Disentangling Menopause and Aging in Women with Multiple Sclerosis: New Research Targets Midlife Disease Progression
核心洞察
Two NIH-funded projects at Cleveland Clinic aim to clarify how reproductive aging and somatic aging independently drive MS disability in midlife women, using biomarkers like AMH and leukocyte telomere length.
Preliminary evidence links lower anti-Müllerian hormone (搜索) levels to faster disability accumulation and greater gray matter atrophy in women with MS, independent of chronological age.
A narrative review highlights that menopause-related symptom overlap with MS often leads to diagnostic delays and potential overtreatment, with 30% of women changing disease-modifying therapy around menopause.
For many women with multiple sclerosis (搜索) (MS), midlife represents a critical clinical crossroads where the onset of progressive disease phenotypes converges at a median age of approximately 45 years — a period that frequently overlaps with perimenopause and menopause. Despite the profound hormonal shifts and accelerating biological aging that characterize this life stage, the intersection of reproductive aging, somatic aging, and MS neurodegeneration remains an understudied research area. Now, two research projects co-directed by investigators at Cleveland Clinic, both supported by new two-year funding awards from the National MS Society (搜索), aim to illuminate this intersection and provide a clearer framework for understanding how the biological transitions of midlife drive MS disability in women.
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 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 (搜索) (AMH) and leukocyte telomere length (LTL) as precise, objective measures of reproductive and somatic aging, respectively.
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.
This cross-sectional, observational study leverages the MS PATHS (Multiple Sclerosis (搜索) 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 LTL via quantitative PCR. Beyond standard clinical metrics, the researchers are assessing serum neurofilament light chain (搜索) (sNfL) as a marker of axonal damage, glial fibrillary acidic protein (搜索) (GFAP) as a marker of astrocyte activation and noninflammatory neurodegeneration, and volumetric MRI including standardized 3T imaging to quantify thalamic, cortical, and deep gray matter volumes.
"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.
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. The investigators are drawing on the NARCOMS (North American Research Committee on Multiple Sclerosis (搜索)) Registry, employing a mixed cross-sectional and longitudinal design that links a spring 2026 survey capturing detailed menopause history and bothersome symptoms to more than 20 years of prospectively collected data. Using interrupted time series analysis, the researchers will compare disease trajectories before, during, and after the menopause transition.
"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."
The clinical ambiguity of midlife symptoms
A comprehensive narrative review published in Frontiers in Neurology underscores the clinical challenges at this intersection. Invisible symptoms of MS — including fatigue, cognitive complaints, sleep disturbance, mood symptoms, and urinary and sexual dysfunction — become more prominent with advancing age and overlap substantially with the symptomatic phenotype of the menopausal transition. Multiple studies report that many women perceive worsening of MS symptoms during peri- and postmenopause.
In a cohort of 559 peri- and postmenopausal women with MS, researchers found that those who reached menopause before MS diagnosis experienced a 3.3-year longer diagnostic delay than those who reached menopause after diagnosis, suggesting potential misattribution of emerging neurological symptoms to menopause. In the same study, 30% changed, initiated, or discontinued disease-modifying therapy in the year of self-reported menopause, consistent with the possibility that menopause-related symptom change is sometimes interpreted as MS disease activity or treatment intolerance rather than reproductive aging.
Vasomotor symptoms are particularly relevant in MS because transient heat exposure can worsen neurological function via temperature-dependent conduction block — Uhthoff's phenomenon. Hot flushes may therefore act as a frequent, recurring amplifier of fatigue, cognitive inefficiency, gait impairment, and sensory symptoms, even in the absence of new inflammatory activity.
Inflammatory activity and neurodegeneration
Inflammatory disease activity in MS generally declines with increasing age, a pattern biologically plausible in the context of immunosenescence. While some longitudinal studies have reported a reduction in annual relapse rates after menopause, these findings appear largely driven by age rather than menopausal status per se. A 2020 meta-analysis found no overall association between menopausal transition and relapse activity.
However, if menopause does not precipitate an increase in inflammatory relapses, it may instead influence neurodegenerative processes. Experimental evidence indicates that estrogen has direct neuroprotective effects in the central nervous system, including suppression of microglial activation, preservation of synaptic integrity, promotion of remyelination, and modulation of mitochondrial and oxidative pathways. Declining estrogen levels during menopause may therefore reduce CNS resilience to injury.
Lower AMH levels have been independently associated with greater disability accumulation and accelerated gray matter atrophy over 10 years in women with MS, even after adjustment for chronological age and disease duration. An MRI study demonstrated less brain atrophy in premenopausal women with MS compared to age-matched men, a difference that was no longer observed after menopause. Another study showed that postmenopausal women with MS had significantly more upper cervical spinal cord atrophy than premenopausal women, with levels comparable to men.
Menopausal hormone therapy: what is known
There is strong evidence that menopausal hormone therapy (MHT) reduces vasomotor symptoms and prevents bone loss. In the general population, potential neuroprotective effects of MHT are thought to depend on timing, with initiation closer to menopause associated with more favorable outcomes. However, data regarding the impact of MHT on neurodegeneration in MS remain limited, and available evidence does not support the use of MHT as a disease-modifying therapy in MS.
A Danish registry study of women with MS did not find an association between MHT use for less than five years and EDSS disability accrual, although the cohort was relatively small. A small study comparing estradiol treatment in menopausal women with MS and healthy controls reported similar improvements in hot flushes, sleep disturbance, and depressive symptoms in both groups. Another small trial of conjugated estrogens plus bazedoxifene in women with MS found greater treatment satisfaction and a non-significant reduction in hot flushes, with no major safety concerns, although the sample size and treatment duration were limited.
Concerns about safety — stemming from the Women's Health Initiative publication in 2002 — have contributed to slow recruitment in interventional trials of MHT in MS. In the absence of contraindications, women with MS should be considered for MHT according to general menopause guidelines. For women with significant disability and reduced mobility who may have elevated baseline thromboembolic risk, route of administration and individual risk factors warrant careful consideration, particularly given the increased venous thromboembolism risk associated with oral estrogen formulations.
Toward personalized MS care
Collectively, the two Cleveland Clinic 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."