A proof-of-concept study on the relationship between lifetime Estrogen exposure, menopausal transition, and neurodegeneration in women with multiple sclerosis

Background: The relationship between menopause-related hormonal changes and disease outcomes in women with multiple sclerosis (WwMS) is still debated. We investigated whether natural estrogen exposure during reproductive years and its decrease at menopause correlate with disease outcomes in WwMS. Methods: Thirty-two perimenopausal WwMS participated in a two-phase study. In the first cross-sectional phase, we calculated the cumulative lifetime estrogen exposure (CLEE) and examined its associations with physical and cognitive disability, as well as optical coherence tomography and magnetic resonance imaging metrics, comparing individuals with long versus short CLEE. In the second longitudinal phase, 21 WwMS returned for follow-up at 6, 12 and 18 months. The cohort was divided into menopause-positive (M+) and menopause-negative (M-) groups, and group differences were analyzed. Results: WwMS with longer CLEE had lower baseline Expanded Disability Status Scale scores (p = 0.03), a thicker optic nerve head (p = 0.04), and a thicker macular retinal nerve fiber layer (p = 0.03). They also performed better on the 9-Hole Peg Test (p = 0.018) and scored lower on the MS Impact Scale-29 (p = 0.002). After 12 months, longer CLEE correlated inversely with loss of the macular ganglion cell-inner plexiform layer (r = -0.532, p = 0.04). Additionally, M+ WwMS experienced greater brain volume loss compared with M- WwMS (p = 0.029). Discussion: A longer duration of CLEE is associated with better outcomes in WwMS, while menopause appears to be linked to increased brain atrophy. Larger clinical studies are warranted to further explore these findings and clarify the relationships between CLEE, menopause and MS outcomes.