Multiple Sclerosis Progression in Midlife Women: Disentangling Reproductive and Somatic Aging

For many women with multiple sclerosis (MS), midlife represents a critical clinical crossroads. The onset of progressive disease phenotypes — i.e., secondary and primary progressive MS — converges at a median age of approximately 45 years. This transition often overlaps with perimenopause and menopause, periods marked by profound hormonal shifts and accelerating biological aging. Despite this, the intersection of reproductive aging, somatic aging and MS neurodegeneration remains an understudied research area.

Two research projects co-directed by investigators at Cleveland Clinic, both supported by new two-year funding awards from the National MS Society, aim to illuminate this intersection. While they use different methodologies — one focusing on objective biological markers of ovarian and cellular aging, and the other on large-scale longitudinal patient-reported outcomes — the projects share a common objective: to provide a clearer framework for understanding how the biological transitions of midlife drive MS disability in women. By moving beyond chronological age, these projects seek to identify specific markers and therapeutic windows to inform personalized management for women with MS during this pivotal life stage.

Ovarian reserve and somatic aging markers

The first project — led by co-principal investigators Le Hua, MD, of Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada, and Jennifer Graves, MD, PhD, of the University of California, San Diego — tackles the limitations of using self-reported menopause as a clinical predictor. Previous studies relying on participants’ recollection of their last menstrual period have yielded inconsistent results regarding MS disability trajectories. Instead, this study proposes to use anti-Müllerian hormone (AMH) and leukocyte telomere length (LTL) as precise, objective measures of reproductive and somatic aging, respectively.

Rationale and preliminary evidence

AMH, secreted by ovarian follicles, is a well-validated biomarker of ovarian reserve that can distinguish “fast” versus “slow” reproductive agers. Preliminary work by Dr. Graves showed that lower AMH levels are associated with faster disability accumulation and reduced gray matter volume in women with MS, regardless of chronological age or MS duration.

LTL serves as a classic marker of somatic biological age, reflecting cumulative oxidative stress and immune system senescence. Shorter LTL has been linked to higher Expanded Disability Status Scale scores and greater brain atrophy in MS populations.

The investigators hypothesize that these two aging processes — reproductive and somatic — contribute independently to MS severity.

Methodology

This cross-sectional, observational study is leveraging the MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) cohort at Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. The researchers are analyzing data from 400 women with MS aged 20 to 60 years and 100 age-matched healthy controls. Using stored serum and DNA samples, the team is measuring AMH with ultrasensitive immunoassays and measuring LTL via quantitative PCR.

A critical component of the study is the integration of advanced fluid and imaging biomarkers. Beyond standard clinical metrics such as Patient-Determined Disease Steps and the Multiple Sclerosis Performance Test, the researchers are assessing the following:

• Serum neurofilament light chain (sNfL), a marker of axonal damage
• Glial fibrillary acidic protein (GFAP), a marker of astrocyte activation and noninflammatory neurodegeneration
• Volumetric MRI, including standardized 3T imaging to quantify thalamic, cortical and deep gray matter volumes

Key assessments

The project aims to achieve three specific goals:

• Replication, i.e., validating the association between AMH and MS disability in an independent cohort
• Assessment of MS disease modification, i.e., determining whether the relationship between ovarian aging and neurodegeneration (as measured by sNfL and GFAP) is more pronounced in women with MS than in healthy controls
• Assessment of independence of effects, i.e., using multivariable models to determine whether AMH and LTL independently drive MS disability or if one mediates the other

“This work promises to offer more than just prognostic clarity,” explains Dr. Hua. “By disentangling reproductive aging from general somatic aging, we suspect we may identify a sex-specific vulnerability in midlife women with MS that can perhaps be targeted therapeutically. If ovarian aging is confirmed to be an important driver of neurodegeneration, it could justify the use of more-aggressive disease-modifying therapies or hormonal interventions during perimenopause.”

Menopausal transitions and symptom burden

Complementing this biomarker-driven approach, a second project — led by Amber Salter, PhD, of University of Texas Southwestern Medical Center and Robert Fox, MD, of Cleveland Clinic’s Mellen Center — focuses on the longitudinal impact of menopause on women with MS. “Menopause is the most common health issue that women with MS encounter, yet many of its symptoms overlap those of MS, complicating clinical management,” Dr. Fox notes.

Rationale and objectives

This project addresses a lack of robust longitudinal data on how the menopause transition — and specifically the use of menopausal hormone therapy — affects MS symptoms, disability and quality of life (QoL). Although early trials of menopausal hormone therapy have suggested possible benefits for hot flashes and QoL in women with MS, evidence on long-term MS disease outcomes remains limited and inconsistent.

Methodology

The investigators are drawing on the NARCOMS (North American Research Committee on Multiple Sclerosis) Registry, a massive longitudinal database. They will employ a mixed cross-sectional and longitudinal design, linking a spring 2026 survey (capturing detailed menopause history via the National Health and Nutrition Examination Survey reproductive health questionnaire and bothersome symptoms via the MenoScores Questionnaire) to more than 20 years of prospectively collected data.

The researchers are using interrupted time series analysis — a quasi-experimental design allowing each participant to act as their own control — to compare disease trajectories in terms of scores assessing clinical metrics, QoL and symptoms — before, during and after the menopause transition.

The project has three primary aims:

• To characterize the prevalence of bothersome symptoms specific to menopause in women with MS and how symptoms correlate with factors such as body mass index, race and physical activity
• To longitudinally characterize MS symptom burden, disability and QoL changes throughout the menopause transition
• To evaluate the efficacy of menopausal hormone therapy on disability worsening, symptoms and QoL relative to nonuse of hormone therapy

“The findings are intended to directly support shared decision-making with patients,” Dr. Fox says. “By understanding the typical trajectory of MS during menopause, clinicians can better counsel patients on which symptoms to expect and whether menopausal hormone therapy or lifestyle modifications might mitigate the impact of some menopausal changes.”

Toward more personalized MS care in midlife women

Collectively, the two projects represent a shift toward age-inclusive and sex-specific care models in MS. “By better understanding the biological drivers of MS progression in women at midlife, we can move closer to a personalized medicine approach that respects the unique physiological transitions of the female lifespan,” Dr. Hua concludes. “Our hope is that this work will ultimately improve outcomes for an understudied and high-priority patient population.”