Estetrol Phase 3 Trial Shows No Impact on Postmenopausal BP, Even in Women at High CV Risk

A phase 3 clinical trial of estetrol (E4), a naturally occurring estrogen under investigation for the treatment of moderate to severe vasomotor symptoms (VMS) in menopause, found no effect on blood pressure after 1 year of treatment, even among women with cardiovascular (CV) risk factors.

The findings, from the E4COMFORT II trial, were presented by Andrew Kaunitz, MD, of the University of Florida College of Medicine–Jacksonville, and colleagues at the 2025 annual meeting of The Menopause Society, October 21-25.

E4COMFORT II was a multicenter, 2-part phase 3 study conducted in the United States and Canada that evaluated the efficacy and safety of estetrol 15 mg and 20 mg in postmenopausal women aged 40 to 65 years. All participants had normal baseline blood pressure (equal to or less than 130/80 mm Hg), according to the study abstract.

In the double-blind, placebo-controlled portion of the study, 579 participants were randomly assigned to receive estetrol 15 mg (n=192), estetrol 20 mg (n=193), or placebo (n=194) once daily for 1 year. The open-label safety phase enrolled 430 participants, all of whom received estetrol 20 mg once daily for an additional year.

The investigators analyzed changes in blood pressure from baseline to one year, using analyses of covariance to compare estetrol and placebo groups.

No Change in BP With Estetrol

Blood pressure fluctuated only slightly during treatment, with minimal increases observed across all groups, including placebo-treated participants. After 1 year, no statistically significant differences in changes from baseline were found between estetrol-treated participants and those receiving placebo (P >.05). The absence of blood pressure effects held true regardless of whether women had normal or elevated baseline HbA1c levels.

Cardiometabolic Risk Factors Common at Baseline. Although only women with normal baseline blood pressure were enrolled, many participants presented with cardiometabolic risk factors:

• HbA1c ≥5.7% (pre-diabetes range): 43.4%
• Total cholesterol ≥6.2 mmol/L: 20.1%
• LDL cholesterol ≥4.1 mmol/L: 20.9%
• Triglycerides ≥2.3 mmol/L: 8.1%
• HDL cholesterol <1.3 mmol/L: 21.4%

These risk factors were evenly distributed among the treatment groups. Baseline mean blood pressure values were similar, and the presence of higher HbA1c levels did not appear to influence blood pressure outcomes.

A Contrast to Estetrol’s Effects in Younger Women

Estetrol 15 mg is already approved as the estrogenic component in a combined oral contraceptive (COC) with drospirenone 3 mg. That formulation has previously been shown to lower blood pressure in premenopausal women up to age 45 with high-normal baseline levels, by an average of −7.6 mm Hg systolic and −4.0 mm Hg diastolic.²

However, the current phase 3 findings in postmenopausal women demonstrate no such blood pressure effect, even at similar or higher estetrol doses and despite the inclusion of women with cardiometabolic risk factors.

The results suggest that estetrol, when used alone for menopausal symptom management, may not alter blood pressure regulation in postmenopausal women, a population in whom cardiovascular safety remains an important consideration in hormone therapy decisions, the authors concluded.

E4COMFORT II Study at a Glance

• Design: Phase 3, multicenter, double-blind, placebo-controlled (efficacy) and open-label (safety) trial
• Population: Postmenopausal women aged 40–65 years with normal baseline blood pressure
• Intervention: Estetrol 15 mg, estetrol 20 mg, or placebo daily for one year
• Findings: No significant change in systolic or diastolic blood pressure vs placebo (p>0.05)
• Conclusion: One-year estetrol treatment had no effect on blood pressure, including in women with prediabetes or lipid abnormalities.

References

1. Kaunitz A, Kapoor E, Taziaux M, Rezette I, Archer D, Doux. A phase 3 trial of estetrol in postmenopausal women with moderate to severe vasomotor symptoms shows no effect on blood pressure, including in women with cardiovascular risk factors. Poster presented at: The Menopause Society’s 2025 Annual Meeting; October 21-25, 2025; Orlando, FL. Accessed October 24, 2025.

2. Lee A, SYed YY. Estetrol/drospirenone: a review in oral contraception. Drugs. 2022;82(10):1117–1125. doi: 10.1007/s40265-022-01738-8