A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life

Abstract

Objective: A phase 2 study showed that 15 mg estetrol (E4) alleviates vasomotor symptoms (VMS). Here, we present the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life.

Methods: In a double-blind, placebo-controlled study, postmenopausal participants (n = 257, 40-65 y) were randomized to receive E4 2.5, 5, 10, or 15 mg or placebo once daily for 12 weeks. Outcomes were the vaginal maturation index and maturation value, genitourinary syndrome of menopause score, and the Menopause Rating Scale to assess health-related quality of life. We focused on E4 15 mg, the dose studied in ongoing phase 3 trials, and tested its effect versus placebo at 12 weeks using analysis of covariance.

Results: Least square (LS) mean percentages of parabasal and intermediate cells decreased, whereas superficial cells increased across E4 doses; for E4 15 mg, the respective changes were -10.81% ( P = 0.0017), -20.96% ( P = 0.0037), and +34.17% ( P < 0.0001). E4 15 mg decreased LS mean intensity score for vaginal dryness and dyspareunia (-0.40, P = 0.03, and -0.47, P = 0.0006, respectively); symptom reporting decreased by 41% and 50%, respectively, and shifted to milder intensity categories. The overall Menopause Rating Scale score decreased with E4 15 mg (LS mean, -3.1; P = 0.069) and across doses was associated with a decreasing frequency and severity of VMS ( r = 0.34 and r = 0.31, P < 0.001).

Conclusions: E4 demonstrated estrogenic effects in the vagina and decreased signs of atrophy. E4 15 mg is a promising treatment option also for important menopausal symptoms other than VMS.

Trial registration: ClinicalTrials.gov NCT04209543 NCT02834312.

FIG. 1

Vaginal MV at baseline and at W12 (LOCF). One participant was randomized to E4 15 mg but temporarily took E4 2.5 mg and was excluded from the analysis. One participant was randomized to E4 2.5 mg and temporarily took E4 10 mg but was included in the 2.5 mg group for the analysis. *P < 0.001 versus placebo, analysis of covariance with fixed factors treatment and pooled site and covariate baseline value, including pairwise comparisons versus placebo (with adjustment for multiple comparisons according to Dunnett). E4, estetrol; LOCF, last observation carried forward; W12, week 12; MV, maturation value.

FIG. 2

Mean shift at W12 (minus baseline values) of the percentage of participants reporting no, mild, moderate, or severe vaginal dryness (A) or vaginal pain with sexual activity (B) in the E4 2.5, 5, 10, and 15 mg and placebo groups and for all participants (total) (LOCF). One participant was randomized to E4 15 mg but temporarily took E4 2.5 mg and was excluded from the analysis. One participant was randomized to E4 2.5 mg and temporarily took E4 10 mg, but was included in the 2.5 mg group for the analysis. E4, estetrol; LOCF, last observation carried forward.