In the treatment of postmenopausal women with moderate-to-severe vasomotor symptoms (VMS), estetrol is well tolerated and helps reduce both the frequency and intensity of symptoms, as shown in the phase III E4COMFORT I study.
Compared with placebo, estetrol at 15 and 20 mg yielded significant reductions in the weekly frequency of moderate-to-severe VMS at week 4 (mean differences, –9.63 and −14.94, respectively; p=0.038 and p<0.001) and at week 12 (mean differences, −16.41 and −22.49, respectively; p<0.001 for both comparisons). [Maturitas 2026;209:108965]
Similarly, the severity of moderate-to-severe VMS episodes substantially decreased with estetrol 15 and 20 mg vs placebo at week 4 (mean differences, −0.27 and −0.29, respectively; p=0.011 and p=0.005) and at week 12 (mean differences, −0.54 and −0.66, respectively; p<0.0001 for both comparisons).
“The proportions of participants achieving 50-percent, 75-percent, and 100-percent reductions in the number of VMS reported per week increased over time with both estetrol doses, with the trend largely maintained through week 12,” the investigators said.
At week 12, 82.5 percent and 87 percent of participants treated with 15- and 20-mg estetrol, respectively, vs 60.5 percent of those who received placebo achieved a 50-percent reduction (p<0.001 for both); 63.3 percent and 74.5 percent vs 39.5 percent, respectively, achieved a 75-percent reduction (p<0.001 for both); and 32.5 percent and 38.5 percent vs 17.4 percent, respectively, achieved complete symptom resolution (p=0.0014 and p<0.001, respectively).
Well-tolerated
“Estetrol treatment was well tolerated, and discontinuation rates were low,” according to the investigators.
Drug-related treatment-emergent adverse events (TEAEs) occurred in 51.6 percent of participants in the estetrol 15-mg group, 57.3 percent in the estetrol 20-mg group, and 20.6 percent in the placebo group.
Drug-related TEAEs included endometrium-related events particularly in non-hysterectomized participants who used non-opposed estetrol. Among these participants, vaginal haemorrhage was the most common, occurring in 47.6 percent in the estetrol 15-mg group and 59.2 percent in the estetrol 20-mg group. The most common non-endometrial drug-related TEAEs were headache, breast pain, breast tenderness, nipple pain, nausea, and vaginal discharge.
TEAEs led to treatment discontinuation in 6.6 percent, 7.5 percent, and 2.3 percent of participants in the estetrol 15-mg, estetrol 20-mg, and placebo groups, respectively.
Unopposed oestrogen
“Our study was designed to assess the efficacy of unopposed estetrol treatment over 12 weeks, and thus, endometrium-related TEAEs were anticipated. The type of endometrium-related TEAEs reported in our study is characteristic of unopposed oestrogen treatment and led to a higher discontinuation rate in non-hysterectomized women,” the investigators explained.
“It should be noted that unopposed oestrogen treatment does not reflect routine clinical practice, where progestogens, either continuous or cyclical, are co-administered to protect the endometrium in non-hysterectomized women,” they added.
Promising option
Overall, the E4COMFORT I study highlights the role of estetrol as a “promising and modern menopausal hormone therapy option, particularly for the growing population of women seeking effective, well-tolerated, and personalized solutions for menopausal symptom management,” the investigators said.
They emphasized the clinical relevance of the findings, noting that VMS may negatively affect overall health, daily activities, sleep, quality of life, and work productivity of menopausal individuals.
E4COMFORT I included 640 hysterectomized and non-hysterectomized participants aged 40–65 years (mean age 53.9 years, 89.2 percent White, mean BMI of 27.5 kg/m2, 51.6 percent had undergone hysterectomy). The mean frequency of moderate-to-severe VMS episodes per week at baseline was between 75.5 and 83.6.
The participants were randomly assigned to receive estetrol 15 mg (n=213), estetrol 20 mg (n=213), or placebo (n=214) for 12 weeks. Non-hysterectomized women received progesterone 200 mg once daily for 14 days after the completion of the estetrol/placebo treatment.