Impact of estetrol and drospirenone combination therapy on alleviation of the pelvic pain of endometriosis: a randomized control trial

F S Rep. 2025 Dec 8;7(1):38-45. doi: 10.1016/j.xfre.2025.12.002. eCollection 2026 Feb.

ABSTRACT

OBJECTIVE: To study the impact of estetrol (E4), a novel native estrogen with selective tissue activity, on endometriosis-associated pelvic pain (EAPP) and global impressions of endometriosis pain.

DESIGN: Multicenter, randomized, open-label, active-controlled study; 88 eligible Japanese participants with endometriosis were randomized to either the E4 15 mg/drospirenone (DRSP) 3 mg group or the ethinyl estradiol (EE) 20 μg/DRSP 3 mg group. Participants received assigned treatment for 12 weeks.

SUBJECTS: Japanese patients aged ≥20 and <50 years diagnosed with endometriosis. Eligibility required an EAPP score ≥40 mm on the visual analogue scale (VAS).

INTERVENTION: Participants were randomized 1:1 to E4/DRSP or EE/DRSP groups.

MAIN OUTCOME MEASURES: Change in EAPP intensity from baseline to week 12, assessed using a 100 mm VAS, and patient's global impression of improvement (PGI-I) and clinician's global impression of improvement (CGI-I) scores after 12 weeks.

RESULTS: Changes in the most severe EAPP from baseline to week 12 were similar between the groups. The VAS score over time profiles showed lower scores with E4/DRSP than with EE/DRSP during the nonmenstrual period. Responders were defined as participants achieving ≥70 mm reduction from the most severe VAS score at baseline on ≥80% of nonmenstrual period days. On Fisher's exact test comparing responders and nonresponders, significant differences in patient's and clinician's global impression of improvement scores were seen. Furthermore, E4/DRSP had significantly higher responder rates than EE/DRSP.

CONCLUSION: The E4/DRSP combination therapy has the potential to improve the quality of life of patients with endometriosis, with greater amelioration of nonmenstrual EAPP than EE/DRSP.

TRIAL REGISTRATION: JPRN-jRCT2080225090.

PMID:41694262 | PMC:PMC12905615 | DOI:10.1016/j.xfre.2025.12.002