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Meta-Analysis
. 2017 Jul 25;7(7):CD009881.
doi: 10.1002/14651858.CD009881.pub2.

Progesterone receptor modulators for endometriosis

Jing Fu  1 , Hao Song, Min Zhou, Huili Zhu, Yuhe Wang, Hengxi Chen, Wei Huang
Affiliations
Meta-Analysis

Progesterone receptor modulators for endometriosis

Jing Fu et al. Cochrane Database Syst Rev. .

Abstract

Background: Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. This condition is oestrogen-dependent and thus is seen primarily during the reproductive years. Owing to their antiproliferative effects in the endometrium, progesterone receptor modulators (PRMs) have been advocated for treatment of endometriosis.

Objectives: To assess the effectiveness and safety of PRMs primarily in terms of pain relief as compared with other treatments or placebo or no treatment in women of reproductive age with endometriosis.

Search methods: We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register of Controlled Trials, the Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, clinicaltrials.gov, and the World Health Organization (WHO) platform, from inception to 28 November 2016. We handsearched reference lists of articles retrieved by the search.

Selection criteria: We included randomised controlled trials (RCTs) published in all languages that examined effects of PRMs for treatment of symptomatic endometriosis.

Data collection and analysis: We used standard methodological procedures as expected by the Cochrane Collaboration. Primary outcomes included measures of pain and side effects.

Main results: We included 10 randomised controlled trials (RCTs) with 960 women. Two RCTs compared mifepristone versus placebo or versus a different dose of mifepristone, one RCT compared asoprisnil versus placebo, one compared ulipristal versus leuprolide acetate, and four compared gestrinone versus danazol, gonadotropin-releasing hormone (GnRH) analogues, or a different dose of gestrinone. The quality of evidence ranged from high to very low. The main limitations were serious risk of bias (associated with poor reporting of methods and high or unclear rates of attrition in most studies), very serious imprecision (associated with low event rates and wide confidence intervals), and indirectness (outcome assessed in a select subgroup of participants). Mifepristone versus placebo One study made this comparison and reported rates of painful symptoms among women who reported symptoms at baseline.At three months, the mifepristone group had lower rates of dysmenorrhoea (odds ratio (OR) 0.08, 95% confidence interval (CI) 0.04 to 0.17; one RCT, n =352; moderate-quality evidence), suggesting that if 40% of women taking placebo experience dysmenorrhoea, then between 3% and 10% of women taking mifepristone will do so. The mifepristone group also had lower rates of dyspareunia (OR 0.23, 95% CI 0.11 to 0.51; one RCT, n = 223; low-quality evidence). However, the mifepristone group had higher rates of side effects: Nearly 90% had amenorrhoea and 24% had hot flushes, although the placebo group reported only one event of each (1%) (high-quality evidence). Evidence was insufficient to show differences in rates of nausea, vomiting, or fatigue, if present. Mifepristone dose comparisons Two studies compared doses of mifepristone and found insufficient evidence to show differences between different doses in terms of effectiveness or safety, if present. However, subgroup analysis of comparisons between mifepristone and placebo suggest that the 2.5 mg dose may be less effective than 5 mg or 10 mg for treating dysmenorrhoea or dyspareunia. Gestrinone comparisons Ons study compared gestrinone with danazol, and another study compared gestrinone with leuprolin.Evidence was insufficient to show differences, if present, between gestrinone and danazol in rate of pain relief (those reporting no or mild pelvic pain) (OR 0.71, 95% CI 0.33 to 1.56; two RCTs, n = 230; very low-quality evidence), dysmenorrhoea (OR 0.72, 95% CI 0.39 to 1.33; two RCTs, n = 214; very low-quality evidence), or dyspareunia (OR 0.83, 95% CI 0.37 to 1.86; two RCTs, n = 222; very low-quality evidence). The gestrinone group had a higher rate of hirsutism (OR 2.63, 95% CI 1.60 to 4.32; two RCTs, n = 302; very low-quality evidence) and a lower rate of decreased breast size (OR 0.62, 95% CI 0.38 to 0.98; two RCTs, n = 302; low-quality evidence). Evidence was insufficient to show differences between groups, if present, in rate of hot flushes (OR 0.79, 95% CI 0.50 to 1.26; two RCTs, n = 302; very low-quality evidence) or acne (OR 1.45, 95% CI 0.90 to 2.33; two RCTs, n = 302; low-quality evidence).When researchers compared gestrinone versus leuprolin through measurements on the 1 to 3 verbal rating scale (lower score denotes benefit), the mean dysmenorrhoea score was higher in the gestrinone group (MD 0.35 points, 95% CI 0.12 to 0.58; one RCT, n = 55; low-quality evidence), but the mean dyspareunia score was lower in this group (MD 0.33 points, 95% CI 0.62 to 0.04; low-quality evidence). The gestrinone group had lower rates of amenorrhoea (OR 0.04, 95% CI 0.01 to 0.38; one RCT, n = 49; low-quality evidence) and hot flushes (OR 0.20, 95% CI 0.06 to 0.63; one study, n = 55; low quality evidence) but higher rates of spotting or bleeding (OR 22.92, 95% CI 2.64 to 198.66; one RCT, n = 49; low-quality evidence).Evidence was insufficient to show differences in effectiveness or safety between different doses of gestrinone, if present. Asoprisnil versus placebo One study (n = 130) made this comparison but did not report data suitable for analysis. Ulipristal versus leuprolide acetate One study (n = 38) made this comparison but did not report data suitable for analysis.

Authors' conclusions: Among women with endometriosis, moderate-quality evidence shows that mifepristone relieves dysmenorrhoea, and low-quality evidence suggests that this agent relieves dyspareunia, although amenorrhoea and hot flushes are common side effects. Data on dosage were inconclusive, although they suggest that the 2.5 mg dose of mifepristone may be less effective than higher doses. We found insufficient evidence to permit firm conclusions about the safety and effectiveness of other progesterone receptor modulators.

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Conflict of interest statement

JF, HS, MZ, HZ, YW, HC and WH have no interests to declare.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, outcome: 1.1 Dysmenorrhoea at three months.
5
5
Forest plot of comparison. 2 Mifepristone versus placebo, patient‐assessed outcomes, outcome: 2.1 Amenorrhoea at three months.
6
6
Forest plot of comparison: side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, outcome: 2.2 Hot flushes at three months.
7
7
Forest plot of comparison: 7 Gestrinone versus leuprolin for six months: efficacy and side effects, outcome: 7.1 Painful periods, visual analogue scale.
8
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.
1.1
1.1. Analysis
Comparison 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, Outcome 1 Dysmenorrhoea at 3 months.
1.2
1.2. Analysis
Comparison 1 Effectiveness of mifepristone versus placebo, patient‐assessed outcomes, Outcome 2 Dyspareunia at 3 months.
2.1
2.1. Analysis
Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 1 Amenorrhoea at 3 months.
2.2
2.2. Analysis
Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 2 Amenorrhoea at 3 months: subgroup analysis.
2.3
2.3. Analysis
Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 3 Hot flushes at 3 months.
2.4
2.4. Analysis
Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 4 Hot flushes at 3 months: subgroup analysis.
2.5
2.5. Analysis
Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 5 Nausea at 3 months.
2.6
2.6. Analysis
Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 6 Vomiting at 3 months.
2.7
2.7. Analysis
Comparison 2 Side effects at three months, mifepristone versus placebo, patient‐assessed outcomes, Outcome 7 Fatigue/Tiredness at 3 months.
3.1
3.1. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 1 Prevalence of dysmenorrhoea.
3.2
3.2. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 2 Dysmenorrhoea score 0‐10 VAS scale.
3.3
3.3. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 3 Prevalence of dyspareunia.
3.4
3.4. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 4 Dyspareunia score 0‐10 VAS scale.
3.5
3.5. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 5 Prevalence of pelvic pain.
3.6
3.6. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 6 Prevalence of amenorrhoea.
3.7
3.7. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 7 Prevalence of hot flushes.
3.8
3.8. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 8 Prevalence of nausea.
3.9
3.9. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 9 Prevalence of vomiting.
3.10
3.10. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 10 Prevalence of fatigue/tiredness.
3.11
3.11. Analysis
Comparison 3 Mifepristone lower dose versus higher dose: efficacy and side effects at six months, Outcome 11 Prevalence of endometrial thickness > 20 mm.
4.1
4.1. Analysis
Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 1 None or mild pelvic pain.
4.2
4.2. Analysis
Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 2 None or mild dysmenorrhoea.
4.3
4.3. Analysis
Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 3 None or mild dyspareunia.
4.4
4.4. Analysis
Comparison 4 Gestrinone versus danazol for six months: efficacy and side effects, Outcome 4 Adverse effects.
5.1
5.1. Analysis
Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 1 Painful periods, visual analogue scale.
5.2
5.2. Analysis
Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 2 Painful periods, verbal rating scale.
5.3
5.3. Analysis
Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 3 Pain on intercourse, visual analogue scale.
5.4
5.4. Analysis
Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 4 Pain on intercourse, verbal rating scale.
5.5
5.5. Analysis
Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 5 Non‐menstrual pain, visual analogue scale.
5.6
5.6. Analysis
Comparison 5 Gestrinone versus leuprolin for six months: efficacy and side effects, Outcome 6 Side effects.
6.1
6.1. Analysis
Comparison 6 Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects, Outcome 1 improvement in pain.
6.2
6.2. Analysis
Comparison 6 Gestrinone 1.25 mg versus gestrinone 2.5 mg: efficacy and side effects, Outcome 2 Side effect.
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Update of

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