Progestagens Show Promise for Pain Relief in Endometriosis, With Nuanced Efficacy Across Comparators

Background

Endometriosis is a chronic, hormone-sensitive inflammatory disorder affecting between 5% and 10% of reproductive-aged women, as well as an unknown number of gender-diverse individuals. It is characterised by the presence of endometrial-like tissue outside the uterus, leading to symptoms such as pelvic pain, dysmenorrhoea, dyspareunia, and infertility. Pain, often severe and debilitating, remains the most common complaint and can significantly impair quality of life. Conventional hormonal treatments aim to control symptoms by suppressing ovarian function and reducing estrogen-driven proliferation of ectopic endometrial tissue.

Progestagens — synthetic progestins — have been investigated for their ability to induce endometrial atrophy and modulate inflammatory pathways. Despite widespread clinical use, uncertainty persists about their comparative efficacy and safety profiles.

Study Design

The Cochrane systematic review analysed randomised controlled trials (RCTs) comparing various forms of progestagens (oral, depot, implantable) with placebo, oral contraceptives, GnRH agonists/antagonists, and other progestagen formulations. The search strategy included CENTRAL, MEDLINE, Embase, and PsycINFO databases up to 29 October 2024, without language restrictions.

Eligible participants were reproductive-aged individuals with laparoscopically confirmed endometriosis and pain symptoms. Outcomes were collected at six months unless otherwise specified.

Primary endpoints included:
– Overall pain
– Pelvic pain
– Dysmenorrhoea

Secondary endpoints:
– Quality of life (QOL)
– Patient satisfaction
– Adverse effects and withdrawal rates

Statistical analyses used mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs), applying a fixed-effect model. Evidence certainty was graded using GRADE methodology.

Key Findings

Oral Progestagens vs Placebo

Eight RCTs demonstrated that oral progestagens probably reduce overall pain (VAS; MD -2.58, 95% CI -3.13 to -2.03; moderate certainty) and dysmenorrhoea at three months (RR 0.21, 95% CI 0.07 to 0.70; moderate certainty). Effects on pelvic pain were less clear (RR 0.70, 95% CI 0.29 to 1.69; low certainty). Quality of life improved significantly (SF-36 score; MD 4.11, 95% CI 2.41 to 5.82; high certainty). Adverse effects and withdrawal rates showed no meaningful differences compared with placebo.

Oral Progestagens vs Oral Contraceptives

Four trials suggested little to no difference in pelvic pain (VAS; MD 0.38, 95% CI -0.46 to 1.22; moderate certainty). The impact on dysmenorrhoea, general health perception, and satisfaction was highly uncertain (very low certainty). Small potential improvements were observed in pain-related QOL (SF-36 pain score; MD 11.5, 95% CI 2.35 to 20.65; low certainty). Side effect profiles appeared similar (RR 1.13, 95% CI 0.80 to 1.60; moderate certainty).

Oral Progestagens vs GnRH Agonists

Ten trials showed low-certainty evidence that oral progestagens may have little to no difference in pain, QOL, or satisfaction compared with GnRH agonists. Notably, cumulative adverse effects were probably higher with progestagens (RR 1.44, 95% CI 1.11 to 1.86; moderate certainty).

Depot Progestagens vs GnRH Agonists

Two studies reported a slight reduction in dysmenorrhoea risk with depot formulations (RR 0.93, 95% CI 0.89 to 0.97; high certainty), with no difference in pelvic pain. Side effect risk was probably lower for depot progestagens (RR 0.03, 95% CI 0.01 to 0.11; moderate certainty).

Depot Progestagens vs GnRH Antagonists

One trial indicated little to no difference in pain outcomes. Withdrawal rates due to side effects may be higher with depot progestagens (RR 2.02, 95% CI 1.04 to 3.94; moderate certainty).

Depot Progestagens vs Etonogestrel Implant

One trial provided very low-certainty evidence on comparative pain relief and side effects, preventing firm conclusions.

Expert Commentary

From a mechanistic standpoint, progestagens act by downregulating estrogen receptors, suppressing endometrial cell proliferation, and reducing inflammatory mediators such as prostaglandins. The results of this comprehensive meta-analysis suggest that oral progestagens are effective for general pain relief and QOL improvement in endometriosis when compared with placebo. However, their benefits compared to other hormonal interventions appear modest and less certain, highlighting the need for head-to-head trials with larger sample sizes.

Clinicians should note that side effect burdens may vary, with depot formulations showing advantages over GnRH agonists in tolerability, yet potentially higher withdrawal rates in some comparisons. Patient-specific factors, including symptom severity, comorbidities, fertility desires, and tolerability history, should guide choice of hormonal therapy.

Conclusion

Oral progestagens represent a viable first-line hormonal option for pain management in endometriosis, with evidence supporting improvement in overall pain, dysmenorrhoea, and QOL. However, comparative advantages over other hormonal therapies are often small or uncertain. Individualised treatment plans balancing efficacy, safety, and patient preference remain essential.

Funding and Trial Registration

ClinicalTrials.gov IDs: NCT04500743, NCT01559480, NCT02271958.

References

Chen I, Kives S, Zakhari A, Nguyen DB, Goldberg HR, Choudhry AJ, Le AL, Kowalczewski E, Schroll JB. Progestagens for pain symptoms associated with endometriosis. Cochrane Database Syst Rev. 2025 Oct 9;10(10):CD002122. doi: 10.1002/14651858.CD002122.pub3. PMID: 41065045; PMCID: PMC12509269.