The impact of menopausal status on disease progression, retinal and brain atrophy in women with multiple sclerosis

Introduction: menopause is characterized by abrupt hormonal fluctuations that may influence the course of multiple sclerosis (MS). However, the clinical impact of these hormonal changes during the menopausal transition in women with MS (WwMS) is not yet well understood. This study explores how natural estrogen exposure and hormone changes related to menopause influence clinical outcomes and neurodegenerative markers in WwMS. Methods: Thirty-two perimenopausal WmMS were consecutively enrolled in a two-phase observational study. In the cross-sectional phase, cumulative lifetime estrogen exposure (CLEE) was calculated in 32 WwMS. Measures of physical and cognitive disability as well as metrics derived from Optical Coherence Tomography (OCT) and magnetic resonance imaging (MRI) were assessed. We then compared those between WwMS and long CLEE (defined as a length above the cohort median value) and those with short CLEE. In the longitudinal phase, 21 of the WwMS were reassessed at 12 and 18 months and stratified into menopause positive (M+, n=11) or menopause negative (M-, n=10), based on menopausal status at follow-up. Group comparisons and correlation analyses were conducted for key clinical, cognitive, radiological, and hormonal measures. Results: WmMS with longer CLEE had lower EDSS scores at baseline (p=0.03), thicker optic head (p=0.04) and macular retinal nerve fiber layer (p=0.03), better 9-hole peg test performance (p=0.018), and lower MS impact scale-29 scores (p=0.002). CLEE was inversely correlated with macular ganglion cell-inner plexiform layer loss at one year (p=0.04). At T1, M+ WmMS had higher follicle-stimulating hormone (FSH) levels (p=0.004) and larger brain volume loss compared to M– (p=0.029). Discussion: these findings suggest a potential association between menopause and accelerated brain atrophy in women with MS. In particular, FSH elevation may contribute to neurodegeneration, while prolonged estrogen exposure appears to exert neuroprotective effects. Conclusions: menopause may trigger worsening in MS progression. Larger clinical studies are warranted to expand upon our results and elucidate further on the potential protective role of estrogens in MS.