni00A0M. The eﬀects of nafarelin and danazol on vertebral\ntrabecular bone mass in patients with endometriosis.. Clinical\nEndocrinology 1990;3(33):365-73. [PMID: MEDLINE: 91070821]\nYlikorkala 1990\nYlikorkala/uni00A0O, Nilsson/uni00A0G, Hirvonen/uni00A0E, Viinikka/uni00A0L. Evidence\nof similar increases in bone turnover during nafarelin and\ndanazol use in women with endometriosis. Gynaecological\nEndocrinology 1990;4(4):251-60. [PMID: MEDLINE: 91188927]\nZhu 2011\nZhu/uni00A0X, Hamilton/uni00A0KD, McNicol/uni00A0ED. Acupuncture for pain\nin endometriosis. Cochrane Database of Systematic\nReviews 2011, Issue 9. Art. No: CD007864. [DOI:\n10.1002/14651858.CD007864.pub2]\nZondervan 2020\nZondervan/uni00A0KT, Becker/uni00A0CM, Missmer/uni00A0SA. Endometriosis. New\nEngland Journal of Medicine 2020 Mar 26;382(13):1244-1256.\n[DOI: 10.1056/NEJMra1810764]\n/uni00A0\nReferences to other published versions of this review\nBrown 2010\nBrown/uni00A0J, Pan/uni00A0A, Hart/uni00A0RJ. Gonadotrophin-releasing hormone\nanalogues for pain associated with endometriosis. Cochrane\nDatabase of Systematic Reviews 2010, Issue 12. Art. No:\nCD008475. [DOI: 10.1002/14651858.CD008475.pub2]\nFarmer 2003\nFarmer/uni00A0JE, Prentice/uni00A0A, Breeze/uni00A0A. Gonadotrophin-releasing\nhormone analogues for endometriosis: bone mineral density.\nCochrane Database of Systematic Reviews 2003, Issue 4. Art. No:\nCD001297. [DOI: 10.1002/14651858.CD001297]\n/uni00A0\n* Indicates the major publication for the study\n/uni00A0\nC H A R A C T E R I S T I C S /uni00A0 O F /uni00A0 S T U D I E S\nCharacteristics of included studies [ordered by study ID]\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 261 women were randomised; 142 women were analysed.\nMean age: Dienogest 29.52 +- 3.32 vs leuprolide 29.77 +- 3.09\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis within 3 months (diagnostic laparoscopy) or within 12\nmonths (therapeutic laparoscopy) of enrolment into the study\n• Subsequent recurrence of pain\nExclusion criteria:/uni00A0\n• Pregnancy\n• Breastfeeding\n• Amenorrhea within 3 months of enrolment\n• Previous use of hormonal agents (e.g. GnRH agonists, progestins, danazol or oral contraceptives) fol-\nlowing laparoscopy\n• Undiagnosed genital bleeding\n• History of severe adverse drug reactions or hypersensitivity to steroid hormones or GnRH agonists\n• History of thrombosis/embolism or depression\n• Patients at risk of decreased bone mineral density (BMD)\nAbdou 2018/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n45\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSetting: Egypt\nTiming: May 2014-December 2016\nInterventions Dienogest 2 mg /uni00A0orally once daily for 12 weeks with the first tablet taken on the first day after onset of\nmenstrual bleeding\nversus\nLeuproline acetate depot 3.75 mg IM every 4 weeks for 12 weeks with the first injection given during the\nfirst 3 days of menstrual bleeding\nOutcomes • Relief of overall pain: pelvic pain, back pain, dyspareunia\n• Adverse effects\n• Mean size of endometrioma\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: no funding\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Patients were divided randomly by using random number table (computer) in-\nto two groups (A and B).\nAllocation concealment\n(selection bias)\nLow risk Software Open Epi version 3.21 was used.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 284 patients met requirements of inclusion criteria, out of which 261 patients\nwere willing to participate in the study and consented for participation.\nPatients who dropped out from follow-up were excluded from the study statis-\ntics and results (9 patients from group A and 10 patients from group B).\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected.\nAbdou 2018/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Prospective randomised double-blind controlled study\nAdamson 1994/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n46\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nParticipants Participants: 213 patients. 124 patients were randomised who reported pain symptoms.\nMean age: not stated\nInclusion:\n• Aged 18 to 48 years with laparoscopically confirmed pelvic endometriosis and dysmenorrhoea, dys-\npareunia or pelvic pain\nExclusion:/uni00A0\n• No surgical procedures were performed during the diagnostic laparoscopy.\n• No patient who had received hormonal treatment during the previous 6 months\nSetting: United States of America\nTiming: not stated\nInterventions Nafarelin acetate 400 mcg twice daily intranasaly + placebo per os or 6 months (n = 45)/uni00A0\nversus/uni00A0\nNafarelin acetate 200 mcg twice daily intranasaly + placebo per os for 6 months (n = 45)/uni00A0\nversus/uni00A0\nDanazol 400 mg twice daily per os + placebo intranasaly for 6 months (n = 34)\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain\nNotes Intention-to-treat analysis: yes\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Authors responded to methods query.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Computerised randomisation\". No further details of method used to generate\nthe randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nLow risk \"Centralised randomisation, sequentially numbered, sealed opaque en-\nvelopes\".\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk All women randomised were analysed with intention-to-treat for main out-\ncome./uni00A0\nAdamson 1994/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n47\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nAdamson 1994/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Multicentre, randomised, double-blind, double-placebo study\"\nParticipants Participants: 208 women were randomised; 192 were analysed.\nMean age: Nafarelin = 29.8 ± 0.6 and LA = 31.7 ± 0.6 (SEM)\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis within 18 months prior to study\n• 19-44 years old\n• Patients demonstrating clinical symptoms and signs\n• Bone mineral density within normal age range\nExclusion criteria:/uni00A0\n• Conditions or drug therapies that may interfere with the study\n• Pregnant or lactating women\n• Danazol use within 6 months prior to study\n• GnRHa use within 12 months prior to study\n• OCP within 30 days prior to study treatment\n• Thyroid disease\nSetting: United States of America/uni00A0\nTiming: not stated\nInterventions Nafarelin 200 mcg twice daily intranasally + placebo every 4 weeks IM for 6 months (n = 105)/uni00A0\nversus/uni00A0\nLeuprolide acetate depot 3.75 mg every 4 weeks IM + placebo twice daily intranasally for 6 months (n =\n103)\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration\n• Bone mineral density\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nAgarwal 1997/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n48\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomisation using permuted blocks of random numbers\". No further de-\ntails of method used to generate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details were provided of method used to conceal allocation to treatment\ngroups.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Details for attrition: 24 women withdrew due to:\n• Ineffectiveness 3 (nafarelin) and 3 (leuprolide acetate)\n• Adverse effects 4 (nafarelin) and 8 (leuprolide acetate)\n• Lost to follow-up 5 (leuprolide acetate)\n• Administrative reasons 1 (leuprolide acetate)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified./uni00A0\nOther bias Low risk No other risk of bias detected\nAgarwal 1997/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Multicentre, open, randomised study\"\nParticipants Participants: 71 women were randomised; 48 were analysed.\nGroup A: patients with/uni00A0infertility associated with endometriosis and who desired pregnancy\nGroup B: other patients (those with symptomatic endometriosis but not desiring pregnancy at time of\nthe study)\nMean age: Goserelin = 29.5 and danazol = 29.85\nGroup A: Mean age: Goserelin = 29.7 (24-36) and danazol = 29.9 (21-35)\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis within 2 months prior to study\n• 18-40 years old\n• rAFS score of equal or greater to 2\n• Normal menstrual cycle (21-42 days)\n• Normal cervical smear for previous 12 months\nExclusion criteria:\n• Pregnant or lactating women\n• Other medical illnesses\n• Hormone use within 2 months prior to study\nAN Zoladex 1996/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n49\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Danazol or GnRHas use within 12 months prior to study\n• Hypersensitivity to trial drugs\n• Showing signs of virilisation\n• Taking anticoagulant therapy\n• Surgical treatment\nSetting: Australia and New Zealand (9 centres)\nTiming: Not stated\nInterventions Goserelin acetate 3.6 mg every 4 weeks SC for 24 weeks (n = 35)/uni00A0\nversus/uni00A0\nDanazol 200 mg three times a day PO for 24 weeks (n = 36)\nOutcomes • Adverse effects\n• Improvement of most troublesome symptoms: dysmenorrhoea, dyspareunia, pelvic pain, pelvic ten-\nderness, induration\n• Pregnancies\n• rAFS score\n• Laboratory data\nNotes Intention-to-treat analysis: yes, analysis was performed on both an 'intention-to-treat' basis and also\non a 'patient-treated' basis. /uni00A0\nSample size calculation: not stated\nFunding: /uni00A0Authors received a grant of ICI Pharmaceuticals Australia and received the supply of goserelin\nacetate./uni00A0\nNote previous version: Authors contacted regarding methods and data; awaiting response.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Patients were randomised in a 1 to 1 ratio\". No further details of method used\nto generate the randomisation sequence were provided./uni00A0\n/uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk No details were provided of method used to conceal allocation to treatment\ngroups./uni00A0\n/uni00A0\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk \"Analysis was performed on both an 'intention-to-treat' basis and also on a\n'patient-treated' basis\"./uni00A0\nAN Zoladex 1996/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n50\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nDetails given for attrition: 19 in danazol and 4 in goserelin group withdrew\ndue to: adverse effects 9 (Dan), unwilling to continue 8 (Dan) and 4 (Gos), with-\ndrawn by investigator 1 (Dan), other 1 (Dan)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nAN Zoladex 1996/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Open, multi-centre, central randomised study\nParticipants Participants: 120 eligible women; 71 were randomised; 55 were analysed/uni00A0\nMean age: 31 ± 5.9 years/uni00A0\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis\n• Symptomatic\n• Recurrence of endometriosis after surgery\n• Over 18 years old\n• No other hormone therapy except insulin\nExclusion criteria:/uni00A0\n• Amenorrhoea\n• Patient having had hysterectomy\n• Pregnant women\n• Serious illness e.g. liver disease\nSetting: France/uni00A0\nTiming: January 1989 to February 1991\nInterventions Leuprorelin 3.75 mg SC depot every 28 days for 24 weeks (n = 33)/uni00A0\nversus/uni00A0\nDanazol 600-800 mg PO daily for 24 weeks (n = 22)\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, induration and pelvic tenderness\n• rAFS score\n• Adverse effects\nNotes Intention-to-treat analysis: yes\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Could not use data unless mean and SD specified; author contacted. Author\nreplied that study was sponsored by a pharmaceutical company who hold the raw data. He is attempt-\ning to locate a contact for further information.\nAudebert 1997/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n51\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Central randomisation\". No further details of method used to generate the\nrandomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk Open-label study. No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No mention of blinding of outcome assessors\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Sufficient reporting of attrition:/uni00A0\n• Refused 2nd laparoscopy n = 1 (leuprolide acetate)\n• Lost to follow-up n = 2 (leuprolide acetate) and n = 9 (danazol)\n• Progression of disease n = 2 (danazol)\n• Not meeting protocol n = 1 (danazol)\n• Other n = 1 (danazol)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nAudebert 1997/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Double-blind randomised study\"\nParticipants Participants: 49 eligible women; 49 were randomised and 47 were analysed/uni00A0\nMean age: mean age not stated, median age 30 years (range 21-46years)/uni00A0\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis\n• Not to use any hormonal preparations during study\n• No hormone treatment in previous 3 months\n• No GnRHas for previous 12 months\n• No steroid therapy for previous 12 months\nExclusion criteria: not stated\nSetting: Europe/uni00A0\nTiming: not stated\nBergqvist 1997/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n52\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nInterventions Nafarelin 200 mcg daily IN + placebo PO for 6 months (n = 12)/uni00A0\nversus/uni00A0\nNafarelin 400 mcg daily IN + placebo PO for 6 months (n = 12)/uni00A0\nversus/uni00A0\nNafarelin 200 mcg daily IN + norethisterone 1.2 mg daily PO for 6 months (n = 25)\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration\n• Adverse effects\n• AFS score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Need raw data for symptom scores. Authors contacted regarding methods and\ndata. No response to date\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"randomisation was carried out on a block basis\". No further details of method\nused to generate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blinded, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blinded, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Two participants (2/25) from the nafareline + norethisterone group withdrew\nfrom the trial due to mood swings (1 participant) and pregnancy (1 partici-\npant).\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nBergqvist 1997/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Prospective, randomised, placebo-controlled, double-blind, parallel study\"\n/uni00A0\nBergqvist 1998/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n53\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nParticipants Participants: 49 women eligible; 49 were randomised and 46 were analysed\nAge: mean of 31 years (19-44years)\nStage: most mild-to-moderate (IV n = 1)\nInclusion criteria:\n• Menstruating regularly 3 months before study\n• Clinical symptoms of endometriosis\n• Not taken oral contraceptive or oral steroid therapy for 3 months\n• Not taken long-acting depot gestagens or GnRHas within past 6 months\n• Not pregnant in prior 3 months\n• Not breastfeeding\n• No history of osteoporosis or coagulation disorders\nExclusion criteria:\n• Intraperitoneal adhesions making visual inspection and careful evaluation of the extension of en-\ndometriotic lesions difficult or impossible\nSetting: Sweden\nTiming: Not stated\nInterventions Triptorelin 3.75 mg IM depot every 4 weeks for 24 weeks (n = 24)\nversus\nPlacebo IM every 4 weeks for 24 weeks (n = 25)\n/uni00A0\nOutcomes • Relief of overall pain\n• Adverse effects\n• Visible endometriosis extension\n• rAFS\n• Frequency and amount of bleeding\n• Serum concentrations of estradiol\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Needs raw score for pain. Authors contacted and awaiting response\n/uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk No details were provided of method used to generate the randomisation se-\nquence./uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk No details were provided of method used to conceal treatment group alloca-\ntion./uni00A0\nBlinding of participants\nand personnel (perfor-\nmance bias)\nLow risk Participants and researchers were blinded through the use of identical kits for\ninjections.\nBergqvist 1998/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n54\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAll outcomes\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Participants and researchers were blinded through the use of identical kits for\ninjections.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Three participants withdrew from the study. Two from the placebo group (1\nprior to the first injection due to pregnancy, and one after 4 months due to lack\nof effect), and one from the triptorelin group due to hypoestrogenic side ef-\nfects and depression.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nBergqvist 1998/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 252 women were randomised; 224 were analysed.\nMean age: 18-45 years (median 31 years)\nInclusion criteria:\n• Regular menstruating\n• Not been on sex hormones (including oral contraceptives) within 2 months of treatment\n• Not received GnRH agonist therapy within the previous 6 months and not for more than 3 months\naltogether\n• Not pregnant or breastfeeding\nExclusion criteria:\n• Women with serious renal, hepatic, hematopoietic or endocrine disease, or with allergic rhinitis\nSetting: Scandinavia (28 centres = 7 centres in Sweden, 8 centres in Norway, 6 centres in Denmark and\n7 centres in Finland)\nTiming: not stated\nInterventions Goserelin depot, 3.6 mg, administered subcutaneously into the anterior abdominal wall every 28 ±3\ndays (Zoladex; AstraZeneca) (n = 130)/uni00A0\nversus/uni00A0\nNafarelin 200 /uni03BCg nasally twice daily, giving a total daily dose of 400 /uni03BCg (Synarel; Syntex) (n = 122)\nOutcomes • Overall relief of pain (pelvic symptoms)\n• Adverse effects\n• Menstrual details\n• Extent of endometriosis (rAFS, ADI scores)\n• Haematological parameters: follicle-stimulation hormone (FSH), luteinising hormone (LH), oestradi-\nol, creatinine, urea, sodium and potassium in plasma\nNotes Intention-to-treat analysis: not stated\nBergqvist 2000/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n55\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSample size calculation: not stated\nFunding: The study was supported by AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield,\nCheshire SK10 4TF, UK.\n/uni00A0\nAuthors contacted regarding methods and data. Awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Randomisation was being performed within each centre. No further details\nwere provided of method used to generate the randomisation sequence./uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk No details were provided of method used to conceal treatment group alloca-\ntion. /uni00A0\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Altogether, 39 women withdrew from the study, four of whom commenced any\ntherapy, two because they changed their minds and two because they became\npregnant between the date of randomisation and the planned date of starting\nthe trial medication. Twenty-four patients withdrew during the active treat-\nment period, adverse events being the most common reason. Sixteen women,\nnine in the goserelin group and seven in the nafarelin group, withdrew owing\nto adverse events, two women in the nafarelin group, withdrew because of lo-\ncal side effects of the treatment such as nasal irritation, one woman because\nof a worsening of symptoms and five for other reasons./uni00A0\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nBergqvist 2000/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Parallel, double-blind, double-dummy randomised trial\nParticipants Participants: 53 women were randomised; 51 were analysed.\nMean age: 23-38 years\nInclusion criteria:/uni00A0\n• Endometriosis diagnosis made laparoscopically within 3 months preceding the study\nExclusion criteria:/uni00A0\nBurry 1989/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n56\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Medical therapy for endometriosis within the preceding 6 months\nSetting: United States of America\nTiming: Not stated\nInterventions Group I: danazol, 800 mg/day (400 mg twice daily) (n = 10)/uni00A0\nGroup II: danazol, 600 mg/day (200 mg three times a day) (n = 8)\nGroup III: intranasal nafarelin, 800 /uni03BCg/day (400 /uni03BCg twice a day) (n = 10)\nGroup IV: intranasal nafarelin, 400 /uni03BCg/day (200 /uni03BCg two times a day) (n = 25)\nOutcomes • Change in symptoms (pelvic pain and vaginal bleeding)\n• Adverse effects\n• Plasma lipids\n• Stage of endometriosis\n• Pregnancy\nNotes Intention-to-treat analysis: No\nSample size calculation: not stated\nFunding: not stated\nIncluded in this review, but did not contribute any data\nNot possible to contact leading author; unfortunately had passed away.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk 'Randomly allocated'. No further details were provided of method used to gen-\nerate the randomisation sequence./uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk No details were provided of method used to conceal treatment group alloca-\ntion. /uni00A0\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk The study had a parallel, double-blind, double-dummy design.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk The study had a parallel, double-blind, double-dummy design.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Group I: Danazol, 800 mg/day (400 mg twice a day): Nine of the 10 patients in-\ncluded in this group completed the study; one withdrew because of severe\nheadaches.\nGroup II: Danazol, 600 mg/day (200 mg three times a day). All eight patients\ncompleted the study.\nGroup III: Nafarelin acetate, 800 /uni03BCg/day (400 /uni03BCg twice a day). Nine of 10 pa-\ntients included in this group completed the study: one withdrew because of\nmood swings.\nBurry 1989/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n57\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nGroup IV: Nafarelin acetate, 400 /uni03BCg/day (200 /uni03BCg twice a day). All 25 patients in-\ncluded in this group completed the study.\nSelective reporting (re-\nporting bias)\nHigh risk Change in symptoms was asked for, but not reported in published article./uni00A0\nOther bias Low risk No other risk of bias detected\nBurry 1989/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Multi-centre, double-blind study\"\nParticipants Participants: 169 women eligible; 169 were randomised and 147 analysed for efficacy.\nMean age: not stated\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis\nExclusion criteria: not stated\nSetting: United States of America\nTiming: not stated\nInterventions Nafarelin 400 /uni03BCg daily IN for 6 months (n = 111)\nversus\nDanazol 600 mg daily PO for 6 months (n = 58)\nOutcomes • Adverse effects\n• Quality of life score\n• Improvement of most troublesome symptom\n• Change in laparoscopic scores\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Need more info on randomisation and participants and raw data for quality of\nlife. Authors contacted, awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk The randomisation procedure assigned two of\nevery three patients to receive nafarelin, 400 /uni03BCg daily (n = 111), and one of\nthree patients to danazol, 600 mg daily (n = 58). No further details were provid-\ned of method used to generate the randomisation sequence./uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk No details were provided of method used to conceal treatment group alloca-\ntion. /uni00A0\nBurry 1992/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n58\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk The study was \"double-blind\". No further details were provided on the method\nof blinding.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk The study was \"double-blind\". No further details were provided on the method\nof blinding.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Sufficient details for attrition:\n• Side effects n = 6 (N) n = 3 (D)\n• Elevated liver enzyme n = 1 (D)\n• Administrative reasons n = 12\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nBurry 1992/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Randomised comparative study\"\nParticipants Participants: 45 women eligible; 45 were randomised and 33 were analysed.\nMean age: 33 years (LA)/uni00A0\nInclusion criteria:/uni00A0\n• Laparoscopic diagnosis of endometriosis\n• Pain symptoms\nExclusion criteria:/uni00A0\nSetting: Taiwan/uni00A0\nTiming: not stated\nInterventions Leuprorelin acetate 3.75 mg SC depot every 28 days for 20 weeks (n = 30)/uni00A0\nversus/uni00A0\nDanazol 200 mg QID (800 mg/day) PO for 20 weeks (n = 15)\nOutcomes • Dysmenorrhoea, dyspareunia, pelvic pain\n• Adverse effects\n• Change in AFS score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nChang 1996/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n59\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nNote previous version: Need raw data for pain. Authors contacted, and additional methodological data\nprovided, no raw data\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomisation was in the ratio two LA to one danazol with this study having\nits randomisation list\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nLow risk \"sequentially numbered, identical containers of identical drugs\". No further\ndetails were provided of method used to conceal allocation to treatment\ngroups.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Outcome assessors were blinded to treatment group.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nUnclear risk No details were provided on attrition.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nChang 1996/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Randomised, parallel, comparative study\"/uni00A0\nParticipants Participants: 59 women eligible; 59 were randomised and 41 were analysed for efficacy.\nMean age: 34.8 ± 6.6 (nafarelin) and 32.4 ± 7.2 (danazol)\nInclusion criteria:\n• Laparoscopically diagnosed within 3 months prior to study\n• Age 18-48 years\n• Barrier contraception\nExclusion criteria:\n• Pregnancy\n• Breastfeeding\n• Menopause or postmenopausal\n• Use of oestrogen, progesterone or contraceptive steroids in previous 3 months\n• Impaired hepatic or renal function\n• Cardiovascular disease\nCheng 2005/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n60\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• AIDS or other sexually transmitted diseases\nSetting: Taiwan\nTiming: started in January 1998 and ended in October 2000\nInterventions Nafarelin acetate 200 /uni03BCg twice daily (400 /uni03BCg/day) IN for 180 days (n = 29)\nversus\nDanazol 200 mg (600 mg/day) PO for 180 days (n = 30)\nOutcomes • Total symptom severity score and physician-assessed pelvic tenderness\n• Change in laparoscopic score\n• Adverse effects\n• Serum lipid levels\n• Haematology and liver function\nNotes Intention-to-treat analysis: yes\nSample size calculation: not stated\nFunding: This study was partly supported by a grant (VGH94- 195) from Taipei Veterans General Hospi-\ntal, Taipei, Taiwan, R.O.C.\nNote previous version: Authors provided additional data on methods.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Randomisation done by a pharmacy. Authors provided additional data to pre-\nvious authors, and therefore this study was assigned as having low risk of bias.\nAllocation concealment\n(selection bias)\nLow risk Sealed, opaque, sequentially numbered, identical envelopes\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Investigators, outcome assessors and clinicians were blinded according to au-\nthor.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Investigators, outcome assessors and clinicians were blinded according to au-\nthor.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk \"All 59 patients were considered as the intent-to-treat population\".\nForty-one of 59 patients (22/29 nafarelin and 19/30 danazol recipients) who\ncompleted 90 days’ treatment, and who underwent laparoscopic examina-\ntions before and after treatment, qualified for the efficacy evaluation.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nCheng 2005/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n61\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nStudy characteristics\nMethods Trial design: \"randomised controlled comparative clinical study\"\nParticipants Participants: 60 women eligible; 60 were randomised and 55 were analysed.\nMean age: 30 ± 0.5 (triptorelin depot) and 30 ± 0.8 (danazol)\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis\n• Premenopausal\n• No medication affecting pituitary or ovarian function in preceding 6 months\nExclusion criteria:\n• Stage I endometriosis\nSetting: Germany\nTiming: February 1989 and December 1990\nInterventions Triptorelin 3.75 mg IM depot every 28 days for 24 weeks (n = 30)\nversus\nDanazol 200 mg three times a day (600 mg/day) PO for 24 weeks (n = 25)\n/uni00A0\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration\n• Adverse effects\n• Change in AFS score\n• Endocrine effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Authors contacted and awaiting response regarding methods\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Patients were allocated to a computer-generated randomisation list.\nAllocation concealment\n(selection bias)\nUnclear risk No further details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk Open-label trial as blinding of study personnel and participants would not\nhave been possible due to nature of the intervention.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nCirkel 1995/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n62\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk Five women assigned to danazol could not be included further: three patients\nrefused to fulfill the protocol after randomisation and two others conceived\nspontaneously before starting medication.\nTwenty-four weeks after the end of endocrine therapy, 20 women (12/30 in the\ntriptorelin and 8/25 in the danazol group) had an additional follow-up for eval-\nuation of clinical symptomatology as well as laboratory parameters.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nCirkel 1995/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Parallel-arm, randomised controlled trial\nParticipants Participants: 30 women randomised (Group 1 - three-monthly leuprolide n = 15, Group 2 - monthly le-\nuprolide n = 15). 27 women analysed (Group 1 - three-monthly leuprolide n = 14, Group 2 - monthly le-\nuprolde n = 13)\nMean age: Group 1: 28.6 ± 6.0, Group 2: 31.0 ± 5.2\nInclusion:/uni00A0\n• Premenopausal women (FSH < 30 mIU/mL)\n• Aged 18-38\n• Symptomatic endometriosis at stage I-IV of the revised American Fertility Society (rAFS) classification,\ndiagnosed at laparoscopy\nExclusion:/uni00A0\n• Any major disease\nSetting: University clinics in Milan, Genoa, Rome, Italy\nTiming: not stated\nInterventions Group 1: Leuprolide acetate 11.25 mg intramuscularly every 84 days /uni00A0for 6 months\nversus/uni00A0\nGroup 2: Leuprolide acetate 3.75 mg every 28 days for 6 months\nOutcomes • Relief of overall pain, according to Biberoglu and Behrman verbal rating scale\n• Bone mineral density\n• Adverse effects\n• rAFS score\n• Acceptability of treatment schedule\n• Serum LH and 17β-oestradiol concentrations\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nCrosignani 1996/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n63\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFunding: Takeda Italia Farmaceutici S p.A., Roma, Italy, for supplying leuprolide depot injections,\npreparing the randomisation procedures, and giving financial support to the study\nNote previous version: Was previously excluded for pain not being an outcome but should be included\nas pain score is an outcome\nContacted authors for more information on concealment, awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Eligible subjects were randomised according to a computer-generated se-\nquence.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk The study was an \"open-label trial\". No further details of the blinding process\nwere provided.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk One woman from group 1 (three monthly) withdrew from study as she did not\nwant to undergo repeated venipunctures and laparoscopy. Two women in\ngroup 2 (monthly) stopped treatment due to a desire to conceive.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nCrosignani 1996/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: randomised, phase III, evaluator-blinded, comparator-controlled clinical trial\nParticipants Participants: Of 300 randomised patients, 299 received at least one dose of study medication. Continu-\nation rates were similar between the treatment groups, with 90.2% of patients receiving DMPA-SC 104\nand 93.2% of those receiving leuprolide completing the 6-month treatment period. Of the patients that\ncompleted the 6-month treatment period, 71.7 and 73.5% of patients in the DMPA-SC 104 and leupro-\nlide groups completed the 12-month follow-up period, respectively.\nMean age: DMPA-SC 31.8 ± 6.7 years, leuprolide 30.9 ± 6.1 years\n• Inclusion criteria: Premenopausal women aged 18–49 years\n• Laparoscopically diagnosed endometriosis\n• Persistent pain symptoms\n• Normal results from a Papanicolaou smear and normal mammogram within the past 12 months\n• Be willing to use a non-hormonal contraceptive method for the duration of the study\n• Exclusion criteria:/uni00A0BMD below acceptable levels (both lumbar spine and total hip t score < –1.0)\n• A history of pathological or compression fractures\nCrosignani 2006/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n64\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Any condition that might render a patient unable to comply with study instructions\nSetting: Europe, Asia, Latin America and New Zealand\nTiming: July 1, 2001, through August 11, 2003\nInterventions 6 months of active treatment with depot medroxyprogesterone acetate 104 mg/0.65 mL ( DMPA-SC\n104)\nversus\n6 months of active treatment with leuprolide 3.75 mg monthly, or in The Netherlands, 11.25 mg once\nevery 3 months\nOutcomes • Relief of overall pain\n• Adverse effects (including changes in the Kupperman Index)\n• Quality of life\n• Decline in bone mineral density\n• Efficacy\nNotes Intention-to-treat analysis: Yes\nSample size calculation: not stated\nFunding: no funding\nNote previous version: Authors contacts as values were given as median percentage change. No re-\nsponse\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk This study randomised patients in a 1:1 ratio.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk This was an evaluator-blinded study, in which the principal investigator and\nany designated sub-investigators and study coordinators at each centre were\nblinded to the randomisation of each patient.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk For the purpose of maintaining the blinding, an independent person main-\ntained the randomisation code, received the study syringes and administered\nthe study medication. This individual was instructed not to reveal the ran-\ndomisation code or to discuss the patient’s route of administration with clin-\nical study site personnel. In addition, patients were instructed not to discuss\nthe route of administration.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk In DMPA-SC 104 group, a total of 54/153 withdrawn during follow-up period\n- 12 adverse events\n- 10 protocol violation\n- 22 consent withdrawn\n- 10 patient contact loss\nCrosignani 2006/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n65\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nIn leuprolide group, a total of 46/146 withdrawn during follow-up period\n- 9 adverse events\n- 10 protocol violation\n- 18 consent withdrawn\n- 9 patient contact loss\n/uni00A0\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nCrosignani 2006/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Prospective, randomised, double-blind study\nParticipants Participants: 12 women were randomised and analysed.\nMean age: The mean age was 29.4 ± 1.6 years for the LA group and 30.5 ± 2.9 years for the danazol\ngroup.\n• Inclusion criteria: No use of specific hormone treatment or oral contraceptive use in the 6 months\nbefore enrolment in the study\n• No previous use of GnRH analogue\nNo surgical treatment was permitted at the time of pretreatment laparoscopy.\nExclusion criteria:/uni00A0\n• Use of contraception other than the barrier method\nSetting: United states of America\nTiming: not stated\nInterventions Group 1: 3.7 mg leuprolide acetate monthly injection + oral placebo every day\nor/uni00A0\nGroup 2: 800 mg danazol orally + monthly placebo injection\nOutcomes • Bone mineral density\n• Hormone determinations\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: supported by a grant from TAP Pharmaceuticals, Inc., Deerfield, Illinois\nThe author has not been reached for no working email address was available.\nRisk of bias\nDawood 1995/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n66\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk 'randomized clinical trial' by randomisation code. No further details of method\nused to generate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No further details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Blinding, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Blinding, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nDawood 1995/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Phase III, randomised, double-blind, multi-centre study\"\n/uni00A0\nParticipants Participants: 63 women eligible; 63 were randomised and 52 were analysed.\nMean age: /uni00A029.8 ± 1.0 leuprolide versus 30.2 ± 1.0 placebo\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis within 3 months of study entry\n• Pain secondary to endometriosis\n• Over 18 years old\n• No previous treatment with leuprolide acetate or other GnRHas\n• At least one ovary intact\n• Non-pregnant\n• Non-lactating\n• No treatment for endometriosis within 3 months of study entry\nExclusion criteria: not stated\nSetting: United States of America\nTiming: Not stated\nInterventions Leuprolide acetate 3.75 mg IM depot every 4 weeks for 20 weeks (n = 32)\nversus\nDlugi 1990/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n67\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nPlacebo (diluent) 2 mL IM every 4 weeks for 20 weeks (n = 31)\nOutcomes • Relief of overall pain: dysmenorrhoea, pelvic pain, dyspareunia, pelvic tenderness, induration\n• Bone mineral density\n• Adverse effects\n• Clinical evaluation of induration and ovarian enlargement\n• Hormone assays\n• Menstrual records\n• Analgesic usage\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Supported by a grant from TAP Pharmaceuticals, North Chicago, Illinois\nNote previous version: Authors contacted for details on allocation concealment and SEMs. Letter re-\nturned to sender; author moved with no forwarding address.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomised\". No further details of method used to generate the randomisa-\ntion sequence were provided.\nAllocation concealment\n(selection bias)\nLow risk \"Patients were assigned a 3 digit patient number in sequential order from\nthose numbers allocated to each investigator. The patient number encoded\nthe random assignment to a treatment group\".\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Patients and investigators were blinded.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Patients and investigators were blinded.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk Sufficient details for attrition:\n7/32 withdrawn as subsequently determined they had failed to meet entry re-\nquirements; 4 excluded because they had received fewer than 3 injections of\nthe study drug.\nThere were partial exclusions for efficacy data due to non-compliance with in-\ntended study procedures and dosing regimens for 15 patients (7 = leuprolide\nand 8 = placebo).\n27/31 placebo (24 terminated because of worsened symptoms, 1 because of\nsalpingitis, 1 became pregnant and 1 was non-compliant) and 3 (2 because of\nintolerable pain and 1 because of an adverse event) leuprolide patients pre-\nmaturely terminated study.\n/uni00A0\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nDlugi 1990/uni00A0/uni00A0(Continued)\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n68\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Open-label, randomised, prospective study\"\nParticipants Participants: 36 women eligible, 36 were randomised and 29 were analysed\nMean age: 30.8 ± 0.6 (SE) (range, 27 to 38 years)\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis within 3 months before enrolment in the study\n• No hormonal treatment 8 months prior to study entry\nExclusion criteria: not stated\nSetting: United States of America\nTiming: Not stated\nInterventions Buserelin 400 /uni03BCg three times a day (1200 /uni03BCg/day) IN for 6 months (n = 10)\nversus\nBuserelin 200 mcg daily SC for 6 months (n = 9)\nversus\nDanazol 200 mg four times a day (800 mg/day) PO for 6 months (n = 10)\n/uni00A0\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain\n• Change in rAFS scores\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: supported in part by a grant from Hoechst-Roussel Pharmaceuticals, Inc.\nNote previous version: Authors contacted regarding allocation concealment\n/uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk 2:1 buserelin: danazol. No further details of method used to generate the ran-\ndomisation sequence were provided.\n\"Those who were randomised into Buserelin were given an option of SC injec-\ntions or IN sprays of the drug\".\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nUnclear risk No details provided of blinding of outcome assessment\nDmowski 1989a/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n69\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAll outcomes\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Detail for attrition:\n3 in SC buserelin, 2 in IN buserelin and 2 in danazol group. 2 withdrew for fam-\nily reasons, 3 were non-compliant, 1 had severe emotional side effects on IN\nbuserelin and 1 was allergic to danazol.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nDmowski 1989a/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 50 women were randomised and analysed.\nMean age: not stated\nInclusion criteria:\n• Laparoscopic confirmed endometriosis\n• Significant pelvic pain\nExclusion criteria:/uni00A0\n• No pelvic pain\nSetting: United Kingdom\nTiming: not stated\nInterventions Group 1: goserelin 3.6 mg/month as SC depot (n = 25)\nversus\nGroup 2: goserelin 3.6 mg/month as SC depot + 17-oestrodiol 25 ug through the skin\ntwice weekly and medroxyprogesterone acetate 5 mg/day PO (n = 25)\nOutcomes • Bone mineral density, measured at the lumbar spine, femoral neck and ward's triangle\n• Improvement of most troublesome symptom: dyspareunia, dysmenorrhoea, pelvic pain, pelvic ten-\nderness, induration combined\n• Endocrine profiles\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\n/uni00A0\nAuthor could not be contacted for further information because of lack of contact information.\nRisk of bias\nEdmonds 1994/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n70\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk 'Randomised controlled trial'. No further details of method used to generate\nthe randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nHigh risk Change in pain-related symptoms was asked for, but not reported in published\narticle./uni00A0\nOther bias Low risk No other risk of bias detected\nEdmonds 1994/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled study\n/uni00A0\nParticipants Participants: 62 women were randomised and analysed.\nMean age: Buserelin = 29.8 ± 3.3 and danazol 31.3 ± 4.3/uni00A0\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis within 3 months prior to study\n• No therapeutic intervention\nExclusion criteria:\n• Bilateral tube occlusion or partner with severe dyspermia\n• Danazol or other sex hormone use within 6 months prior to study\n• Systemic or endocrine disease\nSetting: Italy\nTiming: not stated\nInterventions Buserelin 400 /uni03BCg three times a day IN for 6 months (n = 30)\nversus\nDanazol 200 mg three times a day PO for 6 months (n = 32)\n/uni00A0\nFedele 1989/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n71\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain\n• rAFS score\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Authors contacted for information on raw data for pain scores, and methods. No\nresponse to date\n/uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk The patients were assigned randomly to one of two treatment groups. No fur-\nther details of method used to generate the randomisation sequence were\nprovided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Detail for attrition:\n• 1 subject from buserelin group withdrew due to severe pelvic pain.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFedele 1989/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised, prospective open-labelled study\nParticipants Participants: 44 women with endometriosis (confirmed laparoscopically/histologically), /uni00A0consecutively\nselected at the pain and endoscopy outpatient clinic\nMean age: 28.8 ± 4.9 years for LNG-IUS and 41.4 ± 5.8 years for GnRHa\nInclusion criteria:/uni00A0\n• 18-40 years of age\nFerreira 2010/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n72\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Chronic pelvic pain\n• No use of /uni00A0oral hormone contraceptives for at least 3 months or with depot progestogens or GnRHa\nfor at least 6 months prior to randomisation\nExclusion:/uni00A0\n• Obese patients (BMI > 30kg/m2)\n• Smokers, diabetics, alcohol or drug users\n• Patients wishing to conceive\n• Patients with chronic disease, acute and/or chronic inflammatory and/or infectious processes\n• Family history of thromboembolic events\n• Taking medications known to interfere with inflammation markers for a period of less than 15 days\nbefore the study\nSetting: Brazil\nTiming: not stated\nInterventions Levonorgestrel intrauterine system (LNG-IUS) (n = 22)\nversus\nGnRHas (n = 22) 3.75 mg leuprolide IM monthly treatment for 6 months\nOutcomes • Relief of overall pain: pain score (VAS)\n• Serum markers of cardiovascular risk (lipid profile, inflammatory markers, and markers of endothelial\ninjury)\n• BMI, systolic and diastolic arterial pressure, heart rate\nNotes Intention-to-treat analysis: not stated\nSample size calculation: Yes\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"Randomised by computer program (GraphPad Software) at a 1:1 ratio)\". No\nfurther details of method used to generate the randomisation sequence were\nprovided.\nAllocation concealment\n(selection bias)\nUnclear risk No /uni00A0details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk GnRHa (1 pregnancy before drug administered and 3 moved and lost to fol-\nlow-up)\nFerreira 2010/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n73\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFerreira 2010/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 43 women were randomised and 39 analysed.\nMean age: Group 1: 31 ± 7 years, group 2: 32 ± 7 years\nInclusion criteria:\n• Symptomatic, laparoscopically proven endometriosis\n• Participated in the original study\n• Ovulation was confirmed in the menstrual cycle before entry into the study by a luteal-phase serum\nprogesterone level more than 16 nmol/L (5 ng/dL).\n• Normal serum calcium, inorganic phosphate, alkaline phosphatase, bilirubin, creatinine, free T4 in-\ndex, and PRL concentrations\nExclusion criteria:/uni00A0\n• Women with disorders or taking medications known to affect bone metabolism\n• Oral contraceptive and danazol use was discontinued for at least 2 months and GnRH analog therapy\nwas discontinued for at least 9 months before entry into the study.\nSetting: United States of America\nTiming: not stated\nInterventions GnRH analog nafarelin acetate (Synarel, Syntex Laboratories, Inc, Palo Alto, Calif), 200 /uni03BCg intranasally\ntwice daily, for 12 months (group 1, n = 22)/uni00A0\nversus\nNafarelin acetate plus human PTH-(1-34), 40 /uni03BCg (500 U) subcutaneously daily, for 12 months (group 2, n\n= 21)\nOutcomes • Bone mineral density\n• Adverse effects\n• Improvement of most troublesome symptom\n• Laboratory/biochemical values\nNotes Intention-to-treat analysis: yes\nSample size calculation: not stated\nFunding: This work was supported by National Institutes of Health grants R29 DK43341 and RR1066 and\na National of Institutes of Health Clinical Associate Physician Award (Dr Finkelstein).\nRisk of bias\nBias Authors' judgement Support for judgement\nFinkelstein 1998/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n74\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRandom sequence genera-\ntion (selection bias)\nLow risk Randomisation was conducted by a research biostatistician not otherwise in-\nvolved in the study.\nAllocation concealment\n(selection bias)\nLow risk The women were randomly assigned. Randomisation was performed us-\ning computer-generated cards that were numbered sequentially and kept in\nopaque, sealed envelopes until entry into the study.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk Because we and our local institutional review board felt that the use of place-\nbo hPTH-(1-34) injections was unethical, no placebo was used. Thus, neither\nthe patients nor the investigators were blinded with respect to treatment.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk The person reading the bone density scans, however, was blinded with re-\nspect to treatment assignment, as were the technicians who performed the\nbiochemical analyses.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Four women in group 2 (4/21) withdrew from the study after 3 months (n =\n2) or 6 months (n = 2). Reasons for withdrawal included hot flashes and mild\nweight gain (n = 1), excessive distance from study site (n = 1), discomfort from\ninjections (n = 1), and depression (n = 1). All data from these women are includ-\ned and analysed with their originally assigned group.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFinkelstein 1998/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 38 women were randomised and analysed.\nMean age: Group 1: 34 ± 7 years, group 2: 34 ± 7 years\nInclusion criteria:\n• Symptomatic, laparoscopically proven endometriosis\n• Participated in the original study\n• Ovulation was confirmed by a luteal phase serum progesterone level greater than 5 ng/dL (19, 20).\n• Normal serum calcium, inorganic phosphate, alkaline phosphatase, bilirubin, creatinine, free T4 in-\ndex, and PRL concentrations\nExclusion criteria:/uni00A0\n• Women with disorders or taking medications known to affect bone metabolism\n• Women who received a therapy or who developed a medical condition known to affect BMD during\nthe year after active therapy\nSetting: United States of America\nTiming: not stated\nInterventions Nafarelin acetate (Synarel, Syntex Laboratories, Inc., Palo Alto, CA; 200 mg, intranasally, twice daily)\n(group 1; n /uni00A0= 28)/uni00A0\nFinkelstein 1999/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n75\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nversus\nNafarelin acetate plus human PTH [40 mg (500 U), sc, daily] for 6–12 months (group 2; n = /uni00A023)\nOutcomes • Changes in BMD and bone turnover\n• Biochemical markers of bone turnover\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: This work was supported by NIH Grants R29-DK-43341 and RR1066 and a NIH Clinical Asso-\nciate Physician Award (to J.S.F.).\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk The women were randomly assigned using computer generated cards./uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFinkelstein 1999/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: prospective, randomized, placebo-controlled, double-blind trial\nParticipants Participants: 41 women were randomised, 40 women were analysed.\nMean age: Group 1: 29.9 ± 6.0 years, group 2: 31.2 ± 5.3 years\nInclusion criteria:\n• Endometriosis confirmed by laparoscopy in the 3 months before initiation of treatment\n• AFS-R scores of 2 or more\n• During surgery, no attempt was made to reduce the endometriotic lesions.\nFranke 2000/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n76\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nExclusion criteria: not stated\nSetting: The Netherlands\nTiming: April 1, 1997 until July 1, 1999\nInterventions Group 1: goserelin acetate SC 3.6 mg every 4 weeks + oral placebo (n = 23)\nversus\nGroup 2: goserelin acetate SC 3.6 mg every 4 weeks + 2 mg 17ß-E/two.sups and 1 mg norethisterone acetate dai-\nly (n = 18)\nOutcomes • Bone mineral density\n• Adverse effects\n• Endocrinologic effects\n• Changes in AFS-R score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Trial sponsored by AstraZeneca and Novo Nordisk, who also supplied the\nactive drugs and placebo.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk No details of method used to generate the randomisation sequence were pro-\nvided.\nAllocation concealment\n(selection bias)\nUnclear risk Sequentially numbered envelopes. No further details of method used to con-\nceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 1 participant in group 1 discontinued treatment due to severe climacteric\nsymptoms.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFranke 2000/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nFraser 1991/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n77\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMethods Trial design: \"Double-blind, double-dummy, randomised, parallel study\"\n/uni00A0\nParticipants Participants: 49 women with endometriosis stage 1-3 were randomised and 45 were analysed.\nMean age: not stated\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis\n• Symptomatic\n• Regular menstrual cycle 24-36 days\n• Not pregnant\n• Negative pap smear\n• Barrier contraception\nExclusion criteria:\n• Concurrent disease which may interfere with drug\n• Surgical therapy within 6 months prior to study entry\n• Steroid therapy within 3 months prior to study entry\nSetting: Australia/New Zealand\nTiming: not stated\nInterventions Nafarelin 200 mcg twice a day (400 /uni03BCg/d) IN + placebo PO for 6 months (n = 33)\nversus\nDanazol 200 mg three times a day (600 mg/d) PO + placebo IN for 6 months (n = 16)\n/uni00A0\nSubdivisions were made:\nStage 1-2:\nSubgroup A (27 patients; 2 dropouts) who received intranasal nafarelin acetate 200 pg twice daily,/uni00A0\nor\nSubgroup B (13 patients; no dropouts) who received oral danazol 200 mg 3 times daily.\nStage 3:\nSubgroup A (6 patients; 1 dropout) who received intranasal nafarelin acetate 200 pg twice daily for 6\nmonths followed by conservative laparotomy,\nor/uni00A0\nSubgroup B (3 patients; no dropouts) who received oral danazol 200 mg three times daily followed by\nconservative laparotomy.\nOutcomes - Dyspareunia, pelvic pain, pelvic tenderness, induration\n- Change in rAFS score\n- Adverse effects\n/uni00A0\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFraser 1991/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n78\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFunding: Syntex Pharmaceuticals International supplied nafarelin acetate, and a grant to cover the ex-\npenses of the trial.\nNote previous version: Authors contacted with regards to allocation concealment. Author replied that\nthe data were difficult to find but would try.\n/uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"Computer generated list of random numbers\"\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Placebo pill + placebo nasal spray so patient and investigators were blinded.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Placebo pill + placebo nasal spray so assessors were blinded.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 3/33 participants \"dropped out\" of intranasal nafarelin group; no \"drop outs\"\nfrom danazol group (0/16)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFraser 1991/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: randomised, double-blind, comparative study\nParticipants Participants: 27 women were randomised and analysed.\nMean age: group A: 35 ± 5 years, group P: 34.8 ± 5 years\nInclusion criteria:\n• Age between 18-45\n• Endometriosis score greater than 5 points causing symptoms and/or sterility\n• /uni00A0Normal bone density prior to medication\n• Use of contraceptive devices in the 1st month of treatment\nExclusion criteria: not stated/uni00A0\nSetting: Germany\nTiming: not stated\nFreundl 1998/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n79\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nInterventions Group A: received a combination of leuprorelin acetate depot with 20 mg ethinyloestradiol plus 0.15\nmg desogestrel (n = 14)\nversus\nGroup P: received leuprorelin acetate depot plus placebo (n = 13)\nOutcomes • Relief of overall pain: endometriosis symptoms\n• Bone mineral density\n• Hypooestrogenic symptoms\n• rAFS score\n• Blood/urine chemistry\n• Body weight\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nContact with the author could not be established for further information; he unfortunately passed\naway.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Prospective double-blind, randomised placebo-controlled trial\". No further\ndetails of method used to generate the randomisation sequence were provid-\ned.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFreundl 1998/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nFukushima 1993/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n80\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMethods Trial design: single-blind, single-centre, randomised controlled trial\nParticipants Participants: 28 women were randomised, 19 women were analysed.\nMean age: Buserelin 34.6 ± 5.1 years, danazol 32.6 ± 8.5 years\nInclusion criteria:\n• Regular menstrual cycles\n• Negative cervical cytology\n• Body weight within 25% of the normal range\nExclusion criteria:/uni00A0\n• Conditions that might affect calcium metabolism\n• Administration of drugs known to affect sex hormone levels or bone metabolism during the study\nSetting: Japan\nTiming: not stated\nInterventions Danazol (Bonzol©, Tokyo Tanabe Co., Ltd., Tokyo, Japan) capsules at a dose of 400 mg/day\nversus\nBuserelin (Suprecur© Hoechst Japan, Tokyo, Japan) nasal spray at a dose of 900 /uni03BCg/day\nOutcomes • Bone mineral content\n• Biochemical parameters of efficacy and bone metabolism\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nAuthor could not be contacted due to lack of contact information.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly allocated\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Single-blind (to assessor of bone mineral density)\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk 9/28 did not complete the study due to reasons unrelated to the treatment\nthey had been administered. No further details were provided.\nFukushima 1993/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n81\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nFukushima 1993/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised, double-blind, placebo-controlled, prospective trial\nParticipants Participants: 27 women were randomised and analysed.\nMean age: group 1; 34.8 ± 5 years, group 2; 35 ± 5 years\nInclusion criteria:\n• Laparoscopically confirmed endometriosis (rAFS I-IV)\n• No hormonal pretreatment at least 8 weeks prior to study entry\n• Age 18-45\n• Normal bone mineral density prior to study entry\nExclusion criteria:/uni00A0\nReduced bone mineral density prior to study entry\n• Absolute or relative contraindication against ethinyl oestradiol or desogestrel\n• Pregnancy\n• Medical history or any event of thrombosis\n• Any form of haemoglobin disorders, hypertension, liver function disorders, any history of malignant\ndiseases, any oestrogen-related disorders like otosclerosis, herpes gestationis, history of severe pru-\nritus in pregnancy\n• Additional medication with: antiepileptics, antibiotics, rifampicin, isoniazid, phenylbutazon, griseo-\nfulvin, chlorpromazin, nitrofurantoin or dihydroergotamin\nSetting: Germany\nTiming: not stated\nInterventions Group 1: leuprolin acetate 3.75 mg IM + oral placebo each day\nversus\nGroup 2: leuprolin acetate 3.75 mg IM + 20/uni03BCg ethinyl oestrodiol and 0.15 mg desogestrel\nper day\nOutcomes • Bone mineral density\n• Pyridinoline concentrations in urine\n• Calcium: serum and urinary concentrations\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nAuthor contacted for more information regarding selection bias; awaiting response\nGnoth 1999/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n82\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk By centralised randomisation process. No further details of method used to\ngenerate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blinded, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blinded, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Pretreatment measurements of one women weres not done.\n1 early pregnancy post-treatment. The reply from the authors stated that there\nwere no exclusions post-randomisation or losses to follow-up, but remarked\nthat one woman withdrew directly after the first medical investigation and\nrandomisation. She did not tell the reasons for her decision. There were no\nmeasurements taken\nfrom her. This participant was completely excluded from the evaluation and\nreplaced.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nGnoth 1999/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: randomised, controlled clinical study\nParticipants Participants: 22 women were randomised; 18 were analysed.\nMean age: LNG-IUS = 29.2 ± 5.5 years and Lupron = 32.6 ± 5.3 years\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis made 3 months before enrolment in the study\n• Chronic pelvic pain that was cyclic\n• VAS of 3 or more\n• Regular menstrual cycle (25-35 days) for 3 months or more before study entry\n• Had not used any hormonal therapy for at least 3 months before study entry\n• Had not taken long acting progestins or GnRHas within the preceding 9 months\n• Not pregnant or breastfeeding during the 3 months preceding study\n• No osteoporosis, coagulation disorders or contraindications to LNG-IUS\nExclusion criteria:\nGomes 2007/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n83\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Use of medication outside study\nSetting: Brazil\nTiming: February 2003 to May 2005\nInterventions LNG-IUS IU for 6 months (n = 11)\nversus\nLupron depot 3.75 mg IM every 4 weeks for 6 months (n = 11)\n/uni00A0\nOutcomes • Relief of overall pain (as defined by VAS)\n• Change in laparoscopic outcome as defined by ASRM\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: The levonorgestrel-releasing intrauterine system (Mirena) and GnRH agonist ampules were\nprovided free of charge by Schering, São Paulo, Brazil.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"Computer generated system\". No further details of method used to generate\nthe randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk \"Sealed envelopes\". No further details of method used to conceal allocation\nwere provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Detail given for attrition:\n• 4 withdrawals due to refusal of second laparoscopy (1/11 LNG-IUS group and\n3/11 GNRHa group)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nGomes 2007/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Multicentre, randomised, double-blind trial/uni00A0\nParticipants Participants: 271 women were randomised; 255 women were analysed.\nHarada 2009/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n84\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMean age: Dienogest: 33.5 ± 6.9 years, buserelin 33.8 ± 6.2 years\nInclusion criteria:\n• Age ≥ 20 years\n• Regular menstrual cycles\n• Diagnosis of endometriosis by laparotomy, laparoscopy or imaging analysis\n• Presence of subjective symptoms during menstruation\n• Presence of symptoms during non-menstruation\n• Presence of objective findings\nExclusion criteria:/uni00A0\n• Undiagnosed genital bleeding\n• Class 3 or more on Pap test within 3 months before enrolment\n• Use of GnRHas, testosterone derivatives, hormonal therapy with progesterone and/or oestrogen, oe-\nstrogen antagonists or aromatase inhibitors within 16 weeks of enrolment\n• Pregnant or nursing\n• A history of severe adverse drug reactions or hypersensitivity to steroid hormone or GnRH agonists\n• Past use of GnRH agonist with low bone mineral density\n• Having undergone surgery therapy or surgical examination for endometriosis within a menstrual cycle\nbefore the start of medication\n• Use of drugs that could be expected to affect the release of sex hormones\n• A history of complication of thrombosis/embolism or depression\n• Malignant tumour complication or findings suggestive of a malignant tumour\n• Complication of serious heart, kidney, blood or endocrine disease\n• Participation in another clinical trial within the 4 months before enrolment\n• Patients deemed unsuitable for entry by the investigator\nSetting: Japan\nTiming: June 2003 to February 2005\nInterventions Dienogest 1 mg orally morning and evening (n = 134)\nversus\nBuserelin intranasally 300 micrograms morning, noon and evening (n = 134)\nOutcomes • Relief of overall pain\n• Bone mineral density\n• Adverse effects\n• Quality of life\n• Bone turnover markers\n• Body weight\nNotes Intention-to-treat analysis: not stated\nSample size calculation: yes\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nHarada 2009/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n85\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRandom sequence genera-\ntion (selection bias)\nLow risk The participants were randomised by the centre according to the permuted\nblock method and computer-generated numbers.\nAllocation concealment\n(selection bias)\nLow risk The allocation sequence list was kept centrally to maintain the blindness of\nthe study until the key was disclosed.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk The BMD measurement procedures were performed under double-blind con-\nditions. Assessors were blinded and participants were blinded with double\ndummy.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk The BMD measurement procedures were performed under double-blind con-\nditions. Assessors were blinded and participants were blinded with double\ndummy.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk Intention-to-treat analysis was used for the primary outcome./uni00A0\nIn dienogest group, withdrawn = 16/137/uni00A0\n- 3 consent withdrawn\n- 6 adverse events\n- 1 prohibited concomitant therapy\n- 2 protocol criteria violation\n- 4 other/uni00A0\nIn buserelin acetate group, withdrawn = 20/134/uni00A0\n- 3 consent withdrawn\n- 7 adverse events\n- 2 prohibited concomitant therapy\n- 3 protocol criteria violation\n- 5 other/uni00A0\nBMD was available for only 41/137 patients who had received dienogest and\n46/134 who had received buserelin acetate.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nHarada 2009/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"parallel, randomised, double-placebo design\"\nParticipants Participants: 236 women were randomised; 213 analysed/uni00A0\nAge: not stated (60% were over 30 years old)\nInclusion criteria:/uni00A0\nHenzl 1988/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n86\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• 18-45 years old\n• Laparoscopically diagnosed endometriosis within 3 months prior to study enrolment\n• No hormonal treatment for endometriosis 6 months prior to study\nExclusion critieria: not stated\nSetting: USA, Canada, Sweden/uni00A0\nTiming: not stated\nInterventions Nafarelin IN 200 mcg twice daily + placebo PO for 6 months (n = 77)/uni00A0\nversus/uni00A0\nNafarelin IN 400 mcg twice daily + placebo PO for 6 months (n = 79)/uni00A0\nversus/uni00A0\nDanazol PO 400 mg twice daily+ placebo IN for 6 months (n = 80)\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration\n• Adverse effects\n• Improvement of most troublesome symptom\n• AFS score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Authors contacted regarding randomisation and allocation concealment\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomised\". No further details of method used to generate the randomisa-\ntion sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blinded, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blinded, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Detail given for attrition: 23 were excluded from the analyses:\n9 for reasons not related to the study drugs/uni00A0\n7 in 800 mcg nafarelin and 4 in danazol due to hot flushes/uni00A0\n2 in danazol due to rapid rise in serum enzymes/uni00A0\n1 in danazol because of a lack of efficacy\nHenzl 1988/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n87\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysed:/uni00A0\n70/77: Nafarelin IN 200 mcg BD + placebo PO for 6 months\n73/79: Nafarelin IN 400 mcg BD + placebo PO for 6 months /uni00A0\n70/80: Danazol PO 400 mg BD + placebo IN for 6 months/uni00A0\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nHenzl 1988/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"double-blind, prospective, multi-centre, randomised clinical trial\"\nParticipants Participants: 179 women were randomised and analysed.\nMean age: Group 1 = 31.0 +/- 6.1 years and group 2 = 31.3 +/- 5.7 years\nInclusion criteria:\n• 18-46 years old\n• Laparoscopically diagnosed endometriosis within 24 months prior to study enrolment\n• 24-36 day menstrual cycle\n• Symptomatic endometriosis\nExclusion criteria:\n• Hormone treatment 3 months prior to study\n• Significant illness or lab test abnormality\n• Prior treatment with nafarelin\n• Pregnant or lactating women\nSetting: United States of America\nTiming: not stated\nInterventions Group 1: Nafarelin 200 mcg IN for 3 months + placebo IN for 3 months after (n = 91)\nversus\nGroup 2: Nafarelin 200 mcg IN for 6 months (n = 88)\n/uni00A0\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration\n• Median serum E2 levels\nNotes Intention-to-treat analysis: yes\nSample size calculation: not stated\nFunding: Supported in part by a grant from Syntex Laboratories, Inc., Palo Alto, California\nNote previous version: Authors contacted and replied\n/uni00A0\nHornstein 1995/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n88\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk No details of method used to generate the randomisation sequence were pro-\nvided./uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk \"randomisation was done by a pharmacy\"/uni00A0.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Placebo nasal spray to blind participants; participants, investigators, outcome\nassessors and clinicians were blinded.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Placebo nasal spray to blind participants; participants, investigators, outcome\nassessors and clinicians were blinded.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk All participants who were randomised were followed for a minimum of 12\nmonths after treatment. Of the 179 subjects enrolled, 39 in group I and 43 in\ngroup II patients completed the 18-month study without requiring further\ntreatment other than periodic analgesics.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nHornstein 1995/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods /uni00A0 Trial design: Multi-centre randomised, double-blind, placebo-controlled trial\nParticipants Participants: 201 women were randomised and analysed.\nMean age: Group A: 28.4 ± 6.1, group B: 28.7 ± 6.2, group C: 29.0 ± 5.6, group D: 27.9 ± 5.7\nInclusion criteria:\n• Women\n• Aged 18-43\n• Regular menstrual cycles\n• History of symptomatic endometriosis diagnosed surgically within 12 months of study entry\n• Persistent or recurrent pain\nExclusion criteria: not stated\nSetting: United States of America\nTiming: not stated\nInterventions All patients received GnRH agonist (Lupron depot 3.75 mg every 4 weeks for 52 weeks) and calcium\nsupplementation as elemental calcium 1000 mg daily./uni00A0\nGroup A: received daily oral placebos for progestin and oestrogen (n = 51)\nHornstein 1998/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n89\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nGroup B: received daily oral norethindrone acetate 5 mg with placebo for oestrogen (n = 55)\nGroup C: received norethindrone 5 mg and conjugated equine oestrogens 0.625 mg (n = 47)\nGroup D: received norethindrone 5 mg and conjugated equine oestrogens 1.25 mg (n = 48)\nOutcomes • Relief of overall pain\n• Bone mineral density\n• Serum lipid analyses\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: yes\nFunding: Grant received from TAP Pharmaceuticals Inc.\nMs Castro is a paid employee of TAP Pharmaceuticals Inc; Dr Weissberg was a paid employee of TAP\nPharmaceuticals Inc. at the time the study was undertaken. Drs Hornstein and Surrey have received\nhonoraria for participating in a limited number of lectureships and symposias sponsored by TAP Phar-\nmaceuticals Inc.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Patients were assigned randomly to a treatment group by permuted blocks of\nfour at each of 26 study sites.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nHornstein 1998/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nHowell 1995/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n90\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nParticipants Participants: 50 women were randomised; 48 completed 24 weeks of treatment and underwent second\nlaparoxcopic assessment.\nMean age: Group 1: 29 ± 6 years, group 2: 30 ± 5 years\nInclusion criteria:\n• Pelvic pain and a minimum Pelvic Pain Score (defined below) of 3\n• Regular menstrual cycle (21 to 42 day cycles)\n• Negative cervical smear within the preceding 12 months\n• Use barrier contraception for the duration of the treatment period\n• A minimum revised American Fertility Score (revised AFS) for endometriosis lesions (excluding adhe-\nsions) of four was required.\nExclusion criteria:/uni00A0\n• Drugs known to affect bone metabolism in the 6 months preceding the trial\n• Medical conditions known to affect bone mineral density or bone mineral metabolism\nSetting: United Kingdom\nTiming: not stated\nInterventions Group 1: 3.6 mg SC depot injection of goserelin every 4 weeks\nversus\nGroup 2: 3.6 mg SC injection every four weeks and transdermal oestrogen 25 ug daily and 5 mg medrox-\nyprogesterone acetate daily for 20 weeks commencing with the second goserelin depot\nOutcomes • Relief of overall pain: relief of symptoms and clinical signs\n• Bone mineral density\n• Adverse effects\n• Endometriosis response\n• Endocrinologic effects\n• Serum lipids and lipoproteins\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Study sponsored by Zeneca Pharmaceuticals\nNote previous version: 20 participants did not complete all the bone mineral density assessments - 2\ndid not complete treatment and the other 18 did not complete follow-up./uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Were randomised\". /uni00A0No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nUnclear risk Open-label trial. No further details provided of blinding of participants or per-\nsonnel\nHowell 1995/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n91\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAll outcomes\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk 20/48 participants did not complete all the bone mineral density assessments.\n2/48 did not complete treatment and the other 18/48 did not complete fol-\nlow-up.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nHowell 1995/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: placebo-controlled, prospective, randomised, double-blinded study\nParticipants Participants: 13 women were randomised and analysed.\nMean age: Oestrogen: 28.3 ± 5.0 years, placebo 32.4 ± 5.2 years\nInclusion criteria:\n• Persistent or recurrent chronic pelvic pain after laparoscopic diagnosis and treatment of endometrio-\nsis\nExclusion criteria:/uni00A0\n• History of prior GnRH agonist therapy\n• History of an emotional disorder, pregnancy or lactation\n• Osteoporosis, known or suspected breast cancer, present or past endometrial hyperplasia or carci-\nnoma, a history of thrombosis, thrombophlebitis, or thromboembolism and undiagnosed abnormal\ngenital bleeding\n• Usage of oral contraceptives or other treatment outside the protocol\nSetting: United States of America\nTiming: not stated\nInterventions All were treated with leuprolide acetate (TAP Pharmaceuticals, Deerfield, IL) 3.75 mg intramuscularly\nfor six months. After three months of therapy,/uni00A0\nOral oestradiol 1 mg daily (n = 6)\nversus\nIdentical placebo (n = 7)\nOutcomes • Endometriosis-related symptom variables of pelvic pain, dysmenorrhea, dyspareunia, induration and\npelvic tenderness\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nHurst 2000/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n92\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFunding: not stated\nAuthor contacted regarding information on selection bias; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Subjects were randomly assigned into treatment or placebo groups by the\nhospital’s investigational drug service\". No further details of method used to\ngenerate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nHurst 2000/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 21 women were randomised and analysed.\nMean age: /uni00A0 Group 1: 36.0 ±10.0 years, group 2: 35.5 ± 8.6 years\nInclusion criteria:\n• Negative smear and negative mammogram in 6 months prior to the start of the study\n• No previous hormonal treatment received for endometriosis\nExclusion criteria:/uni00A0not stated\nSetting: Japan\nTiming: not stated\nInterventions Group 1: monthly injection of 3.75 mg leuprolide acetate depot (n = 10)\nversus/uni00A0\nIrahara 2001/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n93\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nGroup 2: monthly injection of 3.75 mg leuprolide acetate + 0.625 mg conjugated equine oestrogen + 2.5\nmg medroxyprogesterone acetate every other day from 2nd month of GnRHa treatment (n = 11)\nOutcomes • Bone mineral density\n• Laboratory results\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nAuthor contacted for further information; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk /uni00A0Randomised controlled trial. No further details of method used to generate\nthe randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nIrahara 2001/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"Open, prospective, randomised, parallel study\", multi-centre\nParticipants Participants: 80 women were randomised; 68 were analysed.\nMedian age: Buserelin = 28 and danazol = 30/uni00A0\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis 18-40 years old\n• Symptomatic disease\n• Active menstrual cycle\nJelley 1986/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n94\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nExclusion criteria:/uni00A0\n• Previous use of danazol or hormone treatment without success\n• Use of danazol within 6 months prior to study\n• Serious endocrine disease or use of other drugs which may interfere with therapy\nSetting: UK/uni00A0\nTiming: not stated\nInterventions Buserelin 300 mcg three times a day intranasally for 7 months (n = 34)/uni00A0\nversus/uni00A0\nDanazol 600 mg once daily per OS for 7 months (n = 34)\nOutcomes • Relief of overall pain: Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration\n• Adverse effects\n• rAFS score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Preliminary findings for the first 68 women treated only. Attempted to contact\nauthor regarding data. Author not contactable\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"The code was derived from random number tables\". No further details were\nprovided of method used to generate the randomisation sequence.\nAllocation concealment\n(selection bias)\nLow risk \"A sealed envelope was provided for each patient, and opened only after the\npatient's name had been entered on it\".\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk Open study, no blinding\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk Open study, no blinding\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Detail for attrition:/uni00A0\n• 1 randomised patient failed to start treatment as her symptoms improved\n• So far 4 have withdrawn from study due to adverse effects: 3 (Dan) and 1 (Bus)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nJelley 1986/uni00A0/uni00A0(Continued)\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n95\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 82 women were randomised and analysed.\nMean age: Nafarelin group was 31.5 ± 5.20 years (range = 21 to 41 years), danazol group 30.2 ± 4.89 years\n(range = 21 to 42 years).\nInclusion criteria:\n• Pelvic pain, dyspareunia, dysmenorrhoea or infertility\n• 24-36-day menstrual cycle over the preceding 4 months\n• No hormonal treatment in the preceding 6 months, barrier comtraception throughout study\nExclusion criteria:/uni00A0not stated\nSetting: United Kingdom\nTiming: not stated\nInterventions Nafarelin 200 /uni03BCg twice daily IN with placebo tablets (n = 55)\nversus\nDanazol 200 mg three times daily orally /uni00A0with placebo nasal spray (n = 27)\nOutcomes • Relief of overall pain: pelvic pain, dyspareunia, dysmenorrhoea\n• Adverse effects\n• Improvement of most troublesome symptom\n• Serum oestradiol levels\n• AFS score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Supported by Syntex (U.K.) Ltd., Maidenhead, United Kingdom\nAuthor could not be contacted due to lack of information.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Randomly allocated, stratification on a 2:1 ratio, according to disease severi-\nty. No further details of method used to generate the randomisation sequence\nwere provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nLow risk Placebo-controlled study\nKennedy 1990/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n96\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAll outcomes\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Eight patients did not complete treatment and their scores were omitted; their\nstages at first laparoscopy were I = 2, II = 4, III = 1, and IV = 1. Four patients with-\ndrew from the nafarelin group because of depression, muscle aches, mastal-\ngia and bloating (1); giddiness, nausea, and vague paraesthesia on the right\nside of the face and le/f_t hand (1); travel abroad (1); and a maculopapular rash\n(1). Two patients withdrew from the danazol group because of a viral illness\n(1) and a maculopapular rash (1). One patient from each group was withdrawn\nfrom the study because of poor compliance.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nKennedy 1990/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Prospective, randomised, double-blind, placebo-controlled, comparative study\nParticipants Participants: 88 women were randomised; 76 women were analysed.\nMean age: Goserelin acetate plus HRT treatment mean 32 years (20-48 years), goserelin acetate plus\nplacebo treatment mean 34 years (21-47 years)\nInclusion criteria:\n• Symptomatic patients with total pelvic symptoms score of > 3 with or without infertility\n• Laparoscopical confirmation of endometriosis within 3 months before initiation of treatment\nExclusion criteria: not stated\nSetting: Finland\nTiming: not stated\nInterventions 3.6 mg SC goserelin acetate plus HRT treatment with combination of 2 mg 17β-E2 and 1 mg norethis-\nterone acetate (NET; Kliogest; Novo Nordisk AS, Bagsvaerd, Denmark) /uni00A0(n = 43)/uni00A0\nversus\n3.6 mg SC goserelin acetate plus placebo /uni00A0(n = 45)\nOutcomes • Relief of overall pain: pelvic symptoms\n• Adverse effects\n• Total revised AFS and total Additive Diameter of Implants scores\n• Serum hormone levels\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Supported by Zeneca Pharma, Helsinki, Finland.\nAuthor could not be contacted due to lack of information.\nKiilholma 1995/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n97\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Prospective, randomized, double-blind, placebo-controlled, comparative\nstudy\". No further details of method used to generate the randomisation se-\nquence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 76/88 completed study. 35/43 goserelin acetate with hormone replacement\ntherapy and 41/45 goserelin acetate plus placebo group.\nTwo patients discontinued the treatment because of side effects that were\nconsidered to be related to the treatment. One of them (goserelin acetate plus\nplacebo) experienced severe depression and the other one had continuous\nbleeding (goserelin acetate plus HRT). Three women had pregnancy confirmed\nduring the post-treatment follow-up period. Two patients underwent surgery\nfor endometriosis, one woman started hormonal contraception, two women\nwere treated with hormonal or IVF therapy for infertility, one patient needed\nhormonal therapy for a disease other than endometriosis, and one patient did\nnot return./uni00A0\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nKiilholma 1995/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised study\n/uni00A0\nParticipants Participants: 13 women were randomised and analysed.\nAge: 24 to 37 years\nInclusion criteria:\n• Laparoscopially diagnosed endometriosis within 6 weeks of study\n• Not received medical treatment in the previous 6 months\nExclusion criteria:\n• Surgery alone or hormonal treatment and surgery were indicated.\nLemay 1988/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n98\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Concurrent serious endocrine or systemic disease\n• History of alcohol or substance abuse\n• Use of an oral contraceptive within the past 2 months\n• Drug-releasing intrauterine device within the past 3 months\nSetting: Canada\nTiming: Not stated\nInterventions Buserelin 400 /uni03BCg three times a day IN (n = 7)\nversus\nBuserelin 200 /uni03BCg once a day SC injection (n = 6)\nOutcomes • Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration\n• AFS score\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Author contacted regarding methods and replied.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Computerised allocation. No further details of method used to generate the\nrandomisation sequence were provided.\nAllocation concealment\n(selection bias)\nLow risk Sealed, opaque, sequentially numbered, identical envelopes\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Outcome assessors were blinded./uni00A0\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nLemay 1988/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nLing 1999/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n99\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMethods Trial design: double-blind, randomised, parallel-group, placebo-controlled trial\nParticipants Participants: 100 women were randomised; 95 women were analysed.\nMean age: /uni00A0Depot leuprolide group: 32.3 years, placebo group 29.4 years\nInclusion criteria:\n• Moderate-to-severe chronic pelvic pain for at least 6 months, with severity being assessed by a physi-\ncian using the four-point Biberoglu and Behrman scale, and that pain was unrelated to menstruation\nand incompletely relieved with nonsteroidal anti-inflammatory drugs.\n• Regular menstrual bleeding and menstrual cycles for 3 months before enrolment\n• Women who had not been sterilised surgically agreed to use barrier contraception during treatment\nand for 6 weeks thereafter.\nExclusion criteria:/uni00A0\n• A previous diagnosis of endometriosis confirmed by laparoscopy, laparotomy, or histology\n• Had received oral contraceptives (OCs) within the previous 3 months or GnRH agonists within the\nprevious 6 months\n• Had undergone surgical treatment for endometriosis\n• Chronic pelvic pain might be related to genitourinary disease or to chronic or recurrent gastrointesti-\nnal disease, including irritable bowel syndrome (defined as a disease characterised by pain relieved\nby defecation and irregular defecation patterns lasting at least 3 months)\n• Histories of alcohol use or other chronic tranquiliser or illicit drug use\nSetting: United States of America (12 sites)\nTiming: June 1995 to January 1997\nInterventions Depot leuprolide injection every 4 weeks, for 3 injections (n = 50)\nversus\nPlacebo injections every 4 weeks, for 3 injections (n = 50)\nOutcomes • Relief of overall pain: pain scores, dysmenorrhoea, pelvic pain, pelvic tenderness, deep dyspareunia,\nand pelvic induration\n• AFS score\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: This study was supported by a grant from TAP Holdings, Inc., which distributes depot leupro-\nlide.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk The randomisation schedules were prepared in random blocks of two and\nfour, with treatment group assignment in a 1:1 ratio. Each group was repre-\nsented once within each block of two and twice within each block of four. The\nschedules were prepared by an administrative staﬀ member using a FORTRAN\nprogram to generate uniform random numbers.\nAllocation concealment\n(selection bias)\nLow risk Study medication was packaged according to the randomisation schedules\nand was sent to each site in sets of four, as needed. Patient numbers were se-\nLing 1999/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n100\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nquential within each set. Patient number assignment started with the lowest\navailable number for each site and proceeded in ascending order. The ran-\ndomisation schedules were kept in one appropriate, secure place. The blind\nwas not broken until enrolment and classification for evaluable patient analy-\nses were complete.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk In placebo group, 46/50 completed study.\n• Noncompliance = 1\n• Patient request = 1\n• Lost to follow-up =1\n• Other =1\nIn leuprolide depot group, 49/50 completed study.\n• Noncompliance = 1\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nLing 1999/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"prospective, randomised, double-blind, parallel, placebo-controlled study\"/uni00A0\nParticipants Participants: 120 women were randomised; 120 were analysed.\nAge: 18-40\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis within 24 months prior to study\n• Elected to have leuprolide acetate as a treatment option\n• Sexually active\n• Not pregnant or breastfeeding\n• Intact uterus and at least one ovary in good health\n• Not received treatment for endometriosis within previous 3 months\n• Not received medroxyprogesterone acetate within previous 6 months\n• No history of use of a GnRHa\nExclusion criteria:\n• Co-existing conditions that might interfere with the conduct or analysis of study\n• Concomitant disease that might cause pain\n• Contraindication to leuprolide\nMiller 2000/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n101\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Unable to complete questionnaires\n• Suspected history of alcohol or drug abuse\nSetting: United States of America\nTiming: not stated\nInterventions Leuprolide acetate 3.75 mg single IM for 4 weeks (n = 60)\nversus\nPlacebo for 4 weeks (n = 60)\nOutcomes • Pain as defined by VAS and ESS\n• Quality of Life SF36\nNotes Intention-to-treat analysis: All participants recruited were analysed.\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Authors contacted regarding methods and raw data; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"assigned to groups in the order in which they were enrolled according to a\ncomputer generated schedule prepared before the start of the study\"\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Stated double-blind. A placebo injection was used to blind participants, but no\nother details of blinding of trial personnel or outcome assessors were provid-\ned./uni00A0\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Stated double-blind. A placebo injection was used to blind participants, but no\nother details of blinding of trial personnel or outcome assessors were provid-\ned./uni00A0\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it wa clear that the published reports\nincluded all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nMiller 2000/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised, multi-centre study\nParticipants Participants: 191 women were randomised and analysed.\nMinaguchi 1986/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n102\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMean age: not stated\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis\n• Over 18 years old patients who have received hormonal therapy\n• Patients with persistent diagnosed endometriosis postoperatively\nExclusion criteria:/uni00A0\n• Patients receiving conservative surgery\nSetting: Japan/uni00A0\nTiming: not stated\nInterventions Buserelin 300 mcg once daily intranasally for 6 months (n = 69)/uni00A0\nversus/uni00A0\nBuserelin 300 mcg twice daily intranasally for 6 months (n = 59)/uni00A0\nversus\nBuserelin 300 mcg three times a day intranasally for 6 months (n = 63)\nOutcomes • Relief of overall pain: Intermenstrual abdominal pain, lumbago, dyspareunia, pain on defecation,\npelvic tenderness\n• Adverse effects\n• Flexibility of the uterus\n• Nodules in the posterior cul-de-sac\n• Endometrial cyst\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: /uni00A0not stated\nNote previous version: Authors contacted regarding methods and data; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk No details were provided of method used to generate the randomisation se-\nquence.\nAllocation concealment\n(selection bias)\nUnclear risk \"Envelope\". No further details were provided of method used to conceal treat-\nment group allocation.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No information about blinding; open-label study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No information about blinding; open-label study\nMinaguchi 1986/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n103\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk All women who were randomised were analysed.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nMinaguchi 1986/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Prospective, placebo-controlled study, open-label for goserelin therapy and double-blind\nfor HRT\nParticipants Participants: 345 women were randomised; 306 women were analysed.\nMean age:/uni00A0\nGroup 1: 29.6 ± 6.6 years,\nGroup 2 30.7 ± 6.0 years\nGroup 3: 29.4 ± /uni00A05.7 years\nInclusion criteria:\n• Premenopausal women\n• 18-45 years of age\n• Confirmed diagnosis of endometriosis\n• Pelvic symptoms\n• If a laparoscopy included therapeutic intervention, patients had to have an initial clinical response,\nrecurrence of pelvic symptoms, and stability in severity of pelvic symptoms for at least three months\nbefore pretreatment assessments.\nExclusion criteria:/uni00A0\n• Positive urine pregnancy test, pregnancy or lactation\n• Use of non-trial hormonal agents such as oestrogen, progesterone, or clomiphene within 60 days be-\nfore pretreatment assessments until the end of the study, use of any drug at doses suppressing the\nhypothalamic-pituitary-adrenal axis, serious concomitant condition\n• Long-term exposure (over three months) to GnRH agonists within 12 months before pretreatment as-\nsessments\n• Baseline bone mineral density measurements over 2 SDs below that of age-matched controls, hyper-\nsensitivity to previous hormone therapy or oestrogen or progestin replacement therapies\n• Any condition that would preclude a patient from receiving study therapy\nSetting: United States of America (42 participating centres)\nTiming: not stated\nInterventions Group 1: goserelin 3.6 mg every 28 days + oral placebo (n = 119)\nGroup 2: goserelin 3.6 mg every 28 days + conjugated oestrogen 0.3 mg daily + medroxyprogesterone\nacetate 5 mg daily (n = 113)\nMoghissi 1998/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n104\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nGroup 3: goserelin 3.6 mg every 28 days + conjugated oestrogen 0.625 mg daily + medroxyprogesterone\n5 mg daily (n = 113)\nOutcomes • Relief of overall pain\n• Bone Mineral Density\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: yes\nFunding: Sponsored by Zeneca Pharmaceuticals, Wilmington, Delaware\nAuthors could not be contacted due to lack of information.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk No details of method used to generate the randomisation sequence were pro-\nvided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk /uni00A0A total of 306/345 patients completed therapy and 39 patients (10 HRT0, 14\nHRT1, and 15 HRT2) were withdrawn.\nGroup 1 10/119\nGroup 2 14/113\nGroup 3 15/113\nThe reasons for withdrawal during therapy included dropout (n = 24), investi-\ngator decision (n = 4), side effects (n = 3), pregnancy (n = 1), and other reasons\n(n = 7). Three patients, one in each group, completed therapy but did not want\nto be observed during the follow-up period.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nMoghissi 1998/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMäkäräinen 1996/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n105\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMethods Trial design: Randomised, double blind, placebo-controlled trial\nParticipants Participants: 38 women were randomised; 29 women were analysed after second-look laparoscopy.\nMean age: 30.6 years (range 22 to 38 years)\nInclusion criteria:\n• Symptomatic pelvic endometriosis\n• Revised American Fertility Society [AFS] score ≥ 2\nExclusion criteria: not stated\nSetting: Finland\nTiming: not stated\nInterventions Once-a-month SC injections of goserelin acetate 3.6 mg (Zoladex depot; Zeneca Pharmaceutics,\nCheshire, United Kingdom) randomly combined with either/uni00A0\nMedroxyprogesterone acetate 100 mg daily (n = 19)/uni00A0\nversus\nPlacebo, one tablet daily (n = 19)/uni00A0\nOutcomes • Relief of overall pain: dysmenorrhea, dyspareunia, pelvic pain\n• Adverse effects\n• Endometriotic implants\n• Biochemical changes\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Zeneca Pharma, Helsinki, Finland, for supplying the active drugs and placebo\nAuthor could not be contacted due to lack of information.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly assigned\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Four patients interrupted the treatment because of side effects (three in\nthe medroxyprogesterone acetate group and one in the placebo group). In-\ncreasing pelvic symptoms in one patient receiving medroxyprogesterone ac-\nMäkäräinen 1996/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n106\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\netate required laparoscopy already 4 months after the end of treatment. Four\nwomen (two in the medroxyprogesterone acetate group and two in the place-\nbo group) became pregnant within 6 months after the treatment. Thus, 29\nwomen (13/19 in the medroxyprogesterone acetate and 16/19 in the placebo\ngroup) were included in the second-look laparoscopy, which was performed 6\nmonths after the end of medical treatment.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nMäkäräinen 1996/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Multi-centre, parallel, randomised, double-blind, double-dummy study\nParticipants Participants: 315 women were randomised, 307 were analysed for safety and 263 were analysed for effi-\ncacy.\nMean age: not stated/uni00A0\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis 18-45 years old\n• Not pregnant\n• Pap smear negative for malignancy\n• Normal menstrual cycle 21-36 days for previous 4 months\n• Weight between 45-110 kg\nExclusion criteria:/uni00A0\n• Amenorrhoea\n• Concurrent disease which may interfere with endometriosis or contraindicate the use of androgenic\ntherapy\n• Surgical treatment at baseline or within 6 months prior to study\n• Use of danazol, androgenic hormones, oestrogens, or progestogens within 3 months prior to study\nSetting: Multiple sites within Europe/uni00A0\nTiming: not stated\nInterventions Nafarelin 200 mcg twice daily intranasal + placebo per os for 6 months (n = 206)/uni00A0\nversus/uni00A0\nDanazol 200 mg three times a day per os + placebo intranasal for 6 months (n = 101)/uni00A0\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration\n• Adverse effects\n• AFS score\nNotes Intention-to-treat analysis: no\nSample size calculation: /uni00A0not stated\nFunding: Supported in part by Syntex Research, Palo Alto, California, US\nNEET 1992/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n107\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nNote previous version: 8 participants who were randomised never took the study medication.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"patients were randomised so that 2 were assigned to receive nafarelin for\nevery 1 assigned to receive danazol\". No further information was provided on\nmethod used to generate random sequence.\nAllocation concealment\n(selection bias)\nUnclear risk No details were provided of method used to conceal treatment group alloca-\ntion.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Detail for attrition:/uni00A0\n• \"307 were included in the safety analyses, of whom 263 also qualified for the\nefficacy analyses (171 nafarelin and 92 danazol recipients)\"\n• 25 had been treated < 150 days\n• 7 were treated > 150 days but refused or otherwise missed the post-treatment\nlaparoscopy\n• 12 violated the study protocol\n• 14 discontinued due to adverse events\n• 4 for intercurrent illness\n• 4 for personal reasons\n• 1 due to ineffective treatment\n• 2 lost to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nNEET 1992/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised study\nParticipants Participants: 21 women were randomised and analysed.\nMean age: 33 ± 5 years\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis\n• Pelvic pain\nOdukoya 1995/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n108\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nExclusion criteria: not stated\nSetting: United Kingdom\nTiming: not stated\nInterventions Leuprolide acetate 3.75 SC monthly for 3 months (n = 10)\nversus\nDanazol 400 mg daily PO for 3 months (n = 11)\n/uni00A0\nOutcomes • Relief of overall pain (Biberoglu + Behrman scale)\n• Serum soluble CD23/uni00A0\nNotes Intention-to-treat analysis: Yes\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Authors contacted regarding methods (blinding) and SD data; awaiting re-\nsponse\n/uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Randomisation was \"computer generated\". No further details of method used\nto generate the randomisation sequence were provided./uni00A0\nAllocation concealment\n(selection bias)\nLow risk \"concealed in an envelope only opened at commencement of treatment\". No\nfurther details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or trial personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nOdukoya 1995/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: randomised, double-blinded, placebo-controlled trial\nOrwoll 1994/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n109\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nParticipants Participants: 183 women were randomised and 137 analysed.\nMean age: /uni00A031 years (range 17 to 46 years)\nInclusion criteria:\n• Symptomatic endometriosis, proved by laparoscopy\n• Bone density measures during treatment\n• Regular menstrual cycles for at least 3 months before enrolment\n• Using a barrier method of contraception\nExclusion criteria:/uni00A0\n• Therapy with danazol, androgenix hormones, oestrogens, progestins, glucocorticoids, GnRH ago-\nnists, or any other medication known to influence bone or mineral metabolism for at least 3 months\nbefore study\n• > 2 ounces of alcohol per day\n• Pregnant or breastfeeding\n• Had a significant laboratory abnormality\nSetting: United States of America (9 academic medical centres)\nTiming: not stated\nInterventions 200 /uni03BCg of nafarelin intranasally twice per day for 6 months (n = 92)/uni00A0\nversus\n200 /uni03BCg of nafarelin intranasally twice per day for 3 months followed by 3 months of placebo (n = 91)\nOutcomes • Bone mineral density\nNotes Intention-to-treat analysis: yes\nSample size calculation: not stated\nFunding: Supported by Syntex Laboratories, Inc\nNote: Drs. Orwoll and Hornstein have been salaried consultants for Syntex Laboratories, Inc.\nAuthor could not be contacted due to lack of information.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Subjects were randomised\". No further details of method used to generate\nthe randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Randomised, double-blinded, placebo-controlled trial\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Randomised, double-blinded, placebo-controlled trial\nOrwoll 1994/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n110\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nUnclear risk Not stated; appeared that all women included also were analysed\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nOrwoll 1994/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: prospective randomised study\nParticipants Participants: 74 women were randomised; 70 women were analysed.\nMean age:/uni00A0\nGroup G: 34.2 ± 5.4 years (32.4–36.1)\nGroup D: 35.4 ± 5.7 years (32.4–36.9)\nInclusion criteria:\n• At least one endometrioma larger than 4 cm\nExclusion criteria:/uni00A0\n• Age older than 45 years\n• Presence of any leiomyoma\n• Diagnosis of endocrine disorders, history of abdominal surgery\n• Presence or history of any concomitant pelvic inflammatory diseases\n• Presence of endocrine disorders\n• History of abdominal surgery, presence of malignant ovarian disease\n• History of hormonal treatment within 3 months before recruitment\nSetting: Japan\nTiming: January 2011 to August 2014\nInterventions Group D received dienogest (Dinagest®, 1 mg; Mochida Pharmaceutical Co., Ltd., Tokyo, Japan) at 2 mg/\nday for 4 months preoperatively.\nGroup G received a low-dose sustained-release goserelin acetate (ZOLADEX®, 1.8 mg; Kissei Pharma-\nceutical Co., Ltd., Nagano, Japan) at 1.8 mg every 4 weeks for a total of administrations preoperatively.\nOutcomes • Adverse effects\n• Improvement of most troublesome symptom\n• Number of uses of nonsteroid anti-inflammatory drugs\n• Diameter of ovarian cysts\n• Postoperative lesion recurrence\n• Laboratory results\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nOzaki 2020/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n111\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nFunding: The authors declared that they had no confict of interest.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Stratifed randomisation was conducted in the participants. \"1:1 ratio comput-\nerized random number function in Microsoft Excel\"\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 74 randomised, 70 analysed\nGroup G: 35/37 were analysed; group D: 35/37 were analysed.\nExcluded in group G due to mucinous cyst (n = 1) and borderline malignancy (n\n= 1)\nExcluded in group D due to mucinous cyst (n = 1) and dincontinued interven-\ntion (n = 1)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nOzaki 2020/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised, open study\nParticipants Participants: 50 women were randomised; 47 were analysed.\nAge: 20-40 years\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis\n• No treatment for endometriosis within previous 12 months\nExclusion criteria: not stated\nSetting: Italy/uni00A0\nTiming: not stated\nInterventions Leuprolide acetate 3.75 mg IM monthly for 6 months (n = 30)/uni00A0\nPalagiano 1994/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n112\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nversus/uni00A0\nDanazol 600 mg once daily per os for 6 months (n = 20)\nOutcomes • Relief of overall pain: Dysmenorrhoea, dyspareunia, pelvic pain\n• Adverse effects\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated/uni00A0\nNote previous version: Authors contacted regarding methods and replied\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"randomly allocated\". No further details were provided of method used to\ngenerate the randomisation sequence.\nAllocation concealment\n(selection bias)\nUnclear risk Randomisation done by a pharmacy. No further details were provided of\nmethod used to conceal treatment group allocation.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk Open study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk Open study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Three participants were lost to follow-up due to adverse effects (leuprolide ac-\netate).\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nPalagiano 1994/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: multi-centre randomised, controlled clinical trial\nParticipants Participants: 83 women were randomised; 71 were analysed.\nMean age: LNG-IUS = 29.4 ± 4.8 years and Lupron depot = 30.5 ± 6.4 /uni00A0years\nInclusion criteria:\n• Laparoscopically and histologically confirmed endometriosis within 3 to 24 months prior to study en-\nrolment\n• 18-40 years old\nPetta 2005/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n113\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Complaints of cyclic chronic pelvic pain with or without dysmenorrhoea\n• VAS pain score of greater or equal to 3 during the pretreatment cycle\n• Regular menstrual cycle of 25-35 days for at least 3 months prior to study\nExclusion criteria:\n• Hormone treatment within 3 months of entering study\n• Long acting progestins or GnRHa within 9 months prior to study\n• Pregnant or breastfeeding within 3 months prior to study\n• Osteoporosis, coagulation disorders or contraindications to LNG-IUS\nSetting: Brazil ( 3 centres)\nTiming: February 2002 to May 2004\nInterventions LNG-IUS (Mirena) 20 mcg/day 5 years IU for 6 months (n = 39)\nversus\nLupron 3.75 mg every 28 days IM for 6 months (n = 43)\n/uni00A0\nOutcomes • Pain as defined by VAS score\n• Psychological general well-being index\nNotes Intention-to-treat analysis: Data analysis did not follow intention-to-treat principles but included only\nthose women who had completed the VAS pain diary correctly throughout the entire study period of 6\nmonths (n = 71).\nSample size calculation: yes\nFunding:The levonorgestrel-releasing intrauterine system (Mirena) and GnRH analogue ampoules were\nprovided free of charge by Schering, Sao Paulo, Brazil.\nNote previous version: Authors contacted regarding data; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk Randomisation was by \"computer generated system\". Three centres partici-\npated in the study and randomisation was performed separately for each cen-\ntre.\nAllocation concealment\n(selection bias)\nUnclear risk \"sealed envelopes\" were used to conceal allocation to treatment groups./uni00A0\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk \"Blinding of participants would not have been possible due to nature of the in-\ntervention\". No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Outcome assessors were blinded according to author.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk \"data analysis did not follow intention-to-treat principles\" but details given for\nattrition:\n• 6 each from both groups withdrew\n• 1 pregnant and 5 did not complete pain diary (LNG-IUS)\nPetta 2005/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n114\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• 6 did not complete pain diary (Lupron)\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nPetta 2005/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"multi-centre, open, parallel study\"\nParticipants Participants: 315 women were randomised and analysed. Only 58 did BMD measurements.\nMean age: Goserelin = 30.4 years and danazol = 29.7 years\nInclusion criteria:\n• Laparoscopically confirmed endometriosis\n• AFS score of ≥ 2\n• Symptomatic (total pelvic score of equal or greater than 3) or asymptomatic disease, with or without\ninfertility\nExclusion criteria:\n• Stage IV disease\nSetting: United States of America (17 centres)\nTiming: not stated\nInterventions Goserelin 3.6 mg every 28 days SC for 24 weeks (n = 208)\nversus\nDanazol 400 mg twice a day PO for 24 weeks (n = 107)\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration\n• Adverse effects\n• Bone Mineral Density\n• rAFS score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Study sponsored by a grant from ICI Pharmaceuticals Group, a business unit of Zeneca Inc,\nWilmington, Delaware\nNote previous version: Authors contacted regarding methods and data; awaiting response/uni00A0\n\"14 participants, with stage IV endometriosis were included because their investigators believed that\nsignificant components of stage IV endometriosis could benefit from hormonal treatment\"./uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRock 1993/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n115\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Randomised 2:1 goserelin: danazol. No further details of method used to gen-\nerate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk \"All randomised subjects were included in the overall analysis of treatment\noutcome\".\nDetails given for attrition:\n• 15/208 in goserelin and 18/107 in danazol group withdrew\n• 6 in goserelin and 13 in danazol group withdrew due to adverse events\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nRock 1993/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: parallel, randomised, double-blind, double-placebo study\nParticipants Participants: 194 women were randomised; 170 were analysed.\nMean age: between 18 and 45 years\nInclusion criteria:\n• Laparoscopically confirmed endometriosis\n• 18-45 years old\n• Body weight of 45-110kg\n• Menstrual cycle of 24-36 days\n• Symptomatic\n• Not pregnant\n• Negative pap smear test\nExclusion criteria:\n• Prescence of amenorrhoea\n• Interfering concurrent disease\n• Surgical treatment at baseline laparoscopy or within 6 months prior to study\n• Gonadal hormone or danazol use within 3 months prior to study\n• Simultaneous participation in other studies\nRolland 1990/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n116\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSetting: 13 medical centres in seven European countries\nTiming: not stated\nInterventions Nafarelin 200 /uni03BCg twice daily IN + placebo PO twice daily for 6 months (n = 127)\nversus\nDanazol 200 mg twice daily PO + placebo IN twice daily for 6 months (n = 67)/uni00A0\nOutcomes • Pain defined by symptoms severity score\n• Adverse effects\n• AFS score\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nAuthors contacted regarding methods and data. Letter returned with author unknown at Department\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Randomised 2:1 nafarelin: danazol. No further details of method used to gen-\nerate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-placebo, double-blind study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-placebo, double-blind study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Details for attrition:\n• 20 in nafarelin and 4 in danazol group withdrew due to:\n/uni25E6adverse effects 7 (Naf) vs 2 (Dan)\n/uni25E6intercurrent illness 1 (Naf) vs 2 (Dan)\n/uni25E6personal reasons 3 (Naf)\n/uni25E6lost to follow-up 3 (Naf)\n/uni25E6lack of drug efficacy 1 (Naf)\n/uni25E6other 5 (Naf)\nNafarelin: 20/127 discontinued treatment.\nDanazol: 4/67 discontinued treatment.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nRolland 1990/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n117\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised trial\nParticipants Participants: 81 women were randomised in a 2:1 ratio to leuprolide n = 54, or danazol n = 27.\nMean age: mean age not provided; median age was 32 years (range 19-41)\nInclusion criteria:/uni00A0\n• Laparoscopically confirmed endometriosis\nExclusion criteria: not stated\nSetting: Italy, fertility centre of the second University of Naples\nTiming: 1992 to 1999\nInterventions Leuprolide acetate 3.75 mg subcutaneously every 28 days, for 6 months\nversus\nDanazol 200 mg orally three times a day for 6 months\nOutcomes • Relief of overall pain: subjective symptom scores using a numerical scale\n• Adverse effects\n• rAFS scores\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Excluded from previous version of this review as pain was not an outcome. In-\ncluded in this review, but did not contribute any data\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"randomly allocated\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nLow risk 3/54 women from leuprolide group and 5/27 from danazol group withdrew\ndue to \"adverse findings\".\nRotondi 2002/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n118\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAll outcomes\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nRotondi 2002/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: single-site, double-masked, randomised, placebo-controlled, dose-ranging trial\nParticipants Participants: 42 women were randomised; 40 women were analysed.\nMean age: 34.0 ± 6.5 years (range 20-44 years)\nInclusion criteria:\n• Endometriosis diagnosed by signs or symptoms or laparoscopy\nExclusion criteria:/uni00A0\n• Amenorrhoea\n• Taking drugs known to affect bone metabolism\n• Evidence of an associated disease\n• Interruption of more than 15 days in the administration of the drug\nSetting: France\nTiming: not stated\nInterventions All participants received triptorelin 3.75 mg IM every four weeks + norgestrel acetate 5 mg/day during\nthe first 3 weeks following injection and then 1 g calcium carbonate daily for 27 weeks./uni00A0\nIn addition:\nGroup 0: placebo intranasal spray,\nGroup 1: salmon calcitonin 100 IU IN daily,/uni00A0\nGroup 2: salmon calcitonin 200 IU IN daily.\nOutcomes • Bone Mineral Density\n• Adverse effects\n• Biochemical changes\nNotes Intention-to-treat analysis: yes\nSample size calculation: yes\nFunding: not stated\nAuthor could not be contacted due to lack of information.\nRisk of bias\nBias Authors' judgement Support for judgement\nRoux 1995/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n119\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly devided\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 2 participants failed to complete the study - one was lost to follow-up and one\nwas excluded due to orthopaedic material in the lumbar spine.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nRoux 1995/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: multi-centre, randomised, evaluator-blinded, comparator-controlled trial\nParticipants Participants: 274 women were randomised; 190 women were analysed.\nMean age: medroxyprogesterone acetate group 29.2 ± 6.3 years, leuprolide group 32.1 ± 6.6 years\nInclusion criteria:\n• Premenopausal women\n• Age from 18 to 49 years\n• Persistent symptoms of pain caused by endometriosis (surgically diagnosed within previous 42\nmonths)\n• Pain must have returned to its previous level within 30 days after a diagnostic laparoscopy or within 3\nmonths after laparoscopy or laparotomy with surgical treatment and must have persisted for a min-\nimum of 3 months.\nExclusion criteria:/uni00A0\n• Baseline BMD at the lumbar spine and hip was < 1 SD below the peak adult bone mass\nSetting: United States of America (43 sites) and Canada (7 sites)\nTiming: not stated\nInterventions Subcutaneous depot medroxyprogesterone acetate (DMPA) (104 mg/0.65 mL) every 3 months (n = 136)/uni00A0\nversus\nLeuprolide (11.25 mg) intramuscular every 3 months (n = 138)\nSchlaﬀ 2006/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n120\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcomes • Bone Mineral Density\n• Pain (Biberoglu and Behrman symptom scale)\n• Quality of life\n• Adverse effects\n• Hypoestrogenic symptoms\n• Bleeding patterns\n• Endometriosis-impact diary\nNotes Intention-to-treat analysis: yes\nSample size calculation: yes\nFunding: not stated\nAuthor contacted; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomised\". No further details of method used to generate the randomisa-\ntion sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk \"An independent person maintained the randomization code, received the\nstudy syringes, and administered the study medication\".\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk In this evaluator-blinded study, the principal investigator and any designated\nsub-investigators and study co-ordinators at each centre were blinded to the\nrandomisation of each participant.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk There was a dropout rate of 35.3% in the DMPA-SC 104 group (48/136) and of\n26.1% in the leuprolide group (36/138) during the 6-month treatment period.\nThe majority of these participants either actively withdrew from the study\n(DMPA-SC 104 = 21, leuprolide = 9) or were lost to follow-up (14 and 11, respec-\ntively). Nine patients in each group (6.6% and 6.5% in the DMPA-SC 104 and le-\nuprolide groups, respectively) discontinued as a result of adverse side effects.\nOf those women who completed the 6 months of active treatment, 51 (58.0%)\nof 88 in the DMPA-SC 104 group and 58 (56.9%) of 102 in the leuprolide group\nle/f_t the study during the 12-month follow-up period.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nSchlaﬀ 2006/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nShaw 1986/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n121\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMethods Trial design: Randomised study\nParticipants Participants: 20 women were randomised; 19 analysed/uni00A0\nMean age: 30.4 +/- 3.8/uni00A0\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed disease\n• No treatment within 4 months prior to study\nExclusion criteria: not stated/uni00A0\nSetting: UK/uni00A0\nTiming: not stated\nInterventions Buserelin 200 mcg three times a day intranasally for 6 months (n = 10)/uni00A0\nversus/uni00A0\nBuserelin 300 mcg three times a day intranasally for 6 months (n = 10)\nOutcomes Symptomatic changes/uni00A0\nrAFS score/uni00A0\nAdverse effects\nNotes Intention-to-treat analysis: No/uni00A0\nSample size calculation: not stated/uni00A0\nFunding: Hoechst UK supplied the Buserelin used in this study. No further details provided\nNote previous version: Authors contacted but unable to provide further details as trial was almost 20\nyears old/uni00A0\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"randomly allocated\". No further details of method used to generate random\nsequence\nAllocation concealment\n(selection bias)\nUnclear risk No details provided of method used to conceal allocation to treatment groups\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk \"this paper reports an open study\" with no further details.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk \"this paper reports an open study\" with no further details.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Detail for attrition: 1 from buserelin 300 mcg TDS group withdrew after 3\nmonths due to adverse effects.\nShaw 1986/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n122\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSelective reporting (re-\nporting bias)\nHigh risk No comparisons between groups for symptomatic changes\nOther bias Low risk No other risk of bias reported\nShaw 1986/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Multi-centre, placebo-controlled, randomised trial\nParticipants 82 women were randomised; 74 were analysed.\nMean age: not stated\nInclusion criteria:\n• Endometriosis\nExclusion criteria: not stated\nSetting: United Kingdom (2 sites)\nTiming: not stated\nInterventions Nafarelin 200 mcg BD IN + placebo PO for 6 months (n = 55)\nversus\nDanazol 200 mg three times a day PO + placebo IN for 6 months (n = 26)\nOutcomes • Improvment of most troublesome symptom: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tender-\nness and induration combined\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nNote previous version: Authors contacted but unable to provide further details as trial was almost 20\nyears old\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomized\". No further details of method used to generate the randomisa-\ntion sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Participants were blinded and received placebo nasal spray or tablets.\nBlinding of outcome as-\nsessment (detection bias)\nLow risk Placebo-controlled study\nShaw 1990/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n123\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAll outcomes\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Details for attrition given: 8 withdrew:\n• Nafarelin = 3 due to side effects, 1 le/f_t country, 1 poor compliance\n• Danazol = 2 due to side effects, 1 poor compliance\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nShaw 1990/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised, double-blind, placebo-controlled, trial\nParticipants Participants: 23 women were randomised.\nMean age: Group A: 29.7 ± 4.5 years, group B: 31.4 ± 3.8 years\nInclusion criteria:\n• Regularly menstruating\n• Laparoscopically proven symptomatic endometriosis\nExclusion criteria:/uni00A0\n• Evidence of osteopenia, osteoporosis or other skeletal disease\n• Significant non-skeletal disease\n• Pregnancy or lactation\n• Use of medications known to interfere with bone metabolism in the 3 months prior to enrolment\n• Psychiatric disorders\nSetting: Germany\nTiming: not stated\nInterventions All patients underwent a six months course of goserelin (Zoladex®, Zeneca GmbH, Plankstadt, Ger-\nmany) 3.6 mg SC every four weeks, the first injection being given on cycle day 3-5 at the initial visit.\nGroup A: additionally placebo /uni00A0(n = 12)\nversus/uni00A0\nGroup B: additionally 5 mg medrogestone orally twice daily (Prothil®, Solvay GmbH, Hannover, Ger-\nmany) (n = 11)\nOutcomes • Bone mineral density\n• Serum oestradiol and FSH levels, bone-specific alkaline phosphatase, /uni00A0osteocalcin\n• Urinary concentrations of total pyridinoline and of total deoxypyridinolin\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nSillem 1999/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n124\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAuthor contacted; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly allocated\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nUnclear risk No information about incomplete outcome data\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nSillem 1999/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Placebo, randomised, parallel study.\nParticipants 34 women were randomised and analysed .\nMean age: GnRHa = 31.02 ± 2.5 and placebo = 32.13 ± 1.5 (SD)/uni00A0\nInclusion criteria:/uni00A0\n• Laparoscopically diagnosed endometriosis\n• Symptomatic\n• Surgically or pharmacologically treated in 6 months prior\n• Regular menstrual cycle in prior 3 months\n• Not pregnant\nExclusion criteria:\n• Cardiovascular burden\n• Hormone-dependent neoplasms\n• Osteoporosis\n• Bilateral oophorecystectomy\n• Abnormal liver and renal tests\nSetting: Poland/uni00A0\nSkrzypulec 2004/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n125\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nTiming: September 2003 to April 2004\nInterventions GnRHa 50 mg once daily per os for 12 weeks (n = 16)/uni00A0\nversus/uni00A0\nPlacebo per os for 12 weeks (n = 18)\nOutcomes Relief of overall pain: reported as dysmenorrhoea, dyspareunia, pelvic pain\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"Randomisation was in the ratio two goserelin: one danazol with each centre\nhaving its randomisation list\", \"The randomised trial of Zoladex and Danazol\nwas a multi-centre trial with randomisation envelopes provided by the spon-\nsors ICI to each of the centres as plain sealed envelopes and computerised ran-\ndomisation lists for each centre\" (author's reply).\nAllocation concealment\n(selection bias)\nUnclear risk \"plain, sealed envelopes\". No other details provided of method used to con-\nceal allocation to treatment groups\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Participants, investigators, outcome assessors and clinicians were all blinded\naccording to author.\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Participants, investigators, outcome assessors and clinicians were all blinded\naccording to author.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk All women who were randomised were analysed.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detetcted\nSkrzypulec 2004/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: The study was a multi-centre, randomised, open-label, parallel-group, non-inferiority\ncomparison.\nParticipants Participants: 252 women were randomised; 229 women were analysed.\nMean age: 18–45 years\nStrowitzki 2012/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n126\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nInclusion criteria:\n• Women aged 18-45 years\n• De novo or recurrent pain associated with a confirmed diagnosis of endometriosis\nExclusion criteria:/uni00A0\n• Amenorrhea (≥ 3 months)\n• Need for surgical treatment\n• Previous use of hormonal treatments within specified times\n• Abnormal findings (other than endometriosis) at gynaecologic examination\n• Pregnancy or breastfeeding\n• Risk factors for decreased bone mineral density\nSetting: Germany\nTiming: not stated\nInterventions Dienogest (DNG) 2 mg/day orally /uni00A0(n = 124)\nversus\nIntramuscular leuprolide acetate 3.75 mg depot every 4 weeks (n = 128)\nOutcomes • Relief of overall pain: pelvic pain, dysmenorrhoea, dyspareunia scores (VAS, Biberoglu and Behrman)\n• Adverse events\n• Quality of life (SF-36)\n• Improvement of most troublesome symptom\n• Markers of bone metabolism\nNotes Intention-to-treat analysis: No. \"Efficacy analyses were based on the per-protocol set (PPS), which in-\ncluded all randomized patients without major protocol deviations (a 'conservative' strategy appropri-\nate for non-inferiority studies)\".\nSample size calculation: yes\nFunding: Funding for the study was provided by Bayer HealthCare.\nJ.M., C.G., T.F., and C.S. are full-time employees of Bayer HealthCare. Editorial support funded by Bay-\ner HealthCare was provided by PAREXEL. This editorial support consisted of the preparation of manu-\nscript dra/f_ts based on detailed author guidance.\nAuthors contacted; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Patients were randomized (1:1 ratio)\". No further details of method used to\ngenerate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk weo details of method used to conceal allocation are provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nStrowitzki 2012/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n127\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Overall, 109/124 (87.9%) women in the DNG group and 120/128 (93.8%)\nwomen in the LA group completed the study.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nStrowitzki 2012/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: prospective randomised trial\nParticipants Participants: 20 women were randomised; 17 women were analysed.\nMean age: group A: 32.9 ± 1.1 years, group B: 28.9 ± 1.7 years\nInclusion criteria:\n• Symptomatic endometriosis diagnosed by laparoscopy\nExclusion criteria:/uni00A0\n• Calcium supplements during the treatment, less than four endometriotic implants\n• Endometrioma greater than 5 cm in diameter\nSetting: United States of America\nTiming: not stated\nInterventions Group 1: leuprolide acetate 3.75 mg IM every 28 days (n = 10)\nversus\nGroup 2: leuprolide acetate 3.75 mg IM every 28 days and norethindrone po 5 mg for the first four\nweeks and then 10 mg daily for the remaining 20 weeks (n = 10)\nOutcomes • Bone mineral density\n• Improvement of most troublesome symptom\n• Laboratory changes\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Sponsored by TAP Pharmaceuticals\nRisk of bias\nBias Authors' judgement Support for judgement\nSurrey 1992/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n128\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRandom sequence genera-\ntion (selection bias)\nLow risk Computerised allocation (author reply). No further details of method used to\ngenerate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 1/20 participants lost to follow-up. One patient assigned to receive GnRHa and\nnorethindrone failed to complete therapy for reasons which were felt to be un-\nrelated to the medication. She was not replaced and data related to this pa-\ntient were excluded from analysis./uni00A0\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nSurrey 1992/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: post-treatment follow-up analysis of a randomised, double-masked, placebo-controlled\ntrial\nParticipants Participants: 201 women were randomised; 99 women were analysed.\nMean age:/uni00A0\nGroup A: 29.0 ± 1.0 years\nGroup B: 29.0 ± 1.1 years\nGroup C: 29.4 ± 1.0 years\nGroup D: 28.9 ± 1.2 years\nInclusion criteria:\nRegular menstrual cycle\n• Symptomatic endometriosis, which had been diagnosed surgically within 12 months of entry with\npersistent or recurrent pain\n• Symptomatic improvement over baseline at the end of the treatment period\n• Did not terminate the treatment protocol because of worsening symptoms\nExclusion criteria:/uni00A0\n• Become pregnant\n• Have surgical or medical intervention for endometriosis\nSurrey 2002/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n129\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n• Have non-endometriosis surgery that could have had an impact on pelvic pain during the treatment\nperiod\nSetting: United States of America (26 study sites)\nTiming: not stated\nInterventions Patients in all groups were to receive a depot preparation of the GnRH agonist leuprolide acetate 3.75\nmg intramuscularly every 4 weeks for 52 weeks./uni00A0\nGroup A: daily oral placebos for oestrogen and progestin add-back (n = 51)\nGroup B: daily oral norethindrone acetate (Aygestin, Lederle, Wayne, NJ) 5 mg and placebo for oestro-\ngen (n = 55)\nGroup C: received oral norethindrone acetate 5 mg and conjugated equine oestrogens (Premarin,\nWyeth-Ayerst, Philadelphia, PA) 0.625 mg daily (n = 47)\nGroup D: received oral norethindrone acetate 5 mg and conjugated equine oestrogens 1.25 mg daily (n\n= 48)\nOutcomes • Relief of overall pain\n• Mean changes in lumbar spine bone mineral density\n• Circulating cholesterol subfractions, triglycerides, and total cholesterol levels\nNotes Intention-to-treat analysis: yes\nSample size calculation: yes/uni00A0\nFunding: This work was supported by a grant from TAP Pharmaceutical Products, Inc., Lake Forest, Illi-\nnois.\nFinancial Disclosure: Drs. Surrey and Hornstein have received grant support and honoraria as members\nof the speaker’s bureau of TAP Pharmaceuticals. Dr. Surrey is also a member of the Medical Advisory\nBoard of TAP Pharmaceuticals. Ms. Fredrick performed the statistical analysis and is an employee of\nAbbott Laboratories, a parent company of TAP Pharmaceuticals.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"Patients were assigned randomly to one of four treatment groups by permut-\ned blocks of four at each of the treatment sites\".\nAllocation concealment\n(selection bias)\nUnclear risk No details were presented on the method of concealment.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-masked, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-masked, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nHigh risk 123/201 completed 280 days of therapy./uni00A0\nBecause of dropouts, the actual group-specific sample sizes in the follow-up\nperiod were lower than the numbers originally enrolled based on the initial\npower analyses. Thus, a post hoc analysis was performed.\nSurrey 2002/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n130\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nSurrey 2002/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Prospective, randomised, longitudinal pilot study\nParticipants Participants: 15 women were randomised and analysed.\nMean age:/uni00A0\nControl group: 35.2 ± 2.6 years\nHalf-dose group: 34.7 ± 5.7 years\nInclusion criteria:\n• Symptomatic endometriosis who were candidates for 6 months of GnRH agonist therapy\n• Diagnosis of endometriosis was confirmed by laparoscopy or laparotomy\n• Menstruated regularly\n• Normal hepatic and renal function\nExclusion criteria:/uni00A0\n• No recent medical treatment for endometriosis\n• Not taking medications known to affect bone metabolism\nSetting: Japan\nTiming: not stated\nInterventions Control group: full-dose intranasal nafarelin treatment (200 /uni03BCg twice daily) for 24 weeks (n = 7)\nversus\nHalf-dose group: full dose intranasal nafarelin treatment (200 /uni03BCg twice daily) for 4 weeks followed by\nhalf-dose intranasal nafarelin treatment (200 /uni03BCg daily) for 20 weeks (n = 8)\nOutcomes • Symptoms of endometriosis (dysmenorrhoea, dyspareunia, and pelvic pain)\n• Vasomotor symptoms (hot flashes or dizziness)\n• Bone mineral density\n• Fasting serum and urine samples\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nTahara 2000/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n131\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nRandom sequence genera-\ntion (selection bias)\nLow risk The patients were assigned, using a random number table, to two groups./uni00A0\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nTahara 2000/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled study\nParticipants Participants: 50 women were randomised and /uni00A0analysed.\nMean age:/uni00A0\nFull-dose group: 31.52 ± 6.38 years\nHalf-dose group: 30.36 ± 5.54 years\nInclusion criteria:\n• Patients with stage III-IV endometriosis\nExclusion criteria:/uni00A0\n• Ovarian reserve decrease (days 1 –3: follicle-stimulating hormone [FSH] > 12 pg/mL) or peri-\nmenopausal status\n• Discontinued follow-up and cooperation\n• Malignancy of genital or other systems\n• Liver, kidney or coagulation system dysfunction\nSetting: Japan\nTiming: June 2014 to June 2016\nInterventions Research group = Half-dose group: “draw-back” treatment with 3.75 mg GnRHa (leuprorelin) in the first\ntwo injections (one injection per 28 days), after which the third injection contained 1.88 mg GnRHa, and\nthis dosage was continued up to and including the sixth injection after achieving the suppression crite-\nria (E2 < 50 pg/mL, endometrial thickness 5 mm; in total four injections at 1.88 mg) (n = 25)\nTang 2017/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n132\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nControl group = full-dose group: 3.75 mg GnRHa for six injections (n = 25)\nOutcomes • Relief of overall pain: degree of dysmenorrhoea\n• Bone mineral density\n• Adverse effects\n• Sex hormones\n• Symptoms of perimenopause\n• Resumption of menses\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: by Science and Technology Development Fund Project of Shenzhen, China (grant no.\nJCYJ20140415162338852), Science and Technology Planning Project of Guangdong Province, China\n(grant no. 2013B021800095), Scientific Research Project of Shenzhen Health Family Planning, Chi-\nna (grant no. 201401038) and Natural Science Foundation of Guangdong Province, China (grant no.\n2015A030313889)\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly divided\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nUnclear risk No information about incomplete outcome data\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected.\nTang 2017/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: /uni00A038 women were randomised and analysed.\nMean age: 31.4 ± 0.6 years\nTummon 1988/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n133\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nInclusion criteria:\n• Laparoscopically diagnosed and staged endometriosis\nExclusion criteria: not stated\nSetting: United States of America\nTiming: not stated\nInterventions /uni00A0GnRHa group: 8 women received leuprolide 1.6 mg daily intranasally, 8 women received buserelin 1.2\nmg daily IN and 9 received buserelin 200 /uni03BCg daily subcutaneously (n = 25)\nversus\nDanazol, 200 mg four times daily orally (n = 13)\nOutcomes • Bone Mineral Density\n• Serum E2, FSH, LH, and progesterone concentrations\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Supported by TAP Pharmaceuticals, Abbott Laboratories, North Chicago, Illinois, and by\nHoechst-Roussel Pharmaceuticals, Somerville, New Jersey\nAuthor could not be contacted due to lack of information.\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly assigned\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No further details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nUnclear risk No information about incomplete outcome data\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nTummon 1988/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n134\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nStudy characteristics\nMethods Trial design: Prospective, randomised study\nParticipants Participants: 15 women were randomised and analysed.\nMean age: 32.1 ± 0.9 years (range 27 to 38 years)\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis within 3 months prior to study\n• Infertile women\n• Regular menstrual cycles\n• Negative beta-subunit human chorionic gonadotropin (hCG)\nExclusion criteria: not stated\nSetting: united States of America\nTiming: not stated\nInterventions Leuprolide /uni00A0daily SC injectons of 0.5 mg for 7 days, then changed to 400 mcg four times a day IN for 26\nweeks (n = 10)\nversus\nDanazol 200 mg four times a day PO for 26 weeks (n = 5)\nOutcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain\n• rAFS score\n• Hypoestrogenic symptoms\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: Supported in part by a grant from Abbott Laboratories, Inc., Chicago, Illinois\nNote previous version: Authors contacted regarding methods and data; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk Randomised 2:1 ratio leuprolide: danazol. No further details of method used to\ngenerate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nTummon 1989/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n135\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nTummon 1989/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Open-label, randomised study\nParticipants Participants: 42 women were randomised and analysed.\nMean age:/uni00A0\nGroup 1: 29 ± 6 years\nGroup 2: 31 ± 6 years\nInclusion criteria:\n• Diagnostic laparoscopy with no attempts at endometriosis reduction other than biopsy up to 3\nmonths before study entry\nExclusion criteria:/uni00A0\n• Treatment for endometriosis other than NSAID in the previous 3 months\n• Usual contraindications for danazol\n• Unwillingness to use barrier contraception\nSetting: Italy\nTiming: not stated\nInterventions Group 1: Danazol only, oraly 50 mg/day for 9 months (n = 21)\nversus\nGroup 2: Leuprolide 3.75 mg in a 28-day IM depot for 3 months, followed by oral danazol 50 mg/day for\n6 months + danazol (n = 21)\nOutcomes • Relief of overall pain: dysmenorrhoea, non-menstrual pelvic pain, deep dyspareunia\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"Computer-generated randomisation list\". No further details of method used\nto generate the randomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nVercellini 1994/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n136\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nUnclear risk No details provided of blinding of outcome assessment\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 5/42 withdrew from this study, one in each group at the fi/f_th month of treat-\nment (for persistent pain) and one in each group during follow-up (they re-\nquested additional therapy). One women in the Danazol group was lost to fol-\nlow-up.\n/uni00A0\nGroup 1: 18/21 completed follow-up.\nGroup 2: 19/21 completed follow-up.\n/uni00A0\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nVercellini 1994/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: a multicentre, randomised, double-blind study\nParticipants Participants: /uni00A055 women were randomised; /uni00A049 women were analysed (41 underwent complete serial\nbone mineral content assessment).\nMean age:/uni00A0\nGestrinone: 31.9 ± 5.4 years\nLeuprolide acetate: 28.6 ± 6.2 years\nInclusion criteria:\n• Diagnostic laparoscopy with no attempts at endometriosis reduction other than biopsy up to 3\nmonths before study entry\nExclusion criteria:/uni00A0\n• Medical or surgical treatments specific for endometriosis\n• Treatment for endometriosis other than nonsteroidal anti-inflammatory drugs in the previous 6\nmonths\n• Concomitant disorders that might cause gynaecologic pain (e.g. pelvic inflammatory disease and ob-\nstructive genital malformations)\n• Contraindications to the use of gestrinone or GnRHas\n• Abnormal baseline mineral bone density values\n• Unwillingness to use barrier contraception\nSetting: Italy\nVercellini 1996/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n137\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nTiming: not stated\nInterventions Oral gestrinone 2.5 mg twice a week (Dimetrose; Poli Industria Chimica, Rozzano, Milano, Italy) (n = 27)\nversus\nLeuprolide acetate IM 3.75 mg depot injections every 4 weeks (Enantone; Takeda Farmaceutici, Roma,\nItaly) (n = 28)\nOutcomes • Relief of overall pain\n• Bone mineral density\n• Adverse effects\n• Plasma lipids and lipoprotein\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated; only a post hoc analysis\nFunding: Supported in part by Poli Industria Chimica, Rozzano, Milano, Italy\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomisation\". No further details of method used to generate the randomi-\nsation sequence were provided.\nAllocation concealment\n(selection bias)\nLow risk Sealed envelopes containing randomisation codes were to be opened only at\ntrial completion or in case of severe side effects.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind, placebo-controlled study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 6/55 women withdrew from the study during the treatment period, 4/27 in the\ngestrinone group (three refused further therapy, in one case because of her\ngeneral practitioner's unfavourable opinion, in two cases because of psycho-\nlogical intolerance to treatment blinding, and one failed to keep clinic appoint-\nments) and 2/28 in the leuprolide acetate group (they stopped treatment for\nconcomitant nongynaecologic diseases).\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nVercellini 1996/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: \"double-blind, multi-centre, randomised trial\"/uni00A0\nWheeler 1992/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n138\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nParticipants Participants: 270 women were randomised and 253 were analysed.\nAge: Leuprolide = 30.8 years and danazol = 29.9 years\nInclusion criteria:\n• Laparoscopically diagnosed endometriosis within 4 months prior to study\n• Over 18 years of age\n• No surgical treatment at time of laparoscopy\n• Premenopausal\n• Not pregnant or lactating\n• Any other treatment completed at least 3 months prior to study\nExclusion criteria\n• Previously taken GnRHa\n• Women with base-line bone densitometry of > 2 SD below the mean\nSetting: United States of America (17 centres)\nTiming: October 14, 1986 to December 21, 1988\nInterventions Leuprolide 3.75 mg monthly IM + placebo once daily PO for 24 weeks (n = 134)\nversus\nDanazol 800 mg once daily PO + placebo monthly IM for 24 weeks (n = 136)\nOutcomes • Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness\n• Bone mineral density\n• Laboratory determinations\n• rAFS score\n• Analgesic use\nNotes Intention-to-treat analysis: not stated\nSample size calculation: yes/uni00A0\nFunding: TAP-Abbott Research and Development\nJudith Knittle is Senior Clinical Project Manager at TAP Pharmaceuticals Inc. In addition to her role in\nthe preparation of this manuscript, she was involved in the design and implementation of the study.\nJames Miller, MD, is currently Medical Director at TAP Pharmaceuticals Inc; during the conduct of this\ntrial, he was in private clinical practice in Seattle and was one of the principal investigators of the study.\nNote previous version: Authors contacted regarding methods and data; awaiting response\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly assigned\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Placebo-controlled, double-blind study\nWheeler 1992/uni00A0/uni00A0(Continued)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n139\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Placebo-controlled, double-blind study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk Details given for attrition: 17 patients were excluded due to:\n• failure to meet inclusion criteria 2 (Leu) and 1 (Dan)\n• non-compliance 3 (Leu) and 10 (Dan)\n• inadvertent dosing with another patient's designated leuprolide 1\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nWheeler 1992/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised controlled trial\nParticipants Participants: 24 women were randomised; 22 women were analysed.\nMean age: Nafarelin 33.7 ± 7 years, danazol 30.0 ± 3.3 years\nInclusion criteria:\n• Endometriosis diagnosed at laparoscopy\nExclusion criteria:/uni00A0\n• Medically unsuitable to undergo quantitative computerised tomography\nSetting: United Kingdom\nTiming: not stated\nInterventions Nafarelin 200 /uni03BCg twice daily by nasal insufflation (n = 15)\nversus\nDanazol 200 mg three times daily orally (n = 9)\nOutcomes • Bone mineral density\n• Serum oestradiol levels\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nUnclear risk \"Randomly allocated\". No further details of method used to generate the ran-\ndomisation sequence were provided.\nWhitehouse 1990/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n140\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nLow risk Double-blind study\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk Double-blind study\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk 2 participants did not complete trial - one became pregnant and one failed to\nreturn for final assessment. The results from these participants were excluded\nfrom analysis.\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nWhitehouse 1990/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nStudy characteristics\nMethods Trial design: Randomised, controlled study\nParticipants Participants: 150 women were randomised and analysed.\nMean age:/uni00A0\nGroup A: 35.8 ± 5.1\nGroup B: 35.1 ± 4.8\nGroup C: 36.1 ± 5.3\nInclusion criteria:\n• Women aged 20–43 years\n• Regular menstrual cycles\n• A history of symptomatic severe endometriosis diagnosed surgically according to the revised Ameri-\ncan Society for Reproductive Medicine classification\n• Recurrence of the disease with pelvic pain, dysmenorrhoea, and dyspareunia\nExclusion criteria: not stated\nSetting: Italy\nTiming: March 1, 2000 to February 28, 2003\nInterventions Group A: GnRH-a plus add-back therapy = leuprolide acetate (Enantone Depot 11.25 mg; Takeda,\nRome, Italy) every 3 months for 12 months plus transdermal E2 (25 /uni03BCg Esclima; Takeda) and daily oral\nnorethindrone (5 mg Primolut-Nor; Schering, Berlin, Germany) (n = 46)\nGroup B: /uni00A0GnRH-a alone = leuprolide acetate (Enantone Depot 11.25 mg; Takeda) every 3 months for 12\nmonths (n = 44)\nZupi 2005/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n141\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nGroup C: oestroprogestin alone = received oral ethinyl E2 (30 /uni03BCg ) plus gestodene daily (0.75 mg Gin-\noden; Schering) for 12 consecutive months (n = 43)\nOutcomes • Bone Mineral Density\n• Quality of life\n• Health-related satisfaction\nNotes Intention-to-treat analysis: not stated\nSample size calculation: yes/uni00A0\nFunding: not stated\nRisk of bias\nBias Authors' judgement Support for judgement\nRandom sequence genera-\ntion (selection bias)\nLow risk \"Randomized by means of a computer-generated randomization number se-\nquence\"\nAllocation concealment\n(selection bias)\nUnclear risk No details of method used to conceal allocation were provided.\nBlinding of participants\nand personnel (perfor-\nmance bias)\nAll outcomes\nUnclear risk No details provided of blinding of participants or personnel\nBlinding of outcome as-\nsessment (detection bias)\nAll outcomes\nLow risk The VAS and SF-36 were administered to the patients by a nurse who was blind\nto the study before treatment, after 6 and 12 months of therapy, and 6 months\nafter discontinuation of treatment.\nIncomplete outcome data\n(attrition bias)\nAll outcomes\nLow risk No losses to follow-up\nSelective reporting (re-\nporting bias)\nLow risk The study protocol was not available but it was clear that the published re-\nports included all expected outcomes, including those that were prespecified.\nOther bias Low risk No other risk of bias detected\nZupi 2005/uni00A0/uni00A0(Continued)\nADI: additive diameter of implants score\nAFS: American Fertility Society\nAIDS: acquired immune deficiency syndrome\nASRM: American Society for Reproductive Medicine\nBD: twice daily\nBMD: bone mineral density\nBMI: Body Mass Index\nDMPA: Depot medroxyprogesterone acetate\nDNG: dienogest\nE2: oestradiol\nESS: Endometriosis symptom severity\nFSH: Follicle-Stimulating Hormone\nGnRHa: Gonadotropin Releasing Hormone Agonist\nHRT: Hormone Replacement Therapy\nIm: intramuscular\nIN: intranasally\nIVF: in vitro fertilization\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n142\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nLA: leuprolid acetate\nLH: luteinizing hormone\nLNG-IUS: Levonorgestrel-Intrauterine System\nNSAID: Nonsteroidal anti-inflammatory drugs\nOC: oral contraceptive\nOCP: oral contracteptive pill\nPap: Papanicolaou\nPO: per os\nPRL: prolactin\nPTH: Parathyroid hormone\nQID: four times a day\nrAFS: revised American Society for Reproductive Medicine\nSC: subcutaneously\nSD: standard deviation\nSEM: standard error of mean\nSF-36: Short Form Health Survey - 36\nT4: Thyroxine\nTDS: three times daily\nIU: intra-uterine\nVAS: Visual Analogue Scale\n17β-E2: 17β-estradiol\n/uni00A0\nCharacteristics of excluded studies [ordered by study ID]\n/uni00A0\nStudy Reason for exclusion\nAcien 1989 Outcome in this article did not match the outcome measurements of this review./uni00A0\nAdiyono 2006 Wrong participants: post-surgical treatment\nAgarwal 2015 The article did not meet the stated inclusion criteria. Wrong comparison\nAl-Azemi 2009 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nBergqvist 1990 Wrong study design; not clearly stated as randomised trial\nCalvo 2000 Outcome in this article did not match the outcome measurements of this review./uni00A0\nChan 1993 Study still awaiting classification, so excluded in this review\nChen 2009 Study still awaiting classification, so excluded in this review\nChoktanasiri 2001 Wrong study design, not clearly stated as randomised trial\nClaesson 1989 Wrong study design; not clearly stated as randomised trial\nCooke 1989 The article did not meet the stated inclusion criteria. Wrong comparison\nDawood 1990 Wrong study design; not clearly stated as randomised trial\nDmowski 1989 The article did not meet the stated inclusion criteria. Wrong comparison\nDodin 1991 Not only women with endometriosis included, but also without endometriosis\nDonnez 1989 The article did not meet the stated inclusion criteria. The outcome measures as viewed in the cur-\nrent review were not answered in this article.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n143\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nStudy Reason for exclusion\nDonnez 2004 The article did not meet the stated inclusion criteria. Wrong comparison\nel-Roeiy 1988 The article did not meet the stated inclusion criteria. The outcome measures as viewed in the cur-\nrent review were not answered in this article.\nEldred 1992 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nFedele 1993 Wrong study design; not clearly stated as randomised trial\nFernandez 2004 The article did not meet the stated inclusion criteria. Wrong comparison\nFerrero 2011 The article did not meet the stated inclusion criteria. Wrong comparison\nFranssen 1992 Retrospective study, so wrong study design\nFraser 1996 Ineligible condition: not about endometriosis but rather menorrhagia\nHarada 2000 Wrong study design; not clearly stated as randomised trial\nHenzl 1990a Wrong study design; not clearly stated as randomised trial\nImani 2009 The article did not meet the stated inclusion criteria. Wrong comparison\nLindsay 1996 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nLuciano 2004 The article did not meet the stated inclusion criteria. Wrong comparison\nMagini 1993 The article did not meet the stated inclusion criteria. Wrong comparison\nMaouris 1991 The outcome measures as viewed in the current review were not answered in this article.\nMatalliotakis 2000 The outcome measures as viewed in the current review were not answered in this article.\nMatalliotakis 2004 Wrong participants: post-surgical treatment\nMatta 1988 Wrong patient population\nMiller 1990 The article did not meet the stated inclusion criteria. Wrong comparison\nMukherjee 1996 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nNewton 1996 The article did not meet the stated inclusion criteria. Wrong comparison\nPierce 2000 Once patients were enrolled, allocation of treatment was carried out according to a patient-cen-\ntred, partially randomised design./uni00A0\nRipps 2003 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nShaw 1992 Study included also patients without complaints; no separate results stated in this article. As de-\nscribed in the Methods section, we decided to exclude this study./uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n144\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nStudy Reason for exclusion\nShaw 2001 The article did not meet the stated inclusion criteria. Wrong comparison\nSomekawa 1999 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nSorensen 1997 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nSowter 1997 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nSoysal 2004 Post-surgical treatment. So, wrong type of intervention\nSurrey 1993 The article did not meet the stated inclusion criteria. Wrong comparison\nSurrey 1995 Not only women with endometriosis included, but also without endometriosis. So, wrong patient\npopulation\nTakaesu 2013 This study was investigating the effect of GnRHas on postoperative outcome measures. This type of\nintervention is excluded from the current review.\nTapanainen 1993 Outcome in this article did not match the outcome measurements of this review./uni00A0\nTaskin 1997 The article did not meet the stated inclusion criteria. Wrong comparison\nToomey 2003 The article did not meet the stated inclusion criteria. Wrong comparison\nValimaki 1989 The outcome measures as viewed in the current review were not answered in this article.\nVercellini 2009 Wrong participants: post-surgical treatment\nWarnock 1998 The article did not meet the stated inclusion criteria. Wrong comparison\nWright 1995 The outcome measures as viewed in the current review were not answered in this article.\nYee 1986 The outcome measures as viewed in the current review were not answered in this article.\nYlikorkala 1995 Ineligible participants\n/uni00A0\nCharacteristics of studies awaiting classification [ordered by study ID]\n/uni00A0\nMethods Randomisation: randomised trial\nParticipants Number of women: 53/uni00A0\nAge: not stated\nInclusion criteria: not stated/uni00A0\nExclusion criteria: not stated /uni00A0\nSetting: Japan\nAisaka 2000/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n145\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nTiming: not stated\nInterventions Group 1: leuprolin + mestranol 0.05 mg and norethisterone 1 mg/tab 1 tab/day\nversus\nGroup 2: leuprolin alone\nOutcomes Bone mineral density\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated/uni00A0\nFunding: not stated\nThis abstract did not contain enough information to make a proper decision about in-/exclusion.\nAisaka 2000/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nMethods Trial design: Randomised trial/uni00A0\nParticipants Participants:/uni00A0\nMean age:\nInclusion criteria:\n• Premenopausal women (18–49 years) with laparoscopically diagnosed endometriosis\n• Persistent, recurrent endometriosis-associated symptoms for at least 3 months\nExclusion criteria:/uni00A0\nSetting: United States and Canada\nTiming: not stated\nInterventions DMPA-SC 104 mg every 3 months/uni00A0\nversus\nLA 11.25 mg given intramuscularly every 3 months\nOutcomes • Relief of overall pain\nNotes Intention-to-treat analysis: yes\nSample size calculation: not stated/uni00A0\nFunding: not stated\n/uni00A0\nThis abstract did not contain enough information to make a proper decision about in-/exclusion./uni00A0\nArcher 2004/uni00A0\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n146\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nMethods Randomisation: by sequential numerical allocation to a randomisation list before commencing tri-\nal\nParticipants Number of women: 40/uni00A0\nAge: Mean age of group 1: 28.3 years and mean age of group 2: 29.1 years\nInclusion criteria:/uni00A0\n• minimum of 4 endometriotic lesions\n• endometriotic symptoms and pelvic pain graded at least 3 (severe)\n• negative cervical smear\nExclusion criteria:/uni00A0\n• smoking\n• medications that might affect bone metabolism\n• medical conditions that could affect bone metabolism\nSetting: Greece\nTiming: not stated\nInterventions Group 1: leuprolide acetate depot 3.75 mg IM every 4 weeks\nversus\nGroup 2: leuprolide acetate depot 3.75 mg every 4 weeks + 1.25 mg daily oral conjugated equine\noestrogens on days 1 to 25 and 5 mg oral medroxyprogesterone acetate on days 16-25\nOutcomes • Bone mineral density\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated/uni00A0\nFunding: not stated\nThis abstract did not contain enough information to make a proper decision about in-/exclusion.\nGregoriou 1997/uni00A0\n/uni00A0\n/uni00A0\nMethods Trial design: randomised trial\nParticipants Participants: 70 women with moderate or severe endometriosis\nMean age: /uni00A0in GnRHa group was 31±7 years and in the add-back group was 32±7 years in those who\ncompleted the study\nInclusion criteria: not stated/uni00A0\nExclusion criteria: not stated/uni00A0\nSetting: China\nTiming: not stated\nInterventions GnRHa Zoladex 3.6 mg every 28 days (x3) (n = 35)/uni00A0\nversus/uni00A0\nLong 2009/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n147\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nZoladex 3.6 mg every 28 days (x3)+ add-back- oestradiol valerate 0.5 mg + dydrogesterone 5 mg\ndaily (n = 35)\nOutcomes • Relief of overall pain\n• Quality of life\n• Bone mineral density\n• Patients satisfaction\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated/uni00A0\nFunding: not stated\n/uni00A0\nThis abstract did not contain enough information to make a proper decision about in-/exclusion./uni00A0\nLong 2009/uni00A0/uni00A0(Continued)\n/uni00A0\n/uni00A0\nMethods Trial design: randomised trial\nParticipants Participants: 30\nMeang age: not stated\nInclusion criteria: not stated/uni00A0\nExclusion criteria: not stated\nSetting: not stated\nTiming: not stated\nInterventions Group 1: goserelin/uni00A0\nversus\nGroup 2: goserelin + premarin (conjugated oestrogens) 1.25 mg\nOutcomes • Bone mineral density\nNotes Intention-to-treat analysis: not stated\nSample size calculation: not stated/uni00A0\nFunding: not stated\n/uni00A0\nThis abstract did not contain enough information to make a proper decision about in-/exclusion./uni00A0\nVella 1995/uni00A0\nDPMA:/uni00A0depot medroxyprogesterone acetate\nGnRHa: gonadotropin-releasing hormone analogues\nIM: intramuscular\nLA: leuprolide acetate\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n148\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nD A T A /uni00A0 A N D /uni00A0 A N A L Y S E S\n/uni00A0\nComparison 1. /uni00A0 GnRHas versus placebo\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n1.1 Relief of overall pain - dichotomous -\ndecrease of pain\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n1.1.1 Decreases in pelvic pain scores - 3\nmonths\n1 87 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.14 [1.41, 3.24]\n1.1.2 Decreases in dysmenorrhoea\nscores - 3 months\n1 85 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.25 [1.59, 3.16]\n1.1.3 Decreases in dyspareunia scores -\n3 months\n1 59 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.21 [1.39, 3.54]\n1.1.4 Decreases in pelvic tenderness\nscores - 3 months\n1 85 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.28 [1.48, 3.50]\n1.1.5 Decreases in pelvic induration\nscores - 3 months\n1 81 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.07 [0.64, 1.79]\n1.2 Adverse effects - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n1.2.1 Hot flushes/flashes - 3 months 1 100 Risk Ratio (M-H, Fixed, 95%\nCI)\n3.08 [1.89, 5.01]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n149\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 1.1. /uni00A0 Comparison 1: GnRHas versus placebo, Outcome\n1: Relief of overall pain - dichotomous - decrease of pain\nStudy or Subgroup\n1.1.1 Decreases in pelvic pain scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.58 (P = 0.0003)\n1.1.2 Decreases in dysmenorrhoea scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 4.63 (P < 0.00001)\n1.1.3 Decreases in dyspareunia scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.33 (P = 0.0009)\n1.1.4 Decreases in pelvic tenderness scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.75 (P = 0.0002)\n1.1.5 Decreases in pelvic induration scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.24 (P = 0.81)\nGnRHEvents\n35\n35\n44\n44\n24\n24\n35\n35\n19\n19\nTotal\n4444\n4444\n2828\n4343\n4444\nPlaceboEvents\n16\n16\n18\n18\n12\n12\n15\n15\n15\n15\nTotal\n4343\n4141\n3131\n4242\n3737\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n2.14 [1.41 , 3.24]2.14 [1.41 , 3.24]\n2.25 [1.59 , 3.16]2.25 [1.59 , 3.16]\n2.21 [1.39 , 3.54]2.21 [1.39 , 3.54]\n2.28 [1.48 , 3.50]2.28 [1.48 , 3.50]\n1.07 [0.64 , 1.79]1.07 [0.64 , 1.79]\nRisk RatioM-H, Fixed, 95% CI\n0.0050.1 1 10 200Favours placeboFavours GnRHas\nRisk of BiasA\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\nC\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n150\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 1.2. /uni00A0 Comparison 1: GnRHas versus placebo, Outcome 2: Adverse eﬀects - dichotomous\nStudy or Subgroup\n1.2.1 Hot flushes/flashes - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 4.52 (P < 0.00001)\nGnRHasEvents\n40\n40\nTotal\n5050\nPlaceboEvents\n13\n13\nTotal\n5050\nWeight\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n3.08 [1.89 , 5.01]3.08 [1.89 , 5.01]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours placeboFavours GnRHas\nRisk of BiasA\n+\nB\n+\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 2. /uni00A0 GnRHas versus placebo - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n2.1 Relief of overall pain - dichoto-\nmous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n2.1.1 Dyspareunia - 6 months 1 49 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.28 [0.09, 0.89]\n2.1.2 Dyschezia/ bowel pressure - 6\nmonths\n1 49 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.26 [0.03, 2.17]\n2.1.3 Pelvic tenderness - 6 months 1 49 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.22 [0.09, 0.55]\n2.2 Relief of overall pain - dichoto-\nmous - decrease of pain\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n2.2.1 Decreases in pelvic pain scores -\n3 months\n1 87 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.14 [1.41, 3.24]\n2.2.2 Decreases in dysmenorrhoea\nscores - 3 months\n1 85 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.25 [1.59, 3.16]\n2.2.3 Decreases in dyspareunia scores\n- 3 months\n1 59 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.21 [1.39, 3.54]\n2.2.4 Decreases in pelvic tenderness\nscores - 3 months\n1 85 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.28 [1.48, 3.50]\n2.2.5 Decreases in pelvic induration\nscores - 3 months\n1 81 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.07 [0.64, 1.79]\n2.3 Relief of overall pain - continuous 1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n151\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n2.3.1 Decrease of overall pain by\nSeverity scale mean scores - 1 month\n1 120 Mean Difference (IV, Fixed,\n95% CI)\n2.90 [2.80, 3.00]\n2.4 Adverse effects - dichotomous 3 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n2.4.1 Hot flushes/flashes - 3 months 1 100 Risk Ratio (M-H, Fixed, 95%\nCI)\n3.08 [1.89, 5.01]\n2.4.2 Vasodilatation - 6 months 1 63 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.69 [1.51, 4.81]\n2.4.3 Headache- 6 months 1 63 Risk Ratio (M-H, Fixed, 95%\nCI)\n3.55 [1.09, 11.53]\n2.4.4 Hot flushes/flashes - 12 months 1 49 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.62 [0.87, 3.02]\n2.4.5 Sleep disturbances - 12 months 1 49 Risk Ratio (M-H, Fixed, 95%\nCI)\n2.31 [1.33, 4.02]\n2.5 Quality of life - continuous 1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n2.5.1 Physical component - 1 month 1 120 Mean Difference (IV, Fixed,\n95% CI)\n-0.46 [-0.48, -0.44]\n2.5.2 Mental component - 1 month 1 120 Mean Difference (IV, Fixed,\n95% CI)\n-0.46 [-0.48, -0.44]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n152\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 2.1. /uni00A0 Comparison 2: GnRHas versus placebo - all studies\nincluded, Outcome 1: Relief of overall pain - dichotomous\nStudy or Subgroup\n2.1.1 Dyspareunia - 6 months\nBergqvist 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.15 (P = 0.03)\n2.1.2 Dyschezia/ bowel pressure - 6 months\nBergqvist 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.24 (P = 0.21)\n2.1.3 Pelvic tenderness - 6 months\nBergqvist 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.23 (P = 0.001)\nGnRHEvents\n3\n3\n1\n1\n4\n4\nTotal\n2424\n2424\n2424\nPlaceboEvents\n11\n11\n4\n4\n19\n19\nTotal\n2525\n2525\n2525\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.28 [0.09 , 0.89]0.28 [0.09 , 0.89]\n0.26 [0.03 , 2.17]0.26 [0.03 , 2.17]\n0.22 [0.09 , 0.55]0.22 [0.09 , 0.55]\nRisk RatioM-H, Fixed, 95% CI\n0.0050.1 1 10 200Favours placeboFavours GnRHas\nRisk of BiasA\n?\n?\n?\nB\n?\n?\n?\nC\n+\n+\n+\nD\n+\n+\n+\nE\n+\n+\n+\nF\n+\n+\n+\nG\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n153\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 2.2. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included,\nOutcome 2: Relief of overall pain - dichotomous - decrease of pain\nStudy or Subgroup\n2.2.1 Decreases in pelvic pain scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.58 (P = 0.0003)\n2.2.2 Decreases in dysmenorrhoea scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 4.63 (P < 0.00001)\n2.2.3 Decreases in dyspareunia scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.33 (P = 0.0009)\n2.2.4 Decreases in pelvic tenderness scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.75 (P = 0.0002)\n2.2.5 Decreases in pelvic induration scores - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.24 (P = 0.81)\nGnRHEvents\n35\n35\n44\n44\n24\n24\n35\n35\n19\n19\nTotal\n4444\n4444\n2828\n4343\n4444\nPlaceboEvents\n16\n16\n18\n18\n12\n12\n15\n15\n15\n15\nTotal\n4343\n4141\n3131\n4242\n3737\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n2.14 [1.41 , 3.24]2.14 [1.41 , 3.24]\n2.25 [1.59 , 3.16]2.25 [1.59 , 3.16]\n2.21 [1.39 , 3.54]2.21 [1.39 , 3.54]\n2.28 [1.48 , 3.50]2.28 [1.48 , 3.50]\n1.07 [0.64 , 1.79]1.07 [0.64 , 1.79]\nRisk RatioM-H, Fixed, 95% CI\n0.0050.1 1 10 200Favours placeboFavours GnRHas\nRisk of BiasA\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\nC\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n154\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 2.3. /uni00A0 Comparison 2: GnRHas versus placebo - all\nstudies included, Outcome 3: Relief of overall pain - continuous\nStudy or Subgroup\n2.3.1 Decrease of overall pain by Severity scale mean scores - 1 monthMiller 2000Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 55.66 (P < 0.00001)\nGnRHasMean\n7.22\nSD\n0.3\nTotal\n6060\nPlaceboMean\n4.32\nSD\n0.27\nTotal\n6060\nWeight\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n2.90 [2.80 , 3.00]2.90 [2.80 , 3.00]\nMean Difference\nIV, Fixed, 95% CI\n-4 -2 0 2 4Favours placeboFavours GnRHas\nRisk of BiasA\n+\nB\n?\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n155\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 2.4. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included, Outcome 4: Adverse eﬀects - dichotomous\nStudy or Subgroup\n2.4.1 Hot flushes/flashes - 3 monthsLing 1999Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 4.52 (P < 0.00001)\n2.4.2 Vasodilatation - 6 monthsDlugi 1990Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 3.34 (P = 0.0008)\n2.4.3 Headache- 6 monthsDlugi 1990Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.11 (P = 0.03)\n2.4.4 Hot flushes/flashes - 12 months\nBergqvist 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.52 (P = 0.13)\n2.4.5 Sleep disturbances - 12 months\nBergqvist 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.98 (P = 0.003)\nGnRHasEvents\n40\n40\n25\n25\n11\n11\n14\n14\n20\n20\nTotal\n5050\n3232\n3232\n2424\n2424\nPlaceboEvents\n13\n13\n9\n9\n3\n3\n9\n9\n9\n9\nTotal\n5050\n3131\n3131\n2525\n2525\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n3.08 [1.89 , 5.01]3.08 [1.89 , 5.01]\n2.69 [1.51 , 4.81]2.69 [1.51 , 4.81]\n3.55 [1.09 , 11.53]\n3.55 [1.09 , 11.53]\n1.62 [0.87 , 3.02]1.62 [0.87 , 3.02]\n2.31 [1.33 , 4.02]2.31 [1.33 , 4.02]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours placeboFavours GnRHas\nRisk of BiasA\n+\n?\n?\n?\n?\nB\n+\n+\n+\n?\n?\nC\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\nE\n+\n−\n−\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n156\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 2.5. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included, Outcome 5: Quality of life - continuous\nStudy or Subgroup\n2.5.1 Physical component - 1 monthMiller 2000Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 38.65 (P < 0.00001)\n2.5.2 Mental component - 1 monthMiller 2000Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 55.65 (P < 0.00001)\nGnRHasMean\n-0.64\n-0.58\nSD\n0.07\n0.05\nTotal\n6060\n6060\nPlaceboMean\n-0.18\n-0.12\nSD\n0.06\n0.04\nTotal\n6060\n6060\nWeight\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-0.46 [-0.48 , -0.44]-0.46 [-0.48 , -0.44]\n-0.46 [-0.48 , -0.44]-0.46 [-0.48 , -0.44]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHasFavours  placebo\nRisk of BiasA\n+\n+\nB\n?\n?\nC\n+\n+\nD\n+\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 3. /uni00A0 GnRHas versus danazol\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n3.1 Relief of overall pain - di-\nchotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n3.1.1 Pelvic tenderness, partly re-\nsolved - 6 months\n1 41 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.49, 2.73]\n3.1.2 Pelvic tenderness, complete\nresolved - 6 months\n1 41 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.67, 1.81]\n3.2 Relief of overall pain - contin-\nuous\n1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n3.2.1 Relief of overall pain- 3\nmonths\n1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-0.30 [-1.66, 1.06]\n3.2.2 Pelvic pain - 3 months 1 41 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.26, 0.66]\n3.2.3 Dysmenorrhoea - 3 months 1 41 Mean Difference (IV, Fixed, 95%\nCI)\n0.10 [-0.49, 0.69]\n3.2.4 Dyspareunia - 3 months 1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-0.20 [-0.77, 0.37]\n3.2.5 Pelvic induration - 3 months 1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-0.10 [-0.59, 0.39]\n3.2.6 Pelvic tenderness - 3\nmonths\n1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-0.20 [-0.78, 0.38]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n157\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n3.2.7 Relief of overall pain - 6\nmonths\n1 41 Mean Difference (IV, Fixed, 95%\nCI)\n0.40 [-0.86, 1.66]\n3.2.8 Pelvic pain - 6 months 1 41 Mean Difference (IV, Fixed, 95%\nCI)\n0.50 [0.10, 0.90]\n3.2.9 Dysmenorrhoea - 6 months 1 41 Mean Difference (IV, Fixed, 95%\nCI)\n0.40 [-0.12, 0.92]\n3.2.10 Dyspareunia - 6 months 1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-0.40 [-0.90, 0.10]\n3.2.11 Pelvic induration - 6\nmonths\n1 41 Mean Difference (IV, Fixed, 95%\nCI)\n0.70 [0.21, 1.19]\n3.2.12 Pelvic tenderness - 6\nmonths\n1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-0.20 [-0.75, 0.35]\n3.3 Adverse effects - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n3.3.1 Vaginal dryness/vaginitis - 6\nmonths\n1 59 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.52, 4.05]\n3.3.2 Hot flushes/flashes - 6\nmonths\n1 59 Risk Ratio (M-H, Fixed, 95% CI) 15.50 [0.93, 259.61]\n3.3.3 Gastrointestinal - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.15 [0.01, 2.74]\n3.3.4 Weight gain - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.08, 0.82]\n3.3.5 Acne - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.08 [0.00, 1.35]\n3.3.6 Generalised spasm - 6\nmonths\n1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.08 [0.00, 1.35]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n158\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.1. /uni00A0 Comparison 3: GnRHas versus danazol, Outcome 1: Relief of overall pain - dichotomous\nStudy or Subgroup\n3.1.1 Pelvic tenderness, partly resolved - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.32 (P = 0.75)\n3.1.2 Pelvic tenderness, complete resolved - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.37 (P = 0.71)\nGnRHasEvents\n8\n8\n14\n14\nTotal\n2222\n2222\nDanazolEvents\n6\n6\n11\n11\nTotal\n1919\n1919\nWeight\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.15 [0.49 , 2.73]1.15 [0.49 , 2.73]\n1.10 [0.67 , 1.81]1.10 [0.67 , 1.81]\nRisk RatioM-H, Fixed, 95% CI\n0.2 0.51 2 5Favours danazolFavours GnRHas\nRisk of BiasA\n+\n+\nB\n+\n+\nC\n+\n+\nD\n+\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n159\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.2. /uni00A0 Comparison 3: GnRHas versus danazol, Outcome 2: Relief of overall pain - continuous\nStudy or Subgroup\n3.2.1 Relief of overall pain- 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.43 (P = 0.67)\n3.2.2 Pelvic pain - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.85 (P = 0.40)\n3.2.3 Dysmenorrhoea - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.33 (P = 0.74)\n3.2.4 Dyspareunia - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.69 (P = 0.49)\n3.2.5 Pelvic induration - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.40 (P = 0.69)\n3.2.6 Pelvic tenderness - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.67 (P = 0.50)\n3.2.7 Relief of overall pain - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.62 (P = 0.53)\n3.2.8 Pelvic pain - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.44 (P = 0.01)\n3.2.9 Dysmenorrhoea - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.51 (P = 0.13)\n3.2.10 Dyspareunia - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.58 (P = 0.11)\n3.2.11 Pelvic induration - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.79 (P = 0.005)\n3.2.12 Pelvic tenderness - 6 monthsCheng 2005Subtotal (95% CI)\nGnRHasMean\n-4.4\n-0.3\n-2\n-0.6\n-0.5\n-0.9\n-4.2\n0\n-2\n-0.6\n0\n-0.9\nSD\n2.7\n0.7\n0.9\n1.2\n0.9\n1\n2.4\n0.6\n0.9\n1\n0.8\n1\nTotal\n2222\n2222\n2222\n2222\n2222\n2222\n2222\n2222\n2222\n2222\n2222\n2222\nDanazolMean\n-4.1\n-0.5\n-2.1\n-0.4\n-0.4\n-0.7\n-4.6\n-0.5\n-2.4\n-0.2\n-0.7\n-0.7\nSD\n1.7\n0.8\n1\n0.6\n0.7\n0.9\n1.7\n0.7\n0.8\n0.6\n0.8\n0.8\nTotal\n1919\n1919\n1919\n1919\n1919\n1919\n1919\n1919\n1919\n1919\n1919\n1919\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-0.30 [-1.66 , 1.06]-0.30 [-1.66 , 1.06]\n0.20 [-0.26 , 0.66]0.20 [-0.26 , 0.66]\n0.10 [-0.49 , 0.69]0.10 [-0.49 , 0.69]\n-0.20 [-0.77 , 0.37]-0.20 [-0.77 , 0.37]\n-0.10 [-0.59 , 0.39]-0.10 [-0.59 , 0.39]\n-0.20 [-0.78 , 0.38]-0.20 [-0.78 , 0.38]\n0.40 [-0.86 , 1.66]0.40 [-0.86 , 1.66]\n0.50 [0.10 , 0.90]0.50 [0.10 , 0.90]\n0.40 [-0.12 , 0.92]0.40 [-0.12 , 0.92]\n-0.40 [-0.90 , 0.10]-0.40 [-0.90 , 0.10]\n0.70 [0.21 , 1.19]0.70 [0.21 , 1.19]\n-0.20 [-0.75 , 0.35]-0.20 [-0.75 , 0.35]\nMean Difference\nIV, Fixed, 95% CI Risk of BiasA\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nC\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n160\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.2. /uni00A0 (Continued)\n3.2.12 Pelvic tenderness - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.71 (P = 0.48)\n-0.9 1 2222 -0.7 0.8 1919100.0%100.0%-0.20 [-0.75 , 0.35]-0.20 [-0.75 , 0.35]\n-2-1 0 1 2Favours GnRHasFavours danazol\n+++++++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n161\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 3.3. /uni00A0 Comparison 3: GnRHas versus danazol, Outcome 3: Adverse eﬀects - dichotomous\nStudy or Subgroup\n3.3.1 Vaginal dryness/vaginitis - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.71 (P = 0.48)\n3.3.2 Hot flushes/flashes - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.91 (P = 0.06)\n3.3.3 Gastrointestinal - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.28 (P = 0.20)\n3.3.4 Weight gain - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.29 (P = 0.02)\n3.3.5 Acne - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.75 (P = 0.08)\n3.3.6 Generalised spasm - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.75 (P = 0.08)\nGnRHasEvents\n7\n7\n7\n7\n0\n0\n3\n3\n0\n0\n0\n0\nTotal\n2929\n2929\n2929\n2929\n2929\n2929\nDanazolEvents\n5\n5\n0\n0\n3\n3\n12\n12\n6\n6\n6\n6\nTotal\n3030\n3030\n3030\n3030\n3030\n3030\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.45 [0.52 , 4.05]1.45 [0.52 , 4.05]\n15.50 [0.93 , 259.61]15.50 [0.93 , 259.61]\n0.15 [0.01 , 2.74]0.15 [0.01 , 2.74]\n0.26 [0.08 , 0.82]0.26 [0.08 , 0.82]\n0.08 [0.00 , 1.35]0.08 [0.00 , 1.35]\n0.08 [0.00 , 1.35]0.08 [0.00 , 1.35]\nRisk RatioM-H, Fixed, 95% CI\n0.0020.1 1 10 500Favours danazolFavours GnRHas\nRisk of BiasA\n+\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\n+\nC\n+\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 4. /uni00A0 GnRHas versus danazol - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n4.1 Relief of overall pain - dichoto-\nmous\n8 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n162\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n4.1.1 Pelvic pain - 6 months 6 625 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.83, 1.11]\n4.1.2 Dysmenorrhoea - 6 months 6 644 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.96, 1.06]\n4.1.3 Dyspareunia - 6 months 5 342 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.90, 1.34]\n4.1.4 Pelvic induration - 6 months 2 151 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.32, 1.89]\n4.1.5 Pelvic tenderness - 6 months 1 96 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.39, 2.00]\n4.1.6 Pelvic tenderness, partly re-\nsolved - 6 months\n2 96 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.59, 2.76]\n4.1.7 Pelvic tenderness, complete\nresolved - 6 months\n2 294 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.84, 1.12]\n4.1.8 Pelvic tenderness and indura-\ntion combined, complete resolved -\n6 months\n1 53 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.59, 1.38]\n4.1.9 Pelvic tenderness and indura-\ntion combined, partly resolved - 6\nmonths\n1 53 Risk Ratio (M-H, Fixed, 95% CI) 1.54 [0.35, 6.89]\n4.2 Relief of overall pain - continu-\nous\n4 /uni00A0 Std. Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n4.2.1 Relief of overall pain- 3 months 1 41 Std. Mean Difference (IV, Fixed,\n95% CI)\n-0.13 [-0.74, 0.49]\n4.2.2 Pelvic pain - 3 months 1 41 Std. Mean Difference (IV, Fixed,\n95% CI)\n0.26 [-0.35, 0.88]\n4.2.3 Dysmenorrhoea - 3 months 1 41 Std. Mean Difference (IV, Fixed,\n95% CI)\n0.10 [-0.51, 0.72]\n4.2.4 Dyspareunia - 3 months 1 41 Std. Mean Difference (IV, Fixed,\n95% CI)\n-0.20 [-0.82, 0.41]\n4.2.5 Pelvic induration - 3 months 1 41 Std. Mean Difference (IV, Fixed,\n95% CI)\n-0.12 [-0.73, 0.49]\n4.2.6 Pelvic tenderness - 3 months 1 41 Std. Mean Difference (IV, Fixed,\n95% CI)\n-0.21 [-0.82, 0.41]\n4.2.7 Relief of overall pain - 6\nmonths\n3 85 Std. Mean Difference (IV, Fixed,\n95% CI)\n-0.00 [-0.46, 0.46]\n4.2.8 Pelvic pain - 6 months 2 90 Std. Mean Difference (IV, Fixed,\n95% CI)\n0.35 [-0.08, 0.79]\n4.2.9 Dysmenorrhoea - 6 months 1 41 Std. Mean Difference (IV, Fixed,\n95% CI)\n0.46 [-0.16, 1.08]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n163\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n4.2.10 Dyspareunia - 6 months 2 90 Std. Mean Difference (IV, Fixed,\n95% CI)\n0.25 [-0.19, 0.69]\n4.2.11 Pelvic induration - 6 months 2 90 Std. Mean Difference (IV, Fixed,\n95% CI)\n0.40 [-0.04, 0.83]\n4.2.12 Pelvic tenderness - 6 months 2 90 Std. Mean Difference (IV, Fixed,\n95% CI)\n-0.59 [-1.03, -0.15]\n4.3 Bone mineral density of spinal\nbone mass - continuous\n3 /uni00A0 Std. Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n4.3.1 Absolute values - 6 months 3 81 Std. Mean Difference (IV, Fixed,\n95% CI)\n0.21 [-0.31, 0.73]\n4.4 Adverse effects - dichotomous 17 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n4.4.1 Vaginal dryness/vaginitis - 6\nmonths\n12 1340 Risk Ratio (M-H, Fixed, 95% CI) 1.82 [1.53, 2.18]\n4.4.2 Hot flushes/flashes - 6 months 17 1998 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [1.42, 1.60]\n4.4.3 Headaches - 6 months 11 1103 Risk Ratio (M-H, Fixed, 95% CI) 1.43 [1.21, 1.69]\n4.4.4 Infections and flu like symp-\ntoms - 6 months\n1 71 Risk Ratio (M-H, Fixed, 95% CI) 3.60 [1.31, 9.88]\n4.4.5 Muscle cramps/myalgia - 6\nmonths\n8 884 Risk Ratio (M-H, Fixed, 95% CI) 0.16 [0.09, 0.29]\n4.4.6 Sleep disturbance/insomnia -\n6 months\n7 881 Risk Ratio (M-H, Fixed, 95% CI) 2.04 [1.61, 2.59]\n4.4.7 Skin rash - 6 months 2 241 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.01, 0.66]\n4.4.8 Gastrointestinal - 6 months 4 339 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.15, 0.74]\n4.4.9 Weight gain - 6 months 9 1081 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.29, 0.49]\n4.4.10 Acne - 6 months 10 1040 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.47, 0.73]\n4.4.11 Breast atrophy/changes - 6\nmonths\n5 646 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.52, 0.85]\n4.4.12 Emotional lability/altered\nmood - 6 months\n2 224 Risk Ratio (M-H, Fixed, 95% CI) 2.66 [1.12, 6.30]\n4.4.13 Oedema/fluid retention - 6\nmonths\n4 519 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.12, 0.40]\n4.4.14 Asthenia - 6 months 3 388 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.09, 0.64]\n4.4.15 Depression - 6 months 4 181 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.20, 0.70]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n164\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n4.4.16 Generalised spasm - 6\nmonths\n1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.08 [0.00, 1.35]\n4.4.17 Voice alteration - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.34]\n4.4.18 Hirsutism - 6 months 3 432 Risk Ratio (M-H, Fixed, 95% CI) 0.18 [0.09, 0.37]\n4.4.19 Seborrhoea - 6 months 4 461 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.19, 0.42]\n4.4.20 Alopecia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.02, 1.75]\n4.4.21 Altered libido - 6 months 9 1286 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [1.30, 1.92]\n4.4.22 Sweating - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.03, 2.51]\n4.4.23 Breast tenderness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.04, 4.33]\n4.4.24 Fatigue - 6 months 2 84 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.40, 1.26]\n4.4.25 Arthralgia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 17.61 [1.08,\n286.40]\n4.4.26 Hunger - 6 months 2 100 Risk Ratio (M-H, Fixed, 95% CI) 0.07 [0.01, 0.54]\n4.4.27 Nervousness - 6 months 2 225 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.07, 0.80]\n4.4.28 Irritability - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 4.74 [1.67, 13.45]\n4.4.29 Nausea - 6 months 3 181 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.35, 1.17]\n4.4.30 Breast pain - 6 months 1 81 Risk Ratio (M-H, Fixed, 95% CI) 3.56 [0.19, 66.61]\n4.4.31 Back distress - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.15, 2.53]\n4.4.32 Paraesthesia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.18, 3.77]\n4.4.33 Agressiveness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.34]\n4.4.34 Pain - 6 months 1 81 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.11, 2.31]\n4.4.35 Oily hair and skin - 6 months 2 126 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.26, 0.82]\n4.4.36 Bleeding - 6 months 2 89 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.22, 1.34]\n4.4.37 Malaise - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.12, 1.39]\n4.4.38 Chest /uni00A0aches - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.15, 6.21]\n4.4.39 Dizzy spells - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 3.78]\n4.4.40 PMS feelings - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.32, 5.06]\n4.5 Improvement of most trouble-\nsome symptoms - dichotomous\n6 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n165\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n4.5.1 Overall improvement - 3\nmonths\n1 53 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.63, 1.57]\n4.5.2 Overall improvement - 6\nmonths\n6 747 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.99, 1.18]\n4.5.3 Complete resolution - 6\nmonths\n5 534 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.99, 1.32]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n166\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.1. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 1: Relief of overall pain -\ndichotomous\nStudy or Subgroup\n4.1.1 Pelvic pain - 6 monthsAdamson 1994Cirkel 1995Fedele 1989\nNEET 1992Palagiano 1994Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 1.06, df = 5 (P = 0.96); I² = 0%\nTest for overall effect: Z = 0.52 (P = 0.60)\n4.1.2 Dysmenorrhoea - 6 monthsAdamson 1994Cirkel 1995Fedele 1989\nNEET 1992Palagiano 1994Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 3.48, df = 5 (P = 0.63); I² = 0%\nTest for overall effect: Z = 0.49 (P = 0.62)\n4.1.3 Dyspareunia - 6 monthsAdamson 1994Cirkel 1995Fedele 1989\nNEET 1992Palagiano 1994Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 4.59, df = 4 (P = 0.33); I² = 13%\nTest for overall effect: Z = 0.90 (P = 0.37)\n4.1.4 Pelvic induration - 6 monthsCirkel 1995\nNEET 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.91, df = 1 (P = 0.34); I² = 0%\nTest for overall effect: Z = 0.55 (P = 0.58)\n4.1.5 Pelvic tenderness - 6 months\nNEET 1992Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.29 (P = 0.77)\n4.1.6 Pelvic tenderness, partly resolved - 6 monthsCheng 2005Cirkel 1995Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.16, df = 1 (P = 0.69); I² = 0%\nTest for overall effect: Z = 0.63 (P = 0.53)\n4.1.7 Pelvic tenderness, complete resolved - 6 monthsCheng 2005Wheeler 1992\nGnRHasEvents\n30725162370\n171\n12530223127\n208\n18727923\n84\n29\n11\n13\n13\n84\n12\n1493\nTotal\n7730307127128363\n9030307127128376\n5730306627210\n306595\n6565\n223052\n22128\nDanazolEvents\n1062781675\n142\n22132017120\n192\n4827218\n59\n44\n8\n7\n7\n62\n8\n1195\nTotal\n2825323220125262\n3425323220125268\n2325323220132\n253156\n3131\n192544\n19125\nWeight\n9.6%4.3%17.1%7.2%12.0%49.7%100.0%\n1.5%\n11.5%15.8%0.3%9.8%61.0%100.0%\n8.9%13.7%40.9%4.2%32.3%100.0%\n44.6%55.4%100.0%\n100.0%100.0%\n74.7%25.3%100.0%\n10.9%89.1%\nRisk RatioM-H, Fixed, 95% CI\n1.09 [0.62 , 1.93]0.97 [0.38 , 2.52]0.99 [0.79 , 1.23]0.90 [0.43 , 1.89]1.06 [0.81 , 1.39]0.91 [0.74 , 1.13]\n0.96 [0.83 , 1.11]\n0.19 [0.02 , 2.02]0.99 [0.78 , 1.25]1.00 [0.94 , 1.06]\n2.29 [0.11 , 46.41]1.00 [0.79 , 1.28]1.03 [0.99 , 1.07]1.01 [0.96 , 1.06]\n1.82 [0.69 , 4.79]0.73 [0.31 , 1.73]1.07 [0.88 , 1.29]2.18 [0.50 , 9.52]0.95 [0.76 , 1.17]1.10 [0.90 , 1.34]\n0.42 [0.08 , 2.09]1.07 [0.36 , 3.22]0.78 [0.32 , 1.89]\n0.89 [0.39 , 2.00]0.89 [0.39 , 2.00]\n1.15 [0.49 , 2.73]1.67 [0.33 , 8.36]1.28 [0.59 , 2.76]\n1.10 [0.67 , 1.81]\n0.96 [0.83 , 1.11]\nRisk RatioM-H, Fixed, 95% CIRisk of BiasA\n?+????\n?+????\n?+???\n+?\n?\n++\n+?\nB\n+?????\n+?????\n+????\n??\n?\n+?\n+?\nC\n+??+?+\n+??+?+\n+??+?\n?+\n+\n+?\n++\nD\n+??+?+\n+??+?+\n+??+?\n?+\n+\n+?\n++\nE\n+−++++\n+−++++\n+−+++\n−+\n+\n+−\n++\nF\n++++++\n++++++\n+++++\n++\n+\n++\n++\nG\n++++++\n++++++\n+++++\n++\n+\n++\n++\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n167\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 4.1. /uni00A0 (Continued)\nCheng 2005Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.28, df = 1 (P = 0.59); I² = 0%\nTest for overall effect: Z = 0.40 (P = 0.69)\n4.1.8 Pelvic tenderness and induration combined, complete resolved - 6 monthsKennedy 1990Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.49 (P = 0.63)\n4.1.9 Pelvic tenderness and induration combined, partly resolved - 6 monthsKennedy 1990Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.57 (P = 0.57)\n1493\n107\n21\n21\n6\n6\n22128150\n3535\n3535\n1195\n106\n12\n12\n2\n2\n19125144\n1818\n1818\n10.9%89.1%100.0%\n100.0%100.0%\n100.0%100.0%\n1.10 [0.67 , 1.81]\n0.96 [0.83 , 1.11]0.97 [0.84 , 1.12]\n0.90 [0.59 , 1.38]0.90 [0.59 , 1.38]\n1.54 [0.35 , 6.89]1.54 [0.35 , 6.89]\n0.2 0.5 1 2 5Favours danazolFavours GnRHas\n+?\n?\n?\n+?\n?\n?\n++\n+\n+\n++\n+\n+\n++\n+\n+\n++\n+\n+\n++\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n168\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.2. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 2: Relief of overall pain -\ncontinuous\nStudy or Subgroup\n4.2.1 Relief of overall pain- 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.41 (P = 0.68)\n4.2.2 Pelvic pain - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.83 (P = 0.40)\n4.2.3 Dysmenorrhoea - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.33 (P = 0.74)\n4.2.4 Dyspareunia - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.64 (P = 0.52)\n4.2.5 Pelvic induration - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.38 (P = 0.70)\n4.2.6 Pelvic tenderness - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.65 (P = 0.51)\n4.2.7 Relief of overall pain - 6 monthsCheng 2005Dmowski 1989a\nTummon 1989Subtotal (95% CI)\nHeterogeneity: Chi² = 10.68, df = 2 (P = 0.005); I² = 81%\nTest for overall effect: Z = 0.00 (P = 1.00)\n4.2.8 Pelvic pain - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI)\nHeterogeneity: Chi² = 2.88, df = 1 (P = 0.09); I² = 65%\nTest for overall effect: Z = 1.59 (P = 0.11)\n4.2.9 Dysmenorrhoea - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.44 (P = 0.15)\n4.2.10 Dyspareunia - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI)\nHeterogeneity: Chi² = 10.30, df = 1 (P = 0.001); I² = 90%\nTest for overall effect: Z = 1.10 (P = 0.27)\n4.2.11 Pelvic induration - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI)\nHeterogeneity: Chi² = 3.67, df = 1 (P = 0.06); I² = 73%\nTest for overall effect: Z = 1.77 (P = 0.08)\nGnRHasMean\n-4.4\n-0.3\n-2\n-0.6\n-0.5\n-0.9\n-4.20.70.4\n00.3\n-2\n-0.60.2\n00.1\nSD\n2.7\n0.7\n0.9\n1.2\n0.9\n1\n2.40.870.2\n0.60.1\n0.9\n10.1\n0.80.1\nTotal\n2222\n2222\n2222\n2222\n2222\n2222\n22191051\n223355\n2222\n223355\n223355\nDanazolMean\n-4.1\n-0.5\n-2.1\n-0.4\n-0.4\n-0.7\n-4.60.41.4\n-0.50.3\n-2.4\n-0.20.1\n-0.70.1\nSD\n1.7\n0.8\n1\n0.6\n0.7\n0.9\n1.70.630.7\n0.70.2\n0.8\n0.60.1\n0.80.1\nTotal\n1919\n1919\n1919\n1919\n1919\n1919\n1910534\n191635\n1919\n191635\n191635\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n54.9%34.8%10.3%100.0%\n46.7%53.3%100.0%\n100.0%100.0%\n50.6%49.4%100.0%\n46.2%53.8%100.0%\nStd. Mean Difference\nIV, Fixed, 95% CI\n-0.13 [-0.74 , 0.49]-0.13 [-0.74 , 0.49]\n0.26 [-0.35 , 0.88]0.26 [-0.35 , 0.88]\n0.10 [-0.51 , 0.72]0.10 [-0.51 , 0.72]\n-0.20 [-0.82 , 0.41]-0.20 [-0.82 , 0.41]\n-0.12 [-0.73 , 0.49]-0.12 [-0.73 , 0.49]\n-0.21 [-0.82 , 0.41]-0.21 [-0.82 , 0.41]\n0.19 [-0.43 , 0.80]0.37 [-0.41 , 1.14]-2.23 [-3.65 , -0.81]-0.00 [-0.46 , 0.46]\n0.76 [0.12 , 1.39]0.00 [-0.60 , 0.60]0.35 [-0.08 , 0.79]\n0.46 [-0.16 , 1.08]0.46 [-0.16 , 1.08]\n-0.47 [-1.09 , 0.16]0.98 [0.35 , 1.61]0.25 [-0.19 , 0.69]\n0.86 [0.21 , 1.50]0.00 [-0.60 , 0.60]0.40 [-0.04 , 0.83]\nStd. Mean Difference\nIV, Fixed, 95% CI Risk of BiasA\n+\n+\n+\n+\n+\n+\n+??\n++\n+\n++\n++\nB\n+\n+\n+\n+\n+\n+\n+??\n+?\n+\n+?\n+?\nC\n+\n+\n+\n+\n+\n+\n+??\n++\n+\n++\n++\nD\n+\n+\n+\n+\n+\n+\n+??\n++\n+\n++\n++\nE\n+\n+\n+\n+\n+\n+\n+++\n++\n+\n++\n++\nF\n+\n+\n+\n+\n+\n+\n+++\n++\n+\n++\n++\nG\n+\n+\n+\n+\n+\n+\n+++\n++\n+\n++\n++\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n169\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 4.2. /uni00A0 (Continued)\nSubtotal (95% CI)\nHeterogeneity: Chi² = 3.67, df = 1 (P = 0.06); I² = 73%\nTest for overall effect: Z = 1.77 (P = 0.08)\n4.2.12 Pelvic tenderness - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI)\nHeterogeneity: Chi² = 2.93, df = 1 (P = 0.09); I² = 66%\nTest for overall effect: Z = 2.63 (P = 0.009)\n-0.90.1 10.1\n55\n223355\n-0.70.2 0.80.1\n35\n191635\n100.0%\n51.2%48.8%100.0%\n0.40 [-0.04 , 0.83]\n-0.21 [-0.83 , 0.40]-0.98 [-1.61 , -0.35]-0.59 [-1.03 , -0.15]\n-2-1 0 1 2Favours GnRHasFavours danazol\n+++? ++++++++++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 4.3. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included,\nOutcome 3: Bone mineral density of spinal bone mass - continuous\nStudy or Subgroup\n4.3.1 Absolute values - 6 monthsFukushima 1993\nTummon 1988Whitehouse 1990Subtotal (95% CI)\nHeterogeneity: Chi² = 32.04, df = 2 (P < 0.00001); I² = 94%\nTest for overall effect: Z = 0.79 (P = 0.43)\nGnRHasMean\n144.11.24150.5\nSD\n11.40.00224.3\nTotal\n10251550\nDanazolMean\n170.81.22157.4\nSD\n9.60.0219\nTotal\n913931\nWeight\n17.3%44.0%38.7%100.0%\nStd. Mean Difference\nIV, Fixed, 95% CI\n-2.41 [-3.65 , -1.16]1.68 [0.90 , 2.46]-0.30 [-1.13 , 0.54]0.21 [-0.31 , 0.73]\nStd. Mean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHasFavours danazol\nRisk of BiasA\n???\nB\n???\nC\n??+\nD\n+?+\nE\n−?+\nF\n+++\nG\n+++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n170\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.4. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 4: Adverse eﬀects - dichotomous\nStudy or Subgroup\n4.4.1 Vaginal dryness/vaginitis - 6 monthsAN Zoladex 1996Audebert 1997Burry 1992Cheng 2005Cirkel 1995Dmowski 1989aFedele 1989Jelley 1986\nNEET 1992Palagiano 1994Rock 1993Rolland 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 12.30, df = 11 (P = 0.34); I² = 11%\nTest for overall effect: Z = 6.65 (P < 0.00001)\n4.4.2 Hot flushes/flashes - 6 monthsAN Zoladex 1996Audebert 1997Burry 1992Chang 1996Cheng 2005Cirkel 1995Dmowski 1989aFedele 1989Fraser 1991Henzl 1988Jelley 1986\nNEET 1992Palagiano 1994Rock 1993Rolland 1990Rotondi 2002Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 51.22, df = 16 (P < 0.0001); I² = 69%\nTest for overall effect: Z = 13.37 (P < 0.00001)\n4.4.3 Headaches - 6 monthsAN Zoladex 1996Audebert 1997Burry 1992Cirkel 1995Dmowski 1989aFedele 1989Fraser 1991Palagiano 1994Rock 1993Rolland 1990Rotondi 2002Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 8.64, df = 10 (P = 0.57); I² = 0%\nTest for overall effect: Z = 4.18 (P < 0.0001)\n4.4.4 Infections and flu like symptoms - 6 monthsAN Zoladex 1996Subtotal (95% CI)\nTotal events:\nGnRHasEvents\n266127137101331515620\n306\n352610229730162813129231542019810652\n113\n1081\n139121913\n1187144133\n252\n14\n14\nTotal\n3533\n111293019302317127208107823\n3533\n1113029301930331432317127208107541341217\n3533\n111301930332720810754687\n3535\nDanazolEvents\n10155534567486\n105\n157442019613548967375451674\n448\n4241264235971\n104\n4\n4\nTotal\n3622583025103222922010763517\n362258153025103216702292201076327136781\n36225825103216201076327416\n3636\nWeight\n7.7%0.9%5.1%3.8%4.3%3.1%3.0%4.0%6.1%6.3%49.6%5.9%100.0%\n2.8%1.5%10.5%0.5%0.1%3.9%1.4%2.3%1.2%\n11.8%1.8%15.9%0.6%18.1%10.3%3.9%13.4%100.0%\n3.0%1.8%4.0%10.0%6.0%3.0%2.1%2.6%59.6%6.7%1.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n2.67 [1.53 , 4.69]4.00 [0.52 , 30.98]1.25 [0.46 , 3.39]1.45 [0.52 , 4.05]2.17 [0.89 , 5.25]1.23 [0.40 , 3.74]2.67 [0.94 , 7.60]2.49 [1.06 , 5.82]2.78 [1.20 , 6.42]0.53 [0.20 , 1.43]1.67 [1.34 , 2.09]1.96 [0.83 , 4.63]1.82 [1.53 , 2.18]\n2.35 [1.61 , 3.45]2.48 [1.31 , 4.68]1.21 [1.04 , 1.41]7.25 [1.99 , 26.39]15.50 [0.93 , 259.61]1.31 [1.05 , 1.65]1.40 [0.82 , 2.41]2.30 [1.50 , 3.53]1.26 [0.54 , 2.92]\n1.32 [1.11 , 1.56]2.37 [1.45 , 3.87]1.24 [1.08 , 1.41]4.94 [1.70 , 14.35]1.36 [1.20 , 1.54]1.39 [1.19 , 1.62]1.63 [1.18 , 2.23]1.55 [1.31 , 1.84]1.50 [1.42 , 1.60]\n3.34 [1.21 , 9.27]3.00 [0.72 , 12.59]1.57 [0.53 , 4.64]1.32 [0.81 , 2.15]1.14 [0.63 , 2.06]2.93 [1.05 , 8.22]1.94 [0.46 , 8.10]1.73 [0.51 , 5.87]1.26 [1.03 , 1.52]1.09 [0.46 , 2.60]1.50 [0.16 , 13.75]1.43 [1.21 , 1.69]\n3.60 [1.31 , 9.88]3.60 [1.31 , 9.88]\nRisk RatioM-H, Fixed, 95% CIRisk of BiasA\n???++???????\n????++??+????????\n???+??+????\n?\nB\n???+???+????\n???++?????+??????\n???????????\n?\nC\n??++????+??+\n??+?+???++?+??+?+\n??+???+??+?\n?\nD\n??++????+??+\n??+++???++?+??+?+\n??+???+??+?\n?\nE\n−+++−+++++++\n−++?+−+++++++++++\n−++−+++++++\n−\nF\n++++++++++++\n+++++++++++++++++\n+++++++++++\n+\nG\n++++++++++++\n+++++++++++++++++\n+++++++++++\n+\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n171\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.4. /uni00A0 (Continued)\nSubtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.49 (P = 0.01)\n4.4.5 Muscle cramps/myalgia - 6 monthsAN Zoladex 1996Burry 1992Cirkel 1995Fedele 1989Fraser 1991Jelley 1986\nNEET 1992Rolland 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 5.13, df = 7 (P = 0.64); I² = 0%\nTest for overall effect: Z = 6.04 (P < 0.00001)\n4.4.6 Sleep disturbance/insomnia - 6 monthsAN Zoladex 1996Cirkel 1995Dmowski 1989aJelley 1986\nNEET 1992Rolland 1990Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 10.92, df = 6 (P = 0.09); I² = 45%\nTest for overall effect: Z = 5.82 (P < 0.00001)\n4.4.7 Skin rash - 6 monthsAN Zoladex 1996Rolland 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.07, df = 1 (P = 0.79); I² = 0%\nTest for overall effect: Z = 2.36 (P = 0.02)\n4.4.8 Gastrointestinal - 6 monthsAudebert 1997Cheng 2005Cirkel 1995Rolland 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 2.55, df = 3 (P = 0.47); I² = 0%\nTest for overall effect: Z = 2.71 (P = 0.007)\n4.4.9 Weight gain - 6 monthsAudebert 1997Burry 1992Cheng 2005Fedele 1989Jelley 1986Palagiano 1994Rock 1993Rotondi 2002Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 22.63, df = 8 (P = 0.004); I² = 65%\nTest for overall effect: Z = 7.42 (P < 0.00001)\n14\n12200034\n12\n316211231423\n182\n00\n0\n3040\n7\n163213025117\n68\n35\n35\n11130303323171107540\n35301923171107126\n511\n35107142\n332930107199\n33\n1112930232720854126641\n4\n673951079\n56\n01303848\n54\n44\n8\n4364\n17\n5\n11122220818736\n139\n36\n3658253216229263344\n362510229263122370\n366399\n22302563140\n22583032222010727122440\n100.0%\n9.0%13.9%5.0%13.9%\n11.1%16.2%13.8%17.1%100.0%\n0.7%1.6%5.7%0.7%72.0%7.3%\n11.8%100.0%\n44.0%56.0%100.0%\n23.5%16.8%32.0%27.6%100.0%\n3.9%9.4%7.7%13.9%13.3%6.3%15.5%6.1%23.8%100.0%\n3.60 [1.31 , 9.88]3.60 [1.31 , 9.88]\n0.17 [0.02 , 1.35]0.15 [0.03 , 0.70]0.56 [0.10 , 3.07]0.06 [0.00 , 0.92]0.05 [0.00 , 0.77]0.05 [0.00 , 0.73]0.23 [0.06 , 0.87]0.26 [0.08 , 0.81]0.16 [0.09 , 0.29]\n7.19 [0.39 , 134.39]13.33 [1.90 , 93.65]0.35 [0.07 , 1.77]2.88 [0.12 , 67.03]1.74 [1.34 , 2.26]2.06 [0.71 , 5.99]2.78 [1.30 , 5.98]2.04 [1.61 , 2.59]\n0.11 [0.01 , 2.05]0.07 [0.00 , 1.20]0.09 [0.01 , 0.66]\n0.50 [0.12 , 2.02]0.15 [0.01 , 2.74]0.56 [0.18 , 1.75]0.07 [0.00 , 1.20]0.34 [0.15 , 0.74]\n0.13 [0.02 , 1.07]\n0.29 [0.11 , 0.73]0.26 [0.08 , 0.82]0.10 [0.02 , 0.38]0.62 [0.42 , 0.91]0.04 [0.00 , 0.72]0.71 [0.41 , 1.25]0.07 [0.01 , 0.55]0.46 [0.27 , 0.77]0.38 [0.29 , 0.49]\n??+?+???\n?+?????\n??\n?++?\n??+??????\n?????+??\n???+???\n??\n?+??\n??+?+????\n?+??+?++\n????+++\n?+\n?+?+\n?++?????+\n?+??+?++\n????+++\n?+\n?+?+\n?++?????+\n−+−+++++\n−−+++++\n−+\n++−+\n+++++++++\n++++++++\n+++++++\n++\n++++\n+++++++++\n++++++++\n+++++++\n++\n++++\n+++++++++\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n172\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.4. /uni00A0 (Continued)\nTest for overall effect: Z = 7.42 (P < 0.00001)\n4.4.10 Acne - 6 monthsAudebert 1997Burry 1992Cheng 2005Cirkel 1995Dmowski 1989aFedele 1989Jelley 1986Rock 1993Rolland 1990Rotondi 2002Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 12.76, df = 9 (P = 0.17); I² = 29%\nTest for overall effect: Z = 4.74 (P < 0.00001)\n4.4.11 Breast atrophy/changes - 6 monthsBurry 1992Cirkel 1995Fedele 1989Jelley 1986Rock 1993Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 6.20, df = 4 (P = 0.18); I² = 35%\nTest for overall effect: Z = 3.20 (P = 0.001)\n4.4.12 Emotional lability/altered mood - 6 monthsBurry 1992Cirkel 1995Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 1.80, df = 1 (P = 0.18); I² = 45%\nTest for overall effect: Z = 2.23 (P = 0.03)\n4.4.13 Oedema/fluid retention - 6 monthsBurry 1992Cirkel 1995Palagiano 1994Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 4.33, df = 3 (P = 0.23); I² = 31%\nTest for overall effect: Z = 4.95 (P < 0.00001)\n4.4.14 Asthenia - 6 monthsBurry 1992Fraser 1991Rolland 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 2.44, df = 2 (P = 0.30); I² = 18%\nTest for overall effect: Z = 2.87 (P = 0.004)\n4.4.15 Depression - 6 monthsChang 1996Dmowski 1989aFedele 1989Jelley 1986Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 7.48, df = 3 (P = 0.06); I² = 60%\nTest for overall effect: Z = 3.06 (P = 0.002)\n2160350465720\n122\n808267\n85\n1310\n23\n3207\n12\n410\n5\n1640\n11\n33\n111293019302320810754644\n111303023208402\n11130141\n1113027126294\n11133107251\n30193023102\n6126969843415\n118\n667054\n73\n15\n6\n351524\n47\n705\n12\n7545\n21\n225830251032221076327396\n58253222107244\n582583\n582520122225\n581663137\n1510322279\n4.9%10.8%4.4%6.7%5.4%6.3%5.6%38.8%3.4%13.7%100.0%\n8.4%7.6%7.2%0.5%76.2%100.0%\n19.4%80.6%100.0%\n7.7%10.6%34.4%47.4%100.0%\n54.8%4.0%41.2%100.0%\n36.8%25.8%15.3%22.1%100.0%\n0.22 [0.05 , 1.00]0.70 [0.35 , 1.37]0.08 [0.00 , 1.35]0.28 [0.08 , 0.92]0.44 [0.18 , 1.09]0.06 [0.00 , 0.92]0.48 [0.17 , 1.36]0.78 [0.57 , 1.06]1.03 [0.31 , 3.38]0.67 [0.41 , 1.08]0.59 [0.47 , 0.73]\n0.70 [0.25 , 1.91]0.06 [0.00 , 1.09]1.22 [0.50 , 2.95]4.79 [0.24 , 94.53]0.64 [0.49 , 0.84]0.66 [0.52 , 0.85]\n6.79 [0.91 , 50.65]1.67 [0.66 , 4.24]2.66 [1.12 , 6.30]\n0.52 [0.11 , 2.51]0.33 [0.07 , 1.57]0.02 [0.00 , 0.38]0.28 [0.13 , 0.63]0.22 [0.12 , 0.40]\n0.30 [0.09 , 0.98]1.50 [0.06 , 34.91]0.05 [0.00 , 0.96]0.25 [0.09 , 0.64]\n0.07 [0.01 , 0.53]0.63 [0.26 , 1.56]1.07 [0.29 , 3.89]0.09 [0.01 , 1.49]0.37 [0.20 , 0.70]\n??++??????\n?+???\n?+\n?+??\n?+?\n????\n??+???+???\n???+?\n??\n????\n???\n+??+\n?++?????+?\n+????\n+?\n+??+\n+++\n????\n?++?????+?\n+????\n+?\n+??+\n+++\n+???\n+++−++++++\n+−+++\n+−\n+−++\n+++\n?+++\n++++++++++\n+++++\n++\n++++\n+++\n++++\n++++++++++\n+++++\n++\n++++\n+++\n++++\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n173\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.4. /uni00A0 (Continued)\nHeterogeneity: Chi² = 7.48, df = 3 (P = 0.06); I² = 60%\nTest for overall effect: Z = 3.06 (P = 0.002)\n4.4.16 Generalised spasm - 6 monthsCheng 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.75 (P = 0.08)\n4.4.17 Voice alteration - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.17 (P = 0.24)\n4.4.18 Hirsutism - 6 monthsCirkel 1995Fedele 1989Rock 1993Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 5.40, df = 2 (P = 0.07); I² = 63%\nTest for overall effect: Z = 4.75 (P < 0.00001)\n4.4.19 Seborrhoea - 6 monthsCirkel 1995Dmowski 1989aFedele 1989Rock 1993Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 1.91, df = 3 (P = 0.59); I² = 0%\nTest for overall effect: Z = 6.30 (P < 0.00001)\n4.4.20 Alopecia - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.45 (P = 0.15)\n4.4.21 Altered libido - 6 monthsCirkel 1995Fedele 1989Jelley 1986\nNEET 1992Palagiano 1994Rock 1993Rolland 1990Rotondi 2002Wheeler 1992Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 18.88, df = 8 (P = 0.02); I² = 58%\nTest for overall effect: Z = 4.64 (P < 0.00001)\n4.4.22 Sweating - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.14 (P = 0.25)\n4.4.23 Breast tenderness - 6 months\n0\n0\n0\n0\n0010\n10\n15025\n31\n1\n1\n1460244129183518\n248\n1\n1\n2929\n3030\n3030208268\n301930208287\n3030\n3030231712720810754126776\n3030\n6\n6\n2\n2\n16614\n36\n46743\n60\n4\n4\n25855452146\n92\n3\n3\n3030\n2525\n2532107164\n251032107174\n2525\n25322292201076327122510\n2525\n100.0%100.0%\n100.0%100.0%\n42.0%14.7%43.3%100.0%\n5.7%10.3%9.5%74.4%100.0%\n100.0%100.0%\n1.9%4.2%7.6%5.7%5.0%51.8%2.2%16.3%5.3%100.0%\n100.0%100.0%\n0.08 [0.00 , 1.35]0.08 [0.00 , 1.35]\n0.17 [0.01 , 3.34]0.17 [0.01 , 3.34]\n0.03 [0.00 , 0.40]0.08 [0.00 , 1.39]0.37 [0.17 , 0.80]0.18 [0.09 , 0.37]\n0.21 [0.02 , 1.75]0.44 [0.18 , 1.09]0.07 [0.00 , 1.19]0.30 [0.19 , 0.46]0.29 [0.19 , 0.42]\n0.21 [0.02 , 1.75]0.21 [0.02 , 1.75]\n5.83 [1.46 , 23.26]1.28 [0.44 , 3.76]0.06 [0.00 , 0.92]2.58 [1.02 , 6.54]0.59 [0.18 , 1.93]1.47 [1.15 , 1.89]5.30 [1.27 , 22.08]1.25 [0.83 , 1.89]2.90 [1.19 , 7.07]1.58 [1.30 , 1.92]\n0.28 [0.03 , 2.51]0.28 [0.03 , 2.51]\n+\n+\n+??\n+???\n+\n+????????\n+\n+\n?\n???\n????\n?\n??+??????\n?\n+\n?\n???\n????\n?\n???+??+?+\n?\n+\n?\n???\n????\n?\n???+??+?+\n?\n+\n−\n−++\n−+++\n−\n−++++++++\n−\n+\n+\n+++\n++++\n+\n+++++++++\n+\n+\n+\n+++\n++++\n+\n+++++++++\n+\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n174\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.4. /uni00A0 (Continued)\nTest for overall effect: Z = 1.14 (P = 0.25)\n4.4.23 Breast tenderness - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.73 (P = 0.46)\n4.4.24 Fatigue - 6 monthsCirkel 1995Dmowski 1989aSubtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 4.30, df = 1 (P = 0.04); I² = 77%\nTest for overall effect: Z = 1.17 (P = 0.24)\n4.4.25 Arthralgia - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.02 (P = 0.04)\n4.4.26 Hunger - 6 monthsCirkel 1995Jelley 1986Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.25, df = 1 (P = 0.62); I² = 0%\nTest for overall effect: Z = 2.57 (P = 0.01)\n4.4.27 Nervousness - 6 monthsCirkel 1995Rolland 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.31, df = 1 (P = 0.58); I² = 0%\nTest for overall effect: Z = 2.32 (P = 0.02)\n4.4.28 Irritability - 6 monthsDmowski 1989aSubtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.92 (P = 0.003)\n4.4.29 Nausea - 6 monthsCirkel 1995Jelley 1986Rotondi 2002Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 3.38, df = 2 (P = 0.18); I² = 41%\nTest for overall effect: Z = 1.45 (P = 0.15)\n4.4.30 Breast pain - 6 monthsRotondi 2002Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.85 (P = 0.39)\n4.4.31 Back distress - 6 monthsCirkel 1995Subtotal (95% CI)\n1\n1\n6\n11\n17\n10\n10\n00\n0\n03\n3\n9\n9\n753\n15\n3\n3\n3\n3030\n301949\n3030\n302353\n30107137\n1919\n302354107\n5454\n3030\n2\n2\n124\n16\n0\n0\n83\n11\n36\n9\n4\n4\n4123\n19\n0\n0\n4\n2525\n251035\n2525\n252247\n256388\n4040\n25222774\n2727\n2525\n100.0%100.0%\n71.4%28.6%100.0%\n100.0%100.0%\n72.1%27.9%100.0%\n33.5%66.5%100.0%\n100.0%100.0%\n21.2%59.5%19.4%100.0%\n100.0%100.0%\n100.0%100.0%\n0.42 [0.04 , 4.33]0.42 [0.04 , 4.33]\n0.42 [0.18 , 0.95]1.45 [0.62 , 3.39]0.71 [0.40 , 1.26]\n17.61 [1.08 , 286.40]17.61 [1.08 , 286.40]\n0.05 [0.00 , 0.81]0.14 [0.01 , 2.51]0.07 [0.01 , 0.54]\n0.12 [0.01 , 2.21]0.29 [0.08 , 1.14]0.24 [0.07 , 0.80]\n4.74 [1.67 , 13.45]4.74 [1.67 , 13.45]\n1.46 [0.48 , 4.42]0.40 [0.17 , 0.95]\n0.50 [0.11 , 2.31]0.64 [0.35 , 1.17]\n3.56 [0.19 , 66.61]3.56 [0.19 , 66.61]\n0.63 [0.15 , 2.53]0.63 [0.15 , 2.53]\n+\n+?\n+\n+?\n+?\n?\n+??\n?\n+\n?\n??\n?\n?+\n??\n?\n?+?\n?\n?\n?\n??\n?\n??\n?+\n?\n???\n?\n?\n?\n??\n?\n??\n?+\n?\n???\n?\n?\n−\n−+\n−\n−+\n−+\n+\n−++\n+\n−\n+\n++\n+\n++\n++\n+\n+++\n+\n+\n+\n++\n+\n++\n++\n+\n+++\n+\n+\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n175\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.4. /uni00A0 (Continued)\n4.4.31 Back distress - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.66 (P = 0.51)\n4.4.32 Paraesthesia - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.24 (P = 0.81)\n4.4.33 Agressiveness - 6 monthsCirkel 1995Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.17 (P = 0.24)\n4.4.34 Pain - 6 monthsRotondi 2002Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.89 (P = 0.38)\n4.4.35 Oily hair and skin - 6 monthsJelley 1986Rotondi 2002Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.40, df = 1 (P = 0.53); I² = 0%\nTest for overall effect: Z = 2.61 (P = 0.009)\n4.4.36 Bleeding - 6 monthsChang 1996Jelley 1986Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 6.69, df = 1 (P = 0.010); I² = 85%\nTest for overall effect: Z = 1.33 (P = 0.18)\n4.4.37 Malaise - 6 monthsJelley 1986Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.43 (P = 0.15)\n4.4.38 Chest  aches - 6 monthsJelley 1986Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.05 (P = 0.96)\n4.4.39 Dizzy spells - 6 monthsJelley 1986Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.09 (P = 0.28)\n4.4.40 PMS feelings - 6 months\n3\n3\n3\n3\n0\n0\n3\n3\n014\n14\n15\n6\n3\n3\n2\n2\n0\n0\n3030\n3030\n3030\n5454\n235477\n302353\n2323\n2323\n2323\n4\n4\n3\n3\n2\n2\n3\n3\n214\n16\n62\n8\n7\n7\n2\n2\n2\n2\n2525\n2525\n2525\n2727\n222749\n152136\n2222\n2222\n2222\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n12.0%88.0%100.0%\n79.3%20.7%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n0.63 [0.15 , 2.53]0.63 [0.15 , 2.53]\n0.83 [0.18 , 3.77]0.83 [0.18 , 3.77]\n0.17 [0.01 , 3.34]0.17 [0.01 , 3.34]\n0.50 [0.11 , 2.31]\n0.50 [0.11 , 2.31]\n0.19 [0.01 , 3.78]0.50 [0.28 , 0.89]0.46 [0.26 , 0.82]\n0.08 [0.01 , 0.63]2.28 [0.49 , 10.54]0.54 [0.22 , 1.34]\n0.41 [0.12 , 1.39]0.41 [0.12 , 1.39]\n0.96 [0.15 , 6.21]0.96 [0.15 , 6.21]\n0.19 [0.01 , 3.78]0.19 [0.01 , 3.78]\n+\n+\n+\n?\n??\n??\n?\n?\n?\n?\n?\n?\n?\n+?\n++\n+\n+\n+\n?\n?\n?\n?\n??\n??\n?\n?\n?\n?\n?\n?\n?\n??\n+?\n?\n?\n?\n−\n−\n−\n+\n++\n?+\n+\n+\n+\n+\n+\n+\n+\n++\n++\n+\n+\n+\n+\n+\n+\n+\n++\n++\n+\n+\n+\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n176\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 4.4. /uni00A0 (Continued)\nTest for overall effect: Z = 1.09 (P = 0.28)\n4.4.40 PMS feelings - 6 monthsJelley 1986Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.35 (P = 0.73)\n4\n4\n2323 3\n3\n2222100.0%100.0%1.28 [0.32 , 5.06]1.28 [0.32 , 5.06]\n0.0020.1 1 10 500Favours danazolFavours GnRHas\n? + ? ? + + +\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 4.5. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included,\nOutcome 5: Improvement of most troublesome symptoms - dichotomous\nStudy or Subgroup\n4.5.1 Overall improvement - 3 monthsKennedy 1990Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.01 (P = 0.99)\n4.5.2 Overall improvement - 6 monthsAN Zoladex 1996Burry 1992Henzl 1988Kennedy 1990Rolland 1990Shaw 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 8.24, df = 5 (P = 0.14); I² = 39%\nTest for overall effect: Z = 1.83 (P = 0.07)\n4.5.3 Complete resolution - 6 monthsAN Zoladex 1996Burry 1992Kennedy 1990Rolland 1990Shaw 1990Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 6.99, df = 4 (P = 0.14); I² = 43%\nTest for overall effect: Z = 1.78 (P = 0.07)\nGnRHasEvents\n25\n25\n3477107476147\n373\n2177296129\n217\nTotal\n3939\n35981435010750483\n35985010750340\nDanazolEvents\n9\n9\n253755203020\n187\n1037143014\n105\nTotal\n1414\n364970236323264\n3649236323194\nWeight\n100.0%100.0%\n10.3%20.5%30.7%\n11.4%15.7%\n11.4%100.0%\n7.3%36.5%14.2%27.9%14.2%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.00 [0.63 , 1.57]1.00 [0.63 , 1.57]\n1.40 [1.12 , 1.75]1.04 [0.86 , 1.26]\n0.95 [0.82 , 1.11]1.08 [0.91 , 1.29]1.20 [0.88 , 1.63]1.08 [0.91 , 1.29]1.08 [0.99 , 1.18]\n2.16 [1.19 , 3.90]1.04 [0.86 , 1.26]0.95 [0.64 , 1.43]1.20 [0.88 , 1.63]0.95 [0.64 , 1.43]1.14 [0.99 , 1.32]\nRisk RatioM-H, Fixed, 95% CI\n0.10.20.51 2 5 10Favours danazolFavours GnRHas\nRisk of BiasA\n?\n??????\n?????\nB\n?\n??????\n?????\nC\n+\n?+++++\n?++++\nD\n+\n?+++++\n?++++\nE\n+\n−+++++\n−++++\nF\n+\n++++++\n+++++\nG\n+\n++++++\n+++++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n177\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\n/uni00A0\nComparison 5. /uni00A0 GnRHas versus intra-uterine progestagen device - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n5.1 Relief of overall pain - continuous 3 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n5.1.1 Relief of overall pain - 6 months 2 58 Mean Difference (IV, Fixed,\n95% CI)\n-0.76 [-1.62, 0.10]\n5.1.2 Decrease of VAS score - 6\nmonths\n1 82 Mean Difference (IV, Fixed,\n95% CI)\n0.00 [-0.11, 0.11]\n5.2 Quality of life - continuous 1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n5.2.1 Psychological Well-Being Ques-\ntionnaire index (PGWBI) - 6 months\n1 81 Mean Difference (IV, Fixed,\n95% CI)\n-2.00 [-10.26, 6.26]\n/uni00A0\n/uni00A0\nAnalysis 5.1. /uni00A0 Comparison 5: GnRHas versus intra-uterine progestagen\ndevice - all studies included, Outcome 1: Relief of overall pain - continuous\nStudy or Subgroup\n5.1.1 Relief of overall pain - 6 monthsFerreira 2010Gomes 2007Subtotal (95% CI)\nHeterogeneity: Chi² = 1.28, df = 1 (P = 0.26); I² = 22%\nTest for overall effect: Z = 1.74 (P = 0.08)\n5.1.2 Decrease of VAS score - 6 monthsPetta 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\nGnRHasMean\n0.70.4\n6\nSD\n1.371.1\n0.3\nTotal\n18826\n4343\nLNG-IUSMean\n1.22.1\n6\nSD\n1.752.7\n0.2\nTotal\n221032\n3939\nWeight\n78.3%21.7%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-0.50 [-1.47 , 0.47]-1.70 [-3.54 , 0.14]-0.76 [-1.62 , 0.10]\n0.00 [-0.11 , 0.11]\n0.00 [-0.11 , 0.11]\nMean Difference\nIV, Fixed, 95% CI\n-2 -1 0 1 2Favours intra- uterine progestagen deviceFavours GnRHas\nRisk of BiasA\n++\n+\nB\n??\n?\nC\n??\n?\nD\n??\n+\nE\n++\n+\nF\n++\n+\nG\n++\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n178\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 5.2. /uni00A0 Comparison 5: GnRHas versus intra-uterine progestagen\ndevice - all studies included, Outcome 2: Quality of life - continuous\nStudy or Subgroup\n5.2.1 Psychological Well-Being Questionnaire index (PGWBI) - 6 monthsPetta 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.47 (P = 0.64)\nGnRHasMean\n93\nSD\n18.9\nTotal\n4242\nLNG-IUSMean\n95\nSD\n19\nTotal\n3939\nWeight\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-2.00 [-10.26 , 6.26]-2.00 [-10.26 , 6.26]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours intra- uterine progestagen deviceFavours GnRHas\nRisk of BiasA\n+\nB\n?\nC\n?\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 6. /uni00A0 GnRHas versus oral or injectable progestogens\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n6.1 Relief of overall pain - con-\ntinuous\n1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only\n6.1.1 Pelvic pain - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) -2.50 [-3.55, -1.45]\n6.1.2 Dyspareunia - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) -2.10 [-2.83, -1.37]\n6.1.3 Back pain - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) 0.50 [-0.40, 1.40]\n6.2 Adverse effects - dichoto-\nmous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n6.2.1 Vaginal bleeding - 3\nmonths\n1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.23, 0.48]\n6.2.2 Headache - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.88, 2.67]\n6.2.3 Weight gain - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.10, 0.92]\n6.2.4 Vaginal dryness - 3\nmonths\n1 242 Risk Ratio (M-H, Fixed, 95% CI) 4.75 [1.66, 13.55]\n6.2.5 Hot flushes - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 2.95 [1.87, 4.65]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n179\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 6.1. /uni00A0 Comparison 6: GnRHas versus oral or injectable\nprogestogens, Outcome 1: Relief of overall pain - continuous\nStudy or Subgroup\n6.1.1 Pelvic pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 4.68 (P < 0.00001)\n6.1.2 Dyspareunia - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 5.67 (P < 0.00001)\n6.1.3 Back pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.09 (P = 0.28)\nGnRHasMean\n26.2\n17.9\n19.5\nSD\n3.01\n2.9\n3.01\nTotal\n131131\n131131\n131131\nOral or injectable progestogensMean\n28.7\n20\n19\nSD\n5.3\n3.08\n4.3\nTotal\n130130\n130130\n130130\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-2.50 [-3.55 , -1.45]-2.50 [-3.55 , -1.45]\n-2.10 [-2.83 , -1.37]-2.10 [-2.83 , -1.37]\n0.50 [-0.40 , 1.40]0.50 [-0.40 , 1.40]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas\nRisk of BiasA\n+\n+\n+\nB\n+\n+\n+\nC\n?\n?\n?\nD\n?\n?\n?\nE\n+\n+\n+\nF\n+\n+\n+\nG\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n180\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 6.2. /uni00A0 Comparison 6: GnRHas versus oral or injectable\nprogestogens, Outcome 2: Adverse eﬀects - dichotomous\nStudy or Subgroup\n6.2.1 Vaginal bleeding - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 5.89 (P < 0.00001)\n6.2.2 Headache - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.50 (P = 0.13)\n6.2.3 Weight gain - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.12 (P = 0.03)\n6.2.4 Vaginal dryness - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.91 (P = 0.004)\n6.2.5 Hot flushes - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 4.65 (P < 0.00001)\nGnRHasEvents\n26\n26\n26\n26\n4\n4\n19\n19\n56\n56\nTotal\n121121\n121121\n121121\n121121\n121121\nOral or injectable progestogensEvents\n78\n78\n17\n17\n13\n13\n4\n4\n19\n19\nTotal\n121121\n121121\n121121\n121121\n121121\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.33 [0.23 , 0.48]0.33 [0.23 , 0.48]\n1.53 [0.88 , 2.67]1.53 [0.88 , 2.67]\n0.31 [0.10 , 0.92]0.31 [0.10 , 0.92]\n4.75 [1.66 , 13.55]4.75 [1.66 , 13.55]\n2.95 [1.87 , 4.65]2.95 [1.87 , 4.65]\nRisk RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas\nRisk of BiasA\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\nC\n?\n?\n?\n?\n?\nD\n?\n?\n?\n?\n?\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 7. /uni00A0 GnRHas versus oral or injectable progestogens - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n7.1 Relief of overall pain - di-\nchotomous\n2 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n7.1.1 Pelvic pain - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.83, 1.15]\n7.1.2 Dysmenorrhoea - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.28, 1.06]\n7.1.3 Dyspareunia - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.67, 1.47]\n7.1.4 Pelvic induration - 6\nmonths\n2 419 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.95, 1.29]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n181\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n7.1.5 Pelvic tenderness - 6\nmonths\n1 229 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.78, 1.40]\n7.2 Relief of overall pain - contin-\nuous\n4 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n7.2.1 Pelvic pain - 3 months 1 261 Mean Difference (IV, Fixed, 95%\nCI)\n-2.50 [-3.55, -1.45]\n7.2.2 Dyspareunia - 3 months 1 261 Mean Difference (IV, Fixed, 95%\nCI)\n-2.10 [-2.83, -1.37]\n7.2.3 Back pain - 3 months 1 261 Mean Difference (IV, Fixed, 95%\nCI)\n0.50 [-0.40, 1.40]\n7.2.4 Overall pain - 6 months 1 253 Mean Difference (IV, Fixed, 95%\nCI)\n0.10 [-0.48, 0.68]\n7.2.5 Pelvic pain - 6 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n-0.60 [-0.88, -0.32]\n7.2.6 Absolute reduction mean\nVAS - 6 months\n1 229 Mean Difference (IV, Fixed, 95%\nCI)\n-1.50 [-8.49, 5.49]\n7.2.7 Dysmenorrhoea - 6 months 1 0 Mean Difference (IV, Fixed, 95%\nCI)\nNot estimable\n7.2.8 Dyspareunia - 6 months 2 172 Mean Difference (IV, Fixed, 95%\nCI)\n-0.10 [-0.42, 0.22]\n7.2.9 Lumbago- mean change - 6\nmonths\n1 253 Mean Difference (IV, Fixed, 95%\nCI)\n-1.60 [-8.20, 5.00]\n7.2.10 Lumbago - 6 months 1 165 Mean Difference (IV, Fixed, 95%\nCI)\n-0.10 [-0.39, 0.19]\n7.2.11 Lower abdominal pain - 6\nmonths\n1 217 Mean Difference (IV, Fixed, 95%\nCI)\n-0.20 [-0.45, 0.05]\n7.2.12 Dyschezia - 6 months 1 75 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.14, 0.54]\n7.2.13 Pain on internal examina-\ntion - 6 months\n1 209 Mean Difference (IV, Fixed, 95%\nCI)\n-0.10 [-0.33, 0.13]\n7.2.14 Lower abdominal pain,\nmean change - 6 months\n1 253 Mean Difference (IV, Fixed, 95%\nCI)\n2.90 [-5.19, 10.99]\n7.2.15 Pelvic induration - 6\nmonths\n1 212 Mean Difference (IV, Fixed, 95%\nCI)\n0.30 [0.04, 0.56]\n7.2.16 Pelvic tenderness- 6\nmonths\n1 231 Mean Difference (IV, Fixed, 95%\nCI)\n-0.10 [-0.33, 0.13]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n182\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n7.2.17 Pelvic pain - 12 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n-0.60 [-0.75, -0.45]\n7.2.18 Overall pain - 12 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n3.80 [-2.13, 9.73]\n7.2.19 Dysmenorrhoea - 12\nmonths\n1 0 Mean Difference (IV, Fixed, 95%\nCI)\nNot estimable\n7.2.20 Dyspareunia - 12 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n0.10 [-0.13, 0.33]\n7.3 Bone mineral density of\nspinal bone mass - continuous\n2 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n7.3.1 Percentage change values -\n6 months\n1 87 Mean Difference (IV, Fixed, 95%\nCI)\n-1.60 [-2.57, -0.63]\n7.3.2 Absolute values - 6 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n-0.04 [-0.08, 0.01]\n7.3.3 Absolute values - 12\nmonths\n1 87 Mean Difference (IV, Fixed, 95%\nCI)\n-0.05 [-0.10, -0.01]\n7.4 Adverse effects - dichoto-\nmous\n6 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n7.4.1 Vaginal bleeding - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.23, 0.48]\n7.4.2 Headache - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.88, 2.67]\n7.4.3 Weight gain - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.10, 0.92]\n7.4.4 Vaginal dryness - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 4.75 [1.66, 13.55]\n7.4.5 Hot flushes - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 2.95 [1.87, 4.65]\n7.4.6 Acne - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.40, 3.57]\n7.4.7 Alopecia - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [0.49, 3.99]\n7.4.8 Decreased libido - 4\nmonths\n1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.48, 2.10]\n7.4.9 Vaginal dryness - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 2.00 [0.54, 7.37]\n7.4.10 Weight gain - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.67 [0.68, 4.09]\n7.4.11 Nausea - 6 months 1 295 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.30, 1.32]\n7.4.12 Headache - 6 months 3 815 Risk Ratio (M-H, Fixed, 95% CI) 1.46 [1.04, 2.03]\n7.4.13 Breast pain - 6 months 1 295 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.22, 1.98]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n183\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n7.4.14 Intermenstrual bleeding -\n6 months\n4 902 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.50, 0.67]\n7.4.15 Hot flushes/flashes - 6\nmonths\n4 902 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [1.70, 2.62]\n7.4.16 Emotional changes - 6\nmonths\n1 87 Risk Ratio (M-H, Fixed, 95% CI) 5.21 [1.64, 16.61]\n7.4.17 Insomnia - 6 months 1 265 Risk Ratio (M-H, Fixed, 95% CI) 2.25 [0.59, 8.50]\n7.4.18 Decreased libido - 6\nmonths\n1 265 Risk Ratio (M-H, Fixed, 95% CI) 2.25 [0.59, 8.50]\n7.5 Adverse effects - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n7.5.1 Climacteric symptoms by\nKupperman index - 4 months\n1 70 Mean Difference (IV, Fixed, 95%\nCI)\n6.80 [2.37, 11.23]\n7.5.2 Hot flushes/flashes - 4\nmonths\n1 70 Mean Difference (IV, Fixed, 95%\nCI)\n1.10 [0.71, 1.49]\n7.5.3 Depression - 4 months 1 70 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.18, 0.58]\n7.5.4 Oedema - 4 months 1 70 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.14, 0.54]\n7.5.5 Headache - 4 months 1 70 Mean Difference (IV, Fixed, 95%\nCI)\n0.10 [-0.32, 0.52]\n7.5.6 Breast pain - 4 months 1 70 Mean Difference (IV, Fixed, 95%\nCI)\n-0.20 [-0.39, -0.01]\n7.5.7 Metrorrhagia - 4 months 1 70 Mean Difference (IV, Fixed, 95%\nCI)\n-0.90 [-1.31, -0.49]\n7.6 Quality of life - continuous 2 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n7.6.1 Bodily pain - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95%\nCI)\n-3.70 [-10.81, 3.41]\n7.6.2 General health - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95%\nCI)\n0.70 [-2.58, 3.98]\n7.6.3 Physical function - 6\nmonths/uni00A0\n1 249 Mean Difference (IV, Fixed, 95%\nCI)\n-1.00 [-3.66, 1.66]\n7.6.4 Role physical - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95%\nCI)\n-3.50 [-12.01, 5.01]\n7.6.5 Role emotional - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95%\nCI)\n-7.80 [-16.67, 1.07]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n184\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n7.6.6 Mental health - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95%\nCI)\n0.10 [-4.04, 4.24]\n7.6.7 Social function - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95%\nCI)\n-4.80 [-9.98, 0.38]\n7.6.8 Vitality - 6 months/uni00A0 1 249 Mean Difference (IV, Fixed, 95%\nCI)\n-0.70 [-5.41, 4.01]\n7.6.9 General health - 12 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n3.70 [-1.97, 9.37]\n7.6.10 Physical function - 12\nmonths\n1 87 Mean Difference (IV, Fixed, 95%\nCI)\n2.00 [-3.72, 7.72]\n7.6.11 Role physical - 12 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n1.30 [-4.15, 6.75]\n7.6.12 Role emotional- 12\nmonths\n1 87 Mean Difference (IV, Fixed, 95%\nCI)\n4.20 [-1.60, 10.00]\n7.6.13 Mental health- 12 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n0.80 [-4.39, 5.99]\n7.6.14 Social function - 12\nmonths\n1 87 Mean Difference (IV, Fixed, 95%\nCI)\n-2.20 [-6.93, 2.53]\n7.6.15 Vitality - 12 months 1 87 Mean Difference (IV, Fixed, 95%\nCI)\n1.70 [-4.94, 8.34]\n7.7 Improvement of most trou-\nblesome symptoms - dichoto-\nmous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n7.7.1 Complete resolution - 6\nmonths\n1 229 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.79, 1.28]\n7.8 Improvement of most trou-\nblesome symptoms - continuous\n2 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n7.8.1 Overall symptoms by nu-\nmerical rating scale - 4 months\n1 70 Mean Difference (IV, Fixed, 95%\nCI)\n2.60 [0.37, 4.83]\n7.8.2 Overall symptoms by ver-\nbal rating scale - 4 months\n1 70 Mean Difference (IV, Fixed, 95%\nCI)\n0.70 [0.06, 1.34]\n7.8.3 Overall symptoms - 6\nmonths\n1 253 Mean Difference (IV, Fixed, 95%\nCI)\n-0.70 [-1.52, 0.12]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n185\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 7.1. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens\n- all studies included, Outcome 1: Relief of overall pain - dichotomous\nStudy or Subgroup\n7.1.1 Pelvic pain - 6 monthsStrowitzki 2012Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.29 (P = 0.77)\n7.1.2 Dysmenorrhoea - 6 monthsStrowitzki 2012Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.78 (P = 0.07)\n7.1.3 Dyspareunia - 6 monthsStrowitzki 2012Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.05 (P = 0.96)\n7.1.4 Pelvic induration - 6 months\nSchlaff 2006Strowitzki 2012Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.71, df = 1 (P = 0.40); I² = 0%\nTest for overall effect: Z = 1.36 (P = 0.18)\n7.1.5 Pelvic tenderness - 6 monthsStrowitzki 2012Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.29 (P = 0.77)\nGnRHasEvents\n86\n86\n12\n12\n36\n36\n8846\n134\n54\n54\nTotal\n120120\n120120\n120120\n102120222\n120120\nOral or injectable progestogensEvents\n80\n80\n20\n20\n33\n33\n6541\n106\n47\n47\nTotal\n109109\n109109\n109109\n88109197\n109109\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n61.9%38.1%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.98 [0.83 , 1.15]0.98 [0.83 , 1.15]\n0.55 [0.28 , 1.06]0.55 [0.28 , 1.06]\n0.99 [0.67 , 1.47]0.99 [0.67 , 1.47]\n1.17 [1.01 , 1.35]1.02 [0.73 , 1.42]\n1.11 [0.95 , 1.29]\n1.04 [0.78 , 1.40]1.04 [0.78 , 1.40]\nRisk RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas\nRisk of BiasA\n?\n?\n?\n??\n?\nB\n?\n?\n?\n??\n?\nC\n?\n?\n?\n??\n?\nD\n?\n?\n?\n+?\n?\nE\n+\n+\n+\n−+\n+\nF\n+\n+\n+\n++\n+\nG\n+\n+\n+\n++\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n186\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 7.2. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 2: Relief\nof overall pain - continuous\nStudy or Subgroup\n7.2.1 Pelvic pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 4.68 (P < 0.00001)\n7.2.2 Dyspareunia - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 5.67 (P < 0.00001)\n7.2.3 Back pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.09 (P = 0.28)\n7.2.4 Overall pain - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.34 (P = 0.74)\n7.2.5 Pelvic pain - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 4.18 (P < 0.0001)\n7.2.6 Absolute reduction mean VAS - 6 monthsStrowitzki 2012Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.42 (P = 0.67)\n7.2.7 Dysmenorrhoea - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Not applicable\n7.2.8 Dyspareunia - 6 monthsHarada 2009Zupi 2005Subtotal (95% CI)\nHeterogeneity: Chi² = 0.00, df = 1 (P = 1.00); I² = 0%\nTest for overall effect: Z = 0.61 (P = 0.54)\n7.2.9 Lumbago- mean change - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.47 (P = 0.63)\n7.2.10 Lumbago - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.67 (P = 0.50)\n7.2.11 Lower abdominal pain - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.55 (P = 0.12)\n7.2.12 Dyschezia - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.15 (P = 0.25)\nGnRHasMean\n26.2\n17.9\n19.5\n2.5\n1.3\n46\n0\n0.62.6\n-17.3\n0.9\n0.7\n0.6\nSD\n3.01\n2.9\n3.01\n2.3\n0.5\n24.8\n0\n0.91.3\n24.8\n0.9\n0.9\n0.8\nTotal\n131131\n131131\n131131\n128128\n4444\n120120\n440\n474491\n125125\n8383\n107107\n3939\nOral or injectable progestogensMean\n28.7\n20\n19\n2.4\n1.9\n47.5\n1.9\n0.72.7\n-15.7\n1\n0.9\n0.4\nSD\n5.3\n3.08\n4.3\n2.4\n0.8\n28.8\n1.1\n0.91.5\n28.7\n1\n1\n0.7\nTotal\n130130\n130130\n130130\n125125\n4343\n109109\n430\n384381\n128128\n8282\n110\n110\n3636\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n70.2%29.8%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-2.50 [-3.55 , -1.45]-2.50 [-3.55 , -1.45]\n-2.10 [-2.83 , -1.37]-2.10 [-2.83 , -1.37]\n0.50 [-0.40 , 1.40]0.50 [-0.40 , 1.40]\n0.10 [-0.48 , 0.68]0.10 [-0.48 , 0.68]\n-0.60 [-0.88 , -0.32]-0.60 [-0.88 , -0.32]\n-1.50 [-8.49 , 5.49]-1.50 [-8.49 , 5.49]\nNot estimableNot estimable\n-0.10 [-0.48 , 0.28]-0.10 [-0.69 , 0.49]-0.10 [-0.42 , 0.22]\n-1.60 [-8.20 , 5.00]-1.60 [-8.20 , 5.00]\n-0.10 [-0.39 , 0.19]-0.10 [-0.39 , 0.19]\n-0.20 [-0.45 , 0.05]-0.20 [-0.45 , 0.05]\n0.20 [-0.14 , 0.54]0.20 [-0.14 , 0.54]\nMean Difference\nIV, Fixed, 95% CI Risk of BiasA\n+\n+\n+\n+\n+\n?\n+\n++\n+\n+\n+\n+\nB\n+\n+\n+\n+\n?\n?\n?\n+?\n+\n+\n+\n+\nC\n?\n?\n?\n+\n?\n?\n?\n+?\n+\n+\n+\n+\nD\n?\n?\n?\n+\n+\n?\n+\n++\n+\n+\n+\n+\nE\n+\n+\n+\n−\n+\n+\n+\n−+\n−\n−\n−\n−\nF\n+\n+\n+\n+\n+\n+\n+\n++\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\n++\n+\n+\n+\n+\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n187\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 7.2. /uni00A0 (Continued)\nHeterogeneity: Not applicable\nTest for overall effect: Z = 1.15 (P = 0.25)\n7.2.13 Pain on internal examination - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.85 (P = 0.40)\n7.2.14 Lower abdominal pain, mean change - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.70 (P = 0.48)\n7.2.15 Pelvic induration - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.27 (P = 0.02)\n7.2.16 Pelvic tenderness- 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.84 (P = 0.40)\n7.2.17 Pelvic pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 7.72 (P < 0.00001)\n7.2.18 Overall pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.26 (P = 0.21)\n7.2.19 Dysmenorrhoea - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Not applicable\n7.2.20 Dyspareunia - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.84 (P = 0.40)\n0.9\n-27.3\n1.2\n0.9\n0.2\n62.1\n0\n1.4\n0.8\n33.8\n1.1\n0.8\n0.1\n14\n0\n0.5\n104104\n125125\n106106\n110\n110\n4444\n4444\n440\n4444\n1\n-30.2\n0.9\n1\n0.8\n58.3\n0.9\n1.3\n0.9\n31.8\n0.8\n1\n0.5\n14.2\n0.5\n0.6\n105105\n128128\n106106\n121121\n4343\n4343\n430\n4343\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n-0.10 [-0.33 , 0.13]-0.10 [-0.33 , 0.13]\n2.90 [-5.19 , 10.99]2.90 [-5.19 , 10.99]\n0.30 [0.04 , 0.56]0.30 [0.04 , 0.56]\n-0.10 [-0.33 , 0.13]-0.10 [-0.33 , 0.13]\n-0.60 [-0.75 , -0.45]-0.60 [-0.75 , -0.45]\n3.80 [-2.13 , 9.73]3.80 [-2.13 , 9.73]\nNot estimableNot estimable\n0.10 [-0.13 , 0.33]0.10 [-0.13 , 0.33]\n-100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n?\n?\n?\n?\n+\n+\n+\n+\n?\n?\n?\n?\n+\n+\n+\n+\n+\n+\n+\n+\n−\n−\n−\n−\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n188\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 7.3. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all\nstudies included, Outcome 3: Bone mineral density of spinal bone mass - continuous\nStudy or Subgroup\n7.3.1 Percentage change values - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 3.24 (P = 0.001)\n7.3.2 Absolute values - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.37 (P = 0.17)\n7.3.3 Absolute values - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.28 (P = 0.02)\nGnRHasMean\n-2.6\n1.005\n0.981\nSD\n2.3\n0.112\n0.099\nTotal\n4646\n4444\n4444\nOral or injectable progestogensMean\n-1\n1.04\n1.035\nSD\n2.3\n0.125\n0.121\nTotal\n4141\n4343\n4343\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-1.60 [-2.57 , -0.63]-1.60 [-2.57 , -0.63]\n-0.04 [-0.08 , 0.01]-0.04 [-0.08 , 0.01]\n-0.05 [-0.10 , -0.01]-0.05 [-0.10 , -0.01]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHasFavours oral or injectable progestogens\nRisk of BiasA\n+\n+\n+\nB\n+\n?\n?\nC\n+\n?\n?\nD\n+\n+\n+\nE\n−\n+\n+\nF\n+\n+\n+\nG\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n189\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 7.4. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 4:\nAdverse eﬀects - dichotomous\nStudy or Subgroup\n7.4.1 Vaginal bleeding - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 5.89 (P < 0.00001)\n7.4.2 Headache - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.50 (P = 0.13)\n7.4.3 Weight gain - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.12 (P = 0.03)\n7.4.4 Vaginal dryness - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.91 (P = 0.004)\n7.4.5 Hot flushes - 3 monthsAbdou 2018Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 4.65 (P < 0.00001)\n7.4.6 Acne - 4 monthsOzaki 2020Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.33 (P = 0.74)\n7.4.7 Alopecia - 4 monthsOzaki 2020Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.63 (P = 0.53)\n7.4.8 Decreased libido - 4 monthsOzaki 2020Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\n7.4.9 Vaginal dryness - 4 monthsOzaki 2020Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.04 (P = 0.30)\n7.4.10 Weight gain - 4 monthsOzaki 2020Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.12 (P = 0.26)\nGnRHasEvents\n26\n26\n26\n26\n4\n4\n19\n19\n56\n56\n6\n6\n7\n7\n10\n10\n6\n6\n10\n10\nTotal\n121121\n121121\n121121\n121121\n121121\n3535\n3535\n3535\n3535\n3535\nOral or injectable progestogensEvents\n78\n78\n17\n17\n13\n13\n4\n4\n19\n19\n5\n5\n5\n5\n10\n10\n3\n3\n6\n6\nTotal\n121121\n121121\n121121\n121121\n121121\n3535\n3535\n3535\n3535\n3535\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.33 [0.23 , 0.48]0.33 [0.23 , 0.48]\n1.53 [0.88 , 2.67]1.53 [0.88 , 2.67]\n0.31 [0.10 , 0.92]0.31 [0.10 , 0.92]\n4.75 [1.66 , 13.55]4.75 [1.66 , 13.55]\n2.95 [1.87 , 4.65]2.95 [1.87 , 4.65]\n1.20 [0.40 , 3.57]1.20 [0.40 , 3.57]\n1.40 [0.49 , 3.99]1.40 [0.49 , 3.99]\n1.00 [0.48 , 2.10]1.00 [0.48 , 2.10]\n2.00 [0.54 , 7.37]2.00 [0.54 , 7.37]\n1.67 [0.68 , 4.09]1.67 [0.68 , 4.09]\nRisk RatioM-H, Fixed, 95% CIRisk of BiasA\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\n?\n?\n?\n?\n?\nC\n?\n?\n?\n?\n?\n?\n?\n?\n?\n?\nD\n?\n?\n?\n?\n?\n?\n?\n?\n?\n?\nE\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n190\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 7.4. /uni00A0 (Continued)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.12 (P = 0.26)\n7.4.11 Nausea - 6 monthsCrosignani 2006Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.23 (P = 0.22)\n7.4.12 Headache - 6 monthsCrosignani 2006Harada 2009\nSchlaff 2006Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 0.83, df = 2 (P = 0.66); I² = 0%\nTest for overall effect: Z = 2.21 (P = 0.03)\n7.4.13 Breast pain - 6 monthsCrosignani 2006Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.73 (P = 0.46)\n7.4.14 Intermenstrual bleeding - 6 monthsCrosignani 2006Harada 2009\nSchlaff 2006Zupi 2005Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 18.82, df = 3 (P = 0.0003); I² = 84%\nTest for overall effect: Z = 7.11 (P < 0.00001)\n7.4.15 Hot flushes/flashes - 6 monthsCrosignani 2006Harada 2009\nSchlaff 2006Zupi 2005Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 25.02, df = 3 (P < 0.0001); I² = 88%\nTest for overall effect: Z = 6.81 (P < 0.00001)\n7.4.16 Emotional changes - 6 monthsZupi 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.79 (P = 0.005)\n7.4.17 Insomnia - 6 months\nSchlaff 2006Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.19 (P = 0.23)\n7.4.18 Decreased libido - 6 months\nSchlaff 2006Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.19 (P = 0.23)\n10\n10\n10\n94314\n66\n5\n5\n18511\n88\n24851534\n158\n16\n16\n7\n7\n7\n7\n143143\n143126135404\n143143\n14312613544448\n14312613544448\n4444\n135135\n135135\n6\n17\n17\n43210\n46\n8\n8\n1912277\n155\n96430\n76\n3\n3\n3\n3\n3\n3\n152152\n152129130\n411\n152152\n15212913043454\n15212913043454\n4343\n130130\n130130\n100.0%100.0%\n8.5%69.2%22.3%100.0%\n100.0%100.0%\n12.0%78.7%4.7%4.6%100.0%\n11.6%83.7%4.0%0.7%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n0.63 [0.30 , 1.32]0.63 [0.30 , 1.32]\n2.39 [0.75 , 7.59]1.38 [0.94 , 2.02]1.35 [0.62 , 2.93]1.46 [1.04 , 2.03]\n0.66 [0.22 , 1.98]0.66 [0.22 , 1.98]\n0.06 [0.01 , 0.41]0.71 [0.63 , 0.81]0.14 [0.02 , 1.10]0.14 [0.02 , 1.09]0.58 [0.50 , 0.67]\n2.83 [1.36 , 5.89]1.36 [1.10 , 1.68]4.81 [1.43 , 16.24]67.47 [4.27 , 1066.73]\n2.11 [1.70 , 2.62]\n5.21 [1.64 , 16.61]5.21 [1.64 , 16.61]\n2.25 [0.59 , 8.50]2.25 [0.59 , 8.50]\n2.25 [0.59 , 8.50]2.25 [0.59 , 8.50]\n0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas\n?\n?+?\n?\n?+?+\n?+?+\n+\n?\n?\n?\n?+?\n?\n?+??\n?+??\n?\n?\n?\n?\n?+?\n?\n?+??\n?+??\n?\n?\n?\n?\n?++\n?\n?+++\n?+++\n+\n+\n+\n+\n+−−\n+\n+−−+\n+−−+\n+\n−\n−\n+\n+++\n+\n++++\n++++\n+\n+\n+\n+\n+++\n+\n++++\n++++\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n191\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 7.4. /uni00A0 (Continued)\n(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 7.5. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens\n- all studies included, Outcome 5: Adverse eﬀects - continuous\nStudy or Subgroup\n7.5.1 Climacteric symptoms by Kupperman index - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 3.01 (P = 0.003)\n7.5.2 Hot flushes/flashes - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 5.58 (P < 0.00001)\n7.5.3 Depression - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.04 (P = 0.30)\n7.5.4 Oedema - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.15 (P = 0.25)\n7.5.5 Headache - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.46 (P = 0.64)\n7.5.6 Breast pain - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.03 (P = 0.04)\n7.5.7 Metrorrhagia - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 4.30 (P < 0.0001)\nGnRHasMean\n16\n1.6\n0.5\n0.4\n0.7\n0.1\n0.1\nSD\n11\n1\n0.9\n0.9\n1\n0.3\n0.3\nTotal\n3535\n3535\n3535\n3535\n3535\n3535\n3535\nOral of injectable progestogensMean\n9.2\n0.5\n0.3\n0.2\n0.6\n0.3\n1\nSD\n7.6\n0.6\n0.7\n0.5\n0.8\n0.5\n1.2\nTotal\n3535\n3535\n3535\n3535\n3535\n3535\n3535\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n6.80 [2.37 , 11.23]\n6.80 [2.37 , 11.23]\n1.10 [0.71 , 1.49]1.10 [0.71 , 1.49]\n0.20 [-0.18 , 0.58]0.20 [-0.18 , 0.58]\n0.20 [-0.14 , 0.54]0.20 [-0.14 , 0.54]\n0.10 [-0.32 , 0.52]0.10 [-0.32 , 0.52]\n-0.20 [-0.39 , -0.01]-0.20 [-0.39 , -0.01]\n-0.90 [-1.31 , -0.49]-0.90 [-1.31 , -0.49]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas\nRisk of BiasA\n+\n+\n+\n+\n+\n+\n+\nB\n?\n?\n?\n?\n?\n?\n?\nC\n?\n?\n?\n?\n?\n?\n?\nD\n?\n?\n?\n?\n?\n?\n?\nE\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n192\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 7.6. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 6:\nQuality of life - continuous\nStudy or Subgroup\n7.6.1 Bodily pain - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.02 (P = 0.31)\n7.6.2 General health - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.42 (P = 0.68)\n7.6.3 Physical function - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.74 (P = 0.46)\n7.6.4 Role physical - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.81 (P = 0.42)\n7.6.5 Role emotional - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.72 (P = 0.08)\n7.6.6 Mental health - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.05 (P = 0.96)\n7.6.7 Social function - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.82 (P = 0.07)\n7.6.8 Vitality - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.29 (P = 0.77)\n7.6.9 General health - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.28 (P = 0.20)\n7.6.10 Physical function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.69 (P = 0.49)\n7.6.11 Role physical - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.47 (P = 0.64)\n7.6.12 Role emotional- 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.42 (P = 0.16)\n7.6.13 Mental health- 12 months\nGnRHasMean\n18.5\n1.8\n-0.2\n0\n-2.5\n3.4\n1.7\n2.1\n54.9\n57.6\n60.1\n62.3\nSD\n28.8\n12.9\n8.2\n33.3\n35.4\n17\n22.3\n18.5\n12.7\n14\n13.9\n15.2\nTotal\n122122\n122122\n122122\n122122\n122122\n122122\n122122\n122122\n4444\n4444\n4444\n4444\nOral or injectable progestogensMean\n22.2\n1.1\n0.8\n3.5\n5.3\n3.3\n6.5\n2.8\n51.2\n55.6\n58.8\n58.1\nSD\n28.4\n13.5\n12.8\n35.2\n36\n16.3\n19.2\n19.4\n14.2\n13.2\n12\n12.3\nTotal\n127127\n127127\n127127\n127127\n127127\n127127\n127127\n127127\n4343\n4343\n4343\n4343\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-3.70 [-10.81 , 3.41]-3.70 [-10.81 , 3.41]\n0.70 [-2.58 , 3.98]0.70 [-2.58 , 3.98]\n-1.00 [-3.66 , 1.66]-1.00 [-3.66 , 1.66]\n-3.50 [-12.01 , 5.01]-3.50 [-12.01 , 5.01]\n-7.80 [-16.67 , 1.07]-7.80 [-16.67 , 1.07]\n0.10 [-4.04 , 4.24]0.10 [-4.04 , 4.24]\n-4.80 [-9.98 , 0.38]-4.80 [-9.98 , 0.38]\n-0.70 [-5.41 , 4.01]-0.70 [-5.41 , 4.01]\n3.70 [-1.97 , 9.37]3.70 [-1.97 , 9.37]\n2.00 [-3.72 , 7.72]2.00 [-3.72 , 7.72]\n1.30 [-4.15 , 6.75]1.30 [-4.15 , 6.75]\n4.20 [-1.60 , 10.00]4.20 [-1.60 , 10.00]\nMean Difference\nIV, Fixed, 95% CI Risk of BiasA\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\n+\n+\n+\n?\n?\n?\n?\nC\n+\n+\n+\n+\n+\n+\n+\n+\n?\n?\n?\n?\nD\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nE\n−\n−\n−\n−\n−\n−\n−\n−\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n193\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 7.6. /uni00A0 (Continued)\nTest for overall effect: Z = 1.42 (P = 0.16)\n7.6.13 Mental health- 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.30 (P = 0.76)\n7.6.14 Social function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.91 (P = 0.36)\n7.6.15 Vitality - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.50 (P = 0.62)\n60.2\n54.5\n57.8\n13.6\n11.5\n11.3\n4444\n4444\n4444\n59.4\n56.7\n56.1\n11\n11\n19.2\n4343\n4343\n4343\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n0.80 [-4.39 , 5.99]0.80 [-4.39 , 5.99]\n-2.20 [-6.93 , 2.53]-2.20 [-6.93 , 2.53]\n1.70 [-4.94 , 8.34]1.70 [-4.94 , 8.34]\n-100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas\n+\n+\n+\n?\n?\n?\n?\n?\n?\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 7.7. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies\nincluded, Outcome 7: Improvement of most troublesome symptoms - dichotomous\nStudy or Subgroup\n7.7.1 Complete resolution - 6 monthsStrowitzki 2012Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.02 (P = 0.99)\nGnRHasEvents\n64\n64\nTotal\n120120\nOral or injectable progestogensEvents\n58\n58\nTotal\n109109\nWeight\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.00 [0.79 , 1.28]1.00 [0.79 , 1.28]\nRisk RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas\nRisk of BiasA\n?\nB\n?\nC\n?\nD\n?\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n194\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 7.8. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies\nincluded, Outcome 8: Improvement of most troublesome symptoms - continuous\nStudy or Subgroup\n7.8.1 Overall symptoms by numerical rating scale - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.28 (P = 0.02)\n7.8.2 Overall symptoms by verbal rating scale - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.13 (P = 0.03)\n7.8.3 Overall symptoms - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.68 (P = 0.09)\nGnRHasMean\n5.3\n1.4\n3.8\nSD\n5.5\n1.6\n3\nTotal\n3535\n3535\n125125\nOral or injectable progestogensMean\n2.7\n0.7\n4.5\nSD\n3.9\n1.1\n3.6\nTotal\n3535\n3535\n128128\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n2.60 [0.37 , 4.83]2.60 [0.37 , 4.83]\n0.70 [0.06 , 1.34]0.70 [0.06 , 1.34]\n-0.70 [-1.52 , 0.12]-0.70 [-1.52 , 0.12]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas\nRisk of BiasA\n+\n+\n+\nB\n?\n?\n+\nC\n?\n?\n+\nD\n?\n?\n+\nE\n+\n+\n−\nF\n+\n+\n+\nG\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 8. /uni00A0 GnRHas versus gestrinone - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n8.1 Relief of overall pain - continu-\nous\n1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n8.1.1 Dysmenorrhoea, visual ana-\nlog scale - 3 months\n1 0 Mean Difference (IV, Fixed, 95%\nCI)\nNot estimable\n8.1.2 Dysmenorrhoea, verbal rat-\ning scale - 3 months\n1 0 Mean Difference (IV, Fixed, 95%\nCI)\nNot estimable\n8.1.3 Dyspareunia, visual analog\nscale - 3 months\n1 52 Mean Difference (IV, Fixed, 95%\nCI)\n1.39 [0.04, 2.74]\n8.1.4 Dyspareunia, verbal rating\nscale - 3 months\n1 52 Mean Difference (IV, Fixed, 95%\nCI)\n0.28 [-0.12, 0.68]\n8.1.5 Non-menstrual pain, visual\nanalog scale - 3 months\n1 55 Mean Difference (IV, Fixed, 95%\nCI)\n0.49 [-0.59, 1.57]\n8.1.6 Non-menstrual pain, verbal\nrating scale - 3 months\n1 55 Mean Difference (IV, Fixed, 95%\nCI)\n0.04 [-0.36, 0.44]\n8.1.7 Dysmenorrhoea, visual ana-\nlog scale - 6 months\n1 55 Mean Difference (IV, Fixed, 95%\nCI)\n-0.82 [-1.49, -0.15]\n8.1.8 Dysmenorrhoea, verbal rat-\ning scale - 6 months\n1 55 Mean Difference (IV, Fixed, 95%\nCI)\n-0.35 [-0.58, -0.12]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n195\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n8.1.9 Dyspareunia, visual analog\nscale - 6 months\n1 52 Mean Difference (IV, Fixed, 95%\nCI)\n1.17 [0.25, 2.09]\n8.1.10 Dyspareunia, verbal rating\nscale - 6 months\n1 52 Mean Difference (IV, Fixed, 95%\nCI)\n0.33 [0.04, 0.62]\n8.1.11 Non-menstrual pain, visual\nanalog scale - 6 months\n1 55 Mean Difference (IV, Fixed, 95%\nCI)\n0.41 [-0.94, 1.76]\n8.1.12 Non-menstrual pain, verbal\nrating scale - 6 months\n1 55 Mean Difference (IV, Fixed, 95%\nCI)\n0.15 [-0.20, 0.50]\n8.2 Bone mineral density of spinal\nbone mass - continuous\n1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n8.2.1 Percentage change values - 6\nmonths\n1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-1.96 [-3.62, -0.30]\n8.2.2 Percentage change values -\n12 months\n1 41 Mean Difference (IV, Fixed, 95%\nCI)\n-5.10 [-7.39, -2.81]\n8.3 Adverse effects - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n8.3.1 Hot flushes/flashes - 6\nmonths\n1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.29 [1.21, 4.32]\n8.3.2 Headache - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.41 [0.51, 11.38]\n8.3.3 Asthenia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.03, 2.02]\n8.3.4 Mood change - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.26, 7.99]\n8.3.5 Dermatitis - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 2.55]\n8.3.6 Dizziness- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01]\n8.3.7 Joint pain- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01]\n8.3.8 Drowsiness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01]\n8.3.9 Swelling - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 3.85]\n8.3.10 Nausea- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01]\n8.3.11 Tachycardia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01]\n8.3.12 Vaginal dryness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 4.83 [0.24, 96.16]\n8.3.13 Insomnia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57]\n8.3.14 Hypertrichosis - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57]\n8.3.15 Seborrhea- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n196\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n8.3.16 Skin rash - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57]\n8.3.17 Constipation - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57]\n8.3.18 Itching - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15]\n8.3.19 Vaginal discharge - 6\nmonths\n1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15]\n8.3.20 Paresthesia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15]\n8.3.21 Cramps - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n197\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 8.1. /uni00A0 Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 1: Relief of overall pain -\ncontinuous\nStudy or Subgroup\n8.1.1 Dysmenorrhoea, visual analog scale - 3 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Not applicable\n8.1.2 Dysmenorrhoea, verbal rating scale - 3 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Not applicable\n8.1.3 Dyspareunia, visual analog scale - 3 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.02 (P = 0.04)\n8.1.4 Dyspareunia, verbal rating scale - 3 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.38 (P = 0.17)\n8.1.5 Non-menstrual pain, visual analog scale - 3 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.89 (P = 0.38)\n8.1.6 Non-menstrual pain, verbal rating scale - 3 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.20 (P = 0.84)\n8.1.7 Dysmenorrhoea, visual analog scale - 6 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.39 (P = 0.02)\n8.1.8 Dysmenorrhoea, verbal rating scale - 6 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.97 (P = 0.003)\n8.1.9 Dyspareunia, visual analog scale - 6 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.49 (P = 0.01)\n8.1.10 Dyspareunia, verbal rating scale - 6 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.26 (P = 0.02)\n8.1.11 Non-menstrual pain, visual analog scale - 6 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.59 (P = 0.55)\n8.1.12 Non-menstrual pain, verbal rating scale - 6 months\nVercellini 1996Subtotal (95% CI)\nGnRHasMean\n0\n0\n2.29\n0.64\n1.73\n0.62\n0.05\n0.04\n1.61\n0.43\n1.64\n0.5\nSD\n0\n0\n3.27\n0.91\n2.29\n0.9\n0.24\n0.2\n2.12\n0.68\n2.46\n0.59\nTotal\n280\n280\n2626\n2626\n2828\n2828\n2828\n2828\n2626\n2626\n2828\n2828\nGestrinoneMean\n0.84\n0.38\n0.9\n0.36\n1.24\n0.58\n0.87\n0.39\n0.44\n0.1\n1.23\n0.35\nSD\n1.91\n0.65\n1.25\n0.49\n1.79\n0.58\n1.77\n0.58\n1.11\n0.3\n2.65\n0.71\nTotal\n270\n270\n2626\n2626\n2727\n2727\n2727\n2727\n2626\n2626\n2727\n2727\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\nNot estimableNot estimable\nNot estimableNot estimable\n1.39 [0.04 , 2.74]1.39 [0.04 , 2.74]\n0.28 [-0.12 , 0.68]0.28 [-0.12 , 0.68]\n0.49 [-0.59 , 1.57]0.49 [-0.59 , 1.57]\n0.04 [-0.36 , 0.44]0.04 [-0.36 , 0.44]\n-0.82 [-1.49 , -0.15]-0.82 [-1.49 , -0.15]\n-0.35 [-0.58 , -0.12]-0.35 [-0.58 , -0.12]\n1.17 [0.25 , 2.09]1.17 [0.25 , 2.09]\n0.33 [0.04 , 0.62]0.33 [0.04 , 0.62]\n0.41 [-0.94 , 1.76]0.41 [-0.94 , 1.76]\n0.15 [-0.20 , 0.50]0.15 [-0.20 , 0.50]\nMean Difference\nIV, Fixed, 95% CI Risk of BiasA\n?\n?\n?\n?\n?\n?\n?\n?\n?\n?\n?\n?\nB\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nC\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n198\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 8.1. /uni00A0 (Continued)\n8.1.12 Non-menstrual pain, verbal rating scale - 6 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.85 (P = 0.40)\n0.5 0.59 2828 0.350.71 2727100.0%100.0%0.15 [-0.20 , 0.50]0.15 [-0.20 , 0.50]\n-4 -2 0 2 4Favours gestrinoneFavours GnRHas\n? ++++++\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 8.2. /uni00A0 Comparison 8: GnRHas versus gestrinone - all studies\nincluded, Outcome 2: Bone mineral density of spinal bone mass - continuous\nStudy or Subgroup\n8.2.1 Percentage change values - 6 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.31 (P = 0.02)\n8.2.2 Percentage change values - 12 months\nVercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 4.36 (P < 0.0001)\nGnRHasMean\n-1.08\n-3.04\nSD\n3.26\n4.77\nTotal\n2222\n2222\nGestrinoneMean\n0.88\n2.06\nSD\n2.12\n2.51\nTotal\n1919\n1919\nWeight\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-1.96 [-3.62 , -0.30]-1.96 [-3.62 , -0.30]\n-5.10 [-7.39 , -2.81]-5.10 [-7.39 , -2.81]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHasFavours gestrinone\nRisk of BiasA\n?\n?\nB\n+\n+\nC\n+\n+\nD\n+\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n199\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 8.3. /uni00A0 Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 3: Adverse eﬀects -\ndichotomous\nStudy or Subgroup\n8.3.1 Hot flushes/flashes - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.56 (P = 0.01)\n8.3.2 Headache - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.11 (P = 0.27)\n8.3.3 Asthenia - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.31 (P = 0.19)\n8.3.4 Mood change - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.42 (P = 0.67)\n8.3.5 Dermatitis - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.33 (P = 0.18)\n8.3.6 Dizziness- 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.61 (P = 0.54)\n8.3.7 Joint pain- 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.61 (P = 0.54)\n8.3.8 Drowsiness - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.61 (P = 0.54)\n8.3.9 Swelling - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nGnRHasEvents\n19\n19\n5\n5\n1\n1\n3\n3\n0\n0\n1\n1\n1\n1\n1\n1\n0\n0\nTotal\n2828\n2828\n2828\n2828\n2828\n2828\n2828\n2828\n2828\nGestrinoneEvents\n8\n8\n2\n2\n4\n4\n2\n2\n3\n3\n2\n2\n2\n2\n2\n2\n2\n2\nTotal\n2727\n2727\n2727\n2727\n2727\n2727\n2727\n2727\n2727\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n2.29 [1.21 , 4.32]2.29 [1.21 , 4.32]\n2.41 [0.51 , 11.38]\n2.41 [0.51 , 11.38]\n0.24 [0.03 , 2.02]0.24 [0.03 , 2.02]\n1.45 [0.26 , 7.99]1.45 [0.26 , 7.99]\n0.14 [0.01 , 2.55]0.14 [0.01 , 2.55]\n0.48 [0.05 , 5.01]0.48 [0.05 , 5.01]\n0.48 [0.05 , 5.01]0.48 [0.05 , 5.01]\n0.48 [0.05 , 5.01]0.48 [0.05 , 5.01]\n0.19 [0.01 , 3.85]0.19 [0.01 , 3.85]\nRisk RatioM-H, Fixed, 95% CIRisk of BiasA\n?\n?\n?\n?\n?\n?\n?\n?\n?\nB\n+\n+\n+\n+\n+\n+\n+\n+\n+\nC\n+\n+\n+\n+\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\n+\n+\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n200\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 8.3. /uni00A0 (Continued)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.08 (P = 0.28)\n8.3.10 Nausea- 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.61 (P = 0.54)\n8.3.11 Tachycardia - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.61 (P = 0.54)\n8.3.12 Vaginal dryness - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.03 (P = 0.30)\n8.3.13 Insomnia - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.70 (P = 0.48)\n8.3.14 Hypertrichosis - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.70 (P = 0.48)\n8.3.15 Seborrhea- 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.70 (P = 0.48)\n8.3.16 Skin rash - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.70 (P = 0.48)\n8.3.17 Constipation - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.70 (P = 0.48)\n8.3.18 Itching - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\n0\n1\n1\n1\n1\n2\n2\n0\n0\n0\n0\n0\n0\n0\n0\n0\n0\n1\n1\n2828\n2828\n2828\n2828\n2828\n2828\n2828\n2828\n2828\n2\n2\n2\n2\n2\n0\n0\n1\n1\n1\n1\n1\n1\n1\n1\n1\n1\n0\n0\n2727\n2727\n2727\n2727\n2727\n2727\n2727\n2727\n2727\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n0.48 [0.05 , 5.01]0.48 [0.05 , 5.01]\n0.48 [0.05 , 5.01]0.48 [0.05 , 5.01]\n4.83 [0.24 , 96.16]4.83 [0.24 , 96.16]\n0.32 [0.01 , 7.57]0.32 [0.01 , 7.57]\n0.32 [0.01 , 7.57]0.32 [0.01 , 7.57]\n0.32 [0.01 , 7.57]0.32 [0.01 , 7.57]\n0.32 [0.01 , 7.57]0.32 [0.01 , 7.57]\n0.32 [0.01 , 7.57]0.32 [0.01 , 7.57]\n2.90 [0.12 , 68.15]2.90 [0.12 , 68.15]\n?\n?\n?\n?\n?\n?\n?\n?\n?\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n201\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 8.3. /uni00A0 (Continued)\nSubtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.66 (P = 0.51)\n8.3.19 Vaginal discharge - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.66 (P = 0.51)\n8.3.20 Paresthesia - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.66 (P = 0.51)\n8.3.21 Cramps - 6 months\nVercellini 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.66 (P = 0.51)\n1\n1\n1\n1\n1\n1\n1\n28\n2828\n2828\n2828\n0\n0\n0\n0\n0\n0\n0\n27\n2727\n2727\n2727\n100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n2.90 [0.12 , 68.15]\n2.90 [0.12 , 68.15]2.90 [0.12 , 68.15]\n2.90 [0.12 , 68.15]2.90 [0.12 , 68.15]\n2.90 [0.12 , 68.15]2.90 [0.12 , 68.15]\n0.01 0.1 1 10 100Favours gestrinoneFavours GnRHas\n?\n?\n?\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 9. /uni00A0 GnRHas versus GnRHas (varying dosage) - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n9.1 Relief of overall pain - 200 /uni03BCg versus\n400 /uni03BCg nafarelin - continuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n9.1.1 Pelvic pain - 2 months 1 15 Mean Difference (IV, Fixed,\n95% CI)\n0.20 [-1.07, 1.47]\n9.1.2 Pelvic pain - 4 months 1 15 Mean Difference (IV, Fixed,\n95% CI)\n-0.10 [-1.07, 0.87]\n9.1.3 Pelvic pain - 6 months 1 15 Mean Difference (IV, Fixed,\n95% CI)\n0.30 [-0.61, 1.21]\n9.2 Relief of overall pain - 400 /uni03BCg versus\n800 /uni03BCg nafarelin - dichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n9.2.1 Pelvic pain - 6 months 1 77 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.24 [0.71, 2.16]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n202\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n9.2.2 Dysmenorrhea - 6 months 1 90 Risk Ratio (M-H, Fixed, 95%\nCI)\n3.00 [0.13, 71.74]\n9.2.3 Dyspareunia - 6 months 1 57 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.05 [0.49, 2.26]\n9.3 Adverse effects - 200 /uni03BCg versus 400\n/uni03BCg nafarelin - dichotomous\n2 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n9.3.1 Vasomotor symptoms (hot flashes\nor dizziness) - 2 months\n1 15 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.44 [0.17, 1.12]\n9.3.2 Vasomotor symptoms (hot flashes\nor dizziness) - 4 months\n1 15 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.35 [0.10, 1.27]\n9.3.3 Vasomotor symptoms (hot flashes\nor dizziness) - 6 months\n1 15 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.29 [0.08, 1.01]\n9.3.4 Rhinitis - 6 months 1 24 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.40 [0.10, 1.67]\n9.3.5 Upper respiratory infection - 6\nmonths\n1 24 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.20 [0.03, 1.47]\n9.3.6 Irregular bleeding - 6 months 1 24 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.71 [0.31, 1.63]\n9.4 Adverse effects - 3.75 mg versus 1.88\nmg leuprolide acetate - continuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n9.4.1 Menopausal symptoms by Kupper-\nman Index - 2 months\n1 50 Mean Difference (IV, Fixed,\n95% CI)\n1.20 [-3.14, 5.54]\n9.4.2 Menopausal symptoms by Kupper-\nman Index - 3 months\n1 50 Mean Difference (IV, Fixed,\n95% CI)\n5.70 [2.12, 9.28]\n9.4.3 Menopausal symptoms by Kupper-\nman Index - 4 months\n1 50 Mean Difference (IV, Fixed,\n95% CI)\n9.50 [6.55, 12.45]\n9.4.4 Menopausal symptoms by Kupper-\nman Index - 5 months\n1 50 Mean Difference (IV, Fixed,\n95% CI)\n13.20 [10.22,\n16.18]\n9.5 Improvement of most troublesome\nsymptoms - 400 /uni03BCg versus 800 /uni03BCg na-\nfarelin - dichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n9.5.1 Overall improvement - 6 months 1 143 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.94 [0.78, 1.14]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n203\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 9.1. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies\nincluded, Outcome 1: Relief of overall pain - 200 /uni03BCg versus 400 /uni03BCg nafarelin - continuous\nStudy or Subgroup\n9.1.1 Pelvic pain - 2 months\nTahara 2000Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.31 (P = 0.76)\n9.1.2 Pelvic pain - 4 months\nTahara 2000Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.20 (P = 0.84)\n9.1.3 Pelvic pain - 6 months\nTahara 2000Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.64 (P = 0.52)\n200 μg nafarelinMean\n4.4\n3.7\n3.8\nSD\n1.2\n1.1\n0.9\nTotal\n88\n88\n88\n400 μg nafarelinMean\n4.2\n3.8\n3.5\nSD\n1.3\n0.8\n0.9\nTotal\n77\n77\n77\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n0.20 [-1.07 , 1.47]0.20 [-1.07 , 1.47]\n-0.10 [-1.07 , 0.87]-0.10 [-1.07 , 0.87]\n0.30 [-0.61 , 1.21]0.30 [-0.61 , 1.21]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours lower doseFavours higher dose\nRisk of BiasA\n+\n+\n+\nB\n?\n?\n?\nC\n?\n?\n?\nD\n?\n?\n?\nE\n+\n+\n+\nF\n+\n+\n+\nG\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n204\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 9.2. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies\nincluded, Outcome 2: Relief of overall pain - 400 /uni03BCg versus 800 /uni03BCg nafarelin - dichotomous\nStudy or Subgroup\n9.2.1 Pelvic pain - 6 monthsAdamson 1994Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.74 (P = 0.46)\n9.2.2 Dysmenorrhea - 6 monthsAdamson 1994Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.68 (P = 0.50)\n9.2.3 Dyspareunia - 6 monthsAdamson 1994Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.12 (P = 0.90)\n400 μg nafarelinEvents\n16\n16\n1\n1\n10\n10\nTotal\n3737\n4545\n3131\n800 μg nafarelinEvents\n14\n14\n0\n0\n8\n8\nTotal\n4040\n4545\n2626\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.24 [0.71 , 2.16]1.24 [0.71 , 2.16]\n3.00 [0.13 , 71.74]3.00 [0.13 , 71.74]\n1.05 [0.49 , 2.26]1.05 [0.49 , 2.26]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours 400μg nafarelinFavours 200μg nafarelin\nRisk of BiasA\n?\n?\n?\nB\n+\n+\n+\nC\n+\n+\n+\nD\n+\n+\n+\nE\n+\n+\n+\nF\n+\n+\n+\nG\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n205\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 9.3. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies\nincluded, Outcome 3: Adverse eﬀects - 200 /uni03BCg versus 400 /uni03BCg nafarelin - dichotomous\nStudy or Subgroup\n9.3.1 Vasomotor symptoms (hot flashes or dizziness) - 2 months\nTahara 2000Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.72 (P = 0.09)\n9.3.2 Vasomotor symptoms (hot flashes or dizziness) - 4 months\nTahara 2000Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.60 (P = 0.11)\n9.3.3 Vasomotor symptoms (hot flashes or dizziness) - 6 months\nTahara 2000Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.95 (P = 0.05)\n9.3.4 Rhinitis - 6 months\nBergqvist 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.25 (P = 0.21)\n9.3.5 Upper respiratory infection - 6 months\nBergqvist 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.58 (P = 0.11)\n9.3.6 Irregular bleeding - 6 months\nBergqvist 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.80 (P = 0.42)\n200 μg nafarelinEvents\n3\n3\n2\n2\n2\n2\n2\n2\n1\n1\n5\n5\nTotal\n88\n88\n88\n1212\n1212\n1212\n400 μg nafarelinEvents\n6\n6\n5\n5\n6\n6\n5\n5\n5\n5\n7\n7\nTotal\n77\n77\n77\n1212\n1212\n1212\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.44 [0.17 , 1.12]0.44 [0.17 , 1.12]\n0.35 [0.10 , 1.27]0.35 [0.10 , 1.27]\n0.29 [0.08 , 1.01]0.29 [0.08 , 1.01]\n0.40 [0.10 , 1.67]0.40 [0.10 , 1.67]\n0.20 [0.03 , 1.47]0.20 [0.03 , 1.47]\n0.71 [0.31 , 1.63]0.71 [0.31 , 1.63]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours 400μg nafarelinFavours 200μg nafarelin\nRisk of BiasA\n+\n+\n+\n?\n?\n?\nB\n?\n?\n?\n?\n?\n?\nC\n?\n?\n?\n+\n+\n+\nD\n?\n?\n?\n+\n+\n+\nE\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n206\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 9.4. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included,\nOutcome 4: Adverse eﬀects - 3.75 mg versus 1.88 mg leuprolide acetate - continuous\nStudy or Subgroup\n9.4.1 Menopausal symptoms by Kupperman Index - 2 months\nTang 2017Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.54 (P = 0.59)\n9.4.2 Menopausal symptoms by Kupperman Index - 3 months\nTang 2017Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 3.12 (P = 0.002)\n9.4.3 Menopausal symptoms by Kupperman Index - 4 months\nTang 2017Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 6.32 (P < 0.00001)\n9.4.4 Menopausal symptoms by Kupperman Index - 5 months\nTang 2017Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 8.69 (P < 0.00001)\n3.75 mg leuprorelin acetateMean\n14\n16.3\n18.2\n19.6\nSD\n8.4\n7.2\n6.7\n7.5\nTotal\n2525\n2525\n2525\n2525\n1.88 mg leuprorelin acetateMean\n12.8\n10.6\n8.7\n6.4\nSD\n7.2\n5.6\n3.4\n1.2\nTotal\n2525\n2525\n2525\n2525\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n1.20 [-3.14 , 5.54]1.20 [-3.14 , 5.54]\n5.70 [2.12 , 9.28]5.70 [2.12 , 9.28]\n9.50 [6.55 , 12.45]9.50 [6.55 , 12.45]\n13.20 [10.22 , 16.18]13.20 [10.22 , 16.18]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours 1.88mg Leuprorelin acetateFavours 3.75mg Leuprorelin acetate\nRisk of BiasA\n?\n?\n?\n?\nB\n?\n?\n?\n?\nC\n?\n?\n?\n?\nD\n?\n?\n?\n?\nE\n?\n?\n?\n?\nF\n+\n+\n+\n+\nG\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 9.5. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome\n5: Improvement of most troublesome symptoms - 400 /uni03BCg versus 800 /uni03BCg nafarelin - dichotomous\nStudy or Subgroup\n9.5.1 Overall improvement - 6 monthsHenzl 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.63 (P = 0.53)\n400 μg nafarelinEvents\n53\n53\nTotal\n7373\n800 μg nafarelinEvents\n54\n54\nTotal\n7070\nWeight\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.94 [0.78 , 1.14]0.94 [0.78 , 1.14]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours 400μg NafarelinFavours 800μg Nafarelin\nRisk of BiasA\n?\nB\n?\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n207\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nComparison 10. /uni00A0 GnRHas versus GnRHas (duration of treatment) - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n10.1 Relief of overall pain - 3 months vs\n6 months - continuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n10.1.1 Pelvic pain - 6 months 1 179 Mean Difference (IV, Fixed,\n95% CI)\n0.16 [0.13, 0.19]\n10.1.2 Dysmenorrhoea - 6 months 1 179 Mean Difference (IV, Fixed,\n95% CI)\n-0.09 [-0.11,\n-0.07]\n10.1.3 Dyspareunia - 6 months 1 179 Mean Difference (IV, Fixed,\n95% CI)\n-0.14 [-0.17,\n-0.11]\n10.1.4 Pelvic induration - 6 months 1 179 Mean Difference (IV, Fixed,\n95% CI)\n-0.03 [-0.06, 0.00]\n10.1.5 Pelvic tenderness - 6 months 1 179 Mean Difference (IV, Fixed,\n95% CI)\n0.05 [0.03, 0.07]\n10.2 Bone mineral density of spinal\nbone mass - 3 months vs 6 months -\ncontinuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n10.2.1 Percentage change values - 6\nmonths\n1 183 Mean Difference (IV, Fixed,\n95% CI)\n1.60 [1.51, 1.69]\n10.3 Bone mineral density of proximal\nfemoral bone - 3 months vs 6 months -\ncontinuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n10.3.1 Percentage change values - 6\nmonths\n1 183 Mean Difference (IV, Fixed,\n95% CI)\n1.90 [1.72, 2.08]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n208\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 10.1. /uni00A0 Comparison 10: GnRHas versus GnRHas (duration of treatment) - all\nstudies included, Outcome 1: Relief of overall pain - 3 months vs 6 months - continuous\nStudy or Subgroup\n10.1.1 Pelvic pain - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 11.89 (P < 0.00001)\n10.1.2 Dysmenorrhoea - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 8.00 (P < 0.00001)\n10.1.3 Dyspareunia - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 8.13 (P < 0.00001)\n10.1.4 Pelvic induration - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.91 (P = 0.06)\n10.1.5 Pelvic tenderness - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 3.93 (P < 0.0001)\n3 monthsMean\n0.75\n0.24\n0.6\n0.51\n0.49\nSD\n0.09\n0.07\n0.11\n0.1\n0.09\nTotal\n9191\n9191\n9191\n9191\n9191\n6 monthsMean\n0.59\n0.33\n0.74\n0.54\n0.44\nSD\n0.09\n0.08\n0.12\n0.11\n0.08\nTotal\n8888\n8888\n8888\n8888\n8888\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n0.16 [0.13 , 0.19]0.16 [0.13 , 0.19]\n-0.09 [-0.11 , -0.07]\n-0.09 [-0.11 , -0.07]\n-0.14 [-0.17 , -0.11]\n-0.14 [-0.17 , -0.11]\n-0.03 [-0.06 , 0.00]-0.03 [-0.06 , 0.00]\n0.05 [0.03 , 0.07]0.05 [0.03 , 0.07]\nMean Difference\nIV, Fixed, 95% CI\n-1 -0.50 0.5 1Favours 3 monthsFavours 6 months\nRisk of BiasA\n?\n?\n?\n?\n?\nB\n?\n?\n?\n?\n?\nC\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 10.2. /uni00A0 Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies\nincluded, Outcome 2: Bone mineral density of spinal bone mass - 3 months vs 6 months - continuous\nStudy or Subgroup\n10.2.1 Percentage change values - 6 monthsOrwoll 1994Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 36.07 (P < 0.00001)\n3 monthsMean\n-2.4\nSD\n0.3\nTotal\n9191\n6 monthsMean\n-4\nSD\n0.3\nTotal\n9292\nWeight\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n1.60 [1.51 , 1.69]1.60 [1.51 , 1.69]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours 3 monthsFavours 6 months\nRisk of BiasA\n?\nB\n?\nC\n+\nD\n+\nE\n?\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n209\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 10.3. /uni00A0 Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies included,\nOutcome 3: Bone mineral density of proximal femoral bone - 3 months vs 6 months - continuous\nStudy or Subgroup\n10.3.1 Percentage change values - 6 monthsOrwoll 1994Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 21.11 (P < 0.00001)\n3 monthsMean\n-1.1\nSD\n0.7\nTotal\n9191\n6 monthsMean\n-3\nSD\n0.5\nTotal\n9292\nWeight\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n1.90 [1.72 , 2.08]1.90 [1.72 , 2.08]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours 3 monthsFavours 6 months\nRisk of BiasA\n?\nB\n?\nC\n+\nD\n+\nE\n?\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 11. /uni00A0 GnRHas versus GnRHas (route of administration)\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n11.1 Relief of overall pain - IN versus\nSC - dichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n11.1.1 Pelvic pain - 6 months 1 5 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.00 [0.53, 1.87]\n11.1.2 Dysmenorrhea - 6 months 1 10 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.22 [0.73, 2.06]\n11.1.3 Dyspareunia - 6 months 1 7 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.00 [0.57, 1.75]\n11.1.4 Pelvic induration - 6 months 1 8 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.86 [0.47, 1.55]\n11.1.5 Pelvic tenderness - 6 months 1 10 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.50 [0.69, 3.27]\n11.2 Adverse effects - IN vs SC - di-\nchotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n11.2.1 Hot flushes/flashes - 6 months 1 13 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.86 [0.48, 1.55]\n11.2.2 Vaginal dryness - 6 months 1 13 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.86 [0.17, 4.37]\n11.2.3 Decreased libido - 6 months 1 13 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.86 [0.07, 10.96]\n11.2.4 Headaches - 6 months 1 13 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.71 [0.20, 14.55]\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n210\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 11.1. /uni00A0 Comparison 11: GnRHas versus GnRHas (route of\nadministration), Outcome 1: Relief of overall pain - IN versus SC - dichotomous\nStudy or Subgroup\n11.1.1 Pelvic pain - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\n11.1.2 Dysmenorrhea - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.75 (P = 0.45)\n11.1.3 Dyspareunia - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\n11.1.4 Pelvic induration - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.51 (P = 0.61)\n11.1.5 Pelvic tenderness - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.02 (P = 0.31)\nIntranasalEvents\n3\n3\n5\n5\n5\n5\n4\n4\n7\n7\nTotal\n33\n55\n55\n55\n77\nSubcutaneousEvents\n2\n2\n4\n4\n2\n2\n3\n3\n2\n2\nTotal\n22\n55\n22\n33\n33\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.00 [0.53 , 1.87]1.00 [0.53 , 1.87]\n1.22 [0.73 , 2.06]1.22 [0.73 , 2.06]\n1.00 [0.57 , 1.75]1.00 [0.57 , 1.75]\n0.86 [0.47 , 1.55]0.86 [0.47 , 1.55]\n1.50 [0.69 , 3.27]1.50 [0.69 , 3.27]\nRisk RatioM-H, Fixed, 95% CI\n0.001 0.1 1 10 1000Favours intranasalFavours subcutaneous\nRisk of BiasA\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\nC\n?\n?\n?\n?\n?\nD\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n211\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 11.2. /uni00A0 Comparison 11: GnRHas versus GnRHas (route of\nadministration), Outcome 2: Adverse eﬀects - IN vs SC - dichotomous\nStudy or Subgroup\n11.2.1 Hot flushes/flashes - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.51 (P = 0.61)\n11.2.2 Vaginal dryness - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.19 (P = 0.85)\n11.2.3 Decreased libido - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.12 (P = 0.91)\n11.2.4 Headaches - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.49 (P = 0.62)\nIntranasalEvents\n5\n5\n2\n2\n1\n1\n2\n2\nTotal\n77\n77\n77\n77\nSubcutaneousEvents\n5\n5\n2\n2\n1\n1\n1\n1\nTotal\n66\n66\n66\n66\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.86 [0.48 , 1.55]0.86 [0.48 , 1.55]\n0.86 [0.17 , 4.37]0.86 [0.17 , 4.37]\n0.86 [0.07 , 10.96]0.86 [0.07 , 10.96]\n1.71 [0.20 , 14.55]1.71 [0.20 , 14.55]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours SubcutaneousFavours Intranasal\nRisk of BiasA\n+\n+\n+\n+\nB\n+\n+\n+\n+\nC\n?\n?\n?\n?\nD\n+\n+\n+\n+\nE\n+\n+\n+\n+\nF\n+\n+\n+\n+\nG\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 12. /uni00A0 GnRHas versus GnRHas (route of administration) - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n12.1 Relief of overall pain - IN ver-\nsus SC - dichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n12.1.1 Pelvic pain - 6 months 1 5 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.53, 1.87]\n12.1.2 Dysmenorrhoea - 6 months 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.73, 2.06]\n12.1.3 Dyspareunia - 6 months 1 7 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.57, 1.75]\n12.1.4 Pelvic induration - 6 months 1 8 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.47, 1.55]\n12.1.5 Pelvic tenderness - 6\nmonths\n1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.69, 3.27]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n212\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n12.2 Relief of overall pain - IN ver-\nsus IM - dichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n12.2.1 Pelvic pain - 6 months 1 192 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.73, 1.26]\n12.2.2 Dysmenorrhoea - 6 months 1 192 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.72, 2.30]\n12.2.3 Dyspareunia - 6 months 1 166 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.62, 1.25]\n12.2.4 Pelvic induration - 6 months 1 190 Risk Ratio (M-H, Fixed, 95% CI) 1.41 [0.82, 2.41]\n12.2.5 Pelvic tenderness - 6\nmonths\n1 192 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.88, 1.73]\n12.3 Adverse effects - IN vs SC - di-\nchotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n12.3.1 Hot flushes/flashes - 6\nmonths\n1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.48, 1.55]\n12.3.2 Vaginal dryness - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.17, 4.37]\n12.3.3 Decreased libido - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.07, 10.96]\n12.3.4 Headaches - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.20, 14.55]\n12.4 Adverse effects - IN versus IM\ndepot - dichotomous\n2 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n12.4.1 Hot flushes/flashes - 6\nmonths\n2 404 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.88, 1.02]\n12.4.2 Headache - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.63, 1.10]\n12.4.3 Sweating - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [0.71, 1.79]\n12.4.4 Vaginal dryness - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.27, 1.00]\n12.4.5 Vaginal bleeding - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 19.19 [1.12, 328.28]\n12.5 Bone mineral density of spinal\nbone mass - IN vs IM depot - con-\ntinuous\n1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n12.5.1 Percentage decrease of BMD\n- 6 months\n1 152 Mean Difference (IV, Fixed, 95%\nCI)\n-2.00 [-2.10, -1.90]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n213\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 12.1. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) -\nall studies included, Outcome 1: Relief of overall pain - IN versus SC - dichotomous\nStudy or Subgroup\n12.1.1 Pelvic pain - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\n12.1.2 Dysmenorrhoea - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.75 (P = 0.45)\n12.1.3 Dyspareunia - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\n12.1.4 Pelvic induration - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.51 (P = 0.61)\n12.1.5 Pelvic tenderness - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.02 (P = 0.31)\nIntranasalEvents\n3\n3\n5\n5\n5\n5\n4\n4\n7\n7\nTotal\n33\n55\n55\n55\n77\nSubcutaneousEvents\n2\n2\n4\n4\n2\n2\n3\n3\n2\n2\nTotal\n22\n55\n22\n33\n33\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.00 [0.53 , 1.87]1.00 [0.53 , 1.87]\n1.22 [0.73 , 2.06]1.22 [0.73 , 2.06]\n1.00 [0.57 , 1.75]1.00 [0.57 , 1.75]\n0.86 [0.47 , 1.55]0.86 [0.47 , 1.55]\n1.50 [0.69 , 3.27]1.50 [0.69 , 3.27]\nRisk RatioM-H, Fixed, 95% CI\n0.001 0.1 1 10 1000Favours intranasalFavours subcutaneous\nRisk of BiasA\n+\n+\n+\n+\n+\nB\n+\n+\n+\n+\n+\nC\n?\n?\n?\n?\n?\nD\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n214\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 12.2. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) -\nall studies included, Outcome 2: Relief of overall pain - IN versus IM - dichotomous\nStudy or Subgroup\n12.2.1 Pelvic pain - 6 monthsAgarwal 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.30 (P = 0.76)\n12.2.2 Dysmenorrhoea - 6 monthsAgarwal 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.87 (P = 0.39)\n12.2.3 Dyspareunia - 6 monthsAgarwal 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.71 (P = 0.48)\n12.2.4 Pelvic induration - 6 monthsAgarwal 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.23 (P = 0.22)\n12.2.5 Pelvic tenderness - 6 monthsAgarwal 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.23 (P = 0.22)\nIntranasalEvents\n50\n50\n22\n22\n34\n34\n26\n26\n46\n46\nTotal\n9999\n9999\n8686\n9999\n9999\nSubcutaneousEvents\n49\n49\n16\n16\n36\n36\n17\n17\n35\n35\nTotal\n9393\n9393\n8080\n9191\n9393\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.96 [0.73 , 1.26]0.96 [0.73 , 1.26]\n1.29 [0.72 , 2.30]1.29 [0.72 , 2.30]\n0.88 [0.62 , 1.25]0.88 [0.62 , 1.25]\n1.41 [0.82 , 2.41]1.41 [0.82 , 2.41]\n1.23 [0.88 , 1.73]1.23 [0.88 , 1.73]\nRisk RatioM-H, Fixed, 95% CI\n0.001 0.1 1 10 1000Favours intranasalFavours subcutaneous\nRisk of BiasA\n?\n?\n?\n?\n?\nB\n?\n?\n?\n?\n?\nC\n+\n+\n+\n+\n+\nD\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n215\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 12.3. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration)\n- all studies included, Outcome 3: Adverse eﬀects - IN vs SC - dichotomous\nStudy or Subgroup\n12.3.1 Hot flushes/flashes - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.51 (P = 0.61)\n12.3.2 Vaginal dryness - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.19 (P = 0.85)\n12.3.3 Decreased libido - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.12 (P = 0.91)\n12.3.4 Headaches - 6 monthsLemay 1988Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.49 (P = 0.62)\nIntranasalEvents\n5\n5\n2\n2\n1\n1\n2\n2\nTotal\n77\n77\n77\n77\nSubcutaneousEvents\n5\n5\n2\n2\n1\n1\n1\n1\nTotal\n66\n66\n66\n66\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.86 [0.48 , 1.55]0.86 [0.48 , 1.55]\n0.86 [0.17 , 4.37]0.86 [0.17 , 4.37]\n0.86 [0.07 , 10.96]0.86 [0.07 , 10.96]\n1.71 [0.20 , 14.55]1.71 [0.20 , 14.55]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours SubcutaneousFavours Intranasal\nRisk of BiasA\n+\n+\n+\n+\nB\n+\n+\n+\n+\nC\n?\n?\n?\n?\nD\n+\n+\n+\n+\nE\n+\n+\n+\n+\nF\n+\n+\n+\n+\nG\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n216\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 12.4. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) -\nall studies included, Outcome 4: Adverse eﬀects - IN versus IM depot - dichotomous\nStudy or Subgroup\n12.4.1 Hot flushes/flashes - 6 monthsAgarwal 1997\nBergqvist 2000Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 1.62, df = 1 (P = 0.20); I² = 38%\nTest for overall effect: Z = 1.52 (P = 0.13)\n12.4.2 Headache - 6 months\nBergqvist 2000Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.29 (P = 0.20)\n12.4.3 Sweating - 6 months\nBergqvist 2000Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.52 (P = 0.60)\n12.4.4 Vaginal dryness - 6 months\nBergqvist 2000Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.95 (P = 0.05)\n12.4.5 Vaginal bleeding - 6 months\nBergqvist 2000Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.04 (P = 0.04)\nIntranasalEvents\n9574\n169\n45\n45\n27\n27\n11\n11\n8\n8\nTotal\n98100198\n100100\n100100\n100100\n100100\nIMdepotEvents\n9391\n184\n61\n61\n27\n27\n24\n24\n0\n0\nTotal\n93\n113206\n113\n113\n113\n113\n113\n113\n113\n113\nWeight\n52.9%47.1%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.97 [0.93 , 1.01]0.92 [0.79 , 1.06]0.95 [0.88 , 1.02]\n0.83 [0.63 , 1.10]0.83 [0.63 , 1.10]\n1.13 [0.71 , 1.79]1.13 [0.71 , 1.79]\n0.52 [0.27 , 1.00]0.52 [0.27 , 1.00]\n19.19 [1.12 , 328.28]19.19 [1.12 , 328.28]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours intranasalFavours IM(depot)\nRisk of BiasA\n??\n?\n?\n?\n?\nB\n??\n?\n?\n?\n?\nC\n+?\n?\n?\n?\n?\nD\n+?\n?\n?\n?\n?\nE\n++\n+\n+\n+\n+\nF\n++\n+\n+\n+\n+\nG\n++\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n217\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 12.5. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) - all studies\nincluded, Outcome 5: Bone mineral density of spinal bone mass - IN vs IM depot - continuous\nStudy or Subgroup\n12.5.1 Percentage decrease of BMD - 6 monthsAgarwal 1997Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 41.08 (P < 0.00001)\nintranasalMean\n3\nSD\n0.3\nTotal\n7878\nIM depotMean\n5\nSD\n0.3\nTotal\n7474\nWeight\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-2.00 [-2.10 , -1.90]-2.00 [-2.10 , -1.90]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas\nRisk of BiasA\n?\nB\n?\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 13. /uni00A0 GnRHas versus GnRHas (diﬀerent treatment regimens) - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n13.1 Relief of overall pain - monthly\nversus 3-monthly depot leuprolide\nacetate - continuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n13.1.1 Non-menstrual pelvic pain - 3\nmonths\n1 30 Mean Difference (IV, Fixed,\n95% CI)\n-0.20 [-0.52, 0.12]\n13.1.2 Dyspareunia - 3 months 1 30 Mean Difference (IV, Fixed,\n95% CI)\n-0.10 [-0.51, 0.31]\n13.1.3 Pelvic induration - 3 months 1 30 Mean Difference (IV, Fixed,\n95% CI)\n0.10 [-0.40, 0.60]\n13.1.4 Pelvic tenderness - 3 months 1 30 Mean Difference (IV, Fixed,\n95% CI)\n-0.30 [-0.71, 0.11]\n13.1.5 Non-menstrual pelvic pain - 6\nmonths\n1 30 Mean Difference (IV, Fixed,\n95% CI)\n0.10 [-0.15, 0.35]\n13.1.6 Dyspareunia - 6 months 1 30 Mean Difference (IV, Fixed,\n95% CI)\n0.00 [-0.50, 0.50]\n13.1.7 Pelvic induration - 6 months 1 30 Mean Difference (IV, Fixed,\n95% CI)\n0.40 [0.10, 0.70]\n13.1.8 Pelvic tenderness - 6 months 1 30 Mean Difference (IV, Fixed,\n95% CI)\n0.40 [-0.10, 0.90]\n13.2 Adverse effects - monthly versus\n3-monthly depot leuprolide acetate -\ndichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n13.2.1 Hot flushes/flashes - 6 months 1 30 Risk Ratio (M-H, Fixed, 95%\nCI)\n1.00 [0.70, 1.43]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n218\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n13.2.2 Vaginal dryness - 6 months 1 30 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.67 [0.13, 3.44]\n13.2.3 Abdominal pain - 6 months 1 30 Risk Ratio (M-H, Fixed, 95%\nCI)\n3.00 [0.13, 68.26]\n13.2.4 Arthralgia - 6 months 1 30 Risk Ratio (M-H, Fixed, 95%\nCI)\n3.00 [0.13, 68.26]\n13.2.5 Depression - 6 months 1 30 Risk Ratio (M-H, Fixed, 95%\nCI)\n3.00 [0.13, 68.26]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n219\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 13.1. /uni00A0 Comparison 13: GnRHas versus GnRHas (diﬀerent treatment regimens) - all studies included,\nOutcome 1: Relief of overall pain - monthly versus 3-monthly depot leuprolide acetate - continuous\nStudy or Subgroup\n13.1.1 Non-menstrual pelvic pain - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.21 (P = 0.23)\n13.1.2 Dyspareunia - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.48 (P = 0.63)\n13.1.3 Pelvic induration - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.39 (P = 0.70)\n13.1.4 Pelvic tenderness - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.44 (P = 0.15)\n13.1.5 Non-menstrual pelvic pain - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.77 (P = 0.44)\n13.1.6 Dyspareunia - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\n13.1.7 Pelvic induration - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 2.66 (P = 0.008)\n13.1.8 Pelvic tenderness - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable\nTest for overall effect: Z = 1.56 (P = 0.12)\nMonthlyMean\n1.2\n1.2\n1.6\n1.5\n1.2\n1.3\n1.5\n1.6\nSD\n0.4\n0.4\n0.7\n0.7\n0.4\n0.7\n0.5\n0.7\nTotal\n1515\n1515\n1515\n1515\n1515\n1515\n1515\n1515\n3-MonthlyMean\n1.4\n1.3\n1.5\n1.8\n1.1\n1.3\n1.1\n1.2\nSD\n0.5\n0.7\n0.7\n0.4\n0.3\n0.7\n0.3\n0.7\nTotal\n1515\n1515\n1515\n1515\n1515\n1515\n1515\n1515\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean Difference\nIV, Fixed, 95% CI\n-0.20 [-0.52 , 0.12]-0.20 [-0.52 , 0.12]\n-0.10 [-0.51 , 0.31]-0.10 [-0.51 , 0.31]\n0.10 [-0.40 , 0.60]0.10 [-0.40 , 0.60]\n-0.30 [-0.71 , 0.11]\n-0.30 [-0.71 , 0.11]\n0.10 [-0.15 , 0.35]0.10 [-0.15 , 0.35]\n0.00 [-0.50 , 0.50]0.00 [-0.50 , 0.50]\n0.40 [0.10 , 0.70]0.40 [0.10 , 0.70]\n0.40 [-0.10 , 0.90]0.40 [-0.10 , 0.90]\nMean Difference\nIV, Fixed, 95% CI\n-100-50 0 50 100Favours 3-monthlyFavours monthly\nRisk of BiasA\n+\n+\n+\n+\n+\n+\n+\n+\nB\n?\n?\n?\n?\n?\n?\n?\n?\nC\n?\n?\n?\n?\n?\n?\n?\n?\nD\n?\n?\n?\n?\n?\n?\n?\n?\nE\n+\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n220\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 13.2. /uni00A0 Comparison 13: GnRHas versus GnRHas (diﬀerent treatment regimens) - all studies\nincluded, Outcome 2: Adverse eﬀects - monthly versus 3-monthly depot leuprolide acetate - dichotomous\nStudy or Subgroup\n13.2.1 Hot flushes/flashes - 6 monthsCrosignani 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.00 (P = 1.00)\n13.2.2 Vaginal dryness - 6 monthsCrosignani 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.48 (P = 0.63)\n13.2.3 Abdominal pain - 6 monthsCrosignani 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.69 (P = 0.49)\n13.2.4 Arthralgia - 6 monthsCrosignani 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.69 (P = 0.49)\n13.2.5 Depression - 6 monthsCrosignani 1996Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.69 (P = 0.49)\nMonthlyEvents\n12\n12\n2\n2\n1\n1\n1\n1\n1\n1\nTotal\n1515\n1515\n1515\n1515\n1515\n3-monthlyEvents\n12\n12\n3\n3\n0\n0\n0\n0\n0\n0\nTotal\n1515\n1515\n1515\n1515\n1515\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.00 [0.70 , 1.43]1.00 [0.70 , 1.43]\n0.67 [0.13 , 3.44]0.67 [0.13 , 3.44]\n3.00 [0.13 , 68.26]3.00 [0.13 , 68.26]\n3.00 [0.13 , 68.26]3.00 [0.13 , 68.26]\n3.00 [0.13 , 68.26]3.00 [0.13 , 68.26]\nRisk RatioM-H, Fixed, 95% CI\n0.01 0.1 1 10 100Favours 3-monthlyFavours monthly\nRisk of BiasA\n+\n+\n+\n+\n+\nB\n?\n?\n?\n?\n?\nC\n?\n?\n?\n?\n?\nD\n?\n?\n?\n?\n?\nE\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 14. /uni00A0 GnRHas versus GnRHas in conjunction with add-back therapy - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n14.1 Relief of overall pain - di-\nchotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n14.1.1 Dysmenorrhoea - 6 months 1 28 Risk Ratio (M-H, Fixed, 95% CI) 9.62 [0.58, 159.04]\n14.1.2 Dyspareunia - 6 months 1 28 Risk Ratio (M-H, Fixed, 95% CI) 6.07 [0.86, 43.04]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n221\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n14.1.3 Non-menstrual pelvic pain\n- 6 months\n1 28 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.26, 6.62]\n14.2 Relief of overall pain - con-\ntinuous\n1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n14.2.1 Pelvic pain - 6 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-0.20 [-0.39, -0.01]\n14.2.2 Dysmenorrhoea - 6 months 1 0 Mean Difference (IV, Fixed, 95%\nCI)\nNot estimable\n14.2.3 Dyspareunia - 6 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.40, 0.80]\n14.2.4 Pelvic pain - 12 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-0.10 [-0.14, -0.06]\n14.2.5 Overall pain - 12 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-1.50 [-7.92, 4.92]\n14.2.6 Dysmenorrhoea - 12\nmonths\n1 0 Mean Difference (IV, Fixed, 95%\nCI)\nNot estimable\n14.2.7 Dyspareunia - 12 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n0.20 [-0.03, 0.43]\n14.3 Bone mineral density of\nspinal bone mass - continuous\n6 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n14.3.1 Percentage change values\n- 6 months\n2 46 Mean Difference (IV, Fixed, 95%\nCI)\n-3.88 [-4.27, -3.49]\n14.3.2 Absolute values - 6 months 5 199 Mean Difference (IV, Fixed, 95%\nCI)\n0.02 [0.02, 0.02]\n14.3.3 Absolute values - 12\nmonths\n1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-0.01 [-0.06, 0.03]\n14.4 Adverse effects - dichoto-\nmous\n6 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only\n14.4.1 Hot flushes/flashes - 3\nmonths\n1 306 Risk Ratio (M-H, Fixed, 95% CI) 1.86 [1.61, 2.15]\n14.4.2 Hot flushes/flashes - 6\nmonths\n4 215 Risk Ratio (M-H, Fixed, 95% CI) 1.59 [1.32, 1.93]\n14.4.3 Loss of libido - 6 months 2 96 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.58, 1.97]\n14.4.4 Vaginal dryness - 6 months 3 404 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [1.11, 1.76]\n14.4.5 Headaches - 6 months 3 126 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.67, 1.24]\n14.4.6 Sweating - 6 months 1 27 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.31, 0.94]\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n222\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n14.4.7 Sleeplessness - 6 months 1 27 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.18, 1.18]\n14.4.8 Peripheral oedema - 6\nmonths\n1 27 Risk Ratio (M-H, Fixed, 95% CI) 2.32 [0.54, 9.95]\n14.4.9 Vaginal bleeding - 6\nmonths\n3 185 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.35, 0.93]\n14.4.10 Rhinitis - 6 months 1 47 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.36, 1.94]\n14.4.11 Upper respiratory infec-\ntion - 6 months\n1 47 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.27, 1.51]\n14.4.12 Emotional changes - 6\nmonths\n1 87 Risk Ratio (M-H, Fixed, 95% CI) 3.13 [1.26, 7.78]\n14.5 Quality of life - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n14.5.1 General health - 12 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-4.70 [-10.15, 0.75]\n14.5.2 Physical function - 12\nmonths\n1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-8.80 [-14.81, -2.79]\n14.5.3 Role physical - 12 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n2.80 [-3.13, 8.73]\n14.5.4 Role emotional - 12\nmonths\n1 90 Mean Difference (IV, Fixed, 95%\nCI)\n2.30 [-3.82, 8.42]\n14.5.5 Mental health - 12 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-0.30 [-6.17, 5.57]\n14.5.6 Social function - 12\nmonths\n1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-3.80 [-8.80, 1.20]\n14.5.7 Vitality - 12 months 1 90 Mean Difference (IV, Fixed, 95%\nCI)\n-10.20 [-15.18,\n-5.22]\n14.6 Improvement of most trou-\nblesome symptoms - continuous/uni00A0\n1 /uni00A0 Mean Difference (IV, Fixed, 95%\nCI)\nSubtotals only\n14.6.1 Improvement overall pain\n- 4 weeks\n1 19 Mean Difference (IV, Fixed, 95%\nCI)\n12.00 [5.59, 18.41]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n223\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 14.1. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-\nback therapy - all studies included, Outcome 1: Relief of overall pain - dichotomous\nStudy or Subgroup\n14.1.1 Dysmenorrhoea - 6 monthsFreundl 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.58 (P = 0.11)\n14.1.2 Dyspareunia - 6 monthsFreundl 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.80 (P = 0.07)\n14.1.3 Non-menstrual pelvic pain - 6 monthsFreundl 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.32 (P = 0.75)\nGnRHasEvents\n5\n5\n7\n7\n3\n3\nTotal\n1515\n1515\n1515\nGnRHas in conjunction with add-back therapyEvents\n0\n0\n1\n1\n2\n2\nTotal\n1313\n1313\n1313\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n9.63 [0.58 , 159.04]9.63 [0.58 , 159.04]\n6.07 [0.86 , 43.04]6.07 [0.86 , 43.04]\n1.30 [0.26 , 6.62]1.30 [0.26 , 6.62]\nRisk RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas\nRisk of BiasA\n?\n?\n?\nB\n?\n?\n?\nC\n+\n+\n+\nD\n+\n+\n+\nE\n+\n+\n+\nF\n+\n+\n+\nG\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n224\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 14.2. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-\nback therapy - all studies included, Outcome 2: Relief of overall pain - continuous\nStudy or Subgroup\n14.2.1 Pelvic pain - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 2.09 (P = 0.04)\n14.2.2 Dysmenorrhoea - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Not applicable\n14.2.3 Dyspareunia - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.65 (P = 0.51)\n14.2.4 Pelvic pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 4.74 (P < 0.00001)\n14.2.5 Overall pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.46 (P = 0.65)\n14.2.6 Dysmenorrhoea - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Not applicable\n14.2.7 Dyspareunia - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.72 (P = 0.09)\nGnRHasMean\n1.3\n0\n2.6\n0.2\n62.1\n0\n1.4\nSD\n0.5\n0\n1.3\n0.1\n14\n0\n0.5\nTotal\n4444\n440\n4444\n4444\n4444\n440\n4444\nGnRHas in conjunction with add-back therapyMean\n1.5\n0\n2.4\n0.3\n63.6\n0\n1.2\nSD\n0.4\n0\n1.6\n0.1\n17\n0\n0.6\nTotal\n4646\n460\n4646\n4646\n4646\n460\n4646\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n-0.20 [-0.39 , -0.01]-0.20 [-0.39 , -0.01]\nNot estimableNot estimable\n0.20 [-0.40 , 0.80]0.20 [-0.40 , 0.80]\n-0.10 [-0.14 , -0.06]-0.10 [-0.14 , -0.06]\n-1.50 [-7.92 , 4.92]-1.50 [-7.92 , 4.92]\nNot estimableNot estimable\n0.20 [-0.03 , 0.43]0.20 [-0.03 , 0.43]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas\nRisk of BiasA\n+\n+\n+\n+\n+\n+\n+\nB\n?\n?\n?\n?\n?\n?\n?\nC\n?\n?\n?\n?\n?\n?\n?\nD\n+\n+\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n225\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 14.3. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy\n- all studies included, Outcome 3: Bone mineral density of spinal bone mass - continuous\nStudy or Subgroup\n14.3.1 Percentage change values - 6 monthsFreundl 1998Surrey 1992Subtotal (95% CI)Heterogeneity: Chi² = 15.20, df = 1 (P < 0.0001); I² = 93%Test for overall effect: Z = 19.44 (P < 0.00001)\n14.3.2 Absolute values - 6 monthsFranke 2000Gnoth 1999Sillem 1999Surrey 1992Zupi 2005Subtotal (95% CI)Heterogeneity: Chi² = 13.47, df = 4 (P = 0.009); I² = 70%Test for overall effect: Z = 12.66 (P < 0.00001)\n14.3.3 Absolute values - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.66 (P = 0.51)\nGnRHasMean\n-6.5-5.6\n1.1551.161.231.0571.005\n0.981\nSD\n0.80.7\n0.1340.040.160.0030.112\n0.099\nTotal\n141024\n2214121044102\n4444\nGnRHas in conjuction with add-back therapyMean\n-2-2.7\n1.2341.221.141.0361.01\n0.995\nSD\n0.50.7\n0.1220.130.10.0040.11\n0.102\nTotal\n13922\n18131194697\n4646\nWeight\n61.4%38.6%100.0%\n0.2%0.2%0.1%99.1%0.5%100.0%\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n-4.50 [-5.00 , -4.00]-2.90 [-3.53 , -2.27]-3.88 [-4.27 , -3.49]\n-0.08 [-0.16 , 0.00]-0.06 [-0.13 , 0.01]0.09 [-0.02 , 0.20]0.02 [0.02 , 0.02]-0.01 [-0.05 , 0.04]0.02 [0.02 , 0.02]\n-0.01 [-0.06 , 0.03]-0.01 [-0.06 , 0.03]\nMean DifferenceIV, Fixed, 95% CI\n-10-5 0 5 10Favours GnRHas in conjunction with add-back therapyFavours GnRHas\nRisk of BiasA\n?+\n???++\n+\nB\n??\n?????\n?\nC\n++\n++++?\n?\nD\n++\n+++++\n+\nE\n++\n++?++\n+\nF\n++\n+++++\n+\nG\n++\n+++++\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n226\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 14.4. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included,\nOutcome 4: Adverse eﬀects - dichotomous\nStudy or Subgroup\n14.4.1 Hot flushes/flashes - 3 monthsMoghissi 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 8.41 (P < 0.00001)\n14.4.2 Hot flushes/flashes - 6 monthsEdmonds 1994Freundl 1998Howell 1995Zupi 2005Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 37.00, df = 3 (P < 0.00001); I² = 92%\nTest for overall effect: Z = 4.82 (P < 0.00001)\n14.4.3 Loss of libido - 6 monthsEdmonds 1994Howell 1995Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 8.78, df = 1 (P = 0.003); I² = 89%\nTest for overall effect: Z = 0.21 (P = 0.84)\n14.4.4 Vaginal dryness - 6 monthsEdmonds 1994Howell 1995Moghissi 1998Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 2.85, df = 2 (P = 0.24); I² = 30%\nTest for overall effect: Z = 2.83 (P = 0.005)\n14.4.5 Headaches - 6 monthsEdmonds 1994Freundl 1998Howell 1995Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 1.10, df = 2 (P = 0.58); I² = 0%\nTest for overall effect: Z = 0.59 (P = 0.56)\n14.4.6 Sweating - 6 monthsFreundl 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.20 (P = 0.03)\n14.4.7 Sleeplessness - 6 monthsFreundl 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.61 (P = 0.11)\n14.4.8 Peripheral oedema - 6 monthsFreundl 1998Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.13 (P = 0.26)\n14.4.9 Vaginal bleeding - 6 months\nBergqvist 1997Howell 1995Zupi 2005Subtotal (95% CI)\nTotal events:\nHeterogeneity: Chi² = 6.74, df = 2 (P = 0.03); I² = 70%\nTest for overall effect: Z = 2.25 (P = 0.02)\n14.4.10 Rhinitis - 6 months\nGnRHasEvents\n103\n103\n2492434\n91\n124\n16\n111056\n77\n12\n11\n11\n34\n7\n7\n4\n4\n5\n5\n1241\n17\nTotal\n109109\n25142444107\n252348\n2524109158\n25142564\n1414\n1414\n1414\n24244492\nGnRHas  in conjunction with add-back therapyEvents\n100\n100\n12122112\n57\n4\n11\n15\n111064\n85\n14913\n36\n12\n12\n8\n8\n2\n2\n11153\n29\nTotal\n197197\n25132446108\n252348\n2524197246\n25132462\n1313\n1313\n1313\n23244693\nWeight\n100.0%100.0%\n20.8%21.6%37.3%20.3%100.0%\n26.7%73.3%100.0%\n16.5%15.0%68.5%100.0%\n38.3%25.5%36.2%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n38.5%51.4%10.1%100.0%\nRisk RatioM-H, Fixed, 95% CI\n1.86 [1.61 , 2.15]1.86 [1.61 , 2.15]\n2.00 [1.32 , 3.03]0.70 [0.46 , 1.06]1.14 [0.96 , 1.35]2.96 [1.77 , 4.94]1.59 [1.32 , 1.93]\n3.00 [1.12 , 8.05]0.36 [0.14 , 0.98]1.07 [0.58 , 1.97]\n1.00 [0.54 , 1.87]1.00 [0.51 , 1.95]1.58 [1.21 , 2.08]\n1.40 [1.11 , 1.76]\n0.86 [0.50 , 1.46]1.13 [0.72 , 1.79]0.81 [0.46 , 1.44]0.91 [0.67 , 1.24]\n0.54 [0.31 , 0.94]0.54 [0.31 , 0.94]\n0.46 [0.18 , 1.18]0.46 [0.18 , 1.18]\n2.32 [0.54 , 9.95]2.32 [0.54 , 9.95]\n1.05 [0.58 , 1.88]0.27 [0.10 , 0.69]0.35 [0.04 , 3.23]0.57 [0.35 , 0.93]\nRisk RatioM-H, Fixed, 95% CIRisk of BiasA\n?\n???+\n??\n???\n???\n?\n?\n?\n??+\nB\n?\n????\n??\n???\n???\n?\n?\n?\n???\nC\n+\n?+??\n??\n??+\n?+?\n+\n+\n+\n+??\nD\n+\n?+?+\n??\n??+\n?+?\n+\n+\n+\n+?+\nE\n+\n++−+\n+−\n+−+\n++−\n+\n+\n+\n+−+\nF\n+\n−+++\n−+\n−++\n−++\n+\n+\n+\n+++\nG\n+\n++++\n++\n+++\n+++\n+\n+\n+\n+++\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n227\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n/uni00A0\nAnalysis 14.4. /uni00A0 (Continued)\nTest for overall effect: Z = 2.25 (P = 0.02)\n14.4.10 Rhinitis - 6 months\nBergqvist 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 0.41 (P = 0.68)\n14.4.11 Upper respiratory infection - 6 months\nBergqvist 1997Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 1.02 (P = 0.31)\n14.4.12 Emotional changes - 6 monthsZupi 2005Subtotal (95% CI)\nTotal events:Heterogeneity: Not applicable\nTest for overall effect: Z = 2.45 (P = 0.01)\n7\n7\n6\n6\n16\n16\n2424\n2424\n4444\n8\n8\n9\n9\n5\n5\n2323\n2323\n4343\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n0.84 [0.36 , 1.94]0.84 [0.36 , 1.94]\n0.64 [0.27 , 1.51]0.64 [0.27 , 1.51]\n3.13 [1.26 , 7.78]3.13 [1.26 , 7.78]\n0.010.1 1 10 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas\n?\n?\n+\n?\n?\n?\n+\n+\n?\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)\n(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n228\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 14.5. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-\nback therapy - all studies included, Outcome 5: Quality of life - continuous\nStudy or Subgroup\n14.5.1 General health - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.69 (P = 0.09)\n14.5.2 Physical function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 2.87 (P = 0.004)\n14.5.3 Role physical - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.93 (P = 0.35)\n14.5.4 Role emotional - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.74 (P = 0.46)\n14.5.5 Mental health - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.10 (P = 0.92)\n14.5.6 Social function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.49 (P = 0.14)\n14.5.7 Vitality - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 4.01 (P < 0.0001)\nGnRHasMean\n54.9\n57.6\n60.1\n62.3\n60.2\n54.5\n57.8\nSD\n12.7\n14\n13.9\n15.2\n13.6\n11.5\n11.3\nTotal\n4444\n4444\n4444\n4444\n4444\n4444\n4444\nGnRHas in conjunction with add-back therapyMean\n59.6\n66.4\n57.3\n60\n60.5\n58.3\n68\nSD\n13.7\n15.1\n14.8\n14.4\n14.8\n12.7\n12.8\nTotal\n4646\n4646\n4646\n4646\n4646\n4646\n4646\nWeight\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n-4.70 [-10.15 , 0.75]-4.70 [-10.15 , 0.75]\n-8.80 [-14.81 , -2.79]-8.80 [-14.81 , -2.79]\n2.80 [-3.13 , 8.73]2.80 [-3.13 , 8.73]\n2.30 [-3.82 , 8.42]2.30 [-3.82 , 8.42]\n-0.30 [-6.17 , 5.57]-0.30 [-6.17 , 5.57]\n-3.80 [-8.80 , 1.20]-3.80 [-8.80 , 1.20]\n-10.20 [-15.18 , -5.22]-10.20 [-15.18 , -5.22]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas\nRisk of BiasA\n+\n+\n+\n+\n+\n+\n+\nB\n?\n?\n?\n?\n?\n?\n?\nC\n?\n?\n?\n?\n?\n?\n?\nD\n+\n+\n+\n+\n+\n+\n+\nE\n+\n+\n+\n+\n+\n+\n+\nF\n+\n+\n+\n+\n+\n+\n+\nG\n+\n+\n+\n+\n+\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 14.6. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy\n- all studies included, Outcome 6: Improvement of most troublesome symptoms - continuous/uni00A0\nStudy or Subgroup\n14.6.1 Improvement overall pain - 4 weeksSurrey 1992Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 3.67 (P = 0.0002)\nGnRHasMean\n32\nSD\n6\nTotal\n1010\nGnRHas in conjunction with add-back therapyMean\n20\nSD\n8\nTotal\n99\nWeight\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n12.00 [5.59 , 18.41]12.00 [5.59 , 18.41]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas\nRisk of BiasA\n+\nB\n?\nC\n+\nD\n+\nE\n+\nF\n+\nG\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n229\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nComparison 15. /uni00A0 GnRHas versus GnRHas in conjunction with calcium-regulating agents\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n15.1 Bone mineral density of spinal\nbone mass - continuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n15.1.1 Anterior-posterior spine - 12\nmonths\n1 43 Mean Difference (IV, Fixed,\n95% CI)\n-7.00 [-7.53, -6.47]\n15.1.2 Lateral spine - 12 months 1 43 Mean Difference (IV, Fixed,\n95% CI)\n-12.40 [-13.31,\n-11.49]\n15.2 Improvement of most trouble-\nsome symptoms - dichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n15.2.1 Overall improvement - 12\nmonths\n1 43 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.96 [0.84, 1.08]\n15.2.2 Complete resolution - 12\nmonths\n1 43 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.95 [0.64, 1.41]\n/uni00A0\n/uni00A0\nAnalysis 15.1. /uni00A0 Comparison 15: GnRHas versus GnRHas in conjunction with calcium-\nregulating agents, Outcome 1: Bone mineral density of spinal bone mass - continuous\nStudy or Subgroup\n15.1.1 Anterior-posterior spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 25.74 (P < 0.00001)\n15.1.2 Lateral spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 26.60 (P < 0.00001)\nGnRHasMean\n-4.9\n-4.9\nSD\n0.6\n1\nTotal\n2222\n2222\nGnRHas in conjunction with calcium-regulating agentsMean\n2.1\n7.5\nSD\n1.1\n1.9\nTotal\n2121\n2121\nWeight\n100.0%100.0%\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n-7.00 [-7.53 , -6.47]-7.00 [-7.53 , -6.47]\n-12.40 [-13.31 , -11.49]-12.40 [-13.31 , -11.49]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas\nRisk of BiasA\n+\n+\nB\n+\n+\nC\n?\n?\nD\n+\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n230\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 15.2. /uni00A0 Comparison 15: GnRHas versus GnRHas in conjunction with calcium-\nregulating agents, Outcome 2: Improvement of most troublesome symptoms - dichotomous\nStudy or Subgroup\n15.2.1 Overall improvement - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.70 (P = 0.49)\n15.2.2 Complete resolution - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.23 (P = 0.82)\nGnRHasEvents\n21\n21\n15\n15\nTotal\n2222\n2222\nGnRHas in conjunction with calcium-regulating agentsEvents\n21\n21\n15\n15\nTotal\n2121\n2121\nWeight\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.96 [0.84 , 1.08]0.96 [0.84 , 1.08]\n0.95 [0.64 , 1.41]0.95 [0.64 , 1.41]\nRisk RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas\nRisk of BiasA\n+\n+\nB\n+\n+\nC\n?\n?\nD\n+\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nComparison 16. /uni00A0 GnRHas versus GnRHas in conjunction with calcium-regulating agents - all studies included\nOutcome or subgroup title No. of studies No. of partici-\npants\nStatistical method Effect size\n16.1 Bone mineral density of spinal\nbone mass - continuous\n1 /uni00A0 Mean Difference (IV, Fixed,\n95% CI)\nSubtotals only\n16.1.1 Anterior-posterior spine - 12\nmonths\n1 43 Mean Difference (IV, Fixed,\n95% CI)\n-7.00 [-7.53, -6.47]\n16.1.2 Lateral spine - 12 months 1 43 Mean Difference (IV, Fixed,\n95% CI)\n-12.40 [-13.31,\n-11.49]\n16.2 Improvement of most trouble-\nsome symptoms - dichotomous\n1 /uni00A0 Risk Ratio (M-H, Fixed, 95%\nCI)\nSubtotals only\n16.2.1 Overall improvement - 12\nmonths\n1 43 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.96 [0.84, 1.08]\n16.2.2 Complete resolution - 12\nmonths\n1 43 Risk Ratio (M-H, Fixed, 95%\nCI)\n0.95 [0.64, 1.41]\n/uni00A0\n/uni00A0\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n231\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nAnalysis 16.1. /uni00A0 Comparison 16: GnRHas versus GnRHas in conjunction with calcium-regulating\nagents - all studies included, Outcome 1: Bone mineral density of spinal bone mass - continuous\nStudy or Subgroup\n16.1.1 Anterior-posterior spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 25.74 (P < 0.00001)\n16.1.2 Lateral spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 26.60 (P < 0.00001)\nGnRHasMean\n-4.9\n-4.9\nSD\n0.6\n1\nTotal\n2222\n2222\nGnRHas in conjuntion with calcium-regulating agentsMean\n2.1\n7.5\nSD\n1.1\n1.9\nTotal\n2121\n2121\nWeight\n100.0%100.0%\n100.0%100.0%\nMean DifferenceIV, Fixed, 95% CI\n-7.00 [-7.53 , -6.47]-7.00 [-7.53 , -6.47]\n-12.40 [-13.31 , -11.49]-12.40 [-13.31 , -11.49]\nMean DifferenceIV, Fixed, 95% CI\n-100-50 0 50 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas\nRisk of BiasA\n+\n+\nB\n+\n+\nC\n?\n?\nD\n+\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nAnalysis 16.2. /uni00A0 Comparison 16: GnRHas versus GnRHas in conjunction with calcium-regulating agents\n- all studies included, Outcome 2: Improvement of most troublesome symptoms - dichotomous\nStudy or Subgroup\n16.2.1 Overall improvement - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.70 (P = 0.49)\n16.2.2 Complete resolution - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.23 (P = 0.82)\nGnRHasEvents\n21\n21\n15\n15\nTotal\n2222\n2222\nGnRHas in conjunction with calcium-regulating agentsEvents\n21\n21\n15\n15\nTotal\n2121\n2121\nWeight\n100.0%100.0%\n100.0%100.0%\nRisk RatioM-H, Fixed, 95% CI\n0.96 [0.84 , 1.08]0.96 [0.84 , 1.08]\n0.95 [0.64 , 1.41]0.95 [0.64 , 1.41]\nRisk RatioM-H, Fixed, 95% CI\n0.010.1 1 10 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas\nRisk of BiasA\n+\n+\nB\n+\n+\nC\n?\n?\nD\n+\n+\nE\n+\n+\nF\n+\n+\nG\n+\n+\nRisk of bias legend(A) Random sequence generation (selection bias)(B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias)(D) Blinding of outcome assessment (detection bias)(E) Incomplete outcome data (attrition bias)(F) Selective reporting (reporting bias)(G) Other bias\n/uni00A0\n/uni00A0\nA P P E N D I C E S\nAppendix 1. Cochrane Gynaecology and Fertility (CGF) specialist register search strategy\nProCite platform\nSearched from inception to 26 May 2022\nKeywords CONTAINS \"endometriosis\" or \"The Endometriosis Health Profile\" or \"dyspareunia\" or \"pelvic pain\" or/uni00A0 \"pain-dyspareunia\" or\n\"pain-endometriosis\" or \"pain-pelvic\" or/uni00A0 \"dyschezia\" or \"bone density\" or \"bone mineral density\" or \"bone turnover\" or \"bone turnover\nestimates\" or \"bone turnover markers\" or \"bone metabolism\" or \"bone metabolism indicators\" or Title CONTAINS \"endometriosis\" or\n\"The Endometriosis Health Profile\" or \"dyspareunia\" or \"pelvic pain\" or/uni00A0 \"pain-dyspareunia\" or \"pain-endometriosis\" or \"pain-pelvic\" or\n/uni00A0 \"dyschezia\" or \"bone density\" or \"bone mineral density\" or \"bone turnover\" or \"bone turnover estimates\" or \"bone turnover markers\"\nor \"bone metabolism\" or \"bone metabolism indicators\"\nAND\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n232\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nKeywords CONTAINS \"Gonadorelin\" or \"GnRh\" or \"GnRHa\" or/uni00A0 \"GnRH agonist\" or \"GnRH agonists\" or \"GnRHa-gonadotropin\" or\n\"Gonadotrophin releasing agonist\" or \"Gonadotrophin releasing hormones\" or \"gonadotrophins\" or \"gonadotropin\" or \"gonadotropin\nreleasing hormone agonist\" or \"goserelin acetate\" or \"Gosereline \" or \"Luteinising hormone releasing hormone\" or \"LHRH\" or \"LHRH\nagonists\" or \"LHRH antagonists\" or \"leuprorelin\" or \"leuprorelin acetate\" or \"leuprolin\" or \"leuprolide depot\" or \"Leuprolide\" or\n\"leuprolide acetate\" or \"buserelin\" or \"Buserelin Acetate\" or \"buserelin naferelin\" or \"busereline\" or \"Nafarelin\" or \"Nafarelin Study Group\"\n/uni00A0 or \"triptorelin\" or \"Zoladex\" or \"Lupron\" or \"luprorelix\" or \"decapeptyl\" or \"decapeptyl\" or \"decapeptyl-daily\" or \"decapeptyl-depot\" or\n\"elagolix\" or \"Relugolix\" or/uni00A0 linzagolix or Title CONTAINS \"GnRH agonist\" or \"GnRH agonists\" or \"Gonadorelin\" or \"GnRh\" or \"GnRHa\"\n(509 records)\nAppendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO) search strategy\nWeb platform\nSearched on 26 May 2022\n#1 bone turnover:TI,AB,KY 3588\n#2 bone loss:TI,AB,KY 5102\n#3 bone adj2 densit*:TI,AB,KY 12767\n#4 MESH DESCRIPTOR Bone Density EXPLODE ALL TREES 4790\n#5 MESH DESCRIPTOR Endometriosis EXPLODE ALL TREES 888\n#6 Endometrio*:TI,AB,KY 3002\n#7 dyspareunia:TI,AB,KY 1187\n#8 (Dyschesia or Dyschezia):TI,AB,KY 52\n#9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 20748\n#10 MESH DESCRIPTOR Gonadotropin-Releasing Hormone EXPLODE ALL TREES 2677\n#11 gonadotropin-releasing:TI,AB,KY 2463\n#12 gonadotrophin-releasing:TI,AB,KY 512\n#13 (luteini?ing hormone-releasing hormone*):TI,AB,KY 500\n#14 (lhrh* or lhfshrh):TI,AB,KY 773\n#15 gonadorelin*:TI,AB,KY 715\n#16 (fsh releasing hormone*):TI,AB,KY 1\n#17 (lh rh*):TI,AB,KY 206\n#18 (buserelin or goserelin or leuprolide):TI,AB,KY 2450\n#19 (triptorelin or nafarelin):TI,AB,KY 990\n#20 (leuprorelin or naferelin):TI,AB,KY 475\n#21 (GnRH* or Gn-RH*):TI,AB,KY 4012\n#22 (leuprorelin or naferelin):TI,AB,KY 475\n#23 (suprecur or suprefact):TI,AB,KY 29\n#24 (Zoladex or lupron):TI,AB,KY 402\n#25 (prostap or enantone):TI,AB,KY 32\n#26 (lucrin or trenantone*):TI,AB,KY 28\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n233\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n#27 (synarel or synarella):TI,AB,KY 10\n#28 (decapeptyl or gonapeptyl):TI,AB,KY 157\n#29 (Elagolix or Relugolix):TI,AB,KY 183\n#30 (luliberin or cystorelin):TI,AB,KY 1\n#31 (dirigestran or factrel or gonadoliberin):TI,AB,KY 7\n#32 linzagolix or deslorelin 124\n#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\nOR #28 OR #29 OR #30 OR #31 OR #32 7631\n#34 #9 AND #33 1028\nAppendix 3. MEDLINE search strategy\nOvid platform\nSearched from 1946 to 26 May 2022\n1 exp Endometriosis/ (24263)\n2 dyspareunia.tw. (4401)\n3 (Dyschesia or Dyschezia).tw. (397)\n4 Endometrio*.tw. (34198)\n5 ((cycl* or menstru*) adj2 pain*).tw. (2194)\n6 Bone Density/ (58624)\n7 (bone adj2 densit*).tw. (59256)\n8 bone loss.tw. (33045)\n9 bone turnover.tw. (13572)\n10 or/1-9 (150269)\n11 exp gonadotropin-releasing hormone/ (33621)\n12 (gonadotropin-releasing or gonadotrophin-releasing).tw. (18551)\n13 (GnRH* or Gn-RH*).tw. (24822)\n14 luteini?ing hormone-releasing hormone*.tw. (5915)\n15 (lhrh* or lhfshrh).tw. (6524)\n16 gonadorelin*.tw. (247)\n17 fsh releasing hormone*.tw. (54)\n18 lh rh*.tw. (3398)\n19 (buserelin or goserelin or leuprolide).tw. (4245)\n20 (triptorelin or nafarelin).tw. (1080)\n21 (leuprorelin or naferelin).tw. (533)\n22 (suprecur or suprefact).tw. (30)\n23 (Zoladex or lupron).tw. (561)\n24 (prostap or enantone).tw. (31)\n25 (lucrin or trenantone$).tw. (18)\n26 (synarel or synarella).tw. (13)\n27 (decapeptyl or gonapeptyl).tw. (225)\n28 (Elagolix or Relugolix).tw. (159)\n29 (luliberin or cystorelin).tw. (190)\n30 (dirigestran or factrel or gonadoliberin).tw. (169)\n31 (linzagolix or deslorelin).tw. (325)\n32 or/11-31 (49323)\n33 10 and 32 (2784)\n34 randomized controlled trial.pt. (568945)\n35 controlled clinical trial.pt. (94879)\n36 randomized.ab. (561946)\n37 randomised.ab. (111642)\n38 placebo.tw. (234504)\n39 clinical trials as topic.sh. (199923)\n40 randomly.ab. (382777)\n41 trial.ti. (262776)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n234\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n42 (crossover or cross-over or cross over).tw. (93495)\n43 or/34-42 (1523247)\n44 exp animals/ not humans.sh. (5009925)\n45 43 not 44 (1401679)\n46 33 and 45 (636)\nAppendix 4. Embase search strategy\nOvid platform\nSearched from 1980/uni00A0to 26 May 2022\n1 exp bone density/ (105245)\n2 (bone adj2 densit*).tw. (85252)\n3 bone loss.tw. (41805)\n4 bone turnover.tw. (19885)\n5 exp endometriosis/ (40870)\n6 Endometrio*.tw. (49868)\n7 dyspareunia.tw. (8221)\n8 (Dyschesia or Dyschezia).tw. (795)\n9 ((cycl* or menstru*) adj2 pain*).tw. (3256)\n10 or/1-9 (220324)\n11 exp gonadorelin/ (35087)\n12 ((gonadotropin-releasing or gonadotrophin-releasing) adj2 (analog* or agonist* or antagonist*)).tw. (6773)\n13 ((GnRH* or Gn-RH*) adj2 (analog* or agonist* or antagonist*)).tw. (15643)\n14 (GnRH a or GnRHa).tw. (4062)\n15 luteini?ing hormone-releasing hormone*.tw. (5572)\n16 (lhrh* or lhfshrh).tw. (7690)\n17 gonadorelin*.tw. (395)\n18 fsh releasing hormone*.tw. (17)\n19 lh rh*.tw. (2759)\n20 (buserelin or goserelin or leuprolide).tw. (6162)\n21 (triptorelin or nafarelin).tw. (1686)\n22 (leuprorelin or naferelin).tw. (822)\n23 (suprecur or suprefact).tw. (1328)\n24 (Zoladex or lupron).tw. (3828)\n25 (prostap or enantone).tw. (418)\n26 (lucrin or trenantone*).tw. (429)\n27 (synarel or synarella).tw. (352)\n28 (decapeptyl or gonapeptyl).tw. (2140)\n29 (Elagolix or Relugolix).tw. (325)\n30 (luliberin or cystorelin).tw. (187)\n31 (dirigestran or factrel or gonadoliberin).tw. (291)\n32 (linzagolix or deslorelin).tw. (396)\n33 or/11-32 (61600)\n34 Clinical Trial/ (1024043)\n35 Randomized Controlled Trial/ (704627)\n36 controlled clinical trial/ (465536)\n37 multicenter study/ (322883)\n38 Phase 3 clinical trial/ (60413)\n39 Phase 4 clinical trial/ (4746)\n40 exp randomization/ (93845)\n41 Single Blind Procedure/ (46061)\n42 Double Blind Procedure/ (191894)\n43 Crossover Procedure/ (70243)\n44 Placebo/ (366605)\n45 Randomi?ed controlled trial$.tw. (284966)\n46 Rct.tw. (46655)\n47 (random$ adj2 allocat$).tw. (49498)\n48 Single blind$.tw. (28511)\n49 Double blind$.tw. (222906)\n50 ((treble or triple) adj blind$).tw. (1528)\n51 placebo$.tw. (336711)\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n235\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\n52 prospective study/ (764038)\n53 or/34-52 (2656999)\n54 case study/ (85016)\n55 case report.tw. (475125)\n56 abstract report/ or letter/ (1191797)\n57 Editorial.pt. (715507)\n58 Letter.pt. (1192288)\n59 Note.pt. (893698)\n60 or/54-59 (3416613)\n61 53 not 60 (2524171)\n62 10 and 33 and 61 (1388)\nAppendix 5. PsycINFO search strategy\nOvid platform\nSearched from 1806/uni00A0to 26 May 2022\n1 exp menstrual disorders/ (1348)\n2 Endometrio*.tw. (362)\n3 1 and 2 (23)\n4 Endometrio*.tw. (362)\n5 dyspareunia.tw. (623)\n6 (Dyschesia or Dyschezia).tw. (9)\n7 4 or 5 or 6 (955)\n8 3 or 7 (955)\n9 exp Gonadotropic Hormones/ (4368)\n10 (gonadotropin-releasing or gonadotrophin-releasing).tw. (1118)\n11 (GnRH* or Gn-RH*).tw. (1121)\n12 luteini?ing hormone-releasing hormone*.tw. (239)\n13 (lhrh* or lhfshrh).tw. (219)\n14 gonadorelin*.tw. (5)\n15 fsh releasing hormone*.tw. (1)\n16 lh rh*.tw. (46)\n17 (buserelin or goserelin or leuprolide).tw. (120)\n18 (triptorelin or nafarelin).tw. (30)\n19 (leuprorelin or naferelin).tw. (12)\n20 (Zoladex or lupron).tw. (25)\n21 (prostap or enantone).tw. (1)\n22 (lucrin or trenantone*).tw. (1)\n23 (decapeptyl or gonapeptyl).tw. (3)\n24 (Elagolix or Relugolix).tw. (2)\n25 (luliberin or cystorelin).tw. (7)\n26 (dirigestran or factrel or gonadoliberin).tw. (2)\n27 (linzagolix or deslorelin).tw. (9)\n28 or/9-27 (5185)\n29 8 and 28 (17)\nH I S T O R Y\nProtocol first published: Issue 7, 2021\nC O N T R I B U T I O N S /uni00A0 O F /uni00A0 A U T H O R S\nVeerle Veth took the lead in developing the review protocol and search strategy; screening the articles; performing risk of bias assessment,\ndata extraction, and data analysis; grading and interpretation; and writing and revising all versions of this review update.\nMajorie van de Kar contributed to the background, search strategy, data extraction, risk of bias, analysis, results, and discussion of the\nreview for this update.\nJames Duﬀy provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review.\nMadelon van Wely provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review.\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n236\n\nCochrane\nLibrary\nTrusted evidence.\nInformed decisions.\nBetter health.\n/uni00A0\n/uni00A0\nCochrane Database of Systematic Reviews\nVelja Mijatovic provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review.\nJacques Maas provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review.\nD E C L A R A T I O N S /uni00A0 O F /uni00A0 I N T E R E S T\nVV: none known\nMvK: none known\nJD: none known\nJM: none known\nMvW: co-ed of Cochrane Gynaecology and Fertility Satellite\nVM: none known\nS O U R C E S /uni00A0 O F /uni00A0 S U P P O R T\nInternal sources\n• No sources of support provided\nExternal sources\n• No sources of support provided\nD I F F E R E N C E S /uni00A0 B E T W E E N /uni00A0 P R O T O C O L /uni00A0 A N D /uni00A0 R E V I E W\nIn the current review, abstracts and articles whose full text was not available were excluded. We applied the core outcome set (COS). Overall\npain is one of the outcome measures recommended with the COS. However, many studies still distinguish between diﬀerent sub-forms of\npain, and do not use overall pain as an outcome measure. In the current review, it was decided to include both overall pain and other sub-\nforms of pain, i.e. dysmenorrhoea, dyspareunia, and pelvic pain. This was to provide as much useful information as possible for shared\ndecision-making with patients. In addition, it was decided to perform the main analysis with only low risk of bias studies, defined as low\nrisk of selection bias and no high risk of bias for any other domain. The sensitivity analysis, on the other hand, was performed with all\nstudies, i.e. both the low risk and the high risk of bias studies. We included only the studies from the main analyses (low risk of bias) in\nthe summary of findings tables.\nN O T E S\nThis review represents a merging of two existing Cochrane Reviews/uni00A0(Brown 2010; Farmer 2003).\nI N D E X /uni00A0 T E R M S\nMedical Subject Headings (MeSH)\nCalcium;/uni00A0 Calcium, Dietary;/uni00A0 Danazol /uni00A0[therapeutic use];/uni00A0 *Drug-Related Side Eﬀects and Adverse Reactions;/uni00A0 Dysmenorrhea;/uni00A0\n*Dyspareunia /uni00A0[drug therapy] /uni00A0[etiology];/uni00A0 *Endometriosis /uni00A0[complications] /uni00A0[drug therapy];/uni00A0 Gestrinone;/uni00A0 Gonadotropin-Releasing\nHormone;/uni00A0 Pelvic Pain /uni00A0[drug therapy] /uni00A0[etiology];/uni00A0 Progestins /uni00A0[therapeutic use]\nMeSH check words\nFemale; Humans\nGonadotropin-releasing hormone analogues for endometriosis (Review)\nCopyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.\n237","source_license":"CC0","license_restricted":false}