. 2010 Dec 8;2010(12):CD008475. doi: 10.1002/14651858.CD008475.pub2

Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

Veerle B Veth ¹, Majorie MA de Kar ¹, Rose McDonnell ², Shital Julania ³, Roger J Hart ^4,^✉

Editor: Cochrane Gynaecology and Fertility Group

PMCID: PMC7388859 PMID: 21154398

Notes

Editorial note

See https://doi.org//10.1002/14651858.CD014788.pub2 for a more recent review that covers this topic and has superseded this review.

Abstract

Background

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

Objectives

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

Search methods

Electronic searches of the Cochrane Menstrual Disorders and Subfertility Group specialist register, CENTRAL, MEDLINE, EMBASE, PSYCInfo and CINAHL were conducted in April 2010 to identify relevant randomised controlled trials (RCTs).

Selection criteria

RCTs of GnRHas as treatment for pain associated with endometriosis versus no treatment, placebo, danazol, intra‐uterine progestagens, or other GnRHas were included. Trials using add‐back therapy, oral contraceptives, surgical intervention, GnRH antagonists or complementary therapies were excluded.

Data collection and analysis

Quality assessment and data extraction were performed independently by two reviewers. The primary outcome was pain relief. Relative risk was used as the measure of effect for dichotomous data. For continuous data, mean differences or standardised mean differences were used.

Main results

Forty one trials (n=4935 women) were included. The evidence was inconsistent as to whether GnRHas were more effective at symptom relief than no treatment/placebo (low quality evidence) (see SoFs 1 and 2). The evidence was also inconsistent as to whether GnRHas were more effective than Danazol (low or very low quality evidence) (see SoF 3) More adverse events were reported in the GnRHa group,There was no statistically significant difference in overall pain relief between GnRHas and levonorgestrel intrauterine system (LNG IUS) SMD ‐0.25 (95%CI ‐0.60 to 0.10, P=0.46, moderate quality evidence). Evidence was limited on optimal dosage,duration and route of administration for treatment for GnRHas.

Authors' conclusions

It is unclear whether GnRHas is more effective at relieving pain associated with endometriosis than no treatment/placebo. There was no consistent evidence of a difference in pain relief between GnRHas and danazol although more adverse events were reported in the GnRHa groups. There was also no evidence of a difference in pain relief between GnRHas and LNG IUS. No studies compared GnRHas with analgesics.

Keywords: Female, Humans, Danazol, Danazol/therapeutic use, Drug Administration Routes, Dysmenorrhea, Dysmenorrhea/drug therapy, Dyspareunia, Dyspareunia/drug therapy, Endometriosis, Endometriosis/drug therapy, Estrogen Antagonists, Estrogen Antagonists/therapeutic use, Gonadotropin-Releasing Hormone, Gonadotropin-Releasing Hormone/analogs & derivatives, Levonorgestrel, Levonorgestrel/therapeutic use, Pain, Pain/drug therapy, Pelvic Pain, Pelvic Pain/drug therapy, Randomized Controlled Trials as Topic

Plain language summary

Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

Endometriosis is a common condition affecting women of child‐bearing age, and is usually due to the presence of endometrial tissue in places other than the uterus. Common symptoms include pain and infertility. GnRHas are a group of drugs often used to treat endometriosis by decreasing hormone levels. This review f it unclear whether treatment with a GnRHa improved symptom relief compared with no treatment or placebo. There was also no evidence of a statistically significant difference when compared with danazol or LNG IUS. However, there more side effects in the GnRHa group compared with the danazol group. The quality of the evidence ranged from very low to moderate,

Summary of findings

Summary of findings 1. GnRHas compared to No treatment for pain associated with endometriosis.

GnRHas compared to no treatment for pain associated with endometriosis
Population: women with pain associated with endometriosis Settings: Gynaecology clinics Intervention: GnRHas Comparison: No treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No treatment	GnRHas
Relief of painful symptoms ‐ Dysmenorrhoea	188 per 1000	737 per 1000 (257 to 1000)	RR 3.93  (1.37 to 11.28)	35 (1 study)	⊕⊕⊝⊝ low^1,2
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

GnRHas compared to Placebo for pain associated with endometriosis
Population: women with pain associated with endometriosis Settings: gynaecology clinic Intervention: GnRHas Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	GnRHas
Relief of painful symptoms ‐ pelvic tenderness	160 per 1000	667 per 1000 (259 to 1709)	RR 4.17 (1.62 to 10.68)	49 (1 study)	⊕⊕⊝⊝ low¹
Pain score ‐ Overall at 4 weeks		The mean overall pain score at 4 weeks was 2.9 points higher in the intervention group (2.11 to 3.69 higher) on a 0‐12 scale		120 (1 study)	⊕⊕⊝⊝ low¹	Endometriosis Symptom Severity Score (ESSS), range 0‐12 points
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

GnRHas compared to Danazol for women with pain due to endometriosis
Population: women with pain due to endometriosis Settings: gynaecological clinics Intervention: GnRHas Comparison: Danazol
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Danazol	GnRHas
Relief of painful symptoms ‐ Dysmenorrhoea	825 per 1000	809 per 1000 (759 to 858)	RR 0.98  (0.92 to 1.04)	666 (7 studies)	⊕⊝⊝⊝ very low^1,2
Overall resolution ‐ Overall resolution/improvement	596 per 1000	655 per 1000 (602 to 721)	RR 1.1  (1.01 to 1.21)	1046 (9 studies)	⊕⊕⊝⊝ low³
The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

GnRHas compared to intra‐ uterine progestogen device for pain associated with endometriosis
Population: women with pain associated with endometriosis Settings: gynaecological clnics Intervention: GnRHas Comparison: LNG IUS intra‐uterine device
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Intra‐ uterine progestagen device	GnRHas
Relief of painful symptoms ‐ Overall		The mean relief of painful symptoms ‐ overall in the intervention groups was 0.25 standard deviations lower (0.6 lower to 0.1 higher)		129 (3 studies)	⊕⊕⊕⊝ moderate¹	Standardised mean difference ‐0.25 (‐0.6 to 0.1), indicating no clinically meaningful difference in pain score between the groups
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Date	Event	Description
27 September 2010	New search has been performed	Two additional studies added to review
8 April 2010	Amended	Authorship amendment made
17 March 2010	Amended	This protocol is a new version of a previously published review which required a major methodological restructure Prentice 1999
17 March 2010	New citation required and major changes	Substantive amendment. Type of intervention has been limited to GnRHas versus placebo or no treatment; GnRHas versus danazol; analgesics; and levonorgestrel.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Relief of painful symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1.1 Dysmenorrhoea	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	3.93 [1.37, 11.28]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Relief of painful symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1.1 pelvic tenderness	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	4.17 [1.62, 10.68]
2.1.2 Dyspareunia	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.57, 2.34]
2.1.3 Defecation pain/pressure	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	11.44 [0.67, 196.30]
2.2 Side effects	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.2.1 Hot flushes/flashes	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [0.87, 3.02]
2.2.2 Sleep disturbances	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	2.31 [1.33, 4.02]
2.3 Pain score	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.3.1 Overall at 4 weeks	1	120	Mean Difference (IV, Fixed, 95% CI)	2.90 [2.11, 3.69]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Relief of painful symptoms	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1.1 Dysmenorrhoea	7	666	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.92, 1.04]
3.1.2 Dyspareunia	7	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.93, 1.12]
3.1.3 Pelvic pain	7	647	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.86, 1.07]
3.1.4 Induration	2	116	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.94, 1.29]
3.1.5 Pelvic tenderness	3	404	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.09]
3.2 Overall resolution	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.2.1 Overall resolution/improvement	9	1046	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [1.01, 1.21]
3.3 Relief of painful symptoms	4		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.3.1 Overall 90 days	1	59	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.13 [‐0.64, 0.38]
3.3.2 Overall 180 days	3	103	Std. Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.30, 0.50]
3.3.3 Dsypareunia	1	49	Std. Mean Difference (IV, Fixed, 95% CI)	0.19 [‐0.41, 0.79]
3.3.4 Pelvic pain	1	49	Std. Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.60, 0.60]
3.3.5 Pelvic tenderness	1	49	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.79, 0.41]
3.3.6 Pelvic induration	1	49	Std. Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.60, 0.60]
3.4 rAFS	10	1012	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.13, 0.12]
3.4.1 change at 180 days	1	59	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐0.81, 0.21]
3.4.2 24 weeks	9	953	Std. Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.12, 0.15]
3.5 Improved rAFS score	4	732	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.98, 1.32]
3.6 Side effects	18		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.6.1 vaginal dryness/vaginitis	15	1798	Risk Ratio (M‐H, Fixed, 95% CI)	2.04 [1.72, 2.42]
3.6.2 Hot flushes/flashes	18	2367	Risk Ratio (M‐H, Fixed, 95% CI)	1.55 [1.46, 1.65]
3.6.3 Headaches	15	1832	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [1.21, 1.64]
3.6.4 Infections and flu like symptoms	1	71	Risk Ratio (M‐H, Fixed, 95% CI)	3.60 [1.31, 9.88]
3.6.5 Muscle cramps/myalgia	10	1537	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.06, 0.18]
3.6.6 Sleep disturbance	6	679	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.46, 2.39]
3.6.7 Skin rash	3	324	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.02, 0.51]
3.6.8 Gastrointestinal	4	363	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.26, 1.05]
3.6.9 Weight gain	11	1493	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.11, 0.21]
3.6.10 Acne	12	1695	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.42, 0.58]
3.6.11 Breast atrophy/changes	7	1035	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.47, 0.76]
3.6.12 Emotional lability/altered mood	3	534	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.60, 1.61]
3.6.13 Oedema/fluid retention	5	626	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.05, 0.20]
3.6.14 Asthenia	5	781	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.23, 0.58]
3.6.15 Bleeding	3	161	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.12, 0.48]
3.6.16 Depression	5	513	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.38, 0.99]
3.6.17 Leukorrhoea	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.23, 4.71]
3.6.18 chest pain	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	7.23 [0.39, 134.16]
3.6.19 Generalised spasm	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.00, 1.35]
3.6.20 pharyngitis	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.74]
3.6.21 Voice alteration	2	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.02, 1.27]
3.6.22 vulvovaginal disorder	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.74]
3.6.23 Hirsutism	6	866	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.11, 0.39]
3.6.24 Seborrhoea	6	835	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.33, 0.53]
3.6.25 Alopecia	2	365	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.02, 0.53]
3.6.26 Altered libido	9	1620	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.88, 1.24]
3.6.27 Sweating	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03, 2.51]
3.6.28 Breast tenderness	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.04, 4.33]
3.6.29 Fatigue	2	84	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.40, 1.26]
3.6.30 Arthralgia	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	17.61 [1.08, 286.40]
3.6.31 Hunger	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.00, 0.81]
3.6.32 Nervousness	2	504	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.20, 1.02]
3.6.33 Irritability	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	4.74 [1.67, 13.45]
3.6.34 Clitoromegaly	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.59]
3.6.35 Appetite increase	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 1.54]
3.6.36 Fatigue/malaise	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.06, 0.61]
3.6.37 Dizziness	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 2.06]
3.6.38 Nausea	2	374	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.31, 0.80]
3.6.39 Breast pain	1	307	Risk Ratio (M‐H, Fixed, 95% CI)	5.05 [0.66, 38.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Relief of painful symptoms	3		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
4.1.1 Overall	3	129	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.25 [‐0.60, 0.10]
4.2 rAFS/ASRM score	1	18	Mean Difference (IV, Fixed, 95% CI)	9.50 [‐10.77, 29.77]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Side effects	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1.1 Sleep disturbance Nafareline 200mcg versus 400mcg	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.63, 1.59]
5.1.2 Rhinitis Nafareline 200mcg versus 400 mcg	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.10, 1.67]
5.1.3 Upper respiratory tract infection Nafareline 200mcg versus 400 mcg	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.03, 1.47]
5.1.4 Hot flushes/flashes Nafareline 200mcg versus 400 mcg	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.51, 1.97]
5.2 rAFS score (400mcg vs 800mcg)	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.17, 1.01]
5.3 relief of painful symptoms	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.3.1 Dsymenorrhoea Nafarelin 400mcg versus 800mcg	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.53, 1.66]
5.3.2 Dyspareunia	1	57	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.79, 1.68]
5.3.3 Pelvic pain	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.67, 1.74]
5.3.4 Overall Nafarelin 400mcg versus 800mcg	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.78, 1.14]
5.3.5 Overall buserelin 300mcg vs 900 mcg	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.94, 2.35]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up	1		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6.1.1 Dysmenorrhoea	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.31, 0.27]
6.1.2 Dyspareunia	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.98 [‐1.29, ‐0.66]
6.1.3 Pelvic pain	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.15, 0.44]
6.1.4 Pelvic tenderness	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.43, 0.15]
6.1.5 Pelvic induration	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.40, 0.18]

*Study characteristics*
Methods	Trial design: Randomised, multiple arm trial.
Participants	Participants: 54 randomised Inclusion criteria: aged 22 to 43 years, with laparoscopically confirmed endometriosis, 14 reguarly menstruating women and 11 post‐menopausal women no on HRT and with no history of post‐menopausal bleeding, endometrial or ovarian carcinoma were comparisons. Exclusion critieria: Setting: UK and Spain Timing:
Interventions	Danazol 600 mg per day for six months (n=20) versus Buserelin 400 mcg 8 hourly intranasally for six months (n=15) versus Zoladex depot 3.6 mg intramuscularly monthly for six months (n=19)
Outcomes	This trial did not report on any outcomes of interest for this review. Serum CA 125 levels
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomised" no further details
Allocation concealment (selection bias)	Unclear risk	No details on methods used to conceal allocation to study groups.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details of blinding of study personnel or participants
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	43/54 participants had 3 and 6 month blood samples.
Selective reporting (reporting bias)	High risk	This paper states that all patients were part of randomised studies assessing the efficacy of Danazol, Buserelin, and Zoladex in the treatement of endometriosis but does not reference these trials.

*Study characteristics*
Methods	Trial design: Prospective randomised double blind controlled study
Participants	Participants: 213 patients. 124 patients were randomised who reported pain symptoms Mean age: Inclusion: aged 18 to 48 years with laparoscopically confirmed pelvic endometriosis and dysmenorrhoea, dyspareunia or pelvic pain. Exclusion: no surgical procedures were performed during the diagnostic laparoscopy, no patient who had received hormonal treatment during the previous 6 months. Setting: Timing:
Interventions	Nafarelin acetate 400mcg bid IN + placebo PO or 6 months (n=45) versus Nafarelin acetate 200mcg bid IN + placebo PO for 6 months (n=45) versus Danazol 400mg bid PO + placebo IN for 6 months (n=34)
Outcomes	Pain: dysmenorrhoea, dyspareunia, pelvic pain.
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors responded to methods query
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computerised randomisation
Allocation concealment (selection bias)	Low risk	Centralised randomisation, sequentially numbered, sealed opaque envelopes
Blinding (performance bias and detection bias) All outcomes	Low risk	All patients received placebo so patients and investigators were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	All women randomised were analysed with intention to treat for main outcome
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: "Multicentre, randomised, double‐blind, double‐placebo study"
Participants	Participants: 208 women were randomised, 192 were analysed Mean age: Nafarelin = 29.8 ± 0.6 and LA = 31.7 ± 0.6 (SEM) Inclusion criteria: Laparoscopically diagnosed endometriosis within 18 months prior to study19‐44 years old Patients demonstrating clinical symptoms and signs Bone mineral density within normal age range Exclusion criteria: Conditions or drug therapies that may interfere with the study Pregnant or lactating women Danazol use within 6 months prior to study GnRHa use within 12 months prior to study OCP within 30 days prior to study treatment Thyroid disease Setting: United States of America Timing:
Interventions	Nafarelin 200mcg BD IN + placebo every 4 weeks IM for 6 months (n=105) versus LA Depot 3.75mg every 4 weeks IM + placebo BD IN for 6 months (n=103)
Outcomes	Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding:
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	'Randomisation using permuted blocks of random numbers'
Allocation concealment (selection bias)	Unclear risk	No details were provided of method used to conceal allocation to treatment group.
Blinding (performance bias and detection bias) All outcomes	Low risk	Placebo nasal spray and injection, "Subjects remained blind regarding the study medication and assignment, and the study coordinator and investigator remained blind as to subject treatment status by having injections prepared and administered by a third party"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Details for attrition: 24 women withdrew due to:ineffectiveness 3 (Naf) and 3 (LA), adverse effects 4 (Naf) and 8 (LA), lost to follow up 5 (LA), administrative reasons 1 (LA)
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: 'Multicentre, open, randomised study'
Participants	Participants: 71 women were randomised, 48 were analysed Mean age: Goserelin = 29.5 and Danazol = 29.85 Stage: I to IV Inclusion criteria: Laparoscopically diagnosed endometriosis within 2 months prior to study 18‐40 years old rAFS score of equal or greater to 2 Normal menstrual cycle (21 ‐ 42 days) Normal cervical smear for previous 12 months Exclusion criteria: Pregnant or lactating women Other medical illnesses Hormone use within 2 months prior to study Danazol or GnRHa use within 12 months prior to study Hypersensitivity to trial drugs Showing signs of virilization Taking anticoagulant therapy Surgical treatment Setting: Australia and New Zealand Timing: Not stated
Interventions	Goserelin acetate 3.6mg every 4 weeks SC for 24 weeks (n=35) versus Danazol 200mg TDS PO for 24 weeks (n=36)
Outcomes	Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness, induration rAFS score Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and data, awaiting response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patients were randomised in a 1 to 1 ratio". No further details of method used to generate the randomisation sequence are provided.
Allocation concealment (selection bias)	Unclear risk	No details were provided of method used to conceal allocation to treatment groups.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Open label trial as blinding of study personnel and participants would not have been possible due to nature of intervention. No details provided of blinding of outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Analysis was performed on both an 'intention to treat' basis and also on a 'patient treated' basis details given for attrition: 19 in Danazol and 4 in Goserelin group withdrew due to: Adverse effect 9 (Dan), Unwilling to continue 8 (Dan) and 4 (Gos), Withdrawn by investigator 1 (Dan), Other 1 (Dan)
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Side effects (IN vs SC)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.1.1 Hot flushes/flashes	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.48, 1.55]
7.1.2 Vaginal dryness	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.17, 4.37]
7.1.3 Decreased libido	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.07, 10.96]
7.1.4 Headaches	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.20, 14.55]
7.2 rAFS score (IN vs SC)	1	19	Mean Difference (IV, Fixed, 95% CI)	9.00 [‐5.93, 23.93]
7.3 Relief of painful symptoms (IN versus IMdepot)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.3.1 Dysmenorrhea	1	192	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.82, 1.08]
7.3.2 Dyspareunia	1	166	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.85, 1.43]
7.3.3 Pelvic pain	1	192	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.78, 1.40]
7.3.4 Tenderness	1	192	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.67, 1.09]
7.3.5 Induration	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.06]
7.4 Side effects (IN versus IMdepot)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.4.1 Hot flushes/flashes	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.93, 1.01]
7.5 Improvement in symptoms (IN versus IMdepot)	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.58, 3.30]
7.6 Relief of painful symptoms (IN versus SC)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.6.1 Pelvic pain	1	5	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.53, 1.87]
7.6.2 Dyspareunia	1	7	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.57, 1.75]
7.6.3 Dysmenorrhoea	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.73, 2.06]
7.6.4 Pelvic tenderness	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.69, 3.27]
7.6.5 Pelvic induration	1	8	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.47, 1.55]

*Study characteristics*
Methods	Trial design: Open, multi‐centre, central randomised study
Participants	Participants: 120 eligible women; 71 were randomised; 55 were analysed Mean age: 31 ± 5.9 years Stage: I ‐ IV Inclusion criteria: Laparoscopically diagnosed endometriosis Symptomatic Recurrence of endometriosis after surgery Over 18 years old No other hormone therapy except insulin Exclusion criteria: Amenorrhoea Patient having had hysterectomy Pregnant women Serious illness e.g. liver disease Setting: France Timing:
Interventions	Leuprorelin 3.75mg SC depot every 28 days for 24 weeks (n=33) versus Danazol 600‐800mg PO daily for 24 weeks (n=22)
Outcomes	Pain: dysmenorrhoea, dyspareunia, pelvic pain, induration and pelvic tenderness rAFS score Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Cannot use data unless mean and SD specified; author contacted. Author replied that study was sponsored by a pharmaceutical company who hold the raw data. He is attempting to locate a contact for further information.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Central randomisation"
Allocation concealment (selection bias)	Low risk	"Central randomisation"
Blinding (performance bias and detection bias) All outcomes	High risk	Open study as blinding would not have been possible due to nature of intervention. No mention of blinding of outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Sufficient reporting of attrition: Refuse 2nd laparoscopy n=1 (L) Lost to follow up n=2 (L) n=9 (D) Progression of disease n=2 (D) Not meeting protocol n=1 (D) Other n=1 (D)
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design:
Participants	Participants: Mean age: Inclusion criteria: Exclusion criteria: Setting: Timing:
Interventions	Intervention: Comparison:
Outcomes
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding:

*Study characteristics*
Methods	Trial design: "Double‐blind randomised study"
Participants	Participants: 49 eligible women; 49 were randomised and 47 were analysed Mean age: mean age not stated, median age 30 years (range 21‐46years) Inclusion criteria: Laparoscopically diagnosed endometriosis Not to use any hormonal preparations during study No hormone treatment in previous 3 months No GnRHas for previous 12 months No steroid therapy for previous 12 months Exclusion criteria: Setting: Europe Timing: not stated
Interventions	Nafarelin 200mcg daily IN + placebo PO for 6 months (n=12) versus Nafarelin 400mcg daily IN + placebo PO for 6 months (n=12) versus Nafarelin 200mcg daily IN + norethisterone 1.2mg daily PO for 6 months (n=25)
Outcomes	Pain: dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration Adverse effects AFS score
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Need raw data for symptom scores. Authors contacted regarding methods and data. No response to date.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	1:1:2 Naf200:Naf400:Naf200+Norethisterone "randomisation was carried out on a block basis"
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal allocation to treatment group.
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and study personnel were blinded to treatment through the use of a placebo
Incomplete outcome data (attrition bias) All outcomes	Low risk	Two participants from the Naf+Norethisterone group withdrew from the trial due to mood swings (1 participant) and pregnancy (1 participant),
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: "Prospective, randomised, placebo‐controlled, double‐blind, parallel study"
Participants	Participants: 49 women eligible; 49 were randomised and 46 were analysed Age: mean of 31 years (19‐44years) Stage: most mild to moderate (IV n=1) Inclusion criteria: Menstruating regularly 3 months before study Clinical symptoms of endometriosis Not taken oral contraceptive or oral steroid therapy for 3 months Not taken long acting depot gestagens or GnRHas within past 6 months Not pregnant in prior 3 months Not breastfeeding No history of osteoporosis or coagulation disorders Exclusion criteria: Intraperitoneal adhesions making visual inspection and careful evaluation of the extension of endometriotic lesions difficult or impossible Setting: Sweden Timing:
Interventions	Triptorelin 3.75mg IM depot every 4 weeks for 24 weeks (n=24) versus Placebo IM every 4 weeks for 24 weeks (n=25)
Outcomes	Pain Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Needs raw score for pain. Authors contacted and awaiting response.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details were provided of method used to generate the randomisation sequence.
Allocation concealment (selection bias)	Unclear risk	No details were provided of method used to conceal treatment group allocation.
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and researchers were blinded through the use of identical kits for injections.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Three participants withdrew from the study. Two from the placebo group (1 prior to the first injection due to pregnancy, and one after 4 months due to lack of effect), and one from the Triptorelin group due to hypoestrogenic side effects and depression.
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: "Multi‐centre, double‐blind study"
Participants	Participants: 169 women eligible; 169 were randomised and 147 analysed for efficacy Mean age: Inclusion criteria: Laparoscopically diagnosed endometriosis Exclusion criteria: Setting: USA Timing:
Interventions	Nafarelin 400mcg daily IN for 6 months (n=111) versus Danazol 600mg daily PO for 6 months (n=58)
Outcomes	Symptoms Change in laparoscopic scores Adverse effects Quality of life score
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Need more info on randomisation and participants and raw data for quality of life. Authors contacted, awaiting response.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	2:1 Nafarelin: Danazol
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	"double‐blind"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Sufficient details for attrition: Side effects n=6 (N) n=3 (D) Elevated liver enzyme n=1 (D) Administrative reasons n=12
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: Randomised, no further detail.
Participants	Participants: 15 participants with laparoscopically diagnosed endometriosis Mean age: Inclusion criteria: Exclusions criteria: Setting: Mexico Timing:
Interventions	Goserelin acetate 3.6 mg every 21 days (n=8) average age 29 years Nafarelin acetate 200 or 400 mcg 12 hourly for six months (n=7) average age 30.4 years
Outcomes	Serum levels of follicle stimulating hormone, luteinising hormone, estradiol and prolactin.
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Article in Spanish. Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details provided of method used to generate random sequence.
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal allocation to treatment group
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided of blinding of participants or personnel.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow up.
Selective reporting (reporting bias)	Unclear risk	Insufficient information to enable a judgement of low risk of bias.

*Study characteristics*
Methods	Trial design: "Randomised comparative study"
Participants	Participants: 45 women eligible; 45 were randomised and 33 were analysed Mean age: 33 years (LA) Stage: I to IV Inclusion criteria: Laparoscopic diagnosis of endometriosis Pain symptoms Exclusion criteria: Setting: Taiwan Timing:
Interventions	Leuprorelin acetate 3.75mg SC depot every 28days for 20 weeks (n=30) versus Danazol 200mg QID (800mg/day) PO for 20 weeks (n=15)
Outcomes	Dysmenorrhoea, dyspareunia, pelvic pain Change in AFS score Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Need raw data for pain. Authors contacted, and additional methodological data provided, no raw data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomisation was in the ratio two LA to one danazol with this study having its randomisation list"
Allocation concealment (selection bias)	Unclear risk	"sequentially numbered, identical containers of identical drugs"
Blinding (performance bias and detection bias) All outcomes	Low risk	Outcome assessors were blinded to treatment group
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No details were provided on attrition
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: "Randomised, parallel, comparative study"
Participants	Participants: 59 women eligible; 59 were randomised and 41 were analysed for efficacy Mean age: 34.8 ± 6.6 (N) and 32.4± 7.2 (D) Inclusion criteria: Laparoscopically diagnosed within 3 months prior to study Age 18‐48 years Barrier contraception Exclusion criteria: Pregnancy Breastfeeding Menopause or post‐menopausal Use of oestrogen, progesterone or contraceptive steroids in previous 3 months Impaired hepatic or renal function Cardiovascular disease AIDS or other sexually transmitted diseases Setting: Taiwan Timing:
Interventions	Nafarelin acetate 200mcg BD (400mcg/day) IN for 180 days (n=29) versus Danazol 200mg TID (600mg/day) PO for 180 days (n=30)
Outcomes	Total symptom severity score and physician assessed pelvic tenderness Change in laparoscopic score Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors provided additional data on methods
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation done by a pharmacy
Allocation concealment (selection bias)	Low risk	Sealed, opaque, sequentially numbered, identical envelopes
Blinding (performance bias and detection bias) All outcomes	Low risk	Investigators, outcome assessors and clinicians were blinded according to author
Incomplete outcome data (attrition bias) All outcomes	Low risk	"All 59 patients were considered as the intent‐to‐treat population" 4 withdrawals due to: Three patients (3/4) underwent Herb drug treatment, withdrawals All patients (4/4) were anxious with side effects, including significant weight gain, acne vagaries, and severe menopausal syndrome. One patient went abroad after randomisation
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: Parallel arm, randomised controllled trial
Participants	Participants: 14 women eligible Age: Group 1 29.3 ±6.1, Group 2 28.9 ±1.7 Inclusion: Women with laparoscopically confirmed endometriosis Severe dysmenorrhea with or without deep dysparunia and pelvic pain Exclusion: Prior hormonal treatment Planning to conceive in the next one to two years Setting: Thailand Timing:
Interventions	Buserelin acetate 6.6 mg implants injected subcutaneously in the lateral region of the anterior abdominal wall: Group 1: every 8 weeks for 3 doses (n=7) Group 2: every 12 weeks for 2 doses (n=7)
Outcomes	Serum estradiol, bone mineral density
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information provided to enable a judgement of low risk.
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided to enable a judegment of low risk.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details provided of blinding of participants or personnel.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No losses to follow up.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes are reported on.

PERMALINK

Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

Veerle B Veth

Majorie MA de Kar

Rose McDonnell

Shital Julania

Roger J Hart

Notes

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. GnRHas compared to No treatment for pain associated with endometriosis.

Summary of findings 2. GnRHas compared to Placebo for pain associated with endometriosis.

Summary of findings 3. GnRHas compared to Danazol for women with pain due to endometriosis.

Summary of findings 4. GnRHas compared to intra‐ uterine progestogen device for pain associated with endometriosis.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

Excluded studies

Risk of bias in included studies

1.

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

1. GnRHas versus no treatment

2. GnRHas versus placebo

3. GnRHas versus analgesics

4. GnRHas versus danazol

3.

4.

5.

6.

5. GnRHas versus intra‐uterine progestogen (LNG‐IUS)

6. GnRHa versus GnRHa (varying dosage)

7.

8.

7. GnRHa versus GnRHa (varying length of treatment)

9.

8. GnRHa versus GnRHa (varying routes of administration)

*Study characteristics*
Methods	Trial design: "controlled comparative clinical study"
Participants	Participants: 60 women eligible; 60 were randomised and 55 were analysed Mean age: 30± 0.5 (T) and 30± 0.8 (D) Stage: II to IV Inclusion criteria: Laparoscopically diagnosed endometriosis No medication affecting pituitary or ovarian function in preceding 6 months Exclusion criteria: Stage I endometriosis Setting: Germany Timing:
Interventions	Triptorelin 3.75mg IM depot every 28 days for 24 weeks (n=30) versus Danazol 200mg TDS (600mg/day) PO for 24 weeks (n=25)
Outcomes	Dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and induration Adverse effects Change in AFS score
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted and awaiting response regarding methods.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation list
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias) All outcomes	Low risk	Sufficient detail for attrition: Refused to fulfil protocol n=3 (D) Pregnancy n=2 (D)
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: "Ongoing, Phase III, multi‐centre, double‐blind, double‐dummy study"
Participants	Participants: 24 women were randomised, 23 were analysed Mean age: 33.9 (N) and 32.6 (D) Inclusion criteria: Exclusion criteria: Setting: Sweden Timing
Interventions	Nafarelin 400mcg daily IN for 6 months (n=16) versus Danazol 600mg daily PO for 6 months (n=8)
Outcomes	Pain, dysmenorrhoea, dyspareunia Changes in AFS score
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted with regards to methods and raw data. Awaiting response.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details, "double blind, double dummy"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Sufficient data on attrition: Intercurrent lower back pain n=1 (N)
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: Multi‐centre, open, randomised study
Participants	Participants: 355 women eligible and 310 were analysed Mean age: Inclusion criteria: Age 20‐40 years old Laparascopically diagnosed endometriosis within 6 weeks of study entry Exclusion criteria: Danazol treatment in last 6 months Oral contraceptives in last 2 months Drugs releasing IUD in last 3 months Any other investigational drug in 4 weeks Conditions for which danazol is contraindicated Setting: USA Timing: Not stated
Interventions	Buserelin 400mcg TDS (1200mcg/day) IN for 6 months (n=149) versus Buserelin 200mcg daily SC for 6 months (n=60) versus Danazol 400‐800mg daily PO for 6 months (n=101)
Outcomes	Intermenstrual pelvic pain, dyspareunia, pelvic tenderness and induration Changes in rAFS score Adversse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methods and raw data for pain.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"assigned to... treatment groups according to a randomisation schedule" 2:1 Buserelin: Danazol. No other details are provided of method used to generate random sequence.
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal allocation to treatment groups.
Blinding (performance bias and detection bias) All outcomes	High risk	Open study
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No details on attrition
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: "Phase III, randomised, double‐blind, multi‐centre study"
Participants	Participants: 63 women eligible; 63 were randomised and 52 were analysed Mean age: 30 years Stage: I to IV Inclusion criteria: Laparoscopically diagnosed endometriosis within 3 months of study entry Pain secondary to endometriosis Over 18 years old No previous treatment with leuprolide acetate or other GnRHas At least one ovary intact Non pregnant Non lactating No treatment for endometriosis within 3 months of study entry Exclusion criteria: Setting: USA Timing: Not stated.
Interventions	Leuprolide acetate 3.75mg IM depot every 4 weeks for 20 weeks (n=32) versus Placebo (diluent) 2ml IM every 4 weeks for 20 weeks (n=31)
Outcomes	Dysmenorrhoea, pelvic pain, dyspareunia, pelvic tenderness, induration
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted for details on allocation concealment and SEMs. Letter returned to sender, author moved with no forwarding address.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patients were assigned a 3 digit patient number in sequential order from those numbers allocated to each investigator. The patient number encoded the random assignment to a treatment group"
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal allocation to treatment group.
Blinding (performance bias and detection bias) All outcomes	Low risk	Patients and investigators were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Sufficient details for attrition: 7 withdrawn as subsequently determined they had failed to meet entry requirements, 4 excluded because they had received less than 3 injections of the study drug. There were partial exclusions for efficacy data due to non‐compliance with intended study procedures and dosing regimens for 15 patients (7=Leuprolide and 8=placebo). 27 placebo (24 terminated because of worsened symptoms, 1 because of salpingitis, 1 became pregnant and 1 was non‐compliant) and 3 (2 because of intolerable pain and 1 because of an adverse event) leuprolide patients prematurely terminated study.
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: "Open‐label, randomised, prospective study"
Participants	Participants: 36 women eligible, 36 were randomised and 29 were analysed Mean age: 30.8 ± 0.6 (SE) Inclusion Criteria: Laparoscopically diagnosed endometriosis, no hormonal treatment 8 months prior to study entry Exclusion criteria: not stated Setting: USA Timing: Not stated.
Interventions	Buserelin 400mcg TDS (1200mcg/day) IN for 6 months (n=10) versus Buserelin 200mcg daily SC for 6 months (n=9) versus Danazol 200mg QDS (800mg/day) PO for 6 months (n=10)
Outcomes	Dysmenorrhoea, dyspareunia, pelvic pain Change in rAFS scores Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding allocation concealment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details were provided of the method used to generate the randomisation sequence. 2:1 Buserelin: Danazol "Those who were randomised into Buserelin were given an option of SC injections or IN sprays of the drug"
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal the allocation to treatment groups.
Blinding (performance bias and detection bias) All outcomes	High risk	"open label"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Detail for attrition: 3 in SC Buserelin, 2 in IN Buserelin and 2 in Danazol group. 2 withdrew for family reasons, 3 were non‐compliant, 1 had sever emotional side effects on IN Buserelin and 1 was allergic to Danazol.
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: Prospective, parallel, randomised controlled trial.
Participants	Participants: 100 women randomised (50 per group). All women randomised appear to have been analysed, Mean age: Group 1: 27.3 ± 4.4, Group 2: 28.2 ± 5.2 Inclusion: Exclusion: Setting: Belgium Timing: January 1985 ‐ December 1987
Interventions	Intervention: Intranasal Buserelin spray 300 μg three times a day for 6 months (n = 50). Comparison: Biodegradable implant containing 6.6 mg Buserelin injected subsutaneously at 0, 6 and 12 weeks (n = 50).
Outcomes	Change in AFS scores between start and end of treatment.
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States "randomized" with no further information of method used to generate the randomisation sequence.
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal allocation to treatment groups.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Blinding of participants and personnel was not possible due to nature of intervention and comparison. Pre and post treatment assessment was carried out by the same observer, however no details are provided as to whether the observer was blinded to treatment group.

*Study characteristics*
Methods	Trial design: Prospective, open label randomised controlled trial.
Participants	Participants: 20 women were randomised and analysed (10 per treatment group. There was also a control group of 250 'normal' women) Mean age: GnRA Group: 31.0 ± 1.1. Danazol Group: 30.7 ± 1.5, Control Group: 31.0 ± 1.0 Inclusion: Laparoscopically diagnosed and staged endometriosis. Exclusion: History and/or symptoms of autoimmune disease, acute or chronic infection, malignancy, or drug abuse, Setting: Chicago, IL, USA Timing: Not stated
Interventions	Intervention: GnRA Group (n=10): Four participants received Buserelin intranasally 0.4 mg three times a day, four received Buserelin subcutaneously 0.2 mg daily, and two received Leuprolide intranasally 1.6 mg daily for 6 months. Danazol Group (n=10): Danazol 200 mg four times a day
Outcomes	Autoantibody production, clinical outcome
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Excluded from previous version of this review as pain is not an outcome. Included in this review, but does not contribute any data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patient assignment was at random". No further details provided of method used to generate random sequence.
Allocation concealment (selection bias)	Unclear risk	Method used to conceal allocation to treatment groups not provided.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Open label trial. All serum collections were coded and stored at a laboratory until tested simultaneously after all data had been reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow up reported.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes are reported on.

*Study characteristics*
Methods	Trial design: Randomised controlled study
Participants	Participants: 62 women were randomised and analysed Mean age: Buserelin = 29.8 ± 3.3 and Danazol 31.3 ± 4.3 Inclusion criteria: Laparoscopically diagnosed endometriosis within 3 months prior to study No therapeutic intervention Exclusion criteria: Bilateral tube occlusion or partner with severe dyspermia Danazol or other sex hormone use within 6 months prior to study Systemic or endocrine disease Setting: Italy Timing:
Interventions	Buserelin 400mcg TDS IN for 6 months (n=30) versus Danazol 200mg TDS PO for 6 months (n=32)
Outcomes	Dysmenorrhoea, dyspareunia, pelvic pain rAFS score Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted for information on raw data for pain scores, and methods. No response to date
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias) All outcomes	Low risk	Detail for attrition: 1 subject from Buserelin group withdrew due to severe pelvic pain
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: Multicentre, randomised controlled study
Participants	Participants: 35 women eligible, 35 were randomised, 35 were analysed Mean age: not stated Inclusion criteria: Laparoscopically diagnosed stage I or II endometriosis One or more of dysmenorrhoea, pelvic pain and deep dyspareunia Exclusion criteria: Setting: Italy Timing: not stated.
Interventions	Buserelin acetate 1200 mcg daily IN for 6 months (n=19) versus Expectant management (n=16) Treatment group followed up for 18 months and expectant management group for 12 months
Outcomes	Dysmenorrhoea, pelvic pain and deep dyspareunia Adverse effects
Notes	Intention‐to‐treat analysis: Sample size calculation: Funding: Authors contacted regarding methodology and data. Still awaiting response.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details provided of method used to generate randomisation sequence.,
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal allocation to treatment groups.
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding was not possible due to the nature of the intervention (Buserelin acetate versus expectant management (no treatment) )
Incomplete outcome data (attrition bias) All outcomes	Low risk	All women who were randomised were analysed
Selective reporting (reporting bias)	Low risk	All primary outcomes stated were reported on

*Study characteristics*
Methods	Trial design: Randomised, prospective open labelled study
Participants	Participants: 44 women with endometriosis (confirmed laparoscopically/histologically), consecutively selected at the pain and endoscopy out‐patient clinic. Mean age: 28.8 ±4.9 years for LNG‐IUS and 41.4±5.8 years for GnRHa Inclusion criteria: 18‐40 years of age chronic pelvic pain. No use of oral hormone contraceptives for at least 3 months or with depot progestogens or GnRHa for at least 6 months prior to randomisation. Exclusion: obese patients (BMI >30kg/m²), smokers, diabetics, alcohol or drug users, patients wishing to conceive, those with chronic disease, acute and/or chronic inflammatory and/or infectious processes, family history of thromboembolic events, taking medications known to interfere with inflammation markers for a period of less than 15 days before the study. Setting: Brazil Timing: not stated.
Interventions	LNG‐IUS (n=22) versus GnRHa (n=22) 3.75mg leuprolide i.m. monthly treatment for 6 months
Outcomes	BMI, SAP, DAP, HR, pain score (VAS), inflammatory markers
Notes	No ITT analysis Intention‐to‐treat analysis: Sample size calculation: Funding:
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	'Randomised by computer programme'
Allocation concealment (selection bias)	Unclear risk	No details provided of method used to conceal allocation to treatment group.
Blinding (performance bias and detection bias) All outcomes	High risk	Open labelled. Blinding not possible due to nature of invtervention and comparison.
Incomplete outcome data (attrition bias) All outcomes	Low risk	GnRHa (1 pregnancy before drug administered and 3 moved and lost to follow‐up)
Selective reporting (reporting bias)	Low risk	All a priori outcomes discussed