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Moduladores de los receptores de progesterona para la endometriosis

Appendices

Appendix 1. Cochrane Gynaecology and Fertility Group specialised register search strategy

From inception to 28 November 2016

Procite platform

Keywords CONTAINS "endometriosis" or "Endometriosis‐Symptoms" or "pelvic pain" or "dyspareunia" or Title CONTAINS "endometriosis" or "Endometriosis‐Symptoms" or "pelvic pain" or "dyspareunia"

AND

Keywords CONTAINS "mifepristone"or"RU486"or"gestrinone"or"Onapristone" or "asoprisnil" or "CBD 2914" or "CDB‐2914" or "CDB‐4124" or "Ulipristal" or "ulipristal acetate" or "progestagen receptor levels" or" progesterone receptor agonist" or "Progesterone Receptor Modulator" or "selective progesterone receptor modulator" or Title CONTAINS "mifepristone"or"RU486"or"gestrinone"or"Onapristone" or "asoprisnil" or "CBD 2914" or "CDB‐2914" or "CDB‐4124" or "Ulipristal" or "ulipristal acetate" or "progestagen receptor levels" or" progesterone receptor agonist" or "Progesterone Receptor Modulator" or "selective progesterone receptor modulator" (44 hits)

Appendix 2. CENTRAL CRSO search strategy

Searched 28 November 2016

Web platform

#1 MESH DESCRIPTOR Endometriosis EXPLODE ALL TREES 513

#2 Endometrio*:TI,AB,KY 1289

#3 (pelvi* pain):TI,AB,KY 878

#4 #1 OR #2 OR #3 1934

#5 MESH DESCRIPTOR Mifepristone EXPLODE ALL TREES 376

#6 mifepristone:TI,AB,KY 714

#7 RU486:TI,AB,KY 47

#8 (progest* adj1 antagonist*):TI,AB,KY 68

#9 (progest* adj1 modulator*):TI,AB,KY 33

#10 (ru 486 or ru486):TI,AB,KY 143

#11 ru38486:TI,AB,KY 5

#12 ru‐38486:TI,AB,KY 1

#13 MESH DESCRIPTOR Gestrinone EXPLODE ALL TREES 29

#14 Gestrinone:TI,AB,KY 58

#15 Onapristone:TI,AB,KY 9

#16 Aglepristone:TI,AB,KY 2

#17 anti‐progestin*:TI,AB,KY 2

#18 antiprogestin*:TI,AB,KY 47

#19 Asoprisnil:TI,AB,KY 10

#20 J867:TI,AB,KY 1

#21 Telapristone:TI,AB,KY 1

#22 CDB‐2914:TI,AB,KY 9

#23 Ulipristal:TI,AB,KY 37

#24 (SPRM* or PRAs or PRA):TI,AB,KY 788

#25 MESH DESCRIPTOR Receptors, Progesterone EXPLODE ALL TREES WITH QUALIFIERS AD,AG,AI,ME,TU 159

#26 #5 OR #6 OR #7 OR #8 OR #9 OR #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 1782

#27 #4 AND #26 65

Appendix 3. MEDLINE search strategy

From 1946 to 28 November 2016

Ovid platform

1 exp Endometriosis/ (19876)
2 Endometri$.tw. (84071)
3 exp Dyspareunia/ (1809)
4 Dyspareunia.tw. (3194)
5 pelvi$ pain.tw. (7650)
6 or/1‐5 (95322)
7 exp Mifepristone/ (5981)
8 mifepristone.tw. (3252)
9 RU486.tw. (2312)
10 (progest$ adj1 antagonist$).tw. (512)
11 (progest$ adj1 modulator$).tw. (11)
12 ru 486.tw. (1780)
13 mifegyne.tw. (13)
14 ru38486.tw. (409)
15 ru‐38486.tw. (465)
16 mifeprex.tw. (12)
17 r38486.tw. (1)
18 exp Gestrinone/ (198)
19 Gestrinone.tw. (192)
20 Lilopristone.tw. (20)
21 Onapristone.tw. (187)
22 Aglepristone.tw. (82)
23 (dimetriose or dimetrose).tw. (1)
24 Nemestran.tw. (4)
25 anti‐progestin$.tw. (151)
26 antiprogestin$.tw. (935)
27 Asoprisnil.tw. (47)
28 J867.tw. (13)
29 Telapristone.tw. (9)
30 CDB‐2914.tw. (48)
31 CDB‐4124.tw. (19)
32 Proellex.tw. (8)
33 Ulipristal.tw. (254)
34 (SPRM$ or PRAs).tw. (340)
35 exp Receptors, Progesterone/me, tu [Metabolism, Therapeutic Use] (9329)
36 or/7‐35 (18327)
37 6 and 36 (2106)
38 randomized controlled trial.pt. (469810)
39 controlled clinical trial.pt. (95074)
40 randomized.ab. (404455)
41 randomised.ab. (81254)
42 placebo.tw. (197050)
43 clinical trials as topic.sh. (189502)
44 randomly.ab. (285441)
45 trial.ti. (178951)
46 (crossover or cross‐over or cross over).tw. (76010)
47 or/38‐46 (1208254)
48 exp animals/ not humans.sh. (4669479)
49 47 not 48 (1114154)
50 37 and 49 (212)

Appendix 4. Embase search strategy

From 1980 to 28 November 2016

Ovid platform

1 exp endometriosis/ (30876)
2 Endometri$.tw. (104349)
3 Dyspareunia.tw. (5475)
4 pelvi$ pain.tw. (11229)
5 or/1‐4 (120810)
6 exp mifepristone/ (11579)
7 mifepristone.tw. (3888)
8 RU486.tw. (2483)
9 (progest$ adj1 antagonist$).tw. (521)
10 exp antigestagen/ (12402)
11 (progest$ adj1 modulator$).tw. (18)
12 exp progesterone receptor modulator/ (586)
13 ru 486.tw. (4148)
14 mifegyne.tw. (181)
15 ru38486.tw. (406)
16 ru‐38486.tw. (913)
17 mifeprex.tw. (111)
18 zk 98296.tw. (3)
19 r38486.tw. (1)
20 exp GESTRINONE/ (621)
21 Gestrinone.tw. (204)
22 Lilopristone.tw. (22)
23 Onapristone.tw. (216)
24 Aglepristone.tw. (80)
25 (dimetriose or dimetrose).tw. (14)
26 Nemestran.tw. (11)
27 anti‐progestin$.tw. (178)
28 antiprogestin$.tw. (968)
29 Asoprisnil.tw. (63)
30 J867.tw. (15)
31 Telapristone.tw. (16)
32 CDB‐2914.tw. (106)
33 CDB‐4124.tw. (47)
34 Proellex.tw. (22)
35 Ulipristal.tw. (466)
36 (SPRM$ or PRAs).tw. (596)
37 exp progesterone receptor/dt, pd [Drug Therapy, Pharmacology] (65)
38 or/6‐37 (14686)
39 5 and 38 (1698)
40 Clinical Trial/ (995452)
41 Randomized Controlled Trial/ (461742)
42 exp randomization/ (83639)
43 Single Blind Procedure/ (27251)
44 Double Blind Procedure/ (136941)
45 Crossover Procedure/ (53825)
46 Placebo/ (321968)
47 Randomi?ed controlled trial$.tw. (149359)
48 Rct.tw. (22353)
49 random allocation.tw. (1629)
50 randomly.tw. (338581)
51 randomly allocated.tw. (26583)
52 allocated randomly.tw. (2208)
53 (allocated adj2 random).tw. (843)
54 Single blind$.tw. (18663)
55 Double blind$.tw. (172862)
56 ((treble or triple) adj blind$).tw. (647)
57 placebo$.tw. (247461)
58 prospective study/ (386445)
59 or/40‐58 (1967839)
60 case study/ (92866)
61 case report.tw. (323319)
62 abstract report/ or letter/ (986309)
63 or/60‐62 (1393358)
64 59 not 63 (1916879)
65 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5725014)
66 64 not 65 (1793800)
67 39 and 66 (434)

Appendix 5. PsycINFO search strategy

From 1806 to 28 November 2016

Ovid platform

1 exp Dyspareunia/ (240)
2 Dyspareunia.tw. (528)
3 Endometriosis.tw. (209)
4 pelvi$ pain.tw. (489)
5 or/1‐4 (1140)
6 mifepristone.tw. (226)
7 RU486.tw. (159)
8 ru 486.tw. (88)
9 Gestrinone.tw. (0)
10 anti‐progestin$.tw. (4)
11 antiprogestin$.tw. (18)
12 (progest$ adj1 antagonist$).tw. (19)
13 Ulipristal.tw. (3)
14 SPRM$.tw. (3)
15 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 (434)
16 5 and 15 (3)
17 random.tw. (48413)
18 control.tw. (375365)
19 double‐blind.tw. (20296)
20 clinical trials/ (10020)
21 placebo/ (4732)
22 exp Treatment/ (669135)
23 or/17‐22 (1033445)
24 16 and 23 (1)

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

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

Forest plot of comparison: 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, outcome: 1.1 Dysmenorrhoea at three months.
Figures and Tables -
Figure 4

Forest plot of comparison: 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, outcome: 1.1 Dysmenorrhoea at three months.

Forest plot of comparison.2 Mifepristone versus placebo, patient‐assessed outcomes, outcome: 2.1 Amenorrhoea at three months.
Figures and Tables -
Figure 5

Forest plot of comparison.

2 Mifepristone versus placebo, patient‐assessed outcomes, outcome: 2.1 Amenorrhoea at three months.

Forest plot of comparison: side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, outcome: 2.2 Hot flushes at three months.
Figures and Tables -
Figure 6

Forest plot of comparison: side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, outcome: 2.2 Hot flushes at three months.

Forest plot of comparison: 7 Gestrinone versus leuprolin for six months: efficacy and side effects, outcome: 7.1 Painful periods, visual analogue scale.
Figures and Tables -
Figure 7

Forest plot of comparison: 7 Gestrinone versus leuprolin for six months: efficacy and side effects, outcome: 7.1 Painful periods, visual analogue scale.

Forest plot of comparison: 7 Gestrinone versus leuprolin for six months: efficacy and side effects, outcome: 7.3 Pain on intercourse, visual analogue scale.
Figures and Tables -
Figure 8

Forest plot of comparison: 7 Gestrinone versus leuprolin for six months: efficacy and side effects, outcome: 7.3 Pain on intercourse, visual analogue scale.

Comparison 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, Outcome 1 Dysmenorrhoea at 3 months.
Figures and Tables -
Analysis 1.1

Comparison 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, Outcome 1 Dysmenorrhoea at 3 months.

Comparison 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, Outcome 2 Dyspareunia at 3 months.
Figures and Tables -
Analysis 1.2

Comparison 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, Outcome 2 Dyspareunia at 3 months.

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 1 Amenorrhoea at 3 months.
Figures and Tables -
Analysis 2.1

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 1 Amenorrhoea at 3 months.

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 2 Amenorrhoea at 3 months: subgroup analysis.
Figures and Tables -
Analysis 2.2

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 2 Amenorrhoea at 3 months: subgroup analysis.

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 3 Hot flushes at 3 months.
Figures and Tables -
Analysis 2.3

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 3 Hot flushes at 3 months.

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 4 Hot flushes at 3 months: subgroup analysis.
Figures and Tables -
Analysis 2.4

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 4 Hot flushes at 3 months: subgroup analysis.

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 5 Nausea at 3 months.
Figures and Tables -
Analysis 2.5

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 5 Nausea at 3 months.

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 6 Vomiting at 3 months.
Figures and Tables -
Analysis 2.6

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 6 Vomiting at 3 months.

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 7 Fatigue/Tiredness at 3 months.
Figures and Tables -
Analysis 2.7

Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 7 Fatigue/Tiredness at 3 months.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 1 Prevalence of dysmenorrhoea.
Figures and Tables -
Analysis 3.1

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 1 Prevalence of dysmenorrhoea.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 2 Dysmenorrhoea score 0‐10 VAS scale.
Figures and Tables -
Analysis 3.2

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 2 Dysmenorrhoea score 0‐10 VAS scale.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 3 Prevalence of dyspareunia.
Figures and Tables -
Analysis 3.3

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 3 Prevalence of dyspareunia.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 4 Dyspareunia score 0‐10 VAS scale.
Figures and Tables -
Analysis 3.4

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 4 Dyspareunia score 0‐10 VAS scale.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 5 Prevalence of pelvic pain.
Figures and Tables -
Analysis 3.5

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 5 Prevalence of pelvic pain.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 6 Prevalence of amenorrhoea.
Figures and Tables -
Analysis 3.6

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 6 Prevalence of amenorrhoea.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 7 Prevalence of hot flushes.
Figures and Tables -
Analysis 3.7

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 7 Prevalence of hot flushes.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 8 Prevalence of nausea.
Figures and Tables -
Analysis 3.8

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 8 Prevalence of nausea.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 9 Prevalence of vomiting.
Figures and Tables -
Analysis 3.9

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 9 Prevalence of vomiting.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 10 Prevalence of fatigue/tiredness.
Figures and Tables -
Analysis 3.10

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 10 Prevalence of fatigue/tiredness.

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 11 Prevalence of endometrial thickness > 20 mm.
Figures and Tables -
Analysis 3.11

Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 11 Prevalence of endometrial thickness > 20 mm.

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 1 None or mild pelvic pain.
Figures and Tables -
Analysis 4.1

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 1 None or mild pelvic pain.

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 2 None or mild dysmenorrhoea.
Figures and Tables -
Analysis 4.2

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 2 None or mild dysmenorrhoea.

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 3 None or mild dyspareunia.
Figures and Tables -
Analysis 4.3

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 3 None or mild dyspareunia.

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 4 Adverse effects.
Figures and Tables -
Analysis 4.4

Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 4 Adverse effects.

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 1 Painful periods, visual analogue scale.
Figures and Tables -
Analysis 5.1

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 1 Painful periods, visual analogue scale.

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 2 Painful periods, verbal rating scale.
Figures and Tables -
Analysis 5.2

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 2 Painful periods, verbal rating scale.

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 3 Pain on intercourse, visual analogue scale.
Figures and Tables -
Analysis 5.3

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 3 Pain on intercourse, visual analogue scale.

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 4 Pain on intercourse, verbal rating scale.
Figures and Tables -
Analysis 5.4

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 4 Pain on intercourse, verbal rating scale.

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 5 Non‐menstrual pain, visual analogue scale.
Figures and Tables -
Analysis 5.5

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 5 Non‐menstrual pain, visual analogue scale.

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 6 Side effects.
Figures and Tables -
Analysis 5.6

Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 6 Side effects.

Comparison 6 Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects, Outcome 1 improvement in pain.
Figures and Tables -
Analysis 6.1

Comparison 6 Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects, Outcome 1 improvement in pain.

Comparison 6 Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects, Outcome 2 Side effect.
Figures and Tables -
Analysis 6.2

Comparison 6 Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects, Outcome 2 Side effect.

Summary of findings for the main comparison. Mifepristone versus placebo for endometriosis

Mifepristone versus placebo for endometriosis

Patient or population: women with symptomatic endometriosis

Settings: gynaecology clinic

Intervention: progesterone receptor modulator (mifepristone)

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

Mifepristone

Prevalence of dysmenorrhoea

Follow‐up: 3 months

402 per 1000

51 per 1000
(26 to 103)

OR 0.08 (0.04 to 0.17)

352
(1)

⊕⊕⊕⊝
Moderatea,b

Prevalence of dyspareunia

Follow‐up: 3 months

288 per 1000

85 per 1000
(43 to 171)

OR 0.23 (0.10 to 0.51)

223
(1)

⊕⊕⊝⊝
Lowa,c

Side effects: amenorrhoea

Follow‐up: 3 months

11 per 1000

884 per 1000
(507 to 983)

OR 686.16 (92.29 to 5101.33)

360
(1)

⊕⊕⊕⊝

High

239/270 events in the mifepristone group vs 1/90 in the placebo group

Side effects: hot flushes

Follow‐up: 3 months

11 per 1000

243 per 1000
(42 to 701)

OR 28.79 (3.93 to 210.73)

360
(1)

⊕⊕⊕⊝

High

66/270 events in the mifepristone group vs 1/90 in the placebo group

*The basis for the assumed risk is the mean 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; OR: odds 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

aDowngraded one level for serious imprecision (wide confidence intervals and/or very few events)

bOutcome applied only to women with dysmenorrhoea at baseline, but this was 352/360 women randomised, so not downgraded for indirectness

cOutcome applied only to women with dyspareunia at baseline, which was 223/360 women randomised. Downgraded one level for serious indirectness

Figures and Tables -
Summary of findings for the main comparison. Mifepristone versus placebo for endometriosis
Summary of findings 2. Gestrinone versus danazol for endometriosis

Gestrinone versus danazol for endometriosis

Patient or population: women with symptomatic endometriosis

Settings: gynaecology clinic

Intervention: progesterone receptor modulator (gestrinone)

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

Gestrinone

Pelvic pain: none or mild

890 per 1000

852 per 1000

(727 to 927)

OR 0.71

(0.33 to 1.56)

230

(2)

⊕⊕⊝⊝
Very lowa,b,c

Dysmenorrhoea: none or mild

Follow‐up: 6 months

721 per 1000

650 per 1000
(502 to 775)

OR 0.72 (0.39 to 1.33)

214
(2)

⊕⊝⊝⊝
Very lowa,b,c

Dyspareunia: none or mild

Follow‐up: 6 months

889 per 1000

869 per 1000
(748 to 937)

OR 0.83 (0.37 to 1.86)

222
(2)

⊕⊝⊝⊝
Very lowa,b,c

Side effects: hirsutism

Follow‐up: 6 months

248 per 1000

464 per 1000
(345 to 587)

OR 2.63 (1.60 to 4.32)

302
(2)

⊕⊝⊝⊝
Very lowb,c,d

I2 = 68%

Decreased breast size

Follow‐up: 6 months

477 per 1000

360 per 1000
(257 to 472)

OR 0.62 (0.38 to 0.98)

302
(2)

⊕⊕⊝⊝
Lowb,c

Side effects: hot flushes

Follow‐up: 6 months

425 per 1000

368 per 1000

(270 to 482)

OR 0.79

(0.50 to 1.26)

302

(2 studies)

⊕⊝⊝⊝
Very lowb,c,d

I2 = 72%

Side effects: acne

Follow‐up: 6 months

556 per 1000

644 per 1000

(529 to 744)

OR 1.45

(0.90 to 2.33)

302

(2 studies)

⊕⊕⊝⊝
Lowb,c

*The basis for the assumed risk is the mean 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; OR: odds 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

aAssessed in all randomised participants. Not all were symptomatic at baseline (although results show no significant differences in baseline symptoms between groups). Outcome therefore applies only to a select subgroup of participants: downgraded one level for serious indirectness

bDowngraded one level for serious risk of bias associated with poor reporting of study methods, high attrition in one study, and high risk of other bias in both studies

cImprecision of results (wide confidence intervals and/or few events), downgraded one level for serious imprecision

dDowngraded one level for serious inconsistency

Figures and Tables -
Summary of findings 2. Gestrinone versus danazol for endometriosis
Summary of findings 3. Gestrinone versus leuprolin for endometriosis

Gestrinone versus leuprolin for endometriosis

Patient or population: women with symptomatic endometriosis

Settings: gynaecology clinic

Intervention: progesterone receptor modulator (gestrinone)

Comparison: leuprolin

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Leuprolin

Gestrinone

Dysmenorrhoea, verbal rating scale

Follow‐up: 6 months

In control group, mean score for dysmenorrhoea on verbal rating scale was 0.04 points

Mean score in gestrinone group was 0.35 points higher (0.12 to 0.58 higher)

55
(1)

⊕⊕⊝⊝
Lowa

Verbal rating scale defines dysmenorrhoea according to limitation of ability to work (mild = 1, moderate = 2, incapacitated = 3)

Dyspareunia, verbal rating scale

Follow‐up: 6 months

In control group, mean score for dyspareunia on verbal rating scale was 0.43 points

Mean score in gestrinone group was 0.33 points lower (0.62 to 0.04 lower)

52
(1)

⊕⊕⊝⊝
Lowa

Verbal rating scale defines dyspareunia according to limitation of sexual activity (discomfort tolerated = 1; pain interrupts intercourse = 2, intercourse avoided owing to pain = 3)

Amenorrhoea

Follow‐up: 6 months

962 per 1000

500 per 1000
(26 to 908)

OR 0.04 (0.01 to 0.38)

49
(1)

⊕⊕⊝⊝
Lowb

Only 55 events overall

Spotting or bleeding

Follow‐up: 6 months

38 per 1000

475 per 1000
(94 to 887)

OR 22.92 (2.64 to 198.66)

49
(1)

⊕⊕⊝⊝
Lowb

Only 12 events overall

Side effects: hot flushes

Follow‐up: 6 months

679 per 1000

297 per 1000

(112 to 571)

OR 0.20

(0.06 to 0.63)

55
(1)

⊕⊕⊝⊝
Lowb

Only 27 events overall

*The basis for the assumed risk is the mean 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; OR: odds 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

aDowngraded two levels for very serious imprecision: confidence intervals were compatible with no clinically meaningful difference between groups, or with small benefit in one group

bDowngraded two levels for very serious imprecision: small overall sample size (n = 55) and low event rates

Figures and Tables -
Summary of findings 3. Gestrinone versus leuprolin for endometriosis
Table 1. Data unsuitable for analysis

Outcome

Study

Comparison

Measure

Int group

Control group

P value

Combined non‐pelvic pain,

dysmenorrhoea, and

dyspareunia

Chwalisz 2004

Asoprisnil: 5 mg (n = 31),

10 mg (n = 33), 25 mg (n = 32)

Placebo (n = 34)

Mean reduction at 3 months

on 0‐4 pain scale

0.5 points for each dose

< 0.1 points

< 0.05

Figures and Tables -
Table 1. Data unsuitable for analysis
Comparison 1. Effectiveness of mifepristone versus placebo, patient‐assessed outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Dysmenorrhoea at 3 months Show forest plot

1

352

Odds Ratio (M‐H, Fixed, 95% CI)

0.08 [0.04, 0.17]

1.1 Mifepristone 2.5 mg

1

114

Odds Ratio (M‐H, Fixed, 95% CI)

0.24 [0.09, 0.64]

1.2 Mifepristone 5 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

0.02 [0.00, 0.16]

1.3 Mifepristone 10 mg

1

118

Odds Ratio (M‐H, Fixed, 95% CI)

0.02 [0.00, 0.17]

2 Dyspareunia at 3 months Show forest plot

1

223

Odds Ratio (M‐H, Fixed, 95% CI)

0.23 [0.10, 0.51]

2.1 Mifepristone 2.5 mg

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

0.62 [0.18, 2.13]

2.2 Mifepristone 5 mg

1

73

Odds Ratio (M‐H, Fixed, 95% CI)

0.04 [0.00, 0.40]

2.3 Mifepristone 10 mg

1

76

Odds Ratio (M‐H, Fixed, 95% CI)

0.13 [0.03, 0.60]

Figures and Tables -
Comparison 1. Effectiveness of mifepristone versus placebo, patient‐assessed outcomes
Comparison 2. Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Amenorrhoea at 3 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Mifepristone all doses

1

360

Odds Ratio (M‐H, Fixed, 95% CI)

686.16 [92.29, 5101.33]

2 Amenorrhoea at 3 months: subgroup analysis Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Mifepristone 2.5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

207.67 [27.50, 1568.36]

2.2 Mifepristone 5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

3916.0 [348.75, 43971.52]

2.3 Mifepristone 10 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

3916.0 [348.75, 43971.52]

3 Hot flushes at 3 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Mifepristone all doses

1

360

Odds Ratio (M‐H, Fixed, 95% CI)

28.79 [3.93, 210.73]

4 Hot flushes at 3 months: subgroup analysis Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Mifepristone 2.5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

19.24 [2.49, 148.54]

4.2 Mifepristone 5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

23.82 [3.11, 182.24]

4.3 Mifepristone 10 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

46.76 [6.21, 351.92]

5 Nausea at 3 months Show forest plot

1

360

Odds Ratio (M‐H, Fixed, 95% CI)

1.72 [0.20, 15.03]

5.1 Mifepristone 2.5 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Mifepristone 5 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

1.02 [0.04, 25.76]

5.3 Mifepristone 10 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

2.44 [0.12, 48.60]

6 Vomiting at 3 months Show forest plot

1

360

Odds Ratio (M‐H, Fixed, 95% CI)

1.02 [0.10, 10.01]

6.1 Mifepristone 2.5 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

1.02 [0.04, 25.76]

6.2 Mifepristone 5 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 Mifepristone 10 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

1.02 [0.04, 25.76]

7 Fatigue/Tiredness at 3 months Show forest plot

1

360

Odds Ratio (M‐H, Fixed, 95% CI)

5.48 [0.71, 42.27]

7.1 Mifepristone 2.5 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

3.92 [0.21, 73.08]

7.2 Mifepristone 5 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 Mifepristone 10 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

7.11 [0.40, 125.92]

Figures and Tables -
Comparison 2. Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes
Comparison 3. Mifepristone lower dose versus higher dose: efficacy and side effects at six months

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Prevalence of dysmenorrhoea Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 2.5 mg vs 5 mg

1

170

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.22, 3.29]

1.2 5 mg vs 10 mg

1

173

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [0.32, 4.71]

2 Dysmenorrhoea score 0‐10 VAS scale Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

2.1 5 mg vs 25 mg

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Prevalence of dyspareunia Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 2.5 mg vs 5 mg

1

108

Odds Ratio (M‐H, Fixed, 95% CI)

6.37 [0.74, 54.81]

3.2 5 mg vs 10 mg

1

109

Odds Ratio (M‐H, Fixed, 95% CI)

0.52 [0.05, 5.90]

4 Dyspareunia score 0‐10 VAS scale Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

4.1 5 mg vs 25 mg

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Prevalence of pelvic pain Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 2.5 mg vs 5 mg

1

110

Odds Ratio (M‐H, Fixed, 95% CI)

1.81 [0.63, 5.17]

5.2 5 mg vs 10 mg

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

3.97 [0.79, 19.97]

6 Prevalence of amenorrhoea Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 2.5 mg vs 5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

0.45 [0.21, 0.97]

6.2 5 mg vs 10 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

1.10 [0.47, 2.56]

6.3 5 mg vs 25 mg

1

26

Odds Ratio (M‐H, Fixed, 95% CI)

0.61 [0.08, 4.41]

7 Prevalence of hot flushes Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.1 2.5 mg vs 5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.38, 1.89]

7.2 5 mg vs 10 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

0.75 [0.35, 1.58]

7.3 5 mg vs 25 mg

1

26

Odds Ratio (M‐H, Fixed, 95% CI)

3.24 [0.12, 87.13]

8 Prevalence of nausea Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

8.1 2.5 mg vs 5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

2.02 [0.18, 22.71]

8.2 5 mg vs 10 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.06, 16.24]

9 Prevalence of vomiting Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

9.1 2.5 mg vs 5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

3.03 [0.12, 75.46]

9.2 5 mg vs 10 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 8.20]

10 Prevalence of fatigue/tiredness Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

10.1 2.5 mg vs 5 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

13.92 [0.77, 250.94]

10.2 5 mg vs 10 mg

1

180

Odds Ratio (M‐H, Fixed, 95% CI)

0.03 [0.00, 0.54]

11 Prevalence of endometrial thickness > 20 mm Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

11.1 5 mg vs 25 mg

1

26

Odds Ratio (M‐H, Fixed, 95% CI)

1.41 [0.28, 7.13]

Figures and Tables -
Comparison 3. Mifepristone lower dose versus higher dose: efficacy and side effects at six months
Comparison 4. Gestrinone versus danazol for six months: efficacy and side effects

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 None or mild pelvic pain Show forest plot

2

230

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.33, 1.56]

2 None or mild dysmenorrhoea Show forest plot

2

214

Odds Ratio (M‐H, Fixed, 95% CI)

0.72 [0.39, 1.33]

3 None or mild dyspareunia Show forest plot

2

222

Odds Ratio (M‐H, Fixed, 95% CI)

0.83 [0.37, 1.86]

4 Adverse effects Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Acne

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [0.90, 2.33]

4.2 Seborrhoea

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

2.73 [1.67, 4.46]

4.3 Hirsutism

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

2.63 [1.60, 4.32]

4.4 Voice problems

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

0.70 [0.34, 1.43]

4.5 Swelling hands/feet

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

1.40 [0.82, 2.38]

4.6 Hot flushes

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.50, 1.26]

4.7 Decreased breast size

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

0.62 [0.38, 0.98]

4.8 Leg or muscle cramps

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

0.49 [0.30, 0.78]

4.9 Headache

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

1.36 [0.84, 2.21]

4.10 Nausea

2

302

Odds Ratio (M‐H, Fixed, 95% CI)

1.36 [0.84, 2.19]

4.11 Vomiting

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

0.67 [0.32, 1.43]

4.12 Loss of appetite

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

1.31 [0.72, 2.37]

4.13 Hunger

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

0.59 [0.36, 0.97]

4.14 Dizziness

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

1.24 [0.75, 2.05]

4.15 Tiredness

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

1.44 [0.84, 2.45]

4.16 Faintness

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

1.23 [0.54, 2.76]

4.17 Skin rash

1

264

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [0.91, 3.20]

4.18 Weight gain

1

38

Odds Ratio (M‐H, Fixed, 95% CI)

0.34 [0.09, 1.27]

4.19 Vaginal dryness

1

38

Odds Ratio (M‐H, Fixed, 95% CI)

0.18 [0.01, 4.00]

4.20 Raised liver transaminases

1

38

Odds Ratio (M‐H, Fixed, 95% CI)

0.18 [0.01, 4.00]

Figures and Tables -
Comparison 4. Gestrinone versus danazol for six months: efficacy and side effects
Comparison 5. Gestrinone versus leuprolin for six months: efficacy and side effects

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Painful periods, visual analogue scale Show forest plot

1

55

Mean Difference (IV, Fixed, 95% CI)

0.82 [0.15, 1.49]

2 Painful periods, verbal rating scale Show forest plot

1

55

Mean Difference (IV, Fixed, 95% CI)

0.35 [0.12, 0.58]

3 Pain on intercourse, visual analogue scale Show forest plot

1

52

Mean Difference (IV, Fixed, 95% CI)

‐1.16 [‐2.08, ‐0.24]

4 Pain on intercourse, verbal rating scale Show forest plot

1

52

Mean Difference (IV, Fixed, 95% CI)

‐0.33 [‐0.62, ‐0.04]

5 Non‐menstrual pain, visual analogue scale Show forest plot

1

55

Mean Difference (IV, Fixed, 95% CI)

‐0.41 [‐1.76, 0.94]

6 Side effects Show forest plot

1

813

Odds Ratio (M‐H, Fixed, 95% CI)

0.65 [0.42, 1.01]

6.1 Seborrhoea

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

3.23 [0.13, 82.71]

6.2 Swelling hands/feet

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

5.59 [0.26, 121.96]

6.3 Hot flushes

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

0.20 [0.06, 0.63]

6.4 Leg or muscle cramps

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 8.55]

6.5 Headache

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

0.20 [0.06, 0.63]

6.6 Nausea

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.06, 17.49]

6.7 Dizziness

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

2.16 [0.18, 25.32]

6.8 Skin rash

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

3.23 [0.13, 82.71]

6.9 Vaginal dryness

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 4.21]

6.10 Mood changes

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

0.67 [0.10, 4.34]

6.11 Joint pain

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

2.16 [0.18, 25.32]

6.12 Drowsiness

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

2.16 [0.18, 25.32]

6.13 Tachycardia

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.06, 17.49]

6.14 Amenorrhoea

1

49

Odds Ratio (M‐H, Fixed, 95% CI)

0.04 [0.01, 0.38]

6.15 Spotting or bleeding

1

49

Odds Ratio (M‐H, Fixed, 95% CI)

22.92 [2.64, 198.66]

Figures and Tables -
Comparison 5. Gestrinone versus leuprolin for six months: efficacy and side effects
Comparison 6. Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 improvement in pain Show forest plot

1

10

Odds Ratio (M‐H, Fixed, 95% CI)

0.27 [0.01, 8.46]

2 Side effect Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Noted any side effect

1

12

Odds Ratio (M‐H, Fixed, 95% CI)

0.04 [0.00, 1.12]

2.2 Discontinued because of headaches

1

12

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.01, 8.42]

2.3 Irregular bleeding

1

12

Odds Ratio (M‐H, Fixed, 95% CI)

2.5 [0.16, 38.60]

Figures and Tables -
Comparison 6. Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects