Women receiving daily oral estetrol reported significantly fewer hot flashes and night sweats than those receiving placebo without any notable effects on blood pressure, according to research presented at The Menopause Society 2025 Annual Meeting.

“In both studies, estetrol 20 mg consistently achieved the most pronounced effect,” Ekta Kapoor, MBBS, an associate professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minnesota, told attendees. “Improvements were observed as early as week 3 and sustained through week 12,” she said, showing that estetrol “represents a promising option for managing vasomotor symptoms in postmenopausal women.”

The data come from two randomized controlled phase 3 trials, E4COMFORT I and E4COMFORT II, which assessed 15 or 20 mg of daily oral estetrol over 12 weeks in 1219 postmenopausal women aged 40-65 years who had reported moderate-to-severe vasomotor symptoms at least seven times a day or at least 50 times a week. The first trial randomly assigned 213 women to receive 15 mg estetrol, 213 women to receive 20 mg estetrol, and 214 women to receive placebo; the second assigned 192 women to 15 mg, 193 women to 20 mg, and 194 women to placebo.

The researchers assessed vasomotor symptoms with the Weekly Weighted Score, which is the sum of double-weighted occurrence of moderate symptoms and triple-weighted occurrence of severe symptoms. The Weekly Weighted Score after baseline was assessed the same way with the addition of single-weighted occurrence of mild symptoms. The researchers used this endpoint to provide “a comprehensive assessment of vasomotor symptoms” that captures “treatment effects that may not be fully reflected by separate frequency and severity analyses,” Kapoor said.

In the first trial, women receiving 15 mg of estetrol had 21.7-point lower scores than placebo at 4 weeks (P < .03) and 40.7-point lower scores than placebo at 12 weeks (P < .0001). In the 20-mg group, women’s scores were an average 22.3 points lower than placebo at 3 weeks and 60.8 points lower at 12 weeks (P < .0001).

The second trial showed similar results. Women in the 15-mg group had 21.6-point lower scores than placebo at 4 weeks (P = .05) and 29.5-point lower scores at 12 weeks (P = .007). In the 20-mg group, women’s scores were 29 points lower than placebo at 4 weeks (P = .006) and 41.1 points lower at 12 weeks (P = .0001).

“The results of this are really encouraging in terms of providing another formulation of hormone therapy that can be effective for reducing vasomotor symptoms,” Mindy Goldman, MD, clinical professor emeritus and director of the Gynecology Center for Cancer Survivors and At-Risk Women at the University of California San Francisco, told Medscape Medical News.

Goldman, who was not involved in the trial noted several differences that make estetrol different from estradiol, the more commonly used form of estrogen in postmenopausal women.

“It doesn’t interfere with liver detoxification pathways so may have fewer drug-drug interactions, it has a long half-life so may be able to be dosed differently, and it has less of an effect on liver coagulation factors, which can mean low risk for clotting,” Goldman said. It seems to have complex effects on the breast, with some data suggesting it may induce breast apoptosis with the potential as a treatment for symptoms in breast cancer survivors, she said. “Certainly, there are more studies needed to fully understand all the mechanisms of action of estetrol, but having other treatment options available for managing menopausal symptoms is only helpful for midlife women.” 

The use of estetrol in the E4COMFORT II trial also revealed no significant signals in blood pressure changes among participants, including those with cardiovascular risk factors, according to data presented by Jonathan Douxfils, PhD. At baseline, 43.4% of the participants had A1c levels ≥ 5.7%, denoting prediabetes, across the three treatment groups. In addition, 20.1% of total participants had elevated total cholesterol levels, 20.9% had elevated low-density lipoprotein levels, 21.4% had reduced high-density lipoprotein, and 8.1% had elevated triglycerides. All groups were similarly normotensive at baseline as well, noted Douxfils, board director and scientific director at QUALIblood and director of the clinical pharmacology and toxicology research unit at the University of Namur, Namur, Belgium.

At 1 year, the average blood pressure was 120.7/76.6 mm Hg in the placebo group, 121.5/75.7 mm Hg in the 15-mg group, and 119.4/76 mm Hg in the 20-mg group (P > .05). Among participants with elevated blood glucose, the average blood pressure at 1 year was 120.6/76.7 mm Hg in the placebo group, 121.2/74.7 mm Hg in the 15-mg group, and 121.3/76.4 mm Hg in the 20-mg group (P > .05).

Janet Wei, MD, chair of women’s cardiovascular research, education, and innovation at Cedars Sinai Medical Center in Los Angeles, was not involved in the trial and told Medscape Medical News she was pleased to see that researchers had specifically investigated cardiovascular effects of estetrol given the burden of cardiovascular disease in midlife women.

“Cardiovascular safety of hormone therapy remains an important consideration in the management of menopausal vasomotor symptoms,” yet there have been limited randomized controlled trials looking at the cardiovascular safety of contemporary estrogen formulations, Wei said.

Prior observational studies have suggested an association between oral estrogen — particularly conjugated equine estrogen — and an increased risk for hypertension, stroke, and myocardial infarction compared with transdermal estradiol, Wei said. “Thus, we need rigorous investigations into the cardiovascular effects of various types of estrogen therapy, including formulation, route of administration, dose, duration, timing of use, and concomitant use of progestin/progesterone.”

The next step would be to find out whether estetrol’s lack of blood pressure effect over 1 year would also apply to women with stage I hypertension or obesity, given that all the participants had normal blood pressure at baseline in the study.

“At least 40% of postmenopausal women develop hypertension and at least 40% of perimenopausal women have obesity,” Wei said. “Therefore, it is important to include these demographics in large randomized clinical trials assessing cardiovascular and thromboembolic safety.”

The research was funded by Estetra SRL, a company of Gedeon Richter PLC. Douxfils reported being founder of QUALIblood and receiving consultancy fees from Gedeon Richter, Estetra, and Mithra Pharmaceuticals. Kapoor reported consulting for Astellas Pharmaceuticals, Estetra SRL, WellFound Inc, Fresenius Kabi USA Inc, and Exeltis. Wei and Goldman had no disclosures.

Tara Haelle is a science/health journalist based in Dallas.