E4 Did Not Significantly Impact Blood Pressure in Postmenopausal Women Receiving Treatment for VMS

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In postmenopausal women, treatment with 15 mg or 20 mg of estetrol (E4) had no impact on blood pressure, including in those with cardiovascular risks, found investigators of research presented at The Menopause Society 2025 Annual Meeting. These findings are from the phase 3 E4COMFORT II trial (NCT04090957), which evaluated the use of E4 for the treatment of moderate to severe vasomotor symptoms (VMS) in menopause.^1,2

E4COMFORT is a clinical study consisting of 2 parts, E4COMFORT I (NCT04209543)³ and E4COMFORT II. Previously, E4COMFORT—a randomized, double-blind, placebo-controlled trial—enrolled 640 postmenopausal women aged 40 to 65 years, both hysterectomized and nonhysterectomized, experiencing at least 7 or more moderate to severe VMS per day or at least 50 per week prior to randomization. Participants were randomly assigned to 1 of 3 arms to receive either E4 (15 mg: n = 213; 20 mg: n = 213) or placebo (n = 214) daily.^3,4

E4COMFORT I demonstrated that, compared with placebo, E4 treatment resulted in a significant complete VMS reduction in weekly frequency beginning week 3 for 15 mg (9.2% vs 4.0%; p < .05) and week 4 for 20 mg (15.4% vs 5.0%; p < .05, χ2 test). By the 12-week point, the 100% responder rates increased to 32.5% for 15 mg of E4 (p < .01) and 38.5% for 20 mg of E4 (p < .0001), compared with 17.4% for placebo. Additionally, 20 mg of E4 consistently showed higher 100% responder rates across all timepoints.⁴

Further, E4 is a natural estrogen with selective tissue action that is approved in 15-mg doses as the estrogenic component in a combined oral contraceptive (COC) with 3 mg of drospirenone. Previously, this COC has been shown to decrease blood pressure by –7.6/–4.0 mmHg (systolic/diastolic) in premenopausal women aged 45 years or younger with high-normal blood pressure (>140/90 mmHg) at initiation of COC. In E4COMFORT II, the investigators demonstrate the efficacy and safety 15 mg and 20 mg of E4 alone when treating VMS and its effects on blood pressure in postmenopausal women.^1,2

For this trial, only participants with a normal baseline blood pressure (≤130/80 mmHg) were enrolled. In the double-blind, placebo-controlled efficacy segment of the trial, participants were randomly assigned to receive either 15 mg (n = 192) or 20 mg (n = 193) of E4 or placebo (n = 194) once per day for a 1-year duration. In the open-label safety part of the trial, all 430 participants received 20 mg of E4 once per day for 1 year. The investigators assessed any cardiovascular risk factors, hemoglobin A_1c (HbA_1c), and lipid profile at baseline and determined changes from baseline blood pressure after 1 year of treatment with E4 compared with placebo using analyses of covariance.¹

At baseline, approximately 43.4% of participants had HbA_1c levels above the prediabetes threshold of 5.7%. Elevations were noted in total cholesterol (≥6.2 mmol/L) in 20.1%, low-density lipoprotein (LDL) cholesterol (≥4.1 mmol/L) in 20.9%, and triglycerides (≥2.3 mmol/L) in 8.1% of participants. High-density lipoprotein (HDL) cholesterol was reduced (<1.3 mml/L) in about 21.4% of participants. These baseline cardiovascular risk factors, according to the investigators, were equally distributed across all treatment groups.¹

Further, baseline mean blood pressure values were comparable among treatment groups, with no notable differences between participants with normal HbA_1c and participants with higher HbA_1c. During treatment, blood pressure fluctuated slightly and presented minimal increases after 1 year of treatment in the 2 E4 treatment groups and placebo. Changes in baseline blood pressure were similar for patients with normal baseline HbA_1c in addition to those with higher levels. Notably, there was no statistically significant difference in changes from baseline between E4 treatment groups and placebo (p > .05).¹

These findings demonstrate that 1 year of treatment with E4 has no significant impact on blood pressure in postmenopausal women, including those with cardiovascular risk factors. Postmenopausal women can feel confident that E4 will not significantly influence their cardiovascular health or blood pressure while receiving E4 treatment for VMS¹; however, patients should still discuss and receive counseling from their health care professionals and pharmacists with guidance regarding treatment or any concerns.

REFERENCES

1. Kaunitz A, Kapoor E, Taziaux M, et al. S-5 – 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. Presented at: The Menopause Society Annual Meeting; Orlando, Florida. October 21–25, 2025.

2. Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort). ClinicalTrials.gov identifier: NCT04090957. Updated July 3, 2023. Accessed October 22, 2025. https://clinicaltrials.gov/study/NCT04090957

3. Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I). ClinicalTrials.gov identifier: NCT04209543. Updated January 29, 2025. Accessed October 22, 2025. https://www.clinicaltrials.gov/study/NCT04209543

4. 1. Simoncini T, Bouchard C, Panay N, Taziaux M, Foidart J. Abstract ID: 25 - Estetrol (E4) provides complete relief from vasomotor symptoms in one-third of participants in the E4COMFORT I phase 3 clinical trial. Maturitas. 2025;199:108292. doi:10.1016/j.maturitas.2025.108292