Estetrol (E4) for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women - Efficacy and Safety Results from the Phase 3 E4COMFORT I Multicenter, Placebo-Controlled Study

Authors

• Tommaso Simoncini, University of Pisa, Pisa, Italy
• Céline Bouchard, Clinique de Recherche en Santé des Femmes
• Marie Cloes, Estetra SRL, a wholly owned subsidiary of Gedeon Richter Plc.
• Mélanie Taziaux, Estetra SRL, a wholly owned subsidiary of Gedeon Richter Plc.
• Santiago Palacios, Salud y Medicina de la Mujer, Madrid, Spain
• Sebastião Freitas de Medeiros, Instituto Tropical de Medicina Reproductiva - Clinica INTRO, Mato Grosso, Brazil
• Valeriu Vrabii, Centrul Medical de Diagnostic si Tratament Ambulatoriu Neomed SRL, Brasov, Romania
• David F. Archer, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
• Nick Panay, Imperial College London

ORCID

0000-0001-7069-5117 (Archer)

Document Type

Article

Publication Date

2026

DOI

10.1016/j.maturitas.2026.108965

Publication Title

Maturitas

Volume

209

Pages

108965

Abstract

Objective

To evaluate the efficacy and safety of estetrol in reducing moderate to severe vasomotor symptoms in postmenopausal women.

Methods

Multicenter, randomized, parallel group (1:1:1), placebo-controlled, double-blind, phase 3 study in hysterectomized and non-hysterectomized participants aged 40-65 years. A total of 640 participants with seven or more moderate to severe hot flashes daily or 50 weekly received estetrol 15 mg, estetrol 20 mg, or placebo for 12 weeks. Co-primary endpoints were the change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12. Comparisons versus placebo were made using a mixed-effects model for repeated measures. The safety of estetrol alone was evaluated in relation to treatment-emergent adverse events.

Results

Estetrol 15 mg and 20 mg produced significant reductions in the weekly frequency of moderate to severe vasomotor symptoms at week 4 (least square means: -9.63, P = 0.038; and - 14.94, P < 0.001) and at week 12 (-16.41, P < 0.001; and - 22.49, P < 0.001), relative to placebo. Vasomotor symptom severity was significantly reduced with both estetrol doses at week 4 (-0.27, P = 0.011; and - 0.29, P = 0.005) and at week 12 (-0.54 and - 0.66 [both P < 0.0001]), compared with placebo. Drug-related treatment-emergent adverse events occurred in 51.6%, 57.3%, and 20.6% of participants in the estetrol 15 mg, 20 mg, and placebo groups, respectively, with discontinuations due to treatment-emergent adverse events in 6.6%, 7.5%, and 2.3%, respectively.

Conclusions

Estetrol reduced the frequency and severity of moderate to severe vasomotor symptoms and was well tolerated, with low discontinuation rates, supporting its use in symptomatic postmenopausal women.

Rights

© 2026 Estetra SRL.

This is an open access article under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Data Availability

Article states: "There are no linked research data sets for this paper. Data will be made available on request."

Original Publication Citation

Simoncini, T., Bouchard, C., Cloes, M., Taziaux, M., Palacios, S., de Medeiros, S. F., Vrabii, V., Archer, D. F., & Panay, N. (2026). Estetrol (E4) for the treatment of moderate to severe vasomotor symptoms in postmenopausal women: Efficacy and safety results from the phase 3 E4COMFORT I multicenter, placebo-controlled study. Maturitas, 209, Article 108965. https://doi.org/10.1016/j.maturitas.2026.108965 

Repository Citation

Simoncini, T., Bouchard, C., Cloes, M., Taziaux, M., Palacios, S., de Medeiros, S. F., Vrabii, V., Archer, D. F., & Panay, N. (2026). Estetrol (E4) for the treatment of moderate to severe vasomotor symptoms in postmenopausal women: Efficacy and safety results from the phase 3 E4COMFORT I multicenter, placebo-controlled study. Maturitas, 209, Article 108965. https://doi.org/10.1016/j.maturitas.2026.108965