MS Minute: Menopause and Multiple Sclerosis

Multiple sclerosis (MS) is a chronic neuroinflammatory demyelinating disorder that affects 3 times as many women as men.¹ Menopause is a female physiologic reproductive transition, characterized by the cessation of menses and substantial hormonal changes (ie, decreases in estrogen and progesterone production).² The median age at natural menopause is approximately 51 years. Because MS typically is diagnosed between 20 and 40 years of age, a majority of women with MS will experience menopause after disease onset. An estimated half of all women with MS are in the perimenopausal or postmenopausal stages.^3-5

Recently, the menopausal transition has come into research focus in MS, and standards for clinical care of women with MS in menopause have begun to be explored. It is well established that counseling about MS and MS disease-modifying therapy (DMT) management should represent a standard of care when treating individuals of childbearing potential; similarly, neurologists treating women with MS in the perimenopausal and postmenopausal stages should be aware of the common experiences of these individuals and how to optimize their neurologic function and quality of life.

Symptomatic Fluctuations and Changes

The stages of reproductive aging include the reproductive phase (during which adolescent girls and women experience menstrual cycles and can become pregnant), the menopausal transition (perimenopause, including the late premenopausal years leading up to the final menstrual period, as well as the early postmenopausal years after the final menstrual period), and the postmenopausal period (which lasts for many decades in humans). Menopause is defined retrospectively: after 1 year of not experiencing menses, women are said to be postmenopausal, and the final menstrual period is considered the date of menopause. Hormonal fluctuations are substantial during the menopause transition as the follicular supply declines; follicle-stimulating hormone levels increase, and ovarian estradiol production fluctuates before eventually decreasing.²

Symptoms of the menopausal transition in the general population vary widely and are typically undertreated. These symptoms include changes in cognition (eg, attention, working memory), mood (eg, depression, anxiety), fatigue, sleep quality, and cardinal vasomotor symptoms (ie, hot flashes). Many of these menopause symptoms can overlap with those of MS (eg, sleep, cognition, mental health), and therefore, individuals with MS whose MS disease activity and symptoms were well-controlled in the years before menopause may experience worsening—sometimes substantial—in their symptoms that warrants more focused care.⁶ One example of these symptomatic changes is depression. Depression is common in people with MS, reduces quality of life in this population, and is associated with structural brain changes found on MRI.⁷ In concert, hormonal changes during the menopause transition may increase the risk of depression⁸ as may changes in sleep quality, energy, or life events (eg, “empty nest syndrome”).

Menopause symptoms may also influence MS symptoms directly. For example, sleep disturbances from menopausal vasomotor fluctuations may exacerbate MS symptoms, reducing daytime energy and physical activity and function, and worsening cognition and mood. Because sleep disturbances affect people with MS disproportionately, a synergistic effect of menopause may occur that exacerbates existing symptoms and further reduces quality of life.^4,9,10

Not only can vasomotor symptoms cause sleep disturbances that then affect MS symptoms, but hot flashes could themselves trigger the Uthoff phenomenon, and consequent worsening of MS symptoms. The Uthoff phenomenon is a temporary reduction in neurologic function caused by an increase in body temperature in people with MS. Because the hormonal changes of menopause cause alterations in core body temperature and hot flashes, people with MS undergoing menopausal vasomotor symptoms may experience transient worsening of neurologic symptoms that are bothersome or worrisome.¹¹

In the postmenopausal period, genitourinary syndrome of menopause (GSM; encompassing vulvovaginal atrophy, atrophic vaginitis, or urogenital atrophy) symptoms can worsen, as can rates of obstructive sleep apnea and bone density loss. In this period, somatic or chronologic aging also gives rise to immunosenescence and to increases in sarcopenia or frailty, cardiometabolic comorbidities, and risk for cancer.¹²

Disease Progression at Midlife

The perimenopausal age (approximately 45 to 55 years) historically has been associated with a shift from relapsing-remitting MS to more progressive forms of MS¹³ (ie, clinical relapses, new or enhancing MRI lesions) and accelerated progression of disability. Sex differences are relevant in this timeframe. Whereas MS is more prevalent in women, men typically have more rapid progression at diagnosis. However, at midlife, these sex differences are attenuated, and the MS disease course becomes more similar between the sexes. In addition, men and women with MS onset after age 50 tend to have more similar rates of disability progression.

Given the observation that gonadal hormones might influence immune activity and neurodegeneration during other life phases, such as during pregnancy, it has been hypothesized that changes in gonadal function at menopause reduce the female “protective” effect and result in acceleration in neurodegeneration. However, it is challenging to identify a specific signal of reproductive aging in women that is distinct from chronologic aging or from other sex differences across the lifespan.¹⁴ To date, some but not all longitudinal cohort studies in MS have reported a reduction in inflammatory activity but an acceleration in disability progression after the final menstrual period that was independent of chronologic age, as evidenced by changes in clinical disability and potentially in functional status and paraclinical markers (eg, blood biomarkers, gray matter atrophy on brain MRI). Given the slowing inflammatory activity as well as immunosenescence, the relative risks and benefits of DMT may evolve with consideration of de-escalating and eventually potentially discontinuing DMT.¹⁵

Implications for Clinical Practice

Advances in DMT utilization and efficacy have resulted in individuals accumulating less physical disability at midlife. Perhaps as a result of this, the current concerns of this population include improving quality of life at midlife and promoting healthy aging. From our clinical experience and some initial research studies, women with MS in menopause have fewer concerns related to physical or ambulatory impairment, presenting more often for treatment of pain, fatigue, and cognitive impairment. For the treating neurologist, a proactive approach to counseling women with MS about their menopause transition and a careful comprehensive symptom history can help disentangle whether symptoms should be attributed to MS activity and progression, menopause, or a combination of both. Early screening for relevant comorbidities, such as depression, is recommended for this population.

A common question in clinical practice is the use of hormone replacement therapy (HRT). For the treatment of bothersome vasomotor symptoms, according to the North American Menopause Society, the benefit/risk ratio for HRT is favorable for people younger than 60 who are within 10 years of menopause onset and have no contraindications. Such treatments may include systemic HRT with estrogen (eg, estradiol) as well as a progestogen for endometrial protection. Because HRT can reduce the frequency and severity of vasomotor symptoms, it can reduce sleep disturbances and their sequelae, including fatigue and mood changes, which exacerbate existing MS symptoms.^16,17 For individuals in whom systemic HRT is contraindicated, other options to manage vasomotor symptoms include antidepressants and the neurokinin 3 receptor antagonist Veozah (fezolinetant; Astellas Pharma, Northbrook, IL), which was approved recently by the Food and Drug Administration. Local intravaginal estrogen therapy can be used to ameliorate GSM symptoms.

There is substantial interest in determining whether systemic HRT can promote neuroprotection. Observational studies in the MS population are notably confounded,¹⁷ and no interventional neuroprotection trials have been conducted in women with MS in menopause. Results from interventional trials in the general population have not clearly identified any neuroprotective effect of HRT. Therefore, whereas HRT can improve vasomotor symptoms and other symptoms that worsen at menopause and consequently improve quality of life and well-being, there is no evidence that their use can prevent neurodegeneration directly in those with MS.

Management of women with MS in menopause requires a proactive, holistic approach to promoting healthy aging and limiting the effects of neurodegeneration. Whereas the neurologist may have served as a general practitioner before the menopause transition, when women with MS reach midlife, their preventive care needs require access to a primary care physician, with the neurologist highlighting the need for active management. Muscle weakness, incoordination, vision impairment, need for orthotics, spasticity, and pain management, which could contribute to sarcopenia, fall risk, and decreased activity, need to be reassessed. Symptoms related to sleep, mood, pain, and fatigue require screening and treatment to improve quality of life. Neuropsychological testing can identify specific cognitive deficits (such as in attention or verbal memory) that may be amenable to rehabilitation. Proactive evaluation of even mild urinary symptoms could improve GSM and reduce the risk of urinary tract infections and urosepsis, especially for individuals taking DMT. Age-appropriate vaccines, cancer screening, and cardiometabolic screening are also recommended. For some individuals, home safety planning, advance care directives, and social needs assessment may be appropriate.

The Table provides a summary of concerns and symptoms of women with MS during perimenopause and postmenopause along with possible interventions.

Future Directions

The past decade has seen a greater appreciation for the importance of the menopausal transition in the lives of women with MS, but many research gaps remain.

From a clinical management perspective, improved clinician awareness and training may be needed, along with an understanding of how to implement new models of comprehensive care, with more frequent visits and increased interdisciplinary and rehabilitation care so as to better facilitate symptom screening and comprehensive rehabilitation needs.

Neuroimaging studies may help uncover whether and how accelerated neurodegeneration occurs in the postmenopausal period. For example, imaging of regions involved in sleep regulation (ie, hypothalamus, brainstem) can uncover mechanisms of sleep disturbances attributable to menopause, MS, or both. Increased studies utilizing new techniques such as magnetic resonance spectroscopy may reveal biomarkers to be used for therapeutic decision making.

The putative neuroprotective and anti-inflammatory effects of sex hormones remain largely unexplored in clinical perimenopausal populations. This is also of relevance to individuals taking exogenous hormones for gender-affirming, fertility, or oncologic purposes. Ongoing investigations, particularly following individuals longitudinally, are needed to clarify the roles of sex hormones on disease progression acceleration at midlife.

Conclusion

Because a majority of people with MS will undergo menopause, the potential ramifications of this transition in terms of symptom management and disease progression are important components of neurologic care in MS. This is particularly relevant as there is a shift in MS progression at midlife, and distinguishing MS worsening from menopause and overlapping symptoms (eg, mood, sleep, cognition, daytime functioning) is critical for alleviating concerns about progression, improving symptom control, and optimizing control of MS activity and progression. Elucidation of the mechanisms by which menopause could influence MS disease progression at midlife (including through the use of neuroimaging studies) as well as how best to improve overall patient functioning and quality of life, whether through hormonal agents or other strategies, represent important research questions. Ultimately, the perimenopausal transition represents an important window through which to optimize current functioning as well as encourage care patterns and behaviors likely to promote wellness during the long postmenopausal period.