Progestagens for pain symptoms associated with endometriosis

Endometriosis is a hormone-sensitive inflammatory condition affecting between 5% and 10% of reproductive-aged women and an unknown number of gender-diverse individuals. It is often associated with debilitating pelvic pain symptoms. Various formulations of progestagens (e.g. oral, depot, implantable) have been studied as potential treatments for endometriosis because they induce atrophy of endometrial tissue.

To determine the benefits and harms of progestagens in the treatment of endometriosis-associated pain symptoms.

We searched CENTRAL, MEDLINE, Embase, and PsycINFO on 29 October 2024 without language restrictions.

We included randomised controlled trials (RCTs) comparing progestagens for symptomatic endometriosis against placebo, other medications, or different doses of progestagens. Studies assessing the levonorgestrel-releasing intrauterine device were ineligible, as a separate Cochrane review covers this intervention. Participants were of reproductive age with a laparoscopic diagnosis of endometriosis and associated pain symptoms. Primary outcomes included endometriosis-associated pain symptoms (overall pain, pelvic pain, and dysmenorrhoea). Secondary outcomes included quality of life, patient satisfaction, and adverse effects.

At least two review authors independently selected studies, extracted data, and assessed risk of bias. We reported dichotomous outcomes as risk ratios (RRs) and continuous outcomes as mean differences (MDs), each with its corresponding 95% confidence interval (CI). The meta-analysis employed a fixed-effect model, and we assessed statistical heterogeneity using the I² statistic. We used GRADE to assess evidence certainty.

We included 33 RCTs involving 5059 participants with symptomatic, laparoscopically diagnosed endometriosis. We judged 13 studies at overall low risk of bias. The following comparisons are limited by the small number of studies reporting each outcome. Pain outcomes, quality of life, and patient satisfaction were measured at six months unless otherwise specified. Oral progestagens versus placebo or no treatment (8 studies) Oral progestagens compared with placebo probably reduce overall pain measured on a visual analogue scale (VAS; MD -2.58, 95% CI -3.13 to -2.03; moderate certainty), and probably reduce dysmenorrhoea at three months (RR 0.21, 95% CI 0.07 to 0.70, moderate certainty), but may have little to no effect on pelvic pain at three months (RR 0.7, 95% CI 0.29 to 1.69; low certainty). Oral progestagens improve quality of life (SF-36 score; MD 4.11, 95% CI 2.41 to 5.82, high certainty). There is probably little to no difference between the interventions in study withdrawal due to adverse effects (RR 2.36, CI 0.74 to 7.52, moderate certainty) and cumulative side effects (RR 1.18, 95% CI 0.94 to 1.46, moderate certainty). Oral progestagens versus oral contraceptives (4 studies) Oral progestagens compared with oral contraceptives probably have little to no effect on pelvic pain measured on a VAS (MD 0.38, 95% CI -0.46 to 1.22, moderate certainty). There was very low-certainty evidence about their effect on dysmenorrhoea at 12 months (MD -0.57, 95% CI -1.29 to 0.15), quality of life (SF-36 general health perception; MD 5.2, 95% CI -1.3 to 11.70), and patient satisfaction (RR 1.18, 95% CI 0.88 to 1.57). Oral progestagens may lead to better quality of life (SF-36 pain score; MD 11.5, 95% CI 2.35 to 20.65, low certainty). There may be little to no difference between oral progestagens and oral contraceptives in study withdrawal due to adverse effects (RR 0.75, 95% CI 0.27 to 2.07, low certainty), and there is probably little to no difference in cumulative side effects (RR 1.13, 95% CI 0.8 to 1.60, moderate certainty). Oral progestagens versus gonadotropin-releasing hormone (GnRH) agonists (10 studies) Oral progestagens compared with GnRH agonists may have little to no effect on overall pain measured on a VAS (MD -0.01, 95% CI -0.30 to 0.28), risk of pelvic pain (RR 1.12, 95% CI 0.80 to 1.59), dysmenorrhoea (RR 1.45, 95% CI 0.71 to 3.00), SF-36 physical health score (MD 0.40, 95% CI -1.58 to 2.38), SF-36 mental health score (MD -0.50, 95% CI -3.75 to 2.75), patient satisfaction (RR 1.08, 95% CI 0.92 to 1.26), and study withdrawal due to adverse effects (RR 0.9, 95% CI 0.34 to 2.43). All these outcomes had low-certainty evidence. The risk of cumulative side effects was probably higher with oral progestagens (RR 1.44, 95% CI 1.11 to 1.86, moderate certainty). Depot progestagens versus GnRH agonists (2 studies) Depot progestagens compared with GnRH agonists reduce dysmenorrhoea risk slightly (RR 0.93, 95% CI 0.89 to 0.97, high certainty) but may have little to no effect on pelvic pain (RR 0.96, 95% CI 0.87 to 1.07, low certainty). The interventions may be similar in study withdrawal due to adverse effects (RR 1.41, 95% CI 0.24 to 8.32, low certainty), but the risk of cumulative side effects is probably lower with depot progestagens (RR 0.03, 95% CI 0.01 to 0.11, moderate certainty). Depot progestagens versus GnRH antagonist (1 study) Depot progestagens compared with GNRH agonists may have little to no effect on pelvic pain (RR 0.85, 95% CI 0.7 to 1.03, low certainty), dysmenorrhoea (RR 0.85, 95% CI 0.7 to 1.03, low certainty), and cumulative adverse effects (RR 1.04, 0.95 to 1.14, low certainty). Study withdrawal due to side effects is likely higher with depot progestagens (RR 2.02, 95% CI 1.04 to 3.94, moderate certainty). Depot progestagens versus the etonogestrel implant (1 study) There was very low-certainty evidence about the effect of depot progestagens versus the etonogestrel implant on overall pain measured on a VAS (MD 0.80, 95% CI - 0.42 to 2.02), patient satisfaction (RR 0.96, 95% CI 0.56 to 1.66), and study withdrawal due to adverse effects (RR 1.84, 95% CI 0.63 to 5.33).

In individuals with endometriosis, oral progestagens compared with placebo likely reduce overall pain and dysmenorrhoea and may reduce pelvic pain. Compared with other hormonal suppression strategies, the evidence is less certain due to the small number of studies for each comparison and outcome. Despite such limitations, this update provides a comprehensive overview and valuable insights on progestagen treatment for endometriosis, emphasising the nuanced balance between efficacy, adverse effects, and patient satisfaction.