Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis

Veerle B Veth; Majorie MA van de Kar; Rose McDonnell; Shital Julania; Roger J Hart

doi:10.1002/14651858.CD008475.pub2

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Figure 1

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.1 Relief of painful symptoms.

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Figure 4

Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.3 Relief of painful symptoms.

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Figure 5

Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.2 Overall resolution.

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Figure 6

Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.6 Side effects.

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Figure 7

Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.3 relief of painful symptoms.

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Figure 8

Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.2 rAFS score (400mcg vs 800mcg).

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Figure 9

Forest plot of comparison: 7 GnRHa versus GnRHa (Length of Treatment), outcome: 7.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up.

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Analysis 1.1

Comparison 1: GnRHas versus no treatment, Outcome 1: Relief of painful symptoms

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Analysis 2.1

Comparison 2: GnRHas versus placebo, Outcome 1: Relief of painful symptoms

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Analysis 2.2

Comparison 2: GnRHas versus placebo, Outcome 2: Side effects

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Analysis 2.3

Comparison 2: GnRHas versus placebo, Outcome 3: Pain score

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Analysis 3.1

Comparison 3: GnRHas versus danazol, Outcome 1: Relief of painful symptoms

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Analysis 3.2

Comparison 3: GnRHas versus danazol, Outcome 2: Overall resolution

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Analysis 3.3

Comparison 3: GnRHas versus danazol, Outcome 3: Relief of painful symptoms

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Analysis 3.4

Comparison 3: GnRHas versus danazol, Outcome 4: rAFS

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Analysis 3.5

Comparison 3: GnRHas versus danazol, Outcome 5: Improved rAFS score

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Analysis 3.6

Comparison 3: GnRHas versus danazol, Outcome 6: Side effects

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Analysis 4.1

Comparison 4: GnRHas versus intra‐ uterine progestagen device, Outcome 1: Relief of painful symptoms

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Analysis 4.2

Comparison 4: GnRHas versus intra‐ uterine progestagen device, Outcome 2: rAFS/ASRM score

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Analysis 5.1

Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 1: Side effects

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Analysis 5.2

Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 2: rAFS score (400mcg vs 800mcg)

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Analysis 5.3

Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 3: relief of painful symptoms

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Analysis 6.1

Comparison 6: GnRHa versus GnRHa (Length of Treatment), Outcome 1: Relief of Painful Symptoms (3months vs 6months) at 6 months follow up

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Analysis 7.1

Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 1: Side effects (IN vs SC)

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Analysis 7.2

Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 2: rAFS score (IN vs SC)

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Analysis 7.3

Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 3: Relief of painful symptoms (IN versus IMdepot)

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Analysis 7.4

Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 4: Side effects (IN versus IMdepot)

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Analysis 7.5

Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 5: Improvement in symptoms (IN versus IMdepot)

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Analysis 7.6

Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 6: Relief of painful symptoms (IN versus SC)

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

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
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
	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.
¹ No blinding ² Evidence based on a single trial which did not describe methods of sequence generation or allocation concealment

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

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

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

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

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

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
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
	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.
¹ Randomisation was inadequately reported in five of the seven trials. Four of the trials failed to described allocation concealment adequately. There was no blinding in two trials and blinding was unclear in two trials. ² I square was 44% which indicated issues of heterogeneity ³ There was a lack of adequate reporting of allocation concealment and/ or randomisation in most of the trials. Three of the nine trials did not give sufficient details for blinding and two trials were open label.

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

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

Outcomes	*Illustrative comparative risks (95% CI)**		No of Participants (studies)	Quality of the evidence (GRADE)	Comments
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
	Assumed risk	Corresponding risk
	Intra‐ uterine progestagen device	GnRHas
Relief of painful symptoms ‐ Overall		The mean relief of painful symptoms ‐ overall in the intervention groups was 0.25 standard deviations lower (0.6 lower to 0.1 higher)	129 (3 studies)	⊕⊕⊕⊝ moderate¹	Standardised mean difference ‐0.25 (‐0.6 to 0.1), indicating no clinically meaningful difference in pain score between the groups
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Two of the three trials were open label and one trial did not provide adequate explanation of allocation concealment

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

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Comparison 1. GnRHas versus no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Relief of painful symptoms Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1.1 Dysmenorrhoea	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	3.93 [1.37, 11.28]

Comparison 1. GnRHas versus no treatment

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Comparison 2. GnRHas versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Relief of painful symptoms Show forest plot	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 Show forest plot	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 Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.3.1 Overall at 4 weeks	1	120	Mean Difference (IV, Fixed, 95% CI)	2.90 [2.11, 3.69]

Comparison 2. GnRHas versus placebo

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Comparison 3. GnRHas versus danazol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Relief of painful symptoms Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	4	732	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.98, 1.32]

3.6 Side effects Show forest plot	18		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.6.1 vaginal dryness/vaginitis	15	1798	Risk Ratio (M‐H, Fixed, 95% CI)	2.04 [1.72, 2.42]
3.6.2 Hot flushes/flashes	18	2367	Risk Ratio (M‐H, Fixed, 95% CI)	1.55 [1.46, 1.65]
3.6.3 Headaches	15	1832	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [1.21, 1.64]
3.6.4 Infections and flu like symptoms	1	71	Risk Ratio (M‐H, Fixed, 95% CI)	3.60 [1.31, 9.88]
3.6.5 Muscle cramps/myalgia	10	1537	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.06, 0.18]
3.6.6 Sleep disturbance	6	679	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.46, 2.39]
3.6.7 Skin rash	3	324	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.02, 0.51]
3.6.8 Gastrointestinal	4	363	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.26, 1.05]
3.6.9 Weight gain	11	1493	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.11, 0.21]
3.6.10 Acne	12	1695	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.42, 0.58]
3.6.11 Breast atrophy/changes	7	1035	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.47, 0.76]
3.6.12 Emotional lability/altered mood	3	534	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.60, 1.61]
3.6.13 Oedema/fluid retention	5	626	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.05, 0.20]
3.6.14 Asthenia	5	781	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.23, 0.58]
3.6.15 Bleeding	3	161	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.12, 0.48]
3.6.16 Depression	5	513	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.38, 0.99]
3.6.17 Leukorrhoea	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.23, 4.71]
3.6.18 chest pain	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	7.23 [0.39, 134.16]
3.6.19 Generalised spasm	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.00, 1.35]
3.6.20 pharyngitis	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.74]
3.6.21 Voice alteration	2	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.02, 1.27]
3.6.22 vulvovaginal disorder	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.74]
3.6.23 Hirsutism	6	866	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.11, 0.39]
3.6.24 Seborrhoea	6	835	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.33, 0.53]
3.6.25 Alopecia	2	365	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.02, 0.53]
3.6.26 Altered libido	9	1620	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.88, 1.24]
3.6.27 Sweating	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03, 2.51]
3.6.28 Breast tenderness	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.04, 4.33]
3.6.29 Fatigue	2	84	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.40, 1.26]
3.6.30 Arthralgia	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	17.61 [1.08, 286.40]
3.6.31 Hunger	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.00, 0.81]
3.6.32 Nervousness	2	504	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.20, 1.02]
3.6.33 Irritability	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	4.74 [1.67, 13.45]
3.6.34 Clitoromegaly	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.59]
3.6.35 Appetite increase	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 1.54]
3.6.36 Fatigue/malaise	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.06, 0.61]
3.6.37 Dizziness	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 2.06]
3.6.38 Nausea	2	374	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.31, 0.80]
3.6.39 Breast pain	1	307	Risk Ratio (M‐H, Fixed, 95% CI)	5.05 [0.66, 38.91]

Comparison 3. GnRHas versus danazol

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Comparison 4. GnRHas versus intra‐ uterine progestagen device

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Relief of painful symptoms Show forest plot	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 Show forest plot	1	18	Mean Difference (IV, Fixed, 95% CI)	9.50 [‐10.77, 29.77]

Comparison 4. GnRHas versus intra‐ uterine progestagen device

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Comparison 5. GnRHa versus GnRHa (Varying Dosage)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Side effects Show forest plot	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) Show forest plot	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.17, 1.01]

5.3 relief of painful symptoms Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.3.1 Dsymenorrhoea Nafarelin 400mcg versus 800mcg	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.53, 1.66]
5.3.2 Dyspareunia	1	57	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.79, 1.68]
5.3.3 Pelvic pain	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.67, 1.74]
5.3.4 Overall Nafarelin 400mcg versus 800mcg	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.78, 1.14]
5.3.5 Overall buserelin 300mcg vs 900 mcg	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.94, 2.35]

Comparison 5. GnRHa versus GnRHa (Varying Dosage)

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Comparison 6. GnRHa versus GnRHa (Length of Treatment)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up Show forest plot	1		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1.1 Dysmenorrhoea	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.31, 0.27]
6.1.2 Dyspareunia	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.98 [‐1.29, ‐0.66]
6.1.3 Pelvic pain	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.15, 0.44]
6.1.4 Pelvic tenderness	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.43, 0.15]
6.1.5 Pelvic induration	1	179	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.40, 0.18]

Comparison 6. GnRHa versus GnRHa (Length of Treatment)

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Comparison 7. GnRHa versus GnRHa (Route of Administration)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Side effects (IN vs SC) Show forest plot	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) Show forest plot	1	19	Mean Difference (IV, Fixed, 95% CI)	9.00 [‐5.93, 23.93]

7.3 Relief of painful symptoms (IN versus IMdepot) Show forest plot	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) Show forest plot	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) Show forest plot	1	100	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.58, 3.30]

7.6 Relief of painful symptoms (IN versus SC) Show forest plot	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]

Comparison 7. GnRHa versus GnRHa (Route of Administration)

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