Gonadotropin-releasing hormone analogues for endometriosis

Endometriosis is a common gynaecological condition affecting 6 to 11% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is medical therapy with gonadotrophin-releasing hormone analogues (GnRHas) to reduce pain due to endometriosis. One of the adverse effects of GnRHas is a decreased bone mineral density. In addition to assessing the effect on pain, quality of life, most troublesome symptom and patients' satisfaction, the current review also evaluated the effect on bone mineral density and risk of adverse effects in women with endometriosis who use GnRHas versus other treatment options.

To assess the effectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis and to determine the effects of GnRHas on bone mineral density of women with endometriosis. Search methods We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and the trial registries in May 2022 together with reference checking and contact with study authors and experts in the field to identify additional studies. Selection criteria We included randomised controlled trials (RCTs) which compared GnRHas with other hormonal treatment options, including analgesics, danazol, intra-uterine progestogens, oral or injectable progestogens, gestrinone and also GnRHas compared with no treatment or placebo. Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) or calcium-regulation agents were also included in this review. Data collection and analysis We used standard methodology as recommended by Cochrane. Primary outcomes are relief of overall pain and the objective measurement of bone mineral density. Secondary outcomes include adverse effects, quality of life, improvement in the most troublesome symptoms and patient satisfaction. Due to high risk of bias associated with some of the studies, primary analyses of all review outcomes were restricted to studies at low risk of selection bias. Sensitivity analysis including all studies was then performed. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Main results Seventy-two studies involving 7355 patients were included. The evidence was very low to low quality: the main limitations of all studies were serious risk of bias due to poor reporting of study methods, and serious imprecision. Trials comparing GnRHas versus no treatment We did not identify any studies. Trials comparing GnRHas versus placebo There 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), dysmenorrhoea 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, 1 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 three months of treatment. We are uncertain of the effect for pelvic induration, based on the results found a/f_ter three months of treatment (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 incidence 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). Trials comparing GnRHas versus danazol For overall pain, for women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved and completely resolved. We are uncertain about the effect on relief of overall pain, when a subdivision was made for overall pain (MD -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- certainty evidence), dysmenorrhoea (MD 0.10; 95% CI -0.49 to 0.69, 1 RCT, n = 41, very low-certainty evidence), dyspareunia (MD -0.20; 95% 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- certainty 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 of 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% CI 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 to danazol, for six months of treatment. Trials comparing GnRHas versus analgesics We did not identify any studies. Trials comparing GnRHas versus intra-uterine progestogens We did not identify any low risk of bias studies. Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents There may be a slight decrease in bone mineral density (BMD) a/f_ter 12 months treatment with GnRHas, compared to GnRHas in conjunction with 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 lateral spine (MD -12.40; 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low-certainty evidence). Authors' conclusions For relief of overall pain, there may be a slight decrease in favour of treatment with GnRHas compared to placebo or oral or injectable progestogens. We are uncertain about the effect when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. For BMD, there may be a slight decrease when women are treated with GnRHas, compared to gestrinone. There was a bigger decrease of BMD in favour of GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. However, there may be a slight increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone. Due to a very low to low certainty of the evidence, a wide range of outcome measures and a wide range of outcome measurement instruments, the results should be interpreted with caution. P L A I N /uni00A0 L A N G U A G E /uni00A0 S U M M A R Y Gonadotrophin-releasing hormone analogues for pain associated with endometriosis What are the benefits and risks of gonadotrophin-releasing hormone analogues (GnRHas) for pain associated with endometriosis? Key messages GnRHas offer more pain reduction compared to placebo or progestogens. However, the largest decrease in bone mineral density (BMD) was found when using GnRHas, compared to a different hormone called gestrinone and GnRHas together with calcium-regulating agents (acting on bone). Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Most adverse effects were hot flushes for patients treated with GnRHas or gestrinone (hormone) and weight gain when treated with danazol (hormone). Further, well-designed research is needed to provide better understanding of the benefits and risks of using GnRHas and other hormonal treatment options for pain associated with endometriosis. What is endometriosis? Endometriosis is a common condition, affecting women of childbearing age, and is usually due to the presence of endometrial-like tissue in places other than the uterus. The most reported symptoms are pain and infertility. What are GnRHas? GnRHas are a group of drugs o/f_ten used to treat endometriosis. GnRHas are a synthetic form of the hormone gonadorelin, released by the hypothalamus in the brain. They stimulate the pituitary gland in the brain to produce luteinising hormone (LH) and follicle- stimulating hormone (FSH), both reproductive hormones. These reproductive hormones further stimulate the production of progesterone and oestrogen in the ovaries, the hormones that control your menstrual cycle. However, continued use of GnRHas results in a suppression of ovarian function and therefore reduces oestrogen and progesterone levels. This will in turn result in a decrease of endometrial tissue and therefore reduce complaints of endometriosis. Because GnRHas temporarily stop the production of reproductive hormones, they mimic symptoms of menopause, including a decrease in bone mineral density (the amount of calcium and other minerals present in your bones). What did we want to find out? In the current review, we looked at women with endometriosis, who were treated with GnRHas, and compared this treatment with other forms of hormonal treatment. We wanted to find out if GnRHas were better than any other hormonal treatment to improve pain and to see their effect on bone mineral density. Additionally, we wanted to find out if GnRHas were associated with an improved quality of life and also unveil any unwanted effects. What did we do? The review involved searching for studies that investigated the effect of GnRHas compared with placebo (dummy treatment) and other hormonal treatment in women with endometriosis. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes. What did we find? We found 72 trials that involved 7355 women with endometriosis. - A difference in overall pain, reported as pain reduction was seen in favour of GnRHas compared to placebo. We also saw that women treated with GnRHas had less pelvic pain reduction and an increase in endometriotic lesions a/f_ter six months of treatment, compared to danazol. - A/f_ter six months of treatment, there was a greater decrease of pain for women treated with GnRHas compared to gestrinone. - No difference was seen in pain scores between women treated with GnRHas compared to other hormonal treatment options. - Most adverse effects were seen in women treated with GnRHas compared to placebo (hot flushes), with danazol (weight gain) and gestrinone (hot flushes). - A greater decrease in bone mineral density was found in GnRHas compared to gestrinone and GnRHas in conjunction with calcium- regulating agents. - For the other comparisons examined in the current review, we are uncertain of the effect between the examined groups. It should be noted, however, that the evidence was o/f_ten of (very) low quality in the analyses undertaken for the other comparisons. What are the limitations of the evidence? The included studies were of low quality mainly due to poor reporting of study methods and the inaccuracy with which the results were reported. How up-to-date is this evidence? Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews The evidence is up-to-date to May 2022. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 S U M M A R Y /uni00A0 O F /uni00A0 F I N D I N G S /uni00A0 Summary of findings 1. /uni00A0 GnRHas compared to no treatment for relief of overall pain associated with endometriosis and its related adverse effects GnRHas compared to no treatment for relief of overall pain associated with endometriosis Population: Women with endometriosis Settings: Gynaecology clinics Intervention: GnRHas Comparison: No treatment Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes No treatment GnRHas Relative effect (95% CI) No of Partici- pants (studies) Quality of the evi- dence (GRADE) Comments No studies included for any outcomes /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. /uni00A0 /uni00A0 Summary of findings 2. /uni00A0 GnRHas compared to placebo for relief of overall pain associated with endometriosis and its related adverse effects GnRHas compared to placebo for relief of overall pain associated with endometriosis Population: Women with endometriosis Settings: Gynaecology clinic Intervention: GnRHas Comparison: Placebo Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Placebo GnRHas Relative effect (95% CI) No of Partici- pants (studies) Quality of the evidence (GRADE) Comments Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Relief of overall pain - reported as pelvic pain - 3 months 372 per 1000 796 per 1000 (525 to 1205) RR 2.14 (1.41 to 3.24) 87 (1 study) ⊕⊕⊝⊝ low1 /uni00A0 Relief of overall pain - reported as dysmen- orrhoea - 3 months 439 per 1000 988 per 1000 (698 to 1387) RR 2.25 (1.59 to 3.16) 87 (1 study) ⊕⊕⊝⊝ low1 /uni00A0 Relief of overall pain - reported as dyspare- unia - 3 months 387 per 1000 855 per 1000 (538 to 1370) RR 2.21 (1.39 to 3.54) 87 (1 study) ⊕⊕⊝⊝ low1 /uni00A0 Relief of overall pain - reported as pelvic tenderness scores- 3 months 357 per 1000 814 per 1000 (529 to 1250) RR 2.28 (1.48 to 3.50) 87 (1 study) ⊕⊕⊝⊝ low1 /uni00A0 Relief of overall pain - reported as pelvic induration scores - 3 months 405 per 1000 434 per 1000 (259 to 726) RR 1.07 (0.64 to 1.79) 87 (1 study) ⊕⊕⊝⊝ low1 /uni00A0 *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Evidence based on a single trial /uni00A0 /uni00A0 Summary of findings 3. /uni00A0 GnRHas compared to analgesics for relief of overall pain associated with endometriosis and its related adverse effects GnRHas compared to analgesics for relief of overall pain associated with endometriosis Population: Women with pain due to endometriosis Settings: Gynaecological clinics Intervention: GnRHas Comparison: Analgesics Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No of Partici- pants (studies) Quality of the evi- dence (GRADE) Comments Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 Assumed risk Corresponding risk Analgesics GnRHas No studies included for any outcomes /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. /uni00A0 /uni00A0 Summary of findings 4. /uni00A0 GnRHas compared to danazol for relief of overall pain associated with endometriosis and its related adverse effects GnRHas compared to danazol for relief of overall pain associated with endometriosis Population: Women with pain due to endometriosis Settings: Gynaecological clinics Intervention: GnRHas Comparison: Danazol Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Danazol GnRHas Relative effect (95% CI) No of Partici- pants (studies) Quality of the evidence (GRADE) Comments Relief of overall pain - re- ported as pelvic tender- ness, partly resolved - 6 months 316 per 1000 363 per 1000 (155 to 862) RR 1.15 (0.49 to 2.73) 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 Relief of overall pain - re- ported as pelvic tender- ness, complete resolved - 6 months 579 per 1000 637 per 1000 (388 to 1048) RR 1.10/uni00A0 (0.67 to 1.81) 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 Relief of overall pain - 6 months The mean relief of over- all pain in the control groups was -4.6 The mean relief of overall pain in the intervention group was 0.4 higher (-0.86 to 1.66) - 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 Relief of overall pain - re- ported as pelvic pain - 6 months The mean relief of pelvic pain in the control groups was -0.5 The mean relief of pelvic pain in the intervention group was 0.5 higher (0.10 to 0.90) - 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 Relief of overall pain - re- ported as dysmenorrhoea - 6 months The mean relief of dys- menorrhoea in the con- trol groups was -2.4 The mean relief of dysmenorrhoea in the intervention group was 0.4 higher (-0.12 to 0.92) - 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 Relief of overall pain - re- ported as pelvic indura- tion - 6 months The mean relief of pelvic induration in the control groups was -0.7 The mean relief of pelvic indura- tion in the intervention group was 0.7 higher (0.21 to 1.19) - 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 Relief of overall pain - re- ported as pelvic tender- ness - 6 months The mean relief of pelvic tenderness in the con- trol groups was -0.7 The mean relief of pelvic tender- ness in the intervention group was 0.2 lower (-0.75 to 0.35) - 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Evidence based on a single trial 2 Small number of events /uni00A0 /uni00A0 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 Summary of findings 5. /uni00A0 GnRHas compared to intra-uterine progestogens device for relief of overall pain associated with endometriosis and its related adverse effects GnRHas compared to intra-uterine progestogens device for relief of overall pain associated with endometriosis Population: Women with pain due to endometriosis Settings: Gynaecological clinics Intervention: GnRHas Comparison: Intra-uterine progestogens device Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Intra-uterine progestogens device GnRHas Relative effect (95% CI) No of Partici- pants (studies) Quality of the evidence (GRADE) Comments No studies included with only low risk of bias /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 /uni00A0 *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. /uni00A0 /uni00A0 Summary of findings 6. /uni00A0 Effect of GnRHas versus other hormonal treatment on bone mineral density Effect of GnRHas versus other hormonal treatment on bone mineral density Population: Women with endometriosis, treated with GnRHas with effect on bone mineral density Settings: Gynaecological clinics/uni00A0 Intervention: GnRHas Comparison: Other hormonal treatment Outcomes Illustrative comparative risks* 95% CI Relative effect /uni00A0 No of partici- pants Quality of the evidence Comments Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 Assumed risk Corresponding risk Other hormonal treat- ment GnRHas (95% CI) (studies) (GRADE) GnRHas vs gestrinone Percentage change values - 6 months The mean percentage change in BMD in the con- trol groups was 0.88 The mean percentage change in BMD in the intervention group was 1.96 lower (3.62 to 0.30) - 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 GnRHas vs gestrinone Percentage change values - 12 months The mean percentage change in BMD in the con- trol groups was 2.06 The mean percentage change in BMD in the intervention group was 5.10 lower (7.39 to 2.81) - 41 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 GnRHas vs GnRHas in con- junction with calcium-reg- ulating agents Anterior-posterior spine - 12 months The mean change in BMD in the control groups was 2.1 The mean change in BMD in the intervention group was 7.00 low- er (7.53 to 6.47) - 43 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 GnRHas vs GnRHas in con- junction with calcium-reg- ulating agents Lateral spine - 12 months The mean change in BMD in the control groups was 7.5 The mean relief of pelvic pain in the intervention group was 12.40lower (13.31 to 11.49) - 43 (1 study) ⊕⊝⊝⊝ very low1,2 /uni00A0 *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Evidence based on a single trial 2 Small number of events /uni00A0 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews B A C K G R O U N D Description of the condition Endometriosis is a common gynaecological condition. Endometriosis is characterised as an inflammatory condition leading to fibrotic tissue formation, predominantly found in the pelvic peritoneum, ovaries and rectovaginal septum (Burney 2012; Vigano 2018). Endometriosis is associated with symptoms such as dysmenorrhoea, dyspareunia, abdominal pain and infertility (Vercellini 2014). It affects 6% to 11% of women of reproductive age, but the prevalence increases in women with infertility or pelvic pain (Darwish 2006; Eskenazi/uni00A01997; Mahmood 1991 ; Meuleman 2009 ; Wheeler 1989). The precise pathogenesis of endometriosis remains unclear, however there are some hypotheses that have widely been accepted. Possible theorised mechanisms of the pathogenesis of endometriosis include induction, in situ development and retrograde menstruation or implantation/uni00A0(Levander 1955; Sampson 1940; Van der Linden 1997). The 'induction theory', introduced by Levander and Normann in 1955, is based on the assumption that specific substances released during the degeneration of the endometrium induce endometriosis from omnipotent blastema, present in connective tissues (Bontis 1997; Levander 1955). The ‘in- situ development theory’ states that endometriosis develops from either the Wolffian duct or knob, or from Müllerian tissue (Batt 2007; Van der Linden 1997). The most common hypothesis is based on retrograde menstruation; this theory proposes that endometriosis arises by the dissemination of endometrial-like tissue to ectopic sites where implantation, hypertrophy and invasion of pelvic structures occurs (Burney 2012; Robboy 2010; Sampson 1940 ; Viganò 2004). This ectopic growth provokes an inflammatory response, resulting in the symptoms mentioned above (Guidice 2010). Endometriosis is generally believed to be an oestrogen- dependent disorder (Zondervan 2020). Local oestradiol stimulates the activation of pain fibres and promotes sprouting of nociceptors that contribute to persistent inflammatory pain, that o/f_ten worsens over time (Guidice 2010). To treat chronic pelvic pain associated with endometriosis, repeated courses of medical therapy or surgical therapy (or both) are o/f_ten required. Hormonal treatment, such as gonadotrophin- releasing hormone analogues (GnRHas), suppress ovarian function and alter the endometrium as well as the endometriosis tissue, which in turn o/f_ten results in amenorrhoea and relief of endometriosis-related pain symptoms (Stratton 2011). In the current review, only the GnRH agonists are included, not the GnRH antagonists. Description of the intervention The GnRHas are a family of compounds that differ from natural gonadotrophin-releasing hormone (GnRH), a ten-amino- acid hormone (decapeptide), by modifications in the decapeptide at positions six and ten (Shaw 1991 ). They may be administered intranasally, or by subcutaneous or intramuscular injection. Buserelin, goserelin, leuprorelin, nafarelin and triptorelin are some of the most common GnRHas. Hypo-oestrogenic side effects (relating to low levels of oestrogen), such as hot flushes, mood swings, sleep disturbances and bone mass loss are common when prescribing GnRHas. This is considered significant as it could increase the risk of women developing osteoporosis and place them at risk of osteoporotic fractures. To prevent bone loss and other hypo-oestrogenic symptoms, it is therefore recommended to prescribe hormonal add-back therapy concomitantly. Other common treatments for endometriosis-associated symptoms (including infertility and pain),/uni00A0are analgesics, danazol and progestogens (Brown 2012), including intra-uterine systems, combined oral contraceptive pills (Brown 2018) and surgical therapies (Bafort 2020)./uni00A0A combination of surgery with hormonal treatment (pre-surgical, post-surgical or pre- and post-surgical hormonal therapy), is also used as a treatment option for people with endometriosis. Only post-surgical medical therapy provides a reduction in pain symptoms, reduced rate of recurrence and increased chance of pregnancy (Chen 2020) The European Society of Human Reproduction and Embryology (ESHRE) recommends the use of GnRHas (nafarelin, leuprorelin, buserelin, goserelin or triptorelin) as one of the options for reducing endometriosis-associated pain, however, evidence is limited regarding dosage or duration of treatment/uni00A0(Becker 2022). In addition, clinicians are recommended to prescribe hormonal add-back therapy to coincide with the start of GnRH agonist therapy, to prevent bone loss and hypo-oestrogenic symptoms during treatment. It is recommended to give careful consideration to the use of GnRHas in young women and adolescents, since these individuals may not have reached maximum bone density (Becker 2022). How the intervention might work Non-analgesic medical treatment of endometriosis aims to suppress the ectopic endometrium deposits in premenopausal women by inducing atrophy within the hormonally dependent ectopic endometrium, making the endometrial-like tissue inactive. The observation that endometriosis is rarely diagnosed in hypo- oestrogenic postmenopausal women led to the concept of medical treatment of endometriosis by induction of a pseudo-menopause. Gonadotrophin-releasing hormone analogues are a potent synthetic analogue of the hypothalamic hormone gonadorelin. This stimulates the pituitary gland to produce luteinising hormone (LH) and follicle-stimulating hormone (FSH). However, with continued use, suppression occurs due to exhaustion and/uni00A0desensitivity of the gonadotrophic pituitary cells. This suppresses ovarian function and therefore reduces oestrogen and progesterone levels, introducing a hypogonadotropic hypogonadal state. In endometriosis, this treatment leads to a reduction in the endometriosis implants and induces atrophy within them/uni00A0(Chen 2020). By reducing the endometriosis implants, GnRHas can provide a reduction in pain and other endometriosis-related complaints. Why it is important to do this review Endometriosis occurs in approximately one in every 10 women within the reproductive general population (Macer 2012). It is a chronic disease with severe pain that impacts negatively on physical, mental and social well-being (Klein 2014). In addition, the cost of endometriosis is high in both economic and psychosocial terms (Matthias 1996,/uni00A0Simoens 2012). Treatment availability is dependent upon available resources but also upon the preferences of the individual woman and Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews the gynaecologist. This particularly relates to their decisions concerning the conservation of fertility or requirements for contraception. One of the available treatment options is treatment with GnRHas. While GnRHas are not free of side effects, it is important to know how well they perform in comparison to other medical/uni00A0treatments and placebo. This review will evaluate the/uni00A0effect of GnRHas specifically on the relief of pain and on bone mineral density in symptomatic women with endometriosis. This review is a combination of two previously published Cochrane Reviews on GnRHas for bone mineral density/uni00A0(Farmer 2003) and for pain associated with endometriosis/uni00A0(Brown 2010). It was decided to merge both reviews, in order to provide the best overview of the use of GnRHas in women with endometriosis. O B J E C T I V E S To assess the effectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis and to determine the effects of GnRHas on bone mineral density of women with endometriosis. M E T H O D S Criteria for considering studies for this review Types of studies All randomised controlled trials (RCTs) comparing the use of GnRHas in the treatment of symptomatic endometriosis were eligible for inclusion. Cross-over trials were included in the review providing that data from before-and-a/f_ter cross-over were available; only the first-arm data were used for analysis. We excluded trials that used self-reporting of endometriosis, as well as quasi-randomised and non-randomised studies (case control studies, cohort studies). Types of participants Premenopausal women with symptoms ascribed to endometriosis were eligible for inclusion. For a trial to be included, the clinical diagnosis of endometriosis must have been made by direct visualisation (laparoscopy or laparotomy) or from ultrasonographic imaging or magnetic resonance imaging (MRI). We excluded women with asymptomatic disease or infertility as the only presenting complaint. Types of interventions We included RCTs reporting the following comparisons for relief of pain associated with endometriosis and its related adverse effects. • GnRHas versus no treatment. • GnRHas versus placebo. • GnRHas versus analgesics. • GnRHas versus danazol. • GnRHas versus intra-uterine progestogens. • GnRHas versus oral or injectable progestogens. • GnRHas versus gestrinone. We also included RCTs comparing the following for relief of pain associated with endometriosis and its related adverse effects. • Different doses of GnRHas. • Different treatment duration of GnRHas. • Different routes of administration of GnRHas. • Different treatment regimens of GnRHas. • GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal). • GnRHas versus GnRHas in conjunction with calcium-regulating agents. When we identified trials that assessed the effect of GnRHas on bone mineral density (BMD), we considered them for inclusion providing the treatment period exceeded six months. The reason for this decision is that shorter treatment periods do not seem to treat the disease effectively (Audebert 1998). The following trials were excluded from this review. • Trials comparing GnRHas with surgical therapies, the combined oral contraceptive pill, progesterone receptor modulators/uni00A0or selective oestrogen receptor modulators (SERMs), as these are included in separate Cochrane Reviews (Bafort 2020; Brown 2018; Fu 2017; Van Hoesel/uni00A02021, respectively). • Trials comparing GnRHas with gonadotrophin antagonists, as this is a registered title of a Cochrane Review to be conducted by Cochrane Gynaecology and Fertility (Houda 2014). • Trials comparing GnRHas with alternative and complementary medicine such as Chinese herbs or acupuncture, as these are addressed by published Cochrane Reviews (Flower 2012; Zhu 2011, respectively). • Trials where GnRHas were administered in post-surgical participants as adjuvant therapy. Types of outcome measures The choice of outcome measures is based on the core outcome set (COS) determined for endometriosis research (Duffy 2020). This COS was developed by conducting a systematic review and a widely-supported Delphi study, in which it was determined which outcome measures in endometriosis research should definitely be assessed in endometriosis trials. The COS is expected to provide a more uniform way for conducting, performing and reporting endometriosis research. Primary outcomes • Overall pain, defined by using both quantitative measures such as visual analogue scales or categorical outcomes, at the end of treatment and at three, six, nine, 12, 18 and 24 months' follow- up, where possible • The objective measurement of bone mineral density (BMD), including dual-energy photon absorptiometry (DPA), dual- energy X-ray absorptiometry (DEXA), single-energy photon absorptiometry (SPA), single-energy X-ray absorptiometry (SXA) and quantitative computed tomography (QCT). Measurements taken at the lumbar spine and femoral head will be considered, whilst those at the distal forearm will be excluded because these measurements are of cortical bone which is less affected by GnRHa therapy (Whitehouse 1990; Ylikorkala 1990). Bone density measurements at the end of treatment and in the follow- up period will be included. Measurements will be grouped Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews according to the anatomical location of measurements and the timing of measurements. For overall pain, we applied the core outcome set (COS). Overall pain is one of the outcome measures recommended with the COS. However, many studies still distinguish between different sub- forms of pain, 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-forms of pain, i.e. dysmenorrhoea, dyspareunia and pelvic pain. This is to provide as much useful information as possible for shared decision-making with patients. Secondary outcomes • Adverse effects (e.g. hot flushes, insomnia, reduced libido, vaginal dryness and headaches), both short-term (during therapy) and long-term (extending beyond the treatment period) • Quality of life and factors affecting quality of life (by quality of life scores) • Improvement in the most troublesome symptoms • Patients' satisfaction with treatment Cost-effectiveness and pregnancy rates are not outcomes of this review. Search methods for identification of studies The search strategy of Cochrane Gynaecology and Fertility was utilised to identify all publications that describe or might describe randomised trials of GnRHas in the treatment of symptomatic endometriosis. Electronic searches There were no language or date restrictions in the searches. The following electronic databases, trial registers and websites were searched: • Cochrane Gynaecology and Fertility Group's specialised register of controlled trials; searched from inception to 26 May 2022, ProCite platform (Appendix 1); • CENTRAL, via the Cochrane Register of Studies Online (CRSO); now containing output from two trials registries (clinicaltrials.gov https://clinicaltrials.gov/ and the International Clinical Trials Registry Platform (ICTRP) https:// www.who.int/clinical-trials-registry-platform) and CINAHL, searched 26 May 2022, Web platform (Appendix 2); • MEDLINE, searched from 1946 to 26 May 2022, Ovid platform (Appendix 3); • Embase, searched from 1980 to 26 May 2022, Ovid platform (Appendix 4); • PsycINFO, searched from 1806 to 26 May 2022, Ovid platform (Appendix 5). The MEDLINE search was/uni00A0combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions ( Lefebvre 2011). The Embase/uni00A0search/uni00A0was/uni00A0combined with the trial filter/uni00A0developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/what-we-do/methodology/search-filters/). Other web-based electronic sources of trials searched were: • ISI Web of Science, for conference abstracts; • LILACS database, as a source of trials from the Portuguese and Spanish/uni00A0regions; • Clinical Study Results, for clinical trial results of marketed pharmaceuticals; • OpenSIGLE database, for grey literature; • Google, for grey literature and for trials that were not yet indexed in the major databases. Searching other resources Any relevant journals and conference abstracts that were not covered in the/uni00A0Cochrane Gynaecology and Fertility specialised register were/uni00A0handsearched in liaison with the Group's Information Specialist, Marian Showell. The reference lists of relevant articles retrieved by the search were/uni00A0handsearched, and we personally communicated with experts in the field to obtain any additional trials. In addition, we approached all distributors of GnRHas for details of unpublished trials of GnRHas known to, or undertaken by, them or their parent companies. Data collection and analysis Selection of studies Two review authors (VV and MK) independently scanned the search results for relevant titles and abstracts and removed those that were clearly irrelevant. The full texts of all potentially eligible studies were/uni00A0retrieved. Two review authors (VV and MK) independently examined the full-text articles for compliance with the inclusion criteria. Authors corresponded with study investigators to clarify study eligibility. Communication with study authors was documented in the appendices. Where required, disagreements regarding study eligibility were/uni00A0resolved by consensus or by the assessment of a third review author (JM). Data extraction and management Data extraction was conducted independently by two review authors (VV and MK). Data extraction forms were developed and pilot-tested by the authors. Where studies had multiple publications, the main trial report was/uni00A0used as the reference and additional details supplemented from secondary papers. Authors corresponded with study investigators in order to resolve any data queries, as required. When disagreements arose/uni00A0between the two review authors, a third review author was contacted to resolve the dispute (JM)./uni00A0 Assessment of risk of bias in included studies Assessment of the risk of bias in the included studies was undertaken by two of the review authors, using the Cochrane risk of bias tool/uni00A0(Higgins 2011). The assessment is based on allocation (random sequence generation and allocation concealment), blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other bias. Where uncertainty arose or there was a discrepancy between the two review authors (VV and MK), a third review author was contacted to make further assessment. When a study protocol was available, we assessed whether there are differences between the study protocol and published results. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews If necessary, additional information was sought from the principal investigator of the original trial. All judgements were fully described and the conclusions presented in the risk of bias table. Measures of treatment effect For continuous data like pain and BMD (bone mineral density) scores, mean differences (MDs) with 95% confidence intervals (CIs) were reported using change-from-baseline scores./uni00A0 When similar outcomes were reported on different scales we intended to calculate standardised mean differences (SMDs). Ordinal data (e.g. quality of life scores) were treated as continuous data. A summary statistic for each outcome was calculated using a fixed-effect model and a 95% CI./uni00A0For dichotomous data, we/uni00A0calculated/uni00A0for each study a/uni00A0Mantel-Haenszel risk ratio (RR) with/uni00A0corresponding/uni00A095% CI. Unit of analysis issues Data were presented according to each woman randomised. In cross-over trials only the first-arm data were used for analysis where data were available, and where data were not available, we intended to contact the primary author. Dealing with missing data The data were analysed on an intention-to-treat basis as far as possible, and attempts were made to obtain missing data from the original investigators. If studies reported sufficient detail to calculate MDs, but provided no information on an associated standard deviation (SD), the outcome was assumed to have an SD equal to the highest SD from other studies within the same analysis. For other outcomes, only the available data were analysed. Assessment of heterogeneity The review authors considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta-analysis to provide a meaningful summary. Statistical heterogeneity was assessed using the I2 statistic (Higgins 2019 ). An I 2 measurement greater than 50% indicates substantial heterogeneity. Sensitivity analyses including all studies were conducted where it was taken into account if the quality of the studies contributed to the heterogeneity. Assessment of reporting biases In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. Data synthesis When studies were sufficiently similar, the data from primary studies were combined using the fixed-effect model./uni00A0The primary analysis only included trials with a low risk of selection bias and no high risk of bias in other domains. Subgroup analysis and investigation of heterogeneity Data derived in all outcome measurements/uni00A0were divided into subgroups by dosage (low or high, as defined by study); duration of treatment (three, six, nine, 12, 18 and 24 months); route of administration (intranasal, intramuscular, subcuticular or depot injection); and drug regimens. Sensitivity analysis Sensitivity analyses were conducted for the primary outcomes to determine whether the conclusions were robust to arbitrary decisions made regarding the eligibility and analysis. These analyses included consideration of whether our conclusions differed in the following situations. • If all studies were included in the analysis (studies with unclear risk of selection bias and high risk of bias in other domains). • If studies with outlying results were excluded. • If alternative imputation strategies were adopted. • If a random-effects model was adopted. Summary of findings and assessment of the certainty of the evidence We prepared a summary of findings table using GRADEpro GDT so/f_tware and Cochrane methods (Schünemann 2021 ). This table evaluated the overall quality of the body of evidence for the main review outcomes, namely overall pain, the objective measurement of BMD, and adverse effects, for the following main comparisons. • GnRHas versus no treatment. • GnRHas versus placebo. • GnRHas versus danazol. Additional summary of findings tables were also prepared for the main review outcomes for other important comparisons (GnRHas versus analgesics; and GnRHas versus intra-uterine progestogen devices). We assessed the quality of the evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness and publication bias. Judgements about evidence quality (high, moderate, low or very low) were made by two review authors working independently, with disagreements resolved by discussion. Judgements were justified, documented, and incorporated into reporting of results for each outcome. We extracted study data, formatted our comparisons in data tables and prepared a summary of findings table before writing the results and

of our review. R E S U L T S Description of studies

of the search This is a combination of two previous reviews (Brown 2010; Farmer 2003). The inclusion and exclusion criteria, as well as the participants, differ slightly from the two previous reviews./uni00A0Brown 2010/uni00A0only included women with a clinical diagnosis of endometriosis, so the diagnosis had to be made by direct visualisation (laparoscopy). In this review, we also include women with a clinical diagnosis of endometriosis from ultrasonographic imaging or magnetic resonance imaging (MRI)./uni00A0Farmer 2003/uni00A0included premenopausal women suffering from endometriosis diagnosed visually by laparoscopy or laparotomy, or presumptively, from symptom history. Here, too, the inclusion criteria differ slightly from each other. A total of seventy-two studies were included. Two studies were still awaiting classification, however, as data were still not available at the current review, we also excluded these articles. A total of fi/f_ty-six studies were excluded, and five are still awaiting Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews classification. See study tables: "Characteristics of included studies", "Characteristics of excluded studies"; "Characteristics of studies awaiting classification"./uni00A0Figure 1/uni00A0summarises the results of the search. /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Figure 1. /uni00A0 Study flow diagram 3980 records identified through database searching 0 records identified through other sources 1969 records after duplicates removed 1969 records screened 1698 records excluded 271 full-text articles assessed for eligibility 194 full-text articles excluded, with reasons 5 studies placed under 'awaiting assessment' 72 studies included in qualitative synthesis 58 studies included in quantitative synthesis (meta-analysis) /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 16 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Included studies Seventy-two randomised controlled trials met our eligibility criteria and were included in this review (Abdou 2018 ; Adamson 1994 ; Agarwal 1997; AN Zoladex 1996; Audebert 1997; Bergqvist 1997; Bergqvist 1998; Bergqvist 2000; Burry 1989; Burry 1992; Chang 1996; Cheng 2005; Cirkel 1995; Crosignani 1996; Crosignani 2006; Dawood 1995; Dlugi 1990; Dmowski 1989a; Edmonds 1994; Fedele 1989; Ferreira 2010; Finkelstein 1998; Finkelstein 1999; Franke 2000; Fraser 1991; Freundl 1998; Fukushima 1993; Gnoth 1999; Gomes 2007; Harada 2009; Henzl 1988 ; Hornstein 1995; Hornstein 1998; Howell 1995; Hurst 2000; Irahara 2001; Jelley 1986; Kennedy 1990; Kiilholma 1995 ; Lemay 1988; Ling 1999 ; Mäkäräinen 1996; Miller 2000; Minaguchi 1986 ; Moghissi 1998 ; NEET 1992 ; Odukoya 1995; Orwoll 1994; Ozaki 2020; Palagiano 1994; Petta 2005; Rock 1993; Rolland 1990; Rotondi 2002; Roux 1995; Schlaff 2006; Shaw 1986; Shaw 1990; Sillem 1999; Skrzypulec 2004; Strowitzki 2012; Surrey 1992; Surrey 2002; Tahara 2000; Tang 2017; Tummon 1988; Tummon 1989; Vercellini 1994; Vercellini 1996; Wheeler 1992 ; Whitehouse 1990; Zupi 2005). /uni00A0 See/uni00A0 Characteristics of included studies/uni00A0for description. All the studies were randomised controlled trials and came from a variety of different countries: Brazil:/uni00A0Ferreira 2010; Gomes 2007; Petta 2005 Canada:/uni00A0Lemay 1988 Egypt:/uni00A0Abdou 2018 France:/uni00A0Audebert 1997; Roux 1995 Finland:/uni00A0Kiilholma 1995; Mäkäräinen 1996 Germany:/uni00A0 Cirkel 1995; Freundl 1998; Gnoth 1999; Sillem 1999 ; Strowitzki 2012 International (multi-centre):/uni00A0AN Zoladex 1996; Bergqvist 1997; Bergqvist 2000; Crosignani 2006; Fraser 1991; Henzl 1988 ; NEET 1992; /uni00A0Rolland 1990 Italy:/uni00A0Crosignani 1996; Fedele 1989; Palagiano 1994; Rotondi 2002; Vercellini 1994; Vercellini 1996; Zupi 2005 Japan:/uni00A0Fukushima 1993; Harada 2009; Irahara 2001; Minaguchi 1986; Ozaki 2020; Tahara 2000; Tang 2017 Netherlands:/uni00A0Franke 2000 Poland:/uni00A0Skrzypulec 2004 Sweden:/uni00A0Bergqvist 1998 Taiwan:/uni00A0Chang 1996; Cheng 2005 United Kingdom:/uni00A0Edmonds 1994; Howell 1995; Jelley 1986; Kennedy 1990; Odukoya 1995; Shaw 1986; Shaw 1990; Whitehouse 1990 United States of America:/uni00A0Adamson 1994; Agarwal 1997; Burry 1989; Burry 1992; Dawood 1995; Dlugi 1990; Dmowski 1989a; Finkelstein 1998; Finkelstein 1999; Hornstein 1995; Hornstein 1998; Hurst 2000; Ling 1999 ; Miller 2000 ; Moghissi 1998 ; Orwoll 1994; Rock 1993; Schlaff 2006 ; Surrey 1992; Surrey 2002; Tummon 1988; Tummon 1989; Wheeler 1992 The included studies comprised 7355 women having complaints of endometriosis. Where reported, ages ranged from 18 to 48 years. All women with endometriosis had a clinical diagnosis of endometriosis made by direct visualisation (laparoscopy or laparotomy) or from ultrasonographic imaging or magnetic resonance imaging (MRI). The following interventions were tested in the included trials: • GnRHas versus placebo (five trials;/uni00A0Bergqvist 1998; Dlugi 1990; Ling 1999; Miller 2000; Skrzypulec 2004) • GnRHas versus danazol (twenty-nine trials;/uni00A0Adamson 1994; AN Zoladex 1996; Audebert 1997; Burry 1989; Burry 1992; Chang 1996; Cheng 2005; Cirkel 1995; Dawood 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Fukushima 1993; Gnoth 1999; Henzl 1988; Jelley 1986; Kennedy 1990; NEET 1992 ; Odukoya 1995; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002; Shaw 1990; Tummon 1988; Tummon 1989; Vercellini 1994; Wheeler 1992; Whitehouse 1990) • GnRHas versus intra-uterine progestogens (three trials;/uni00A0Ferreira 2010; Gomes 2007; Petta 2005) • GnRHas versus /uni00A0oral or injectable progestogens (seven trials;/uni00A0 Abdou 2018 ; Crosignani 2006; Harada 2009; Ozaki 2020; Schlaff 2006; Strowitzki 2012; Zupi 2005) • GnRHas versus gestrinone (one trial;/uni00A0Vercellini 1996) • Trials comparing different doses of GnRHas (eight trials;/uni00A0 Adamson 1994 ; Bergqvist 1997; Burry 1989; Henzl 1988 ; Minaguchi 1986; Shaw 1986; Tahara 2000; Tang 2017) • Trials comparing different treatment duration of GnRHas (two trials;/uni00A0Hornstein 1995; Orwoll 1994) • Trials comparing different route of administration of GnRHas (four trials;/uni00A0Agarwal 1997; Bergqvist 2000; Dmowski 1989a; Lemay 1988) • Trials comparing different GnRHas treatment regimens (one trial;/uni00A0Crosignani 1996) • Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) (seventeen trials;/uni00A0Bergqvist 1997; Edmonds 1994; Franke 2000; Freundl 1998; Gnoth 1999; Hornstein 1998; Howell 1995; Hurst 2000; Irahara 2001; Kiilholma 1995 ; Mäkäräinen 1996; Moghissi 1998 ; Sillem 1999; Surrey 1992; Surrey 2002; Vercellini 1994; Zupi 2005) • Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents (three trials;/uni00A0Finkelstein 1998; Finkelstein 1999;/uni00A0/uni00A0Roux 1995) • Trials mentioning the effect of GnRHas on BMD (thirty trials;/uni00A0 Crosignani 1996; Crosignani 2006; Dawood 1995; Dlugi 1990; Edmonds 1994; Finkelstein 1998; Finkelstein 1999; Franke 2000; Freundl 1998; Fukushima 1993; Gnoth 1999; Harada 2009; Hornstein 1998; Howell 1995; Irahara 2001; Moghissi 1998 ; Orwoll 1994; Rock 1993; Roux 1995; Schlaff 2006; Sillem 1999; Surrey 1992; Surrey 2002; Tahara 2000; Tang 2017; Tummon 1988; Vercellini 1996; Wheeler 1992 ; Whitehouse 1990; Zupi 2005) No trials comparing GnRHas versus no treatment or trials comparing GnRH analogues versus analgesics were identified. Six trials were included in two different comparisons, due to the fact that these trials included three different treatment groups, and therefore could be included in different comparisons (Adamson 1994; Bergqvist 1997; Burry 1989; Dmowski 1989a; Henzl 1988 ; Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 17 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Zupi 2005)./uni00A0Adamson 1994,/uni00A0Burry 1989,/uni00A0Dmowski 1989a, and/uni00A0Henzl 1988/uni00A0compared varying dosage of GnRHas in addition to a comparison with danazol,/uni00A0and/uni00A0Bergqvist 1997/uni00A0compared varying dosage of GnRHas in addition to a comparison with add-back therapy (hormonal or non-hormonal)./uni00A0Zupi 2005/uni00A0compared GnRHas with GnRHas in conjunction with add-back, and compared GnRHas with oral or injectable progestogens. Excluded studies Of the fi/f_ty-six studies that were excluded, ten studies did not have the stated outcome measures (Acien 1989; Calvo 2000;Donnez 1989; el-Roeiy 1988; Maouris 1991; Matalliotakis 2000; Tapanainen 1993; Valimaki 1989; Wright 1995 ; Yee 1986). Fi/f_teen studies reported wrong comparisons, see 'Types of Interventions' for details (Agarwal 2015; Cooke 1989; Dmowski 1989; Donnez 2004 ; Fernandez 2004; Ferrero 2011; Imani 2009 ; Luciano 2004; Magini 1993; Miller 1990 ; Newton 1996; Shaw 2001 ; Surrey 1993; Taskin 1997; Toomey 2003; Warnock 1998). Four studies looked at the outcome in post-surgical participants (Adiyono 2006; Matalliotakis 2004; Soysal 2004; Takaesu 2013); endometriosis was not the main condition discussed in eleven studies (Al-Azemi 2009; Dodin 1991; Eldred 1992; Fraser 1996; Lindsay 1996 ; Matta 1988; /uni00A0 Mukherjee 1996; Ripps 2003 /uni00A0 Somekawa 1999; Sorensen 1997; Sowter 1997; Surrey 1995); and two studies had included a wrong population (Shaw 1992 ; Ylikorkala 1995). Nine studies were not randomised controlled trials (Bergqvist 1990; Choktanasiri 2001; Claesson 1989; Dawood 1990; Fedele 1993; Franssen 1992; Harada 2000/uni00A0 Pierce 2000; Vercellini 2009)./uni00A0 Chan 1993 /uni00A0 and/uni00A0 Chen 2009 /uni00A0were both still awaiting assessment, as they were in the original review (Brown 2010) and therefore they were excluded. The other five studies have been placed under 'awaiting classification'. These are abstracts of articles that are not available in full text and do not contain enough information to enable us to make a decision about inclusion or exclusion. Therefore, we decided to place these five studies under 'awaiting classification' (Aisaka 2000; Archer 2004; Gregoriou 1997;/uni00A0 /uni00A0 Long 2009; Vella 1995). Risk of bias in included studies Details on the quality of each individual study are described in the table/uni00A0Characteristics of included studies/uni00A0where the individual quality criteria were rated for each study. Authors have been contacted for more information when required. Of the seventy-two articles included, only three were at overall low risk of bias (Cheng 2005 ; Ling 1999 ; Vercellini 1996). Ten of these seventy-two were indicated as having high risk of bias (AN Zoladex 1996; Burry 1989; Cirkel 1995; Dlugi 1990; Edmonds 1994; Fukushima 1993; Harada 2009; Howell 1995; Schlaff 2006 ; Surrey 2002). The other fi/f_ty-nine were assigned as having overall unclear risk of bias. For selection bias, six studies reported low risk of bias, without high risk of bias on the other domains, and were therefore included in the main analysis ( Abdou 2018 ; Cheng 2005 ; Finkelstein 1998; Lemay 1988; Ling 1999; Odukoya 1995). See/uni00A0Figure 2/uni00A0for the risk of bias graph and/uni00A0Figure 3/uni00A0for the risk of bias summary. /uni00A0 Figure 2. /uni00A0 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias): All outcomes Blinding of outcome assessment (detection bias): All outcomes Incomplete outcome data (attrition bias): All outcomes Selective reporting (reporting bias) Other bias 0% 25% 50% 75% 100% Low risk of bias Unclear risk of bias High risk of bias /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 18 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Figure 3. /uni00A0 Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias): All outcomes Blinding of outcome assessment (detection bias): All outcomes Incomplete outcome data (attrition bias): All outcomes Selective reporting (reporting bias) Other bias Abdou 2018+ + ? ? + + + Adamson 1994? + + + + + + Agarwal 1997? ? + + + + + AN Zoladex 1996? ? ? ? − + + Audebert 1997? ? ? ? + + + Bergqvist 1997 ? ? + + + + + Bergqvist 1998 ? ? + + + + + Bergqvist 2000 ? ? ? ? + + + Burry 1989? ? + + + − + Burry 1992? ? + + + + + Chang 1996? + ? + ? + + Cheng 2005+ + + + + + + Cirkel 1995+ ? ? ? − + + Crosignani 1996+ ? ? ? + + + Crosignani 2006? ? ? ? + + + Dawood 1995? ? + + + + + Dlugi 1990? + + + − + + /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 19 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Figure 3. /uni00A0 (Continued) Dlugi 1990? + + + − + + Dmowski 1989a? ? ? ? + + + Edmonds 1994? ? ? ? + − + Fedele 1989? ? ? ? + + + Ferreira 2010+ ? ? ? + + + Finkelstein 1998+ + ? + + + + Finkelstein 1999+ ? ? ? + + + Franke 2000? ? + + + + + Fraser 1991+ ? + + + + + Freundl 1998? ? + + + + + Fukushima 1993? ? ? + − + + Gnoth 1999? ? + + + + + Gomes 2007+ ? ? ? + + + Harada 2009+ + + + − + + Henzl 1988? ? + + + + + Hornstein 1995? ? + + + + + Hornstein 1998? ? + + + + + Howell 1995? ? ? ? − + + Hurst 2000? ? + + + + + Irahara 2001? ? ? ? + + + Jelley 1986? + ? ? + + + Kennedy 1990? ? + + + + + Kiilholma 1995? ? + + + + + Lemay 1988+ + ? + + + + Ling 1999+ + + + + + + Mäkäräinen 1996? ? + + + + + Miller 2000+ ? + + + + + Minaguchi 1986? ? ? ? + + + Moghissi 1998? ? + + + + + NEET 1992 ? ? + + + + + Odukoya 1995+ + ? ? + + + Orwoll 1994? ? + + ? + + Ozaki 2020+ ? ? ? + + + Palagiano 1994? ? ? ? + + + Petta 2005+ ? ? + + + + Rock 1993? ? ? ? + + + /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 20 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Figure 3. /uni00A0 (Continued) Petta 2005+ ? ? + + + + Rock 1993? ? ? ? + + + Rolland 1990? ? + + + + + Rotondi 2002? ? ? ? + + + Roux 1995? ? + + + + + Schlaff 2006 ? ? ? + − + + Shaw 1986? ? ? ? + − + Shaw 1990? ? + + + + + Sillem 1999? ? + + ? + + Skrzypulec 2004+ ? + + + + + Strowitzki 2012? ? ? ? + + + Surrey 1992+ ? + + + + + Surrey 2002+ ? + + − + + Tahara 2000 + ? ? ? + + + Tang 2017 ? ? ? ? ? + + Tummon 1988 ? ? ? ? ? + + Tummon 1989 ? ? ? ? + + + Vercellini 1994 + ? ? ? + + + Vercellini 1996 ? + + + + + + Wheeler 1992? ? + + + + + Whitehouse 1990? ? + + + + + Zupi 2005+ ? ? + + + + /uni00A0 Allocation Twenty-two trials were at low risk of selection bias related to random sequence generation, as they used computer randomisation or random number tables (Abdou 2018 ; Cheng 2005; Cirkel 1995; Crosignani 1996; Ferreira 2010; Finkelstein 1998; Finkelstein 1999; Fraser 1991; Gomes 2007 ; Harada 2009; Lemay 1988; Ling 1999 ; Miller 2000 ; Odukoya 1995; Ozaki 2020; Petta 2005; Skrzypulec 2004; Surrey 1992; Surrey 2002; Tahara 2000; Vercellini 1994;/uni00A0 /uni00A0 Zupi 2005. The remaining trials were at unclear risk of selection bias as they did not describe the method of randomisation used. Twelve trials were at low risk of selection bias related to allocation concealment (Abdou 2018 ; Adamson 1994 ; Chang 1996 ; /uni00A0 Cheng 2005; Dlugi 1990; Finkelstein 1998; Harada 2009; Jelley 1986; Lemay 1988; Ling 1999 ; Odukoya 1995;/uni00A0 /uni00A0 Vercellini 1996). The remaining trials did not describe allocation concealment and were at unclear risk of this bias. Blinding Thirty-six studies described blinding of patients and personnel, and they were judged to be at low risk of performance bias (Adamson 1994 ; Agarwal 1997; Bergqvist 1997; Bergqvist 1998; Burry 1989; Burry 1992; Cheng 2005 ; Dawood 1995; Dlugi 1990 ; Franke 2000; Fraser 1991; Freundl 1998; Gnoth 1999; Harada 2009; Henzl 1988; Hornstein 1995; Hornstein 1998; Hurst 2000; Kennedy 1990; Kiilholma 1995 ; Ling 1999 ; Mäkäräinen 1996; Miller 2000 ; Moghissi 1998; NEET 1992; Orwoll 1994; Rolland 1990; Roux 1995; Shaw 1990; Sillem 1999; Skrzypulec 2004; Surrey 1992; Surrey 2002; Vercellini 1996; Wheeler 1992 ; Whitehouse 1990). The remaining trials were assigned as having unclear risk of bias. Forty-two studies described blinding of outcome assessors, and they were judged to be at low risk of detection bias (Adamson 1994; Agarwal 1997; Bergqvist 1997; Bergqvist 1998; Burry 1989; Burry 1992; Chang 1996 ; Cheng 2005 ; Dawood 1995; Dlugi 1990 ; Franke 2000; Fraser 1991; Freundl 1998; Fukushima 1993; Gnoth 1999; Harada 2009; Henzl 1988 ; Hornstein 1995; Hornstein 1998; Hurst 2000; Kennedy 1990; Kiilholma 1995; Lemay 1988; Ling 1999; Mäkäräinen 1996; Miller 2000 ; Moghissi 1998 ; NEET 1992 ; Orwoll 1994; Petta 2005; Rolland 1990; Roux 1995; Schlaff 2006; Shaw 1990; Sillem 1999; Skrzypulec 2004; Surrey 1992; Surrey 2002; Vercellini 1996; Wheeler 1992; Whitehouse 1990; Zupi 2005). The remaining trials were assigned as having unclear risk of bias. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 21 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Incomplete outcome data Eight trials were considered to be at high risk of attrition bias due to high loss to follow-up (AN Zoladex 1996; Cirkel 1995; Dlugi 1990; Fukushima 1993; Harada 2009; Howell 1995; Schlaff 2006 ; Surrey 2002). Five trials were considered to be at unclear risk of bias due to insufficient data (Chang 1996; Orwoll 1994; Sillem 1999; Tang 2017; Tummon 1988) and the rest of the trials were assigned as having low risk of bias. Selective reporting None of the protocols from the original review were viewed but almost all the published reports of all included articles included all expected outcomes and were therefore judged to be at low risk of reporting bias. Only/uni00A0Burry 1989,/uni00A0Edmonds 1994/uni00A0and/uni00A0Shaw 1986/uni00A0did not report any results of changes in symptoms, while this had been asked and reported during follow-up; they were assessed as being at high risk of reporting bias. Other potential sources of bias There was no evidence of other potential sources of bias identified. Effects of interventions See: Summary of findings 1 GnRHas compared to no treatment for relief of overall pain associated with endometriosis and its related adverse effects; Summary of findings 2 GnRHas compared to placebo for relief of overall pain associated with endometriosis and its related adverse effects; Summary of findings 3 GnRHas compared to analgesics for relief of overall pain associated with endometriosis and its related adverse effects; Summary of findings 4 GnRHas compared to danazol for relief of overall pain associated with endometriosis and its related adverse effects; Summary of findings 5 GnRHas compared to intra- uterine progestogens device for relief of overall pain associated with endometriosis and its related adverse effects; Summary of findings 6 Effect of GnRHas versus other hormonal treatment on bone mineral density We identified six studies at low risk of selection bias and not at high risk of any other bias (Abdou 2018 ; Cheng 2005 ; Finkelstein 1998; Lemay 1988; Ling 1999; Odukoya 1995). The results of these studies were included in the original reviews. We also performed a sensitivity analysis, which included all studies. Results are stated below. 1. GnRHas versus no treatment for relief of overall pain associated with endometriosis and its related adverse effects In a previous version of this review, there was only one study which compared GnRHas with no treatment (Fedele 1993) for the outcome of overall pain, reported as relief of painful symptoms (dysmenorrhoea). We have excluded this study from the current review because it was not possible to read this article in full text. No further studies comparing GnRHas versus no treatment were identified. 2. GnRHas versus placebo for relief of overall pain associated with endometriosis and its related adverse effects Five studies were identified which compared GnRHas with placebo, all with a different outcome measure (Bergqvist 1998; Dlugi 1990; Ling 1999; Miller 2000; Skrzypulec 2004). Only/uni00A0Ling 1999/uni00A0was at low risk of bias. Four were included in sensitivity analysis, however, these results should be interpreted with caution./uni00A0Skrzypulec 2004/uni00A0did not provide usable data. 2.1 Relief of overall pain Relief of overall pain (reported as decrease in pain scores) was reported by three studies (Bergqvist 1998; Ling 1999; Miller 2000), but only/uni00A0one study (Ling 1999) was included in the primary analysis. /uni00A0 GnRHas may improve pelvic pain compared to placebo (RR 2.14; 95% CI 1.41 to 3.24, 1 RCT, n = 87), dysmenorrhoea (RR 2.25; 95% CI 1.59 to 3.16, 1 RCT, n = 87), dyspareunia (RR 2.21; 95% CI 1.39 to 3.54, 1 RCT, n = 59) and pelvic tenderness (RR 2.28; 95% CI 1.48 to 3.50,1 RCT, n = 85) a/f_ter three months of treatment. We are uncertain of the effect of GnRHas compared to placebo for pelvic induration, based on the results a/f_ter three months of treatment (RR 1.07; 95% CI 0.64 to 1.79, 1 RCT, n = 81). We graded all outcomes as having low- certainty evidence;/uni00A0Analysis 1.1. The sensitivity analysis including the studies with unclear or high risk of bias/uni00A0suggested treatment with GnRHas compared to placebo (Analysis 2.1,/uni00A0Bergqvist 1998) at six months follow up may improve the relief of dyspareunia (RR 0.28; 95% CI 0.09 to 0.89, 1 RCT, n = 49) and pelvic tenderness (RR 0.22; 95% CI 0. 09 to 0.55, 1 RCT, n = 49). We are uncertain of the effect of GnRHas compared to placebo for dyschezia (RR 0.26 95%CI 0.03 to 2.17, 1 RCT, n = 49). One/uni00A0study (Analysis 2.1 .;/uni00A0 Miller 2000 ) found pain, using the Endometriosis Symptom Severity Score (ESSS), may improve following GnRHa therapy compared to placebo with an MD 2.90 (95% CI 2.80 to 3.00, 1 RCT, n = 120,/uni00A0Analysis 2.3), as measured one month a/f_ter treatment. 2.2 Bone mineral density No studies at overall low risk of bias were included in this analysis. In the sensitivity analysis including unclear or high risk of bias studies,/uni00A0Dlugi 1990/uni00A0was the only study that reported effects on BMD. "Due to the variety of different methodologies and anatomic sites used to assess changes in bone mineral density, sample sizes were small. In addition, very few placebo patients had data included in the analysis. Consequently, between treatment group data could not be adequately evaluated. Nevertheless, 15 patients treated with leuprolide acetate, who had spinal bone mineral density assessed by dual photon absorptiometry demonstrated a mean decrease of 3.6% (P = 0.001) from baseline to the end of treatment. Eight patients treated with leuprolide acetate had spinal bone mineral density measured by quantitative computed tomography. These patients had a mean decrease in their bone mineral density of 11.8% (P < 0.001)". 2.3 Adverse effects Again, only/uni00A0Ling 1999 /uni00A0was included in the primary analysis. Treatment with GnRHas may be associated with greater incidence 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)/uni00A0(Analysis 1.2). We performed a sensitivity analysis including the studies with unclear or high risk of bias and found treatment with GnRHas may also be associated with greater incidence of vasodilatation (RR 2.69; 95% CI 1.51 to 4.81, 1 RCT, n = 63) and headache (RR 3.55; 95% CI 1.09 to 11.53, 1 RCT, n = 63) at six months of treatment (Dlugi 1990) and sleep disturbances at 12 months treatment (RR 2.31; 95% CI 1.33 to 4.02, 1 RCT, n = 49,/uni00A0Bergqvist 1998) compared to placebo. We Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 22 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews are uncertain of the effect of GnRHas compared to placebo, for hot flushes at 12 months treatment (RR 1.62; 95% CI 0.87 to 3.02, 1 RCT, n = 49,/uni00A0 Bergqvist 1998)/uni00A0 (Analysis 2.4 ). Nevertheless, these results should be interpreted with caution in view of the high risk of bias in these studies. 2.4 Quality of life No studies with overall low risk of bias were included in this analysis. One high risk of bias study reported on quality of life (Miller 2000). /uni00A0At one month of follow-up, GnRHas treatment resulted in lower physical and mental health according to the Short Form (36) Health Survey (SF-36) questionnaire (MD -0.46; 95% CI -0.48 - 0.44, 1 RCT, n = 120,/uni00A0Analysis 2.5). 3. GnRHas versus analgesics for relief of overall pain associated with endometriosis and its related adverse effects No studies comparing GnRHas and analgesics were identified. 4. GnRHas versus danazol for relief of overall pain associated with endometriosis and its related adverse effects Twenty-nine studies were identified which compared GnRHas with danazol (Adamson 1994 ; AN Zoladex 1996; Audebert 1997; Burry 1989; Burry 1992; Chang 1996 ; Cheng 2005 ; Cirkel 1995; Dawood 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Fukushima 1993; Gnoth 1999; Henzl 1988 ; Jelley 1986; Kennedy 1990; NEET 1992 ; Odukoya 1995; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002; Shaw 1990 ; Tummon 1988; Tummon 1989; Vercellini 1994; Wheeler 1992; Whitehouse 1990). Of these twenty-nine studies, only two were low risk of selection bias ( Cheng 2005 ; Odukoya 1995). All twenty-nine studies were included in sensitivity analysis, nevertheless, these results should be interpreted with caution. 4.1 Relief of overall pain Relief of overall pain was reported by/uni00A0Cheng 2005 /uni00A0 and/uni00A0 Odukoya 1995. Dichotomous data suggested very low-certainty evidence of the effect of GnRHas versus danazol on relief of overall pain, reported as partly and completely resolved pelvic tenderness, a/f_ter six months of treatment ((RR 1.15, 95% CI 0.49 to 2.73, 1 RCT, n = 41) and (RR 1.10, 95% CI 0.67 to 1.81, 1 RCT, n = 41)), respectively (Cheng 2005)./uni00A0/uni00A0One study reported that "there was no difference between the two drugs (aka leuprolide acetate versus danazol) in the relief of pain symptoms at the end of three months, but the mean score was lower at the end of three months with leuprolide acetate injections" (Odukoya 1995). Continuous data suggested very low-certainty evidence of the effect of GnRHas versus danazol on relief of overall pain (MD -0.13, 95% CI -0.74 to 0.49, 1 RCT, n = 41), pelvic pain (MD 0.26, 95% CI -0.35 to 0.88, 1 RCT, n = 41), dysmenorrhoea (MD 0.10, 95% CI -0.51 to 0.72, 1 RCT, n = 41), dyspareunia (MD -0.20, 95% CI -0.82 to 0.41, 1 RCT, n = 41), pelvic induration (MD -0.12, 95% CI -0.73 to 0.49, 1 RCT, n = 41 (Cheng 2005)) and pelvic tenderness (MD -0.21, 95% CI -0.82 to 0.41, 1 RCT, n = 41), all a/f_ter three months of treatment (Cheng 2005). Similarly, a/f_ter six months of treatment, we found very low- certainty evidence of the effect of GnRHas versus danazol on relief of overall pain (MD 0.40, 95% CI -0.86 to 1.66, 1 RCT, n = 41), pelvic pain (MD 0.50, 95% CI 0.10 to 0.90, 1 RCT, n = 41), dysmenorrhoea (MD 0.40, 95% CI -0.12 to 0.792, 1 RCT, n = 41), dyspareunia (MD -0.40, 95% CI -0.90 to 0.10, 1 RCT, n = 41) and pelvic tenderness (MD -0.20, 95% CI -0.75 to 0.35, 1 RCT, n = 41) (Cheng 2005). We performed a sensitivity analysis including unclear or high risk of bias studies and found pain scores were reported by twenty-two studies (Adamson 1994; Audebert 1997; Chang 1996; Cheng 2005; Cirkel 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Fukushima 1993; Henzl 1988; Jelley 1986; /uni00A0Kennedy 1990; NEET 1992; Odukoya 1995; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002; Tummon 1989; Vercellini 1994; Wheeler 1992 ; Whitehouse 1990), but only thirteen of them could be included in meta-analyses (Adamson 1994 ; Audebert 1997; Chang 1996 ; Cheng 2005 ; Cirkel 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Jelley 1986; NEET 1992; Palagiano 1994; Tummon 1989; Wheeler 1992). Dichotomous data showed probably little or no difference in the effect of GnRHas versus danazol on overall pain relief a/f_ter six months of treatment: reported as pelvic pain (RR 0.96, 95% CI 0.83 to 1.11, I2 = 0%, 6 RCTs, n = 625, (Adamson 1994 ; Cirkel 1995; Fedele 1989; NEET 1992; Palagiano 1994; Wheeler 1992 )), dysmenorrhoea (RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 6 RCTs, n = 644, (Adamson 1994 ; Cirkel 1995; Fedele 1989; NEET 1992 ; Palagiano 1994; Wheeler 1992)), dyspareunia (RR 1.10, 95% CI 0.90 to 1.34, I2 = 13%, 5 RCTs, n = 342, ( Adamson 1994 ; Cirkel 1995; Fedele 1989; NEET 1992 ; Palagiano 1994)), pelvic induration (RR 0.78, 95% CI 0.32 to 1.89, I2 = 0%, 2 RCTs, n = 151, (Cirkel 1995; NEET 1992), pelvic tenderness partly resolved (RR 1.28, 95% CI 0.59 to 2.76, I2 = 0%, 2 RCTs, n = 96, ( Cheng 2005; Cirkel 1995) and pelvic tenderness completely resolved (RR 0.97, 95% CI 0.84 to 1.12, I2 = 0%, 2 RCTs, n = 194 (Cheng 2005; Wheeler 1992))./uni00A0Also, we are uncertain of the effect on pain reduction when pelvic induration and pelvic tenderness were combined (Kennedy 1990; Analysis 4.1). Continuous data suggested very low-certainty evidence of the effect of GnRHas versus danazol on relief of overall pain (SMD 0.00, 95% CI -0.46 to 0.46, I2 = 81%, 3 RCTs, n = 85 (Cheng 2005; Dmowski 1989a; Tummon 1989)), pelvic pain (SMD 0.35, 95% CI -0.08 to 0.79, I2 = 65%, 2 RCTs, n = 90 (Cheng 2005 ; Fraser 1991)), dyspareunia (SMD 0.25, 95% CI -0.19 to 0.69, I2 = 90%, 2 RCTs, n = 90 (Cheng 2005; Fraser 1991)) and pelvic induration (SMD 0.40 95% CI -0.04 to 0.83, I2 = 73%, 2 RCTs, n = 90 (Cheng 2005 ; Fraser 1991)), all a/f_ter six months of treatment. Pelvic tenderness a/f_ter six months of treatment with GnRHas compared to danazol may be decreased /uni00A0in favour of GnRHas with SMD -0.59 (95% CI -1.03 to -0.15, I2 = 66%, 2 RCTs, n = 90 (Cheng 2005; Fraser 1991))/uni00A0(Analysis 4.2). Two studies that could not be included in the meta-analyses of continuous pain outcomes reported similar results. One study reported "The investigators' symptom severity scores also dropped a/f_ter 6 months for both the nafarelin and danazol groups. There were no symptoms in 57% of the patients in the nafarelin group or 48% of patients in the danazol group" (Rolland 1990). This is comparable with/uni00A0Rotondi 2002, who stated that "Both treatments were associated with a significant reduction in mean total subjective scores but with no difference between the treatments", respectively. /uni00A0Nevertheless, as we included all types of risk of bias, these results should be interpreted with caution. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 23 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews No/uni00A0usable data could be extracted from/uni00A0Henzl 1988 ,/uni00A0 Rock 1993/uni00A0and/uni00A0Vercellini 1994. 4.2 Bone mineral density No studies with overall low risk of bias were identified for this analysis. When we included all studies in the analysis, six studies reported data on BMD (Dawood 1995; Fukushima 1993; Rock 1993; Tummon 1988; Wheeler 1992; Whitehouse 1990). Two studies (Dawood 1995; Wheeler 1992 ) reported the percentage change values of BMD at the lumbar spine a/f_ter six months of treatment. /uni00A0Three studies (Fukushima 1993; Tummon 1988; Whitehouse 1990) reported absolute values of BMD at the lumbar spine a/f_ter six months of treatment. We are uncertain of the effect of GnRHas or danazol between the two groups for absolute values of BMD (SMD 0.21 95% CI -0.31 to 0.73, I2 = 94%, 3 RCTs, n = 81)/uni00A0(Analysis 4.3). Data reported by/uni00A0Rock 1993/uni00A0could not be used in a meta-analysis; it was reported that "the mean percent loss following 12 and 24 weeks of Zoladex therapy was 3.6% (n = 37; 95% CI -5.0 to -2.2) and 5.4% (n = 38; 95% CI -7.2 to -3.6), respectively. Danazol-treated women showed a mean percent loss in bone mineral density at week 12 of 0.4% (n = 17; 95% CI -2.9 to +2.1) and a mean percent increase in 1.0% (n = 17; 95% CI -1.4 to +3.4) at week 24". 4.3 Adverse effects Cheng 2005/uni00A0reported adverse effects. We are uncertain about the effect of GnRHas compared to danazol on adverse effects reported by patients treated for six months. The adverse effects mentioned were vaginal dryness (RR 1.45, 95% CI 0.52 to 4.05, 1 RCT, n = 59), hot flushes (RR 15.50, 95% CI 0.93 to 259.61, 1 RCT, n = 59), gastrointestinal complaints (RR 0.15, 95% CI 0.01 to 2.74, 1 RCT, n = 59), weight gain (RR 0.26, 95% CI 0.08 to 0.82, 1 RCT, n = 59) acne (RR 0.08, 95% CI 0.00 to 1.35, 1 RCT, n = 59) and generalised spasm (RR 0.08, 95% CI 0.00 to 1.35, 1 RCT, n = 59), all very low-certainty evidence. We performed a sensitivity analysis including /uni00A0unclear or high risk of bias studies and found eighteen studies that reported on adverse effects (AN Zoladex 1996; Audebert 1997; Burry 1989; Burry 1992; Chang 1996; Cheng 2005; Cirkel 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Henzl 1988 ; Jelley 1986; Kennedy 1990; NEET 1992; Rock 1993; Rolland 1990; Rotondi 2002; Wheeler 1992 ). A total of forty different types of adverse effects were reported, of which a meta-analysis could be performed in twenty-three studies. Eight of the most commonly reported adverse effects were vaginal dryness, hot flushes, headaches, muscle cramps/myalgia, sleep disturbance/insomnia, altered libido, weight gain and acne. Adverse effects were more frequently reported in groups receiving GnRHas than those receiving danazol. The evidence suggested that, compared to danazol, GnRHas probably lead to more vaginal dryness (RR 1.82, 95% CI 1.53 to 2.18, I2 = 11%, 12 RCTs, n = 1340 ( AN Zoladex 1996; Audebert 1997; Burry 1992; Cheng 2005 ; Cirkel 1995; Dmowski 1989a; Fedele 1989; Jelley 1986; NEET 1992; Palagiano 1994; Rock 1993; Rolland 1990)), more hot flushes (RR 1.50, 95% CI 1.42 to 1.60, I2 = 69%, 16 RCTs, n = 1998 (AN Zoladex 1996; Audebert 1997; Burry 1992; Chang 1996; Cheng 2005; Cirkel 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Henzl 1988; Jelley 1986; NEET 1992; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002; Wheeler 1992 )), more headaches (RR 1.43, 95% CI 1.21 to 1.69, I2 = 0%, 12 RCTs, n = 1103 (AN Zoladex 1996; Audebert 1997; Burry 1992; Cirkel 1995; Dmowski 1989a; Fedele 1989; Fraser 1991; Palagiano 1994; Rock 1993; Rolland 1990; Rotondi 2002)), more sleep disturbance/insomnia (RR 2.04, 95% CI 1.61 to 2.59, I2 = 45%, 7 RCTs, n = 881,/uni00A0AN Zoladex 1996; Cirkel 1995; Dmowski 1989a; Jelley 1986; NEET 1992; Rolland 1990; Wheeler 1992)), and more altered libido (RR 1.58, 95% CI 1.30 to 1.92, I2 = 58%, 9 RCTs, n = 1286). /uni00A0On the other hand, compared to danazol, GnRHas probably lead to fewer muscle cramps/myalgia (RR 0.16, 95% CI 0.09 to 0.29, I2 = 0%, 8 RCTs, n = 884 (AN Zoladex 1996; Burry 1992; Cirkel 1995; Fedele 1989; Fraser 1991; Jelley 1986; NEET 1992; Rolland 1990)), less weight gain (RR 0.38 (95% CI 0.29 to 0.49, I2 = 65%, 9 RCTs, n = 1081 (Audebert 1997; Burry 1992; Cheng 2005; Fedele 1989; Jelley 1986; Palagiano 1994; Rock 1993; Rotondi 2002; Wheeler 1992)) and less acne (RR 0.59, 95% CI 0.47 to 0.73, I2 = 29%, 10 RCTs, n = 1040 (Audebert 1997; Burry 1992; Cheng 2005; Cirkel 1995; Dmowski 1989a; Fedele 1989; Jelley 1986; Rock 1993; Rolland 1990; Rotondi 2002)). All adverse effects reported in the previously mentioned eighteen articles, are reported in/uni00A0Analysis 4.4. The results, reported by/uni00A0Adamson 1994,/uni00A0Burry 1989/uni00A0and/uni00A0Kennedy 1990, could not be extracted for current analyses. 4.4 Quality of life No studies with overall low risk of bias were identified for this analysis. For the sensitivity analysis, including all studies, only one study mentioned the effect of GnRHas compared to danazol on quality of life (Burry 1992), but results could not be extracted for current analyses. "The quality of life measurements in the U.S. study were obtained by a questionnaire composed of 22 simple questions that comprised the Psychological General Well-Being Index plus a modification of Part II of the Nottingham Health Profile, which requires only a patient's visual qualification of psychological state rather than a numerical quantification. The results of these questionnaires failed to reveal statistically significant differences between the entire treatment group." 4.5 Improvement of most troublesome symptoms No studies with overall low risk of bias were identified for this analysis. In the sensitivity analysis, including studies with unclear or high risk of bias, six studies could be included that reported on "improvement of most troublesome symptom" (AN Zoladex 1996; Burry 1992; Henzl 1988; Kennedy 1990; Rolland 1990; Shaw 1990). A distinction was made between overall improvement and complete resolution, both a/f_ter six months of treatment. We are uncertain of the effect between the two groups (RR 1.08, 95% CI 0.99 to 1.18, I2 = 39%, /uni00A0RCTs, n = 747 (AN Zoladex 1996; Burry 1992; Henzl 1988; Kennedy 1990; Rolland 1990; Shaw 1990) and RR 1.14, 95% CI 0.99 to 1.32, I2 = 43%, 5 RCTs, n = 534, (AN Zoladex 1996; Burry 1992; Kennedy 1990; Rolland 1990; Shaw 1990 ), respectively)/uni00A0(Analysis 4.5). Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 24 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 5. GnRHas versus intra-uterine progestogens for relief of overall pain associated with endometriosis and its related adverse effects Three studies assessed outcome measures when GnRHas were compared to intra-uterine progestogens (Ferreira 2010; Gomes 2007; Petta 2005). 5.1 Relief of overall pain No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including high risk of bias studies and found very low-certainty evidence for an effect on relief of overall pain between groups for the effectiveness of pain relief, measured a/f_ter six months of treatment with GnRHas or intra- uterine progestogens (MD -0.76, 95% CI -1.62 to 0.10, I2 = 22%, 2 RCTs, n = 58 (Ferreira 2010; Gomes 2007))/uni00A0(Analysis 5.1). 5.2 Quality of life No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including high risk of bias studies and found very low-certainty evidence for an effect on quality of life scores, measured by the psychological well- being questionnaire index (PGWBI) between both groups, a/f_ter six months of treatment (MD -2.00, 95% CI -10.26 to 6.26, 1 RCT, n = 82,/uni00A0Petta 2005)/uni00A0(Analysis 5.2). 6. GnRHas versus oral or injectable progestogens for relief of overall pain associated with endometriosis and its related adverse effects Seven studies were identified which compared GnRHas with oral or injectable progestogens (Abdou 2018 ; Crosignani 2006; Harada 2009; Ozaki 2020; Schlaff 2006 ; Strowitzki 2012; Zupi 2005)./uni00A0 Crosignani 2006/uni00A0did not provide usable data on relief of overall pain and changes in BMD. Data about adverse effects were provided, and included in meta-analysis./uni00A0Abdou 2018 /uni00A0was considered at low risk of selection bias, and was included in the original review. 6.1 Relief of overall pain Only one study reported relief of overall pain, a/f_ter three months of treatment with either GnRHas or oral progestogens (Abdou 2018). There may be an improvement in overall pain, reported as pelvic pain (MD -2.50, 95% CI -3.55 to -1.45, 1 RCT, n = 261, low certainty of evidence) and dyspareunia (MD -2.10, 95% CI -2.83 to -1.37, 1 RCT, n = 261, low certainty of evidence) a/f_ter three months of treatment, in favour of oral progestogens. We are uncertain about the effect on back pain of both GnRHas and oral progestogens (MD 0.50, 95% CI -0.40 to 1.40, 1 RCT, n = 261)/uni00A0(Analysis 6.1). We performed a sensitivity analysis including all studies. Two studies (Schlaff 2006; Strowitzki 2012) reported relief of overall pain in dichotomous data, comparing GnRHas with oral or injectable progestogens./uni00A0Schlaff 2006 /uni00A0did not provide usable data on relief of overall pain, except for pelvic tenderness, but stated that, "treatment with DMPA-SC 104 was statistically equivalent (P < 0.02) to treatment with leuprolide at month 6 for the reduction of four of the five signs and symptoms, namely dysmenorrhoea, dyspareunia, pelvic pain, and pelvic tenderness"./uni00A0Strowitzki 2012/uni00A0reported results on different outcome measurements, namely pelvic pain, dysmenorrhoea, dyspareunia, pelvic induration and pelvic tenderness. For both, all reported outcomes were a/f_ter six months of treatment. Therefore, a meta-analysis could only be performed for pelvic tenderness; we are uncertain whether the two groups differ in effects on pelvic tenderness (RR 1.11, 95% CI 0.95 to 1.29, I2 = 0%, 2 RCTs, n = 419)/uni00A0(Analysis 7.1). Continuous outcome data were reported by four studies (Abdou 2018; Harada 2009; Strowitzki 2012; Zupi 2005). However, these studies had different specific outcome measurements and treatment periods. Consequently, meta-analysis could only be performed for dyspareunia a/f_ter six months of treatment with GnRHas or oral or injectable progestogens. The results of/uni00A0Harada 2009/uni00A0 and/uni00A0 Zupi 2005/uni00A0were combined, and we are uncertain about the effect of GnRHas or oral or injectable progestogens between both groups (MD -0.10 95% CI -0.10 to 0.22, I2 = 0%, 2 RCTs, n = 180)/uni00A0(Analysis 7.2). Crosignani 2006/uni00A0only mentioned the results of overall pain in figures, but stated that "6 months of treatment with subcutaneous formulation of depot medroxyprogesterone acetate 104 mg/0.65 mL (DMPA-SC 104) resulted in statistically equivalent (P < 0.02) reductions of all five signs and symptoms of endometriosis (dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration) compared with leuprolide treatment. Similarly, scores for all three prespecified scales of the SF-36 (physical function, role physical and social functioning) significantly improved at month 6 relative to pre-treatment in both treatment groups, (P ≤ 0.001)". 6.2 Bone mineral density No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including high risk of bias studies. Four studies reported the effect of GnRHas and oral versus injectable progestogens on bone mineral density (Crosignani 2006; Harada 2009; Schlaff 2006 ; Zupi 2005). Again, however, different outcome measures have been used, namely percentage change in BMD and absolute values a/f_ter six and 12 months of treatment. This means that a meta-analysis could not be undertaken. The difference in percentage change values a/f_ter six months of treatment may decrease according to one study (MD -1.60, 95% CI -2.57 to -0.63, 1 RCT, n = 87,/uni00A0Harada 2009). One study found an uncertain difference (Zupi 2005)/uni00A0a/f_ter six months (MD -0.04 95% CI -0.08 to 0.01, 1 RCT, n = 87), but BMD may decrease following GnRHas versus oral or injectable progestogens a/f_ter 12 months of treatment (MD -0.05 95% CI -0.10 to -0.01, 1 RCT, n = 87)/uni00A0(Analysis 7.3). Crosignani 2006/uni00A0could not be included in meta-analysis, but "In the leuprolide group, significant (P < 0.001) reductions from pre-treatment in both total hip and lumbar spine BMD (median percentage changes of –2.10 and –4.00, respectively) were observed at month 6. However, the DMPA-SC 104 group showed significant reduction from pre-treatment (P < 0.001) only in lumbar spine BMD (median percentage changes: total hip, –0.50; lumbar spine, –1.00). Compared with the leuprolide group, reductions in both total hip and lumbar spine BMD were significantly smaller (P < 0.001) in the DMPA-SC 104 group". Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 25 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews "The leuprolide group experienced significant (P < 0.001) reductions from baseline in both total hip and lumbar spine BMD at month 6 (median percentage changes of -1.65 and -3.95, respectively). In comparison, the DMPA-SC 104 group showed a significant reduction from baseline in lumbar spine BMD only (median percentage changes were as follows: total hip BMD, -0.30 [P = 0.063]; lumbar spine BMD, -1.10 [P < 0.001]). Compared with leuprolide, reductions in both total hip and lumbar spine BMD were significantly less (P < 0.001) for the DMPA-SC 104 group" (Schlaff 2006). 6.3 Adverse effects Only one study was included in the original analysis (Abdou 2018); it had with low-certainty evidence. There may be a decrease of vaginal bleeding seen in women treated with GnRHas, compared to oral progestogens (RR 0.33, 95% CI 0.23 to 0.48, 1 RCT, n = 242). Also, there may be less weight gain in women treated with GnRHas instead of oral progestogens (RR 0.31, 95% CI 0.10 to 0.92, 1 RCT, n = 242). We are uncertain about the effect of GnRHas compared to oral progestogens, for headache, a/f_ter three months of treatment (RR 1.53, 95% CI 0.88 to 2.67, 1 RCT, n = 242)/uni00A0(Analysis 6.2). We performed a sensitivity analysis including high risk of bias studies. All the seven studies who were identified, mentioned adverse effects when comparing GnRHas with oral or injectable progestogens (Abdou 2018 ; Crosignani 2006; Harada 2009; Ozaki 2020; Schlaff 2006 ; Strowitzki 2012; Zupi 2005). A meta-analysis could be performed for headache, intermenstrual bleeding and hot flushes a/f_ter six months of treatment. For headache, an improvement was found between both groups in favour of GnRHas compared to oral or injectable progestogens (RR 1.46 95% CI 1.04 to 2.03, I2 = 0%, 3 RCTs, n = 110, (Crosignani 2006; Harada 2009; Schlaff 2006 )). Hot flushes may improve in women treated with GnRHas, compared to oral or injectable progestogens (RR 2.11, 95% CI 1.70 to 2.62, I2 = 88%, 4 RCTs, n = 902, ( Crosignani 2006; Harada 2009; Schlaff 2006 ; Zupi 2005)). In contrast, intermenstrual bleeding was decreased in women treated with GnRHas, compared to oral or injectable progestogens (RR 0.58 95% CI 0.50 to 0.67, I2 = 84%, 4 RCTs, n = 902, (Crosignani 2006; Harada 2009; Schlaff 2006; Zupi 2005))/uni00A0(Analysis 7.4). There may be an increase in the number of menopausal symptoms by the Kupperman Index (MD 6.80, 95% CI 2.37 to 11.23, 1 RCT, n = 70) and hot flushes (MD 1.10, 95% CI 0.71 to 1.49, 1 RCT, n = 70) in favour of GnRHas, and a decrease of breast pain (MD -0.20, 95% CI -0.39 to -0.01, 1 RCT, n = 70), and metrorrhagia (MD -0.90, 95% CI -1.31 to -0.49, 1 RCT, n = 70). We are uncertain about the effect of GnRH compared to oral or injectable progestogens, when results are reported a/f_ter four months of treatment, when compared for depression (MD 0.20, 95% CI -0.18 to 0.58, 1 RCT, n = 70), oedema (MD 0.20, 95% CI -0.14 to 0.54, 1 RCT, n = 70), and headache (MD 0.10, 95% CI -0.32 to 0.52, 1 RCT, n = 70)/uni00A0(Analysis 7.5). 6.4 Quality of life No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including high risk of bias studies. Quality of life, measured by SF-36 was reported by four studies (Harada 2009; Schlaff 2006 ; Strowitzki 2012; Zupi 2005)./uni00A0Harada 2009/uni00A0reported results a/f_ter six months of treatment and for all domains, but we are uncertain about the effect found between two groups. A/f_ter 12 months of treatment,/uni00A0Zupi 2005/uni00A0also reported no significant differences in the results of the SF-36/uni00A0(Analysis 7.6). Crosignani 2006/uni00A0data were not usable for meta-analysis, but stated that "mean scores for all four prespecified Endometriosis Health Profile-30 (EHP-30) scales (pain, emotional well-being, self-image and intercourse) as well as the two remaining scales (social support, control and powerlessness), significantly improved in both groups at month six compared with pretreatment. Similarly, scores for all three prespecified scales of the SF-36 (physical function, role physical and social functioning) significantly improved at month six relative to pretreatment". In addition, "mean scores for all four prespecified EHP-30 scales (pain, emotional well-being, self-image, and intercourse) and two additional EHP-30 scales (social support as well as control and powerlessness) significantly improved in both groups at month six compared with the case of baseline (P < 0.05), and these improvements were maintained at the 12-month post-treatment follow-up. Similarly, scores for all three prespecified scales of the SF-36 (physical function, role-physical, and social functioning) significantly improved at month six relative to baseline, with improvements maintained through 12 months of follow-up, in both groups (P < 0.05)" (Schlaff 2006 )./uni00A0 Strowitzki 2012/uni00A0stated that "at the end of treatment, QoL showed more pronounced absolute improvements in the dienogest (DNG) group than in the leuprolide acetate group, including both the physical health (DNG, 10.2 points; LA, 7.0 points) and the mental health (DNG, 3.3 points; LA, 1.9 points) summary scale scores. Compared with LA, DNG was also associated with greater relative improvements in specific SF-36 scale categories. In particular, DNG produced greater improvements in the categories 'physical functioning' (DNG, 18.0%; LA, 6.8%), 'role-physical' (DNG, 75.7%; LA, 33.6%), 'vitality' (DNG, 28.3%; LA, 12.3%), and 'social functioning' (DNG, 21.4%; LA, 8.7%), which relate to everyday physical activity, productivity at work, energy levels, and ability to interact in society, respectively". 6.5 Improvement of most troublesome symptom No studies with overall low risk of bias were identified for this analysis. For the sensitivity analysis,/uni00A0Strowitzki 2012/uni00A0was the only study that reported dichotomous results on improvement of the most troublesome symptom. We are uncertain about the effect between the two groups a/f_ter six months of treatment (RR 1.00, 95% CI 0.79 to 1.28, 1 RCT, n = 229)/uni00A0(Analysis 7.7). Harada 2009/uni00A0 and/uni00A0 Ozaki 2020/uni00A0both reported values for overall symptoms./uni00A0Harada 2009/uni00A0reported no difference between two groups, a/f_ter six months of treatment (MD -0.70, 95% CI -1.52 to 0.12, 1 RCT, n = 253)./uni00A0Ozaki 2020/uni00A0reported results a/f_ter four months of treatment, and used a numerical rating scale (NRS) and a verbal rating scale (VRS). For GnRHas compared to oral or injectable progestogens, there may be an improvement for NRS a/f_ter four months of treatment (MD 2.60, 95% CI 0.37 to 4.83, 1 RCT, n = 70) and also for "improvement of most troublesome symptom" measured by VRS (MD 0.70, 95% CI 0.06 to 1.34, 1 RCT, n = 70)/uni00A0(Analysis 7.8). Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 26 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 7. GnRHas versus gestrinone for relief of overall pain associated with endometriosis and its related adverse effects Only one study compared GnRHas with gestrinone/uni00A0(Vercellini 1996), with unclear and low risk for selection bias. This study was not included in the original review, but results below are from the sensitivity analyses. 7.1 Relief of overall pain Vercellini 1996/uni00A0reported relief of overall pain on a continuous scale, a/f_ter three and six months of treatment with GnRHas or gestrinone. We are uncertain about the effect found for overall pain, reported as dysmenorrhoea, dyspareunia, and non-menstrual pelvic pain, all measured on a NRS and VRS scale/uni00A0(Analysis 8.1). 7.2 Bone mineral density BMD was measured by/uni00A0Vercellini 1996, who reported the percentage of change a/f_ter six and 12 months of treatment with either GnRHas or gestrinone. A/f_ter both treatment periods, there may be a decrease found in favour of GnRHas ((MD -1.96 95% CI -3.62 to -0.30, 1 RCT, n = 41) and (MD -5.10 95% CI -7.39 to -2.81, 1 RCT, n = 41), respectively)/uni00A0(Analysis 8.2). 7.3 Adverse effects A/f_ter six months of treatment, there may be an improvement for hot flushes a/f_ter treatment with GnRHas, compared to gestrinone (RR 2.29 95% CI 1.21 to 4.32, 1 RCT, n = 55). For the remainder of all the reported adverse effects, we are uncertain about the effect on BMD between the two groups (Analysis 8.3). 8. Trials comparing different doses of GnRHas for relief of overall pain associated with endometriosis and its related adverse effects A total of eight trials compared different doses of GnRHas (Adamson 1994; Bergqvist 1997; Burry 1989; Henzl 1988 ; Minaguchi 1986 ; Shaw 1986 ; Tahara 2000; Tang 2017)./uni00A0 Tahara 2000/uni00A0 and/uni00A0 Bergqvist 1997/uni00A0 both compared 200 /uni03BCg nafarelin with 400 /uni03BCg nafarelin for a treatment period of six months./uni00A0Adamson 1994 ,/uni00A0 Burry 1989/uni00A0 and/uni00A0 Henzl 1988 /uni00A0 all compared 400 /uni03BCg nafarelin with 800 /uni03BCg nafarelin for a treatment period of six months./uni00A0Tang 2017/uni00A0compared 1.88 mg leuprorelin with 3.75 mg leuprorelin for a treatment period of six months. As this comparison only included studies with unclear or high risk of bias, results stated below are results of the sensitivity analysis. Results from/uni00A0Minaguchi 1986 /uni00A0 and/uni00A0 Shaw 1986/uni00A0could not be used for meta-analysis. 8.1 Relief of overall pain No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies suited for meta-analysis. We are uncertain about the effect found for overall pain, reported as pelvic pain a/f_ter two months (MD 0.20, 95% CI -1.07 to 1.47, 1 RCT, n = 15), four months (MD -0.10, 95% CI -1.07 to 0.87, 1 RCT, n = 15) and six months (MD 0.30, 95% CI -0.61 to 1.21, 1 RCT, n = 15) of treatment with 200 /uni03BCg nafarelin compared to 400 /uni03BCg nafarelin (Tahara 2000)/uni00A0(Analysis 9.1). Besides, we are also uncertain about the effect found for overall pain, reported as pelvic pain (RR 1.24, 95% CI 0.71 to 2.16, 1 RCT, n = 77), dysmenorrhoea (RR 3.00, 95% CI 0.13 to 71.74, 1 RCT, n = 90), and dyspareunia (RR 1.05, 95% CI 0.49 to 2.26, 1 RCT, n = 57) a/f_ter six months of treatment with 400 /uni03BCg nafarelin compared to 800 /uni03BCg nafarelin (Adamson 1994)/uni00A0(Analysis 9.2). Bergqvist 1997,/uni00A0Henzl 1988/uni00A0and/uni00A0Tang 2017/uni00A0did not provide sufficient data to include them in the meta-analysis. 8.2 Bone mineral density No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies suited for meta-analysis. In one study, it was reported that "bone mineral density of the lumbar spine at 24 weeks of treatment was significantly lower than before treatment in the control group, with a mean bone loss of 5.56%. The decrease in bone mineral content was less in the half-dose group, with a mean bone loss of 1.38%. It has been reported that nafarelin at a dosage of 200 mg daily does not cause the significant reduction in bone density that is seen with a dosage of 400 mg daily. Our data show that loss of BMD was largely eliminated with half-dose nafarelin during 6 months of GnRH agonist therapy" (Tahara 2000). Tang 2017/uni00A0stated that "the BMD was decreased in both groups at 20 weeks a/f_ter treatment, and the degree of loss of BMD in the control group (= 3.75 mg leuprorelin) (5.6%) was higher than in the research group (= 1.88 mg leuprorelin)(1.2%; P < 0.05)". 8.3 Adverse effects No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies suited for meta-analysis. We are uncertain about the effect found for vasomotor symptoms a/f_ter two months, four months and six months of treatment with 200 /uni03BCg nafarelin compared to 400 /uni03BCg nafarelin (Tahara 2000). In addition, rhinitis, upper respiratory infections, and irregular bleeding were reported without any significant difference between either group (Bergqvist 1997) (Analysis 9.3). Tang 2017/uni00A0compared 1.88 mg leuprorelin with 3.75 mg leuprorelin for a treatment period of two, three, four and six months. A/f_ter two months, there was no difference in menopausal symptoms, measured by the Kupperman Index (MD 1.20, 95% CI -3.14 to 5.54, 1 RCT, n = 50). However, a/f_ter three, four and six months, there may be a difference in favour of 3.75 mg leuprorelin compared to 1.88 mg leuprorelin ((MD 5.70, 95% CI 2.12 to 9.28, 1 RCT, n = 50) (MD 9.50, 95% CI 6.55 to 12.45, 1 RCT, n = 50) (MD 13.20, 95% CI 10.22 to 16.18, 1 RCT, n = 50), respectively)/uni00A0(Analysis 9.4). Burry 1989/uni00A0reported the results of weight gain during treatment, but it was not possible to extract data for meta-analysis. 8.4 Improvement of most troublesome symptom No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies./uni00A0Henzl 1988/uni00A0measured overall improvement, and we are uncertain about Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 27 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews the effect between 400 /uni03BCg nafarelin with 80 0/uni03BCg nafarelin for a treatment period of six months (RR 0.94, 95% CI 0.78 to 1.14, 1 RCT, n = 143)/uni00A0(Analysis 9.5). 9. Trials comparing different treatment duration of GnRHas for relief of overall pain associated with endometriosis and its related adverse effects Two trial mentioned the effect of different treatment duration of GnRHas (two trials;/uni00A0Hornstein 1995; Orwoll 1994). As this comparison only included studies with unclear or high risk of bias,

stated below are the results of the sensitivity analysis. Hornstein 1995/uni00A0and/uni00A0Orwoll 1994/uni00A0both compared a total treatment period of three months with intranasal 200 /uni03BCg nafarelin twice daily combined with three consecutive months of placebo use, with a total treatment period of six months with intranasal 200 /uni03BCg nafarelin twice daily. 9.1 Relief of overall pain No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies./uni00A0Hornstein 1995/uni00A0measured relief of overall pain, with a comparison of a total treatment period of three months with a total treatment period of six months with intranasal 200 /uni03BCg nafarelin twice daily. There may be an improvement /uni00A0for pelvic pain (MD 0.16, 95% CI 0.13 to 0.19, 1 RCT, n = 179) and pelvic tenderness (MD 0.05, 95% CI 0.03 to 0.07, 1 RCT, n = 179) a/f_ter six months of treatment, in favour of six months treatment compared to three months of treatment (with intranasal 200 /uni03BCg nafarelin twice daily and three months of placebo). For overall pain, reported as dysmenorrhoea (MD -0.09, 95% CI -0.11 to -0.07, 1 RCT, n = 179) and dyspareunia (MD -0.14, 95% CI -0.17 to -0.11, 1 RCT, n = 179), the opposite results were found. There may be a slight decrease a/f_ter six months of treatment, in favour of three months treatment, compared to six months of treatment with intranasal 200 /uni03BCg nafarelin twice daily. No significant difference was found for pelvic induration between the two groups (MD -0.03, 95% CI -0.06 to 0.00, 1 RCT, n = 179)/uni00A0(Analysis 10.1). 9.2 Bone mineral density No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies. For BMD, a/f_ter a total treatment period of three months with intranasal 200 /uni03BCg nafarelin twice daily combined with three consecutive months of placebo use, there might be a decrease in BMD, compared with a total treatment period of six months with intranasal 200 /uni03BCg nafarelin twice daily. This applied to both spinal bone mass (MD 1.60, 95% CI 1.51 to 1.69, 1 RCT, n = 183) and proximal femoral bone (MD 1.90, 95% CI 1.72 to 2.08, 1 RCT, n = 183) (Orwoll 1994)/uni00A0(Analysis 10.2/uni00A0and/uni00A0Analysis 10.3). 10. Trials comparing different route of administration of GnRHas for relief of overall pain associated with endometriosis and its related adverse effects Four trials comparing different route of administration of GnRHas were included in this comparison (Agarwal 1997; Bergqvist 2000; Dmowski 1989a; Lemay 1988). Bergqvist 2000/uni00A0compared subcutaneously administered goserelin depot with intranasal nafarelin 200 /uni03BCg twice daily./uni00A0Dmowski 1989a/uni00A0 and/uni00A0 Lemay 1988/uni00A0both compared subcutaneously administered buserelin depot 200 /uni03BCg once daily with intranasal buserelin 200 /uni03BCg thrice daily. The results of/uni00A0Dmowski 1989a/uni00A0could not be used, because no distinction was made in the article between subcutaneously administered buserelin depot 200 /uni03BCg once daily and intranasal nafarelin 200 /uni03BCg buserelin thrice daily. 10.1 Relief of overall pain Lemay 1988/uni00A0compared subcutaneously administered buserelin depot 200 /uni03BCg once daily with intranasal 400 /uni03BCg buserelin thrice daily. We are uncertain about the effect on pelvic pain (RR 1.00, 95% CI 0.53 to 1.87, 1 RCT, n = 5), dysmenorrhoea (RR 1.22, 95% CI 0.73 to 2.06, 1 RCT, n = 9), dyspareunia (RR 1.00, 95% CI 0.57 to 1.75, 1 RCT, n = 7), pelvic induration (RR 0.86, 95% CI 0.47 to 1.55, 1 RCT, n = 8) and pelvic tenderness (RR 1.50, 95% CI 0.69 to 3.27, 1 RCT, n = 10) between either group, a/f_ter six months of treatment/uni00A0(Analysis 11.1). As this comparison included only one low-risk study, a sensitivity analysis reported comparable results. Agarwal 1997/uni00A0compared intramuscularly administered leuprolide acetate depot 3.75 mg once monthly with intranasal nafarelin 200 /uni03BCg twice daily. We are uncertain about the effect on overall pain, reported as pelvic pain (RR 0.96, 95% CI 0.73 to 1.26, 1 RCT, n = 192), dysmenorrhoea (RR 1.29, 95% CI 0.72 to 2.30, 1 RCT, n = 192), dyspareunia (RR 0.88, 95% CI 0.62 to 1.25, 1 RCT, n = 166), pelvic induration (RR 1.41, 95% CI 0.82 to 2.41, 1 RCT, n = 192) and pelvic tenderness (RR 1.23, 95% CI 0.88 to 1.73, 1 RCT, n = 192) between either group, a/f_ter six months of treatment/uni00A0(Analysis 12.1; Analysis 12.2). Bergqvist 2000/uni00A0reported that "the total pain score, i.e. the three parameters dysmenorrhoea, dyspareunia and pelvic pain, was reduced in both groups, for goserelin by 45% and for nafarelin by 43% 3 months a/f_ter the end of treatment". 10.2 Adverse effects Lemay 1988/uni00A0compared subcutaneously administered buserelin depot 200 /uni03BCg once daily with intranasal 400 /uni03BCg buserelin thrice daily. For hot flushes (RR 0.86, 95% CI 0.48 to 1.55, 1 RCT, n = 13), vaginal dryness (RR 0.86, 95% CI 0.17 to 4.37, 1 RCT, n = 13), decreased libido (RR 0.86, 95% CI 0.07 to 10.96, /uni00A01 RCT, n = 13) and headaches (RR 1.71, 95% CI 0.20 to 14.55, 1 RCT, n = 13), we are uncertain about the effects found between the two groups/uni00A0(Analysis 11.2). As this comparison included only one low-risk study, a sensitivity analysis reported comparable results/uni00A0(Analysis 12.3). Bergqvist 2000/uni00A0 and/uni00A0 Agarwal 1997/uni00A0reported adverse effects a/f_ter comparing intramuscular administered goserelin or leoprolide acetate depot with intranasal nafarelin 200 /uni03BCg twice daily. For hot flushes (RR 0.95, 95% CI 0.88 to 1.02, I2 = 38%, 2 RCTs, n = 404), headaches (RR 0.83, 95% CI 0.63 to 1.10, 1 RCT, n = 213), sweating (RR 1.13, 95% CI 0.71 to 1.79, 1 RCT, n = 213), and vaginal dryness (RR 0.52, 95% CI 0.27 to 1.00, 1 RCT, n = 213), we are uncertain about the effect found between the two groups. This is in contrast with the results of vaginal bleeding, because there may be an improvement in favour of subcutaneously administered goserelin Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 28 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews depot compared to intranasal nafarelin 200 /uni03BCg twice daily (RR 19.19, 95% CI 1.12 to 328.28, 1 RCT, n = 213) (Analysis 12.4). 10.3 /uni00A0Bone mineral density Agarwal 1997/uni00A0stated the percentage of decrease of BMD when intranasal nafarelin was compared to intramuscular leuprolide acetate. A/f_ter six months of treatment, there may be a reduction in BMD in favour of nafarelin (MD -2.00, 95% CI -2.10 to -1.90, 1 RCT, n = 152). 11. Trials comparing different GnRHas treatment regimens for relief of overall pain associated with endometriosis and its related adverse effects There was only one trial included, comparing different GnRHa treatment regimens (Crosignani 1996)./uni00A0Crosignani 1996/uni00A0compared a monthly injection of leuprolide with a three-monthly injection of leuprolide. As this comparison only included one study with an unclear risk of bias, the results stated below are the results of the sensitivity analysis. 11.1 Relief of overall pain No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies. Only/uni00A0 Crosignani 1996/uni00A0was included in the comparison 'Trials comparing different GnRHa treatment regimens for revealing painful symptoms associated with endometriosis and its related adverse effects'. We are uncertain about the effect found for overall pain, reported as pain symptom scores a/f_ter three and six months of treatment./uni00A0Results were subdivided into non-menstrual pelvic pain (MD -0.20, 95% CI -0.52 to 0.12, 1 RCT, n = 30), dyspareunia (MD -0.10, 95% CI -0.51 to 0.31, 1 RCT, n = 30), pelvic induration (MD 0.10, 95% CI -0.40 to 0.60, 1 RCT, n = 30) and pelvic tenderness (MD -0.30, 95% CI -0.71 to 0.11, 1 RCT, n = 30), during a treatment period of three months. For a treatment period of six months, the results were similar for non-menstrual pelvic pain (MD 0.10, 95% CI -0.15 to 0.35, 1 RCT, n = 30), dyspareunia (MD 0.00, 95% CI -0.50 to 0.50, 1 RCT, n = 30), and pelvic tenderness (MD 0.40, 95% CI -0.10 to 0.90, 1 RCT, n = 30). However, for pelvic induration a/f_ter six months of treatment, there may be a difference between the two groups (MD 0.40, 95% CI 0.10 to 0.70, 1 RCT, n = 30) (Analysis 13.1). 11.2 Adverse effects No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies. Adverse effects were reported by/uni00A0Crosignani 1996; we are uncertain about the effect on hot flushes (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 24), vaginal dryness (RR 0.67, 95% CI 0.13 to 3.44, 1 RCT, n = 30), abdominal pain (RR 3.00, 95% CI 0.13 to 68.26, 1 RCT, n = 30), arthralgia (RR 3.00, 95% CI 0.13 to 68.26, 1 RCT, n = 30) and depression (RR 3.00, 95% CI 0.13 to 68.26, 1 RCT, n = 30), a/f_ter six months of treatment when a monthly injection of leuprolide was compared with a three-monthly injection of leuprolide/uni00A0(Analysis 13.2). 11.3 Bone mineral density No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies./uni00A0Crosignani 1996/uni00A0reported the results of monthly versus three-monthly doses of leuprolide acetate on BMD. The trial stated that there might be a slight variation of lumbar spine bone mineral density observed at the end of GnRHa treatment in both study groups (P < 0.01), the percentage decrease over basal being 5.2% and 4.9%, respectively. But the study did not provide sufficient data for comparison of the groups; authors were contacted for the previous version of the review, but have not replied to date. 12. Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) for relief of overall pain associated with endometriosis and its related adverse effects Sixteen trials compared GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) (Bergqvist 1997; Edmonds 1994; Franke 2000; Freundl 1998; Gnoth 1999; Hornstein 1998; Howell 1995; Hurst 2000; Irahara 2001; Kiilholma 1995; Mäkäräinen 1996; Moghissi 1998 ; Sillem 1999 ; Surrey 1992; Surrey 2002; Vercellini 1994; Zupi 2005). As this comparison only included studies with unclear or high risk of bias, the results stated below are the results of the sensitivity analysis. 12.1 Relief of overall pain No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies. A total of ten studies reported relief of overall pain as a primary or secondary outcome measure (Bergqvist 1997; Freundl 1998; Hornstein 1998; Howell 1995; Hurst 2000; Mäkäräinen 1996; Moghissi 1998; Surrey 2002; Vercellini 1994; Zupi 2005). Relief of overall pain was presented both as a dichotomous and as a continuous outcome measure./uni00A0Freundl 1998/uni00A0was the only study that reported dichotomous outcomes; we are uncertain about the effect between GnRHas and GnRHas in conjunction with add-back therapy (dysmenorrhoea, RR 0.63, 95% CI 0.58 to 159.04, 1 RCT, n = 28; dyspareunia, RR 6.07, 95% CI 0.86 to 43.04, 1 RCT, n = 28; and non-menstrual pelvic pain, RR 1.30, 95% CI 0.26 to 6.62, 1 RCT, n = 28)/uni00A0(Analysis 14.1)./uni00A0Zupi 2005/uni00A0reported continuous outcomes; we are uncertain about the effect found between groups for overall pain, reported as dysmenorrhoea a/f_ter six months of treatment (not estimable), dyspareunia a/f_ter six months of treatment (MD -0.20, 95% CI -0.40 to 0.80, 1 RCT, n = 90), and overall pain (MD -1.50, 95% CI -7.92 to 4.92, 1 RCT, n = 90); or dysmenorrhoea (not estimable) and dyspareunia (MD 0.20, 95% CI -0.03 to 0.43, 1 RCT, n = 90) both a/f_ter 12 months of treatment. In contrast, values for pelvic pain may improve slightly in favour of GnRHas in conjunction with add-back therapy. This applied to both six months of treatment (MD -0.20, 95% CI -0.39 to -0.01, 1 RCT, n = 90) and 12 months of treatment (MD -0.10, 95% CI -0.14 to -0.06, 1 RCT, n = 90)/uni00A0(Analysis 14.2). This corresponds partly to the data extracted from/uni00A0Howell 1995, which stated that "both groups showed similar improvement in pelvic symptoms (dysmenorrhoea, dyspareunia, and other pelvic pain) and pelvic signs (tenderness and induration) during the course of treatment with no significant difference between the two groups (P > 0.05)". Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 29 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Hornstein 1998/uni00A0did not include data in the meta-analysis, but no significant difference was found between GnRHas alone (group A), compared with three different add-back groups (group B received daily oral norethindrone acetate 5 mg with placebo for oestrogen; group C received norethindrone 5 mg and conjugated equine oestrogens 0.625 mg; group D received norethindrone 5 mg and conjugated equine oestrogens 1.25 mg), comparing dysmenorrhoea, non-menstrual pelvic pain, and pelvic tenderness. "The mean decreases in group D were significantly less than those of group A at week 4, 8 (P < 0.05), 12 (P < 0.01), and 48 (P < 0.05)" ( Hornstein 1998). All participants in the study of/uni00A0Kiilholma 1995/uni00A0showed subjective improvement on goserelin acetate therapy. The authors reported that "the response was equally good in patients with or without HRT (P = not significant [NS]). The pelvic symptoms score decreased from 4.7 and 4.7 in goserelin acetate plus HRT and goserelin acetate plus placebo patients to 0.9 and 0.5 a/f_ter 6 months, respectively". Bergqvist 1997,/uni00A0 Hurst 2000,/uni00A0 Mäkäräinen 1996,/uni00A0 Moghissi 1998/uni00A0and/uni00A0Vercellini 1994/uni00A0did not provide sufficient data to include their data in the meta-analysis. Surrey 2002/uni00A0compared four different groups, all receiving GnRHas. Group A received daily oral placebos for oestrogen and progestin add-back. Patients included in group B received daily oral norethindrone acetate 5 mg and placebo for oestrogen. Patients in group C received oral norethindrone acetate 5 mg and conjugated equine oestrogens 0.625 mg daily. Those in group D received oral norethindrone acetate 5 mg and conjugated equine oestrogens 1.25 mg daily. The authors reported that "the median changes in overall pelvic pain, dysmenorrhoea, and dyspareunia scores from pre-therapy baseline throughout the follow-up period for the four groups are displayed in Figures 1–3, respectively. Decreases in symptom scores from baseline remained statistically significant through month 12 of follow-up for all groups with the exceptions of dysmenorrhoea for groups A and D and deep dyspareunia for group D, which all remained suppressed through month 8 of follow- up. The only significant difference between groups regarding return to baseline scores occurred between groups A and D for dysmenorrhoea, where group D patients returned to baseline levels sooner". 12.2 Bone mineral density No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies. The effect of add-back therapy on the GnRHas-induced loss of bone mineral density was reported by/uni00A0thirteen studies (Edmonds 1994,/uni00A0 Franke 2000; Freundl 1998; Gnoth 1999; Hornstein 1998; Howell 1995; Irahara 2001; Moghissi 1998; Schlaff 2006; Sillem 1999; Surrey 1992; Surrey 2002; Zupi 2005). A meta-analysis was undertaken for continuous outcome measures, and subdivided into percentage change values and absolute values. The percentage change may improve when treated with GnRHas compared with GnRHas in conjunction with add- back therapy (MD -3.88, 95% CI -4.27 to -3.49, I2 = 93%, 2 RCTs, n = 46,/uni00A0Freundl 1998; Surrey 1992)./uni00A0Gnoth 1999/uni00A0also mentioned a significant loss of BMD in the lumbar spine for the GnRHa + placebo group compared to that for the GnRHa + add-back group (6.5 vs. 2.0%, respectively, P = 0.001). For absolute values, a/f_ter six months of treatment with either GnRHas or GnRHas in conjunction with add-back therapy, there may be a difference in change in favour of GnRHas in conjunction with add-back therapy (MD 0.02, 95% CI 0.02 to 0.02, I2 = 70%, 5 RCTs, n = 199,/uni00A0Gnoth 1999; Sillem 1999; Surrey 1992; Zupi 2005). Only/uni00A0Zupi 2005/uni00A0reported results a/f_ter 12 months of treatment, without any changes between either group/uni00A0(Analysis 14.3). Bone mineral density loss is reduced by 50% to 2.5% overall by the addition of add-back therapy and there may be an improvement in the rate of return to normal of bone mineral density during post-treatment follow-up (Edmonds 1994)./uni00A0We are uncertain about the effect on BMD a/f_ter six months of treatment with GnRHas, compared to GnRHas in conjunction with add-back therapy (Franke 2000)./uni00A0Another study,/uni00A0Howell 1995, reported a "reduction of bone mineral density at the lumbar spine in group 1 (= GnRHas) of -4.1% compared with -2.3% in group 2 (= GnRHas + add-back)". There was for both groups a reduction compared to baseline. /uni00A0A comparison between the two groups has not been made./uni00A0Hornstein 1998/uni00A0compared GnRHas alone (group A), and three different add- back groups (group B: received daily oral norethindrone acetate 5 mg with placebo for oestrogen; group C: received norethindrone 5 mg and conjugated equine oestrogens 0.625 mg; group D: received norethindrone 5 mg and conjugated equine oestrogens 1.25 mg). "All three add-back groups had significantly less bone loss than the agonist-only group at 24- and 52-week measurements (P ≤ 0.001)". This corresponds to/uni00A0the results found by/uni00A0Irahara 2001/uni00A0and/uni00A0Sillem 1999. "The control group (= GnRHas alone) significantly (P < 0.01) decreased BMD of the lumber spine (mean percentage change: –6.3%) a/f_ter six months of treatment; however, add-back therapy prevented this BMD reduction (mean percentage change: –0.8%)" ( Irahara 2001) and "both groups, a significant decrease in lumbar bone mineral density (LBMD) was observed a/f_ter six months of treatment. When compared to baseline values, the mean relative bone loss was 4%, in both groups equally (P < 0.01, 0 months vs. 6 months). Absolute values decreased from 1.28 ± 0.18 g/cm2 (mean ± standard deviation) to 1.23 ± 0.16 g/cm2 in group A and from 1.19 ± 0.11 g/cm2 to 1.14 ± 0.1 g/cm2 in group B. No change in bone mineral density was observed at the femoral neck or Ward's triangle" (Sillem 1999)./uni00A0Moghissi 1998/uni00A0reported that the mean percentage loss was significantly higher in the group without add-back therapy than in either group with once daily doses of 0.3 mg of conjugated oestrogen and 5 mg of medroxyprogesterone acetate, or once daily doses of 0.625 mg of conjugated oestrogen and 5 mg of medroxyprogesterone acetate at week 12 (P < 0.001). Data could not be included in meta-analyses. 12.3 Adverse effects No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies. Eleven studies reported adverse effects when comparing GnRHas with GnRHas in conjunction with add-back therapy (Bergqvist 1997; Edmonds 1994; Franke 2000; Freundl 1998; Hornstein 1998; Howell 1995; Hurst 2000; Kiilholma 1995; Mäkäräinen 1996; Moghissi 1998; Zupi 2005). Only six of them could be included in meta-analysis, namely for assessment of hot flushes, loss of libido, vaginal dryness, headache and vaginal bleeding, all a/f_ter six months of treatment. For hot flushes and vaginal dryness, there may be an improvement in both groups, in favour of GnRHas (RR 1.59, 95% Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 30 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews CI 1.32 to 1.93, I2 = 92%, 4 RCTs, n = 215 (Edmonds 1994; Freundl 1998; Howell 1995; Zupi 2005) and RR 1.40, 95% CI 1.11 to 1.76, I2 = 30%, 3 RCTs, n = 404 (Edmonds 1994; Howell 1995; Moghissi 1998), respectively). "Hot flushes were reported more frequently by the patients receiving goserelin acetate plus placebo than by those receiving HRT. The difference was significant (P < 0.01) a/f_ter 4 weeks of trial medication and highly significant at 6 months (P < 0.0001)" ( Kiilholma 1995 ). In addition,/uni00A0 Hornstein 1998, who compared the GnRHas alone (group A) with three different add- back groups (group B: received daily oral norethindrone acetate 5 mg with placebo for oestrogen; group C: received norethindrone 5 mg and conjugated equine oestrogens 0.625 mg; group D: received norethindrone 5 mg and conjugated equine oestrogens 1.25 mg) stated that "the percentage of patients experiencing hot flashes was dramatically less in the three add-back groups than in group A", a/f_ter 52 weeks of treatment. We are uncertain of the effect found between GnRHas and GnRHas in conjunction with add-back therapy for loss of libido (RR 1.07, 95% CI 0.58 to 1.97, I2 = 89%, 2 RCTs, n = 96,/uni00A0Edmonds 1994; Howell 1995) and headache (RR 0.91, 95% CI 0.67 to 1.24, I2 = 0%, 3 RCTs, n = 126,/uni00A0Edmonds 1994; Freundl 1998; Howell 1995). Vaginal bleeding was seen more commonly in women treated with GnRH in conjunction with add-back therapy (RR 0.57, 95% CI 0.35 to 0.93, I2 = 70%, 3 RCTs, n = 185,/uni00A0Bergqvist 1997; Howell 1995; Zupi 2005)/uni00A0(Analysis 14.4). This is comparable to the results of/uni00A0Mäkäräinen 1996, who stated: "significantly fewer patients in the MPA group (=GnRHas + add-back) had hot flushes and sweating at 3 and 6 months than in the placebo group (=GnRHas alone). Other side effects recorded occurred with similar frequency in both groups". The results mentioned above, are partly in contrast to/uni00A0Hurst 2000, who reported "as expected, hot flush and headache mean scores during time period three are usually lower for the oestradiol group than for the placebo group, although these differences were not statistically significant". Besides these outcome measures, "in the GnRH agonist plus placebo group, the Kupperman index score decreased by 75% at 4 weeks, 129% at 12 weeks, and 113% at 24 weeks (P = 0.0004). The difference between groups at 24 weeks was statistically significant (P = 0.003)" (Franke 2000). The results reported by/uni00A0Surrey 2002/uni00A0could not be extracted for current analyses. 12.4 Quality of life No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies. Quality of life, measured by SF-36, was reported by only one study (Zupi 2005). A/f_ter 12 months of treatment,/uni00A0Zupi 2005/uni00A0reported that there may be a slight difference in the results of the SF-36, in the domains 'physical function' and 'vitality'. /uni00A0Both domains reported better quality of life in women treated with GnRHas in conjunction with add-back therapy. /uni00A0For the other domains, we are uncertain of the effect a/f_ter 12 months of treatment/uni00A0(Analysis 14.5). 12.5 Improvement of most troublesome symptom No studies with overall low risk of bias were identified for this analysis. We performed a sensitivity analysis including all studies./uni00A0Surrey 1992/uni00A0reported results of improvement of overall pain, a/f_ter four weeks of treatment with either GnRHas of GnRHas in conjunction with add-back therapy. There may be a greater improvement in women treated with GnRHas, compared to GnRHas in conjunction with add-back/uni00A0(Analysis 14.6). This is in contrast to/uni00A0Edmonds 1994, which reported no difference in pain scores a/f_ter six months of treatment with GnRHas or with GnRHas in conjunction with add-back therapy. 13. Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents for relief of overall pain associated with endometriosis and its related adverse effects A total of three trials compared GnRHas versus GnRHas in conjunction with calcium-regulating agents (Finkelstein 1998; Finkelstein 1999; Roux 1995). Since/uni00A0Finkelstein 1998/uni00A0reported the same results for BMD as/uni00A0 Finkelstein 1999, only/uni00A0 Finkelstein 1998/uni00A0was included in the analysis on BMD. As this comparison only included one study with a low risk of bias, the results stated below are the results of the sensitivity analysis. 13.1 Bone mineral density Finkelstein 1998/uni00A0reported that there may be a slight decrease in BMD a/f_ter 12 months treatment (MD -7.00 95% CI -7.53 to -6.47, 1 RCT, n = 43) with GnRHas, compared to GnRHas in conjunction with calcium-regulating agents (Analysis 15.1; Analysis 16.1). Roux 1995/uni00A0compared triptorelin alone (group 0) with triptorelin and salmon calcitonin 100 IU daily (group 1) and triptorelin and salmon calcitonin 200 IU daily (group 2). A/f_ter six months of treatment, the mean values (± SD) of BMD (g/cm2) of group 0 were 1.031 ± 0.091, compared to 1.009 ± 0.152 in group 1 and 0.987 ± 0.143 in group 2. 13.2 Adverse effects Finkelstein 1998/uni00A0reported results about adverse effects, but it was not possible to report these outcomes in a meta-analysis. "Mild nausea (P < 0.001) and arthralgias (P = 0.05) were reported more common in the women who received human parathyroid hormone, although only 1 woman reported that these symptoms affected her routine activities". Data of/uni00A0Roux 1995/uni00A0could not be used in the meta-analysis, but "[t]here was no difference in side effects in the three groups (GnRHas combined with placebo (group 0), salmon calcitonin 100 IU daily (group 1) and salmon calcitonin 200 IU daily (group 2)). Nasal symptoms were reported by 12 (31%) patients. Thirty patients (75%) experienced hot flushes, which were attributed to the menopausal status rather than the spray. However, 11 of 40 patients (27.5%) experienced arthralgia, predominantly of the hand joints, including 3 patients with a clinical diagnosis of carpal syndrome and 1 patient with spontaneous knee effusion". 13.3 Improvement of most troublesome symptom We are uncertain about the effect mentioned by/uni00A0Finkelstein 1998/uni00A0related to improvement of the most troublesome symptom, both overall improvement (RR 0.96, 95% CI 0.84 to 1.08, 1 RCT, n = 43) and complete resolution (RR 0.95, 95% CI 0.64 to 1.41, 1 RCT, n = 43), when GnRHas were compared to GnRHas in Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 31 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews conjunction with calcium-regulating agents for a treatment period of 12 months/uni00A0(Analysis 15.2; Analysis 16.2). 14. Trials assessing the effect of GnRHas on BMD Thirty-one trials were included, across the 13 comparisons (Agarwal 1997; Crosignani 1996; Crosignani 2006; Dawood 1995; Dlugi 1990 ; Edmonds 1994; Finkelstein 1998; Finkelstein 1999; Franke 2000; Freundl 1998; Fukushima 1993; Gnoth 1999; Harada 2009; Hornstein 1998; Howell 1995; Irahara 2001; Moghissi 1998 ; Orwoll 1994; Rock 1993; Roux 1995; Schlaff 2006 ; Sillem 1999 ; Surrey 1992; Surrey 2002; Tahara 2000; Tang 2017; Tummon 1988; Vercellini 1996; Wheeler 1992 ; Whitehouse 1990; Zupi 2005). The effects on BMD are reported separately in the relevant comparisons and are also visible in/uni00A0Analysis 4.3 ; Analysis 7.3 ; Analysis 8.2 ; Analysis 10.2 ; Analysis 10.3 ; Analysis 12.5 ; Analysis 14.3 ; Analysis 15.1; Analysis 16.1. D I S C U S S I O N Summary of main results There were no studies found comparing GnRHas with either no treatment or analgesics. Trials comparing GnRHas versus placebo for relief of overall pain associated with endometriosis and its related adverse effects There may be a decrease in reported pelvic pain scores, dysmenorrhoea scores, dyspareunia scores, and pelvic tenderness scores a/f_ter three months of treatment. We are uncertain of the effect of GnRHas compared to placebo for pelvic induration, based on the results found a/f_ter three months of treatment. Additionally, treatment with GnRHas may be associated slightly with a greater incidence of hot flushes at three months of treatment. Trials comparing GnRHas versus danazol for relief of overall pain associated with endometriosis and its related adverse effects For pelvic pain in women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved and completely resolved. These dichotomous data indicated the uncertainty of the effect of GnRHas or danazol for the effectiveness of pelvic tenderness a/f_ter six months of treatment with either GnRHas or danazol. We are uncertain about the effect of GnRHas compared to danazol for relief of overall pain, when a subdivision was made for overall pain, pelvic pain, dysmenorrhoea, dyspareunia, pelvic induration, and pelvic tenderness. For all results, this was a/f_ter three months of treatment. A/f_ter six months of treatment, we are still uncertain about the effect of GnRHas or danazol on overall pain, dysmenorrhoea, dyspareunia, and pelvic tenderness. For pelvic pain and pelvic induration, these complaints may decrease a/f_ter treatment with GnRHas, compared to danazol, during six months of treatment. Trials comparing GnRHas versus intra-uterine progestogens for relief of overall pain associated with endometriosis and its related adverse effects We are uncertain about the effect on VAS scores between groups a/f_ter six months of treatment. Besides, we are also uncertain about the effect of GnRHas compared to intra-uterine progestogens for relief of overall pain a/f_ter six months of treatment. For quality of life, we are uncertain about the effects, measured by the psychological well-being questionnaire index (PGWBI) between groups, a/f_ter six months of treatment. Trials comparing GnRHas versus oral or injectable progestogens for relief of overall pain associated with endometriosis and its related adverse effects There may be an improvement in pelvic pain and dyspareunia a/f_ter three months of treatment, in favour of oral progestogens. We are uncertain about the effects on back pain of both GnRHas and oral progestogens a/f_ter three months of treatment. Additionally, there may be a decrease of vaginal bleeding in women treated with GnRHas, compared to oral progestogens. Also, there may be slightly less weight gain in women treated with GnRHas instead of oral progestogens. We are uncertain about the effect of GnRHas compared to oral progestogens, for headache, a/f_ter three months of treatment. Trials comparing GnRHas versus gestrinone for relief of overall pain associated with endometriosis and its related adverse effects We are uncertain about the effects found for dysmenorrhoea, dyspareunia, and non-menstrual pelvic pain, all measured on NRS and VRS scales. For BMD, there may be a decrease found in favour of GnRHas a/f_ter six and 12 months of treatment with either GnRHas or gestrinone. A/f_ter six months of treatment, there may be an improvement in hot flushes a/f_ter treatment with GnRHas compared to gestrinone. Trials comparing different route of administration of GnRHas for relief of overall pain associated with endometriosis and its related adverse effects We are uncertain about the effect on pelvic pain, dysmenorrhoea, dyspareunia, pelvic induration and pelvic tenderness when comparing buserelin depot 200 /uni03BCg once daily with intranasal buserelin 200 /uni03BCg thrice daily, a/f_ter six months of treatment. When comparing subcutaneously administered buserelin depot 200 /uni03BCg once daily with intranasal buserelin 200 /uni03BCg thrice daily, for hot flushes, vaginal dryness, decreased libido and headaches, we are uncertain about the effects found between the two groups. Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents for relief of overall pain associated with endometriosis and its related adverse effects There may be a slightly bigger decrease in BMD a/f_ter 12 months treatment with GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 32 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews We are uncertain about the effect related to improvement of the most troublesome symptom, both overall improvement and complete resolution, when GnRHas were compared to GnRHas in conjunction with calcium-regulating agents for a treatment period of 12 months. Overall completeness and applicability of evidence Unfortunately, some data are still missing. Despite the attempts made to contact the authors, the missing data could not be included in the review. Nevertheless, it is believed that, due to the large number of patients included (7355 in total), the evidence is comprehensive and has covered a variety of treatment options and outcome measurements. In particular, the comparisons comparing GnRHas with danazol, including 23 studies, and GnRHas compared with GnRHas in conjunction with add-back therapy, including 17 studies, cover a wide number of studies. One issue of concern is the methods of reporting relief of overall pain in the trials. Some trials report overall pain whilst others provide details of specific endometriosis-associated pain such as dysmenorrhoea, dyspareunia, pelvic pain, pelvic induration, and pelvic tenderness. In addition, these outcome measures were requested at many different follow-up periods. This means that a meta-analysis was impossible at times. When it was possible, the analysis contained only a limited amount of studies. In addition, it should be noted that not all hormonal treatment options (e.g. gestrinone and danazol) reported in this review are still common treatment options for women with endometriosis. Since they are still treatment options that might be available, it has been decided to include these comparisons in the current review. Quality of the evidence This was a systematic review of 72 trials including 7355 women. We prepared Summary of findings tables using GRADEpro and Cochrane methods. We judged the evidence for the comparisons included in the main analysis as low quality. This is primarily due to few studies with small sizes reporting each outcome. For the sensitivity analysis, due to poorly reported methods, the quality of evidence reviewed was either very low or low. Overall, the quality of the evidence was very mixed with only six of 72 trials reporting adequate details on all assessed categories, and so the evidence has therefore been declared as having an overall low risk of bias. A total of nine studies were at low risk for selection bias, without having high risk of bias in other domains, and were therefore included in the original analysis. Ten of 72 studies reported high risk of bias on one category, and most of the studies reported unclear risk of bias, due to missing data, mainly for 'selection bias'. A strength of this review is that all the included studies involved premenopausal women with symptoms of endometriosis. The diagnosis of endometriosis was made by direct visualisation (laparoscopically or laparotomically diagnosed endometriosis) or from ultrasonographic imaging/MRI. In this way, an attempt was made to include all women with complaints, with a clear diagnosis of endometriosis. Women without complaints, for example, women with only infertility, were not included. This is especially important for the outcome measures 'relief of overall pain', 'quality of life', 'improvement of most troublesome symptom' and 'patient satisfaction'. Weaknesses of this review are that the included studies were small and many were at unclear of high risk of bias. In addition to the above points, the form of reporting results by some included articles is debatable. Some included articles have described the results for continuous outcome measures (such as pain complaints) as a dichotomous outcome measure (improvement, yes/no). This can cause the results to be interpreted incorrectly and the effects to be underestimated or overestimated. We would therefore recommend that continuous outcomes should not be reported as dichotomous outcomes. /uni00A0This allows for a more careful way of reporting results. Potential biases in the review process The searches for this review included electronic searching by multiple sources and is felt to be comprehensive. At least two review authors independently extracted data and conducted the risk of bias assessment. The publications included spanned over 34 years (from 1988 to 2022) during which time the methods and data reporting practices have changed significantly. Especially for older publications, attempts to contact authors were o/f_ten unsuccessful, resulting in poor scoring in risk of bias assessment due to inadequate information. Inaccessibility to useful information available with these authors, but not included in papers, might have also limited the meta-analysis and especially the Summary of findings tables. Agreements and disagreements with other studies or reviews Other reviews concerning the use of GnRHas in treating endometriosis-associated pain agree with GnRHas being effective in reducing overall pain (Jackson 2006 ; Kalaitzopoulos 2021; Rafique 2017). There are several proposals within reviews and guidelines on the specific duration of treatment available, varying between six and 12 months. This does not completely correlate with the findings of our review, as we as well have found that GnRHas could be effective in reducing pelvic tenderness. However, our evidence is still of very low certainty. Most reviews describe danazol as an effective orally used treatment in reducing endometriosis-associated pain. However, in the current ESHRE, WES and SOGC guidelines, danazol is no longer described as a recommended treatment option because of a high risk of quality of life-reducing side effects. ACOG is the only guideline that still recommends danazol as a treatment option (Kalaitzopoulos 2021). A U T H O R S ' /uni00A0 C O N C L U S I O N S Implications for practice Women who have complaints of endometriosis can be treated in different ways. The current review suggests that, for relief of overall pain, there may be a decrease in favour of treatment with GnRHas compared to placebo or oral or injectable progestogens. We are uncertain about the effects when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. Not all aspects of pain relief are discussed in all the trials and generalisability about the relief of specific aspects of pain may be difficult. This review showed that there may be a slight decrease in BMD when women were treated with GnRHas, compared to gestrinone. There was also a greater decrease of BMD when women were Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 33 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews treated with GnRHas alone, compared to GnRHas in conjunction with calcium-regulating agents. Thus, there may be an increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone. This must be taken into account in the decision-making process together with the patient, as endometriosis is a common disease, with many different treatment options that need to be individualised to the wishes and stage of life of the individual patient. Implications for research Due to the limited number of low-risk studies and the high heterogeneity in the sensitivity analyses, we recommend further research into the effects of GnRHas and other hormonal treatment options on our stated outcome measures. We recommend considering a modern large study with low risk of bias to validate the practice that has become common practice. In addition, it remains important to clearly describe the method in future articles, so that more articles can be labelled as low risk of bias in future reviews. A C K N O W L E D G E M E N T S We thank everyone at Cochrane Gynaecology and Fertility, in particular Marian Showell, Information Specialist, who contributed to the search strategy. We would like to thank Julie Brown, Alice Pan, Roger Hart, Jessica E. Farmer, Andrew Prentice, Andrew Breeze, Gaity Ahmad, Andrew Watson, and Andy Pick for contributing to the previous versions of the review. We would like to thank the following peer reviewers for their valuable comments: Dr Andrew Watson, Consultant Obstetrician and Gynaecologist. Tameside Hospital, Greater Manchester, UK Jack Wilkinson, Centre for Biostatistics, University of Manchester Edgardo Somigliana, Università degli Studi di Milano and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy Angela Beros, Cochrane Gynaecology and Fertility Group. We thank Anne Lethaby for copy-editing the review. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 34 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

/uni00A0

to studies included in this review Abdou 2018 {published data only} */uni00A0 Abdou/uni00A0AM, Ammar/uni00A0IMM, Alenmr/uni00A0AAA, Abdelrhman/uni00A0AA. Dienogest versus leuprolide acetate for recurrent pelvic pain following laparoscopic treatment of endometriosis. Journal of Obstetrics and Gynecology of India Aug 2018;4:306-13. [PMID: DOI: 10.1007/s13224-018-1119-3] Adamson 1994 {published data only} */uni00A0 Adamson/uni00A0GD, Kwei/uni00A0L, Edgren/uni00A0RA. Pain of endometriosis: effects of nafarelin and danazol therapy. International Journal of Fertility & Menopausal Studies 1994;39(4):215-7. Agarwal 1997 {published data only} */uni00A0 Agarwal/uni00A0SK, Hamrang/uni00A0C, Henzl/uni00A0MR, Judd/uni00A0HL. Nafarelin vs. leuprolide acetate depot for endometriosis. Changes in bone mineral density and vasomotor symptoms. Nafarelin Study Group. Journal of Reproductive Medicine 1997;42(7):413-23. AN Zoladex 1996 {published data only} */uni00A0 AN Zoladex. Goserelin depot versus danazol in the treatment of endometriosis the Australian/New Zealand experience. Australian & New Zealand Journal of Obstetrics & Gynaecology 1996;36(1):55-60. Audebert 1997 {published data only} */uni00A0 Audebert/uni00A0A, Lucas/uni00A0C, Joubert-Collin/uni00A0M. Efficacy and safety of slow-release leuprorelin 3,75 mg compared to danazol treatment./uni00A0 [Efficacite et tolerance de la leuproreline 3,75 MG a liberation prolongeedans le traitement de l'endometriose en comparaison au danazol]. References en Gynecologie Obstetrique 1997;5(1):49-57. Bergqvist 1997 {published data only} */uni00A0 Bergqvist/uni00A0A, Jacobson/uni00A0J, Harris/uni00A0S. A double-blind randomized study of the treatment of endometriosis with nafarelin or nafarelin plus norethisterone. Gynecological Endocrinology 1997;11(3):187-94. [DOI: 10.3109/09513599709152533] Bergqvist 1998 {published data only} */uni00A0 Bergqvist/uni00A0A, Bergh/uni00A0T, Hogstrom/uni00A0L, Mattsson/uni00A0S, Nordenskjold/uni00A0F, Rasmussen/uni00A0C. Effects of triptorelin versus placebo on the symptoms of endometriosis. Fertility & Sterility 1998;69(4):702-8. Bergqvist 2000 {published data only} */uni00A0 Bergqvist A and SCANDET group. A comparative study of the acceptability and effect of goserelin and nafarelin on endometriosis. Gynecological Endocrinology Aug 2000;14:425-432. [DOI: https:// doi.org/10.3109/09513590009167714] Burry 1989 {published data only} */uni00A0 Burry/uni00A0KA, Patton/uni00A0PE, Illingworth/uni00A0DR. Metabolic changes during medical treatment of endometriosis: nafarelin acetate versus danazol.. American Journal of Obstetrics & Gynecology 1989;160(6):1454-9; discussion 1459-61. Burry 1992 {published data only} Burry/uni00A0K. Nafarelin in the management of endometriosis: quality of life assessment. American Journal of Obstetrics & Gynecology 1992;166:735-9. */uni00A0 Burry/uni00A0KA, Buttram/uni00A0V, Moghissi/uni00A0KMF. Quality of life during and a/f_ter treatment of endometriosis with Nafarelin or Danazol (abstract). Fertility & Sterility 1990;54(pp.s13):0-029. Chang 1996 {published data only} */uni00A0 Chang/uni00A0SP, Ng/uni00A0HT. A randomized comparative study of the effect of leuprorelin acetate depot and danazol in the treatment of endometriosis. Chung Hua i Hsueh Tsa Chih - Chinese Medical Journal 1996;57(6):431-7. Cheng 2005 {published data only} */uni00A0 Cheng/uni00A0MH, Yu/uni00A0BK, Chang/uni00A0SP, Wang/uni00A0PH. A randomized, parallel, comparative study of the efficacy and safety of nafarelin versus danazol in the treatment of endometriosis in Taiwan. Journal of the Chinese Medical Association 2005;68(7):307-14. Cirkel 1995 {published data only} */uni00A0 Cirkel/uni00A0U, Ochs/uni00A0H, Schneider/uni00A0HP. A randomized, comparative trial of triptorelin depot (D-Trp6-LHRH) and danazol in the treatment of endometriosis. European Journal of Obstetrics, Gynecology, & Reproductive Biology 1995;59(1):61-9. Cirkel/uni00A0U, Ochs/uni00A0H, Schneider/uni00A0HPG. GnRH analogue depot (triptorelin) versus danazol in the treatment of endometriosis. Gynecological Endocrinology (3rd International Symposium) 1993;7(Supp 2):43. Ochs/uni00A0H, Cirkel/uni00A0U, Schneider/uni00A0HP. Correlation between extent of ovarian suppression and regression of endometriosis: decapeptyl vs danazol. Gynecological Endocrinology (3rd International Symposium) 1993;7(Supp 2):43. Crosignani 1996 {published data only} */uni00A0 Crosignani/uni00A0PG, De Cecco/uni00A0L, Gastaldi/uni00A0A, Venturini/uni00A0PL, Oldani/uni00A0S, Vegetti/uni00A0W, et al. Leuprolide in a 3-monthly versus a monthly depot formulation for the treatment of symptomatic endometriosis: a pilot study. Human Reproduction 1996;11(12):2732-5. [DOI: 10.1093/ oxfordjournals.humrep.a019199] Crosignani 2006 {published data only} */uni00A0 Crosignani/uni00A0PG, Luciano/uni00A0A, Ray/uni00A0A, Bergqvist/uni00A0A. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Human Reproduction Sep 2006;21:248-56. [DOI: 10.1093/humrep/ dei290] Dawood 1995 {published data only} */uni00A0 Dawood/uni00A0MY, Ramos/uni00A0J, Khan-Dawood/uni00A0F. Depot leuprolide acetate versus danazol for treatment of pelvic endometriosis: changes in vertebral bone mass and serum estradiol and calcitonin. Fertility & Sterility 1995;63:1177-1183. [DOI: 10.1016/ s0015-0282(16)57593-1] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 35 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Dlugi 1990 {published data only} */uni00A0 Dlugi/uni00A0AM, Miller/uni00A0JD, Knittle/uni00A0J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group. Fertility & Sterility 1990;54(3):419-27. [DOI: 10.1016/s0015-0282(16)53755-8] Dmowski 1989a {published data only} */uni00A0 Dmowski/uni00A0WP, Radwanska/uni00A0E, Binor/uni00A0Z, Tummon/uni00A0I, Pepping/uni00A0P. Ovarian suppression induced with Buserelin or danazol in the management of endometriosis: a randomized, comparative study. Fertility & Sterility 1989;51(3):395-400. [DOI: 10.1016/ s0015-0282(16)60543-5] Edmonds 1994 {published data only} */uni00A0 Edmonds/uni00A0DK, Howell/uni00A0R. Can hormone replacement therapy be used during medical therapy of endometriosis? British Journal of Obstetrics and Gynaecology May 1994;101:24-26. [DOI: 10.1111/j.1471-0528.1994.tb13681.x] Fedele 1989 {published data only} Fedele/uni00A0L, Bianchi/uni00A0S, Arcaini/uni00A0L, Vercellini/uni00A0P, Candiani/uni00A0GB. Buserelin versus danazol in the treatment of endometriosis-associated infertility. American Journal of Obstetrics & Gynecology 1989;161(4):871-6. [DOI: 10.1016/0002-9378(89)90739-4] */uni00A0 Fedele/uni00A0L, Marchini/uni00A0M, Bianchi/uni00A0S, Baglioni/uni00A0A, Zanotti/uni00A0F. Vaginal patterns during danazol and buserelin acetate therapy for endometriosis: structural and ultrastructural study. Fertility & Sterility 1993;59(6):1191-5. Ferreira 2010 {published data only} */uni00A0 Ferreira/uni00A0RA, Vieira/uni00A0C, Rosa-e-Silava/uni00A0J, Rosa-e-Silva/uni00A0A, Nogueira/uni00A0A, Ferriani/uni00A0R. Effects of the levonorgestrel-releasing intrauterine system on cardiovascular risk markers in patients with endometriosis: a comparative study with the GnRH analogue. Contraception 2010;81:117-122. [DOI: 10.1016/ j.contraception.2009.08.003] Finkelstein 1998 {published data only} */uni00A0 Finkelstein/uni00A0JS, Klibanski/uni00A0A, Arnold/uni00A0AL, Toth/uni00A0TL, Hornstein/uni00A0MD, Neer/uni00A0RM. Prevention of estrogen deficiency–related bone loss with human parathyroid hormone–(1-34). Journal of the American Medical Association 1998;280:1067-1073. [DOI: 10.1001/jama.280.12.1067] Finkelstein 1999 {published data only} */uni00A0 Finkelstein/uni00A0JS, Arnold AL/uni00A0. Increases in bone mineral density a/f_ter discontinuation of daily human parathyroid hormone and gonadotropin-releasing hormone analog administration in women with endometriosis. Journal of Clinical Endocrinology & Metabolism 1999;84:1214-1219. [DOI: 10.1210/jcem.84.4.5643] Franke 2000 {published data only} */uni00A0 Franke/uni00A0HR, Van der Weijer/uni00A0PHM, Pennings/uni00A0TMM, Van der Mooren/uni00A0MJ. Gonadotropin-releasing hormone agonist plus “add-back” hormone replacement therapy for treatment of endometriosis: a prospective, randomized, placebo-controlled, double-blind trial. Fertility & Sterility Sept 2000;74:534-539. [DOI: 10.1016/s0015-0282(00)00690-7] Fraser 1991 {published data only} */uni00A0 Fraser/uni00A0IS, Shearman/uni00A0RP, Jansen/uni00A0RP, Sutherland/uni00A0PD. A comparative treatment trial of endometriosis using the gonadotrophin-releasing hormone agonist, nafarelin, and the synthetic steroid, danazol. Australian & New Zealand Journal of Obstetrics & Gynaecology 1991;31(2):158-63. [DOI: 10.1111/ j.1479-828x.1991.tb01807.x] Freundl 1998 {published data only} */uni00A0 Freundl/uni00A0G, Gödtke/uni00A0K, Gnotha/uni00A0C, Godehardt/uni00A0E, Kienle E. Steroidal ‘Add-Back’ Therapy in Patients Treated with GnRH Agonists. Gynecologic and Obstetric Investigation 1998;45:22-30. [DOI: 10.1159/000052848] Fukushima 1993 {published data only} Fukushima/uni00A0M, Shindo/uni00A0M, Sato/uni00A0K. Hormone treatment related bone mineral content changes in Japanese women with endometriosis. Asia-Oceania Journal of Obstetrics and Gynaecology 1993;19(3):299-307. [DOI: 10.1111/ j.1447-0756.1993.tb00389.x] */uni00A0 Fukushima M/uni00A0. Changes in bone mineral content following hormone treatment for endometriosis./uni00A0. International Journal of Gynecology & Obstetrics 1995;50:S17-S21. [DOI: 10.1016/0020-7292(95)02510-j] Gnoth 1999 {published data only} */uni00A0 Gnoth/uni00A0C, Gödtke/uni00A0K, Freundl/uni00A0G, Godehardt/uni00A0E, Kienle/uni00A0E. Effects of add-back therapy on bone mineral density and pyridinium crosslinks in patients with endometriosis treated with gonadotropin-releasing hormone agonists. Gynecologic and Obstetric Investigation 1999;47:37-41. [DOI: 10.1159/000010059] Gomes 2007 {published data only} */uni00A0 Gomes/uni00A0MK, Ferriani/uni00A0RA, Rosa e Silva/uni00A0JC, Japur de Sa Rosa e Silva/uni00A0AC, Vieira/uni00A0CS, Candido dos Reis/uni00A0FJ. The levonorgestrel- releasing intrauterine system and endometriosis staging. Fertility & Sterility 2007;87(5):1231-4. [DOI: 10.1016/ j.fertnstert.2006.11.044] Harada 2009 {published data only} */uni00A0 Harada/uni00A0T, Momoeda/uni00A0M, Taketani/uni00A0Y, Aso/uni00A0T, Fukunaga/uni00A0M, Hagino/uni00A0H, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis—a randomized, double-blind, multicenter, controlled trial. Fertility & Sterility 2009;91(3):675-681. [DOI: 10.1016/j.fertnstert.2007.12.080] Henzl 1988 {published data only} Henzl/uni00A0MR, Corson/uni00A0SL, Moghissi/uni00A0K, Buttram/uni00A0VC, Berqvist/uni00A0C, Jacobson/uni00A0J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. New England Journal of Medicine 1988;318(8):485-9. Henzl/uni00A0MR. Role of nafarelin in the management of endometriosis. Journal of Reproductive Medicine 1989;34(12 Suppl):1021-4. Jacobs/uni00A0L, Field/uni00A0C, Thie/uni00A0J, Coulam/uni00A0C. Treatment of endometriosis with the GnRH agonist naferelin acetate. International Journal of Fertility 1991;36:30-5. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 36 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews */uni00A0 Moghissi/uni00A0KS, Corson/uni00A0SL, Buttram/uni00A0V, Henzl/uni00A0MR. Evaluation of a GnRH agonist (nafarelin) versus danazol for treatment of endometriosis. Contributions to Gynecology & Obstetrics 1987;16:266. Hornstein 1995 {published data only} Hornstein/uni00A0M, Yuzpe/uni00A0A, Burry/uni00A0K, Heinrichs/uni00A0L, Orwoll/uni00A0E. A prospective randomised double-blind trial of 3 versus 6 months nafarelin therapy for symptoms of endometriosis. Fertility & Sterility 1992;58:S84. */uni00A0 Hornstein/uni00A0MD, Yuzpe/uni00A0AA, Burry/uni00A0KA, Heinrichs/uni00A0LR, Buttram VL Jr, et al. Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertility & Sterility 1995;63(5):955-62. [PMID: 7720940] Hornstein 1998 {published data only} */uni00A0 Hornstein/uni00A0MD, Surrey/uni00A0ES, Weisberg/uni00A0GW, Casino LA LUPRON add-back study group. Leuprolide acetate depot and hormonal add-back in endometriosis: A 12- month study. Obstetrics and Gynecology Jan 1998;1:16-24. [DOI: 10.1016/ s0029-7844(97)00620-0] Howell 1995 {published data only} */uni00A0 Howell/uni00A0R, Edmonds/uni00A0DK, Dowsett/uni00A0M, Crook/uni00A0D, Lees/uni00A0B, Stevenson/uni00A0JC. Gonadotropin-releasing hormone analogue (goserelin) plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial. Fertility & Sterility 1995;64(3):474-481. [DOI: 10.1016/ s0015-0282(16)57779-6.] Hurst 2000 {published data only} */uni00A0 Hurst/uni00A0BS, Gardner/uni00A0SC, Tucker/uni00A0KE, Awoniyi/uni00A0CA, Schlaff/uni00A0WD. Delayed oral estradiol combined with leuprolide increases endometriosis-related pain. Journal of the Society of Laparoendoscopic Surgeons 2000;4:97-101. [PMID: PMC3015370] Irahara 2001 {published data only} */uni00A0 Irahara/uni00A0M, /uni00A0Uemura/uni00A0H, Yasui/uni00A0T, Kinoshita/uni00A0H, Yamada/uni00A0M, Tezuka/uni00A0M, et al. Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis. Gynecologic and Obstetric Investigation 2001;52:217-222. [DOI: 10.1159/000052978] Jelley 1986 {published data only} Jelley/uni00A0RY, Magill/uni00A0PJ. The effect of LHRH agonist therapy in the treatment of endometriosis (English experience). Progress in Clinical & Biological Research 1986;225:227-38. */uni00A0 Jelley/uni00A0RY. Multicentre open comparative study of buserelin and danazol in the treatment of endometriosis. British Journal of Clinical Practice 1986;48(Suppl):64-8. Kennedy 1990 {published data only} */uni00A0 Kennedy/uni00A0SH, Williams/uni00A0IA, Brodribb/uni00A0J, Barlow/uni00A0DH, Shaw/uni00A0RW. A comparison of nafarelin acetate and danazol in the treatment of endometriosis. Fertility & Sterility June 1990;53(6):998-1003. [DOI: 10.1016/s0015-0282(16)53574-2] Kiilholma 1995 {published data only} */uni00A0 Kiilholma/uni00A0P, Tuimala/uni00A0R, Kivinen/uni00A0S, Korhonen/uni00A0M, Hagman E. Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis. Fertility & Sterility 1995;64(5):903-908. [DOI: 10.1016/s0015-0282(16)57900-x] Lemay 1988 {published data only} Lemay/uni00A0A, Maheux/uni00A0R, Huot/uni00A0C, Blanchet/uni00A0J, Faure/uni00A0N. Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment of endometriosis. American Journal of Obstetrics & Gynecology 1988;158(2):233-6. [DOI: 10.1016/0002-9378(88)90128-7] */uni00A0 Lemay/uni00A0A, Maheux/uni00A0R, Quesnel/uni00A0G, Bureau M, Faure/uni00A0N, Merat/uni00A0P. LH-RH agonist treatment of endometriosis. Contributions to Gynecology and Obstetrics 1987;16:247-53. Ling 1999 {published data only} */uni00A0 Ling/uni00A0FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic pain study group. Obstetrics & Gynecology 1999;93(1):51-58. [DOI: 10.1016/s0029-7844(98)00341-x] Mäkäräinen 1996 {published data only} */uni00A0 Makarainen/uni00A0L, Rönnberg/uni00A0L, Kauppila/uni00A0A. Medroxyprogesterone acetate supplementation diminishes the hypoestrogenic side effects of gonadotropin-releasing hormone agonist without changing its efficacy in endometriosis. Fertility & Sterility 1996;65(1):29-34. [DOI: 10.1016/s0015-0282(16)58023-6] Miller 2000 {published data only} */uni00A0 Miller/uni00A0JD. Quantification of endometriosis-associated pain and quality of life during the stimulatory phase of gonadotropin-releasing hormone agonist therapy: a double- blind, randomized, placebo-controlled trial. American Journal of Obstetrics & Gynecology 2000;182(6):1483-1488. [DOI: 10.1067/ mob.2000.106846] Minaguchi 1986 {published data only} */uni00A0 Minaguchi/uni00A0H, Uemura/uni00A0T, Shirasu/uni00A0K. Clinical study on finding optimal dose of a potent LHRH agonist (buserelin) for the treatment of endometriosis--multicenter trial in Japan. Progress in Clinical & Biological Research 1986;225:211-25. [PMID: 3097667] Moghissi 1998 {published data only} */uni00A0 Moghissi/uni00A0KS, Schlaff/uni00A0WD, Olive/uni00A0DL, Skinner/uni00A0MA, Yin/uni00A0H. Goserelin acetate (Zoladex) with or without hormone replacement. Therapy for the treatment of endometriosis. Fertility & Sterility June 1998;69(6):1056-1062. [DOI: 10.1016/ s0015-0282(98)00086-7] NEET 1992 {published data only} Kennedy/uni00A0SH, Williams/uni00A0IA, Brodribb/uni00A0J, Barlow/uni00A0DH, Shaw/uni00A0RW. A comparison of nafarelin acetate and danazol in the treatment of endometriosis. Fertility & Sterility 1990;53(6):998-1003. */uni00A0 NEET. Nafarelin for endometriosis: a large-scale, danazol- controlled trial of efficacy and safety, with 1-year follow-up The Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 37 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Nafarelin European Endometriosis Trial Group (NEET)/uni00A0. Fertility & Sterility 1992;57(3):514-22. [PMID: 1531464] Odukoya 1995 {published data only} */uni00A0 Odukoya/uni00A0OA, Bansal/uni00A0A, Wilson/uni00A0AP, Weetman/uni00A0AP, Cooke/uni00A0ID. Serum-soluble CD23 in patients with endometriosis and the effect of treatment with danazol and leuprolide acetate depot injection. Human Reproduction 1995;10(4):942-946. [DOI: 10.1093/oxfordjournals.humrep.a136067] Orwoll 1994 {published data only} */uni00A0 Orwoll/uni00A0ES, Yuzpe/uni00A0AA, Burry/uni00A0KA, Heinrichs/uni00A0L, Buttram/uni00A0VC, /uni00A0Hornstein/uni00A0MD. Nafarelin therapy in endometriosis: long- term effects on bone mineral density. American Journal of Obstetrics and Gynecology Nov 1994;171(5):1221-1225. [DOI: 10.1016/0002-9378(94)90136-8] Ozaki 2020 {published data only} */uni00A0 Ozaki/uni00A0R, /uni00A0Kumakiri/uni00A0J, Jinushi/uni00A0M, Ikuma/uni00A0S, Murakami/uni00A0K, Kawasaki/uni00A0Y, et al. Comparison of effect of preoperative dienogest and gonadotropin‑releasing hormone agonist administration on laparoscopic cystectomy for ovarian endometriomas. Archives of Gynecology and Obstetrics/uni00A0 July 2020;302:969-976. [DOI: 10.1007/s00404-020-05691-3] Palagiano 1994 {published data only} */uni00A0 Palagiano/uni00A0A, Capuano/uni00A0V. Medical treatment of endometriosis: comparative study of leuprolide acetate and danazol. Minerva Ginecologica 1994;46(4):173-7. [PMID: 8065590] Petta 2005 {published data only} Petta/uni00A0CA, Ferriani/uni00A0RA, Abrao/uni00A0MS, Hassan/uni00A0D, Rosa/uni00A0ESJC, Podgaec/uni00A0S, et al. Randomized clinical trial of a levonorgestrel- releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Human Reproduction 2005;20(7):1993-8. [DOI: 10.1093/humrep/deh869] Vieira/uni00A0CS, Ferreira/uni00A0RA, Rosa e Silva/uni00A0JC, Rosa e Silva/uni00A0ACJS, Gomes/uni00A0MK, Ferriani/uni00A0RA. Comparative study of the influence of the levonorgestrel intra-uterine system and the GnRH analogues on cardiovascular risk markers in patients with endometriosis. Fertility & Sterility 2007;88(Suppl 1):211. */uni00A0 de/uni00A0Sa Rosa e Silva/uni00A0AC, Rosa e Silva/uni00A0JC, Nogueira/uni00A0AA, Petta/uni00A0CA, Abrao/uni00A0MS, Ferriani/uni00A0RA. The levonorgestrel-releasing intrauterine device reduces CA-125 serum levels in patients with endometriosis. Fertility & Sterility 2006;86(3):742-4. Rock 1993 {published data only} Allen/uni00A0TW. Zoladex versus danazol in endometriosis therapy. Journal of the American Osteopathic Association 1993;93(10):1013. Rock/uni00A0JA, Truglia/uni00A0JA, Caplan/uni00A0RJ. Zoladex (goserelin acetate implant) in the treatment of endometriosis: a randomized comparison with danazol. Obstetrics & Gynecology 1993;82(2):198-205. [PMID: 8336864] */uni00A0 Rock/uni00A0JA. A multicenter comparison of GnRH agonist (Zoladex) and danazol in the treatment of endometriosis/uni00A0. Fertility & Sterility 1991;56(pp.s49). Rolland 1990 {published data only} */uni00A0 Rolland/uni00A0R, van der/uni00A0Heijden/uni00A0PF. Nafarelin versus danazol in the treatment of endometriosis. American Journal of Obstetrics & Gynecology 1990;162(2):586-8. [DOI: 10.1016/0002-9378(90)90437-c] Rotondi 2002 {published data only} */uni00A0 Rotondi/uni00A0M, Labriola/uni00A0D, Ammaturo/uni00A0FP, Amato/uni00A0G, Carella/uni00A0C, Izzo/uni00A0A, et al. Depot leuprorelin acetate versus danazol in the treatment of infertile women with symptomatic endometriosis. European Journal of Gynaecological Oncology 2002;23(6):523-526. [PMID: 12556096] Roux 1995 {published data only} */uni00A0 Roux/uni00A0C, Pelissier/uni00A0C, Listrat/uni00A0V, Kolta/uni00A0S, Simonetta/uni00A0C, Guignard/uni00A0M, et al. Bone loss during gonadotropin releasing hormone agonist treatment and use of nasal calcitonin. Osteoporosis International 1995;5:185-190. [DOI: 10.1007/BF02106098] Schlaff 2006 {published data only} */uni00A0 Schlaff/uni00A0WD, Carson/uni00A0SA, Luciano/uni00A0A, Ross/uni00A0D, Bergqvist/uni00A0A. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain. Fertility & Sterility February 2006;85(2):314-325. [DOI: 10.1016/j.fertnstert.2005.07.1315.] Shaw 1986 {published data only} */uni00A0 Shaw/uni00A0RW, Matta/uni00A0W. Reversible pituitary ovarian suppression induced by an LHRH agonist in the treatment of endometriosis - comparison of two dose regimens. Clinical Reproduction and Fertility 1986;4(5):329-36. [PMID: 3100012] Shaw 1990 {published data only} */uni00A0 Shaw/uni00A0RW. Nafarelin in the treatment of pelvic pain caused by endometriosis. American Journal of Obstetrics & Gynecology 1990;162(2):574-6. [DOI: 10.1016/0002-9378(90)90433-8] Sillem 1999 {published data only} */uni00A0 Sillem/uni00A0M, Parviz/uni00A0M, Woitge/uni00A0HW, Kiesel/uni00A0L, Ulrich/uni00A0U, von/uni00A0Holst/uni00A0T, et al. Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin. Experimental and Clinical Endocrinology & Diabetes 1999;107:379-385. [DOI: 10.1055/s-0029-1212129] Skrzypulec 2004 {published data only} */uni00A0 Skrzypulec/uni00A0V, Walaszek/uni00A0A, Drosdzol/uni00A0A, Nowosielski/uni00A0K, Piela/uni00A0B, Rozmus-Warcholinska/uni00A0W. Influence of GnRH analogue on the intensification of endometriosis symptoms and infertility treatment. Wiadomosci Lekarskie 2004;57 Suppl 1:301-4. [PMID: 15884262] Strowitzki 2012 {published data only} Strowitzki/uni00A0T, Marr/uni00A0J, Gerlinger/uni00A0C, Faustmann/uni00A0T, Seitz/uni00A0C. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. International Journal of Gynecology and Obstetrics 2012;117(3):228-233. [DOI: 10.1016/j.ijgo.2012.01.009] */uni00A0 Strowitzki/uni00A0T, Marr/uni00A0J, Gerlinger/uni00A0C, Faustmann/uni00A0T, Seitz/uni00A0C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 38 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews multicentre, open-label trial. Human Reproduction January 2010;25(3):633-641. [DOI: 10.1093/humrep/dep46] Surrey 1992 {published data only} */uni00A0 Surrey/uni00A0ES, Judd/uni00A0HL. Reduction of vasomotor symptoms and bone mineral density loss with combined norethindrone and long-acting gonadotropin-releasing hormone agonist therapy of symptomatic endometriosis: A prospective randomized trial. Journal of Clinical Endocrinology and Metabolism 1992;75(2):558-563. [DOI: 10.1210/jcem.75.2.1386374] Surrey 2002 {published data only} */uni00A0 Surrey/uni00A0ES, Hornstein/uni00A0MD. Prolonged GnRH agonist and add- back therapy for symptomatic endometriosis: long-term follow- up. Obstetrics and Gynecology 2002;99(5 Pt 1):709-719. [DOI: 10.1016/s0029-7844(02)01945-2] Tahara 2000 {published data only} */uni00A0 Tahara/uni00A0M, Matsuoka/uni00A0T, Yokoi/uni00A0T, Tasaka/uni00A0K, Kurachi/uni00A0H, Murata/uni00A0Y. Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy ("draw-back" therapy). Fertility & Sterility 2000;73(4):799-804. [DOI: 10.1016/ s0015-0282(99)00636-6] Tang 2017 {published data only} */uni00A0 Tang/uni00A0H, Wu/uni00A0R, Li/uni00A0X, Zhou/uni00A0Y, Liu/uni00A0Z, Wang/uni00A0C, Chen/uni00A0Y, et al. Curative effect of 1.88-mg and 3.75-mg gonadotrophin-releasing hormone agonist on stage III–IV endometriosis: Randomized controlled study. The Journal of Obstetrics and Gynaecology Research October 2017;43(10):1550-1554. [DOI: 10.1111/ jog.13420] Tummon 1988 {published data only} */uni00A0 Tummon/uni00A0IS, Ali/uni00A0A, Pepping/uni00A0ME, Radwanska/uni00A0E, Binor/uni00A0Z, Dmowski/uni00A0WP. Bone mineral density in women with endometriosis before and during ovarian suppression with gonadotropin-releasing hormone agonists or danazol. Fertility & Sterility May 1988;49(5):792-796. [PMID: 3129312] Tummon 1989 {published data only} */uni00A0 Tummon/uni00A0IS, Pepping/uni00A0ME, Binor/uni00A0Z, Radwanska/uni00A0E, Dmowski/uni00A0WP. A randomized, prospective comparison of endocrine changes induced with intranasal leuprolide or danazol for treatment of endometriosis. Fertility & Sterility 1989;51(3):390-4. [DOI: 10.1016/s0015-0282(16)60542-3] Vercellini 1994 {published data only} */uni00A0 Vercellini/uni00A0P, Trespidi/uni00A0L, Panazza/uni00A0S, Bramante/uni00A0T, Mauro/uni00A0F, Crosignani/uni00A0PG. Very low dose danazol for relief of endometriosis-associated pelvic pain: a pilot study. Fertility & Sterility 1994;62(6):1136-42. [PMID: 7525359] Vercellini 1996 {published data only} */uni00A0 Vercellini/uni00A0P, Soma/uni00A0M, Moro/uni00A0GL. Gestrinone versus a gonadotropin-releasing hormone agonist for the treatment of pelvic pain associated with endometriosis: A multicenter, randomized, double-blind study. Fertility & Sterility 196;66(6):911-919. [DOI: 10.1016/s0015-0282(16)58682-8] Wheeler 1992 {published data only} Wheeler/uni00A0JM, Knittle/uni00A0JD, Miller/uni00A0JD. Depot leuprolide acetate versus danazol in the treatment of women with symptomatic endometriosis: a multicenter, double-blind randomized clinical trial. II. Assessment of safety. The Lupron Endometriosis Study Group. American Journal of Obstetrics & Gynecology 1993;169(1):26-33. */uni00A0 Wheeler/uni00A0JM, Knittle/uni00A0JD, Miller/uni00A0JD. Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. American Journal of Obstetrics & Gynecology 1992;167(5):1367-71. [DOI: 10.1016/0002-9378(93)90126-4.] Whitehouse 1990 {published data only} */uni00A0 Whitehouse/uni00A0RW, Adams/uni00A0JE, Bancro/f_t/uni00A0K, Vaughan-Williams/uni00A0CA, Elstein/uni00A0M. The effects of nafarelin and danazol on vertebral trabecular bone mass in patients with endometriosis. Clinical Endocrinology 1990;33(3):365-373. [DOI: 10.1016/ s0015-0282(16)58682-8] Zupi 2005 {published data only} */uni00A0 Zupi/uni00A0E, Sbracia/uni00A0M, Marconi/uni00A0D, Sorrenti/uni00A0G, Zullo/uni00A0F, Palomba/uni00A0S. Role of medical therapy in the treatment of endometriosis associated pelvic pain: a randomized controlled study. Journal of Minimally Invasive Gynecology 2005;12(5):S6. [DOI: 10.3390/ jcm10051085] /uni00A0

to studies excluded from this review Acien 1989 {published data only} */uni00A0 Acien/uni00A0P, Shaw/uni00A0RW, Irvine/uni00A0L, Burford/uni00A0GRG. CA 125 levels in endometriosis patients before, during and a/f_ter treatment with danazol or LHRH agonists. European Journal of Gynaecological Oncology 1989;32(1):241-6. Adiyono 2006 {published data only} */uni00A0 Adiyono/uni00A0W, Adisusianto/uni00A0I. The impact of combination laparoscopic surgery and GNRH analog on quality of life endometriosis patients. In: XVIII FIGO World Congress of Gynecology and Obstetrics. Vol. 2. 5-10 November Kuala Lumpur, Malaysia, 2006:143. Agarwal 2015 {published data only} Agarwal/uni00A0AK, Daniels/uni00A0A, Drosman/uni00A0SR, Udoff/uni00A0L, Foster/uni00A0WG, /uni00A0Pike/uni00A0MC, /uni00A0et al. Treatment of endometriosis with the GnRHa deslorelin and add-back estradiol and supplementary testosterone. BioMed Research International 2015;2015:1-9. [PMID: 10.1155/2015/934164] Al-Azemi 2009 {published data only} */uni00A0 Al-Azemi/uni00A0M, Jones/uni00A0G, Sirkeci/uni00A0F, Walters/uni00A0S, Houdmont/uni00A0M, Ledger/uni00A0W. Immediate and delayed add-back hormonal replacement therapy during ultra long GnRH agonist treatment of chronic cyclical pelvic pain. British Journal of Obstetrics and Gynaecology 2009;116:1646-1656. [DOI: 10.1111/ j.1471-0528.2009.02319.x] Bergqvist 1990 {published data only} */uni00A0 Bergquist C. Effects of nafarelin versus danazol on lipids and calcium metabolism. American Journal of Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 39 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Obstetrics and Gynecology 1990;162(2):589-591. [DOI: 10.1016/0002-9378(90)90438-d] Calvo 2000 {published data only} */uni00A0 Calvo Lugo/uni00A0GE, Sauceda Gonzalez/uni00A0LF, Jimenez Perea/uni00A0ML, Diaz Arias/uni00A0FJ. Treatment of pelvic endometriosis with goserelin acetate or nafarelin acetate. Comparative study. Ginecologia y Obstetricia de Mexico 2000;68:7-14. Chan 1993 {published data only} */uni00A0 Chan/uni00A0CLK, Soon/uni00A0SB, Loh/uni00A0FH. Comparative study of gestrinone, danazol and decapeptyl CR in the treatment of endometriosis. 2nd International Scientific Meeting of the Royal College of Obstetricians 1993:82. Chen 2009 {published data only} */uni00A0 Chen Q-Y, Bian M-L, Qiao/uni00A0J, Zhang Z-Y, Lin J-F, Zuo Y-W. Randomized blind, parallel-controlled and multiple centre clinical trial on the effectiveness and safety of leuprolide acetate in the treatment of endometriosis. Chinese Journal of New Drugs - Zhongguo 2009;18(9):797-801. Choktanasiri 2001 {published data only} */uni00A0 Choktanasiri/uni00A0W, Rojanasakul/uni00A0A. Buserelin acetate implants in the treatment of pain in endometriosis. Journal of the Medical Association of Thailand 2001;84(5):656-60. Claesson 1989 {published data only} */uni00A0 Claesson/uni00A0B, Bergquist/uni00A0C. Clinical experience treating endometriosis with nafarelin. Journal of Reproductive Medicine 1989;34(12 Suppl):1025-1028. [PMID: 2533617] Cooke 1989 {published data only} */uni00A0 Cooke/uni00A0ID, Thomas/uni00A0EJ. The medical treatment of mild endometriosis. Acta Obstetricia et Gynecologica Scandinavica - Supplement 1989;150:27-30. Dawood 1990 {published data only} */uni00A0 Dawood/uni00A0MY. A comparison of the efficacy and safety of buserelin vs danazol in the treatment of endometriosis. Current Concepts in Endometriosis 1990:253-67. Dmowski 1989 {published data only} */uni00A0 Dmowski/uni00A0WP. Comparitive study of buserelin versus danazol in the management of endometriosis. Gynecological Endocrinology 1989;3(Suppl 2):21-31. Dodin 1991 {published data only} */uni00A0 Dodin/uni00A0S, Lemay/uni00A0A, Maheux/uni00A0R, Dumont/uni00A0M, Turcot-Lemay L. Bone mass in endometriosis patients treated with GnRH agonist implant or danazol. Obstetrics and Gynecology 1991;77(3):410-415. [PMID: 1825135] Donnez 1989 {published data only} */uni00A0 Donnez/uni00A0J, Nisolle-Pochet/uni00A0M, Clerckx-Braun/uni00A0F, Sandow/uni00A0J, Casanas-Roux/uni00A0F. Administration of nasal buserelin as compared with subcutaneous buserelin implant for endometriosis. Fertility & Sterility 1989;52(1):27-30. Donnez 2004 {published data only} */uni00A0 Donnez/uni00A0J, Dewart/uni00A0PJ, Hedon/uni00A0B, Perino/uni00A0A, Schindler/uni00A0AE, Blumberg/uni00A0J, et al. Equivalence of the 3-month and 28-day formulations of triptorelin with regard to achievement and maintenance of medical castration in women with endometriosis. Fertility & Sterility 2004;81(2):297-304. Eldred 1992 {published data only} */uni00A0 Eldred/uni00A0JM, Haynes/uni00A0PJ, Thomas/uni00A0EJ. A randomized double blind placebo controlled trial of the effects on bone metabolism of the combination of nafarelin acetate and norethisterone. Clinical Endocrinology 1992;37:354-359. [DOI: 10.1111/ j.1365-2265.1992.tb02338.x] el-Roeiy 1988 {published data only} */uni00A0 el-Roeiy/uni00A0A, Dmowski/uni00A0WP, Gleicher/uni00A0N, Radwanska/uni00A0E, Harlow/uni00A0L, Binor/uni00A0Z, et al. Danazol but not gonadotropin-releasing hormone agonists suppresses autoantibodies in endometriosis. Fertility & Sterility 1988;50(6):864-71. Fedele 1993 {published data only} */uni00A0 Fedele/uni00A0L, Bianchi/uni00A0S, Bocciolone/uni00A0L, Di Nola/uni00A0G, Franchi/uni00A0D. Buserelin acetate in the treatment of pelvic pain associated with minimal and mild endometriosis: a controlled study. Fertility & Sterility 1993;59(3):516-21. Fernandez 2004 {published data only} */uni00A0 Fernandez H, Lucas/uni00A0C, Hédon B , Meyer JL, Mayenga JM and Roux C. One year comparison between two add-back therapies in patients treated with a GnRH agonist for symptomatic endometriosis: a randomized double-blind trial. Human Reproduction April 2004;19:1465-1471. [DOI: 10.1093/humrep/ deh250] Ferrero 2011 {published data only} */uni00A0 Ferrero/uni00A0S, Venturini/uni00A0PL, Gillott/uni00A0DJ, Remorgida/uni00A0V. Letrozole and norethisterone acetate versus letrozole and triptorelin in the treatment of endometriosis related pain symptoms: a randomized controlled trial. Reproductive Biology and Endocrinology 2011;9:1-7. [DOI: 10.1186/1477-7827-9-88] Franssen 1992 {published data only} */uni00A0 Franssen/uni00A0AM, van der/uni00A0Heijden/uni00A0PF, Thomas/uni00A0CM, Doesburg/uni00A0WH, Willemsen/uni00A0WN, Rolland/uni00A0R. On the origin and significance of serum CA-125 concentrations in 97 patients with endometriosis before, during, and a/f_ter buserelin acetate, nafarelin, or danazol. Fertility & Sterility 1992;57(5):974-9. Fraser 1996 {published data only} */uni00A0 Fraser/uni00A0IS, Healy/uni00A0DL, Torode/uni00A0H, Song/uni00A0JY, Mamers/uni00A0P, Wilde/uni00A0F. Depot goserelin and danazol pre-treatment before rollerball endometrial ablation for menorrhagia. Obstetrics & Gynecology 1996;87(4):544-50. Harada 2000 {published data only} */uni00A0 Harada/uni00A0T. Empirical leuprolide treatment of women with suspected endometriosis was effective in reducing chronic pain. Evidence-based Obstetrics and Gynecology 2000;2:45. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 40 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Henzl 1990a {published data only} */uni00A0 Henzl/uni00A0MR, Monroe/uni00A0SE. Nafarelin: a new medical therapy for endometriosis. Progress in Clinical & Biological Research 1990;323:343-55. Imani 2009 {published data only} */uni00A0 Imani/uni00A0R, Thai-Cuarto/uni00A0D, Jimenez/uni00A0R, Burke/uni00A0J, Kroll/uni00A0R, O'Brien/uni00A0C. Petal study: Safety, tolerability and effectiveness of elagolix, an oral GnRH antagonist for endometriosis. In: Fertility & Sterility. Vol. 92. 2009:S111-S112. [DOI: 10.1016/j.fertnstert.2009.07.1100] Lindsay 1996 {published data only} */uni00A0 Lindsay/uni00A0PC, Shaw/uni00A0RW, Bennink/uni00A0HJC, Kicovic/uni00A0P. The effect of add-back treatment with tibolone (Livial) on patients treated with the gonadotropin-releasing hormone agonist triptorelin (decapeptyl). Fertility & Sterility 1996;65(2):342-348. [DOI: 10.1016/s0015-0282(16)58096-0] Luciano 2004 {published data only} */uni00A0 Luciano/uni00A0AA. Leuprolide acetate in the management of endometriosis-associated pain: A multicenter, evaluator- blind, comparative clinical trial. Global Congress of Gynecologic Endoscopy 33rd Annual Meeting of the AAGL "Advancing Minimally Invasive Gynecology Worldwide" 2004;11(Suppl 3):s5. Magini 1993 {published data only} */uni00A0 Magini/uni00A0A, Pellegrini/uni00A0S, Tavella/uni00A0K, Forti/uni00A0G, Massi/uni00A0GB, Serio/uni00A0M. Estrogenic suppression by different administration schedules of goserelin depot for treatment of endometriosis. Journal of Endocrinological Investigation 1993;16(10):775-80. Maouris 1991 {published data only} */uni00A0 Maouris/uni00A0P, Dowsett/uni00A0M, Nichols/uni00A0J, Rose/uni00A0G, Edmonds/uni00A0DK. Pseudomenopause treatment for endometriosis: The endocrine effects of danazol compared with the use of the LH-RH agonist goserelin. Journal of Obstetrics & Gynaecology 1991;11:123-127. [DOI: 10.1016/s0015-0282(16)58023-6] Maouris/uni00A0P, Dowsett/uni00A0M, Rose/uni00A0G, D E. Comparison of the endocrine effects of danazol and the LHRH agonist goserelin (Zoladex) in the treament of endometriosis. Silver Jubilee British Congress of Obstetrics and Gynaecology 1989:61. Matalliotakis 2000 {published data only} */uni00A0 Matalliotakis/uni00A0IM, Neonaki/uni00A0MA, Koumantaki/uni00A0YG, Goumenou/uni00A0AG, Kyriakou/uni00A0DS, Koumantakis/uni00A0EE. A randomized comparison of danazol and leuprolide acetate suppression of serum-soluble CD23 levels in endometriosis. Obstetrics & Gynecology 2000;95(6 Pt 1):810-813. [DOI: 10.1016/s0029-7844(99)00635-3] Matalliotakis 2004 {published data only} */uni00A0 Matalliotakis/uni00A0IM, Arici/uni00A0A, Goumenou/uni00A0AG, Katassos/uni00A0T, Karkavitsas/uni00A0N, Koumantakis/uni00A0EE. Comparison of the effects of leuprorelin acetate and danazol treatments on serum CA-125 levels in women with endometriosis. International Journal of Fertility & Womens Medicine 2004;49(2):75-8. Matta 1988 {published data only} */uni00A0 Matta/uni00A0W, Shaw/uni00A0R. A comparative study between buserelin and danazol in the treatment of endometriosis. The British Journal of Clinical Practice 1988;40(4):69-72. Miller 1990 {published data only} */uni00A0 Miller/uni00A0JD. Leuprolide acetate for the treatment of endometriosis. Progress in Clinical & Biological Research 1990;323:337-41. Mukherjee 1996 {published data only} */uni00A0 Mukherjee/uni00A0T, Barad/uni00A0D, Turk/uni00A0R, Reeman/uni00A0R. A randomized, placebo-controlled study on the effect of cyclic intermittent etidronate therapy on the bone mineral density changes associated with six months of gonadotropin-releasing hormone agonist treatment. American Journal of Obstetrics and Gynecology/uni00A0 1997;175(1):105-109. [DOI: 10.1016/ S0002-9378(96)70258-2] Newton 1996 {published data only} */uni00A0 Newton/uni00A0C, Slota/uni00A0D, Yuzpe/uni00A0AA, Tummon/uni00A0IS. Memory complaints associated with the use of gonadotropin-releasing hormone agonists: a preliminary study. Fertility & Sterility 1996;65(6):1253-5. Pierce 2000 {published data only} */uni00A0 Pierce/uni00A0SJ, Gazvani/uni00A0RM, Farquharson/uni00A0RG. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up. Fertility & Sterility Nov 2000;74(5):964-968. [DOI: 10.1016/s0015-0282(00)01537-5] Ripps 2003 {published data only} */uni00A0 Ripps/uni00A0BA, VanGilder/uni00A0K, Minhas/uni00A0B, Welford/uni00A0M, Mamish/uni00A0Z. Alendronate for the prevention of bone mineral loss during gonadotropin-releasing hormone agonist therapy. The Journal of Reproductive Medicine October 2003/uni00A0;48(10):761-766. [PMID: 14619641] Shaw 1992 {published data only} Shaw/uni00A0RW. A randomised comparative study of the effects of goserelin and danazol for the treatment of endometriosis. Gynecological Endocrinology 1990;4(70 Suppl 2):45. Shaw/uni00A0RW. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Zoladex Endometriosis Study Team. Fertility & Sterility 1992;58(2):265-272. [DOI: 10.1016/ s0015-0282(16)55205-4] */uni00A0 Shaw/uni00A0RW. Goserelin depot: an analog of LHRH for the treatment of endometriosis. Drugs Under Experimental & Clinical Research 1990;16(Suppl):69-75. Shaw 2001 {published data only} */uni00A0 Shaw/uni00A0R, Garry/uni00A0R, McMillan/uni00A0L, Sutton/uni00A0C, Wood/uni00A0S, Harrison/uni00A0R, et al. A prospective randomized open study comparing goserelin (Zoladex) plus surgery and surgery alone in the management of ovarian endometriomas. Gynaecological Endoscopy 2001;10(3):151-7. Somekawa 1999 {published data only} */uni00A0 Somekawa/uni00A0Y, Chigughi/uni00A0M, Harada/uni00A0M, Ishibashi/uni00A0T. Use of vitamin K2 (Menatetrenone) and 1,25- dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 41 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews The Journal of Clinical Endocrinology & Metabolism Aug 1999;84(8):2700-2704. [DOI: 10.1210/jcem.84.8.5920] Sorensen 1997 {published data only} */uni00A0 Sorensen/uni00A0SS, Colov/uni00A0NP, Vejerslev/uni00A0LO. Pre- and postoperative therapy with GnRH agonist for endometrial resection. A prospective, randomized study. Acta Obstetricia et Gynecologica Scandinavica 1997;76(4):340-4. Sowter 1997 {published data only} */uni00A0 Sowter/uni00A0MC, Bidgood/uni00A0K, Richardson/uni00A0JA. A prospective randomized trial of the effect of preoperative endometrial inhibition on the long-term outcome of transcervical endometrial resection. Gynaecological Endoscopy 1997;6(1):33-7. Soysal 2004 {published data only} */uni00A0 Soysal/uni00A0S, Soysal/uni00A0ME, Ozer/uni00A0S, Gul/uni00A0N, Gezgin/uni00A0T. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Human Reproduction 2004;19(1):160-167. [DOI: 10.1093/humrep/ deh035] Surrey 1993 {published data only} */uni00A0 Surrey/uni00A0ES, Fournet/uni00A0N, Voigt/uni00A0B, Judd/uni00A0HL. Effects of sodium etidronate in combination with low-dose norethindrone in patients administered a long-acting GnRH agonist: a preliminary report. Obstetrics & Gynecology 1993;81(4):581-6. Surrey 1995 {published data only} */uni00A0 Surrey/uni00A0ES, Voigt/uni00A0B, Fournet/uni00A0N, Judd/uni00A0HL. Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic endometriosis: the role of cyclic sodium etidronate and low-dose norethindrone "add-back" therapy. Fertility & Sterility 1995;63(4):747-55. Takaesu 2013 {published data only} */uni00A0 Takaesu/uni00A0Y, Nishi/uni00A0H, Kojima/uni00A0J, Sasaki/uni00A0T, Nagamitsu/uni00A0Y, Kato/uni00A0R, et al. Dienogest compared with gonadotropin-releasing hormone agonist a/f_ter conservative surgery for endometriosis. The Journal of Obstetrics and Gynaecology Research Sept 2016;42(9):1152-1158. [DOI: 10.1111/jog.13023] Tapanainen 1993 {published data only} */uni00A0 Tapanainen/uni00A0J, Hovatta/uni00A0O, Juntunen/uni00A0K, Martikainen/uni00A0H, Ratsula/uni00A0K, Tuppala/uni00A0M, et al. Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: a randomized comparative study. Human Reproduction 1993;8(12):2052-5. Taskin 1997 {published data only} */uni00A0 Taskin/uni00A0O, Yalcinoglu/uni00A0AI, Kucuk/uni00A0S, Uryan/uni00A0I, Buhur/uni00A0A, F B. Effectiveness of tibolone on hypoestrogenic symptoms induced by goserelin treatment in patients with endometriosis. Fertility & Sterility 1997;67(1):40-5. Toomey 2003 {published data only} */uni00A0 Toomey/uni00A0C, Krauss/uni00A0B, Hammerschlag/uni00A0R, Burry/uni00A0K. Endometriosis: traditional medicine vs hormone therapy. National Centre for Complementary and Alternative Medicine 2003. Valimaki 1989 {published data only} */uni00A0 Valimaki/uni00A0M, Nilsson/uni00A0CG, Roine/uni00A0R, Ylikorkala/uni00A0O. Comparison between the effects of nafarelin and danazol on serum lipids and lipoproteins in patients with endometriosis. The Journal of Clinical Endocrinology and Metabolism 1989;69(6):1097-103. [DOI: 10.1210/jcem-69-6-1097] Vercellini 2009 {published data only} */uni00A0 Vercellini/uni00A0P, Somigliana/uni00A0E, Vigano/uni00A0P, Abbiati/uni00A0A, Barbara/uni00A0G, Crosignani/uni00A0PG. Endometriosis: current therapies and new pharmacological developments. Drugs 2009;69(6):649-75. Warnock 1998 {published data only} */uni00A0 Warnock/uni00A0JK, Bundren/uni00A0JC, Morris/uni00A0DW. Depressive symptoms associated with gonadotropin-releasing hormone agonists. Depression and Anxiety 1998;7(4):171-7. Wright 1995 {published data only} */uni00A0 Wright/uni00A0S, Valdes/uni00A0CT, Dunn/uni00A0RC, Franklin/uni00A0RR. Short-term lupron or danazol therapy for pelvic endometriosis. Fertility & Sterility 1995;63(3):504-7. [PMID: 7851578] Yee 1986 {published data only} */uni00A0 Yee/uni00A0B. A preliminary report on the comparative use of buserelin (Hoe 766) and danazol in the treatment of endometriosis: the university of Southern California experience. Progress in Clinical & Biological Research 1986;225:175-88. Ylikorkala 1995 {published data only} */uni00A0 Ylikorkala/uni00A0O, Tiitinen/uni00A0A, Hulkko/uni00A0S, Kivinen/uni00A0S, Nummi/uni00A0S. Decrease in symptoms, blood loss and uterine size with nafarelin acetate before abdominal hysterectomy: a placebo- controlled, double-blind study. Human Reproduction 1995;10(6):1470-4. /uni00A0

to studies awaiting assessment Aisaka 2000 {published data only} */uni00A0 Aisaka/uni00A0K, Nakagawa/uni00A0K, Uesato/uni00A0T, Miwa/uni00A0A, Koshino/uni00A0T, Ooka/uni00A0F, et al. Effectiveness of long term GN-RH agonist administration for treatment of endometriosis combined with estrogen- progestogen add back therapy. In: XVI FIGO World Congress of O & G 2000. 2000. [DOI: doi.org/10.1016/S0020-7292(00)82576-X] Archer 2004 {published data only} */uni00A0 Archer/uni00A0DF, Luciano/uni00A0A, Carson/uni00A0S, VilosG /uni00A0. New low dose depot medroxyprogesterone acetate subcutaneous injection is equivalent to leuprolide acetate for endometriosis- associated pain. In: Fertility & Sterility. Oct 2004. [DOI: https:// doi.org/10.1016/j.fertnstert.2004.07.182] Gregoriou 1997 {published data only} */uni00A0 Gregoriou/uni00A0O, Konidaris/uni00A0S, Vitoratos/uni00A0N, Papadias/uni00A0C, Papoulias/uni00A0I, Chryssicopoulos/uni00A0A. Gonadotropin-releasing hormone analoque (leuprolide) plus hormone replacement therapy for the treatment of endometriosis: a randomised controlled trial. Acta Obstetricia et Gynecologica Scandinavica 1997;67:no pagination. [PMID: 9459084] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 42 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Long 2009 {published data only} */uni00A0 Long/uni00A0Q, Zhang S. A randomized clinical trial of GnRHa and add-back therapy in the treatment of endometriosis. In: International Journal of Gynecology and Obstetrics/uni00A0. Vol. 107. 2009:S247. [DOI: 10.1016/S0020-7292] Vella 1995 {published data only} */uni00A0 Vella/uni00A0A, Brincat/uni00A0M, Galea/uni00A0R, Muscat Baron/uni00A0Y. Skin thickness and bone density: effect of add-back therapy in women on GnRh analogue. In: 27th British Congress of Obstetrics and Gynaecology. Vol. 155. 1995. /uni00A0 Additional references Audebert 1998 Audebert/uni00A0A, /uni00A0Descamps/uni00A0P, Marret/uni00A0H, /uni00A0Ory-Lavollee/uni00A0L, Bailleul/uni00A0F, Hamamah/uni00A0S. Pre or post-operative medical treatment with nafarelin in stage III-IV endometriosis: a French multicenter study. European Journal of Obstetrics, Gynecology and Reproductive Biology 1998;79(2):145-48. [DOI: 10.1016/ s0301-2115(98)00028-1] Bafort 2020 Bafort/uni00A0C, Beebeejaun/uni00A0Y, Tomassetti/uni00A0C, Bosteels/uni00A0J, Duffy/uni00A0JMN. Laparoscopic surgery for endometriosis. Cochrane Database of Systematic Reviews 2020, Issue 10. Art. No: CD011031. [DOI: 10.1002/14651858.CD011031] Batt 2007 Batt/uni00A0RE, Smith/uni00A0RA, Buck Louis/uni00A0GM, Martin/uni00A0DC, Chapron/uni00A0C, Koninckx/uni00A0PR, Yeh/uni00A0J. Müllerianosis. Histology & Histopathology 22-10-2007;10:1161-6. Becker 2022 Becker/uni00A0CM, Bokor/uni00A0A, Heikinheimo/uni00A0O, Horne/uni00A0A, Jansen/uni00A0F, Kiesel/uni00A0L, King/uni00A0K, Kvaskoff/uni00A0M, Nap/uni00A0A, /uni00A0Petersen/uni00A0K, Saridogan/uni00A0E, Tomassetti/uni00A0C, van/uni00A0Hanegem/uni00A0N, Vulliemoz/uni00A0N, /uni00A0Vermeulen/uni00A0N, ESHRE Endometriosis Guideline Group. ESHRE guideline: management of women with endometriosis.. Human Reproduction Open 2022;2:1-26. [DOI: 10.1093/hropen/hoac009] Bontis 1997 Bontis/uni00A0JN, Vavilis/uni00A0DT. Etiopathology of endometriosis. Annals of the New York Academy of Sciences 17-06-1997;816:305-9. Brown 2012 Brown/uni00A0J, Kives/uni00A0S, Akhtar/uni00A0M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No: CD002122. [DOI: 10.1002/14651858.CD002122.pub2] Brown 2018 Brown/uni00A0J, Crawford/uni00A0TJ, Datta/uni00A0S, Prentice/uni00A0A. Oral contraceptives for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2018, Issue 5. Art. No: CD001019. [DOI: 10.1002/14651858.CD001019] Burney 2012 Burney/uni00A0RO, /uni00A0Giudice/uni00A0LC. Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility 2012;3:511-9. [DOI: 10.1016/ j.fertnstert.2012.06.029] Chen 2020 Chen/uni00A0I, Veth/uni00A0VB, Choudhry/uni00A0AJ, Murji/uni00A0A, Zakhari/uni00A0A, Black/uni00A0AY, et al. Pre- and postsurgical medical therapy for endometriosis surgery. Cochrane Database of Systematic Reviews 2020, Issue 11. Art. No: CD003678. [DOI: 10.1002/14651858.CD003678.pub3] Darwish 2006 Darwish/uni00A0A, Hassanin/uni00A0MS, Abou Sekkin IA. Epidemiology and risk factors associated with laparoscopicaly diagnosed typical and atypical endometriosis among Egyptian women. Middle East Fertility Society Journal 2006;11:196-201. Duffy 2020 Duffy/uni00A0JMN, Hirsch/uni00A0M, /uni00A0/uni00A0Vercoe/uni00A0M, Abbott/uni00A0J, Barker/uni00A0C, /uni00A0Collura/uni00A0B, et al. A core outcome set for future endometriosis research: an international consensus development study [A core outcome set for future endometriosis research: an international consensus development study]. British Journal of Obstetrics and Gynaecology 2020;127(8):967-74. [DOI: 10.1111/1471-0528.16157] [PMID: 32227676] Eskenazi/uni00A01997 Eskenazi/uni00A0B, Warner/uni00A0ML. Epidemiology of endometriosis. Obstetrics and Gynecology Clinics of North America 1997;24:235-58. [DOI: 10.1016/s0889-8545(05)70302-8 Abstract] [PMID: 9163765] Flower 2012 Flower/uni00A0A, Liu/uni00A0JP, Lewith/uni00A0G, Little/uni00A0P, Li/uni00A0Q. Chinese herbal medicine for endometriosis. Cochrane Database of Systematic Reviews 2012, Issue 5. Art. No: CD006568. [DOI: 10.1002/14651858.CD006568.pub3] Fu 2017 Fu/uni00A0J, Song/uni00A0H, Zhou/uni00A0M, Zhu/uni00A0H, Wang/uni00A0Y, Chen/uni00A0H, Huang/uni00A0W. Progesterone receptor modulators for endometriosis. Cochrane Database of Systematic Reviews 2017, Issue 7. Art. No: CD009881. [DOI: 10.1002/14651858.CD009881.pub2] Guidice 2010 Giudice/uni00A0LC. Clinical practice: endometriosis. New England Journal of Medicine 2010;25:2389-98. [DOI: 10.1056/ NEJMcp1000274] Higgins 2011 Higgins/uni00A0JPT, Altman/uni00A0DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors)./uni00A0Cochrane Handbook for Systematic Reviews of Interventions/uni00A0Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from training.cochrane.org/ handbook. Houda 2014 Houda/uni00A0/uni00A0MR, Grant/uni00A0/uni00A0NH. Gonadotrophin antagonists for pain associated with endometriosis. Cochrane Database of Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 43 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Systematic Reviews 2014, Issue 12. Art. No: CD011446. [DOI: 10.1002/14651858.CD011446] Jackson 2006 Jackson/uni00A0B, Telner/uni00A0DE. Managing the misplaced: approach to endometriosis. Canadian Family Physician/uni00A0 2006;11:1420-1424. [PMID: PMC1783710] Kalaitzopoulos 2021 Kalaitzopoulos/uni00A0DR, Samartzis/uni00A0N, Kolovos/uni00A0GN, Mareti/uni00A0E, Samartzis/uni00A0EP, Eberhard/uni00A0M, Dinas/uni00A0K, Daniilidis/uni00A0A. Treatment of endometriosis: a review with comparison of 8 guidelines. BMC Womens Health 2021;1:397. [DOI: 10.1186/s12905-021-01545-5] Klein 2014 Klein/uni00A0S, D'Hooghe/uni00A0T, /uni00A0Meuleman/uni00A0C, /uni00A0Dirksen/uni00A0C, /uni00A0Dunselman/uni00A0G, /uni00A0Simoens/uni00A0S. What is the societal burden of endometriosis- associated symptoms? a prospective Belgian study. Reproductive Biomedical Online 2013;28(1):116-224. [DOI: 10.1016/j.rbmo.2013.09.020] Lefebvre 2011 Lefebvre/uni00A0C, Manheimer/uni00A0E, Glanville/uni00A0J. Chapter 6: Searching for studies. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. /uni00A0Available from training.cochrane.org/handbook. Levander 1955 Levander/uni00A0G, /uni00A0Normann/uni00A0P. The pathogenesis of endometriosis; an experimental study. Acta Obstetricia et Gynecologica Scandinavica 1955;34(4):366-98. [DOI: 10.3109/00016345509158287] Macer 2012 Macer ML and Taylor/uni00A0HS. Endometriosis and Infertility: A review of the pathogenesis and treatment of endometriosis-associated infertility. Obstetrics and Gynecology Clinics of North America 2013;39(4):535-549. [DOI: 10.1016/j.ogc.2012.10.002] Mahmood 1991 Mahmood/uni00A0TA, Templeton/uni00A0A. Prevalence and genesis of endometriosis. Human Reproduction 1991;6:544-9. [PMID: 1918305] Matthias 1996 Mathias/uni00A0SD, Kuppermann/uni00A0M, /uni00A0Liberman/uni00A0RF, Lipschutz RC/uni00A0, /uni00A0Steege JF/uni00A0. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstetrics and Gynecology 1996;87(3):321-7. [DOI: 10.1016/0029-7844(95)00458-0] Meuleman 2009 Meuleman/uni00A0C, Vandenabeele/uni00A0B, Fieuws/uni00A0S, Spiessend/uni00A0C, Timmermans/uni00A0D, D'Hooghe/uni00A0T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners.. Fertility and Sterility 2009;92(1):68-74. [DOI: 10.1016/ j.fertnstert.2008.04.056] Rafique 2017 Rafique/uni00A0S, Decherney/uni00A0AH. Medical Management of Endometriosis. Clinical Obstetrics and Gynecology 2017;3:485-496. [DOI: 10.1097/GRF.0000000000000292] Robboy 2010 Robboy, S J, & Bean, S M. Pathogenesis of endometriosis. Reproductive Biomedicine Online 01-07-2010;21(1):4-5. Sampson 1940 Sampson/uni00A0JA. The development of the implantation theory for the origin of peritoneal endometriosis. American Journal of Obstetrics and Gynecology October 01, 1940;40(4):549-557. [DOI: 10.1016/S0002-9378(40)91238-8] Schünemann 2021 Schünemann/uni00A0HJ, Higgins/uni00A0JPT, Vist/uni00A0GE, Glasziou/uni00A0P, Akl/uni00A0EA, Skoetz/uni00A0N, Guyatt/uni00A0GH. Chapter 14: Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February/uni00A02021). Cochrane, 2021. Available from www.training.cochrane.org/handbook 2021. Shaw 1991 Shaw/uni00A0RW. GnRH analogues in the treatment of endometriosis -rationale and efficacy. London: Kluwer Academic Publishers, 1991. Simoens 2012 Simoens/uni00A0S, /uni00A0Dunselman/uni00A0G, /uni00A0Dirksen/uni00A0C, /uni00A0Hummelshoj/uni00A0L, /uni00A0Bokor/uni00A0A, /uni00A0Brandes/uni00A0I, /uni00A0et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Human Reproduction 2021;27(5):1292-9. [DOI: 10.1093/ humrep/des073] Stratton 2011 Stratton/uni00A0P, /uni00A0Berkley/uni00A0KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Human Reproduction Update 2011;17(3):327–46. [PMID: https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3072022/] Van der Linden 1997 van der/uni00A0Linden/uni00A0PJ. Theories on the pathogenesis of endometriosis. Human Reproduction 1996;3:53-65. [DOI: 10.1093/humrep/11.suppl_3.53.] Van Hoesel/uni00A02021 Van Hoesel/uni00A0MH, Chen/uni00A0YL, Zheng/uni00A0A, Wan/uni00A0Q, Mourad/uni00A0SM. Selective oestrogen receptor modulators (SERMs) for endometriosis. Cochrane Database of Systematic Reviews 2021, Issue 5. Art. No: CD011169. [DOI: 10.1002/14651858.CD011169.pub2] Vercellini 2014 Vercellini/uni00A0P, Viganò/uni00A0P, Somigliana/uni00A0E, Fedele/uni00A0L. Endometriosis: pathogenesis and treatment. Nature Reviews, Endocrinology 2014;5:261-75. [DOI: 10.1038/nrendo.2013.255] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 44 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Vigano 2018 Vigano/uni00A0P, /uni00A0Candiani/uni00A0M, /uni00A0Monno/uni00A0A, /uni00A0Giacomini/uni00A0E, /uni00A0Vercellini/uni00A0P, Somigliana/uni00A0E. Time to redefine endometriosis including its pro-fibrotic nature. Human Reproduction 2018;1(33(3)):347-52. [PMID: https://pubmed.ncbi.nlm.nih.gov/29206943/] Viganò 2004 Viganò/uni00A0P, Parazzini/uni00A0F, Somigliana/uni00A0E, Vercellini/uni00A0P, . Endometriosis: epidemiology and aetiological factors. Best Practice & Research Clinical Obstetrics & Gynaecology 2004;18(2):177-200. [DOI: 10.1016/j.bpobgyn.2004.01.007] Wheeler 1989 Wheeler/uni00A0JM. Epidemiology of endometriosis-associated infertility. Journal of Reproductive Medicine 1989;34:41-6. [PMID: 2704007] Whitehouse 1990 Whitehouse/uni00A0RW, Adams/uni00A0JE, Bancro/f_t/uni00A0K, Vaughan-Williams/uni00A0CA, Elstein/uni00A0M. The effects of nafarelin and danazol on vertebral trabecular bone mass in patients with endometriosis.. Clinical Endocrinology 1990;3(33):365-73. [PMID: MEDLINE: 91070821] Ylikorkala 1990 Ylikorkala/uni00A0O, Nilsson/uni00A0G, Hirvonen/uni00A0E, Viinikka/uni00A0L. Evidence of similar increases in bone turnover during nafarelin and danazol use in women with endometriosis. Gynaecological Endocrinology 1990;4(4):251-60. [PMID: MEDLINE: 91188927] Zhu 2011 Zhu/uni00A0X, Hamilton/uni00A0KD, McNicol/uni00A0ED. Acupuncture for pain in endometriosis. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No: CD007864. [DOI: 10.1002/14651858.CD007864.pub2] Zondervan 2020 Zondervan/uni00A0KT, Becker/uni00A0CM, Missmer/uni00A0SA. Endometriosis. New England Journal of Medicine 2020 Mar 26;382(13):1244-1256. [DOI: 10.1056/NEJMra1810764] /uni00A0

to other published versions of this review Brown 2010 Brown/uni00A0J, Pan/uni00A0A, Hart/uni00A0RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No: CD008475. [DOI: 10.1002/14651858.CD008475.pub2] Farmer 2003 Farmer/uni00A0JE, Prentice/uni00A0A, Breeze/uni00A0A. Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No: CD001297. [DOI: 10.1002/14651858.CD001297] /uni00A0 * Indicates the major publication for the study /uni00A0 C 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 Characteristics of included studies [ordered by study ID] /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 261 women were randomised; 142 women were analysed. Mean age: Dienogest 29.52 +- 3.32 vs leuprolide 29.77 +- 3.09 Inclusion criteria: • Laparoscopically diagnosed endometriosis within 3 months (diagnostic laparoscopy) or within 12 months (therapeutic laparoscopy) of enrolment into the study • Subsequent recurrence of pain Exclusion criteria:/uni00A0 • Pregnancy • Breastfeeding • Amenorrhea within 3 months of enrolment • Previous use of hormonal agents (e.g. GnRH agonists, progestins, danazol or oral contraceptives) fol- lowing laparoscopy • Undiagnosed genital bleeding • History of severe adverse drug reactions or hypersensitivity to steroid hormones or GnRH agonists • History of thrombosis/embolism or depression • Patients at risk of decreased bone mineral density (BMD) Abdou 2018/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 45 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Setting: Egypt Timing: May 2014-December 2016 Interventions Dienogest 2 mg /uni00A0orally once daily for 12 weeks with the first tablet taken on the first day after onset of menstrual bleeding versus Leuproline acetate depot 3.75 mg IM every 4 weeks for 12 weeks with the first injection given during the first 3 days of menstrual bleeding Outcomes • Relief of overall pain: pelvic pain, back pain, dyspareunia • Adverse effects • Mean size of endometrioma Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: no funding Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Patients were divided randomly by using random number table (computer) in- to two groups (A and B). Allocation concealment (selection bias) Low risk Software Open Epi version 3.21 was used. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk 284 patients met requirements of inclusion criteria, out of which 261 patients were willing to participate in the study and consented for participation. Patients who dropped out from follow-up were excluded from the study statis- tics and results (9 patients from group A and 10 patients from group B). Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected. Abdou 2018/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Prospective randomised double-blind controlled study Adamson 1994/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 46 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Participants Participants: 213 patients. 124 patients were randomised who reported pain symptoms. Mean age: not stated Inclusion: • Aged 18 to 48 years with laparoscopically confirmed pelvic endometriosis and dysmenorrhoea, dys- pareunia or pelvic pain Exclusion:/uni00A0 • No surgical procedures were performed during the diagnostic laparoscopy. • No patient who had received hormonal treatment during the previous 6 months Setting: United States of America Timing: not stated Interventions Nafarelin acetate 400 mcg twice daily intranasaly + placebo per os or 6 months (n = 45)/uni00A0 versus/uni00A0 Nafarelin acetate 200 mcg twice daily intranasaly + placebo per os for 6 months (n = 45)/uni00A0 versus/uni00A0 Danazol 400 mg twice daily per os + placebo intranasaly for 6 months (n = 34) Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain Notes Intention-to-treat analysis: yes Sample size calculation: not stated Funding: not stated Note previous version: Authors responded to methods query. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Computerised randomisation". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Low risk "Centralised randomisation, sequentially numbered, sealed opaque en- velopes". Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk All women randomised were analysed with intention-to-treat for main out- come./uni00A0 Adamson 1994/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 47 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Adamson 1994/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Multicentre, randomised, double-blind, double-placebo study" Participants Participants: 208 women were randomised; 192 were analysed. Mean age: Nafarelin = 29.8 ± 0.6 and LA = 31.7 ± 0.6 (SEM) Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis within 18 months prior to study • 19-44 years old • Patients demonstrating clinical symptoms and signs • Bone mineral density within normal age range Exclusion criteria:/uni00A0 • Conditions or drug therapies that may interfere with the study • Pregnant or lactating women • Danazol use within 6 months prior to study • GnRHa use within 12 months prior to study • OCP within 30 days prior to study treatment • Thyroid disease Setting: United States of America/uni00A0 Timing: not stated Interventions Nafarelin 200 mcg twice daily intranasally + placebo every 4 weeks IM for 6 months (n = 105)/uni00A0 versus/uni00A0 Leuprolide acetate depot 3.75 mg every 4 weeks IM + placebo twice daily intranasally for 6 months (n = 103) Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration • Bone mineral density • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Agarwal 1997/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 48 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Random sequence genera- tion (selection bias) Unclear risk "Randomisation using permuted blocks of random numbers". No further de- tails of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details were provided of method used to conceal allocation to treatment groups. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk Details for attrition: 24 women withdrew due to: • Ineffectiveness 3 (nafarelin) and 3 (leuprolide acetate) • Adverse effects 4 (nafarelin) and 8 (leuprolide acetate) • Lost to follow-up 5 (leuprolide acetate) • Administrative reasons 1 (leuprolide acetate) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified./uni00A0 Other bias Low risk No other risk of bias detected Agarwal 1997/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Multicentre, open, randomised study" Participants Participants: 71 women were randomised; 48 were analysed. Group A: patients with/uni00A0infertility associated with endometriosis and who desired pregnancy Group B: other patients (those with symptomatic endometriosis but not desiring pregnancy at time of the study) Mean age: Goserelin = 29.5 and danazol = 29.85 Group A: Mean age: Goserelin = 29.7 (24-36) and danazol = 29.9 (21-35) Inclusion criteria: • Laparoscopically diagnosed endometriosis within 2 months prior to study • 18-40 years old • rAFS score of equal or greater to 2 • Normal menstrual cycle (21-42 days) • Normal cervical smear for previous 12 months Exclusion criteria: • Pregnant or lactating women • Other medical illnesses • Hormone use within 2 months prior to study AN Zoladex 1996/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 49 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Danazol or GnRHas use within 12 months prior to study • Hypersensitivity to trial drugs • Showing signs of virilisation • Taking anticoagulant therapy • Surgical treatment Setting: Australia and New Zealand (9 centres) Timing: Not stated Interventions Goserelin acetate 3.6 mg every 4 weeks SC for 24 weeks (n = 35)/uni00A0 versus/uni00A0 Danazol 200 mg three times a day PO for 24 weeks (n = 36) Outcomes • Adverse effects • Improvement of most troublesome symptoms: dysmenorrhoea, dyspareunia, pelvic pain, pelvic ten- derness, induration • Pregnancies • rAFS score • Laboratory data Notes Intention-to-treat analysis: yes, analysis was performed on both an 'intention-to-treat' basis and also on a 'patient-treated' basis. /uni00A0 Sample size calculation: not stated Funding: /uni00A0Authors received a grant of ICI Pharmaceuticals Australia and received the supply of goserelin acetate./uni00A0 Note previous version: Authors contacted regarding methods and data; awaiting response. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Patients were randomised in a 1 to 1 ratio". No further details of method used to generate the randomisation sequence were provided./uni00A0 /uni00A0 Allocation concealment (selection bias) Unclear risk No details were provided of method used to conceal allocation to treatment groups./uni00A0 /uni00A0 Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes High risk "Analysis was performed on both an 'intention-to-treat' basis and also on a 'patient-treated' basis"./uni00A0 AN Zoladex 1996/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 50 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Details given for attrition: 19 in danazol and 4 in goserelin group withdrew due to: adverse effects 9 (Dan), unwilling to continue 8 (Dan) and 4 (Gos), with- drawn by investigator 1 (Dan), other 1 (Dan) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected AN Zoladex 1996/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Open, multi-centre, central randomised study Participants Participants: 120 eligible women; 71 were randomised; 55 were analysed/uni00A0 Mean age: 31 ± 5.9 years/uni00A0 Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis • Symptomatic • Recurrence of endometriosis after surgery • Over 18 years old • No other hormone therapy except insulin Exclusion criteria:/uni00A0 • Amenorrhoea • Patient having had hysterectomy • Pregnant women • Serious illness e.g. liver disease Setting: France/uni00A0 Timing: January 1989 to February 1991 Interventions Leuprorelin 3.75 mg SC depot every 28 days for 24 weeks (n = 33)/uni00A0 versus/uni00A0 Danazol 600-800 mg PO daily for 24 weeks (n = 22) Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, induration and pelvic tenderness • rAFS score • Adverse effects Notes Intention-to-treat analysis: yes Sample size calculation: not stated Funding: not stated Note previous version: Could not use data unless mean and SD specified; author contacted. Author replied that study was sponsored by a pharmaceutical company who hold the raw data. He is attempt- ing to locate a contact for further information. Audebert 1997/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 51 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Central randomisation". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk Open-label study. No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No mention of blinding of outcome assessors Incomplete outcome data (attrition bias) All outcomes Low risk Sufficient reporting of attrition:/uni00A0 • Refused 2nd laparoscopy n = 1 (leuprolide acetate) • Lost to follow-up n = 2 (leuprolide acetate) and n = 9 (danazol) • Progression of disease n = 2 (danazol) • Not meeting protocol n = 1 (danazol) • Other n = 1 (danazol) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Audebert 1997/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Double-blind randomised study" Participants Participants: 49 eligible women; 49 were randomised and 47 were analysed/uni00A0 Mean age: mean age not stated, median age 30 years (range 21-46years)/uni00A0 Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis • Not to use any hormonal preparations during study • No hormone treatment in previous 3 months • No GnRHas for previous 12 months • No steroid therapy for previous 12 months Exclusion criteria: not stated Setting: Europe/uni00A0 Timing: not stated Bergqvist 1997/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 52 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Interventions Nafarelin 200 mcg daily IN + placebo PO for 6 months (n = 12)/uni00A0 versus/uni00A0 Nafarelin 400 mcg daily IN + placebo PO for 6 months (n = 12)/uni00A0 versus/uni00A0 Nafarelin 200 mcg daily IN + norethisterone 1.2 mg daily PO for 6 months (n = 25) Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration • Adverse effects • AFS score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Need raw data for symptom scores. Authors contacted regarding methods and data. No response to date Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "randomisation was carried out on a block basis". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blinded, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blinded, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk Two participants (2/25) from the nafareline + norethisterone group withdrew from the trial due to mood swings (1 participant) and pregnancy (1 partici- pant). Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Bergqvist 1997/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Prospective, randomised, placebo-controlled, double-blind, parallel study" /uni00A0 Bergqvist 1998/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 53 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Participants Participants: 49 women eligible; 49 were randomised and 46 were analysed Age: mean of 31 years (19-44years) Stage: most mild-to-moderate (IV n = 1) Inclusion criteria: • Menstruating regularly 3 months before study • Clinical symptoms of endometriosis • Not taken oral contraceptive or oral steroid therapy for 3 months • Not taken long-acting depot gestagens or GnRHas within past 6 months • Not pregnant in prior 3 months • Not breastfeeding • No history of osteoporosis or coagulation disorders Exclusion criteria: • Intraperitoneal adhesions making visual inspection and careful evaluation of the extension of en- dometriotic lesions difficult or impossible Setting: Sweden Timing: Not stated Interventions Triptorelin 3.75 mg IM depot every 4 weeks for 24 weeks (n = 24) versus Placebo IM every 4 weeks for 24 weeks (n = 25) /uni00A0 Outcomes • Relief of overall pain • Adverse effects • Visible endometriosis extension • rAFS • Frequency and amount of bleeding • Serum concentrations of estradiol Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Needs raw score for pain. Authors contacted and awaiting response /uni00A0 Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk No details were provided of method used to generate the randomisation se- quence./uni00A0 Allocation concealment (selection bias) Unclear risk No details were provided of method used to conceal treatment group alloca- tion./uni00A0 Blinding of participants and personnel (perfor- mance bias) Low risk Participants and researchers were blinded through the use of identical kits for injections. Bergqvist 1998/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 54 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews All outcomes Blinding of outcome as- sessment (detection bias) All outcomes Low risk Participants and researchers were blinded through the use of identical kits for injections. Incomplete outcome data (attrition bias) All outcomes Low risk Three participants withdrew from the study. Two from the placebo group (1 prior to the first injection due to pregnancy, and one after 4 months due to lack of effect), and one from the triptorelin group due to hypoestrogenic side ef- fects and depression. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Bergqvist 1998/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 252 women were randomised; 224 were analysed. Mean age: 18-45 years (median 31 years) Inclusion criteria: • Regular menstruating • Not been on sex hormones (including oral contraceptives) within 2 months of treatment • Not received GnRH agonist therapy within the previous 6 months and not for more than 3 months altogether • Not pregnant or breastfeeding Exclusion criteria: • Women with serious renal, hepatic, hematopoietic or endocrine disease, or with allergic rhinitis Setting: Scandinavia (28 centres = 7 centres in Sweden, 8 centres in Norway, 6 centres in Denmark and 7 centres in Finland) Timing: not stated Interventions Goserelin depot, 3.6 mg, administered subcutaneously into the anterior abdominal wall every 28 ±3 days (Zoladex; AstraZeneca) (n = 130)/uni00A0 versus/uni00A0 Nafarelin 200 /uni03BCg nasally twice daily, giving a total daily dose of 400 /uni03BCg (Synarel; Syntex) (n = 122) Outcomes • Overall relief of pain (pelvic symptoms) • Adverse effects • Menstrual details • Extent of endometriosis (rAFS, ADI scores) • Haematological parameters: follicle-stimulation hormone (FSH), luteinising hormone (LH), oestradi- ol, creatinine, urea, sodium and potassium in plasma Notes Intention-to-treat analysis: not stated Bergqvist 2000/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 55 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Sample size calculation: not stated Funding: The study was supported by AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TF, UK. /uni00A0 Authors contacted regarding methods and data. Awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk Randomisation was being performed within each centre. No further details were provided of method used to generate the randomisation sequence./uni00A0 Allocation concealment (selection bias) Unclear risk No details were provided of method used to conceal treatment group alloca- tion. /uni00A0 Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk Altogether, 39 women withdrew from the study, four of whom commenced any therapy, two because they changed their minds and two because they became pregnant between the date of randomisation and the planned date of starting the trial medication. Twenty-four patients withdrew during the active treat- ment period, adverse events being the most common reason. Sixteen women, nine in the goserelin group and seven in the nafarelin group, withdrew owing to adverse events, two women in the nafarelin group, withdrew because of lo- cal side effects of the treatment such as nasal irritation, one woman because of a worsening of symptoms and five for other reasons./uni00A0 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Bergqvist 2000/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Parallel, double-blind, double-dummy randomised trial Participants Participants: 53 women were randomised; 51 were analysed. Mean age: 23-38 years Inclusion criteria:/uni00A0 • Endometriosis diagnosis made laparoscopically within 3 months preceding the study Exclusion criteria:/uni00A0 Burry 1989/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 56 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Medical therapy for endometriosis within the preceding 6 months Setting: United States of America Timing: Not stated Interventions Group I: danazol, 800 mg/day (400 mg twice daily) (n = 10)/uni00A0 Group II: danazol, 600 mg/day (200 mg three times a day) (n = 8) Group III: intranasal nafarelin, 800 /uni03BCg/day (400 /uni03BCg twice a day) (n = 10) Group IV: intranasal nafarelin, 400 /uni03BCg/day (200 /uni03BCg two times a day) (n = 25) Outcomes • Change in symptoms (pelvic pain and vaginal bleeding) • Adverse effects • Plasma lipids • Stage of endometriosis • Pregnancy Notes Intention-to-treat analysis: No Sample size calculation: not stated Funding: not stated Included in this review, but did not contribute any data Not possible to contact leading author; unfortunately had passed away. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk 'Randomly allocated'. No further details were provided of method used to gen- erate the randomisation sequence./uni00A0 Allocation concealment (selection bias) Unclear risk No details were provided of method used to conceal treatment group alloca- tion. /uni00A0 Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk The study had a parallel, double-blind, double-dummy design. Blinding of outcome as- sessment (detection bias) All outcomes Low risk The study had a parallel, double-blind, double-dummy design. Incomplete outcome data (attrition bias) All outcomes Low risk Group I: Danazol, 800 mg/day (400 mg twice a day): Nine of the 10 patients in- cluded in this group completed the study; one withdrew because of severe headaches. Group II: Danazol, 600 mg/day (200 mg three times a day). All eight patients completed the study. Group III: Nafarelin acetate, 800 /uni03BCg/day (400 /uni03BCg twice a day). Nine of 10 pa- tients included in this group completed the study: one withdrew because of mood swings. Burry 1989/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 57 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Group IV: Nafarelin acetate, 400 /uni03BCg/day (200 /uni03BCg twice a day). All 25 patients in- cluded in this group completed the study. Selective reporting (re- porting bias) High risk Change in symptoms was asked for, but not reported in published article./uni00A0 Other bias Low risk No other risk of bias detected Burry 1989/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Multi-centre, double-blind study" Participants Participants: 169 women eligible; 169 were randomised and 147 analysed for efficacy. Mean age: not stated Inclusion criteria: • Laparoscopically diagnosed endometriosis Exclusion criteria: not stated Setting: United States of America Timing: not stated Interventions Nafarelin 400 /uni03BCg daily IN for 6 months (n = 111) versus Danazol 600 mg daily PO for 6 months (n = 58) Outcomes • Adverse effects • Quality of life score • Improvement of most troublesome symptom • Change in laparoscopic scores Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Need more info on randomisation and participants and raw data for quality of life. Authors contacted, awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk The randomisation procedure assigned two of every three patients to receive nafarelin, 400 /uni03BCg daily (n = 111), and one of three patients to danazol, 600 mg daily (n = 58). No further details were provid- ed of method used to generate the randomisation sequence./uni00A0 Allocation concealment (selection bias) Unclear risk No details were provided of method used to conceal treatment group alloca- tion. /uni00A0 Burry 1992/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 58 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk The study was "double-blind". No further details were provided on the method of blinding. Blinding of outcome as- sessment (detection bias) All outcomes Low risk The study was "double-blind". No further details were provided on the method of blinding. Incomplete outcome data (attrition bias) All outcomes Low risk Sufficient details for attrition: • Side effects n = 6 (N) n = 3 (D) • Elevated liver enzyme n = 1 (D) • Administrative reasons n = 12 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Burry 1992/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Randomised comparative study" Participants Participants: 45 women eligible; 45 were randomised and 33 were analysed. Mean age: 33 years (LA)/uni00A0 Inclusion criteria:/uni00A0 • Laparoscopic diagnosis of endometriosis • Pain symptoms Exclusion criteria:/uni00A0 Setting: Taiwan/uni00A0 Timing: not stated Interventions Leuprorelin acetate 3.75 mg SC depot every 28 days for 20 weeks (n = 30)/uni00A0 versus/uni00A0 Danazol 200 mg QID (800 mg/day) PO for 20 weeks (n = 15) Outcomes • Dysmenorrhoea, dyspareunia, pelvic pain • Adverse effects • Change in AFS score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Chang 1996/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 59 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Note previous version: Need raw data for pain. Authors contacted, and additional methodological data provided, no raw data Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomisation was in the ratio two LA to one danazol with this study having its randomisation list". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Low risk "sequentially numbered, identical containers of identical drugs". No further details were provided of method used to conceal allocation to treatment groups. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Low risk Outcome assessors were blinded to treatment group. Incomplete outcome data (attrition bias) All outcomes Unclear risk No details were provided on attrition. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Chang 1996/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Randomised, parallel, comparative study"/uni00A0 Participants Participants: 59 women eligible; 59 were randomised and 41 were analysed for efficacy. Mean age: 34.8 ± 6.6 (nafarelin) and 32.4 ± 7.2 (danazol) Inclusion criteria: • Laparoscopically diagnosed within 3 months prior to study • Age 18-48 years • Barrier contraception Exclusion criteria: • Pregnancy • Breastfeeding • Menopause or postmenopausal • Use of oestrogen, progesterone or contraceptive steroids in previous 3 months • Impaired hepatic or renal function • Cardiovascular disease Cheng 2005/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 60 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • AIDS or other sexually transmitted diseases Setting: Taiwan Timing: started in January 1998 and ended in October 2000 Interventions Nafarelin acetate 200 /uni03BCg twice daily (400 /uni03BCg/day) IN for 180 days (n = 29) versus Danazol 200 mg (600 mg/day) PO for 180 days (n = 30) Outcomes • Total symptom severity score and physician-assessed pelvic tenderness • Change in laparoscopic score • Adverse effects • Serum lipid levels • Haematology and liver function Notes Intention-to-treat analysis: yes Sample size calculation: not stated Funding: This study was partly supported by a grant (VGH94- 195) from Taipei Veterans General Hospi- tal, Taipei, Taiwan, R.O.C. Note previous version: Authors provided additional data on methods. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Randomisation done by a pharmacy. Authors provided additional data to pre- vious authors, and therefore this study was assigned as having low risk of bias. Allocation concealment (selection bias) Low risk Sealed, opaque, sequentially numbered, identical envelopes Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Investigators, outcome assessors and clinicians were blinded according to au- thor. Blinding of outcome as- sessment (detection bias) All outcomes Low risk Investigators, outcome assessors and clinicians were blinded according to au- thor. Incomplete outcome data (attrition bias) All outcomes Low risk "All 59 patients were considered as the intent-to-treat population". Forty-one of 59 patients (22/29 nafarelin and 19/30 danazol recipients) who completed 90 days’ treatment, and who underwent laparoscopic examina- tions before and after treatment, qualified for the efficacy evaluation. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Cheng 2005/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 61 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Study characteristics

Trial design: "randomised controlled comparative clinical study" Participants Participants: 60 women eligible; 60 were randomised and 55 were analysed. Mean age: 30 ± 0.5 (triptorelin depot) and 30 ± 0.8 (danazol) Inclusion criteria: • Laparoscopically diagnosed endometriosis • Premenopausal • No medication affecting pituitary or ovarian function in preceding 6 months Exclusion criteria: • Stage I endometriosis Setting: Germany Timing: February 1989 and December 1990 Interventions Triptorelin 3.75 mg IM depot every 28 days for 24 weeks (n = 30) versus Danazol 200 mg three times a day (600 mg/day) PO for 24 weeks (n = 25) /uni00A0 Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration • Adverse effects • Change in AFS score • Endocrine effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Authors contacted and awaiting response regarding methods Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Patients were allocated to a computer-generated randomisation list. Allocation concealment (selection bias) Unclear risk No further details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk Open-label trial as blinding of study personnel and participants would not have been possible due to nature of the intervention. Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Cirkel 1995/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 62 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Incomplete outcome data (attrition bias) All outcomes High risk Five women assigned to danazol could not be included further: three patients refused to fulfill the protocol after randomisation and two others conceived spontaneously before starting medication. Twenty-four weeks after the end of endocrine therapy, 20 women (12/30 in the triptorelin and 8/25 in the danazol group) had an additional follow-up for eval- uation of clinical symptomatology as well as laboratory parameters. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Cirkel 1995/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Parallel-arm, randomised controlled trial Participants Participants: 30 women randomised (Group 1 - three-monthly leuprolide n = 15, Group 2 - monthly le- uprolide n = 15). 27 women analysed (Group 1 - three-monthly leuprolide n = 14, Group 2 - monthly le- uprolde n = 13) Mean age: Group 1: 28.6 ± 6.0, Group 2: 31.0 ± 5.2 Inclusion:/uni00A0 • Premenopausal women (FSH < 30 mIU/mL) • Aged 18-38 • Symptomatic endometriosis at stage I-IV of the revised American Fertility Society (rAFS) classification, diagnosed at laparoscopy Exclusion:/uni00A0 • Any major disease Setting: University clinics in Milan, Genoa, Rome, Italy Timing: not stated Interventions Group 1: Leuprolide acetate 11.25 mg intramuscularly every 84 days /uni00A0for 6 months versus/uni00A0 Group 2: Leuprolide acetate 3.75 mg every 28 days for 6 months Outcomes • Relief of overall pain, according to Biberoglu and Behrman verbal rating scale • Bone mineral density • Adverse effects • rAFS score • Acceptability of treatment schedule • Serum LH and 17β-oestradiol concentrations Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Crosignani 1996/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 63 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Funding: Takeda Italia Farmaceutici S p.A., Roma, Italy, for supplying leuprolide depot injections, preparing the randomisation procedures, and giving financial support to the study Note previous version: Was previously excluded for pain not being an outcome but should be included as pain score is an outcome Contacted authors for more information on concealment, awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Eligible subjects were randomised according to a computer-generated se- quence. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk The study was an "open-label trial". No further details of the blinding process were provided. Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk One woman from group 1 (three monthly) withdrew from study as she did not want to undergo repeated venipunctures and laparoscopy. Two women in group 2 (monthly) stopped treatment due to a desire to conceive. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Crosignani 1996/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: randomised, phase III, evaluator-blinded, comparator-controlled clinical trial Participants Participants: Of 300 randomised patients, 299 received at least one dose of study medication. Continu- ation rates were similar between the treatment groups, with 90.2% of patients receiving DMPA-SC 104 and 93.2% of those receiving leuprolide completing the 6-month treatment period. Of the patients that completed the 6-month treatment period, 71.7 and 73.5% of patients in the DMPA-SC 104 and leupro- lide groups completed the 12-month follow-up period, respectively. Mean age: DMPA-SC 31.8 ± 6.7 years, leuprolide 30.9 ± 6.1 years • Inclusion criteria: Premenopausal women aged 18–49 years • Laparoscopically diagnosed endometriosis • Persistent pain symptoms • Normal results from a Papanicolaou smear and normal mammogram within the past 12 months • Be willing to use a non-hormonal contraceptive method for the duration of the study • Exclusion criteria:/uni00A0BMD below acceptable levels (both lumbar spine and total hip t score < –1.0) • A history of pathological or compression fractures Crosignani 2006/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 64 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Any condition that might render a patient unable to comply with study instructions Setting: Europe, Asia, Latin America and New Zealand Timing: July 1, 2001, through August 11, 2003 Interventions 6 months of active treatment with depot medroxyprogesterone acetate 104 mg/0.65 mL ( DMPA-SC 104) versus 6 months of active treatment with leuprolide 3.75 mg monthly, or in The Netherlands, 11.25 mg once every 3 months Outcomes • Relief of overall pain • Adverse effects (including changes in the Kupperman Index) • Quality of life • Decline in bone mineral density • Efficacy Notes Intention-to-treat analysis: Yes Sample size calculation: not stated Funding: no funding Note previous version: Authors contacts as values were given as median percentage change. No re- sponse Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk This study randomised patients in a 1:1 ratio. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk This was an evaluator-blinded study, in which the principal investigator and any designated sub-investigators and study coordinators at each centre were blinded to the randomisation of each patient. Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk For the purpose of maintaining the blinding, an independent person main- tained the randomisation code, received the study syringes and administered the study medication. This individual was instructed not to reveal the ran- domisation code or to discuss the patient’s route of administration with clin- ical study site personnel. In addition, patients were instructed not to discuss the route of administration. Incomplete outcome data (attrition bias) All outcomes Low risk In DMPA-SC 104 group, a total of 54/153 withdrawn during follow-up period - 12 adverse events - 10 protocol violation - 22 consent withdrawn - 10 patient contact loss Crosignani 2006/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 65 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews In leuprolide group, a total of 46/146 withdrawn during follow-up period - 9 adverse events - 10 protocol violation - 18 consent withdrawn - 9 patient contact loss /uni00A0 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Crosignani 2006/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Prospective, randomised, double-blind study Participants Participants: 12 women were randomised and analysed. Mean age: The mean age was 29.4 ± 1.6 years for the LA group and 30.5 ± 2.9 years for the danazol group. • Inclusion criteria: No use of specific hormone treatment or oral contraceptive use in the 6 months before enrolment in the study • No previous use of GnRH analogue No surgical treatment was permitted at the time of pretreatment laparoscopy. Exclusion criteria:/uni00A0 • Use of contraception other than the barrier method Setting: United states of America Timing: not stated Interventions Group 1: 3.7 mg leuprolide acetate monthly injection + oral placebo every day or/uni00A0 Group 2: 800 mg danazol orally + monthly placebo injection Outcomes • Bone mineral density • Hormone determinations Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: supported by a grant from TAP Pharmaceuticals, Inc., Deerfield, Illinois The author has not been reached for no working email address was available. Risk of bias Dawood 1995/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 66 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk 'randomized clinical trial' by randomisation code. No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No further details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Blinding, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Blinding, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Dawood 1995/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Phase III, randomised, double-blind, multi-centre study" /uni00A0 Participants Participants: 63 women eligible; 63 were randomised and 52 were analysed. Mean age: /uni00A029.8 ± 1.0 leuprolide versus 30.2 ± 1.0 placebo Inclusion criteria: • Laparoscopically diagnosed endometriosis within 3 months of study entry • Pain secondary to endometriosis • Over 18 years old • No previous treatment with leuprolide acetate or other GnRHas • At least one ovary intact • Non-pregnant • Non-lactating • No treatment for endometriosis within 3 months of study entry Exclusion criteria: not stated Setting: United States of America Timing: Not stated Interventions Leuprolide acetate 3.75 mg IM depot every 4 weeks for 20 weeks (n = 32) versus Dlugi 1990/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 67 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Placebo (diluent) 2 mL IM every 4 weeks for 20 weeks (n = 31) Outcomes • Relief of overall pain: dysmenorrhoea, pelvic pain, dyspareunia, pelvic tenderness, induration • Bone mineral density • Adverse effects • Clinical evaluation of induration and ovarian enlargement • Hormone assays • Menstrual records • Analgesic usage Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Supported by a grant from TAP Pharmaceuticals, North Chicago, Illinois Note previous version: Authors contacted for details on allocation concealment and SEMs. Letter re- turned to sender; author moved with no forwarding address. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomised". No further details of method used to generate the randomisa- tion sequence were provided. Allocation concealment (selection bias) Low risk "Patients were assigned a 3 digit patient number in sequential order from those numbers allocated to each investigator. The patient number encoded the random assignment to a treatment group". Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Patients and investigators were blinded. Blinding of outcome as- sessment (detection bias) All outcomes Low risk Patients and investigators were blinded. Incomplete outcome data (attrition bias) All outcomes High risk Sufficient details for attrition: 7/32 withdrawn as subsequently determined they had failed to meet entry re- quirements; 4 excluded because they had received fewer than 3 injections of the study drug. There were partial exclusions for efficacy data due to non-compliance with in- tended study procedures and dosing regimens for 15 patients (7 = leuprolide and 8 = placebo). 27/31 placebo (24 terminated because of worsened symptoms, 1 because of salpingitis, 1 became pregnant and 1 was non-compliant) and 3 (2 because of intolerable pain and 1 because of an adverse event) leuprolide patients pre- maturely terminated study. /uni00A0 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Dlugi 1990/uni00A0/uni00A0(Continued) /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 68 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Study characteristics

Trial design: "Open-label, randomised, prospective study" Participants Participants: 36 women eligible, 36 were randomised and 29 were analysed Mean age: 30.8 ± 0.6 (SE) (range, 27 to 38 years) Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis within 3 months before enrolment in the study • No hormonal treatment 8 months prior to study entry Exclusion criteria: not stated Setting: United States of America Timing: Not stated Interventions Buserelin 400 /uni03BCg three times a day (1200 /uni03BCg/day) IN for 6 months (n = 10) versus Buserelin 200 mcg daily SC for 6 months (n = 9) versus Danazol 200 mg four times a day (800 mg/day) PO for 6 months (n = 10) /uni00A0 Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain • Change in rAFS scores • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: supported in part by a grant from Hoechst-Roussel Pharmaceuticals, Inc. Note previous version: Authors contacted regarding allocation concealment /uni00A0 Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk 2:1 buserelin: danazol. No further details of method used to generate the ran- domisation sequence were provided. "Those who were randomised into Buserelin were given an option of SC injec- tions or IN sprays of the drug". Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) Unclear risk No details provided of blinding of outcome assessment Dmowski 1989a/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 69 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews All outcomes Incomplete outcome data (attrition bias) All outcomes Low risk Detail for attrition: 3 in SC buserelin, 2 in IN buserelin and 2 in danazol group. 2 withdrew for fam- ily reasons, 3 were non-compliant, 1 had severe emotional side effects on IN buserelin and 1 was allergic to danazol. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Dmowski 1989a/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 50 women were randomised and analysed. Mean age: not stated Inclusion criteria: • Laparoscopic confirmed endometriosis • Significant pelvic pain Exclusion criteria:/uni00A0 • No pelvic pain Setting: United Kingdom Timing: not stated Interventions Group 1: goserelin 3.6 mg/month as SC depot (n = 25) versus Group 2: goserelin 3.6 mg/month as SC depot + 17-oestrodiol 25 ug through the skin twice weekly and medroxyprogesterone acetate 5 mg/day PO (n = 25) Outcomes • Bone mineral density, measured at the lumbar spine, femoral neck and ward's triangle • Improvement of most troublesome symptom: dyspareunia, dysmenorrhoea, pelvic pain, pelvic ten- derness, induration combined • Endocrine profiles Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated /uni00A0 Author could not be contacted for further information because of lack of contact information. Risk of bias Edmonds 1994/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 70 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk 'Randomised controlled trial'. No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) High risk Change in pain-related symptoms was asked for, but not reported in published article./uni00A0 Other bias Low risk No other risk of bias detected Edmonds 1994/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled study /uni00A0 Participants Participants: 62 women were randomised and analysed. Mean age: Buserelin = 29.8 ± 3.3 and danazol 31.3 ± 4.3/uni00A0 Inclusion criteria: • Laparoscopically diagnosed endometriosis within 3 months prior to study • No therapeutic intervention Exclusion criteria: • Bilateral tube occlusion or partner with severe dyspermia • Danazol or other sex hormone use within 6 months prior to study • Systemic or endocrine disease Setting: Italy Timing: not stated Interventions Buserelin 400 /uni03BCg three times a day IN for 6 months (n = 30) versus Danazol 200 mg three times a day PO for 6 months (n = 32) /uni00A0 Fedele 1989/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 71 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain • rAFS score • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Authors contacted for information on raw data for pain scores, and methods. No response to date /uni00A0 Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk The patients were assigned randomly to one of two treatment groups. No fur- ther details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk Detail for attrition: • 1 subject from buserelin group withdrew due to severe pelvic pain. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Fedele 1989/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised, prospective open-labelled study Participants Participants: 44 women with endometriosis (confirmed laparoscopically/histologically), /uni00A0consecutively selected at the pain and endoscopy outpatient clinic Mean age: 28.8 ± 4.9 years for LNG-IUS and 41.4 ± 5.8 years for GnRHa Inclusion criteria:/uni00A0 • 18-40 years of age Ferreira 2010/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 72 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Chronic pelvic pain • No use of /uni00A0oral hormone contraceptives for at least 3 months or with depot progestogens or GnRHa for at least 6 months prior to randomisation Exclusion:/uni00A0 • Obese patients (BMI > 30kg/m2) • Smokers, diabetics, alcohol or drug users • Patients wishing to conceive • Patients with chronic disease, acute and/or chronic inflammatory and/or infectious processes • Family history of thromboembolic events • Taking medications known to interfere with inflammation markers for a period of less than 15 days before the study Setting: Brazil Timing: not stated Interventions Levonorgestrel intrauterine system (LNG-IUS) (n = 22) versus GnRHas (n = 22) 3.75 mg leuprolide IM monthly treatment for 6 months Outcomes • Relief of overall pain: pain score (VAS) • Serum markers of cardiovascular risk (lipid profile, inflammatory markers, and markers of endothelial injury) • BMI, systolic and diastolic arterial pressure, heart rate Notes Intention-to-treat analysis: not stated Sample size calculation: Yes Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "Randomised by computer program (GraphPad Software) at a 1:1 ratio)". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No /uni00A0details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk GnRHa (1 pregnancy before drug administered and 3 moved and lost to fol- low-up) Ferreira 2010/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 73 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Ferreira 2010/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 43 women were randomised and 39 analysed. Mean age: Group 1: 31 ± 7 years, group 2: 32 ± 7 years Inclusion criteria: • Symptomatic, laparoscopically proven endometriosis • Participated in the original study • Ovulation was confirmed in the menstrual cycle before entry into the study by a luteal-phase serum progesterone level more than 16 nmol/L (5 ng/dL). • Normal serum calcium, inorganic phosphate, alkaline phosphatase, bilirubin, creatinine, free T4 in- dex, and PRL concentrations Exclusion criteria:/uni00A0 • Women with disorders or taking medications known to affect bone metabolism • Oral contraceptive and danazol use was discontinued for at least 2 months and GnRH analog therapy was discontinued for at least 9 months before entry into the study. Setting: United States of America Timing: not stated Interventions GnRH analog nafarelin acetate (Synarel, Syntex Laboratories, Inc, Palo Alto, Calif), 200 /uni03BCg intranasally twice daily, for 12 months (group 1, n = 22)/uni00A0 versus Nafarelin acetate plus human PTH-(1-34), 40 /uni03BCg (500 U) subcutaneously daily, for 12 months (group 2, n = 21) Outcomes • Bone mineral density • Adverse effects • Improvement of most troublesome symptom • Laboratory/biochemical values Notes Intention-to-treat analysis: yes Sample size calculation: not stated Funding: This work was supported by National Institutes of Health grants R29 DK43341 and RR1066 and a National of Institutes of Health Clinical Associate Physician Award (Dr Finkelstein). Risk of bias Bias Authors' judgement Support for judgement Finkelstein 1998/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 74 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Random sequence genera- tion (selection bias) Low risk Randomisation was conducted by a research biostatistician not otherwise in- volved in the study. Allocation concealment (selection bias) Low risk The women were randomly assigned. Randomisation was performed us- ing computer-generated cards that were numbered sequentially and kept in opaque, sealed envelopes until entry into the study. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk Because we and our local institutional review board felt that the use of place- bo hPTH-(1-34) injections was unethical, no placebo was used. Thus, neither the patients nor the investigators were blinded with respect to treatment. Blinding of outcome as- sessment (detection bias) All outcomes Low risk The person reading the bone density scans, however, was blinded with re- spect to treatment assignment, as were the technicians who performed the biochemical analyses. Incomplete outcome data (attrition bias) All outcomes Low risk Four women in group 2 (4/21) withdrew from the study after 3 months (n = 2) or 6 months (n = 2). Reasons for withdrawal included hot flashes and mild weight gain (n = 1), excessive distance from study site (n = 1), discomfort from injections (n = 1), and depression (n = 1). All data from these women are includ- ed and analysed with their originally assigned group. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Finkelstein 1998/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 38 women were randomised and analysed. Mean age: Group 1: 34 ± 7 years, group 2: 34 ± 7 years Inclusion criteria: • Symptomatic, laparoscopically proven endometriosis • Participated in the original study • Ovulation was confirmed by a luteal phase serum progesterone level greater than 5 ng/dL (19, 20). • Normal serum calcium, inorganic phosphate, alkaline phosphatase, bilirubin, creatinine, free T4 in- dex, and PRL concentrations Exclusion criteria:/uni00A0 • Women with disorders or taking medications known to affect bone metabolism • Women who received a therapy or who developed a medical condition known to affect BMD during the year after active therapy Setting: United States of America Timing: not stated Interventions Nafarelin acetate (Synarel, Syntex Laboratories, Inc., Palo Alto, CA; 200 mg, intranasally, twice daily) (group 1; n /uni00A0= 28)/uni00A0 Finkelstein 1999/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 75 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews versus Nafarelin acetate plus human PTH [40 mg (500 U), sc, daily] for 6–12 months (group 2; n = /uni00A023) Outcomes • Changes in BMD and bone turnover • Biochemical markers of bone turnover Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: This work was supported by NIH Grants R29-DK-43341 and RR1066 and a NIH Clinical Asso- ciate Physician Award (to J.S.F.). Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk The women were randomly assigned using computer generated cards./uni00A0 Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Finkelstein 1999/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: prospective, randomized, placebo-controlled, double-blind trial Participants Participants: 41 women were randomised, 40 women were analysed. Mean age: Group 1: 29.9 ± 6.0 years, group 2: 31.2 ± 5.3 years Inclusion criteria: • Endometriosis confirmed by laparoscopy in the 3 months before initiation of treatment • AFS-R scores of 2 or more • During surgery, no attempt was made to reduce the endometriotic lesions. Franke 2000/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 76 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Exclusion criteria: not stated Setting: The Netherlands Timing: April 1, 1997 until July 1, 1999 Interventions Group 1: goserelin acetate SC 3.6 mg every 4 weeks + oral placebo (n = 23) versus Group 2: goserelin acetate SC 3.6 mg every 4 weeks + 2 mg 17ß-E/two.sups and 1 mg norethisterone acetate dai- ly (n = 18) Outcomes • Bone mineral density • Adverse effects • Endocrinologic effects • Changes in AFS-R score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Trial sponsored by AstraZeneca and Novo Nordisk, who also supplied the active drugs and placebo. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk No details of method used to generate the randomisation sequence were pro- vided. Allocation concealment (selection bias) Unclear risk Sequentially numbered envelopes. No further details of method used to con- ceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind study Incomplete outcome data (attrition bias) All outcomes Low risk 1 participant in group 1 discontinued treatment due to severe climacteric symptoms. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Franke 2000/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics Fraser 1991/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 77 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

Trial design: "Double-blind, double-dummy, randomised, parallel study" /uni00A0 Participants Participants: 49 women with endometriosis stage 1-3 were randomised and 45 were analysed. Mean age: not stated Inclusion criteria: • Laparoscopically diagnosed endometriosis • Symptomatic • Regular menstrual cycle 24-36 days • Not pregnant • Negative pap smear • Barrier contraception Exclusion criteria: • Concurrent disease which may interfere with drug • Surgical therapy within 6 months prior to study entry • Steroid therapy within 3 months prior to study entry Setting: Australia/New Zealand Timing: not stated Interventions Nafarelin 200 mcg twice a day (400 /uni03BCg/d) IN + placebo PO for 6 months (n = 33) versus Danazol 200 mg three times a day (600 mg/d) PO + placebo IN for 6 months (n = 16) /uni00A0 Subdivisions were made: Stage 1-2: Subgroup A (27 patients; 2 dropouts) who received intranasal nafarelin acetate 200 pg twice daily,/uni00A0 or Subgroup B (13 patients; no dropouts) who received oral danazol 200 mg 3 times daily. Stage 3: Subgroup A (6 patients; 1 dropout) who received intranasal nafarelin acetate 200 pg twice daily for 6 months followed by conservative laparotomy, or/uni00A0 Subgroup B (3 patients; no dropouts) who received oral danazol 200 mg three times daily followed by conservative laparotomy. Outcomes - Dyspareunia, pelvic pain, pelvic tenderness, induration - Change in rAFS score - Adverse effects /uni00A0 Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Fraser 1991/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 78 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Funding: Syntex Pharmaceuticals International supplied nafarelin acetate, and a grant to cover the ex- penses of the trial. Note previous version: Authors contacted with regards to allocation concealment. Author replied that the data were difficult to find but would try. /uni00A0 Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "Computer generated list of random numbers" Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Placebo pill + placebo nasal spray so patient and investigators were blinded. Blinding of outcome as- sessment (detection bias) All outcomes Low risk Placebo pill + placebo nasal spray so assessors were blinded. Incomplete outcome data (attrition bias) All outcomes Low risk 3/33 participants "dropped out" of intranasal nafarelin group; no "drop outs" from danazol group (0/16) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Fraser 1991/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: randomised, double-blind, comparative study Participants Participants: 27 women were randomised and analysed. Mean age: group A: 35 ± 5 years, group P: 34.8 ± 5 years Inclusion criteria: • Age between 18-45 • Endometriosis score greater than 5 points causing symptoms and/or sterility • /uni00A0Normal bone density prior to medication • Use of contraceptive devices in the 1st month of treatment Exclusion criteria: not stated/uni00A0 Setting: Germany Timing: not stated Freundl 1998/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 79 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Interventions Group A: received a combination of leuprorelin acetate depot with 20 mg ethinyloestradiol plus 0.15 mg desogestrel (n = 14) versus Group P: received leuprorelin acetate depot plus placebo (n = 13) Outcomes • Relief of overall pain: endometriosis symptoms • Bone mineral density • Hypooestrogenic symptoms • rAFS score • Blood/urine chemistry • Body weight Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Contact with the author could not be established for further information; he unfortunately passed away. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Prospective double-blind, randomised placebo-controlled trial". No further details of method used to generate the randomisation sequence were provid- ed. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Freundl 1998/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics Fukushima 1993/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 80 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

Trial design: single-blind, single-centre, randomised controlled trial Participants Participants: 28 women were randomised, 19 women were analysed. Mean age: Buserelin 34.6 ± 5.1 years, danazol 32.6 ± 8.5 years Inclusion criteria: • Regular menstrual cycles • Negative cervical cytology • Body weight within 25% of the normal range Exclusion criteria:/uni00A0 • Conditions that might affect calcium metabolism • Administration of drugs known to affect sex hormone levels or bone metabolism during the study Setting: Japan Timing: not stated Interventions Danazol (Bonzol©, Tokyo Tanabe Co., Ltd., Tokyo, Japan) capsules at a dose of 400 mg/day versus Buserelin (Suprecur© Hoechst Japan, Tokyo, Japan) nasal spray at a dose of 900 /uni03BCg/day Outcomes • Bone mineral content • Biochemical parameters of efficacy and bone metabolism Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Author could not be contacted due to lack of contact information. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomly allocated". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Low risk Single-blind (to assessor of bone mineral density) Incomplete outcome data (attrition bias) All outcomes High risk 9/28 did not complete the study due to reasons unrelated to the treatment they had been administered. No further details were provided. Fukushima 1993/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 81 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Fukushima 1993/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised, double-blind, placebo-controlled, prospective trial Participants Participants: 27 women were randomised and analysed. Mean age: group 1; 34.8 ± 5 years, group 2; 35 ± 5 years Inclusion criteria: • Laparoscopically confirmed endometriosis (rAFS I-IV) • No hormonal pretreatment at least 8 weeks prior to study entry • Age 18-45 • Normal bone mineral density prior to study entry Exclusion criteria:/uni00A0 Reduced bone mineral density prior to study entry • Absolute or relative contraindication against ethinyl oestradiol or desogestrel • Pregnancy • Medical history or any event of thrombosis • Any form of haemoglobin disorders, hypertension, liver function disorders, any history of malignant diseases, any oestrogen-related disorders like otosclerosis, herpes gestationis, history of severe pru- ritus in pregnancy • Additional medication with: antiepileptics, antibiotics, rifampicin, isoniazid, phenylbutazon, griseo- fulvin, chlorpromazin, nitrofurantoin or dihydroergotamin Setting: Germany Timing: not stated Interventions Group 1: leuprolin acetate 3.75 mg IM + oral placebo each day versus Group 2: leuprolin acetate 3.75 mg IM + 20/uni03BCg ethinyl oestrodiol and 0.15 mg desogestrel per day Outcomes • Bone mineral density • Pyridinoline concentrations in urine • Calcium: serum and urinary concentrations Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Author contacted for more information regarding selection bias; awaiting response Gnoth 1999/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 82 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk By centralised randomisation process. No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blinded, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blinded, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk Pretreatment measurements of one women weres not done. 1 early pregnancy post-treatment. The reply from the authors stated that there were no exclusions post-randomisation or losses to follow-up, but remarked that one woman withdrew directly after the first medical investigation and randomisation. She did not tell the reasons for her decision. There were no measurements taken from her. This participant was completely excluded from the evaluation and replaced. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Gnoth 1999/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: randomised, controlled clinical study Participants Participants: 22 women were randomised; 18 were analysed. Mean age: LNG-IUS = 29.2 ± 5.5 years and Lupron = 32.6 ± 5.3 years Inclusion criteria: • Laparoscopically diagnosed endometriosis made 3 months before enrolment in the study • Chronic pelvic pain that was cyclic • VAS of 3 or more • Regular menstrual cycle (25-35 days) for 3 months or more before study entry • Had not used any hormonal therapy for at least 3 months before study entry • Had not taken long acting progestins or GnRHas within the preceding 9 months • Not pregnant or breastfeeding during the 3 months preceding study • No osteoporosis, coagulation disorders or contraindications to LNG-IUS Exclusion criteria: Gomes 2007/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 83 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Use of medication outside study Setting: Brazil Timing: February 2003 to May 2005 Interventions LNG-IUS IU for 6 months (n = 11) versus Lupron depot 3.75 mg IM every 4 weeks for 6 months (n = 11) /uni00A0 Outcomes • Relief of overall pain (as defined by VAS) • Change in laparoscopic outcome as defined by ASRM Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: The levonorgestrel-releasing intrauterine system (Mirena) and GnRH agonist ampules were provided free of charge by Schering, São Paulo, Brazil. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "Computer generated system". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk "Sealed envelopes". No further details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk Detail given for attrition: • 4 withdrawals due to refusal of second laparoscopy (1/11 LNG-IUS group and 3/11 GNRHa group) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Gomes 2007/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Multicentre, randomised, double-blind trial/uni00A0 Participants Participants: 271 women were randomised; 255 women were analysed. Harada 2009/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 84 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Mean age: Dienogest: 33.5 ± 6.9 years, buserelin 33.8 ± 6.2 years Inclusion criteria: • Age ≥ 20 years • Regular menstrual cycles • Diagnosis of endometriosis by laparotomy, laparoscopy or imaging analysis • Presence of subjective symptoms during menstruation • Presence of symptoms during non-menstruation • Presence of objective findings Exclusion criteria:/uni00A0 • Undiagnosed genital bleeding • Class 3 or more on Pap test within 3 months before enrolment • Use of GnRHas, testosterone derivatives, hormonal therapy with progesterone and/or oestrogen, oe- strogen antagonists or aromatase inhibitors within 16 weeks of enrolment • Pregnant or nursing • A history of severe adverse drug reactions or hypersensitivity to steroid hormone or GnRH agonists • Past use of GnRH agonist with low bone mineral density • Having undergone surgery therapy or surgical examination for endometriosis within a menstrual cycle before the start of medication • Use of drugs that could be expected to affect the release of sex hormones • A history of complication of thrombosis/embolism or depression • Malignant tumour complication or findings suggestive of a malignant tumour • Complication of serious heart, kidney, blood or endocrine disease • Participation in another clinical trial within the 4 months before enrolment • Patients deemed unsuitable for entry by the investigator Setting: Japan Timing: June 2003 to February 2005 Interventions Dienogest 1 mg orally morning and evening (n = 134) versus Buserelin intranasally 300 micrograms morning, noon and evening (n = 134) Outcomes • Relief of overall pain • Bone mineral density • Adverse effects • Quality of life • Bone turnover markers • Body weight Notes Intention-to-treat analysis: not stated Sample size calculation: yes Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Harada 2009/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 85 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Random sequence genera- tion (selection bias) Low risk The participants were randomised by the centre according to the permuted block method and computer-generated numbers. Allocation concealment (selection bias) Low risk The allocation sequence list was kept centrally to maintain the blindness of the study until the key was disclosed. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk The BMD measurement procedures were performed under double-blind con- ditions. Assessors were blinded and participants were blinded with double dummy. Blinding of outcome as- sessment (detection bias) All outcomes Low risk The BMD measurement procedures were performed under double-blind con- ditions. Assessors were blinded and participants were blinded with double dummy. Incomplete outcome data (attrition bias) All outcomes High risk Intention-to-treat analysis was used for the primary outcome./uni00A0 In dienogest group, withdrawn = 16/137/uni00A0 - 3 consent withdrawn - 6 adverse events - 1 prohibited concomitant therapy - 2 protocol criteria violation - 4 other/uni00A0 In buserelin acetate group, withdrawn = 20/134/uni00A0 - 3 consent withdrawn - 7 adverse events - 2 prohibited concomitant therapy - 3 protocol criteria violation - 5 other/uni00A0 BMD was available for only 41/137 patients who had received dienogest and 46/134 who had received buserelin acetate. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Harada 2009/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "parallel, randomised, double-placebo design" Participants Participants: 236 women were randomised; 213 analysed/uni00A0 Age: not stated (60% were over 30 years old) Inclusion criteria:/uni00A0 Henzl 1988/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 86 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • 18-45 years old • Laparoscopically diagnosed endometriosis within 3 months prior to study enrolment • No hormonal treatment for endometriosis 6 months prior to study Exclusion critieria: not stated Setting: USA, Canada, Sweden/uni00A0 Timing: not stated Interventions Nafarelin IN 200 mcg twice daily + placebo PO for 6 months (n = 77)/uni00A0 versus/uni00A0 Nafarelin IN 400 mcg twice daily + placebo PO for 6 months (n = 79)/uni00A0 versus/uni00A0 Danazol PO 400 mg twice daily+ placebo IN for 6 months (n = 80) Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration • Adverse effects • Improvement of most troublesome symptom • AFS score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Authors contacted regarding randomisation and allocation concealment Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomised". No further details of method used to generate the randomisa- tion sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blinded, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blinded, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk Detail given for attrition: 23 were excluded from the analyses: 9 for reasons not related to the study drugs/uni00A0 7 in 800 mcg nafarelin and 4 in danazol due to hot flushes/uni00A0 2 in danazol due to rapid rise in serum enzymes/uni00A0 1 in danazol because of a lack of efficacy Henzl 1988/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 87 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysed:/uni00A0 70/77: Nafarelin IN 200 mcg BD + placebo PO for 6 months 73/79: Nafarelin IN 400 mcg BD + placebo PO for 6 months /uni00A0 70/80: Danazol PO 400 mg BD + placebo IN for 6 months/uni00A0 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Henzl 1988/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "double-blind, prospective, multi-centre, randomised clinical trial" Participants Participants: 179 women were randomised and analysed. Mean age: Group 1 = 31.0 +/- 6.1 years and group 2 = 31.3 +/- 5.7 years Inclusion criteria: • 18-46 years old • Laparoscopically diagnosed endometriosis within 24 months prior to study enrolment • 24-36 day menstrual cycle • Symptomatic endometriosis Exclusion criteria: • Hormone treatment 3 months prior to study • Significant illness or lab test abnormality • Prior treatment with nafarelin • Pregnant or lactating women Setting: United States of America Timing: not stated Interventions Group 1: Nafarelin 200 mcg IN for 3 months + placebo IN for 3 months after (n = 91) versus Group 2: Nafarelin 200 mcg IN for 6 months (n = 88) /uni00A0 Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration • Median serum E2 levels Notes Intention-to-treat analysis: yes Sample size calculation: not stated Funding: Supported in part by a grant from Syntex Laboratories, Inc., Palo Alto, California Note previous version: Authors contacted and replied /uni00A0 Hornstein 1995/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 88 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk No details of method used to generate the randomisation sequence were pro- vided./uni00A0 Allocation concealment (selection bias) Unclear risk "randomisation was done by a pharmacy"/uni00A0. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Placebo nasal spray to blind participants; participants, investigators, outcome assessors and clinicians were blinded. Blinding of outcome as- sessment (detection bias) All outcomes Low risk Placebo nasal spray to blind participants; participants, investigators, outcome assessors and clinicians were blinded. Incomplete outcome data (attrition bias) All outcomes Low risk All participants who were randomised were followed for a minimum of 12 months after treatment. Of the 179 subjects enrolled, 39 in group I and 43 in group II patients completed the 18-month study without requiring further treatment other than periodic analgesics. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Hornstein 1995/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

/uni00A0 Trial design: Multi-centre randomised, double-blind, placebo-controlled trial Participants Participants: 201 women were randomised and analysed. Mean 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 Inclusion criteria: • Women • Aged 18-43 • Regular menstrual cycles • History of symptomatic endometriosis diagnosed surgically within 12 months of study entry • Persistent or recurrent pain Exclusion criteria: not stated Setting: United States of America Timing: not stated Interventions All patients received GnRH agonist (Lupron depot 3.75 mg every 4 weeks for 52 weeks) and calcium supplementation as elemental calcium 1000 mg daily./uni00A0 Group A: received daily oral placebos for progestin and oestrogen (n = 51) Hornstein 1998/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 89 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Group B: received daily oral norethindrone acetate 5 mg with placebo for oestrogen (n = 55) Group C: received norethindrone 5 mg and conjugated equine oestrogens 0.625 mg (n = 47) Group D: received norethindrone 5 mg and conjugated equine oestrogens 1.25 mg (n = 48) Outcomes • Relief of overall pain • Bone mineral density • Serum lipid analyses • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: yes Funding: Grant received from TAP Pharmaceuticals Inc. Ms Castro is a paid employee of TAP Pharmaceuticals Inc; Dr Weissberg was a paid employee of TAP Pharmaceuticals Inc. at the time the study was undertaken. Drs Hornstein and Surrey have received honoraria for participating in a limited number of lectureships and symposias sponsored by TAP Phar- maceuticals Inc. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk Patients were assigned randomly to a treatment group by permuted blocks of four at each of 26 study sites. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Hornstein 1998/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Howell 1995/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 90 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Participants Participants: 50 women were randomised; 48 completed 24 weeks of treatment and underwent second laparoxcopic assessment. Mean age: Group 1: 29 ± 6 years, group 2: 30 ± 5 years Inclusion criteria: • Pelvic pain and a minimum Pelvic Pain Score (defined below) of 3 • Regular menstrual cycle (21 to 42 day cycles) • Negative cervical smear within the preceding 12 months • Use barrier contraception for the duration of the treatment period • A minimum revised American Fertility Score (revised AFS) for endometriosis lesions (excluding adhe- sions) of four was required. Exclusion criteria:/uni00A0 • Drugs known to affect bone metabolism in the 6 months preceding the trial • Medical conditions known to affect bone mineral density or bone mineral metabolism Setting: United Kingdom Timing: not stated Interventions Group 1: 3.6 mg SC depot injection of goserelin every 4 weeks versus Group 2: 3.6 mg SC injection every four weeks and transdermal oestrogen 25 ug daily and 5 mg medrox- yprogesterone acetate daily for 20 weeks commencing with the second goserelin depot Outcomes • Relief of overall pain: relief of symptoms and clinical signs • Bone mineral density • Adverse effects • Endometriosis response • Endocrinologic effects • Serum lipids and lipoproteins Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Study sponsored by Zeneca Pharmaceuticals Note previous version: 20 participants did not complete all the bone mineral density assessments - 2 did not complete treatment and the other 18 did not complete follow-up./uni00A0 Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Were randomised". /uni00A0No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) Unclear risk Open-label trial. No further details provided of blinding of participants or per- sonnel Howell 1995/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 91 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews All outcomes Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes High risk 20/48 participants did not complete all the bone mineral density assessments. 2/48 did not complete treatment and the other 18/48 did not complete fol- low-up. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Howell 1995/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: placebo-controlled, prospective, randomised, double-blinded study Participants Participants: 13 women were randomised and analysed. Mean age: Oestrogen: 28.3 ± 5.0 years, placebo 32.4 ± 5.2 years Inclusion criteria: • Persistent or recurrent chronic pelvic pain after laparoscopic diagnosis and treatment of endometrio- sis Exclusion criteria:/uni00A0 • History of prior GnRH agonist therapy • History of an emotional disorder, pregnancy or lactation • Osteoporosis, known or suspected breast cancer, present or past endometrial hyperplasia or carci- noma, a history of thrombosis, thrombophlebitis, or thromboembolism and undiagnosed abnormal genital bleeding • Usage of oral contraceptives or other treatment outside the protocol Setting: United States of America Timing: not stated Interventions All were treated with leuprolide acetate (TAP Pharmaceuticals, Deerfield, IL) 3.75 mg intramuscularly for six months. After three months of therapy,/uni00A0 Oral oestradiol 1 mg daily (n = 6) versus Identical placebo (n = 7) Outcomes • Endometriosis-related symptom variables of pelvic pain, dysmenorrhea, dyspareunia, induration and pelvic tenderness • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Hurst 2000/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 92 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Funding: not stated Author contacted regarding information on selection bias; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Subjects were randomly assigned into treatment or placebo groups by the hospital’s investigational drug service". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Hurst 2000/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 21 women were randomised and analysed. Mean age: /uni00A0 Group 1: 36.0 ±10.0 years, group 2: 35.5 ± 8.6 years Inclusion criteria: • Negative smear and negative mammogram in 6 months prior to the start of the study • No previous hormonal treatment received for endometriosis Exclusion criteria:/uni00A0not stated Setting: Japan Timing: not stated Interventions Group 1: monthly injection of 3.75 mg leuprolide acetate depot (n = 10) versus/uni00A0 Irahara 2001/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 93 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Group 2: monthly injection of 3.75 mg leuprolide acetate + 0.625 mg conjugated equine oestrogen + 2.5 mg medroxyprogesterone acetate every other day from 2nd month of GnRHa treatment (n = 11) Outcomes • Bone mineral density • Laboratory results Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Author contacted for further information; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk /uni00A0Randomised controlled trial. No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Irahara 2001/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "Open, prospective, randomised, parallel study", multi-centre Participants Participants: 80 women were randomised; 68 were analysed. Median age: Buserelin = 28 and danazol = 30/uni00A0 Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis 18-40 years old • Symptomatic disease • Active menstrual cycle Jelley 1986/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 94 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Exclusion criteria:/uni00A0 • Previous use of danazol or hormone treatment without success • Use of danazol within 6 months prior to study • Serious endocrine disease or use of other drugs which may interfere with therapy Setting: UK/uni00A0 Timing: not stated Interventions Buserelin 300 mcg three times a day intranasally for 7 months (n = 34)/uni00A0 versus/uni00A0 Danazol 600 mg once daily per OS for 7 months (n = 34) Outcomes • Relief of overall pain: Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration • Adverse effects • rAFS score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Preliminary findings for the first 68 women treated only. Attempted to contact author regarding data. Author not contactable Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "The code was derived from random number tables". No further details were provided of method used to generate the randomisation sequence. Allocation concealment (selection bias) Low risk "A sealed envelope was provided for each patient, and opened only after the patient's name had been entered on it". Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk Open study, no blinding Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk Open study, no blinding Incomplete outcome data (attrition bias) All outcomes Low risk Detail for attrition:/uni00A0 • 1 randomised patient failed to start treatment as her symptoms improved • So far 4 have withdrawn from study due to adverse effects: 3 (Dan) and 1 (Bus) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Jelley 1986/uni00A0/uni00A0(Continued) /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 95 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 82 women were randomised and analysed. Mean age: Nafarelin group was 31.5 ± 5.20 years (range = 21 to 41 years), danazol group 30.2 ± 4.89 years (range = 21 to 42 years). Inclusion criteria: • Pelvic pain, dyspareunia, dysmenorrhoea or infertility • 24-36-day menstrual cycle over the preceding 4 months • No hormonal treatment in the preceding 6 months, barrier comtraception throughout study Exclusion criteria:/uni00A0not stated Setting: United Kingdom Timing: not stated Interventions Nafarelin 200 /uni03BCg twice daily IN with placebo tablets (n = 55) versus Danazol 200 mg three times daily orally /uni00A0with placebo nasal spray (n = 27) Outcomes • Relief of overall pain: pelvic pain, dyspareunia, dysmenorrhoea • Adverse effects • Improvement of most troublesome symptom • Serum oestradiol levels • AFS score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Supported by Syntex (U.K.) Ltd., Maidenhead, United Kingdom Author could not be contacted due to lack of information. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk Randomly allocated, stratification on a 2:1 ratio, according to disease severi- ty. No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Placebo-controlled study Blinding of outcome as- sessment (detection bias) Low risk Placebo-controlled study Kennedy 1990/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 96 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews All outcomes Incomplete outcome data (attrition bias) All outcomes Low risk Eight patients did not complete treatment and their scores were omitted; their stages at first laparoscopy were I = 2, II = 4, III = 1, and IV = 1. Four patients with- drew from the nafarelin group because of depression, muscle aches, mastal- gia and bloating (1); giddiness, nausea, and vague paraesthesia on the right side of the face and le/f_t hand (1); travel abroad (1); and a maculopapular rash (1). Two patients withdrew from the danazol group because of a viral illness (1) and a maculopapular rash (1). One patient from each group was withdrawn from the study because of poor compliance. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Kennedy 1990/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Prospective, randomised, double-blind, placebo-controlled, comparative study Participants Participants: 88 women were randomised; 76 women were analysed. Mean age: Goserelin acetate plus HRT treatment mean 32 years (20-48 years), goserelin acetate plus placebo treatment mean 34 years (21-47 years) Inclusion criteria: • Symptomatic patients with total pelvic symptoms score of > 3 with or without infertility • Laparoscopical confirmation of endometriosis within 3 months before initiation of treatment Exclusion criteria: not stated Setting: Finland Timing: not stated Interventions 3.6 mg SC goserelin acetate plus HRT treatment with combination of 2 mg 17β-E2 and 1 mg norethis- terone acetate (NET; Kliogest; Novo Nordisk AS, Bagsvaerd, Denmark) /uni00A0(n = 43)/uni00A0 versus 3.6 mg SC goserelin acetate plus placebo /uni00A0(n = 45) Outcomes • Relief of overall pain: pelvic symptoms • Adverse effects • Total revised AFS and total Additive Diameter of Implants scores • Serum hormone levels Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Supported by Zeneca Pharma, Helsinki, Finland. Author could not be contacted due to lack of information. Kiilholma 1995/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 97 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Prospective, randomized, double-blind, placebo-controlled, comparative study". No further details of method used to generate the randomisation se- quence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk 76/88 completed study. 35/43 goserelin acetate with hormone replacement therapy and 41/45 goserelin acetate plus placebo group. Two patients discontinued the treatment because of side effects that were considered to be related to the treatment. One of them (goserelin acetate plus placebo) experienced severe depression and the other one had continuous bleeding (goserelin acetate plus HRT). Three women had pregnancy confirmed during the post-treatment follow-up period. Two patients underwent surgery for endometriosis, one woman started hormonal contraception, two women were treated with hormonal or IVF therapy for infertility, one patient needed hormonal therapy for a disease other than endometriosis, and one patient did not return./uni00A0 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Kiilholma 1995/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised study /uni00A0 Participants Participants: 13 women were randomised and analysed. Age: 24 to 37 years Inclusion criteria: • Laparoscopially diagnosed endometriosis within 6 weeks of study • Not received medical treatment in the previous 6 months Exclusion criteria: • Surgery alone or hormonal treatment and surgery were indicated. Lemay 1988/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 98 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Concurrent serious endocrine or systemic disease • History of alcohol or substance abuse • Use of an oral contraceptive within the past 2 months • Drug-releasing intrauterine device within the past 3 months Setting: Canada Timing: Not stated Interventions Buserelin 400 /uni03BCg three times a day IN (n = 7) versus Buserelin 200 /uni03BCg once a day SC injection (n = 6) Outcomes • Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration • AFS score • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Author contacted regarding methods and replied. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Computerised allocation. No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Low risk Sealed, opaque, sequentially numbered, identical envelopes Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Low risk Outcome assessors were blinded./uni00A0 Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Lemay 1988/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics Ling 1999/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 99 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

Trial design: double-blind, randomised, parallel-group, placebo-controlled trial Participants Participants: 100 women were randomised; 95 women were analysed. Mean age: /uni00A0Depot leuprolide group: 32.3 years, placebo group 29.4 years Inclusion criteria: • Moderate-to-severe chronic pelvic pain for at least 6 months, with severity being assessed by a physi- cian using the four-point Biberoglu and Behrman scale, and that pain was unrelated to menstruation and incompletely relieved with nonsteroidal anti-inflammatory drugs. • Regular menstrual bleeding and menstrual cycles for 3 months before enrolment • Women who had not been sterilised surgically agreed to use barrier contraception during treatment and for 6 weeks thereafter. Exclusion criteria:/uni00A0 • A previous diagnosis of endometriosis confirmed by laparoscopy, laparotomy, or histology • Had received oral contraceptives (OCs) within the previous 3 months or GnRH agonists within the previous 6 months • Had undergone surgical treatment for endometriosis • Chronic pelvic pain might be related to genitourinary disease or to chronic or recurrent gastrointesti- nal disease, including irritable bowel syndrome (defined as a disease characterised by pain relieved by defecation and irregular defecation patterns lasting at least 3 months) • Histories of alcohol use or other chronic tranquiliser or illicit drug use Setting: United States of America (12 sites) Timing: June 1995 to January 1997 Interventions Depot leuprolide injection every 4 weeks, for 3 injections (n = 50) versus Placebo injections every 4 weeks, for 3 injections (n = 50) Outcomes • Relief of overall pain: pain scores, dysmenorrhoea, pelvic pain, pelvic tenderness, deep dyspareunia, and pelvic induration • AFS score • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: This study was supported by a grant from TAP Holdings, Inc., which distributes depot leupro- lide. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk The randomisation schedules were prepared in random blocks of two and four, with treatment group assignment in a 1:1 ratio. Each group was repre- sented once within each block of two and twice within each block of four. The schedules were prepared by an administrative staff member using a FORTRAN program to generate uniform random numbers. Allocation concealment (selection bias) Low risk Study medication was packaged according to the randomisation schedules and was sent to each site in sets of four, as needed. Patient numbers were se- Ling 1999/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 100 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews quential within each set. Patient number assignment started with the lowest available number for each site and proceeded in ascending order. The ran- domisation schedules were kept in one appropriate, secure place. The blind was not broken until enrolment and classification for evaluable patient analy- ses were complete. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk In placebo group, 46/50 completed study. • Noncompliance = 1 • Patient request = 1 • Lost to follow-up =1 • Other =1 In leuprolide depot group, 49/50 completed study. • Noncompliance = 1 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Ling 1999/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "prospective, randomised, double-blind, parallel, placebo-controlled study"/uni00A0 Participants Participants: 120 women were randomised; 120 were analysed. Age: 18-40 Inclusion criteria: • Laparoscopically diagnosed endometriosis within 24 months prior to study • Elected to have leuprolide acetate as a treatment option • Sexually active • Not pregnant or breastfeeding • Intact uterus and at least one ovary in good health • Not received treatment for endometriosis within previous 3 months • Not received medroxyprogesterone acetate within previous 6 months • No history of use of a GnRHa Exclusion criteria: • Co-existing conditions that might interfere with the conduct or analysis of study • Concomitant disease that might cause pain • Contraindication to leuprolide Miller 2000/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 101 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Unable to complete questionnaires • Suspected history of alcohol or drug abuse Setting: United States of America Timing: not stated Interventions Leuprolide acetate 3.75 mg single IM for 4 weeks (n = 60) versus Placebo for 4 weeks (n = 60) Outcomes • Pain as defined by VAS and ESS • Quality of Life SF36 Notes Intention-to-treat analysis: All participants recruited were analysed. Sample size calculation: not stated Funding: not stated Note previous version: Authors contacted regarding methods and raw data; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "assigned to groups in the order in which they were enrolled according to a computer generated schedule prepared before the start of the study" Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Stated double-blind. A placebo injection was used to blind participants, but no other details of blinding of trial personnel or outcome assessors were provid- ed./uni00A0 Blinding of outcome as- sessment (detection bias) All outcomes Low risk Stated double-blind. A placebo injection was used to blind participants, but no other details of blinding of trial personnel or outcome assessors were provid- ed./uni00A0 Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it wa clear that the published reports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Miller 2000/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised, multi-centre study Participants Participants: 191 women were randomised and analysed. Minaguchi 1986/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 102 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Mean age: not stated Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis • Over 18 years old patients who have received hormonal therapy • Patients with persistent diagnosed endometriosis postoperatively Exclusion criteria:/uni00A0 • Patients receiving conservative surgery Setting: Japan/uni00A0 Timing: not stated Interventions Buserelin 300 mcg once daily intranasally for 6 months (n = 69)/uni00A0 versus/uni00A0 Buserelin 300 mcg twice daily intranasally for 6 months (n = 59)/uni00A0 versus Buserelin 300 mcg three times a day intranasally for 6 months (n = 63) Outcomes • Relief of overall pain: Intermenstrual abdominal pain, lumbago, dyspareunia, pain on defecation, pelvic tenderness • Adverse effects • Flexibility of the uterus • Nodules in the posterior cul-de-sac • Endometrial cyst Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: /uni00A0not stated Note previous version: Authors contacted regarding methods and data; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk No details were provided of method used to generate the randomisation se- quence. Allocation concealment (selection bias) Unclear risk "Envelope". No further details were provided of method used to conceal treat- ment group allocation. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No information about blinding; open-label study Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No information about blinding; open-label study Minaguchi 1986/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 103 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Incomplete outcome data (attrition bias) All outcomes Low risk All women who were randomised were analysed. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Minaguchi 1986/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Prospective, placebo-controlled study, open-label for goserelin therapy and double-blind for HRT Participants Participants: 345 women were randomised; 306 women were analysed. Mean age:/uni00A0 Group 1: 29.6 ± 6.6 years, Group 2 30.7 ± 6.0 years Group 3: 29.4 ± /uni00A05.7 years Inclusion criteria: • Premenopausal women • 18-45 years of age • Confirmed diagnosis of endometriosis • Pelvic symptoms • If a laparoscopy included therapeutic intervention, patients had to have an initial clinical response, recurrence of pelvic symptoms, and stability in severity of pelvic symptoms for at least three months before pretreatment assessments. Exclusion criteria:/uni00A0 • Positive urine pregnancy test, pregnancy or lactation • Use of non-trial hormonal agents such as oestrogen, progesterone, or clomiphene within 60 days be- fore pretreatment assessments until the end of the study, use of any drug at doses suppressing the hypothalamic-pituitary-adrenal axis, serious concomitant condition • Long-term exposure (over three months) to GnRH agonists within 12 months before pretreatment as- sessments • Baseline bone mineral density measurements over 2 SDs below that of age-matched controls, hyper- sensitivity to previous hormone therapy or oestrogen or progestin replacement therapies • Any condition that would preclude a patient from receiving study therapy Setting: United States of America (42 participating centres) Timing: not stated Interventions Group 1: goserelin 3.6 mg every 28 days + oral placebo (n = 119) Group 2: goserelin 3.6 mg every 28 days + conjugated oestrogen 0.3 mg daily + medroxyprogesterone acetate 5 mg daily (n = 113) Moghissi 1998/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 104 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Group 3: goserelin 3.6 mg every 28 days + conjugated oestrogen 0.625 mg daily + medroxyprogesterone 5 mg daily (n = 113) Outcomes • Relief of overall pain • Bone Mineral Density • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: yes Funding: Sponsored by Zeneca Pharmaceuticals, Wilmington, Delaware Authors could not be contacted due to lack of information. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk No details of method used to generate the randomisation sequence were pro- vided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind study Incomplete outcome data (attrition bias) All outcomes Low risk /uni00A0A total of 306/345 patients completed therapy and 39 patients (10 HRT0, 14 HRT1, and 15 HRT2) were withdrawn. Group 1 10/119 Group 2 14/113 Group 3 15/113 The reasons for withdrawal during therapy included dropout (n = 24), investi- gator decision (n = 4), side effects (n = 3), pregnancy (n = 1), and other reasons (n = 7). Three patients, one in each group, completed therapy but did not want to be observed during the follow-up period. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Moghissi 1998/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics Mäkäräinen 1996/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 105 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

Trial design: Randomised, double blind, placebo-controlled trial Participants Participants: 38 women were randomised; 29 women were analysed after second-look laparoscopy. Mean age: 30.6 years (range 22 to 38 years) Inclusion criteria: • Symptomatic pelvic endometriosis • Revised American Fertility Society [AFS] score ≥ 2 Exclusion criteria: not stated Setting: Finland Timing: not stated Interventions Once-a-month SC injections of goserelin acetate 3.6 mg (Zoladex depot; Zeneca Pharmaceutics, Cheshire, United Kingdom) randomly combined with either/uni00A0 Medroxyprogesterone acetate 100 mg daily (n = 19)/uni00A0 versus Placebo, one tablet daily (n = 19)/uni00A0 Outcomes • Relief of overall pain: dysmenorrhea, dyspareunia, pelvic pain • Adverse effects • Endometriotic implants • Biochemical changes Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Zeneca Pharma, Helsinki, Finland, for supplying the active drugs and placebo Author could not be contacted due to lack of information. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomly assigned". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk Four patients interrupted the treatment because of side effects (three in the medroxyprogesterone acetate group and one in the placebo group). In- creasing pelvic symptoms in one patient receiving medroxyprogesterone ac- Mäkäräinen 1996/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 106 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews etate required laparoscopy already 4 months after the end of treatment. Four women (two in the medroxyprogesterone acetate group and two in the place- bo group) became pregnant within 6 months after the treatment. Thus, 29 women (13/19 in the medroxyprogesterone acetate and 16/19 in the placebo group) were included in the second-look laparoscopy, which was performed 6 months after the end of medical treatment. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Mäkäräinen 1996/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Multi-centre, parallel, randomised, double-blind, double-dummy study Participants Participants: 315 women were randomised, 307 were analysed for safety and 263 were analysed for effi- cacy. Mean age: not stated/uni00A0 Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis 18-45 years old • Not pregnant • Pap smear negative for malignancy • Normal menstrual cycle 21-36 days for previous 4 months • Weight between 45-110 kg Exclusion criteria:/uni00A0 • Amenorrhoea • Concurrent disease which may interfere with endometriosis or contraindicate the use of androgenic therapy • Surgical treatment at baseline or within 6 months prior to study • Use of danazol, androgenic hormones, oestrogens, or progestogens within 3 months prior to study Setting: Multiple sites within Europe/uni00A0 Timing: not stated Interventions Nafarelin 200 mcg twice daily intranasal + placebo per os for 6 months (n = 206)/uni00A0 versus/uni00A0 Danazol 200 mg three times a day per os + placebo intranasal for 6 months (n = 101)/uni00A0 Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration • Adverse effects • AFS score Notes Intention-to-treat analysis: no Sample size calculation: /uni00A0not stated Funding: Supported in part by Syntex Research, Palo Alto, California, US NEET 1992/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 107 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Note previous version: 8 participants who were randomised never took the study medication. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "patients were randomised so that 2 were assigned to receive nafarelin for every 1 assigned to receive danazol". No further information was provided on

used to generate random sequence. Allocation concealment (selection bias) Unclear risk No details were provided of method used to conceal treatment group alloca- tion. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind study Incomplete outcome data (attrition bias) All outcomes Low risk Detail for attrition:/uni00A0 • "307 were included in the safety analyses, of whom 263 also qualified for the efficacy analyses (171 nafarelin and 92 danazol recipients)" • 25 had been treated 150 days but refused or otherwise missed the post-treatment laparoscopy • 12 violated the study protocol • 14 discontinued due to adverse events • 4 for intercurrent illness • 4 for personal reasons • 1 due to ineffective treatment • 2 lost to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected NEET 1992/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised study Participants Participants: 21 women were randomised and analysed. Mean age: 33 ± 5 years Inclusion criteria: • Laparoscopically diagnosed endometriosis • Pelvic pain Odukoya 1995/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 108 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Exclusion criteria: not stated Setting: United Kingdom Timing: not stated Interventions Leuprolide acetate 3.75 SC monthly for 3 months (n = 10) versus Danazol 400 mg daily PO for 3 months (n = 11) /uni00A0 Outcomes • Relief of overall pain (Biberoglu + Behrman scale) • Serum soluble CD23/uni00A0 Notes Intention-to-treat analysis: Yes Sample size calculation: not stated Funding: not stated Note previous version: Authors contacted regarding methods (blinding) and SD data; awaiting re- sponse /uni00A0 Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Randomisation was "computer generated". No further details of method used to generate the randomisation sequence were provided./uni00A0 Allocation concealment (selection bias) Low risk "concealed in an envelope only opened at commencement of treatment". No further details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or trial personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Odukoya 1995/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: randomised, double-blinded, placebo-controlled trial Orwoll 1994/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 109 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Participants Participants: 183 women were randomised and 137 analysed. Mean age: /uni00A031 years (range 17 to 46 years) Inclusion criteria: • Symptomatic endometriosis, proved by laparoscopy • Bone density measures during treatment • Regular menstrual cycles for at least 3 months before enrolment • Using a barrier method of contraception Exclusion criteria:/uni00A0 • Therapy with danazol, androgenix hormones, oestrogens, progestins, glucocorticoids, GnRH ago- nists, or any other medication known to influence bone or mineral metabolism for at least 3 months before study • > 2 ounces of alcohol per day • Pregnant or breastfeeding • Had a significant laboratory abnormality Setting: United States of America (9 academic medical centres) Timing: not stated Interventions 200 /uni03BCg of nafarelin intranasally twice per day for 6 months (n = 92)/uni00A0 versus 200 /uni03BCg of nafarelin intranasally twice per day for 3 months followed by 3 months of placebo (n = 91) Outcomes • Bone mineral density Notes Intention-to-treat analysis: yes Sample size calculation: not stated Funding: Supported by Syntex Laboratories, Inc Note: Drs. Orwoll and Hornstein have been salaried consultants for Syntex Laboratories, Inc. Author could not be contacted due to lack of information. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Subjects were randomised". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Randomised, double-blinded, placebo-controlled trial Blinding of outcome as- sessment (detection bias) All outcomes Low risk Randomised, double-blinded, placebo-controlled trial Orwoll 1994/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 110 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Incomplete outcome data (attrition bias) All outcomes Unclear risk Not stated; appeared that all women included also were analysed Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Orwoll 1994/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: prospective randomised study Participants Participants: 74 women were randomised; 70 women were analysed. Mean age:/uni00A0 Group G: 34.2 ± 5.4 years (32.4–36.1) Group D: 35.4 ± 5.7 years (32.4–36.9) Inclusion criteria: • At least one endometrioma larger than 4 cm Exclusion criteria:/uni00A0 • Age older than 45 years • Presence of any leiomyoma • Diagnosis of endocrine disorders, history of abdominal surgery • Presence or history of any concomitant pelvic inflammatory diseases • Presence of endocrine disorders • History of abdominal surgery, presence of malignant ovarian disease • History of hormonal treatment within 3 months before recruitment Setting: Japan Timing: January 2011 to August 2014 Interventions Group D received dienogest (Dinagest®, 1 mg; Mochida Pharmaceutical Co., Ltd., Tokyo, Japan) at 2 mg/ day for 4 months preoperatively. Group G received a low-dose sustained-release goserelin acetate (ZOLADEX®, 1.8 mg; Kissei Pharma- ceutical Co., Ltd., Nagano, Japan) at 1.8 mg every 4 weeks for a total of administrations preoperatively. Outcomes • Adverse effects • Improvement of most troublesome symptom • Number of uses of nonsteroid anti-inflammatory drugs • Diameter of ovarian cysts • Postoperative lesion recurrence • Laboratory results Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Ozaki 2020/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 111 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Funding: The authors declared that they had no confict of interest. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Stratifed randomisation was conducted in the participants. "1:1 ratio comput- erized random number function in Microsoft Excel" Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk 74 randomised, 70 analysed Group G: 35/37 were analysed; group D: 35/37 were analysed. Excluded in group G due to mucinous cyst (n = 1) and borderline malignancy (n = 1) Excluded in group D due to mucinous cyst (n = 1) and dincontinued interven- tion (n = 1) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Ozaki 2020/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised, open study Participants Participants: 50 women were randomised; 47 were analysed. Age: 20-40 years Inclusion criteria: • Laparoscopically diagnosed endometriosis • No treatment for endometriosis within previous 12 months Exclusion criteria: not stated Setting: Italy/uni00A0 Timing: not stated Interventions Leuprolide acetate 3.75 mg IM monthly for 6 months (n = 30)/uni00A0 Palagiano 1994/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 112 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews versus/uni00A0 Danazol 600 mg once daily per os for 6 months (n = 20) Outcomes • Relief of overall pain: Dysmenorrhoea, dyspareunia, pelvic pain • Adverse effects Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated/uni00A0 Note previous version: Authors contacted regarding methods and replied Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "randomly allocated". No further details were provided of method used to generate the randomisation sequence. Allocation concealment (selection bias) Unclear risk Randomisation done by a pharmacy. No further details were provided of

used to conceal treatment group allocation. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk Open study Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk Open study Incomplete outcome data (attrition bias) All outcomes Low risk Three participants were lost to follow-up due to adverse effects (leuprolide ac- etate). Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Palagiano 1994/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: multi-centre randomised, controlled clinical trial Participants Participants: 83 women were randomised; 71 were analysed. Mean age: LNG-IUS = 29.4 ± 4.8 years and Lupron depot = 30.5 ± 6.4 /uni00A0years Inclusion criteria: • Laparoscopically and histologically confirmed endometriosis within 3 to 24 months prior to study en- rolment • 18-40 years old Petta 2005/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 113 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Complaints of cyclic chronic pelvic pain with or without dysmenorrhoea • VAS pain score of greater or equal to 3 during the pretreatment cycle • Regular menstrual cycle of 25-35 days for at least 3 months prior to study Exclusion criteria: • Hormone treatment within 3 months of entering study • Long acting progestins or GnRHa within 9 months prior to study • Pregnant or breastfeeding within 3 months prior to study • Osteoporosis, coagulation disorders or contraindications to LNG-IUS Setting: Brazil ( 3 centres) Timing: February 2002 to May 2004 Interventions LNG-IUS (Mirena) 20 mcg/day 5 years IU for 6 months (n = 39) versus Lupron 3.75 mg every 28 days IM for 6 months (n = 43) /uni00A0 Outcomes • Pain as defined by VAS score • Psychological general well-being index Notes Intention-to-treat analysis: Data analysis did not follow intention-to-treat principles but included only those women who had completed the VAS pain diary correctly throughout the entire study period of 6 months (n = 71). Sample size calculation: yes Funding:The levonorgestrel-releasing intrauterine system (Mirena) and GnRH analogue ampoules were provided free of charge by Schering, Sao Paulo, Brazil. Note previous version: Authors contacted regarding data; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk Randomisation was by "computer generated system". Three centres partici- pated in the study and randomisation was performed separately for each cen- tre. Allocation concealment (selection bias) Unclear risk "sealed envelopes" were used to conceal allocation to treatment groups./uni00A0 Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk "Blinding of participants would not have been possible due to nature of the in- tervention". No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Low risk Outcome assessors were blinded according to author. Incomplete outcome data (attrition bias) All outcomes Low risk "data analysis did not follow intention-to-treat principles" but details given for attrition: • 6 each from both groups withdrew • 1 pregnant and 5 did not complete pain diary (LNG-IUS) Petta 2005/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 114 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • 6 did not complete pain diary (Lupron) Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Petta 2005/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "multi-centre, open, parallel study" Participants Participants: 315 women were randomised and analysed. Only 58 did BMD measurements. Mean age: Goserelin = 30.4 years and danazol = 29.7 years Inclusion criteria: • Laparoscopically confirmed endometriosis • AFS score of ≥ 2 • Symptomatic (total pelvic score of equal or greater than 3) or asymptomatic disease, with or without infertility Exclusion criteria: • Stage IV disease Setting: United States of America (17 centres) Timing: not stated Interventions Goserelin 3.6 mg every 28 days SC for 24 weeks (n = 208) versus Danazol 400 mg twice a day PO for 24 weeks (n = 107) Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration • Adverse effects • Bone Mineral Density • rAFS score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Study sponsored by a grant from ICI Pharmaceuticals Group, a business unit of Zeneca Inc, Wilmington, Delaware Note previous version: Authors contacted regarding methods and data; awaiting response/uni00A0 "14 participants, with stage IV endometriosis were included because their investigators believed that significant components of stage IV endometriosis could benefit from hormonal treatment"./uni00A0 Risk of bias Bias Authors' judgement Support for judgement Rock 1993/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 115 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Random sequence genera- tion (selection bias) Unclear risk Randomised 2:1 goserelin: danazol. No further details of method used to gen- erate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk "All randomised subjects were included in the overall analysis of treatment outcome". Details given for attrition: • 15/208 in goserelin and 18/107 in danazol group withdrew • 6 in goserelin and 13 in danazol group withdrew due to adverse events Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Rock 1993/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: parallel, randomised, double-blind, double-placebo study Participants Participants: 194 women were randomised; 170 were analysed. Mean age: between 18 and 45 years Inclusion criteria: • Laparoscopically confirmed endometriosis • 18-45 years old • Body weight of 45-110kg • Menstrual cycle of 24-36 days • Symptomatic • Not pregnant • Negative pap smear test Exclusion criteria: • Prescence of amenorrhoea • Interfering concurrent disease • Surgical treatment at baseline laparoscopy or within 6 months prior to study • Gonadal hormone or danazol use within 3 months prior to study • Simultaneous participation in other studies Rolland 1990/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 116 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Setting: 13 medical centres in seven European countries Timing: not stated Interventions Nafarelin 200 /uni03BCg twice daily IN + placebo PO twice daily for 6 months (n = 127) versus Danazol 200 mg twice daily PO + placebo IN twice daily for 6 months (n = 67)/uni00A0 Outcomes • Pain defined by symptoms severity score • Adverse effects • AFS score Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Authors contacted regarding methods and data. Letter returned with author unknown at Department Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk Randomised 2:1 nafarelin: danazol. No further details of method used to gen- erate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-placebo, double-blind study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-placebo, double-blind study Incomplete outcome data (attrition bias) All outcomes Low risk Details for attrition: • 20 in nafarelin and 4 in danazol group withdrew due to: /uni25E6adverse effects 7 (Naf) vs 2 (Dan) /uni25E6intercurrent illness 1 (Naf) vs 2 (Dan) /uni25E6personal reasons 3 (Naf) /uni25E6lost to follow-up 3 (Naf) /uni25E6lack of drug efficacy 1 (Naf) /uni25E6other 5 (Naf) Nafarelin: 20/127 discontinued treatment. Danazol: 4/67 discontinued treatment. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Rolland 1990/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 117 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised trial Participants Participants: 81 women were randomised in a 2:1 ratio to leuprolide n = 54, or danazol n = 27. Mean age: mean age not provided; median age was 32 years (range 19-41) Inclusion criteria:/uni00A0 • Laparoscopically confirmed endometriosis Exclusion criteria: not stated Setting: Italy, fertility centre of the second University of Naples Timing: 1992 to 1999 Interventions Leuprolide acetate 3.75 mg subcutaneously every 28 days, for 6 months versus Danazol 200 mg orally three times a day for 6 months Outcomes • Relief of overall pain: subjective symptom scores using a numerical scale • Adverse effects • rAFS scores Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Excluded from previous version of this review as pain was not an outcome. In- cluded in this review, but did not contribute any data Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "randomly allocated". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) Low risk 3/54 women from leuprolide group and 5/27 from danazol group withdrew due to "adverse findings". Rotondi 2002/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 118 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews All outcomes Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Rotondi 2002/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: single-site, double-masked, randomised, placebo-controlled, dose-ranging trial Participants Participants: 42 women were randomised; 40 women were analysed. Mean age: 34.0 ± 6.5 years (range 20-44 years) Inclusion criteria: • Endometriosis diagnosed by signs or symptoms or laparoscopy Exclusion criteria:/uni00A0 • Amenorrhoea • Taking drugs known to affect bone metabolism • Evidence of an associated disease • Interruption of more than 15 days in the administration of the drug Setting: France Timing: not stated Interventions All participants received triptorelin 3.75 mg IM every four weeks + norgestrel acetate 5 mg/day during the first 3 weeks following injection and then 1 g calcium carbonate daily for 27 weeks./uni00A0 In addition: Group 0: placebo intranasal spray, Group 1: salmon calcitonin 100 IU IN daily,/uni00A0 Group 2: salmon calcitonin 200 IU IN daily. Outcomes • Bone Mineral Density • Adverse effects • Biochemical changes Notes Intention-to-treat analysis: yes Sample size calculation: yes Funding: not stated Author could not be contacted due to lack of information. Risk of bias Bias Authors' judgement Support for judgement Roux 1995/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 119 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Random sequence genera- tion (selection bias) Unclear risk "Randomly devided". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk 2 participants failed to complete the study - one was lost to follow-up and one was excluded due to orthopaedic material in the lumbar spine. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Roux 1995/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: multi-centre, randomised, evaluator-blinded, comparator-controlled trial Participants Participants: 274 women were randomised; 190 women were analysed. Mean age: medroxyprogesterone acetate group 29.2 ± 6.3 years, leuprolide group 32.1 ± 6.6 years Inclusion criteria: • Premenopausal women • Age from 18 to 49 years • Persistent symptoms of pain caused by endometriosis (surgically diagnosed within previous 42 months) • Pain must have returned to its previous level within 30 days after a diagnostic laparoscopy or within 3 months after laparoscopy or laparotomy with surgical treatment and must have persisted for a min- imum of 3 months. Exclusion criteria:/uni00A0 • Baseline BMD at the lumbar spine and hip was < 1 SD below the peak adult bone mass Setting: United States of America (43 sites) and Canada (7 sites) Timing: not stated Interventions Subcutaneous depot medroxyprogesterone acetate (DMPA) (104 mg/0.65 mL) every 3 months (n = 136)/uni00A0 versus Leuprolide (11.25 mg) intramuscular every 3 months (n = 138) Schlaff 2006/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 120 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcomes • Bone Mineral Density • Pain (Biberoglu and Behrman symptom scale) • Quality of life • Adverse effects • Hypoestrogenic symptoms • Bleeding patterns • Endometriosis-impact diary Notes Intention-to-treat analysis: yes Sample size calculation: yes Funding: not stated Author contacted; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomised". No further details of method used to generate the randomisa- tion sequence were provided. Allocation concealment (selection bias) Unclear risk "An independent person maintained the randomization code, received the study syringes, and administered the study medication". Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Low risk In this evaluator-blinded study, the principal investigator and any designated sub-investigators and study co-ordinators at each centre were blinded to the randomisation of each participant. Incomplete outcome data (attrition bias) All outcomes High risk There was a dropout rate of 35.3% in the DMPA-SC 104 group (48/136) and of 26.1% in the leuprolide group (36/138) during the 6-month treatment period. The majority of these participants either actively withdrew from the study (DMPA-SC 104 = 21, leuprolide = 9) or were lost to follow-up (14 and 11, respec- tively). Nine patients in each group (6.6% and 6.5% in the DMPA-SC 104 and le- uprolide groups, respectively) discontinued as a result of adverse side effects. Of those women who completed the 6 months of active treatment, 51 (58.0%) of 88 in the DMPA-SC 104 group and 58 (56.9%) of 102 in the leuprolide group le/f_t the study during the 12-month follow-up period. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Schlaff 2006/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics Shaw 1986/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 121 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

Trial design: Randomised study Participants Participants: 20 women were randomised; 19 analysed/uni00A0 Mean age: 30.4 +/- 3.8/uni00A0 Inclusion criteria:/uni00A0 • Laparoscopically diagnosed disease • No treatment within 4 months prior to study Exclusion criteria: not stated/uni00A0 Setting: UK/uni00A0 Timing: not stated Interventions Buserelin 200 mcg three times a day intranasally for 6 months (n = 10)/uni00A0 versus/uni00A0 Buserelin 300 mcg three times a day intranasally for 6 months (n = 10) Outcomes Symptomatic changes/uni00A0 rAFS score/uni00A0 Adverse effects Notes Intention-to-treat analysis: No/uni00A0 Sample size calculation: not stated/uni00A0 Funding: Hoechst UK supplied the Buserelin used in this study. No further details provided Note previous version: Authors contacted but unable to provide further details as trial was almost 20 years old/uni00A0 Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "randomly allocated". No further details of method used to generate random sequence Allocation concealment (selection bias) Unclear risk No details provided of method used to conceal allocation to treatment groups Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk "this paper reports an open study" with no further details. Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk "this paper reports an open study" with no further details. Incomplete outcome data (attrition bias) All outcomes Low risk Detail for attrition: 1 from buserelin 300 mcg TDS group withdrew after 3 months due to adverse effects. Shaw 1986/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 122 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Selective reporting (re- porting bias) High risk No comparisons between groups for symptomatic changes Other bias Low risk No other risk of bias reported Shaw 1986/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Multi-centre, placebo-controlled, randomised trial Participants 82 women were randomised; 74 were analysed. Mean age: not stated Inclusion criteria: • Endometriosis Exclusion criteria: not stated Setting: United Kingdom (2 sites) Timing: not stated Interventions Nafarelin 200 mcg BD IN + placebo PO for 6 months (n = 55) versus Danazol 200 mg three times a day PO + placebo IN for 6 months (n = 26) Outcomes • Improvment of most troublesome symptom: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tender- ness and induration combined Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Note previous version: Authors contacted but unable to provide further details as trial was almost 20 years old Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomized". No further details of method used to generate the randomisa- tion sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Participants were blinded and received placebo nasal spray or tablets. Blinding of outcome as- sessment (detection bias) Low risk Placebo-controlled study Shaw 1990/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 123 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews All outcomes Incomplete outcome data (attrition bias) All outcomes Low risk Details for attrition given: 8 withdrew: • Nafarelin = 3 due to side effects, 1 le/f_t country, 1 poor compliance • Danazol = 2 due to side effects, 1 poor compliance Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Shaw 1990/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised, double-blind, placebo-controlled, trial Participants Participants: 23 women were randomised. Mean age: Group A: 29.7 ± 4.5 years, group B: 31.4 ± 3.8 years Inclusion criteria: • Regularly menstruating • Laparoscopically proven symptomatic endometriosis Exclusion criteria:/uni00A0 • Evidence of osteopenia, osteoporosis or other skeletal disease • Significant non-skeletal disease • Pregnancy or lactation • Use of medications known to interfere with bone metabolism in the 3 months prior to enrolment • Psychiatric disorders Setting: Germany Timing: not stated Interventions All patients underwent a six months course of goserelin (Zoladex®, Zeneca GmbH, Plankstadt, Ger- many) 3.6 mg SC every four weeks, the first injection being given on cycle day 3-5 at the initial visit. Group A: additionally placebo /uni00A0(n = 12) versus/uni00A0 Group B: additionally 5 mg medrogestone orally twice daily (Prothil®, Solvay GmbH, Hannover, Ger- many) (n = 11) Outcomes • Bone mineral density • Serum oestradiol and FSH levels, bone-specific alkaline phosphatase, /uni00A0osteocalcin • Urinary concentrations of total pyridinoline and of total deoxypyridinolin Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Sillem 1999/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 124 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Author contacted; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomly allocated". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Unclear risk No information about incomplete outcome data Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Sillem 1999/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Placebo, randomised, parallel study. Participants 34 women were randomised and analysed . Mean age: GnRHa = 31.02 ± 2.5 and placebo = 32.13 ± 1.5 (SD)/uni00A0 Inclusion criteria:/uni00A0 • Laparoscopically diagnosed endometriosis • Symptomatic • Surgically or pharmacologically treated in 6 months prior • Regular menstrual cycle in prior 3 months • Not pregnant Exclusion criteria: • Cardiovascular burden • Hormone-dependent neoplasms • Osteoporosis • Bilateral oophorecystectomy • Abnormal liver and renal tests Setting: Poland/uni00A0 Skrzypulec 2004/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 125 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Timing: September 2003 to April 2004 Interventions GnRHa 50 mg once daily per os for 12 weeks (n = 16)/uni00A0 versus/uni00A0 Placebo per os for 12 weeks (n = 18) Outcomes Relief of overall pain: reported as dysmenorrhoea, dyspareunia, pelvic pain Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "Randomisation was in the ratio two goserelin: one danazol with each centre having its randomisation list", "The randomised trial of Zoladex and Danazol was a multi-centre trial with randomisation envelopes provided by the spon- sors ICI to each of the centres as plain sealed envelopes and computerised ran- domisation lists for each centre" (author's reply). Allocation concealment (selection bias) Unclear risk "plain, sealed envelopes". No other details provided of method used to con- ceal allocation to treatment groups Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Participants, investigators, outcome assessors and clinicians were all blinded according to author. Blinding of outcome as- sessment (detection bias) All outcomes Low risk Participants, investigators, outcome assessors and clinicians were all blinded according to author. Incomplete outcome data (attrition bias) All outcomes Low risk All women who were randomised were analysed. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detetcted Skrzypulec 2004/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: The study was a multi-centre, randomised, open-label, parallel-group, non-inferiority comparison. Participants Participants: 252 women were randomised; 229 women were analysed. Mean age: 18–45 years Strowitzki 2012/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 126 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Inclusion criteria: • Women aged 18-45 years • De novo or recurrent pain associated with a confirmed diagnosis of endometriosis Exclusion criteria:/uni00A0 • Amenorrhea (≥ 3 months) • Need for surgical treatment • Previous use of hormonal treatments within specified times • Abnormal findings (other than endometriosis) at gynaecologic examination • Pregnancy or breastfeeding • Risk factors for decreased bone mineral density Setting: Germany Timing: not stated Interventions Dienogest (DNG) 2 mg/day orally /uni00A0(n = 124) versus Intramuscular leuprolide acetate 3.75 mg depot every 4 weeks (n = 128) Outcomes • Relief of overall pain: pelvic pain, dysmenorrhoea, dyspareunia scores (VAS, Biberoglu and Behrman) • Adverse events • Quality of life (SF-36) • Improvement of most troublesome symptom • Markers of bone metabolism Notes Intention-to-treat analysis: No. "Efficacy analyses were based on the per-protocol set (PPS), which in- cluded all randomized patients without major protocol deviations (a 'conservative' strategy appropri- ate for non-inferiority studies)". Sample size calculation: yes Funding: Funding for the study was provided by Bayer HealthCare. J.M., C.G., T.F., and C.S. are full-time employees of Bayer HealthCare. Editorial support funded by Bay- er HealthCare was provided by PAREXEL. This editorial support consisted of the preparation of manu- script dra/f_ts based on detailed author guidance. Authors contacted; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Patients were randomized (1:1 ratio)". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk weo details of method used to conceal allocation are provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Strowitzki 2012/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 127 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk Overall, 109/124 (87.9%) women in the DNG group and 120/128 (93.8%) women in the LA group completed the study. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Strowitzki 2012/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: prospective randomised trial Participants Participants: 20 women were randomised; 17 women were analysed. Mean age: group A: 32.9 ± 1.1 years, group B: 28.9 ± 1.7 years Inclusion criteria: • Symptomatic endometriosis diagnosed by laparoscopy Exclusion criteria:/uni00A0 • Calcium supplements during the treatment, less than four endometriotic implants • Endometrioma greater than 5 cm in diameter Setting: United States of America Timing: not stated Interventions Group 1: leuprolide acetate 3.75 mg IM every 28 days (n = 10) versus Group 2: leuprolide acetate 3.75 mg IM every 28 days and norethindrone po 5 mg for the first four weeks and then 10 mg daily for the remaining 20 weeks (n = 10) Outcomes • Bone mineral density • Improvement of most troublesome symptom • Laboratory changes Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Sponsored by TAP Pharmaceuticals Risk of bias Bias Authors' judgement Support for judgement Surrey 1992/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 128 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Random sequence genera- tion (selection bias) Low risk Computerised allocation (author reply). No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk 1/20 participants lost to follow-up. One patient assigned to receive GnRHa and norethindrone failed to complete therapy for reasons which were felt to be un- related to the medication. She was not replaced and data related to this pa- tient were excluded from analysis./uni00A0 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Surrey 1992/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: post-treatment follow-up analysis of a randomised, double-masked, placebo-controlled trial Participants Participants: 201 women were randomised; 99 women were analysed. Mean age:/uni00A0 Group A: 29.0 ± 1.0 years Group B: 29.0 ± 1.1 years Group C: 29.4 ± 1.0 years Group D: 28.9 ± 1.2 years Inclusion criteria: Regular menstrual cycle • Symptomatic endometriosis, which had been diagnosed surgically within 12 months of entry with persistent or recurrent pain • Symptomatic improvement over baseline at the end of the treatment period • Did not terminate the treatment protocol because of worsening symptoms Exclusion criteria:/uni00A0 • Become pregnant • Have surgical or medical intervention for endometriosis Surrey 2002/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 129 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews • Have non-endometriosis surgery that could have had an impact on pelvic pain during the treatment period Setting: United States of America (26 study sites) Timing: not stated Interventions Patients in all groups were to receive a depot preparation of the GnRH agonist leuprolide acetate 3.75 mg intramuscularly every 4 weeks for 52 weeks./uni00A0 Group A: daily oral placebos for oestrogen and progestin add-back (n = 51) Group B: daily oral norethindrone acetate (Aygestin, Lederle, Wayne, NJ) 5 mg and placebo for oestro- gen (n = 55) Group C: received oral norethindrone acetate 5 mg and conjugated equine oestrogens (Premarin, Wyeth-Ayerst, Philadelphia, PA) 0.625 mg daily (n = 47) Group D: received oral norethindrone acetate 5 mg and conjugated equine oestrogens 1.25 mg daily (n = 48) Outcomes • Relief of overall pain • Mean changes in lumbar spine bone mineral density • Circulating cholesterol subfractions, triglycerides, and total cholesterol levels Notes Intention-to-treat analysis: yes Sample size calculation: yes/uni00A0 Funding: This work was supported by a grant from TAP Pharmaceutical Products, Inc., Lake Forest, Illi- nois. Financial Disclosure: Drs. Surrey and Hornstein have received grant support and honoraria as members of the speaker’s bureau of TAP Pharmaceuticals. Dr. Surrey is also a member of the Medical Advisory Board of TAP Pharmaceuticals. Ms. Fredrick performed the statistical analysis and is an employee of Abbott Laboratories, a parent company of TAP Pharmaceuticals. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "Patients were assigned randomly to one of four treatment groups by permut- ed blocks of four at each of the treatment sites". Allocation concealment (selection bias) Unclear risk No details were presented on the method of concealment. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-masked, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-masked, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes High risk 123/201 completed 280 days of therapy./uni00A0 Because of dropouts, the actual group-specific sample sizes in the follow-up period were lower than the numbers originally enrolled based on the initial power analyses. Thus, a post hoc analysis was performed. Surrey 2002/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 130 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Surrey 2002/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Prospective, randomised, longitudinal pilot study Participants Participants: 15 women were randomised and analysed. Mean age:/uni00A0 Control group: 35.2 ± 2.6 years Half-dose group: 34.7 ± 5.7 years Inclusion criteria: • Symptomatic endometriosis who were candidates for 6 months of GnRH agonist therapy • Diagnosis of endometriosis was confirmed by laparoscopy or laparotomy • Menstruated regularly • Normal hepatic and renal function Exclusion criteria:/uni00A0 • No recent medical treatment for endometriosis • Not taking medications known to affect bone metabolism Setting: Japan Timing: not stated Interventions Control group: full-dose intranasal nafarelin treatment (200 /uni03BCg twice daily) for 24 weeks (n = 7) versus Half-dose group: full dose intranasal nafarelin treatment (200 /uni03BCg twice daily) for 4 weeks followed by half-dose intranasal nafarelin treatment (200 /uni03BCg daily) for 20 weeks (n = 8) Outcomes • Symptoms of endometriosis (dysmenorrhoea, dyspareunia, and pelvic pain) • Vasomotor symptoms (hot flashes or dizziness) • Bone mineral density • Fasting serum and urine samples Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Tahara 2000/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 131 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Random sequence genera- tion (selection bias) Low risk The patients were assigned, using a random number table, to two groups./uni00A0 Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Tahara 2000/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled study Participants Participants: 50 women were randomised and /uni00A0analysed. Mean age:/uni00A0 Full-dose group: 31.52 ± 6.38 years Half-dose group: 30.36 ± 5.54 years Inclusion criteria: • Patients with stage III-IV endometriosis Exclusion criteria:/uni00A0 • Ovarian reserve decrease (days 1 –3: follicle-stimulating hormone [FSH] > 12 pg/mL) or peri- menopausal status • Discontinued follow-up and cooperation • Malignancy of genital or other systems • Liver, kidney or coagulation system dysfunction Setting: Japan Timing: June 2014 to June 2016 Interventions Research group = Half-dose group: “draw-back” treatment with 3.75 mg GnRHa (leuprorelin) in the first two injections (one injection per 28 days), after which the third injection contained 1.88 mg GnRHa, and this dosage was continued up to and including the sixth injection after achieving the suppression crite- ria (E2 < 50 pg/mL, endometrial thickness 5 mm; in total four injections at 1.88 mg) (n = 25) Tang 2017/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 132 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Control group = full-dose group: 3.75 mg GnRHa for six injections (n = 25) Outcomes • Relief of overall pain: degree of dysmenorrhoea • Bone mineral density • Adverse effects • Sex hormones • Symptoms of perimenopause • Resumption of menses Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: by Science and Technology Development Fund Project of Shenzhen, China (grant no. JCYJ20140415162338852), Science and Technology Planning Project of Guangdong Province, China (grant no. 2013B021800095), Scientific Research Project of Shenzhen Health Family Planning, Chi- na (grant no. 201401038) and Natural Science Foundation of Guangdong Province, China (grant no. 2015A030313889) Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomly divided". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Unclear risk No information about incomplete outcome data Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected. Tang 2017/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: /uni00A038 women were randomised and analysed. Mean age: 31.4 ± 0.6 years Tummon 1988/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 133 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Inclusion criteria: • Laparoscopically diagnosed and staged endometriosis Exclusion criteria: not stated Setting: United States of America Timing: not stated Interventions /uni00A0GnRHa group: 8 women received leuprolide 1.6 mg daily intranasally, 8 women received buserelin 1.2 mg daily IN and 9 received buserelin 200 /uni03BCg daily subcutaneously (n = 25) versus Danazol, 200 mg four times daily orally (n = 13) Outcomes • Bone Mineral Density • Serum E2, FSH, LH, and progesterone concentrations Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Supported by TAP Pharmaceuticals, Abbott Laboratories, North Chicago, Illinois, and by Hoechst-Roussel Pharmaceuticals, Somerville, New Jersey Author could not be contacted due to lack of information. Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomly assigned". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No further details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Unclear risk No information about incomplete outcome data Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Tummon 1988/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 134 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Study characteristics

Trial design: Prospective, randomised study Participants Participants: 15 women were randomised and analysed. Mean age: 32.1 ± 0.9 years (range 27 to 38 years) Inclusion criteria: • Laparoscopically diagnosed endometriosis within 3 months prior to study • Infertile women • Regular menstrual cycles • Negative beta-subunit human chorionic gonadotropin (hCG) Exclusion criteria: not stated Setting: united States of America Timing: not stated Interventions Leuprolide /uni00A0daily SC injectons of 0.5 mg for 7 days, then changed to 400 mcg four times a day IN for 26 weeks (n = 10) versus Danazol 200 mg four times a day PO for 26 weeks (n = 5) Outcomes • Relief of overall pain: dysmenorrhoea, dyspareunia, pelvic pain • rAFS score • Hypoestrogenic symptoms Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: Supported in part by a grant from Abbott Laboratories, Inc., Chicago, Illinois Note previous version: Authors contacted regarding methods and data; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk Randomised 2:1 ratio leuprolide: danazol. No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Tummon 1989/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 135 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Tummon 1989/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Open-label, randomised study Participants Participants: 42 women were randomised and analysed. Mean age:/uni00A0 Group 1: 29 ± 6 years Group 2: 31 ± 6 years Inclusion criteria: • Diagnostic laparoscopy with no attempts at endometriosis reduction other than biopsy up to 3 months before study entry Exclusion criteria:/uni00A0 • Treatment for endometriosis other than NSAID in the previous 3 months • Usual contraindications for danazol • Unwillingness to use barrier contraception Setting: Italy Timing: not stated Interventions Group 1: Danazol only, oraly 50 mg/day for 9 months (n = 21) versus Group 2: Leuprolide 3.75 mg in a 28-day IM depot for 3 months, followed by oral danazol 50 mg/day for 6 months + danazol (n = 21) Outcomes • Relief of overall pain: dysmenorrhoea, non-menstrual pelvic pain, deep dyspareunia Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "Computer-generated randomisation list". No further details of method used to generate the randomisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Vercellini 1994/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 136 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Unclear risk No details provided of blinding of outcome assessment Incomplete outcome data (attrition bias) All outcomes Low risk 5/42 withdrew from this study, one in each group at the fi/f_th month of treat- ment (for persistent pain) and one in each group during follow-up (they re- quested additional therapy). One women in the Danazol group was lost to fol- low-up. /uni00A0 Group 1: 18/21 completed follow-up. Group 2: 19/21 completed follow-up. /uni00A0 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Vercellini 1994/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: a multicentre, randomised, double-blind study Participants Participants: /uni00A055 women were randomised; /uni00A049 women were analysed (41 underwent complete serial bone mineral content assessment). Mean age:/uni00A0 Gestrinone: 31.9 ± 5.4 years Leuprolide acetate: 28.6 ± 6.2 years Inclusion criteria: • Diagnostic laparoscopy with no attempts at endometriosis reduction other than biopsy up to 3 months before study entry Exclusion criteria:/uni00A0 • Medical or surgical treatments specific for endometriosis • Treatment for endometriosis other than nonsteroidal anti-inflammatory drugs in the previous 6 months • Concomitant disorders that might cause gynaecologic pain (e.g. pelvic inflammatory disease and ob- structive genital malformations) • Contraindications to the use of gestrinone or GnRHas • Abnormal baseline mineral bone density values • Unwillingness to use barrier contraception Setting: Italy Vercellini 1996/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 137 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Timing: not stated Interventions Oral gestrinone 2.5 mg twice a week (Dimetrose; Poli Industria Chimica, Rozzano, Milano, Italy) (n = 27) versus Leuprolide acetate IM 3.75 mg depot injections every 4 weeks (Enantone; Takeda Farmaceutici, Roma, Italy) (n = 28) Outcomes • Relief of overall pain • Bone mineral density • Adverse effects • Plasma lipids and lipoprotein Notes Intention-to-treat analysis: not stated Sample size calculation: not stated; only a post hoc analysis Funding: Supported in part by Poli Industria Chimica, Rozzano, Milano, Italy Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomisation". No further details of method used to generate the randomi- sation sequence were provided. Allocation concealment (selection bias) Low risk Sealed envelopes containing randomisation codes were to be opened only at trial completion or in case of severe side effects. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind, placebo-controlled study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind, placebo-controlled study Incomplete outcome data (attrition bias) All outcomes Low risk 6/55 women withdrew from the study during the treatment period, 4/27 in the gestrinone group (three refused further therapy, in one case because of her general practitioner's unfavourable opinion, in two cases because of psycho- logical intolerance to treatment blinding, and one failed to keep clinic appoint- ments) and 2/28 in the leuprolide acetate group (they stopped treatment for concomitant nongynaecologic diseases). Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Vercellini 1996/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: "double-blind, multi-centre, randomised trial"/uni00A0 Wheeler 1992/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 138 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Participants Participants: 270 women were randomised and 253 were analysed. Age: Leuprolide = 30.8 years and danazol = 29.9 years Inclusion criteria: • Laparoscopically diagnosed endometriosis within 4 months prior to study • Over 18 years of age • No surgical treatment at time of laparoscopy • Premenopausal • Not pregnant or lactating • Any other treatment completed at least 3 months prior to study Exclusion criteria • Previously taken GnRHa • Women with base-line bone densitometry of > 2 SD below the mean Setting: United States of America (17 centres) Timing: October 14, 1986 to December 21, 1988 Interventions Leuprolide 3.75 mg monthly IM + placebo once daily PO for 24 weeks (n = 134) versus Danazol 800 mg once daily PO + placebo monthly IM for 24 weeks (n = 136) Outcomes • Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness • Bone mineral density • Laboratory determinations • rAFS score • Analgesic use Notes Intention-to-treat analysis: not stated Sample size calculation: yes/uni00A0 Funding: TAP-Abbott Research and Development Judith Knittle is Senior Clinical Project Manager at TAP Pharmaceuticals Inc. In addition to her role in the preparation of this manuscript, she was involved in the design and implementation of the study. James Miller, MD, is currently Medical Director at TAP Pharmaceuticals Inc; during the conduct of this trial, he was in private clinical practice in Seattle and was one of the principal investigators of the study. Note previous version: Authors contacted regarding methods and data; awaiting response Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomly assigned". No further details of method used to generate the ran- domisation sequence were provided. Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Placebo-controlled, double-blind study Wheeler 1992/uni00A0/uni00A0(Continued) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 139 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Blinding of outcome as- sessment (detection bias) All outcomes Low risk Placebo-controlled, double-blind study Incomplete outcome data (attrition bias) All outcomes Low risk Details given for attrition: 17 patients were excluded due to: • failure to meet inclusion criteria 2 (Leu) and 1 (Dan) • non-compliance 3 (Leu) and 10 (Dan) • inadvertent dosing with another patient's designated leuprolide 1 Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Wheeler 1992/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised controlled trial Participants Participants: 24 women were randomised; 22 women were analysed. Mean age: Nafarelin 33.7 ± 7 years, danazol 30.0 ± 3.3 years Inclusion criteria: • Endometriosis diagnosed at laparoscopy Exclusion criteria:/uni00A0 • Medically unsuitable to undergo quantitative computerised tomography Setting: United Kingdom Timing: not stated Interventions Nafarelin 200 /uni03BCg twice daily by nasal insufflation (n = 15) versus Danazol 200 mg three times daily orally (n = 9) Outcomes • Bone mineral density • Serum oestradiol levels Notes Intention-to-treat analysis: not stated Sample size calculation: not stated Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Unclear risk "Randomly allocated". No further details of method used to generate the ran- domisation sequence were provided. Whitehouse 1990/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 140 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Low risk Double-blind study Blinding of outcome as- sessment (detection bias) All outcomes Low risk Double-blind study Incomplete outcome data (attrition bias) All outcomes Low risk 2 participants did not complete trial - one became pregnant and one failed to return for final assessment. The results from these participants were excluded from analysis. Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Whitehouse 1990/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0 Study characteristics

Trial design: Randomised, controlled study Participants Participants: 150 women were randomised and analysed. Mean age:/uni00A0 Group A: 35.8 ± 5.1 Group B: 35.1 ± 4.8 Group C: 36.1 ± 5.3 Inclusion criteria: • Women aged 20–43 years • Regular menstrual cycles • A history of symptomatic severe endometriosis diagnosed surgically according to the revised Ameri- can Society for Reproductive Medicine classification • Recurrence of the disease with pelvic pain, dysmenorrhoea, and dyspareunia Exclusion criteria: not stated Setting: Italy Timing: March 1, 2000 to February 28, 2003 Interventions Group A: GnRH-a plus add-back therapy = leuprolide acetate (Enantone Depot 11.25 mg; Takeda, Rome, Italy) every 3 months for 12 months plus transdermal E2 (25 /uni03BCg Esclima; Takeda) and daily oral norethindrone (5 mg Primolut-Nor; Schering, Berlin, Germany) (n = 46) Group B: /uni00A0GnRH-a alone = leuprolide acetate (Enantone Depot 11.25 mg; Takeda) every 3 months for 12 months (n = 44) Zupi 2005/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 141 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Group C: oestroprogestin alone = received oral ethinyl E2 (30 /uni03BCg ) plus gestodene daily (0.75 mg Gin- oden; Schering) for 12 consecutive months (n = 43) Outcomes • Bone Mineral Density • Quality of life • Health-related satisfaction Notes Intention-to-treat analysis: not stated Sample size calculation: yes/uni00A0 Funding: not stated Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- tion (selection bias) Low risk "Randomized by means of a computer-generated randomization number se- quence" Allocation concealment (selection bias) Unclear risk No details of method used to conceal allocation were provided. Blinding of participants and personnel (perfor- mance bias) All outcomes Unclear risk No details provided of blinding of participants or personnel Blinding of outcome as- sessment (detection bias) All outcomes Low risk The VAS and SF-36 were administered to the patients by a nurse who was blind to the study before treatment, after 6 and 12 months of therapy, and 6 months after discontinuation of treatment. Incomplete outcome data (attrition bias) All outcomes Low risk No losses to follow-up Selective reporting (re- porting bias) Low risk The study protocol was not available but it was clear that the published re- ports included all expected outcomes, including those that were prespecified. Other bias Low risk No other risk of bias detected Zupi 2005/uni00A0/uni00A0(Continued) ADI: additive diameter of implants score AFS: American Fertility Society AIDS: acquired immune deficiency syndrome ASRM: American Society for Reproductive Medicine BD: twice daily BMD: bone mineral density BMI: Body Mass Index DMPA: Depot medroxyprogesterone acetate DNG: dienogest E2: oestradiol ESS: Endometriosis symptom severity FSH: Follicle-Stimulating Hormone GnRHa: Gonadotropin Releasing Hormone Agonist HRT: Hormone Replacement Therapy Im: intramuscular IN: intranasally IVF: in vitro fertilization Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 142 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews LA: leuprolid acetate LH: luteinizing hormone LNG-IUS: Levonorgestrel-Intrauterine System NSAID: Nonsteroidal anti-inflammatory drugs OC: oral contraceptive OCP: oral contracteptive pill Pap: Papanicolaou PO: per os PRL: prolactin PTH: Parathyroid hormone QID: four times a day rAFS: revised American Society for Reproductive Medicine SC: subcutaneously SD: standard deviation SEM: standard error of mean SF-36: Short Form Health Survey - 36 T4: Thyroxine TDS: three times daily IU: intra-uterine VAS: Visual Analogue Scale 17β-E2: 17β-estradiol /uni00A0 Characteristics of excluded studies [ordered by study ID] /uni00A0 Study Reason for exclusion Acien 1989 Outcome in this article did not match the outcome measurements of this review./uni00A0 Adiyono 2006 Wrong participants: post-surgical treatment Agarwal 2015 The article did not meet the stated inclusion criteria. Wrong comparison Al-Azemi 2009 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Bergqvist 1990 Wrong study design; not clearly stated as randomised trial Calvo 2000 Outcome in this article did not match the outcome measurements of this review./uni00A0 Chan 1993 Study still awaiting classification, so excluded in this review Chen 2009 Study still awaiting classification, so excluded in this review Choktanasiri 2001 Wrong study design, not clearly stated as randomised trial Claesson 1989 Wrong study design; not clearly stated as randomised trial Cooke 1989 The article did not meet the stated inclusion criteria. Wrong comparison Dawood 1990 Wrong study design; not clearly stated as randomised trial Dmowski 1989 The article did not meet the stated inclusion criteria. Wrong comparison Dodin 1991 Not only women with endometriosis included, but also without endometriosis Donnez 1989 The article did not meet the stated inclusion criteria. The outcome measures as viewed in the cur- rent review were not answered in this article. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 143 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Study Reason for exclusion Donnez 2004 The article did not meet the stated inclusion criteria. Wrong comparison el-Roeiy 1988 The article did not meet the stated inclusion criteria. The outcome measures as viewed in the cur- rent review were not answered in this article. Eldred 1992 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Fedele 1993 Wrong study design; not clearly stated as randomised trial Fernandez 2004 The article did not meet the stated inclusion criteria. Wrong comparison Ferrero 2011 The article did not meet the stated inclusion criteria. Wrong comparison Franssen 1992 Retrospective study, so wrong study design Fraser 1996 Ineligible condition: not about endometriosis but rather menorrhagia Harada 2000 Wrong study design; not clearly stated as randomised trial Henzl 1990a Wrong study design; not clearly stated as randomised trial Imani 2009 The article did not meet the stated inclusion criteria. Wrong comparison Lindsay 1996 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Luciano 2004 The article did not meet the stated inclusion criteria. Wrong comparison Magini 1993 The article did not meet the stated inclusion criteria. Wrong comparison Maouris 1991 The outcome measures as viewed in the current review were not answered in this article. Matalliotakis 2000 The outcome measures as viewed in the current review were not answered in this article. Matalliotakis 2004 Wrong participants: post-surgical treatment Matta 1988 Wrong patient population Miller 1990 The article did not meet the stated inclusion criteria. Wrong comparison Mukherjee 1996 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Newton 1996 The article did not meet the stated inclusion criteria. Wrong comparison Pierce 2000 Once patients were enrolled, allocation of treatment was carried out according to a patient-cen- tred, partially randomised design./uni00A0 Ripps 2003 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Shaw 1992 Study included also patients without complaints; no separate results stated in this article. As de- scribed in the Methods section, we decided to exclude this study./uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 144 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Study Reason for exclusion Shaw 2001 The article did not meet the stated inclusion criteria. Wrong comparison Somekawa 1999 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Sorensen 1997 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Sowter 1997 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Soysal 2004 Post-surgical treatment. So, wrong type of intervention Surrey 1993 The article did not meet the stated inclusion criteria. Wrong comparison Surrey 1995 Not only women with endometriosis included, but also without endometriosis. So, wrong patient population Takaesu 2013 This study was investigating the effect of GnRHas on postoperative outcome measures. This type of intervention is excluded from the current review. Tapanainen 1993 Outcome in this article did not match the outcome measurements of this review./uni00A0 Taskin 1997 The article did not meet the stated inclusion criteria. Wrong comparison Toomey 2003 The article did not meet the stated inclusion criteria. Wrong comparison Valimaki 1989 The outcome measures as viewed in the current review were not answered in this article. Vercellini 2009 Wrong participants: post-surgical treatment Warnock 1998 The article did not meet the stated inclusion criteria. Wrong comparison Wright 1995 The outcome measures as viewed in the current review were not answered in this article. Yee 1986 The outcome measures as viewed in the current review were not answered in this article. Ylikorkala 1995 Ineligible participants /uni00A0 Characteristics of studies awaiting classification [ordered by study ID] /uni00A0

Randomisation: randomised trial Participants Number of women: 53/uni00A0 Age: not stated Inclusion criteria: not stated/uni00A0 Exclusion criteria: not stated /uni00A0 Setting: Japan Aisaka 2000/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 145 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Timing: not stated Interventions Group 1: leuprolin + mestranol 0.05 mg and norethisterone 1 mg/tab 1 tab/day versus Group 2: leuprolin alone Outcomes Bone mineral density Notes Intention-to-treat analysis: not stated Sample size calculation: not stated/uni00A0 Funding: not stated This abstract did not contain enough information to make a proper decision about in-/exclusion. Aisaka 2000/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0

Trial design: Randomised trial/uni00A0 Participants Participants:/uni00A0 Mean age: Inclusion criteria: • Premenopausal women (18–49 years) with laparoscopically diagnosed endometriosis • Persistent, recurrent endometriosis-associated symptoms for at least 3 months Exclusion criteria:/uni00A0 Setting: United States and Canada Timing: not stated Interventions DMPA-SC 104 mg every 3 months/uni00A0 versus LA 11.25 mg given intramuscularly every 3 months Outcomes • Relief of overall pain Notes Intention-to-treat analysis: yes Sample size calculation: not stated/uni00A0 Funding: not stated /uni00A0 This abstract did not contain enough information to make a proper decision about in-/exclusion./uni00A0 Archer 2004/uni00A0 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 146 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

Randomisation: by sequential numerical allocation to a randomisation list before commencing tri- al Participants Number of women: 40/uni00A0 Age: Mean age of group 1: 28.3 years and mean age of group 2: 29.1 years Inclusion criteria:/uni00A0 • minimum of 4 endometriotic lesions • endometriotic symptoms and pelvic pain graded at least 3 (severe) • negative cervical smear Exclusion criteria:/uni00A0 • smoking • medications that might affect bone metabolism • medical conditions that could affect bone metabolism Setting: Greece Timing: not stated Interventions Group 1: leuprolide acetate depot 3.75 mg IM every 4 weeks versus Group 2: leuprolide acetate depot 3.75 mg every 4 weeks + 1.25 mg daily oral conjugated equine oestrogens on days 1 to 25 and 5 mg oral medroxyprogesterone acetate on days 16-25 Outcomes • Bone mineral density Notes Intention-to-treat analysis: not stated Sample size calculation: not stated/uni00A0 Funding: not stated This abstract did not contain enough information to make a proper decision about in-/exclusion. Gregoriou 1997/uni00A0 /uni00A0 /uni00A0

Trial design: randomised trial Participants Participants: 70 women with moderate or severe endometriosis Mean age: /uni00A0in GnRHa group was 31±7 years and in the add-back group was 32±7 years in those who completed the study Inclusion criteria: not stated/uni00A0 Exclusion criteria: not stated/uni00A0 Setting: China Timing: not stated Interventions GnRHa Zoladex 3.6 mg every 28 days (x3) (n = 35)/uni00A0 versus/uni00A0 Long 2009/uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 147 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Zoladex 3.6 mg every 28 days (x3)+ add-back- oestradiol valerate 0.5 mg + dydrogesterone 5 mg daily (n = 35) Outcomes • Relief of overall pain • Quality of life • Bone mineral density • Patients satisfaction Notes Intention-to-treat analysis: not stated Sample size calculation: not stated/uni00A0 Funding: not stated /uni00A0 This abstract did not contain enough information to make a proper decision about in-/exclusion./uni00A0 Long 2009/uni00A0/uni00A0(Continued) /uni00A0 /uni00A0

Trial design: randomised trial Participants Participants: 30 Meang age: not stated Inclusion criteria: not stated/uni00A0 Exclusion criteria: not stated Setting: not stated Timing: not stated Interventions Group 1: goserelin/uni00A0 versus Group 2: goserelin + premarin (conjugated oestrogens) 1.25 mg Outcomes • Bone mineral density Notes Intention-to-treat analysis: not stated Sample size calculation: not stated/uni00A0 Funding: not stated /uni00A0 This abstract did not contain enough information to make a proper decision about in-/exclusion./uni00A0 Vella 1995/uni00A0 DPMA:/uni00A0depot medroxyprogesterone acetate GnRHa: gonadotropin-releasing hormone analogues IM: intramuscular LA: leuprolide acetate /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 148 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews D A T A /uni00A0 A N D /uni00A0 A N A L Y S E S /uni00A0 Comparison 1. /uni00A0 GnRHas versus placebo Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 1.1 Relief of overall pain - dichotomous - decrease of pain 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 1.1.1 Decreases in pelvic pain scores - 3 months 1 87 Risk Ratio (M-H, Fixed, 95% CI) 2.14 [1.41, 3.24] 1.1.2 Decreases in dysmenorrhoea scores - 3 months 1 85 Risk Ratio (M-H, Fixed, 95% CI) 2.25 [1.59, 3.16] 1.1.3 Decreases in dyspareunia scores - 3 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 2.21 [1.39, 3.54] 1.1.4 Decreases in pelvic tenderness scores - 3 months 1 85 Risk Ratio (M-H, Fixed, 95% CI) 2.28 [1.48, 3.50] 1.1.5 Decreases in pelvic induration scores - 3 months 1 81 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.64, 1.79] 1.2 Adverse effects - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 1.2.1 Hot flushes/flashes - 3 months 1 100 Risk Ratio (M-H, Fixed, 95% CI) 3.08 [1.89, 5.01] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 149 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 1.1. /uni00A0 Comparison 1: GnRHas versus placebo, Outcome 1: Relief of overall pain - dichotomous - decrease of pain Study or Subgroup 1.1.1 Decreases in pelvic pain scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.58 (P = 0.0003) 1.1.2 Decreases in dysmenorrhoea scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 4.63 (P < 0.00001) 1.1.3 Decreases in dyspareunia scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.33 (P = 0.0009) 1.1.4 Decreases in pelvic tenderness scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.75 (P = 0.0002) 1.1.5 Decreases in pelvic induration scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.24 (P = 0.81) GnRHEvents 35 35 44 44 24 24 35 35 19 19 Total 4444 4444 2828 4343 4444 PlaceboEvents 16 16 18 18 12 12 15 15 15 15 Total 4343 4141 3131 4242 3737 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 2.14 [1.41 , 3.24]2.14 [1.41 , 3.24] 2.25 [1.59 , 3.16]2.25 [1.59 , 3.16] 2.21 [1.39 , 3.54]2.21 [1.39 , 3.54] 2.28 [1.48 , 3.50]2.28 [1.48 , 3.50] 1.07 [0.64 , 1.79]1.07 [0.64 , 1.79] Risk RatioM-H, Fixed, 95% CI 0.0050.1 1 10 200Favours placeboFavours GnRHas Risk of BiasA + + + + + B + + + + + C + + + + + D + + + + + E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 150 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 1.2. /uni00A0 Comparison 1: GnRHas versus placebo, Outcome 2: Adverse effects - dichotomous Study or Subgroup 1.2.1 Hot flushes/flashes - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 4.52 (P < 0.00001) GnRHasEvents 40 40 Total 5050 PlaceboEvents 13 13 Total 5050 Weight 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 3.08 [1.89 , 5.01]3.08 [1.89 , 5.01] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours placeboFavours GnRHas Risk of BiasA + B + C + D + E + F + G + Risk 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 /uni00A0 /uni00A0 Comparison 2. /uni00A0 GnRHas versus placebo - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 2.1 Relief of overall pain - dichoto- mous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 2.1.1 Dyspareunia - 6 months 1 49 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.09, 0.89] 2.1.2 Dyschezia/ bowel pressure - 6 months 1 49 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.03, 2.17] 2.1.3 Pelvic tenderness - 6 months 1 49 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.09, 0.55] 2.2 Relief of overall pain - dichoto- mous - decrease of pain 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 2.2.1 Decreases in pelvic pain scores - 3 months 1 87 Risk Ratio (M-H, Fixed, 95% CI) 2.14 [1.41, 3.24] 2.2.2 Decreases in dysmenorrhoea scores - 3 months 1 85 Risk Ratio (M-H, Fixed, 95% CI) 2.25 [1.59, 3.16] 2.2.3 Decreases in dyspareunia scores - 3 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 2.21 [1.39, 3.54] 2.2.4 Decreases in pelvic tenderness scores - 3 months 1 85 Risk Ratio (M-H, Fixed, 95% CI) 2.28 [1.48, 3.50] 2.2.5 Decreases in pelvic induration scores - 3 months 1 81 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.64, 1.79] 2.3 Relief of overall pain - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 151 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 2.3.1 Decrease of overall pain by Severity scale mean scores - 1 month 1 120 Mean Difference (IV, Fixed, 95% CI) 2.90 [2.80, 3.00] 2.4 Adverse effects - dichotomous 3 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 2.4.1 Hot flushes/flashes - 3 months 1 100 Risk Ratio (M-H, Fixed, 95% CI) 3.08 [1.89, 5.01] 2.4.2 Vasodilatation - 6 months 1 63 Risk Ratio (M-H, Fixed, 95% CI) 2.69 [1.51, 4.81] 2.4.3 Headache- 6 months 1 63 Risk Ratio (M-H, Fixed, 95% CI) 3.55 [1.09, 11.53] 2.4.4 Hot flushes/flashes - 12 months 1 49 Risk Ratio (M-H, Fixed, 95% CI) 1.62 [0.87, 3.02] 2.4.5 Sleep disturbances - 12 months 1 49 Risk Ratio (M-H, Fixed, 95% CI) 2.31 [1.33, 4.02] 2.5 Quality of life - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 2.5.1 Physical component - 1 month 1 120 Mean Difference (IV, Fixed, 95% CI) -0.46 [-0.48, -0.44] 2.5.2 Mental component - 1 month 1 120 Mean Difference (IV, Fixed, 95% CI) -0.46 [-0.48, -0.44] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 152 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 2.1. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included, Outcome 1: Relief of overall pain - dichotomous Study or Subgroup 2.1.1 Dyspareunia - 6 months Bergqvist 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.15 (P = 0.03) 2.1.2 Dyschezia/ bowel pressure - 6 months Bergqvist 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.24 (P = 0.21) 2.1.3 Pelvic tenderness - 6 months Bergqvist 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.23 (P = 0.001) GnRHEvents 3 3 1 1 4 4 Total 2424 2424 2424 PlaceboEvents 11 11 4 4 19 19 Total 2525 2525 2525 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.28 [0.09 , 0.89]0.28 [0.09 , 0.89] 0.26 [0.03 , 2.17]0.26 [0.03 , 2.17] 0.22 [0.09 , 0.55]0.22 [0.09 , 0.55] Risk RatioM-H, Fixed, 95% CI 0.0050.1 1 10 200Favours placeboFavours GnRHas Risk of BiasA ? ? ? B ? ? ? C + + + D + + + E + + + F + + + G + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 153 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 2.2. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included, Outcome 2: Relief of overall pain - dichotomous - decrease of pain Study or Subgroup 2.2.1 Decreases in pelvic pain scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.58 (P = 0.0003) 2.2.2 Decreases in dysmenorrhoea scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 4.63 (P < 0.00001) 2.2.3 Decreases in dyspareunia scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.33 (P = 0.0009) 2.2.4 Decreases in pelvic tenderness scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.75 (P = 0.0002) 2.2.5 Decreases in pelvic induration scores - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.24 (P = 0.81) GnRHEvents 35 35 44 44 24 24 35 35 19 19 Total 4444 4444 2828 4343 4444 PlaceboEvents 16 16 18 18 12 12 15 15 15 15 Total 4343 4141 3131 4242 3737 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 2.14 [1.41 , 3.24]2.14 [1.41 , 3.24] 2.25 [1.59 , 3.16]2.25 [1.59 , 3.16] 2.21 [1.39 , 3.54]2.21 [1.39 , 3.54] 2.28 [1.48 , 3.50]2.28 [1.48 , 3.50] 1.07 [0.64 , 1.79]1.07 [0.64 , 1.79] Risk RatioM-H, Fixed, 95% CI 0.0050.1 1 10 200Favours placeboFavours GnRHas Risk of BiasA + + + + + B + + + + + C + + + + + D + + + + + E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 154 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 2.3. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included, Outcome 3: Relief of overall pain - continuous Study or Subgroup 2.3.1 Decrease of overall pain by Severity scale mean scores - 1 monthMiller 2000Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 55.66 (P < 0.00001) GnRHasMean 7.22 SD 0.3 Total 6060 PlaceboMean 4.32 SD 0.27 Total 6060 Weight 100.0%100.0% Mean Difference IV, Fixed, 95% CI 2.90 [2.80 , 3.00]2.90 [2.80 , 3.00] Mean Difference IV, Fixed, 95% CI -4 -2 0 2 4Favours placeboFavours GnRHas Risk of BiasA + B ? C + D + E + F + G + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 155 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 2.4. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included, Outcome 4: Adverse effects - dichotomous Study or Subgroup 2.4.1 Hot flushes/flashes - 3 monthsLing 1999Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 4.52 (P < 0.00001) 2.4.2 Vasodilatation - 6 monthsDlugi 1990Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 3.34 (P = 0.0008) 2.4.3 Headache- 6 monthsDlugi 1990Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.11 (P = 0.03) 2.4.4 Hot flushes/flashes - 12 months Bergqvist 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.52 (P = 0.13) 2.4.5 Sleep disturbances - 12 months Bergqvist 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.98 (P = 0.003) GnRHasEvents 40 40 25 25 11 11 14 14 20 20 Total 5050 3232 3232 2424 2424 PlaceboEvents 13 13 9 9 3 3 9 9 9 9 Total 5050 3131 3131 2525 2525 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 3.08 [1.89 , 5.01]3.08 [1.89 , 5.01] 2.69 [1.51 , 4.81]2.69 [1.51 , 4.81] 3.55 [1.09 , 11.53] 3.55 [1.09 , 11.53] 1.62 [0.87 , 3.02]1.62 [0.87 , 3.02] 2.31 [1.33 , 4.02]2.31 [1.33 , 4.02] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours placeboFavours GnRHas Risk of BiasA + ? ? ? ? B + + + ? ? C + + + + + D + + + + + E + − − + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 156 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 2.5. /uni00A0 Comparison 2: GnRHas versus placebo - all studies included, Outcome 5: Quality of life - continuous Study or Subgroup 2.5.1 Physical component - 1 monthMiller 2000Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 38.65 (P < 0.00001) 2.5.2 Mental component - 1 monthMiller 2000Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 55.65 (P < 0.00001) GnRHasMean -0.64 -0.58 SD 0.07 0.05 Total 6060 6060 PlaceboMean -0.18 -0.12 SD 0.06 0.04 Total 6060 6060 Weight 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -0.46 [-0.48 , -0.44]-0.46 [-0.48 , -0.44] -0.46 [-0.48 , -0.44]-0.46 [-0.48 , -0.44] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours GnRHasFavours  placebo Risk of BiasA + + B ? ? C + + D + + E + + F + + G + + Risk 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 /uni00A0 /uni00A0 Comparison 3. /uni00A0 GnRHas versus danazol Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 3.1 Relief of overall pain - di- chotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 3.1.1 Pelvic tenderness, partly re- solved - 6 months 1 41 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.49, 2.73] 3.1.2 Pelvic tenderness, complete resolved - 6 months 1 41 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.67, 1.81] 3.2 Relief of overall pain - contin- uous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 3.2.1 Relief of overall pain- 3 months 1 41 Mean Difference (IV, Fixed, 95% CI) -0.30 [-1.66, 1.06] 3.2.2 Pelvic pain - 3 months 1 41 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.26, 0.66] 3.2.3 Dysmenorrhoea - 3 months 1 41 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.49, 0.69] 3.2.4 Dyspareunia - 3 months 1 41 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.77, 0.37] 3.2.5 Pelvic induration - 3 months 1 41 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.59, 0.39] 3.2.6 Pelvic tenderness - 3 months 1 41 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.78, 0.38] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 157 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 3.2.7 Relief of overall pain - 6 months 1 41 Mean Difference (IV, Fixed, 95% CI) 0.40 [-0.86, 1.66] 3.2.8 Pelvic pain - 6 months 1 41 Mean Difference (IV, Fixed, 95% CI) 0.50 [0.10, 0.90] 3.2.9 Dysmenorrhoea - 6 months 1 41 Mean Difference (IV, Fixed, 95% CI) 0.40 [-0.12, 0.92] 3.2.10 Dyspareunia - 6 months 1 41 Mean Difference (IV, Fixed, 95% CI) -0.40 [-0.90, 0.10] 3.2.11 Pelvic induration - 6 months 1 41 Mean Difference (IV, Fixed, 95% CI) 0.70 [0.21, 1.19] 3.2.12 Pelvic tenderness - 6 months 1 41 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.75, 0.35] 3.3 Adverse effects - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 3.3.1 Vaginal dryness/vaginitis - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.52, 4.05] 3.3.2 Hot flushes/flashes - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 15.50 [0.93, 259.61] 3.3.3 Gastrointestinal - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.15 [0.01, 2.74] 3.3.4 Weight gain - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.08, 0.82] 3.3.5 Acne - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.08 [0.00, 1.35] 3.3.6 Generalised spasm - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.08 [0.00, 1.35] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 158 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 3.1. /uni00A0 Comparison 3: GnRHas versus danazol, Outcome 1: Relief of overall pain - dichotomous Study or Subgroup 3.1.1 Pelvic tenderness, partly resolved - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.32 (P = 0.75) 3.1.2 Pelvic tenderness, complete resolved - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.37 (P = 0.71) GnRHasEvents 8 8 14 14 Total 2222 2222 DanazolEvents 6 6 11 11 Total 1919 1919 Weight 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 1.15 [0.49 , 2.73]1.15 [0.49 , 2.73] 1.10 [0.67 , 1.81]1.10 [0.67 , 1.81] Risk RatioM-H, Fixed, 95% CI 0.2 0.51 2 5Favours danazolFavours GnRHas Risk of BiasA + + B + + C + + D + + E + + F + + G + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 159 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 3.2. /uni00A0 Comparison 3: GnRHas versus danazol, Outcome 2: Relief of overall pain - continuous Study or Subgroup 3.2.1 Relief of overall pain- 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.43 (P = 0.67) 3.2.2 Pelvic pain - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.85 (P = 0.40) 3.2.3 Dysmenorrhoea - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.33 (P = 0.74) 3.2.4 Dyspareunia - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.69 (P = 0.49) 3.2.5 Pelvic induration - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.40 (P = 0.69) 3.2.6 Pelvic tenderness - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.67 (P = 0.50) 3.2.7 Relief of overall pain - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.62 (P = 0.53) 3.2.8 Pelvic pain - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.44 (P = 0.01) 3.2.9 Dysmenorrhoea - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.51 (P = 0.13) 3.2.10 Dyspareunia - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.58 (P = 0.11) 3.2.11 Pelvic induration - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.79 (P = 0.005) 3.2.12 Pelvic tenderness - 6 monthsCheng 2005Subtotal (95% CI) GnRHasMean -4.4 -0.3 -2 -0.6 -0.5 -0.9 -4.2 0 -2 -0.6 0 -0.9 SD 2.7 0.7 0.9 1.2 0.9 1 2.4 0.6 0.9 1 0.8 1 Total 2222 2222 2222 2222 2222 2222 2222 2222 2222 2222 2222 2222 DanazolMean -4.1 -0.5 -2.1 -0.4 -0.4 -0.7 -4.6 -0.5 -2.4 -0.2 -0.7 -0.7 SD 1.7 0.8 1 0.6 0.7 0.9 1.7 0.7 0.8 0.6 0.8 0.8 Total 1919 1919 1919 1919 1919 1919 1919 1919 1919 1919 1919 1919 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -0.30 [-1.66 , 1.06]-0.30 [-1.66 , 1.06] 0.20 [-0.26 , 0.66]0.20 [-0.26 , 0.66] 0.10 [-0.49 , 0.69]0.10 [-0.49 , 0.69] -0.20 [-0.77 , 0.37]-0.20 [-0.77 , 0.37] -0.10 [-0.59 , 0.39]-0.10 [-0.59 , 0.39] -0.20 [-0.78 , 0.38]-0.20 [-0.78 , 0.38] 0.40 [-0.86 , 1.66]0.40 [-0.86 , 1.66] 0.50 [0.10 , 0.90]0.50 [0.10 , 0.90] 0.40 [-0.12 , 0.92]0.40 [-0.12 , 0.92] -0.40 [-0.90 , 0.10]-0.40 [-0.90 , 0.10] 0.70 [0.21 , 1.19]0.70 [0.21 , 1.19] -0.20 [-0.75 , 0.35]-0.20 [-0.75 , 0.35] Mean Difference IV, Fixed, 95% CI Risk of BiasA + + + + + + + + + + + + B + + + + + + + + + + + + C + + + + + + + + + + + + D + + + + + + + + + + + + E + + + + + + + + + + + + F + + + + + + + + + + + + G + + + + + + + + + + + + /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 160 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 3.2. /uni00A0 (Continued) 3.2.12 Pelvic tenderness - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.71 (P = 0.48) -0.9 1 2222 -0.7 0.8 1919100.0%100.0%-0.20 [-0.75 , 0.35]-0.20 [-0.75 , 0.35] -2-1 0 1 2Favours GnRHasFavours danazol +++++++ Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 161 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 3.3. /uni00A0 Comparison 3: GnRHas versus danazol, Outcome 3: Adverse effects - dichotomous Study or Subgroup 3.3.1 Vaginal dryness/vaginitis - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.71 (P = 0.48) 3.3.2 Hot flushes/flashes - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.91 (P = 0.06) 3.3.3 Gastrointestinal - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.28 (P = 0.20) 3.3.4 Weight gain - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.29 (P = 0.02) 3.3.5 Acne - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.75 (P = 0.08) 3.3.6 Generalised spasm - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.75 (P = 0.08) GnRHasEvents 7 7 7 7 0 0 3 3 0 0 0 0 Total 2929 2929 2929 2929 2929 2929 DanazolEvents 5 5 0 0 3 3 12 12 6 6 6 6 Total 3030 3030 3030 3030 3030 3030 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 1.45 [0.52 , 4.05]1.45 [0.52 , 4.05] 15.50 [0.93 , 259.61]15.50 [0.93 , 259.61] 0.15 [0.01 , 2.74]0.15 [0.01 , 2.74] 0.26 [0.08 , 0.82]0.26 [0.08 , 0.82] 0.08 [0.00 , 1.35]0.08 [0.00 , 1.35] 0.08 [0.00 , 1.35]0.08 [0.00 , 1.35] Risk RatioM-H, Fixed, 95% CI 0.0020.1 1 10 500Favours danazolFavours GnRHas Risk of BiasA + + + + + + B + + + + + + C + + + + + + D + + + + + + E + + + + + + F + + + + + + G + + + + + + Risk 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 /uni00A0 /uni00A0 Comparison 4. /uni00A0 GnRHas versus danazol - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 4.1 Relief of overall pain - dichoto- mous 8 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 162 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 4.1.1 Pelvic pain - 6 months 6 625 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.83, 1.11] 4.1.2 Dysmenorrhoea - 6 months 6 644 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.96, 1.06] 4.1.3 Dyspareunia - 6 months 5 342 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.90, 1.34] 4.1.4 Pelvic induration - 6 months 2 151 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.32, 1.89] 4.1.5 Pelvic tenderness - 6 months 1 96 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.39, 2.00] 4.1.6 Pelvic tenderness, partly re- solved - 6 months 2 96 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.59, 2.76] 4.1.7 Pelvic tenderness, complete resolved - 6 months 2 294 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.84, 1.12] 4.1.8 Pelvic tenderness and indura- tion combined, complete resolved - 6 months 1 53 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.59, 1.38] 4.1.9 Pelvic tenderness and indura- tion combined, partly resolved - 6 months 1 53 Risk Ratio (M-H, Fixed, 95% CI) 1.54 [0.35, 6.89] 4.2 Relief of overall pain - continu- ous 4 /uni00A0 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.2.1 Relief of overall pain- 3 months 1 41 Std. Mean Difference (IV, Fixed, 95% CI) -0.13 [-0.74, 0.49] 4.2.2 Pelvic pain - 3 months 1 41 Std. Mean Difference (IV, Fixed, 95% CI) 0.26 [-0.35, 0.88] 4.2.3 Dysmenorrhoea - 3 months 1 41 Std. Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.51, 0.72] 4.2.4 Dyspareunia - 3 months 1 41 Std. Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.82, 0.41] 4.2.5 Pelvic induration - 3 months 1 41 Std. Mean Difference (IV, Fixed, 95% CI) -0.12 [-0.73, 0.49] 4.2.6 Pelvic tenderness - 3 months 1 41 Std. Mean Difference (IV, Fixed, 95% CI) -0.21 [-0.82, 0.41] 4.2.7 Relief of overall pain - 6 months 3 85 Std. Mean Difference (IV, Fixed, 95% CI) -0.00 [-0.46, 0.46] 4.2.8 Pelvic pain - 6 months 2 90 Std. Mean Difference (IV, Fixed, 95% CI) 0.35 [-0.08, 0.79] 4.2.9 Dysmenorrhoea - 6 months 1 41 Std. Mean Difference (IV, Fixed, 95% CI) 0.46 [-0.16, 1.08] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 163 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 4.2.10 Dyspareunia - 6 months 2 90 Std. Mean Difference (IV, Fixed, 95% CI) 0.25 [-0.19, 0.69] 4.2.11 Pelvic induration - 6 months 2 90 Std. Mean Difference (IV, Fixed, 95% CI) 0.40 [-0.04, 0.83] 4.2.12 Pelvic tenderness - 6 months 2 90 Std. Mean Difference (IV, Fixed, 95% CI) -0.59 [-1.03, -0.15] 4.3 Bone mineral density of spinal bone mass - continuous 3 /uni00A0 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only 4.3.1 Absolute values - 6 months 3 81 Std. Mean Difference (IV, Fixed, 95% CI) 0.21 [-0.31, 0.73] 4.4 Adverse effects - dichotomous 17 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 4.4.1 Vaginal dryness/vaginitis - 6 months 12 1340 Risk Ratio (M-H, Fixed, 95% CI) 1.82 [1.53, 2.18] 4.4.2 Hot flushes/flashes - 6 months 17 1998 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [1.42, 1.60] 4.4.3 Headaches - 6 months 11 1103 Risk Ratio (M-H, Fixed, 95% CI) 1.43 [1.21, 1.69] 4.4.4 Infections and flu like symp- toms - 6 months 1 71 Risk Ratio (M-H, Fixed, 95% CI) 3.60 [1.31, 9.88] 4.4.5 Muscle cramps/myalgia - 6 months 8 884 Risk Ratio (M-H, Fixed, 95% CI) 0.16 [0.09, 0.29] 4.4.6 Sleep disturbance/insomnia - 6 months 7 881 Risk Ratio (M-H, Fixed, 95% CI) 2.04 [1.61, 2.59] 4.4.7 Skin rash - 6 months 2 241 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.01, 0.66] 4.4.8 Gastrointestinal - 6 months 4 339 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.15, 0.74] 4.4.9 Weight gain - 6 months 9 1081 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.29, 0.49] 4.4.10 Acne - 6 months 10 1040 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.47, 0.73] 4.4.11 Breast atrophy/changes - 6 months 5 646 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.52, 0.85] 4.4.12 Emotional lability/altered mood - 6 months 2 224 Risk Ratio (M-H, Fixed, 95% CI) 2.66 [1.12, 6.30] 4.4.13 Oedema/fluid retention - 6 months 4 519 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.12, 0.40] 4.4.14 Asthenia - 6 months 3 388 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.09, 0.64] 4.4.15 Depression - 6 months 4 181 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.20, 0.70] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 164 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 4.4.16 Generalised spasm - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 0.08 [0.00, 1.35] 4.4.17 Voice alteration - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.34] 4.4.18 Hirsutism - 6 months 3 432 Risk Ratio (M-H, Fixed, 95% CI) 0.18 [0.09, 0.37] 4.4.19 Seborrhoea - 6 months 4 461 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.19, 0.42] 4.4.20 Alopecia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.02, 1.75] 4.4.21 Altered libido - 6 months 9 1286 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [1.30, 1.92] 4.4.22 Sweating - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.03, 2.51] 4.4.23 Breast tenderness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.04, 4.33] 4.4.24 Fatigue - 6 months 2 84 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.40, 1.26] 4.4.25 Arthralgia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 17.61 [1.08, 286.40] 4.4.26 Hunger - 6 months 2 100 Risk Ratio (M-H, Fixed, 95% CI) 0.07 [0.01, 0.54] 4.4.27 Nervousness - 6 months 2 225 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.07, 0.80] 4.4.28 Irritability - 6 months 1 59 Risk Ratio (M-H, Fixed, 95% CI) 4.74 [1.67, 13.45] 4.4.29 Nausea - 6 months 3 181 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.35, 1.17] 4.4.30 Breast pain - 6 months 1 81 Risk Ratio (M-H, Fixed, 95% CI) 3.56 [0.19, 66.61] 4.4.31 Back distress - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.15, 2.53] 4.4.32 Paraesthesia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.18, 3.77] 4.4.33 Agressiveness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.34] 4.4.34 Pain - 6 months 1 81 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.11, 2.31] 4.4.35 Oily hair and skin - 6 months 2 126 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.26, 0.82] 4.4.36 Bleeding - 6 months 2 89 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.22, 1.34] 4.4.37 Malaise - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.12, 1.39] 4.4.38 Chest /uni00A0aches - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.15, 6.21] 4.4.39 Dizzy spells - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 3.78] 4.4.40 PMS feelings - 6 months 1 45 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.32, 5.06] 4.5 Improvement of most trouble- some symptoms - dichotomous 6 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 165 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 4.5.1 Overall improvement - 3 months 1 53 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.63, 1.57] 4.5.2 Overall improvement - 6 months 6 747 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.99, 1.18] 4.5.3 Complete resolution - 6 months 5 534 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.99, 1.32] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 166 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.1. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 1: Relief of overall pain - dichotomous Study or Subgroup 4.1.1 Pelvic pain - 6 monthsAdamson 1994Cirkel 1995Fedele 1989 NEET 1992Palagiano 1994Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 1.06, df = 5 (P = 0.96); I² = 0% Test for overall effect: Z = 0.52 (P = 0.60) 4.1.2 Dysmenorrhoea - 6 monthsAdamson 1994Cirkel 1995Fedele 1989 NEET 1992Palagiano 1994Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 3.48, df = 5 (P = 0.63); I² = 0% Test for overall effect: Z = 0.49 (P = 0.62) 4.1.3 Dyspareunia - 6 monthsAdamson 1994Cirkel 1995Fedele 1989 NEET 1992Palagiano 1994Subtotal (95% CI) Total events: Heterogeneity: Chi² = 4.59, df = 4 (P = 0.33); I² = 13% Test for overall effect: Z = 0.90 (P = 0.37) 4.1.4 Pelvic induration - 6 monthsCirkel 1995 NEET 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.91, df = 1 (P = 0.34); I² = 0% Test for overall effect: Z = 0.55 (P = 0.58) 4.1.5 Pelvic tenderness - 6 months NEET 1992Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.29 (P = 0.77) 4.1.6 Pelvic tenderness, partly resolved - 6 monthsCheng 2005Cirkel 1995Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.16, df = 1 (P = 0.69); I² = 0% Test for overall effect: Z = 0.63 (P = 0.53) 4.1.7 Pelvic tenderness, complete resolved - 6 monthsCheng 2005Wheeler 1992 GnRHasEvents 30725162370 171 12530223127 208 18727923 84 29 11 13 13 84 12 1493 Total 7730307127128363 9030307127128376 5730306627210 306595 6565 223052 22128 DanazolEvents 1062781675 142 22132017120 192 4827218 59 44 8 7 7 62 8 1195 Total 2825323220125262 3425323220125268 2325323220132 253156 3131 192544 19125 Weight 9.6%4.3%17.1%7.2%12.0%49.7%100.0% 1.5% 11.5%15.8%0.3%9.8%61.0%100.0% 8.9%13.7%40.9%4.2%32.3%100.0% 44.6%55.4%100.0% 100.0%100.0% 74.7%25.3%100.0% 10.9%89.1% Risk RatioM-H, Fixed, 95% CI 1.09 [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] 0.96 [0.83 , 1.11] 0.19 [0.02 , 2.02]0.99 [0.78 , 1.25]1.00 [0.94 , 1.06] 2.29 [0.11 , 46.41]1.00 [0.79 , 1.28]1.03 [0.99 , 1.07]1.01 [0.96 , 1.06] 1.82 [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] 0.42 [0.08 , 2.09]1.07 [0.36 , 3.22]0.78 [0.32 , 1.89] 0.89 [0.39 , 2.00]0.89 [0.39 , 2.00] 1.15 [0.49 , 2.73]1.67 [0.33 , 8.36]1.28 [0.59 , 2.76] 1.10 [0.67 , 1.81] 0.96 [0.83 , 1.11] Risk RatioM-H, Fixed, 95% CIRisk of BiasA ?+???? ?+???? ?+??? +? ? ++ +? B +????? +????? +???? ?? ? +? +? C +??+?+ +??+?+ +??+? ?+ + +? ++ D +??+?+ +??+?+ +??+? ?+ + +? ++ E +−++++ +−++++ +−+++ −+ + +− ++ F ++++++ ++++++ +++++ ++ + ++ ++ G ++++++ ++++++ +++++ ++ + ++ ++ /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 167 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 4.1. /uni00A0 (Continued) Cheng 2005Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.28, df = 1 (P = 0.59); I² = 0% Test for overall effect: Z = 0.40 (P = 0.69) 4.1.8 Pelvic tenderness and induration combined, complete resolved - 6 monthsKennedy 1990Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.49 (P = 0.63) 4.1.9 Pelvic tenderness and induration combined, partly resolved - 6 monthsKennedy 1990Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.57 (P = 0.57) 1493 107 21 21 6 6 22128150 3535 3535 1195 106 12 12 2 2 19125144 1818 1818 10.9%89.1%100.0% 100.0%100.0% 100.0%100.0% 1.10 [0.67 , 1.81] 0.96 [0.83 , 1.11]0.97 [0.84 , 1.12] 0.90 [0.59 , 1.38]0.90 [0.59 , 1.38] 1.54 [0.35 , 6.89]1.54 [0.35 , 6.89] 0.2 0.5 1 2 5Favours danazolFavours GnRHas +? ? ? +? ? ? ++ + + ++ + + ++ + + ++ + + ++ + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 168 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.2. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 2: Relief of overall pain - continuous Study or Subgroup 4.2.1 Relief of overall pain- 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.41 (P = 0.68) 4.2.2 Pelvic pain - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.83 (P = 0.40) 4.2.3 Dysmenorrhoea - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.33 (P = 0.74) 4.2.4 Dyspareunia - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.64 (P = 0.52) 4.2.5 Pelvic induration - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.38 (P = 0.70) 4.2.6 Pelvic tenderness - 3 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.65 (P = 0.51) 4.2.7 Relief of overall pain - 6 monthsCheng 2005Dmowski 1989a Tummon 1989Subtotal (95% CI) Heterogeneity: Chi² = 10.68, df = 2 (P = 0.005); I² = 81% Test for overall effect: Z = 0.00 (P = 1.00) 4.2.8 Pelvic pain - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI) Heterogeneity: Chi² = 2.88, df = 1 (P = 0.09); I² = 65% Test for overall effect: Z = 1.59 (P = 0.11) 4.2.9 Dysmenorrhoea - 6 monthsCheng 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.44 (P = 0.15) 4.2.10 Dyspareunia - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI) Heterogeneity: Chi² = 10.30, df = 1 (P = 0.001); I² = 90% Test for overall effect: Z = 1.10 (P = 0.27) 4.2.11 Pelvic induration - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI) Heterogeneity: Chi² = 3.67, df = 1 (P = 0.06); I² = 73% Test for overall effect: Z = 1.77 (P = 0.08) GnRHasMean -4.4 -0.3 -2 -0.6 -0.5 -0.9 -4.20.70.4 00.3 -2 -0.60.2 00.1 SD 2.7 0.7 0.9 1.2 0.9 1 2.40.870.2 0.60.1 0.9 10.1 0.80.1 Total 2222 2222 2222 2222 2222 2222 22191051 223355 2222 223355 223355 DanazolMean -4.1 -0.5 -2.1 -0.4 -0.4 -0.7 -4.60.41.4 -0.50.3 -2.4 -0.20.1 -0.70.1 SD 1.7 0.8 1 0.6 0.7 0.9 1.70.630.7 0.70.2 0.8 0.60.1 0.80.1 Total 1919 1919 1919 1919 1919 1919 1910534 191635 1919 191635 191635 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 54.9%34.8%10.3%100.0% 46.7%53.3%100.0% 100.0%100.0% 50.6%49.4%100.0% 46.2%53.8%100.0% Std. Mean Difference IV, Fixed, 95% CI -0.13 [-0.74 , 0.49]-0.13 [-0.74 , 0.49] 0.26 [-0.35 , 0.88]0.26 [-0.35 , 0.88] 0.10 [-0.51 , 0.72]0.10 [-0.51 , 0.72] -0.20 [-0.82 , 0.41]-0.20 [-0.82 , 0.41] -0.12 [-0.73 , 0.49]-0.12 [-0.73 , 0.49] -0.21 [-0.82 , 0.41]-0.21 [-0.82 , 0.41] 0.19 [-0.43 , 0.80]0.37 [-0.41 , 1.14]-2.23 [-3.65 , -0.81]-0.00 [-0.46 , 0.46] 0.76 [0.12 , 1.39]0.00 [-0.60 , 0.60]0.35 [-0.08 , 0.79] 0.46 [-0.16 , 1.08]0.46 [-0.16 , 1.08] -0.47 [-1.09 , 0.16]0.98 [0.35 , 1.61]0.25 [-0.19 , 0.69] 0.86 [0.21 , 1.50]0.00 [-0.60 , 0.60]0.40 [-0.04 , 0.83] Std. Mean Difference IV, Fixed, 95% CI Risk of BiasA + + + + + + +?? ++ + ++ ++ B + + + + + + +?? +? + +? +? C + + + + + + +?? ++ + ++ ++ D + + + + + + +?? ++ + ++ ++ E + + + + + + +++ ++ + ++ ++ F + + + + + + +++ ++ + ++ ++ G + + + + + + +++ ++ + ++ ++ /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 169 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 4.2. /uni00A0 (Continued) Subtotal (95% CI) Heterogeneity: Chi² = 3.67, df = 1 (P = 0.06); I² = 73% Test for overall effect: Z = 1.77 (P = 0.08) 4.2.12 Pelvic tenderness - 6 monthsCheng 2005Fraser 1991Subtotal (95% CI) Heterogeneity: Chi² = 2.93, df = 1 (P = 0.09); I² = 66% Test for overall effect: Z = 2.63 (P = 0.009) -0.90.1 10.1 55 223355 -0.70.2 0.80.1 35 191635 100.0% 51.2%48.8%100.0% 0.40 [-0.04 , 0.83] -0.21 [-0.83 , 0.40]-0.98 [-1.61 , -0.35]-0.59 [-1.03 , -0.15] -2-1 0 1 2Favours GnRHasFavours danazol +++? ++++++++++ Risk 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 /uni00A0 /uni00A0 Analysis 4.3. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 3: Bone mineral density of spinal bone mass - continuous Study or Subgroup 4.3.1 Absolute values - 6 monthsFukushima 1993 Tummon 1988Whitehouse 1990Subtotal (95% CI) Heterogeneity: Chi² = 32.04, df = 2 (P < 0.00001); I² = 94% Test for overall effect: Z = 0.79 (P = 0.43) GnRHasMean 144.11.24150.5 SD 11.40.00224.3 Total 10251550 DanazolMean 170.81.22157.4 SD 9.60.0219 Total 913931 Weight 17.3%44.0%38.7%100.0% Std. Mean Difference IV, Fixed, 95% CI -2.41 [-3.65 , -1.16]1.68 [0.90 , 2.46]-0.30 [-1.13 , 0.54]0.21 [-0.31 , 0.73] Std. Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours GnRHasFavours danazol Risk of BiasA ??? B ??? C ??+ D +?+ E −?+ F +++ G +++ Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 170 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.4. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 4: Adverse effects - dichotomous Study or Subgroup 4.4.1 Vaginal dryness/vaginitis - 6 monthsAN Zoladex 1996Audebert 1997Burry 1992Cheng 2005Cirkel 1995Dmowski 1989aFedele 1989Jelley 1986 NEET 1992Palagiano 1994Rock 1993Rolland 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 12.30, df = 11 (P = 0.34); I² = 11% Test for overall effect: Z = 6.65 (P < 0.00001) 4.4.2 Hot flushes/flashes - 6 monthsAN Zoladex 1996Audebert 1997Burry 1992Chang 1996Cheng 2005Cirkel 1995Dmowski 1989aFedele 1989Fraser 1991Henzl 1988Jelley 1986 NEET 1992Palagiano 1994Rock 1993Rolland 1990Rotondi 2002Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 51.22, df = 16 (P < 0.0001); I² = 69% Test for overall effect: Z = 13.37 (P < 0.00001) 4.4.3 Headaches - 6 monthsAN Zoladex 1996Audebert 1997Burry 1992Cirkel 1995Dmowski 1989aFedele 1989Fraser 1991Palagiano 1994Rock 1993Rolland 1990Rotondi 2002Subtotal (95% CI) Total events: Heterogeneity: Chi² = 8.64, df = 10 (P = 0.57); I² = 0% Test for overall effect: Z = 4.18 (P < 0.0001) 4.4.4 Infections and flu like symptoms - 6 monthsAN Zoladex 1996Subtotal (95% CI) Total events: GnRHasEvents 266127137101331515620 306 352610229730162813129231542019810652 113 1081 139121913 1187144133 252 14 14 Total 3533 111293019302317127208107823 3533 1113029301930331432317127208107541341217 3533 111301930332720810754687 3535 DanazolEvents 10155534567486 105 157442019613548967375451674 448 4241264235971 104 4 4 Total 3622583025103222922010763517 362258153025103216702292201076327136781 36225825103216201076327416 3636 Weight 7.7%0.9%5.1%3.8%4.3%3.1%3.0%4.0%6.1%6.3%49.6%5.9%100.0% 2.8%1.5%10.5%0.5%0.1%3.9%1.4%2.3%1.2% 11.8%1.8%15.9%0.6%18.1%10.3%3.9%13.4%100.0% 3.0%1.8%4.0%10.0%6.0%3.0%2.1%2.6%59.6%6.7%1.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 2.67 [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] 2.35 [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] 1.32 [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] 3.34 [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] 3.60 [1.31 , 9.88]3.60 [1.31 , 9.88] Risk RatioM-H, Fixed, 95% CIRisk of BiasA ???++??????? ????++??+???????? ???+??+???? ? B ???+???+???? ???++?????+?????? ??????????? ? C ??++????+??+ ??+?+???++?+??+?+ ??+???+??+? ? D ??++????+??+ ??+++???++?+??+?+ ??+???+??+? ? E −+++−+++++++ −++?+−+++++++++++ −++−+++++++ − F ++++++++++++ +++++++++++++++++ +++++++++++ + G ++++++++++++ +++++++++++++++++ +++++++++++ + /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 171 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.4. /uni00A0 (Continued) Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.49 (P = 0.01) 4.4.5 Muscle cramps/myalgia - 6 monthsAN Zoladex 1996Burry 1992Cirkel 1995Fedele 1989Fraser 1991Jelley 1986 NEET 1992Rolland 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 5.13, df = 7 (P = 0.64); I² = 0% Test for overall effect: Z = 6.04 (P < 0.00001) 4.4.6 Sleep disturbance/insomnia - 6 monthsAN Zoladex 1996Cirkel 1995Dmowski 1989aJelley 1986 NEET 1992Rolland 1990Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 10.92, df = 6 (P = 0.09); I² = 45% Test for overall effect: Z = 5.82 (P < 0.00001) 4.4.7 Skin rash - 6 monthsAN Zoladex 1996Rolland 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.07, df = 1 (P = 0.79); I² = 0% Test for overall effect: Z = 2.36 (P = 0.02) 4.4.8 Gastrointestinal - 6 monthsAudebert 1997Cheng 2005Cirkel 1995Rolland 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 2.55, df = 3 (P = 0.47); I² = 0% Test for overall effect: Z = 2.71 (P = 0.007) 4.4.9 Weight gain - 6 monthsAudebert 1997Burry 1992Cheng 2005Fedele 1989Jelley 1986Palagiano 1994Rock 1993Rotondi 2002Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 22.63, df = 8 (P = 0.004); I² = 65% Test for overall effect: Z = 7.42 (P < 0.00001) 14 12200034 12 316211231423 182 00 0 3040 7 163213025117 68 35 35 11130303323171107540 35301923171107126 511 35107142 332930107199 33 1112930232720854126641 4 673951079 56 01303848 54 44 8 4364 17 5 11122220818736 139 36 3658253216229263344 362510229263122370 366399 22302563140 22583032222010727122440 100.0% 9.0%13.9%5.0%13.9% 11.1%16.2%13.8%17.1%100.0% 0.7%1.6%5.7%0.7%72.0%7.3% 11.8%100.0% 44.0%56.0%100.0% 23.5%16.8%32.0%27.6%100.0% 3.9%9.4%7.7%13.9%13.3%6.3%15.5%6.1%23.8%100.0% 3.60 [1.31 , 9.88]3.60 [1.31 , 9.88] 0.17 [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] 7.19 [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] 0.11 [0.01 , 2.05]0.07 [0.00 , 1.20]0.09 [0.01 , 0.66] 0.50 [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] 0.13 [0.02 , 1.07] 0.29 [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] ??+?+??? ?+????? ?? ?++? ??+?????? ?????+?? ???+??? ?? ?+?? ??+?+???? ?+??+?++ ????+++ ?+ ?+?+ ?++?????+ ?+??+?++ ????+++ ?+ ?+?+ ?++?????+ −+−+++++ −−+++++ −+ ++−+ +++++++++ ++++++++ +++++++ ++ ++++ +++++++++ ++++++++ +++++++ ++ ++++ +++++++++ /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 172 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.4. /uni00A0 (Continued) Test for overall effect: Z = 7.42 (P < 0.00001) 4.4.10 Acne - 6 monthsAudebert 1997Burry 1992Cheng 2005Cirkel 1995Dmowski 1989aFedele 1989Jelley 1986Rock 1993Rolland 1990Rotondi 2002Subtotal (95% CI) Total events: Heterogeneity: Chi² = 12.76, df = 9 (P = 0.17); I² = 29% Test for overall effect: Z = 4.74 (P < 0.00001) 4.4.11 Breast atrophy/changes - 6 monthsBurry 1992Cirkel 1995Fedele 1989Jelley 1986Rock 1993Subtotal (95% CI) Total events: Heterogeneity: Chi² = 6.20, df = 4 (P = 0.18); I² = 35% Test for overall effect: Z = 3.20 (P = 0.001) 4.4.12 Emotional lability/altered mood - 6 monthsBurry 1992Cirkel 1995Subtotal (95% CI) Total events: Heterogeneity: Chi² = 1.80, df = 1 (P = 0.18); I² = 45% Test for overall effect: Z = 2.23 (P = 0.03) 4.4.13 Oedema/fluid retention - 6 monthsBurry 1992Cirkel 1995Palagiano 1994Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 4.33, df = 3 (P = 0.23); I² = 31% Test for overall effect: Z = 4.95 (P < 0.00001) 4.4.14 Asthenia - 6 monthsBurry 1992Fraser 1991Rolland 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 2.44, df = 2 (P = 0.30); I² = 18% Test for overall effect: Z = 2.87 (P = 0.004) 4.4.15 Depression - 6 monthsChang 1996Dmowski 1989aFedele 1989Jelley 1986Subtotal (95% CI) Total events: Heterogeneity: Chi² = 7.48, df = 3 (P = 0.06); I² = 60% Test for overall effect: Z = 3.06 (P = 0.002) 2160350465720 122 808267 85 1310 23 3207 12 410 5 1640 11 33 111293019302320810754644 111303023208402 11130141 1113027126294 11133107251 30193023102 6126969843415 118 667054 73 15 6 351524 47 705 12 7545 21 225830251032221076327396 58253222107244 582583 582520122225 581663137 1510322279 4.9%10.8%4.4%6.7%5.4%6.3%5.6%38.8%3.4%13.7%100.0% 8.4%7.6%7.2%0.5%76.2%100.0% 19.4%80.6%100.0% 7.7%10.6%34.4%47.4%100.0% 54.8%4.0%41.2%100.0% 36.8%25.8%15.3%22.1%100.0% 0.22 [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] 0.70 [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] 6.79 [0.91 , 50.65]1.67 [0.66 , 4.24]2.66 [1.12 , 6.30] 0.52 [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] 0.30 [0.09 , 0.98]1.50 [0.06 , 34.91]0.05 [0.00 , 0.96]0.25 [0.09 , 0.64] 0.07 [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] ??++?????? ?+??? ?+ ?+?? ?+? ???? ??+???+??? ???+? ?? ???? ??? +??+ ?++?????+? +???? +? +??+ +++ ???? ?++?????+? +???? +? +??+ +++ +??? +++−++++++ +−+++ +− +−++ +++ ?+++ ++++++++++ +++++ ++ ++++ +++ ++++ ++++++++++ +++++ ++ ++++ +++ ++++ /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 173 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.4. /uni00A0 (Continued) Heterogeneity: Chi² = 7.48, df = 3 (P = 0.06); I² = 60% Test for overall effect: Z = 3.06 (P = 0.002) 4.4.16 Generalised spasm - 6 monthsCheng 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.75 (P = 0.08) 4.4.17 Voice alteration - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.17 (P = 0.24) 4.4.18 Hirsutism - 6 monthsCirkel 1995Fedele 1989Rock 1993Subtotal (95% CI) Total events: Heterogeneity: Chi² = 5.40, df = 2 (P = 0.07); I² = 63% Test for overall effect: Z = 4.75 (P < 0.00001) 4.4.19 Seborrhoea - 6 monthsCirkel 1995Dmowski 1989aFedele 1989Rock 1993Subtotal (95% CI) Total events: Heterogeneity: Chi² = 1.91, df = 3 (P = 0.59); I² = 0% Test for overall effect: Z = 6.30 (P < 0.00001) 4.4.20 Alopecia - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.45 (P = 0.15) 4.4.21 Altered libido - 6 monthsCirkel 1995Fedele 1989Jelley 1986 NEET 1992Palagiano 1994Rock 1993Rolland 1990Rotondi 2002Wheeler 1992Subtotal (95% CI) Total events: Heterogeneity: Chi² = 18.88, df = 8 (P = 0.02); I² = 58% Test for overall effect: Z = 4.64 (P < 0.00001) 4.4.22 Sweating - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.14 (P = 0.25) 4.4.23 Breast tenderness - 6 months 0 0 0 0 0010 10 15025 31 1 1 1460244129183518 248 1 1 2929 3030 3030208268 301930208287 3030 3030231712720810754126776 3030 6 6 2 2 16614 36 46743 60 4 4 25855452146 92 3 3 3030 2525 2532107164 251032107174 2525 25322292201076327122510 2525 100.0%100.0% 100.0%100.0% 42.0%14.7%43.3%100.0% 5.7%10.3%9.5%74.4%100.0% 100.0%100.0% 1.9%4.2%7.6%5.7%5.0%51.8%2.2%16.3%5.3%100.0% 100.0%100.0% 0.08 [0.00 , 1.35]0.08 [0.00 , 1.35] 0.17 [0.01 , 3.34]0.17 [0.01 , 3.34] 0.03 [0.00 , 0.40]0.08 [0.00 , 1.39]0.37 [0.17 , 0.80]0.18 [0.09 , 0.37] 0.21 [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] 0.21 [0.02 , 1.75]0.21 [0.02 , 1.75] 5.83 [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] 0.28 [0.03 , 2.51]0.28 [0.03 , 2.51] + + +?? +??? + +???????? + + ? ??? ???? ? ??+?????? ? + ? ??? ???? ? ???+??+?+ ? + ? ??? ???? ? ???+??+?+ ? + − −++ −+++ − −++++++++ − + + +++ ++++ + +++++++++ + + + +++ ++++ + +++++++++ + /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 174 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.4. /uni00A0 (Continued) Test for overall effect: Z = 1.14 (P = 0.25) 4.4.23 Breast tenderness - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.73 (P = 0.46) 4.4.24 Fatigue - 6 monthsCirkel 1995Dmowski 1989aSubtotal (95% CI) Total events: Heterogeneity: Chi² = 4.30, df = 1 (P = 0.04); I² = 77% Test for overall effect: Z = 1.17 (P = 0.24) 4.4.25 Arthralgia - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.02 (P = 0.04) 4.4.26 Hunger - 6 monthsCirkel 1995Jelley 1986Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.25, df = 1 (P = 0.62); I² = 0% Test for overall effect: Z = 2.57 (P = 0.01) 4.4.27 Nervousness - 6 monthsCirkel 1995Rolland 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.31, df = 1 (P = 0.58); I² = 0% Test for overall effect: Z = 2.32 (P = 0.02) 4.4.28 Irritability - 6 monthsDmowski 1989aSubtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.92 (P = 0.003) 4.4.29 Nausea - 6 monthsCirkel 1995Jelley 1986Rotondi 2002Subtotal (95% CI) Total events: Heterogeneity: Chi² = 3.38, df = 2 (P = 0.18); I² = 41% Test for overall effect: Z = 1.45 (P = 0.15) 4.4.30 Breast pain - 6 monthsRotondi 2002Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.85 (P = 0.39) 4.4.31 Back distress - 6 monthsCirkel 1995Subtotal (95% CI) 1 1 6 11 17 10 10 00 0 03 3 9 9 753 15 3 3 3 3030 301949 3030 302353 30107137 1919 302354107 5454 3030 2 2 124 16 0 0 83 11 36 9 4 4 4123 19 0 0 4 2525 251035 2525 252247 256388 4040 25222774 2727 2525 100.0%100.0% 71.4%28.6%100.0% 100.0%100.0% 72.1%27.9%100.0% 33.5%66.5%100.0% 100.0%100.0% 21.2%59.5%19.4%100.0% 100.0%100.0% 100.0%100.0% 0.42 [0.04 , 4.33]0.42 [0.04 , 4.33] 0.42 [0.18 , 0.95]1.45 [0.62 , 3.39]0.71 [0.40 , 1.26] 17.61 [1.08 , 286.40]17.61 [1.08 , 286.40] 0.05 [0.00 , 0.81]0.14 [0.01 , 2.51]0.07 [0.01 , 0.54] 0.12 [0.01 , 2.21]0.29 [0.08 , 1.14]0.24 [0.07 , 0.80] 4.74 [1.67 , 13.45]4.74 [1.67 , 13.45] 1.46 [0.48 , 4.42]0.40 [0.17 , 0.95] 0.50 [0.11 , 2.31]0.64 [0.35 , 1.17] 3.56 [0.19 , 66.61]3.56 [0.19 , 66.61] 0.63 [0.15 , 2.53]0.63 [0.15 , 2.53] + +? + +? +? ? +?? ? + ? ?? ? ?+ ?? ? ?+? ? ? ? ?? ? ?? ?+ ? ??? ? ? ? ?? ? ?? ?+ ? ??? ? ? − −+ − −+ −+ + −++ + − + ++ + ++ ++ + +++ + + + ++ + ++ ++ + +++ + + /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 175 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.4. /uni00A0 (Continued) 4.4.31 Back distress - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.66 (P = 0.51) 4.4.32 Paraesthesia - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.24 (P = 0.81) 4.4.33 Agressiveness - 6 monthsCirkel 1995Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.17 (P = 0.24) 4.4.34 Pain - 6 monthsRotondi 2002Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.89 (P = 0.38) 4.4.35 Oily hair and skin - 6 monthsJelley 1986Rotondi 2002Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.40, df = 1 (P = 0.53); I² = 0% Test for overall effect: Z = 2.61 (P = 0.009) 4.4.36 Bleeding - 6 monthsChang 1996Jelley 1986Subtotal (95% CI) Total events: Heterogeneity: Chi² = 6.69, df = 1 (P = 0.010); I² = 85% Test for overall effect: Z = 1.33 (P = 0.18) 4.4.37 Malaise - 6 monthsJelley 1986Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.43 (P = 0.15) 4.4.38 Chest  aches - 6 monthsJelley 1986Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.05 (P = 0.96) 4.4.39 Dizzy spells - 6 monthsJelley 1986Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.09 (P = 0.28) 4.4.40 PMS feelings - 6 months 3 3 3 3 0 0 3 3 014 14 15 6 3 3 2 2 0 0 3030 3030 3030 5454 235477 302353 2323 2323 2323 4 4 3 3 2 2 3 3 214 16 62 8 7 7 2 2 2 2 2525 2525 2525 2727 222749 152136 2222 2222 2222 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 12.0%88.0%100.0% 79.3%20.7%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 0.63 [0.15 , 2.53]0.63 [0.15 , 2.53] 0.83 [0.18 , 3.77]0.83 [0.18 , 3.77] 0.17 [0.01 , 3.34]0.17 [0.01 , 3.34] 0.50 [0.11 , 2.31] 0.50 [0.11 , 2.31] 0.19 [0.01 , 3.78]0.50 [0.28 , 0.89]0.46 [0.26 , 0.82] 0.08 [0.01 , 0.63]2.28 [0.49 , 10.54]0.54 [0.22 , 1.34] 0.41 [0.12 , 1.39]0.41 [0.12 , 1.39] 0.96 [0.15 , 6.21]0.96 [0.15 , 6.21] 0.19 [0.01 , 3.78]0.19 [0.01 , 3.78] + + + ? ?? ?? ? ? ? ? ? ? ? +? ++ + + + ? ? ? ? ?? ?? ? ? ? ? ? ? ? ?? +? ? ? ? − − − + ++ ?+ + + + + + + + ++ ++ + + + + + + + ++ ++ + + + /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 176 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 4.4. /uni00A0 (Continued) Test for overall effect: Z = 1.09 (P = 0.28) 4.4.40 PMS feelings - 6 monthsJelley 1986Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.35 (P = 0.73) 4 4 2323 3 3 2222100.0%100.0%1.28 [0.32 , 5.06]1.28 [0.32 , 5.06] 0.0020.1 1 10 500Favours danazolFavours GnRHas ? + ? ? + + + Risk 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 /uni00A0 /uni00A0 Analysis 4.5. /uni00A0 Comparison 4: GnRHas versus danazol - all studies included, Outcome 5: Improvement of most troublesome symptoms - dichotomous Study or Subgroup 4.5.1 Overall improvement - 3 monthsKennedy 1990Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.01 (P = 0.99) 4.5.2 Overall improvement - 6 monthsAN Zoladex 1996Burry 1992Henzl 1988Kennedy 1990Rolland 1990Shaw 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 8.24, df = 5 (P = 0.14); I² = 39% Test for overall effect: Z = 1.83 (P = 0.07) 4.5.3 Complete resolution - 6 monthsAN Zoladex 1996Burry 1992Kennedy 1990Rolland 1990Shaw 1990Subtotal (95% CI) Total events: Heterogeneity: Chi² = 6.99, df = 4 (P = 0.14); I² = 43% Test for overall effect: Z = 1.78 (P = 0.07) GnRHasEvents 25 25 3477107476147 373 2177296129 217 Total 3939 35981435010750483 35985010750340 DanazolEvents 9 9 253755203020 187 1037143014 105 Total 1414 364970236323264 3649236323194 Weight 100.0%100.0% 10.3%20.5%30.7% 11.4%15.7% 11.4%100.0% 7.3%36.5%14.2%27.9%14.2%100.0% Risk RatioM-H, Fixed, 95% CI 1.00 [0.63 , 1.57]1.00 [0.63 , 1.57] 1.40 [1.12 , 1.75]1.04 [0.86 , 1.26] 0.95 [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] 2.16 [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] Risk RatioM-H, Fixed, 95% CI 0.10.20.51 2 5 10Favours danazolFavours GnRHas Risk of BiasA ? ?????? ????? B ? ?????? ????? C + ?+++++ ?++++ D + ?+++++ ?++++ E + −+++++ −++++ F + ++++++ +++++ G + ++++++ +++++ Risk 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 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 177 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 /uni00A0 Comparison 5. /uni00A0 GnRHas versus intra-uterine progestagen device - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 5.1 Relief of overall pain - continuous 3 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 5.1.1 Relief of overall pain - 6 months 2 58 Mean Difference (IV, Fixed, 95% CI) -0.76 [-1.62, 0.10] 5.1.2 Decrease of VAS score - 6 months 1 82 Mean Difference (IV, Fixed, 95% CI) 0.00 [-0.11, 0.11] 5.2 Quality of life - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 5.2.1 Psychological Well-Being Ques- tionnaire index (PGWBI) - 6 months 1 81 Mean Difference (IV, Fixed, 95% CI) -2.00 [-10.26, 6.26] /uni00A0 /uni00A0 Analysis 5.1. /uni00A0 Comparison 5: GnRHas versus intra-uterine progestagen device - all studies included, Outcome 1: Relief of overall pain - continuous Study or Subgroup 5.1.1 Relief of overall pain - 6 monthsFerreira 2010Gomes 2007Subtotal (95% CI) Heterogeneity: Chi² = 1.28, df = 1 (P = 0.26); I² = 22% Test for overall effect: Z = 1.74 (P = 0.08) 5.1.2 Decrease of VAS score - 6 monthsPetta 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) GnRHasMean 0.70.4 6 SD 1.371.1 0.3 Total 18826 4343 LNG-IUSMean 1.22.1 6 SD 1.752.7 0.2 Total 221032 3939 Weight 78.3%21.7%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -0.50 [-1.47 , 0.47]-1.70 [-3.54 , 0.14]-0.76 [-1.62 , 0.10] 0.00 [-0.11 , 0.11] 0.00 [-0.11 , 0.11] Mean Difference IV, Fixed, 95% CI -2 -1 0 1 2Favours intra- uterine progestagen deviceFavours GnRHas Risk of BiasA ++ + B ?? ? C ?? ? D ?? + E ++ + F ++ + G ++ + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 178 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 5.2. /uni00A0 Comparison 5: GnRHas versus intra-uterine progestagen device - all studies included, Outcome 2: Quality of life - continuous Study or Subgroup 5.2.1 Psychological Well-Being Questionnaire index (PGWBI) - 6 monthsPetta 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.47 (P = 0.64) GnRHasMean 93 SD 18.9 Total 4242 LNG-IUSMean 95 SD 19 Total 3939 Weight 100.0%100.0% Mean Difference IV, Fixed, 95% CI -2.00 [-10.26 , 6.26]-2.00 [-10.26 , 6.26] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours intra- uterine progestagen deviceFavours GnRHas Risk of BiasA + B ? C ? D + E + F + G + Risk 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 /uni00A0 /uni00A0 Comparison 6. /uni00A0 GnRHas versus oral or injectable progestogens Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 6.1 Relief of overall pain - con- tinuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 6.1.1 Pelvic pain - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) -2.50 [-3.55, -1.45] 6.1.2 Dyspareunia - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) -2.10 [-2.83, -1.37] 6.1.3 Back pain - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) 0.50 [-0.40, 1.40] 6.2 Adverse effects - dichoto- mous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 6.2.1 Vaginal bleeding - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.23, 0.48] 6.2.2 Headache - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.88, 2.67] 6.2.3 Weight gain - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.10, 0.92] 6.2.4 Vaginal dryness - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 4.75 [1.66, 13.55] 6.2.5 Hot flushes - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 2.95 [1.87, 4.65] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 179 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 6.1. /uni00A0 Comparison 6: GnRHas versus oral or injectable progestogens, Outcome 1: Relief of overall pain - continuous Study or Subgroup 6.1.1 Pelvic pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 4.68 (P < 0.00001) 6.1.2 Dyspareunia - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 5.67 (P < 0.00001) 6.1.3 Back pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.09 (P = 0.28) GnRHasMean 26.2 17.9 19.5 SD 3.01 2.9 3.01 Total 131131 131131 131131 Oral or injectable progestogensMean 28.7 20 19 SD 5.3 3.08 4.3 Total 130130 130130 130130 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -2.50 [-3.55 , -1.45]-2.50 [-3.55 , -1.45] -2.10 [-2.83 , -1.37]-2.10 [-2.83 , -1.37] 0.50 [-0.40 , 1.40]0.50 [-0.40 , 1.40] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas Risk of BiasA + + + B + + + C ? ? ? D ? ? ? E + + + F + + + G + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 180 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 6.2. /uni00A0 Comparison 6: GnRHas versus oral or injectable progestogens, Outcome 2: Adverse effects - dichotomous Study or Subgroup 6.2.1 Vaginal bleeding - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 5.89 (P < 0.00001) 6.2.2 Headache - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.50 (P = 0.13) 6.2.3 Weight gain - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.12 (P = 0.03) 6.2.4 Vaginal dryness - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.91 (P = 0.004) 6.2.5 Hot flushes - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 4.65 (P < 0.00001) GnRHasEvents 26 26 26 26 4 4 19 19 56 56 Total 121121 121121 121121 121121 121121 Oral or injectable progestogensEvents 78 78 17 17 13 13 4 4 19 19 Total 121121 121121 121121 121121 121121 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.33 [0.23 , 0.48]0.33 [0.23 , 0.48] 1.53 [0.88 , 2.67]1.53 [0.88 , 2.67] 0.31 [0.10 , 0.92]0.31 [0.10 , 0.92] 4.75 [1.66 , 13.55]4.75 [1.66 , 13.55] 2.95 [1.87 , 4.65]2.95 [1.87 , 4.65] Risk RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas Risk of BiasA + + + + + B + + + + + C ? ? ? ? ? D ? ? ? ? ? E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Comparison 7. /uni00A0 GnRHas versus oral or injectable progestogens - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 7.1 Relief of overall pain - di- chotomous 2 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 7.1.1 Pelvic pain - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.83, 1.15] 7.1.2 Dysmenorrhoea - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.28, 1.06] 7.1.3 Dyspareunia - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.67, 1.47] 7.1.4 Pelvic induration - 6 months 2 419 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.95, 1.29] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 181 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 7.1.5 Pelvic tenderness - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.78, 1.40] 7.2 Relief of overall pain - contin- uous 4 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 7.2.1 Pelvic pain - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) -2.50 [-3.55, -1.45] 7.2.2 Dyspareunia - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) -2.10 [-2.83, -1.37] 7.2.3 Back pain - 3 months 1 261 Mean Difference (IV, Fixed, 95% CI) 0.50 [-0.40, 1.40] 7.2.4 Overall pain - 6 months 1 253 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.48, 0.68] 7.2.5 Pelvic pain - 6 months 1 87 Mean Difference (IV, Fixed, 95% CI) -0.60 [-0.88, -0.32] 7.2.6 Absolute reduction mean VAS - 6 months 1 229 Mean Difference (IV, Fixed, 95% CI) -1.50 [-8.49, 5.49] 7.2.7 Dysmenorrhoea - 6 months 1 0 Mean Difference (IV, Fixed, 95% CI) Not estimable 7.2.8 Dyspareunia - 6 months 2 172 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.42, 0.22] 7.2.9 Lumbago- mean change - 6 months 1 253 Mean Difference (IV, Fixed, 95% CI) -1.60 [-8.20, 5.00] 7.2.10 Lumbago - 6 months 1 165 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.39, 0.19] 7.2.11 Lower abdominal pain - 6 months 1 217 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.45, 0.05] 7.2.12 Dyschezia - 6 months 1 75 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.14, 0.54] 7.2.13 Pain on internal examina- tion - 6 months 1 209 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.33, 0.13] 7.2.14 Lower abdominal pain, mean change - 6 months 1 253 Mean Difference (IV, Fixed, 95% CI) 2.90 [-5.19, 10.99] 7.2.15 Pelvic induration - 6 months 1 212 Mean Difference (IV, Fixed, 95% CI) 0.30 [0.04, 0.56] 7.2.16 Pelvic tenderness- 6 months 1 231 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.33, 0.13] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 182 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 7.2.17 Pelvic pain - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) -0.60 [-0.75, -0.45] 7.2.18 Overall pain - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 3.80 [-2.13, 9.73] 7.2.19 Dysmenorrhoea - 12 months 1 0 Mean Difference (IV, Fixed, 95% CI) Not estimable 7.2.20 Dyspareunia - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.13, 0.33] 7.3 Bone mineral density of spinal bone mass - continuous 2 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 7.3.1 Percentage change values - 6 months 1 87 Mean Difference (IV, Fixed, 95% CI) -1.60 [-2.57, -0.63] 7.3.2 Absolute values - 6 months 1 87 Mean Difference (IV, Fixed, 95% CI) -0.04 [-0.08, 0.01] 7.3.3 Absolute values - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) -0.05 [-0.10, -0.01] 7.4 Adverse effects - dichoto- mous 6 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 7.4.1 Vaginal bleeding - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.23, 0.48] 7.4.2 Headache - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.88, 2.67] 7.4.3 Weight gain - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.10, 0.92] 7.4.4 Vaginal dryness - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 4.75 [1.66, 13.55] 7.4.5 Hot flushes - 3 months 1 242 Risk Ratio (M-H, Fixed, 95% CI) 2.95 [1.87, 4.65] 7.4.6 Acne - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.40, 3.57] 7.4.7 Alopecia - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [0.49, 3.99] 7.4.8 Decreased libido - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.48, 2.10] 7.4.9 Vaginal dryness - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 2.00 [0.54, 7.37] 7.4.10 Weight gain - 4 months 1 70 Risk Ratio (M-H, Fixed, 95% CI) 1.67 [0.68, 4.09] 7.4.11 Nausea - 6 months 1 295 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.30, 1.32] 7.4.12 Headache - 6 months 3 815 Risk Ratio (M-H, Fixed, 95% CI) 1.46 [1.04, 2.03] 7.4.13 Breast pain - 6 months 1 295 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.22, 1.98] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 183 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 7.4.14 Intermenstrual bleeding - 6 months 4 902 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.50, 0.67] 7.4.15 Hot flushes/flashes - 6 months 4 902 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [1.70, 2.62] 7.4.16 Emotional changes - 6 months 1 87 Risk Ratio (M-H, Fixed, 95% CI) 5.21 [1.64, 16.61] 7.4.17 Insomnia - 6 months 1 265 Risk Ratio (M-H, Fixed, 95% CI) 2.25 [0.59, 8.50] 7.4.18 Decreased libido - 6 months 1 265 Risk Ratio (M-H, Fixed, 95% CI) 2.25 [0.59, 8.50] 7.5 Adverse effects - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 7.5.1 Climacteric symptoms by Kupperman index - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) 6.80 [2.37, 11.23] 7.5.2 Hot flushes/flashes - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) 1.10 [0.71, 1.49] 7.5.3 Depression - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.18, 0.58] 7.5.4 Oedema - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.14, 0.54] 7.5.5 Headache - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.32, 0.52] 7.5.6 Breast pain - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.39, -0.01] 7.5.7 Metrorrhagia - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) -0.90 [-1.31, -0.49] 7.6 Quality of life - continuous 2 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 7.6.1 Bodily pain - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95% CI) -3.70 [-10.81, 3.41] 7.6.2 General health - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95% CI) 0.70 [-2.58, 3.98] 7.6.3 Physical function - 6 months/uni00A0 1 249 Mean Difference (IV, Fixed, 95% CI) -1.00 [-3.66, 1.66] 7.6.4 Role physical - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95% CI) -3.50 [-12.01, 5.01] 7.6.5 Role emotional - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95% CI) -7.80 [-16.67, 1.07] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 184 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 7.6.6 Mental health - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95% CI) 0.10 [-4.04, 4.24] 7.6.7 Social function - 6 months/uni00A01 249 Mean Difference (IV, Fixed, 95% CI) -4.80 [-9.98, 0.38] 7.6.8 Vitality - 6 months/uni00A0 1 249 Mean Difference (IV, Fixed, 95% CI) -0.70 [-5.41, 4.01] 7.6.9 General health - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 3.70 [-1.97, 9.37] 7.6.10 Physical function - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 2.00 [-3.72, 7.72] 7.6.11 Role physical - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 1.30 [-4.15, 6.75] 7.6.12 Role emotional- 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 4.20 [-1.60, 10.00] 7.6.13 Mental health- 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 0.80 [-4.39, 5.99] 7.6.14 Social function - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) -2.20 [-6.93, 2.53] 7.6.15 Vitality - 12 months 1 87 Mean Difference (IV, Fixed, 95% CI) 1.70 [-4.94, 8.34] 7.7 Improvement of most trou- blesome symptoms - dichoto- mous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 7.7.1 Complete resolution - 6 months 1 229 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.79, 1.28] 7.8 Improvement of most trou- blesome symptoms - continuous 2 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 7.8.1 Overall symptoms by nu- merical rating scale - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) 2.60 [0.37, 4.83] 7.8.2 Overall symptoms by ver- bal rating scale - 4 months 1 70 Mean Difference (IV, Fixed, 95% CI) 0.70 [0.06, 1.34] 7.8.3 Overall symptoms - 6 months 1 253 Mean Difference (IV, Fixed, 95% CI) -0.70 [-1.52, 0.12] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 185 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 7.1. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 1: Relief of overall pain - dichotomous Study or Subgroup 7.1.1 Pelvic pain - 6 monthsStrowitzki 2012Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.29 (P = 0.77) 7.1.2 Dysmenorrhoea - 6 monthsStrowitzki 2012Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.78 (P = 0.07) 7.1.3 Dyspareunia - 6 monthsStrowitzki 2012Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.05 (P = 0.96) 7.1.4 Pelvic induration - 6 months Schlaff 2006Strowitzki 2012Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.71, df = 1 (P = 0.40); I² = 0% Test for overall effect: Z = 1.36 (P = 0.18) 7.1.5 Pelvic tenderness - 6 monthsStrowitzki 2012Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.29 (P = 0.77) GnRHasEvents 86 86 12 12 36 36 8846 134 54 54 Total 120120 120120 120120 102120222 120120 Oral or injectable progestogensEvents 80 80 20 20 33 33 6541 106 47 47 Total 109109 109109 109109 88109197 109109 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 61.9%38.1%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.98 [0.83 , 1.15]0.98 [0.83 , 1.15] 0.55 [0.28 , 1.06]0.55 [0.28 , 1.06] 0.99 [0.67 , 1.47]0.99 [0.67 , 1.47] 1.17 [1.01 , 1.35]1.02 [0.73 , 1.42] 1.11 [0.95 , 1.29] 1.04 [0.78 , 1.40]1.04 [0.78 , 1.40] Risk RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas Risk of BiasA ? ? ? ?? ? B ? ? ? ?? ? C ? ? ? ?? ? D ? ? ? +? ? E + + + −+ + F + + + ++ + G + + + ++ + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 186 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 7.2. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 2: Relief of overall pain - continuous Study or Subgroup 7.2.1 Pelvic pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 4.68 (P < 0.00001) 7.2.2 Dyspareunia - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 5.67 (P < 0.00001) 7.2.3 Back pain - 3 monthsAbdou 2018Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.09 (P = 0.28) 7.2.4 Overall pain - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.34 (P = 0.74) 7.2.5 Pelvic pain - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 4.18 (P < 0.0001) 7.2.6 Absolute reduction mean VAS - 6 monthsStrowitzki 2012Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.42 (P = 0.67) 7.2.7 Dysmenorrhoea - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Not applicable 7.2.8 Dyspareunia - 6 monthsHarada 2009Zupi 2005Subtotal (95% CI) Heterogeneity: Chi² = 0.00, df = 1 (P = 1.00); I² = 0% Test for overall effect: Z = 0.61 (P = 0.54) 7.2.9 Lumbago- mean change - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.47 (P = 0.63) 7.2.10 Lumbago - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.67 (P = 0.50) 7.2.11 Lower abdominal pain - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.55 (P = 0.12) 7.2.12 Dyschezia - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.15 (P = 0.25) GnRHasMean 26.2 17.9 19.5 2.5 1.3 46 0 0.62.6 -17.3 0.9 0.7 0.6 SD 3.01 2.9 3.01 2.3 0.5 24.8 0 0.91.3 24.8 0.9 0.9 0.8 Total 131131 131131 131131 128128 4444 120120 440 474491 125125 8383 107107 3939 Oral or injectable progestogensMean 28.7 20 19 2.4 1.9 47.5 1.9 0.72.7 -15.7 1 0.9 0.4 SD 5.3 3.08 4.3 2.4 0.8 28.8 1.1 0.91.5 28.7 1 1 0.7 Total 130130 130130 130130 125125 4343 109109 430 384381 128128 8282 110 110 3636 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 70.2%29.8%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -2.50 [-3.55 , -1.45]-2.50 [-3.55 , -1.45] -2.10 [-2.83 , -1.37]-2.10 [-2.83 , -1.37] 0.50 [-0.40 , 1.40]0.50 [-0.40 , 1.40] 0.10 [-0.48 , 0.68]0.10 [-0.48 , 0.68] -0.60 [-0.88 , -0.32]-0.60 [-0.88 , -0.32] -1.50 [-8.49 , 5.49]-1.50 [-8.49 , 5.49] Not estimableNot estimable -0.10 [-0.48 , 0.28]-0.10 [-0.69 , 0.49]-0.10 [-0.42 , 0.22] -1.60 [-8.20 , 5.00]-1.60 [-8.20 , 5.00] -0.10 [-0.39 , 0.19]-0.10 [-0.39 , 0.19] -0.20 [-0.45 , 0.05]-0.20 [-0.45 , 0.05] 0.20 [-0.14 , 0.54]0.20 [-0.14 , 0.54] Mean Difference IV, Fixed, 95% CI Risk of BiasA + + + + + ? + ++ + + + + B + + + + ? ? ? +? + + + + C ? ? ? + ? ? ? +? + + + + D ? ? ? + + ? + ++ + + + + E + + + − + + + −+ − − − − F + + + + + + + ++ + + + + G + + + + + + + ++ + + + + /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 187 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 7.2. /uni00A0 (Continued) Heterogeneity: Not applicable Test for overall effect: Z = 1.15 (P = 0.25) 7.2.13 Pain on internal examination - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.85 (P = 0.40) 7.2.14 Lower abdominal pain, mean change - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48) 7.2.15 Pelvic induration - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.27 (P = 0.02) 7.2.16 Pelvic tenderness- 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.84 (P = 0.40) 7.2.17 Pelvic pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 7.72 (P < 0.00001) 7.2.18 Overall pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.26 (P = 0.21) 7.2.19 Dysmenorrhoea - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Not applicable 7.2.20 Dyspareunia - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.84 (P = 0.40) 0.9 -27.3 1.2 0.9 0.2 62.1 0 1.4 0.8 33.8 1.1 0.8 0.1 14 0 0.5 104104 125125 106106 110 110 4444 4444 440 4444 1 -30.2 0.9 1 0.8 58.3 0.9 1.3 0.9 31.8 0.8 1 0.5 14.2 0.5 0.6 105105 128128 106106 121121 4343 4343 430 4343 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% -0.10 [-0.33 , 0.13]-0.10 [-0.33 , 0.13] 2.90 [-5.19 , 10.99]2.90 [-5.19 , 10.99] 0.30 [0.04 , 0.56]0.30 [0.04 , 0.56] -0.10 [-0.33 , 0.13]-0.10 [-0.33 , 0.13] -0.60 [-0.75 , -0.45]-0.60 [-0.75 , -0.45] 3.80 [-2.13 , 9.73]3.80 [-2.13 , 9.73] Not estimableNot estimable 0.10 [-0.13 , 0.33]0.10 [-0.13 , 0.33] -100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas + + + + + + + + + + + + ? ? ? ? + + + + ? ? ? ? + + + + + + + + − − − − + + + + + + + + + + + + + + + + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 188 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 7.3. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 3: Bone mineral density of spinal bone mass - continuous Study or Subgroup 7.3.1 Percentage change values - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 3.24 (P = 0.001) 7.3.2 Absolute values - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.37 (P = 0.17) 7.3.3 Absolute values - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.28 (P = 0.02) GnRHasMean -2.6 1.005 0.981 SD 2.3 0.112 0.099 Total 4646 4444 4444 Oral or injectable progestogensMean -1 1.04 1.035 SD 2.3 0.125 0.121 Total 4141 4343 4343 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -1.60 [-2.57 , -0.63]-1.60 [-2.57 , -0.63] -0.04 [-0.08 , 0.01]-0.04 [-0.08 , 0.01] -0.05 [-0.10 , -0.01]-0.05 [-0.10 , -0.01] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours GnRHasFavours oral or injectable progestogens Risk of BiasA + + + B + ? ? C + ? ? D + + + E − + + F + + + G + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 189 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 7.4. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 4: Adverse effects - dichotomous Study or Subgroup 7.4.1 Vaginal bleeding - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 5.89 (P < 0.00001) 7.4.2 Headache - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.50 (P = 0.13) 7.4.3 Weight gain - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.12 (P = 0.03) 7.4.4 Vaginal dryness - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.91 (P = 0.004) 7.4.5 Hot flushes - 3 monthsAbdou 2018Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 4.65 (P < 0.00001) 7.4.6 Acne - 4 monthsOzaki 2020Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.33 (P = 0.74) 7.4.7 Alopecia - 4 monthsOzaki 2020Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.63 (P = 0.53) 7.4.8 Decreased libido - 4 monthsOzaki 2020Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) 7.4.9 Vaginal dryness - 4 monthsOzaki 2020Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.04 (P = 0.30) 7.4.10 Weight gain - 4 monthsOzaki 2020Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.12 (P = 0.26) GnRHasEvents 26 26 26 26 4 4 19 19 56 56 6 6 7 7 10 10 6 6 10 10 Total 121121 121121 121121 121121 121121 3535 3535 3535 3535 3535 Oral or injectable progestogensEvents 78 78 17 17 13 13 4 4 19 19 5 5 5 5 10 10 3 3 6 6 Total 121121 121121 121121 121121 121121 3535 3535 3535 3535 3535 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.33 [0.23 , 0.48]0.33 [0.23 , 0.48] 1.53 [0.88 , 2.67]1.53 [0.88 , 2.67] 0.31 [0.10 , 0.92]0.31 [0.10 , 0.92] 4.75 [1.66 , 13.55]4.75 [1.66 , 13.55] 2.95 [1.87 , 4.65]2.95 [1.87 , 4.65] 1.20 [0.40 , 3.57]1.20 [0.40 , 3.57] 1.40 [0.49 , 3.99]1.40 [0.49 , 3.99] 1.00 [0.48 , 2.10]1.00 [0.48 , 2.10] 2.00 [0.54 , 7.37]2.00 [0.54 , 7.37] 1.67 [0.68 , 4.09]1.67 [0.68 , 4.09] Risk RatioM-H, Fixed, 95% CIRisk of BiasA + + + + + + + + + + B + + + + + ? ? ? ? ? C ? ? ? ? ? ? ? ? ? ? D ? ? ? ? ? ? ? ? ? ? E + + + + + + + + + + F + + + + + + + + + + G + + + + + + + + + + /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 190 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 7.4. /uni00A0 (Continued) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.12 (P = 0.26) 7.4.11 Nausea - 6 monthsCrosignani 2006Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.23 (P = 0.22) 7.4.12 Headache - 6 monthsCrosignani 2006Harada 2009 Schlaff 2006Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.83, df = 2 (P = 0.66); I² = 0% Test for overall effect: Z = 2.21 (P = 0.03) 7.4.13 Breast pain - 6 monthsCrosignani 2006Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.73 (P = 0.46) 7.4.14 Intermenstrual bleeding - 6 monthsCrosignani 2006Harada 2009 Schlaff 2006Zupi 2005Subtotal (95% CI) Total events: Heterogeneity: Chi² = 18.82, df = 3 (P = 0.0003); I² = 84% Test for overall effect: Z = 7.11 (P < 0.00001) 7.4.15 Hot flushes/flashes - 6 monthsCrosignani 2006Harada 2009 Schlaff 2006Zupi 2005Subtotal (95% CI) Total events: Heterogeneity: Chi² = 25.02, df = 3 (P < 0.0001); I² = 88% Test for overall effect: Z = 6.81 (P < 0.00001) 7.4.16 Emotional changes - 6 monthsZupi 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.79 (P = 0.005) 7.4.17 Insomnia - 6 months Schlaff 2006Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.19 (P = 0.23) 7.4.18 Decreased libido - 6 months Schlaff 2006Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.19 (P = 0.23) 10 10 10 94314 66 5 5 18511 88 24851534 158 16 16 7 7 7 7 143143 143126135404 143143 14312613544448 14312613544448 4444 135135 135135 6 17 17 43210 46 8 8 1912277 155 96430 76 3 3 3 3 3 3 152152 152129130 411 152152 15212913043454 15212913043454 4343 130130 130130 100.0%100.0% 8.5%69.2%22.3%100.0% 100.0%100.0% 12.0%78.7%4.7%4.6%100.0% 11.6%83.7%4.0%0.7%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 0.63 [0.30 , 1.32]0.63 [0.30 , 1.32] 2.39 [0.75 , 7.59]1.38 [0.94 , 2.02]1.35 [0.62 , 2.93]1.46 [1.04 , 2.03] 0.66 [0.22 , 1.98]0.66 [0.22 , 1.98] 0.06 [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] 2.83 [1.36 , 5.89]1.36 [1.10 , 1.68]4.81 [1.43 , 16.24]67.47 [4.27 , 1066.73] 2.11 [1.70 , 2.62] 5.21 [1.64 , 16.61]5.21 [1.64 , 16.61] 2.25 [0.59 , 8.50]2.25 [0.59 , 8.50] 2.25 [0.59 , 8.50]2.25 [0.59 , 8.50] 0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas ? ?+? ? ?+?+ ?+?+ + ? ? ? ?+? ? ?+?? ?+?? ? ? ? ? ?+? ? ?+?? ?+?? ? ? ? ? ?++ ? ?+++ ?+++ + + + + +−− + +−−+ +−−+ + − − + +++ + ++++ ++++ + + + + +++ + ++++ ++++ + + + Risk of bias legend(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)(C) Blinding of participants and personnel (performance bias) /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 191 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 7.4. /uni00A0 (Continued) (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 /uni00A0 /uni00A0 Analysis 7.5. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 5: Adverse effects - continuous Study or Subgroup 7.5.1 Climacteric symptoms by Kupperman index - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 3.01 (P = 0.003) 7.5.2 Hot flushes/flashes - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 5.58 (P < 0.00001) 7.5.3 Depression - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.04 (P = 0.30) 7.5.4 Oedema - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.15 (P = 0.25) 7.5.5 Headache - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.46 (P = 0.64) 7.5.6 Breast pain - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.03 (P = 0.04) 7.5.7 Metrorrhagia - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 4.30 (P < 0.0001) GnRHasMean 16 1.6 0.5 0.4 0.7 0.1 0.1 SD 11 1 0.9 0.9 1 0.3 0.3 Total 3535 3535 3535 3535 3535 3535 3535 Oral of injectable progestogensMean 9.2 0.5 0.3 0.2 0.6 0.3 1 SD 7.6 0.6 0.7 0.5 0.8 0.5 1.2 Total 3535 3535 3535 3535 3535 3535 3535 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI 6.80 [2.37 , 11.23] 6.80 [2.37 , 11.23] 1.10 [0.71 , 1.49]1.10 [0.71 , 1.49] 0.20 [-0.18 , 0.58]0.20 [-0.18 , 0.58] 0.20 [-0.14 , 0.54]0.20 [-0.14 , 0.54] 0.10 [-0.32 , 0.52]0.10 [-0.32 , 0.52] -0.20 [-0.39 , -0.01]-0.20 [-0.39 , -0.01] -0.90 [-1.31 , -0.49]-0.90 [-1.31 , -0.49] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas Risk of BiasA + + + + + + + B ? ? ? ? ? ? ? C ? ? ? ? ? ? ? D ? ? ? ? ? ? ? E + + + + + + + F + + + + + + + G + + + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 192 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 7.6. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 6: Quality of life - continuous Study or Subgroup 7.6.1 Bodily pain - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.02 (P = 0.31) 7.6.2 General health - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.42 (P = 0.68) 7.6.3 Physical function - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.74 (P = 0.46) 7.6.4 Role physical - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.81 (P = 0.42) 7.6.5 Role emotional - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.72 (P = 0.08) 7.6.6 Mental health - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.05 (P = 0.96) 7.6.7 Social function - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.82 (P = 0.07) 7.6.8 Vitality - 6 months Harada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.29 (P = 0.77) 7.6.9 General health - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.28 (P = 0.20) 7.6.10 Physical function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.69 (P = 0.49) 7.6.11 Role physical - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.47 (P = 0.64) 7.6.12 Role emotional- 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.42 (P = 0.16) 7.6.13 Mental health- 12 months GnRHasMean 18.5 1.8 -0.2 0 -2.5 3.4 1.7 2.1 54.9 57.6 60.1 62.3 SD 28.8 12.9 8.2 33.3 35.4 17 22.3 18.5 12.7 14 13.9 15.2 Total 122122 122122 122122 122122 122122 122122 122122 122122 4444 4444 4444 4444 Oral or injectable progestogensMean 22.2 1.1 0.8 3.5 5.3 3.3 6.5 2.8 51.2 55.6 58.8 58.1 SD 28.4 13.5 12.8 35.2 36 16.3 19.2 19.4 14.2 13.2 12 12.3 Total 127127 127127 127127 127127 127127 127127 127127 127127 4343 4343 4343 4343 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -3.70 [-10.81 , 3.41]-3.70 [-10.81 , 3.41] 0.70 [-2.58 , 3.98]0.70 [-2.58 , 3.98] -1.00 [-3.66 , 1.66]-1.00 [-3.66 , 1.66] -3.50 [-12.01 , 5.01]-3.50 [-12.01 , 5.01] -7.80 [-16.67 , 1.07]-7.80 [-16.67 , 1.07] 0.10 [-4.04 , 4.24]0.10 [-4.04 , 4.24] -4.80 [-9.98 , 0.38]-4.80 [-9.98 , 0.38] -0.70 [-5.41 , 4.01]-0.70 [-5.41 , 4.01] 3.70 [-1.97 , 9.37]3.70 [-1.97 , 9.37] 2.00 [-3.72 , 7.72]2.00 [-3.72 , 7.72] 1.30 [-4.15 , 6.75]1.30 [-4.15 , 6.75] 4.20 [-1.60 , 10.00]4.20 [-1.60 , 10.00] Mean Difference IV, Fixed, 95% CI Risk of BiasA + + + + + + + + + + + + B + + + + + + + + ? ? ? ? C + + + + + + + + ? ? ? ? D + + + + + + + + + + + + E − − − − − − − − + + + + F + + + + + + + + + + + + G + + + + + + + + + + + + /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 193 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 7.6. /uni00A0 (Continued) Test for overall effect: Z = 1.42 (P = 0.16) 7.6.13 Mental health- 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.30 (P = 0.76) 7.6.14 Social function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.91 (P = 0.36) 7.6.15 Vitality - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.50 (P = 0.62) 60.2 54.5 57.8 13.6 11.5 11.3 4444 4444 4444 59.4 56.7 56.1 11 11 19.2 4343 4343 4343 100.0%100.0% 100.0%100.0% 100.0%100.0% 0.80 [-4.39 , 5.99]0.80 [-4.39 , 5.99] -2.20 [-6.93 , 2.53]-2.20 [-6.93 , 2.53] 1.70 [-4.94 , 8.34]1.70 [-4.94 , 8.34] -100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas + + + ? ? ? ? ? ? + + + + + + + + + + + + Risk 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 /uni00A0 /uni00A0 Analysis 7.7. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 7: Improvement of most troublesome symptoms - dichotomous Study or Subgroup 7.7.1 Complete resolution - 6 monthsStrowitzki 2012Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.02 (P = 0.99) GnRHasEvents 64 64 Total 120120 Oral or injectable progestogensEvents 58 58 Total 109109 Weight 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 1.00 [0.79 , 1.28]1.00 [0.79 , 1.28] Risk RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Favours oral or injectable progestogensFavours GnRHas Risk of BiasA ? B ? C ? D ? E + F + G + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 194 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 7.8. /uni00A0 Comparison 7: GnRHas versus oral or injectable progestogens - all studies included, Outcome 8: Improvement of most troublesome symptoms - continuous Study or Subgroup 7.8.1 Overall symptoms by numerical rating scale - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.28 (P = 0.02) 7.8.2 Overall symptoms by verbal rating scale - 4 monthsOzaki 2020Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.13 (P = 0.03) 7.8.3 Overall symptoms - 6 monthsHarada 2009Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.68 (P = 0.09) GnRHasMean 5.3 1.4 3.8 SD 5.5 1.6 3 Total 3535 3535 125125 Oral or injectable progestogensMean 2.7 0.7 4.5 SD 3.9 1.1 3.6 Total 3535 3535 128128 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI 2.60 [0.37 , 4.83]2.60 [0.37 , 4.83] 0.70 [0.06 , 1.34]0.70 [0.06 , 1.34] -0.70 [-1.52 , 0.12]-0.70 [-1.52 , 0.12] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours oral or injectable progestogensFavours GnRHas Risk of BiasA + + + B ? ? + C ? ? + D ? ? + E + + − F + + + G + + + Risk 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 /uni00A0 /uni00A0 Comparison 8. /uni00A0 GnRHas versus gestrinone - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 8.1 Relief of overall pain - continu- ous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 8.1.1 Dysmenorrhoea, visual ana- log scale - 3 months 1 0 Mean Difference (IV, Fixed, 95% CI) Not estimable 8.1.2 Dysmenorrhoea, verbal rat- ing scale - 3 months 1 0 Mean Difference (IV, Fixed, 95% CI) Not estimable 8.1.3 Dyspareunia, visual analog scale - 3 months 1 52 Mean Difference (IV, Fixed, 95% CI) 1.39 [0.04, 2.74] 8.1.4 Dyspareunia, verbal rating scale - 3 months 1 52 Mean Difference (IV, Fixed, 95% CI) 0.28 [-0.12, 0.68] 8.1.5 Non-menstrual pain, visual analog scale - 3 months 1 55 Mean Difference (IV, Fixed, 95% CI) 0.49 [-0.59, 1.57] 8.1.6 Non-menstrual pain, verbal rating scale - 3 months 1 55 Mean Difference (IV, Fixed, 95% CI) 0.04 [-0.36, 0.44] 8.1.7 Dysmenorrhoea, visual ana- log scale - 6 months 1 55 Mean Difference (IV, Fixed, 95% CI) -0.82 [-1.49, -0.15] 8.1.8 Dysmenorrhoea, verbal rat- ing scale - 6 months 1 55 Mean Difference (IV, Fixed, 95% CI) -0.35 [-0.58, -0.12] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 195 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 8.1.9 Dyspareunia, visual analog scale - 6 months 1 52 Mean Difference (IV, Fixed, 95% CI) 1.17 [0.25, 2.09] 8.1.10 Dyspareunia, verbal rating scale - 6 months 1 52 Mean Difference (IV, Fixed, 95% CI) 0.33 [0.04, 0.62] 8.1.11 Non-menstrual pain, visual analog scale - 6 months 1 55 Mean Difference (IV, Fixed, 95% CI) 0.41 [-0.94, 1.76] 8.1.12 Non-menstrual pain, verbal rating scale - 6 months 1 55 Mean Difference (IV, Fixed, 95% CI) 0.15 [-0.20, 0.50] 8.2 Bone mineral density of spinal bone mass - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 8.2.1 Percentage change values - 6 months 1 41 Mean Difference (IV, Fixed, 95% CI) -1.96 [-3.62, -0.30] 8.2.2 Percentage change values - 12 months 1 41 Mean Difference (IV, Fixed, 95% CI) -5.10 [-7.39, -2.81] 8.3 Adverse effects - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 8.3.1 Hot flushes/flashes - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.29 [1.21, 4.32] 8.3.2 Headache - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.41 [0.51, 11.38] 8.3.3 Asthenia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.03, 2.02] 8.3.4 Mood change - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.26, 7.99] 8.3.5 Dermatitis - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 2.55] 8.3.6 Dizziness- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01] 8.3.7 Joint pain- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01] 8.3.8 Drowsiness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01] 8.3.9 Swelling - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 3.85] 8.3.10 Nausea- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01] 8.3.11 Tachycardia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.05, 5.01] 8.3.12 Vaginal dryness - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 4.83 [0.24, 96.16] 8.3.13 Insomnia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57] 8.3.14 Hypertrichosis - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57] 8.3.15 Seborrhea- 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 196 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 8.3.16 Skin rash - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57] 8.3.17 Constipation - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.01, 7.57] 8.3.18 Itching - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15] 8.3.19 Vaginal discharge - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15] 8.3.20 Paresthesia - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15] 8.3.21 Cramps - 6 months 1 55 Risk Ratio (M-H, Fixed, 95% CI) 2.90 [0.12, 68.15] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 197 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 8.1. /uni00A0 Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 1: Relief of overall pain - continuous Study or Subgroup 8.1.1 Dysmenorrhoea, visual analog scale - 3 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Not applicable 8.1.2 Dysmenorrhoea, verbal rating scale - 3 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Not applicable 8.1.3 Dyspareunia, visual analog scale - 3 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.02 (P = 0.04) 8.1.4 Dyspareunia, verbal rating scale - 3 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.38 (P = 0.17) 8.1.5 Non-menstrual pain, visual analog scale - 3 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.89 (P = 0.38) 8.1.6 Non-menstrual pain, verbal rating scale - 3 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.20 (P = 0.84) 8.1.7 Dysmenorrhoea, visual analog scale - 6 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.39 (P = 0.02) 8.1.8 Dysmenorrhoea, verbal rating scale - 6 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.97 (P = 0.003) 8.1.9 Dyspareunia, visual analog scale - 6 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.49 (P = 0.01) 8.1.10 Dyspareunia, verbal rating scale - 6 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.26 (P = 0.02) 8.1.11 Non-menstrual pain, visual analog scale - 6 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.59 (P = 0.55) 8.1.12 Non-menstrual pain, verbal rating scale - 6 months Vercellini 1996Subtotal (95% CI) GnRHasMean 0 0 2.29 0.64 1.73 0.62 0.05 0.04 1.61 0.43 1.64 0.5 SD 0 0 3.27 0.91 2.29 0.9 0.24 0.2 2.12 0.68 2.46 0.59 Total 280 280 2626 2626 2828 2828 2828 2828 2626 2626 2828 2828 GestrinoneMean 0.84 0.38 0.9 0.36 1.24 0.58 0.87 0.39 0.44 0.1 1.23 0.35 SD 1.91 0.65 1.25 0.49 1.79 0.58 1.77 0.58 1.11 0.3 2.65 0.71 Total 270 270 2626 2626 2727 2727 2727 2727 2626 2626 2727 2727 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI Not estimableNot estimable Not estimableNot estimable 1.39 [0.04 , 2.74]1.39 [0.04 , 2.74] 0.28 [-0.12 , 0.68]0.28 [-0.12 , 0.68] 0.49 [-0.59 , 1.57]0.49 [-0.59 , 1.57] 0.04 [-0.36 , 0.44]0.04 [-0.36 , 0.44] -0.82 [-1.49 , -0.15]-0.82 [-1.49 , -0.15] -0.35 [-0.58 , -0.12]-0.35 [-0.58 , -0.12] 1.17 [0.25 , 2.09]1.17 [0.25 , 2.09] 0.33 [0.04 , 0.62]0.33 [0.04 , 0.62] 0.41 [-0.94 , 1.76]0.41 [-0.94 , 1.76] 0.15 [-0.20 , 0.50]0.15 [-0.20 , 0.50] Mean Difference IV, Fixed, 95% CI Risk of BiasA ? ? ? ? ? ? ? ? ? ? ? ? B + + + + + + + + + + + + C + + + + + + + + + + + + D + + + + + + + + + + + + E + + + + + + + + + + + + F + + + + + + + + + + + + G + + + + + + + + + + + + /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 198 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 8.1. /uni00A0 (Continued) 8.1.12 Non-menstrual pain, verbal rating scale - 6 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.85 (P = 0.40) 0.5 0.59 2828 0.350.71 2727100.0%100.0%0.15 [-0.20 , 0.50]0.15 [-0.20 , 0.50] -4 -2 0 2 4Favours gestrinoneFavours GnRHas ? ++++++ Risk 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 /uni00A0 /uni00A0 Analysis 8.2. /uni00A0 Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 2: Bone mineral density of spinal bone mass - continuous Study or Subgroup 8.2.1 Percentage change values - 6 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.31 (P = 0.02) 8.2.2 Percentage change values - 12 months Vercellini 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 4.36 (P < 0.0001) GnRHasMean -1.08 -3.04 SD 3.26 4.77 Total 2222 2222 GestrinoneMean 0.88 2.06 SD 2.12 2.51 Total 1919 1919 Weight 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -1.96 [-3.62 , -0.30]-1.96 [-3.62 , -0.30] -5.10 [-7.39 , -2.81]-5.10 [-7.39 , -2.81] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours GnRHasFavours gestrinone Risk of BiasA ? ? B + + C + + D + + E + + F + + G + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 199 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 8.3. /uni00A0 Comparison 8: GnRHas versus gestrinone - all studies included, Outcome 3: Adverse effects - dichotomous Study or Subgroup 8.3.1 Hot flushes/flashes - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.56 (P = 0.01) 8.3.2 Headache - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.11 (P = 0.27) 8.3.3 Asthenia - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.31 (P = 0.19) 8.3.4 Mood change - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.42 (P = 0.67) 8.3.5 Dermatitis - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.33 (P = 0.18) 8.3.6 Dizziness- 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.61 (P = 0.54) 8.3.7 Joint pain- 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.61 (P = 0.54) 8.3.8 Drowsiness - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.61 (P = 0.54) 8.3.9 Swelling - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable GnRHasEvents 19 19 5 5 1 1 3 3 0 0 1 1 1 1 1 1 0 0 Total 2828 2828 2828 2828 2828 2828 2828 2828 2828 GestrinoneEvents 8 8 2 2 4 4 2 2 3 3 2 2 2 2 2 2 2 2 Total 2727 2727 2727 2727 2727 2727 2727 2727 2727 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 2.29 [1.21 , 4.32]2.29 [1.21 , 4.32] 2.41 [0.51 , 11.38] 2.41 [0.51 , 11.38] 0.24 [0.03 , 2.02]0.24 [0.03 , 2.02] 1.45 [0.26 , 7.99]1.45 [0.26 , 7.99] 0.14 [0.01 , 2.55]0.14 [0.01 , 2.55] 0.48 [0.05 , 5.01]0.48 [0.05 , 5.01] 0.48 [0.05 , 5.01]0.48 [0.05 , 5.01] 0.48 [0.05 , 5.01]0.48 [0.05 , 5.01] 0.19 [0.01 , 3.85]0.19 [0.01 , 3.85] Risk RatioM-H, Fixed, 95% CIRisk of BiasA ? ? ? ? ? ? ? ? ? B + + + + + + + + + C + + + + + + + + + D + + + + + + + + + E + + + + + + + + + F + + + + + + + + + G + + + + + + + + + /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 200 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 8.3. /uni00A0 (Continued) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.08 (P = 0.28) 8.3.10 Nausea- 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.61 (P = 0.54) 8.3.11 Tachycardia - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.61 (P = 0.54) 8.3.12 Vaginal dryness - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.03 (P = 0.30) 8.3.13 Insomnia - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48) 8.3.14 Hypertrichosis - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48) 8.3.15 Seborrhea- 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48) 8.3.16 Skin rash - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48) 8.3.17 Constipation - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.48) 8.3.18 Itching - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable 0 1 1 1 1 2 2 0 0 0 0 0 0 0 0 0 0 1 1 2828 2828 2828 2828 2828 2828 2828 2828 2828 2 2 2 2 2 0 0 1 1 1 1 1 1 1 1 1 1 0 0 2727 2727 2727 2727 2727 2727 2727 2727 2727 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 0.48 [0.05 , 5.01]0.48 [0.05 , 5.01] 0.48 [0.05 , 5.01]0.48 [0.05 , 5.01] 4.83 [0.24 , 96.16]4.83 [0.24 , 96.16] 0.32 [0.01 , 7.57]0.32 [0.01 , 7.57] 0.32 [0.01 , 7.57]0.32 [0.01 , 7.57] 0.32 [0.01 , 7.57]0.32 [0.01 , 7.57] 0.32 [0.01 , 7.57]0.32 [0.01 , 7.57] 0.32 [0.01 , 7.57]0.32 [0.01 , 7.57] 2.90 [0.12 , 68.15]2.90 [0.12 , 68.15] ? ? ? ? ? ? ? ? ? + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 201 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 8.3. /uni00A0 (Continued) Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.66 (P = 0.51) 8.3.19 Vaginal discharge - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.66 (P = 0.51) 8.3.20 Paresthesia - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.66 (P = 0.51) 8.3.21 Cramps - 6 months Vercellini 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.66 (P = 0.51) 1 1 1 1 1 1 1 28 2828 2828 2828 0 0 0 0 0 0 0 27 2727 2727 2727 100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 2.90 [0.12 , 68.15] 2.90 [0.12 , 68.15]2.90 [0.12 , 68.15] 2.90 [0.12 , 68.15]2.90 [0.12 , 68.15] 2.90 [0.12 , 68.15]2.90 [0.12 , 68.15] 0.01 0.1 1 10 100Favours gestrinoneFavours GnRHas ? ? ? + + + + + + + + + + + + + + + + + + Risk 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 /uni00A0 /uni00A0 Comparison 9. /uni00A0 GnRHas versus GnRHas (varying dosage) - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 9.1 Relief of overall pain - 200 /uni03BCg versus 400 /uni03BCg nafarelin - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 9.1.1 Pelvic pain - 2 months 1 15 Mean Difference (IV, Fixed, 95% CI) 0.20 [-1.07, 1.47] 9.1.2 Pelvic pain - 4 months 1 15 Mean Difference (IV, Fixed, 95% CI) -0.10 [-1.07, 0.87] 9.1.3 Pelvic pain - 6 months 1 15 Mean Difference (IV, Fixed, 95% CI) 0.30 [-0.61, 1.21] 9.2 Relief of overall pain - 400 /uni03BCg versus 800 /uni03BCg nafarelin - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 9.2.1 Pelvic pain - 6 months 1 77 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.71, 2.16] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 202 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 9.2.2 Dysmenorrhea - 6 months 1 90 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.13, 71.74] 9.2.3 Dyspareunia - 6 months 1 57 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.49, 2.26] 9.3 Adverse effects - 200 /uni03BCg versus 400 /uni03BCg nafarelin - dichotomous 2 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 9.3.1 Vasomotor symptoms (hot flashes or dizziness) - 2 months 1 15 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.17, 1.12] 9.3.2 Vasomotor symptoms (hot flashes or dizziness) - 4 months 1 15 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.10, 1.27] 9.3.3 Vasomotor symptoms (hot flashes or dizziness) - 6 months 1 15 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.08, 1.01] 9.3.4 Rhinitis - 6 months 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.10, 1.67] 9.3.5 Upper respiratory infection - 6 months 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.20 [0.03, 1.47] 9.3.6 Irregular bleeding - 6 months 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.31, 1.63] 9.4 Adverse effects - 3.75 mg versus 1.88 mg leuprolide acetate - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 9.4.1 Menopausal symptoms by Kupper- man Index - 2 months 1 50 Mean Difference (IV, Fixed, 95% CI) 1.20 [-3.14, 5.54] 9.4.2 Menopausal symptoms by Kupper- man Index - 3 months 1 50 Mean Difference (IV, Fixed, 95% CI) 5.70 [2.12, 9.28] 9.4.3 Menopausal symptoms by Kupper- man Index - 4 months 1 50 Mean Difference (IV, Fixed, 95% CI) 9.50 [6.55, 12.45] 9.4.4 Menopausal symptoms by Kupper- man Index - 5 months 1 50 Mean Difference (IV, Fixed, 95% CI) 13.20 [10.22, 16.18] 9.5 Improvement of most troublesome symptoms - 400 /uni03BCg versus 800 /uni03BCg na- farelin - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 9.5.1 Overall improvement - 6 months 1 143 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.78, 1.14] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 203 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 9.1. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 1: Relief of overall pain - 200 /uni03BCg versus 400 /uni03BCg nafarelin - continuous Study or Subgroup 9.1.1 Pelvic pain - 2 months Tahara 2000Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.31 (P = 0.76) 9.1.2 Pelvic pain - 4 months Tahara 2000Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.20 (P = 0.84) 9.1.3 Pelvic pain - 6 months Tahara 2000Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.64 (P = 0.52) 200 μg nafarelinMean 4.4 3.7 3.8 SD 1.2 1.1 0.9 Total 88 88 88 400 μg nafarelinMean 4.2 3.8 3.5 SD 1.3 0.8 0.9 Total 77 77 77 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI 0.20 [-1.07 , 1.47]0.20 [-1.07 , 1.47] -0.10 [-1.07 , 0.87]-0.10 [-1.07 , 0.87] 0.30 [-0.61 , 1.21]0.30 [-0.61 , 1.21] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours lower doseFavours higher dose Risk of BiasA + + + B ? ? ? C ? ? ? D ? ? ? E + + + F + + + G + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 204 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 9.2. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 2: Relief of overall pain - 400 /uni03BCg versus 800 /uni03BCg nafarelin - dichotomous Study or Subgroup 9.2.1 Pelvic pain - 6 monthsAdamson 1994Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.74 (P = 0.46) 9.2.2 Dysmenorrhea - 6 monthsAdamson 1994Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.68 (P = 0.50) 9.2.3 Dyspareunia - 6 monthsAdamson 1994Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.12 (P = 0.90) 400 μg nafarelinEvents 16 16 1 1 10 10 Total 3737 4545 3131 800 μg nafarelinEvents 14 14 0 0 8 8 Total 4040 4545 2626 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 1.24 [0.71 , 2.16]1.24 [0.71 , 2.16] 3.00 [0.13 , 71.74]3.00 [0.13 , 71.74] 1.05 [0.49 , 2.26]1.05 [0.49 , 2.26] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours 400μg nafarelinFavours 200μg nafarelin Risk of BiasA ? ? ? B + + + C + + + D + + + E + + + F + + + G + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 205 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 9.3. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 3: Adverse effects - 200 /uni03BCg versus 400 /uni03BCg nafarelin - dichotomous Study or Subgroup 9.3.1 Vasomotor symptoms (hot flashes or dizziness) - 2 months Tahara 2000Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.72 (P = 0.09) 9.3.2 Vasomotor symptoms (hot flashes or dizziness) - 4 months Tahara 2000Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.60 (P = 0.11) 9.3.3 Vasomotor symptoms (hot flashes or dizziness) - 6 months Tahara 2000Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.95 (P = 0.05) 9.3.4 Rhinitis - 6 months Bergqvist 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.25 (P = 0.21) 9.3.5 Upper respiratory infection - 6 months Bergqvist 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.58 (P = 0.11) 9.3.6 Irregular bleeding - 6 months Bergqvist 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.80 (P = 0.42) 200 μg nafarelinEvents 3 3 2 2 2 2 2 2 1 1 5 5 Total 88 88 88 1212 1212 1212 400 μg nafarelinEvents 6 6 5 5 6 6 5 5 5 5 7 7 Total 77 77 77 1212 1212 1212 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.44 [0.17 , 1.12]0.44 [0.17 , 1.12] 0.35 [0.10 , 1.27]0.35 [0.10 , 1.27] 0.29 [0.08 , 1.01]0.29 [0.08 , 1.01] 0.40 [0.10 , 1.67]0.40 [0.10 , 1.67] 0.20 [0.03 , 1.47]0.20 [0.03 , 1.47] 0.71 [0.31 , 1.63]0.71 [0.31 , 1.63] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours 400μg nafarelinFavours 200μg nafarelin Risk of BiasA + + + ? ? ? B ? ? ? ? ? ? C ? ? ? + + + D ? ? ? + + + E + + + + + + F + + + + + + G + + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 206 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 9.4. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 4: Adverse effects - 3.75 mg versus 1.88 mg leuprolide acetate - continuous Study or Subgroup 9.4.1 Menopausal symptoms by Kupperman Index - 2 months Tang 2017Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.54 (P = 0.59) 9.4.2 Menopausal symptoms by Kupperman Index - 3 months Tang 2017Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 3.12 (P = 0.002) 9.4.3 Menopausal symptoms by Kupperman Index - 4 months Tang 2017Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 6.32 (P < 0.00001) 9.4.4 Menopausal symptoms by Kupperman Index - 5 months Tang 2017Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 8.69 (P < 0.00001) 3.75 mg leuprorelin acetateMean 14 16.3 18.2 19.6 SD 8.4 7.2 6.7 7.5 Total 2525 2525 2525 2525 1.88 mg leuprorelin acetateMean 12.8 10.6 8.7 6.4 SD 7.2 5.6 3.4 1.2 Total 2525 2525 2525 2525 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI 1.20 [-3.14 , 5.54]1.20 [-3.14 , 5.54] 5.70 [2.12 , 9.28]5.70 [2.12 , 9.28] 9.50 [6.55 , 12.45]9.50 [6.55 , 12.45] 13.20 [10.22 , 16.18]13.20 [10.22 , 16.18] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours 1.88mg Leuprorelin acetateFavours 3.75mg Leuprorelin acetate Risk of BiasA ? ? ? ? B ? ? ? ? C ? ? ? ? D ? ? ? ? E ? ? ? ? F + + + + G + + + + Risk 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 /uni00A0 /uni00A0 Analysis 9.5. /uni00A0 Comparison 9: GnRHas versus GnRHas (varying dosage) - all studies included, Outcome 5: Improvement of most troublesome symptoms - 400 /uni03BCg versus 800 /uni03BCg nafarelin - dichotomous Study or Subgroup 9.5.1 Overall improvement - 6 monthsHenzl 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.63 (P = 0.53) 400 μg nafarelinEvents 53 53 Total 7373 800 μg nafarelinEvents 54 54 Total 7070 Weight 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.94 [0.78 , 1.14]0.94 [0.78 , 1.14] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours 400μg NafarelinFavours 800μg Nafarelin Risk of BiasA ? B ? C + D + E + F + G + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 207 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Comparison 10. /uni00A0 GnRHas versus GnRHas (duration of treatment) - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 10.1 Relief of overall pain - 3 months vs 6 months - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 10.1.1 Pelvic pain - 6 months 1 179 Mean Difference (IV, Fixed, 95% CI) 0.16 [0.13, 0.19] 10.1.2 Dysmenorrhoea - 6 months 1 179 Mean Difference (IV, Fixed, 95% CI) -0.09 [-0.11, -0.07] 10.1.3 Dyspareunia - 6 months 1 179 Mean Difference (IV, Fixed, 95% CI) -0.14 [-0.17, -0.11] 10.1.4 Pelvic induration - 6 months 1 179 Mean Difference (IV, Fixed, 95% CI) -0.03 [-0.06, 0.00] 10.1.5 Pelvic tenderness - 6 months 1 179 Mean Difference (IV, Fixed, 95% CI) 0.05 [0.03, 0.07] 10.2 Bone mineral density of spinal bone mass - 3 months vs 6 months - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 10.2.1 Percentage change values - 6 months 1 183 Mean Difference (IV, Fixed, 95% CI) 1.60 [1.51, 1.69] 10.3 Bone mineral density of proximal femoral bone - 3 months vs 6 months - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 10.3.1 Percentage change values - 6 months 1 183 Mean Difference (IV, Fixed, 95% CI) 1.90 [1.72, 2.08] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 208 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 10.1. /uni00A0 Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies included, Outcome 1: Relief of overall pain - 3 months vs 6 months - continuous Study or Subgroup 10.1.1 Pelvic pain - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 11.89 (P < 0.00001) 10.1.2 Dysmenorrhoea - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 8.00 (P < 0.00001) 10.1.3 Dyspareunia - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 8.13 (P < 0.00001) 10.1.4 Pelvic induration - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.91 (P = 0.06) 10.1.5 Pelvic tenderness - 6 monthsHornstein 1995Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 3.93 (P < 0.0001) 3 monthsMean 0.75 0.24 0.6 0.51 0.49 SD 0.09 0.07 0.11 0.1 0.09 Total 9191 9191 9191 9191 9191 6 monthsMean 0.59 0.33 0.74 0.54 0.44 SD 0.09 0.08 0.12 0.11 0.08 Total 8888 8888 8888 8888 8888 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI 0.16 [0.13 , 0.19]0.16 [0.13 , 0.19] -0.09 [-0.11 , -0.07] -0.09 [-0.11 , -0.07] -0.14 [-0.17 , -0.11] -0.14 [-0.17 , -0.11] -0.03 [-0.06 , 0.00]-0.03 [-0.06 , 0.00] 0.05 [0.03 , 0.07]0.05 [0.03 , 0.07] Mean Difference IV, Fixed, 95% CI -1 -0.50 0.5 1Favours 3 monthsFavours 6 months Risk of BiasA ? ? ? ? ? B ? ? ? ? ? C + + + + + D + + + + + E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Analysis 10.2. /uni00A0 Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies included, Outcome 2: Bone mineral density of spinal bone mass - 3 months vs 6 months - continuous Study or Subgroup 10.2.1 Percentage change values - 6 monthsOrwoll 1994Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 36.07 (P < 0.00001) 3 monthsMean -2.4 SD 0.3 Total 9191 6 monthsMean -4 SD 0.3 Total 9292 Weight 100.0%100.0% Mean Difference IV, Fixed, 95% CI 1.60 [1.51 , 1.69]1.60 [1.51 , 1.69] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours 3 monthsFavours 6 months Risk of BiasA ? B ? C + D + E ? F + G + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 209 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 10.3. /uni00A0 Comparison 10: GnRHas versus GnRHas (duration of treatment) - all studies included, Outcome 3: Bone mineral density of proximal femoral bone - 3 months vs 6 months - continuous Study or Subgroup 10.3.1 Percentage change values - 6 monthsOrwoll 1994Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 21.11 (P < 0.00001) 3 monthsMean -1.1 SD 0.7 Total 9191 6 monthsMean -3 SD 0.5 Total 9292 Weight 100.0%100.0% Mean Difference IV, Fixed, 95% CI 1.90 [1.72 , 2.08]1.90 [1.72 , 2.08] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours 3 monthsFavours 6 months Risk of BiasA ? B ? C + D + E ? F + G + Risk 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 /uni00A0 /uni00A0 Comparison 11. /uni00A0 GnRHas versus GnRHas (route of administration) Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 11.1 Relief of overall pain - IN versus SC - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 11.1.1 Pelvic pain - 6 months 1 5 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.53, 1.87] 11.1.2 Dysmenorrhea - 6 months 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.73, 2.06] 11.1.3 Dyspareunia - 6 months 1 7 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.57, 1.75] 11.1.4 Pelvic induration - 6 months 1 8 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.47, 1.55] 11.1.5 Pelvic tenderness - 6 months 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.69, 3.27] 11.2 Adverse effects - IN vs SC - di- chotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 11.2.1 Hot flushes/flashes - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.48, 1.55] 11.2.2 Vaginal dryness - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.17, 4.37] 11.2.3 Decreased libido - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.07, 10.96] 11.2.4 Headaches - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.20, 14.55] /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 210 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 11.1. /uni00A0 Comparison 11: GnRHas versus GnRHas (route of administration), Outcome 1: Relief of overall pain - IN versus SC - dichotomous Study or Subgroup 11.1.1 Pelvic pain - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) 11.1.2 Dysmenorrhea - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.75 (P = 0.45) 11.1.3 Dyspareunia - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) 11.1.4 Pelvic induration - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.51 (P = 0.61) 11.1.5 Pelvic tenderness - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.02 (P = 0.31) IntranasalEvents 3 3 5 5 5 5 4 4 7 7 Total 33 55 55 55 77 SubcutaneousEvents 2 2 4 4 2 2 3 3 2 2 Total 22 55 22 33 33 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 1.00 [0.53 , 1.87]1.00 [0.53 , 1.87] 1.22 [0.73 , 2.06]1.22 [0.73 , 2.06] 1.00 [0.57 , 1.75]1.00 [0.57 , 1.75] 0.86 [0.47 , 1.55]0.86 [0.47 , 1.55] 1.50 [0.69 , 3.27]1.50 [0.69 , 3.27] Risk RatioM-H, Fixed, 95% CI 0.001 0.1 1 10 1000Favours intranasalFavours subcutaneous Risk of BiasA + + + + + B + + + + + C ? ? ? ? ? D + + + + + E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 211 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 11.2. /uni00A0 Comparison 11: GnRHas versus GnRHas (route of administration), Outcome 2: Adverse effects - IN vs SC - dichotomous Study or Subgroup 11.2.1 Hot flushes/flashes - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.51 (P = 0.61) 11.2.2 Vaginal dryness - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.19 (P = 0.85) 11.2.3 Decreased libido - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.12 (P = 0.91) 11.2.4 Headaches - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.49 (P = 0.62) IntranasalEvents 5 5 2 2 1 1 2 2 Total 77 77 77 77 SubcutaneousEvents 5 5 2 2 1 1 1 1 Total 66 66 66 66 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.86 [0.48 , 1.55]0.86 [0.48 , 1.55] 0.86 [0.17 , 4.37]0.86 [0.17 , 4.37] 0.86 [0.07 , 10.96]0.86 [0.07 , 10.96] 1.71 [0.20 , 14.55]1.71 [0.20 , 14.55] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours SubcutaneousFavours Intranasal Risk of BiasA + + + + B + + + + C ? ? ? ? D + + + + E + + + + F + + + + G + + + + Risk 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 /uni00A0 /uni00A0 Comparison 12. /uni00A0 GnRHas versus GnRHas (route of administration) - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 12.1 Relief of overall pain - IN ver- sus SC - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 12.1.1 Pelvic pain - 6 months 1 5 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.53, 1.87] 12.1.2 Dysmenorrhoea - 6 months 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.73, 2.06] 12.1.3 Dyspareunia - 6 months 1 7 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.57, 1.75] 12.1.4 Pelvic induration - 6 months 1 8 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.47, 1.55] 12.1.5 Pelvic tenderness - 6 months 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.69, 3.27] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 212 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 12.2 Relief of overall pain - IN ver- sus IM - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 12.2.1 Pelvic pain - 6 months 1 192 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.73, 1.26] 12.2.2 Dysmenorrhoea - 6 months 1 192 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.72, 2.30] 12.2.3 Dyspareunia - 6 months 1 166 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.62, 1.25] 12.2.4 Pelvic induration - 6 months 1 190 Risk Ratio (M-H, Fixed, 95% CI) 1.41 [0.82, 2.41] 12.2.5 Pelvic tenderness - 6 months 1 192 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.88, 1.73] 12.3 Adverse effects - IN vs SC - di- chotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 12.3.1 Hot flushes/flashes - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.48, 1.55] 12.3.2 Vaginal dryness - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.17, 4.37] 12.3.3 Decreased libido - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.07, 10.96] 12.3.4 Headaches - 6 months 1 13 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.20, 14.55] 12.4 Adverse effects - IN versus IM depot - dichotomous 2 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 12.4.1 Hot flushes/flashes - 6 months 2 404 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.88, 1.02] 12.4.2 Headache - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.63, 1.10] 12.4.3 Sweating - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [0.71, 1.79] 12.4.4 Vaginal dryness - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.27, 1.00] 12.4.5 Vaginal bleeding - 6 months 1 213 Risk Ratio (M-H, Fixed, 95% CI) 19.19 [1.12, 328.28] 12.5 Bone mineral density of spinal bone mass - IN vs IM depot - con- tinuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 12.5.1 Percentage decrease of BMD - 6 months 1 152 Mean Difference (IV, Fixed, 95% CI) -2.00 [-2.10, -1.90] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 213 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 12.1. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 1: Relief of overall pain - IN versus SC - dichotomous Study or Subgroup 12.1.1 Pelvic pain - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) 12.1.2 Dysmenorrhoea - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.75 (P = 0.45) 12.1.3 Dyspareunia - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) 12.1.4 Pelvic induration - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.51 (P = 0.61) 12.1.5 Pelvic tenderness - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.02 (P = 0.31) IntranasalEvents 3 3 5 5 5 5 4 4 7 7 Total 33 55 55 55 77 SubcutaneousEvents 2 2 4 4 2 2 3 3 2 2 Total 22 55 22 33 33 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 1.00 [0.53 , 1.87]1.00 [0.53 , 1.87] 1.22 [0.73 , 2.06]1.22 [0.73 , 2.06] 1.00 [0.57 , 1.75]1.00 [0.57 , 1.75] 0.86 [0.47 , 1.55]0.86 [0.47 , 1.55] 1.50 [0.69 , 3.27]1.50 [0.69 , 3.27] Risk RatioM-H, Fixed, 95% CI 0.001 0.1 1 10 1000Favours intranasalFavours subcutaneous Risk of BiasA + + + + + B + + + + + C ? ? ? ? ? D + + + + + E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 214 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 12.2. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 2: Relief of overall pain - IN versus IM - dichotomous Study or Subgroup 12.2.1 Pelvic pain - 6 monthsAgarwal 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.30 (P = 0.76) 12.2.2 Dysmenorrhoea - 6 monthsAgarwal 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.87 (P = 0.39) 12.2.3 Dyspareunia - 6 monthsAgarwal 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.71 (P = 0.48) 12.2.4 Pelvic induration - 6 monthsAgarwal 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.23 (P = 0.22) 12.2.5 Pelvic tenderness - 6 monthsAgarwal 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.23 (P = 0.22) IntranasalEvents 50 50 22 22 34 34 26 26 46 46 Total 9999 9999 8686 9999 9999 SubcutaneousEvents 49 49 16 16 36 36 17 17 35 35 Total 9393 9393 8080 9191 9393 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.96 [0.73 , 1.26]0.96 [0.73 , 1.26] 1.29 [0.72 , 2.30]1.29 [0.72 , 2.30] 0.88 [0.62 , 1.25]0.88 [0.62 , 1.25] 1.41 [0.82 , 2.41]1.41 [0.82 , 2.41] 1.23 [0.88 , 1.73]1.23 [0.88 , 1.73] Risk RatioM-H, Fixed, 95% CI 0.001 0.1 1 10 1000Favours intranasalFavours subcutaneous Risk of BiasA ? ? ? ? ? B ? ? ? ? ? C + + + + + D + + + + + E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 215 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 12.3. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 3: Adverse effects - IN vs SC - dichotomous Study or Subgroup 12.3.1 Hot flushes/flashes - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.51 (P = 0.61) 12.3.2 Vaginal dryness - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.19 (P = 0.85) 12.3.3 Decreased libido - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.12 (P = 0.91) 12.3.4 Headaches - 6 monthsLemay 1988Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.49 (P = 0.62) IntranasalEvents 5 5 2 2 1 1 2 2 Total 77 77 77 77 SubcutaneousEvents 5 5 2 2 1 1 1 1 Total 66 66 66 66 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.86 [0.48 , 1.55]0.86 [0.48 , 1.55] 0.86 [0.17 , 4.37]0.86 [0.17 , 4.37] 0.86 [0.07 , 10.96]0.86 [0.07 , 10.96] 1.71 [0.20 , 14.55]1.71 [0.20 , 14.55] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours SubcutaneousFavours Intranasal Risk of BiasA + + + + B + + + + C ? ? ? ? D + + + + E + + + + F + + + + G + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 216 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 12.4. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 4: Adverse effects - IN versus IM depot - dichotomous Study or Subgroup 12.4.1 Hot flushes/flashes - 6 monthsAgarwal 1997 Bergqvist 2000Subtotal (95% CI) Total events: Heterogeneity: Chi² = 1.62, df = 1 (P = 0.20); I² = 38% Test for overall effect: Z = 1.52 (P = 0.13) 12.4.2 Headache - 6 months Bergqvist 2000Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.29 (P = 0.20) 12.4.3 Sweating - 6 months Bergqvist 2000Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.52 (P = 0.60) 12.4.4 Vaginal dryness - 6 months Bergqvist 2000Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.95 (P = 0.05) 12.4.5 Vaginal bleeding - 6 months Bergqvist 2000Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.04 (P = 0.04) IntranasalEvents 9574 169 45 45 27 27 11 11 8 8 Total 98100198 100100 100100 100100 100100 IMdepotEvents 9391 184 61 61 27 27 24 24 0 0 Total 93 113206 113 113 113 113 113 113 113 113 Weight 52.9%47.1%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.97 [0.93 , 1.01]0.92 [0.79 , 1.06]0.95 [0.88 , 1.02] 0.83 [0.63 , 1.10]0.83 [0.63 , 1.10] 1.13 [0.71 , 1.79]1.13 [0.71 , 1.79] 0.52 [0.27 , 1.00]0.52 [0.27 , 1.00] 19.19 [1.12 , 328.28]19.19 [1.12 , 328.28] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours intranasalFavours IM(depot) Risk of BiasA ?? ? ? ? ? B ?? ? ? ? ? C +? ? ? ? ? D +? ? ? ? ? E ++ + + + + F ++ + + + + G ++ + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 217 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 12.5. /uni00A0 Comparison 12: GnRHas versus GnRHas (route of administration) - all studies included, Outcome 5: Bone mineral density of spinal bone mass - IN vs IM depot - continuous Study or Subgroup 12.5.1 Percentage decrease of BMD - 6 monthsAgarwal 1997Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 41.08 (P < 0.00001) intranasalMean 3 SD 0.3 Total 7878 IM depotMean 5 SD 0.3 Total 7474 Weight 100.0%100.0% Mean Difference IV, Fixed, 95% CI -2.00 [-2.10 , -1.90]-2.00 [-2.10 , -1.90] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas Risk of BiasA ? B ? C + D + E + F + G + Risk 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 /uni00A0 /uni00A0 Comparison 13. /uni00A0 GnRHas versus GnRHas (different treatment regimens) - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 13.1 Relief of overall pain - monthly versus 3-monthly depot leuprolide acetate - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 13.1.1 Non-menstrual pelvic pain - 3 months 1 30 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.52, 0.12] 13.1.2 Dyspareunia - 3 months 1 30 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.51, 0.31] 13.1.3 Pelvic induration - 3 months 1 30 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.40, 0.60] 13.1.4 Pelvic tenderness - 3 months 1 30 Mean Difference (IV, Fixed, 95% CI) -0.30 [-0.71, 0.11] 13.1.5 Non-menstrual pelvic pain - 6 months 1 30 Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.15, 0.35] 13.1.6 Dyspareunia - 6 months 1 30 Mean Difference (IV, Fixed, 95% CI) 0.00 [-0.50, 0.50] 13.1.7 Pelvic induration - 6 months 1 30 Mean Difference (IV, Fixed, 95% CI) 0.40 [0.10, 0.70] 13.1.8 Pelvic tenderness - 6 months 1 30 Mean Difference (IV, Fixed, 95% CI) 0.40 [-0.10, 0.90] 13.2 Adverse effects - monthly versus 3-monthly depot leuprolide acetate - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 13.2.1 Hot flushes/flashes - 6 months 1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.70, 1.43] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 218 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 13.2.2 Vaginal dryness - 6 months 1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.13, 3.44] 13.2.3 Abdominal pain - 6 months 1 30 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.13, 68.26] 13.2.4 Arthralgia - 6 months 1 30 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.13, 68.26] 13.2.5 Depression - 6 months 1 30 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.13, 68.26] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 219 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 13.1. /uni00A0 Comparison 13: GnRHas versus GnRHas (different treatment regimens) - all studies included, Outcome 1: Relief of overall pain - monthly versus 3-monthly depot leuprolide acetate - continuous Study or Subgroup 13.1.1 Non-menstrual pelvic pain - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.21 (P = 0.23) 13.1.2 Dyspareunia - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.48 (P = 0.63) 13.1.3 Pelvic induration - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.39 (P = 0.70) 13.1.4 Pelvic tenderness - 3 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.44 (P = 0.15) 13.1.5 Non-menstrual pelvic pain - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.77 (P = 0.44) 13.1.6 Dyspareunia - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) 13.1.7 Pelvic induration - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 2.66 (P = 0.008) 13.1.8 Pelvic tenderness - 6 monthsCrosignani 1996Subtotal (95% CI)Heterogeneity: Not applicable Test for overall effect: Z = 1.56 (P = 0.12) MonthlyMean 1.2 1.2 1.6 1.5 1.2 1.3 1.5 1.6 SD 0.4 0.4 0.7 0.7 0.4 0.7 0.5 0.7 Total 1515 1515 1515 1515 1515 1515 1515 1515 3-MonthlyMean 1.4 1.3 1.5 1.8 1.1 1.3 1.1 1.2 SD 0.5 0.7 0.7 0.4 0.3 0.7 0.3 0.7 Total 1515 1515 1515 1515 1515 1515 1515 1515 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean Difference IV, Fixed, 95% CI -0.20 [-0.52 , 0.12]-0.20 [-0.52 , 0.12] -0.10 [-0.51 , 0.31]-0.10 [-0.51 , 0.31] 0.10 [-0.40 , 0.60]0.10 [-0.40 , 0.60] -0.30 [-0.71 , 0.11] -0.30 [-0.71 , 0.11] 0.10 [-0.15 , 0.35]0.10 [-0.15 , 0.35] 0.00 [-0.50 , 0.50]0.00 [-0.50 , 0.50] 0.40 [0.10 , 0.70]0.40 [0.10 , 0.70] 0.40 [-0.10 , 0.90]0.40 [-0.10 , 0.90] Mean Difference IV, Fixed, 95% CI -100-50 0 50 100Favours 3-monthlyFavours monthly Risk of BiasA + + + + + + + + B ? ? ? ? ? ? ? ? C ? ? ? ? ? ? ? ? D ? ? ? ? ? ? ? ? E + + + + + + + + F + + + + + + + + G + + + + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 220 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 13.2. /uni00A0 Comparison 13: GnRHas versus GnRHas (different treatment regimens) - all studies included, Outcome 2: Adverse effects - monthly versus 3-monthly depot leuprolide acetate - dichotomous Study or Subgroup 13.2.1 Hot flushes/flashes - 6 monthsCrosignani 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) 13.2.2 Vaginal dryness - 6 monthsCrosignani 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.48 (P = 0.63) 13.2.3 Abdominal pain - 6 monthsCrosignani 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.69 (P = 0.49) 13.2.4 Arthralgia - 6 monthsCrosignani 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.69 (P = 0.49) 13.2.5 Depression - 6 monthsCrosignani 1996Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.69 (P = 0.49) MonthlyEvents 12 12 2 2 1 1 1 1 1 1 Total 1515 1515 1515 1515 1515 3-monthlyEvents 12 12 3 3 0 0 0 0 0 0 Total 1515 1515 1515 1515 1515 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 1.00 [0.70 , 1.43]1.00 [0.70 , 1.43] 0.67 [0.13 , 3.44]0.67 [0.13 , 3.44] 3.00 [0.13 , 68.26]3.00 [0.13 , 68.26] 3.00 [0.13 , 68.26]3.00 [0.13 , 68.26] 3.00 [0.13 , 68.26]3.00 [0.13 , 68.26] Risk RatioM-H, Fixed, 95% CI 0.01 0.1 1 10 100Favours 3-monthlyFavours monthly Risk of BiasA + + + + + B ? ? ? ? ? C ? ? ? ? ? D ? ? ? ? ? E + + + + + F + + + + + G + + + + + Risk 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 /uni00A0 /uni00A0 Comparison 14. /uni00A0 GnRHas versus GnRHas in conjunction with add-back therapy - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 14.1 Relief of overall pain - di- chotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 14.1.1 Dysmenorrhoea - 6 months 1 28 Risk Ratio (M-H, Fixed, 95% CI) 9.62 [0.58, 159.04] 14.1.2 Dyspareunia - 6 months 1 28 Risk Ratio (M-H, Fixed, 95% CI) 6.07 [0.86, 43.04] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 221 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 14.1.3 Non-menstrual pelvic pain - 6 months 1 28 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.26, 6.62] 14.2 Relief of overall pain - con- tinuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 14.2.1 Pelvic pain - 6 months 1 90 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.39, -0.01] 14.2.2 Dysmenorrhoea - 6 months 1 0 Mean Difference (IV, Fixed, 95% CI) Not estimable 14.2.3 Dyspareunia - 6 months 1 90 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.40, 0.80] 14.2.4 Pelvic pain - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.14, -0.06] 14.2.5 Overall pain - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -1.50 [-7.92, 4.92] 14.2.6 Dysmenorrhoea - 12 months 1 0 Mean Difference (IV, Fixed, 95% CI) Not estimable 14.2.7 Dyspareunia - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.03, 0.43] 14.3 Bone mineral density of spinal bone mass - continuous 6 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 14.3.1 Percentage change values - 6 months 2 46 Mean Difference (IV, Fixed, 95% CI) -3.88 [-4.27, -3.49] 14.3.2 Absolute values - 6 months 5 199 Mean Difference (IV, Fixed, 95% CI) 0.02 [0.02, 0.02] 14.3.3 Absolute values - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -0.01 [-0.06, 0.03] 14.4 Adverse effects - dichoto- mous 6 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 14.4.1 Hot flushes/flashes - 3 months 1 306 Risk Ratio (M-H, Fixed, 95% CI) 1.86 [1.61, 2.15] 14.4.2 Hot flushes/flashes - 6 months 4 215 Risk Ratio (M-H, Fixed, 95% CI) 1.59 [1.32, 1.93] 14.4.3 Loss of libido - 6 months 2 96 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.58, 1.97] 14.4.4 Vaginal dryness - 6 months 3 404 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [1.11, 1.76] 14.4.5 Headaches - 6 months 3 126 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.67, 1.24] 14.4.6 Sweating - 6 months 1 27 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.31, 0.94] Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 222 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 14.4.7 Sleeplessness - 6 months 1 27 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.18, 1.18] 14.4.8 Peripheral oedema - 6 months 1 27 Risk Ratio (M-H, Fixed, 95% CI) 2.32 [0.54, 9.95] 14.4.9 Vaginal bleeding - 6 months 3 185 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.35, 0.93] 14.4.10 Rhinitis - 6 months 1 47 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.36, 1.94] 14.4.11 Upper respiratory infec- tion - 6 months 1 47 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.27, 1.51] 14.4.12 Emotional changes - 6 months 1 87 Risk Ratio (M-H, Fixed, 95% CI) 3.13 [1.26, 7.78] 14.5 Quality of life - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 14.5.1 General health - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -4.70 [-10.15, 0.75] 14.5.2 Physical function - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -8.80 [-14.81, -2.79] 14.5.3 Role physical - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) 2.80 [-3.13, 8.73] 14.5.4 Role emotional - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) 2.30 [-3.82, 8.42] 14.5.5 Mental health - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -0.30 [-6.17, 5.57] 14.5.6 Social function - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -3.80 [-8.80, 1.20] 14.5.7 Vitality - 12 months 1 90 Mean Difference (IV, Fixed, 95% CI) -10.20 [-15.18, -5.22] 14.6 Improvement of most trou- blesome symptoms - continuous/uni00A0 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 14.6.1 Improvement overall pain - 4 weeks 1 19 Mean Difference (IV, Fixed, 95% CI) 12.00 [5.59, 18.41] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 223 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 14.1. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add- back therapy - all studies included, Outcome 1: Relief of overall pain - dichotomous Study or Subgroup 14.1.1 Dysmenorrhoea - 6 monthsFreundl 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.58 (P = 0.11) 14.1.2 Dyspareunia - 6 monthsFreundl 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.80 (P = 0.07) 14.1.3 Non-menstrual pelvic pain - 6 monthsFreundl 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.32 (P = 0.75) GnRHasEvents 5 5 7 7 3 3 Total 1515 1515 1515 GnRHas in conjunction with add-back therapyEvents 0 0 1 1 2 2 Total 1313 1313 1313 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 9.63 [0.58 , 159.04]9.63 [0.58 , 159.04] 6.07 [0.86 , 43.04]6.07 [0.86 , 43.04] 1.30 [0.26 , 6.62]1.30 [0.26 , 6.62] Risk RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas Risk of BiasA ? ? ? B ? ? ? C + + + D + + + E + + + F + + + G + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 224 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 14.2. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add- back therapy - all studies included, Outcome 2: Relief of overall pain - continuous Study or Subgroup 14.2.1 Pelvic pain - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 2.09 (P = 0.04) 14.2.2 Dysmenorrhoea - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Not applicable 14.2.3 Dyspareunia - 6 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.65 (P = 0.51) 14.2.4 Pelvic pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 4.74 (P < 0.00001) 14.2.5 Overall pain - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.46 (P = 0.65) 14.2.6 Dysmenorrhoea - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Not applicable 14.2.7 Dyspareunia - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.72 (P = 0.09) GnRHasMean 1.3 0 2.6 0.2 62.1 0 1.4 SD 0.5 0 1.3 0.1 14 0 0.5 Total 4444 440 4444 4444 4444 440 4444 GnRHas in conjunction with add-back therapyMean 1.5 0 2.4 0.3 63.6 0 1.2 SD 0.4 0 1.6 0.1 17 0 0.6 Total 4646 460 4646 4646 4646 460 4646 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI -0.20 [-0.39 , -0.01]-0.20 [-0.39 , -0.01] Not estimableNot estimable 0.20 [-0.40 , 0.80]0.20 [-0.40 , 0.80] -0.10 [-0.14 , -0.06]-0.10 [-0.14 , -0.06] -1.50 [-7.92 , 4.92]-1.50 [-7.92 , 4.92] Not estimableNot estimable 0.20 [-0.03 , 0.43]0.20 [-0.03 , 0.43] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas Risk of BiasA + + + + + + + B ? ? ? ? ? ? ? C ? ? ? ? ? ? ? D + + + + + + + E + + + + + + + F + + + + + + + G + + + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 225 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 14.3. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome 3: Bone mineral density of spinal bone mass - continuous Study or Subgroup 14.3.1 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) 14.3.2 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) 14.3.3 Absolute values - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.66 (P = 0.51) GnRHasMean -6.5-5.6 1.1551.161.231.0571.005 0.981 SD 0.80.7 0.1340.040.160.0030.112 0.099 Total 141024 2214121044102 4444 GnRHas in conjuction with add-back therapyMean -2-2.7 1.2341.221.141.0361.01 0.995 SD 0.50.7 0.1220.130.10.0040.11 0.102 Total 13922 18131194697 4646 Weight 61.4%38.6%100.0% 0.2%0.2%0.1%99.1%0.5%100.0% 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI -4.50 [-5.00 , -4.00]-2.90 [-3.53 , -2.27]-3.88 [-4.27 , -3.49] -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] -0.01 [-0.06 , 0.03]-0.01 [-0.06 , 0.03] Mean DifferenceIV, Fixed, 95% CI -10-5 0 5 10Favours GnRHas in conjunction with add-back therapyFavours GnRHas Risk of BiasA ?+ ???++ + B ?? ????? ? C ++ ++++? ? D ++ +++++ + E ++ ++?++ + F ++ +++++ + G ++ +++++ + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 226 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 14.4. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome 4: Adverse effects - dichotomous Study or Subgroup 14.4.1 Hot flushes/flashes - 3 monthsMoghissi 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 8.41 (P < 0.00001) 14.4.2 Hot flushes/flashes - 6 monthsEdmonds 1994Freundl 1998Howell 1995Zupi 2005Subtotal (95% CI) Total events: Heterogeneity: Chi² = 37.00, df = 3 (P < 0.00001); I² = 92% Test for overall effect: Z = 4.82 (P < 0.00001) 14.4.3 Loss of libido - 6 monthsEdmonds 1994Howell 1995Subtotal (95% CI) Total events: Heterogeneity: Chi² = 8.78, df = 1 (P = 0.003); I² = 89% Test for overall effect: Z = 0.21 (P = 0.84) 14.4.4 Vaginal dryness - 6 monthsEdmonds 1994Howell 1995Moghissi 1998Subtotal (95% CI) Total events: Heterogeneity: Chi² = 2.85, df = 2 (P = 0.24); I² = 30% Test for overall effect: Z = 2.83 (P = 0.005) 14.4.5 Headaches - 6 monthsEdmonds 1994Freundl 1998Howell 1995Subtotal (95% CI) Total events: Heterogeneity: Chi² = 1.10, df = 2 (P = 0.58); I² = 0% Test for overall effect: Z = 0.59 (P = 0.56) 14.4.6 Sweating - 6 monthsFreundl 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.20 (P = 0.03) 14.4.7 Sleeplessness - 6 monthsFreundl 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.61 (P = 0.11) 14.4.8 Peripheral oedema - 6 monthsFreundl 1998Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.13 (P = 0.26) 14.4.9 Vaginal bleeding - 6 months Bergqvist 1997Howell 1995Zupi 2005Subtotal (95% CI) Total events: Heterogeneity: Chi² = 6.74, df = 2 (P = 0.03); I² = 70% Test for overall effect: Z = 2.25 (P = 0.02) 14.4.10 Rhinitis - 6 months GnRHasEvents 103 103 2492434 91 124 16 111056 77 12 11 11 34 7 7 4 4 5 5 1241 17 Total 109109 25142444107 252348 2524109158 25142564 1414 1414 1414 24244492 GnRHas  in conjunction with add-back therapyEvents 100 100 12122112 57 4 11 15 111064 85 14913 36 12 12 8 8 2 2 11153 29 Total 197197 25132446108 252348 2524197246 25132462 1313 1313 1313 23244693 Weight 100.0%100.0% 20.8%21.6%37.3%20.3%100.0% 26.7%73.3%100.0% 16.5%15.0%68.5%100.0% 38.3%25.5%36.2%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 38.5%51.4%10.1%100.0% Risk RatioM-H, Fixed, 95% CI 1.86 [1.61 , 2.15]1.86 [1.61 , 2.15] 2.00 [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] 3.00 [1.12 , 8.05]0.36 [0.14 , 0.98]1.07 [0.58 , 1.97] 1.00 [0.54 , 1.87]1.00 [0.51 , 1.95]1.58 [1.21 , 2.08] 1.40 [1.11 , 1.76] 0.86 [0.50 , 1.46]1.13 [0.72 , 1.79]0.81 [0.46 , 1.44]0.91 [0.67 , 1.24] 0.54 [0.31 , 0.94]0.54 [0.31 , 0.94] 0.46 [0.18 , 1.18]0.46 [0.18 , 1.18] 2.32 [0.54 , 9.95]2.32 [0.54 , 9.95] 1.05 [0.58 , 1.88]0.27 [0.10 , 0.69]0.35 [0.04 , 3.23]0.57 [0.35 , 0.93] Risk RatioM-H, Fixed, 95% CIRisk of BiasA ? ???+ ?? ??? ??? ? ? ? ??+ B ? ???? ?? ??? ??? ? ? ? ??? C + ?+?? ?? ??+ ?+? + + + +?? D + ?+?+ ?? ??+ ?+? + + + +?+ E + ++−+ +− +−+ ++− + + + +−+ F + −+++ −+ −++ −++ + + + +++ G + ++++ ++ +++ +++ + + + +++ /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 227 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews /uni00A0 Analysis 14.4. /uni00A0 (Continued) Test for overall effect: Z = 2.25 (P = 0.02) 14.4.10 Rhinitis - 6 months Bergqvist 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 0.41 (P = 0.68) 14.4.11 Upper respiratory infection - 6 months Bergqvist 1997Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 1.02 (P = 0.31) 14.4.12 Emotional changes - 6 monthsZupi 2005Subtotal (95% CI) Total events:Heterogeneity: Not applicable Test for overall effect: Z = 2.45 (P = 0.01) 7 7 6 6 16 16 2424 2424 4444 8 8 9 9 5 5 2323 2323 4343 100.0%100.0% 100.0%100.0% 100.0%100.0% 0.84 [0.36 , 1.94]0.84 [0.36 , 1.94] 0.64 [0.27 , 1.51]0.64 [0.27 , 1.51] 3.13 [1.26 , 7.78]3.13 [1.26 , 7.78] 0.010.1 1 10 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas ? ? + ? ? ? + + ? + + + + + + + + + + + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 228 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 14.5. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add- back therapy - all studies included, Outcome 5: Quality of life - continuous Study or Subgroup 14.5.1 General health - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.69 (P = 0.09) 14.5.2 Physical function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 2.87 (P = 0.004) 14.5.3 Role physical - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.93 (P = 0.35) 14.5.4 Role emotional - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.74 (P = 0.46) 14.5.5 Mental health - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 0.10 (P = 0.92) 14.5.6 Social function - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 1.49 (P = 0.14) 14.5.7 Vitality - 12 monthsZupi 2005Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 4.01 (P < 0.0001) GnRHasMean 54.9 57.6 60.1 62.3 60.2 54.5 57.8 SD 12.7 14 13.9 15.2 13.6 11.5 11.3 Total 4444 4444 4444 4444 4444 4444 4444 GnRHas in conjunction with add-back therapyMean 59.6 66.4 57.3 60 60.5 58.3 68 SD 13.7 15.1 14.8 14.4 14.8 12.7 12.8 Total 4646 4646 4646 4646 4646 4646 4646 Weight 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI -4.70 [-10.15 , 0.75]-4.70 [-10.15 , 0.75] -8.80 [-14.81 , -2.79]-8.80 [-14.81 , -2.79] 2.80 [-3.13 , 8.73]2.80 [-3.13 , 8.73] 2.30 [-3.82 , 8.42]2.30 [-3.82 , 8.42] -0.30 [-6.17 , 5.57]-0.30 [-6.17 , 5.57] -3.80 [-8.80 , 1.20]-3.80 [-8.80 , 1.20] -10.20 [-15.18 , -5.22]-10.20 [-15.18 , -5.22] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas Risk of BiasA + + + + + + + B ? ? ? ? ? ? ? C ? ? ? ? ? ? ? D + + + + + + + E + + + + + + + F + + + + + + + G + + + + + + + Risk 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 /uni00A0 /uni00A0 Analysis 14.6. /uni00A0 Comparison 14: GnRHas versus GnRHas in conjunction with add-back therapy - all studies included, Outcome 6: Improvement of most troublesome symptoms - continuous/uni00A0 Study or Subgroup 14.6.1 Improvement overall pain - 4 weeksSurrey 1992Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 3.67 (P = 0.0002) GnRHasMean 32 SD 6 Total 1010 GnRHas in conjunction with add-back therapyMean 20 SD 8 Total 99 Weight 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI 12.00 [5.59 , 18.41]12.00 [5.59 , 18.41] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Favours GnRHas in conjunction with add-back therapyFavours GnRHas Risk of BiasA + B ? C + D + E + F + G + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 229 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Comparison 15. /uni00A0 GnRHas versus GnRHas in conjunction with calcium-regulating agents Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 15.1 Bone mineral density of spinal bone mass - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 15.1.1 Anterior-posterior spine - 12 months 1 43 Mean Difference (IV, Fixed, 95% CI) -7.00 [-7.53, -6.47] 15.1.2 Lateral spine - 12 months 1 43 Mean Difference (IV, Fixed, 95% CI) -12.40 [-13.31, -11.49] 15.2 Improvement of most trouble- some symptoms - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 15.2.1 Overall improvement - 12 months 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.84, 1.08] 15.2.2 Complete resolution - 12 months 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.64, 1.41] /uni00A0 /uni00A0 Analysis 15.1. /uni00A0 Comparison 15: GnRHas versus GnRHas in conjunction with calcium- regulating agents, Outcome 1: Bone mineral density of spinal bone mass - continuous Study or Subgroup 15.1.1 Anterior-posterior spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 25.74 (P < 0.00001) 15.1.2 Lateral spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 26.60 (P < 0.00001) GnRHasMean -4.9 -4.9 SD 0.6 1 Total 2222 2222 GnRHas in conjunction with calcium-regulating agentsMean 2.1 7.5 SD 1.1 1.9 Total 2121 2121 Weight 100.0%100.0% 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI -7.00 [-7.53 , -6.47]-7.00 [-7.53 , -6.47] -12.40 [-13.31 , -11.49]-12.40 [-13.31 , -11.49] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas Risk of BiasA + + B + + C ? ? D + + E + + F + + G + + Risk 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 /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 230 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 15.2. /uni00A0 Comparison 15: GnRHas versus GnRHas in conjunction with calcium- regulating agents, Outcome 2: Improvement of most troublesome symptoms - dichotomous Study or Subgroup 15.2.1 Overall improvement - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.70 (P = 0.49) 15.2.2 Complete resolution - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.23 (P = 0.82) GnRHasEvents 21 21 15 15 Total 2222 2222 GnRHas in conjunction with calcium-regulating agentsEvents 21 21 15 15 Total 2121 2121 Weight 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.96 [0.84 , 1.08]0.96 [0.84 , 1.08] 0.95 [0.64 , 1.41]0.95 [0.64 , 1.41] Risk RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas Risk of BiasA + + B + + C ? ? D + + E + + F + + G + + Risk 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 /uni00A0 /uni00A0 Comparison 16. /uni00A0 GnRHas versus GnRHas in conjunction with calcium-regulating agents - all studies included Outcome or subgroup title No. of studies No. of partici- pants Statistical method Effect size 16.1 Bone mineral density of spinal bone mass - continuous 1 /uni00A0 Mean Difference (IV, Fixed, 95% CI) Subtotals only 16.1.1 Anterior-posterior spine - 12 months 1 43 Mean Difference (IV, Fixed, 95% CI) -7.00 [-7.53, -6.47] 16.1.2 Lateral spine - 12 months 1 43 Mean Difference (IV, Fixed, 95% CI) -12.40 [-13.31, -11.49] 16.2 Improvement of most trouble- some symptoms - dichotomous 1 /uni00A0 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 16.2.1 Overall improvement - 12 months 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.84, 1.08] 16.2.2 Complete resolution - 12 months 1 43 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.64, 1.41] /uni00A0 /uni00A0 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 231 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Analysis 16.1. /uni00A0 Comparison 16: GnRHas versus GnRHas in conjunction with calcium-regulating agents - all studies included, Outcome 1: Bone mineral density of spinal bone mass - continuous Study or Subgroup 16.1.1 Anterior-posterior spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 25.74 (P < 0.00001) 16.1.2 Lateral spine - 12 monthsFinkelstein 1998Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 26.60 (P < 0.00001) GnRHasMean -4.9 -4.9 SD 0.6 1 Total 2222 2222 GnRHas in conjuntion with calcium-regulating agentsMean 2.1 7.5 SD 1.1 1.9 Total 2121 2121 Weight 100.0%100.0% 100.0%100.0% Mean DifferenceIV, Fixed, 95% CI -7.00 [-7.53 , -6.47]-7.00 [-7.53 , -6.47] -12.40 [-13.31 , -11.49]-12.40 [-13.31 , -11.49] Mean DifferenceIV, Fixed, 95% CI -100-50 0 50 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas Risk of BiasA + + B + + C ? ? D + + E + + F + + G + + Risk 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 /uni00A0 /uni00A0 Analysis 16.2. /uni00A0 Comparison 16: GnRHas versus GnRHas in conjunction with calcium-regulating agents - all studies included, Outcome 2: Improvement of most troublesome symptoms - dichotomous Study or Subgroup 16.2.1 Overall improvement - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.70 (P = 0.49) 16.2.2 Complete resolution - 12 monthsFinkelstein 1998Subtotal (95% CI)Total events:Heterogeneity: Not applicableTest for overall effect: Z = 0.23 (P = 0.82) GnRHasEvents 21 21 15 15 Total 2222 2222 GnRHas in conjunction with calcium-regulating agentsEvents 21 21 15 15 Total 2121 2121 Weight 100.0%100.0% 100.0%100.0% Risk RatioM-H, Fixed, 95% CI 0.96 [0.84 , 1.08]0.96 [0.84 , 1.08] 0.95 [0.64 , 1.41]0.95 [0.64 , 1.41] Risk RatioM-H, Fixed, 95% CI 0.010.1 1 10 100Favours GnRHas in conjunction with calcium-regulating agentsFavours GnRHas Risk of BiasA + + B + + C ? ? D + + E + + F + + G + + Risk 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 /uni00A0 /uni00A0 A P P E N D I C E S Appendix 1. Cochrane Gynaecology and Fertility (CGF) specialist register search strategy ProCite platform Searched from inception to 26 May 2022

CONTAINS "endometriosis" or "The Endometriosis Health Profile" or "dyspareunia" or "pelvic pain" or/uni00A0 "pain-dyspareunia" or "pain-endometriosis" or "pain-pelvic" or/uni00A0 "dyschezia" or "bone density" or "bone mineral density" or "bone turnover" or "bone turnover estimates" or "bone turnover markers" or "bone metabolism" or "bone metabolism indicators" or Title CONTAINS "endometriosis" or "The Endometriosis Health Profile" or "dyspareunia" or "pelvic pain" or/uni00A0 "pain-dyspareunia" or "pain-endometriosis" or "pain-pelvic" or /uni00A0 "dyschezia" or "bone density" or "bone mineral density" or "bone turnover" or "bone turnover estimates" or "bone turnover markers" or "bone metabolism" or "bone metabolism indicators" AND Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 232 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews

CONTAINS "Gonadorelin" or "GnRh" or "GnRHa" or/uni00A0 "GnRH agonist" or "GnRH agonists" or "GnRHa-gonadotropin" or "Gonadotrophin releasing agonist" or "Gonadotrophin releasing hormones" or "gonadotrophins" or "gonadotropin" or "gonadotropin releasing hormone agonist" or "goserelin acetate" or "Gosereline " or "Luteinising hormone releasing hormone" or "LHRH" or "LHRH agonists" or "LHRH antagonists" or "leuprorelin" or "leuprorelin acetate" or "leuprolin" or "leuprolide depot" or "Leuprolide" or "leuprolide acetate" or "buserelin" or "Buserelin Acetate" or "buserelin naferelin" or "busereline" or "Nafarelin" or "Nafarelin Study Group" /uni00A0 or "triptorelin" or "Zoladex" or "Lupron" or "luprorelix" or "decapeptyl" or "decapeptyl" or "decapeptyl-daily" or "decapeptyl-depot" or "elagolix" or "Relugolix" or/uni00A0 linzagolix or Title CONTAINS "GnRH agonist" or "GnRH agonists" or "Gonadorelin" or "GnRh" or "GnRHa" (509 records) Appendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO) search strategy Web platform Searched on 26 May 2022 #1 bone turnover:TI,AB,KY 3588 #2 bone loss:TI,AB,KY 5102 #3 bone adj2 densit*:TI,AB,KY 12767 #4 MESH DESCRIPTOR Bone Density EXPLODE ALL TREES 4790 #5 MESH DESCRIPTOR Endometriosis EXPLODE ALL TREES 888 #6 Endometrio*:TI,AB,KY 3002 #7 dyspareunia:TI,AB,KY 1187 #8 (Dyschesia or Dyschezia):TI,AB,KY 52 #9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 20748 #10 MESH DESCRIPTOR Gonadotropin-Releasing Hormone EXPLODE ALL TREES 2677 #11 gonadotropin-releasing:TI,AB,KY 2463 #12 gonadotrophin-releasing:TI,AB,KY 512 #13 (luteini?ing hormone-releasing hormone*):TI,AB,KY 500 #14 (lhrh* or lhfshrh):TI,AB,KY 773 #15 gonadorelin*:TI,AB,KY 715 #16 (fsh releasing hormone*):TI,AB,KY 1 #17 (lh rh*):TI,AB,KY 206 #18 (buserelin or goserelin or leuprolide):TI,AB,KY 2450 #19 (triptorelin or nafarelin):TI,AB,KY 990 #20 (leuprorelin or naferelin):TI,AB,KY 475 #21 (GnRH* or Gn-RH*):TI,AB,KY 4012 #22 (leuprorelin or naferelin):TI,AB,KY 475 #23 (suprecur or suprefact):TI,AB,KY 29 #24 (Zoladex or lupron):TI,AB,KY 402 #25 (prostap or enantone):TI,AB,KY 32 #26 (lucrin or trenantone*):TI,AB,KY 28 Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 233 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews #27 (synarel or synarella):TI,AB,KY 10 #28 (decapeptyl or gonapeptyl):TI,AB,KY 157 #29 (Elagolix or Relugolix):TI,AB,KY 183 #30 (luliberin or cystorelin):TI,AB,KY 1 #31 (dirigestran or factrel or gonadoliberin):TI,AB,KY 7 #32 linzagolix or deslorelin 124 #33 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 7631 #34 #9 AND #33 1028 Appendix 3. MEDLINE search strategy Ovid platform Searched from 1946 to 26 May 2022 1 exp Endometriosis/ (24263) 2 dyspareunia.tw. (4401) 3 (Dyschesia or Dyschezia).tw. (397) 4 Endometrio*.tw. (34198) 5 ((cycl* or menstru*) adj2 pain*).tw. (2194) 6 Bone Density/ (58624) 7 (bone adj2 densit*).tw. (59256) 8 bone loss.tw. (33045) 9 bone turnover.tw. (13572) 10 or/1-9 (150269) 11 exp gonadotropin-releasing hormone/ (33621) 12 (gonadotropin-releasing or gonadotrophin-releasing).tw. (18551) 13 (GnRH* or Gn-RH*).tw. (24822) 14 luteini?ing hormone-releasing hormone*.tw. (5915) 15 (lhrh* or lhfshrh).tw. (6524) 16 gonadorelin*.tw. (247) 17 fsh releasing hormone*.tw. (54) 18 lh rh*.tw. (3398) 19 (buserelin or goserelin or leuprolide).tw. (4245) 20 (triptorelin or nafarelin).tw. (1080) 21 (leuprorelin or naferelin).tw. (533) 22 (suprecur or suprefact).tw. (30) 23 (Zoladex or lupron).tw. (561) 24 (prostap or enantone).tw. (31) 25 (lucrin or trenantone$).tw. (18) 26 (synarel or synarella).tw. (13) 27 (decapeptyl or gonapeptyl).tw. (225) 28 (Elagolix or Relugolix).tw. (159) 29 (luliberin or cystorelin).tw. (190) 30 (dirigestran or factrel or gonadoliberin).tw. (169) 31 (linzagolix or deslorelin).tw. (325) 32 or/11-31 (49323) 33 10 and 32 (2784) 34 randomized controlled trial.pt. (568945) 35 controlled clinical trial.pt. (94879) 36 randomized.ab. (561946) 37 randomised.ab. (111642) 38 placebo.tw. (234504) 39 clinical trials as topic.sh. (199923) 40 randomly.ab. (382777) 41 trial.ti. (262776) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 234 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 42 (crossover or cross-over or cross over).tw. (93495) 43 or/34-42 (1523247) 44 exp animals/ not humans.sh. (5009925) 45 43 not 44 (1401679) 46 33 and 45 (636) Appendix 4. Embase search strategy Ovid platform Searched from 1980/uni00A0to 26 May 2022 1 exp bone density/ (105245) 2 (bone adj2 densit*).tw. (85252) 3 bone loss.tw. (41805) 4 bone turnover.tw. (19885) 5 exp endometriosis/ (40870) 6 Endometrio*.tw. (49868) 7 dyspareunia.tw. (8221) 8 (Dyschesia or Dyschezia).tw. (795) 9 ((cycl* or menstru*) adj2 pain*).tw. (3256) 10 or/1-9 (220324) 11 exp gonadorelin/ (35087) 12 ((gonadotropin-releasing or gonadotrophin-releasing) adj2 (analog* or agonist* or antagonist*)).tw. (6773) 13 ((GnRH* or Gn-RH*) adj2 (analog* or agonist* or antagonist*)).tw. (15643) 14 (GnRH a or GnRHa).tw. (4062) 15 luteini?ing hormone-releasing hormone*.tw. (5572) 16 (lhrh* or lhfshrh).tw. (7690) 17 gonadorelin*.tw. (395) 18 fsh releasing hormone*.tw. (17) 19 lh rh*.tw. (2759) 20 (buserelin or goserelin or leuprolide).tw. (6162) 21 (triptorelin or nafarelin).tw. (1686) 22 (leuprorelin or naferelin).tw. (822) 23 (suprecur or suprefact).tw. (1328) 24 (Zoladex or lupron).tw. (3828) 25 (prostap or enantone).tw. (418) 26 (lucrin or trenantone*).tw. (429) 27 (synarel or synarella).tw. (352) 28 (decapeptyl or gonapeptyl).tw. (2140) 29 (Elagolix or Relugolix).tw. (325) 30 (luliberin or cystorelin).tw. (187) 31 (dirigestran or factrel or gonadoliberin).tw. (291) 32 (linzagolix or deslorelin).tw. (396) 33 or/11-32 (61600) 34 Clinical Trial/ (1024043) 35 Randomized Controlled Trial/ (704627) 36 controlled clinical trial/ (465536) 37 multicenter study/ (322883) 38 Phase 3 clinical trial/ (60413) 39 Phase 4 clinical trial/ (4746) 40 exp randomization/ (93845) 41 Single Blind Procedure/ (46061) 42 Double Blind Procedure/ (191894) 43 Crossover Procedure/ (70243) 44 Placebo/ (366605) 45 Randomi?ed controlled trial$.tw. (284966) 46 Rct.tw. (46655) 47 (random$ adj2 allocat$).tw. (49498) 48 Single blind$.tw. (28511) 49 Double blind$.tw. (222906) 50 ((treble or triple) adj blind$).tw. (1528) 51 placebo$.tw. (336711) Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 235 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews 52 prospective study/ (764038) 53 or/34-52 (2656999) 54 case study/ (85016) 55 case report.tw. (475125) 56 abstract report/ or letter/ (1191797) 57 Editorial.pt. (715507) 58 Letter.pt. (1192288) 59 Note.pt. (893698) 60 or/54-59 (3416613) 61 53 not 60 (2524171) 62 10 and 33 and 61 (1388) Appendix 5. PsycINFO search strategy Ovid platform Searched from 1806/uni00A0to 26 May 2022 1 exp menstrual disorders/ (1348) 2 Endometrio*.tw. (362) 3 1 and 2 (23) 4 Endometrio*.tw. (362) 5 dyspareunia.tw. (623) 6 (Dyschesia or Dyschezia).tw. (9) 7 4 or 5 or 6 (955) 8 3 or 7 (955) 9 exp Gonadotropic Hormones/ (4368) 10 (gonadotropin-releasing or gonadotrophin-releasing).tw. (1118) 11 (GnRH* or Gn-RH*).tw. (1121) 12 luteini?ing hormone-releasing hormone*.tw. (239) 13 (lhrh* or lhfshrh).tw. (219) 14 gonadorelin*.tw. (5) 15 fsh releasing hormone*.tw. (1) 16 lh rh*.tw. (46) 17 (buserelin or goserelin or leuprolide).tw. (120) 18 (triptorelin or nafarelin).tw. (30) 19 (leuprorelin or naferelin).tw. (12) 20 (Zoladex or lupron).tw. (25) 21 (prostap or enantone).tw. (1) 22 (lucrin or trenantone*).tw. (1) 23 (decapeptyl or gonapeptyl).tw. (3) 24 (Elagolix or Relugolix).tw. (2) 25 (luliberin or cystorelin).tw. (7) 26 (dirigestran or factrel or gonadoliberin).tw. (2) 27 (linzagolix or deslorelin).tw. (9) 28 or/9-27 (5185) 29 8 and 28 (17) H I S T O R Y Protocol first published: Issue 7, 2021 C O N T R I B U T I O N S /uni00A0 O F /uni00A0 A U T H O R S Veerle Veth took the lead in developing the review protocol and search strategy; screening the articles; performing risk of bias assessment, data extraction, and data analysis; grading and interpretation; and writing and revising all versions of this review update. Majorie van de Kar contributed to the background, search strategy, data extraction, risk of bias, analysis, results, and discussion of the review for this update. James Duffy provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review. Madelon van Wely provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review. Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 236 Cochrane Library Trusted evidence. Informed decisions. Better health. /uni00A0 /uni00A0 Cochrane Database of Systematic Reviews Velja Mijatovic provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review. Jacques Maas provided feedback on the methodology of design, data extraction, risk of bias, interpretation, and manuscript review. D E C L A R A T I O N S /uni00A0 O F /uni00A0 I N T E R E S T VV: none known MvK: none known JD: none known JM: none known MvW: co-ed of Cochrane Gynaecology and Fertility Satellite VM: none known S O U R C E S /uni00A0 O F /uni00A0 S U P P O R T Internal sources • No sources of support provided External sources • No sources of support provided D 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 In the current review, abstracts and articles whose full text was not available were excluded. We applied the core outcome set (COS). Overall pain is one of the outcome measures recommended with the COS. However, many studies still distinguish between different sub-forms of pain, 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- forms of pain, i.e. dysmenorrhoea, dyspareunia, and pelvic pain. This was to provide as much useful information as possible for shared decision-making with patients. In addition, it was decided to perform the main analysis with only low risk of bias studies, defined as low risk of selection bias and no high risk of bias for any other domain. The sensitivity analysis, on the other hand, was performed with all studies, 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 the summary of findings tables. N O T E S This review represents a merging of two existing Cochrane Reviews/uni00A0(Brown 2010; Farmer 2003). I N D E X /uni00A0 T E R M S Medical Subject Headings (MeSH) Calcium;/uni00A0 Calcium, Dietary;/uni00A0 Danazol /uni00A0[therapeutic use];/uni00A0 *Drug-Related Side Effects and Adverse Reactions;/uni00A0 Dysmenorrhea;/uni00A0 *Dyspareunia /uni00A0[drug therapy] /uni00A0[etiology];/uni00A0 *Endometriosis /uni00A0[complications] /uni00A0[drug therapy];/uni00A0 Gestrinone;/uni00A0 Gonadotropin-Releasing Hormone;/uni00A0 Pelvic Pain /uni00A0[drug therapy] /uni00A0[etiology];/uni00A0 Progestins /uni00A0[therapeutic use] MeSH check words Female; Humans Gonadotropin-releasing hormone analogues for endometriosis (Review) Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 237