Highlight
- Menopause does not significantly increase the risk of confirmed disability progression or conversion to secondary progressive MS in women with relapse-onset MS.
- The median age of menopause onset observed was 48.5 years in the studied cohort.
- Longitudinal analysis shows no inflection point in disability worsening associated with menopausal transition.
- Reproductive aging may complement but does not independently drive disability progression in MS.
Study Background and Disease Burden
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system, predominantly affecting young adults and disproportionately women. Disability accrual over time remains a major clinical concern, impacting quality of life and functional independence. As most women with MS live through midlife and beyond, many experience menopause during the disease course. Menopause, characterized by cessation of ovarian function and subsequent hormonal changes, could theoretically influence MS disease activity and progression, possibly through immunomodulatory and neuroprotective pathways linked to estrogen. However, the precise impact of menopause on MS disability progression remains poorly understood, representing an unmet need in gender-specific MS management and counseling.
Study Design
A retrospective cohort framework was applied utilizing prospectively collected data from the MSBase Registry, a global observational clinical research platform. Data extraction occurred on July 1, 2023, with analysis spanning from January 2023 through February 2025. The study population comprised 1468 women aged 18 years or older recruited from eight Australian neuroimmunology centers (one private practice and seven tertiary referral centers) between 2018 and 2021.
The primary analytic cohort included 987 women with relapse-onset MS who had at least three recorded Expanded Disability Status Scale (EDSS) measurements and reported menopausal status. A secondary cohort of 209 women had EDSS data preceding and following menopausal onset, enabling longitudinal trajectory analysis.
The main exposure variable was menopausal status, operationalized as a time-varying covariate in Cox proportional hazards regression models. These models assessed time to 6-month confirmed disability progression (CDP) and time to secondary progressive MS (SPMS). Key covariates adjusted for included age at MS onset, baseline disease duration, baseline EDSS score, recent relapses, and use of high-efficacy disease-modifying therapies (DMTs).
Key Findings
The primary analysis encompassed 583 premenopausal and 404 postmenopausal women. The median age at menopause was 48.5 years, consistent with general population norms. After adjusting for confounders, menopause was not associated with increased risk of disability progression (hazard ratio [HR] for CDP: 0.95; 95% confidence interval [CI], 0.70–1.29; P = .70) or transition to SPMS (HR: 1.00; 95% CI, 0.60–1.67; P = 1.00).
The secondary inflection point analysis likewise demonstrated no significant change in the slope of EDSS worsening before versus after menopause, indicating that the menopausal transition does not temporally accelerate disability accrual.
These findings suggest that while biological aging contributes to disability in MS, the hormonal changes intrinsic to menopause are not independently predictive of clinical progression milestones.
Expert Commentary
These results offer important clarification in an area previously dominated by anecdotal observations and small cohorts. The use of a large, well-characterized registry with longitudinal clinical data and rigorous adjustment for confounders strengthens the reliability of these conclusions.
It is plausible that reproductive aging interacts with somatic aging and disease biology in a complex manner not fully captured by menopausal status alone. Estrogen’s neuroprotective and immunomodulatory roles may be buffered by other factors such as disease-modifying treatment, genetic influences, and comorbidities.
Limitations include potential recall bias in self-reported menopausal status and the observational design that cannot establish causality. Additionally, hormonal replacement therapy (HRT) effects were not addressed, which could be an important modifier of outcomes.
Future research might further delineate menopause-related symptomatology in MS and investigate hormonal interventions as adjunct therapies to improve quality of life and potentially modulate disease mechanisms.
Conclusion
This comprehensive study does not support menopause as a leading factor in driving disability progression in women with relapse-onset MS. While reproductive aging may additively influence overall aging and health status, the transition through menopause per se should not be overemphasized in clinical prognostication or management plans.
Clinicians should continue to focus on established risk factors and evidence-based therapies to mitigate disability accrual, while addressing menopausal symptoms through appropriate symptomatic treatments and multidisciplinary care. Understanding sex-specific nuances in MS remains critical to optimizing personalized care for women across the lifespan.
References
Bridge F, Sanfilippo PG, Zhu C, Skibina O, Nguyen AL, Kalincik T, Buzzard K, Taylor BV, MacIntyre J, Hall LA, Slee M, Macdonell R, Maltby V, Lechner-Scott J, McCombe P, Butzkueven H, van der Walt A, Jokubaitis VG. Menopause Impact on Multiple Sclerosis Disability Progression. JAMA Neurol. 2025 Sep 29. doi: 10.1001/jamaneurol.2025.3538
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