Does menopause affect MS progression? Evidence and ongoing debates

1. Topic commentary

1.1. Sex differences and menopausal effects on MS

Autoimmune diseases, including multiple sclerosis (MS), occur more frequently in females. Notably, males and females differ in the activity and severity of MS, with females exhibiting more inflammatory disease activity than males until midlife, after which the progression of disability becomes similar [1]. Thus, a change in the disease course appears to occur in females around menopausal age, prompting a debate about the potential detrimental effects of menopausal transition on disease progression. However, what evidence do we currently have regarding how menopause affects the trajectory of MS? Menopausal transition marks the end of a woman’s reproductive life, physiologically manifesting around the age of 50 years. It is associated with a series of biological, hormonal, and immunological changes [2] that potentially affect the pathogenesis, clinical manifestations, and progression of MS [3]. After menopause, a significantly decreased annualized relapse rate (ARR) has been reported [3]. In addition, worsening of the MS disease trajectory, measured using the clinician-rated Expanded Disability Status Scale (EDSS), was observed in some studies [4–6]. In particular, in a clinical cohort followed longitudinally for over 10 years, Bove et al. reported an increase in the rate of EDSS change by 0.13 units per year after menopause [6]. Similarly, Baroncini et al. reported a mean increase of 0.4 points 3.5 years post menopause, representing a significant change from the premenopausal period [4]. Conversely, other studies have not reported any negative effects of menopausal transition on the course of MS [5]. Among these, a recent study by Simonsen et al., involving 559 peri-/postmenopausal female and 386 male participants of similar age, found no significant difference in EDSS progression or ARR in the 5 years before and after menopause. Furthermore, EDSS progressed more slowly in females after menopause than in males, indicating that sex-related differences in the MS trajectory persist [7]. However, it has been widely discussed that the EDSS has several limitations in capturing disease progression in MS because of its limited sensitivity in the early stages, focus on motor disability, and low sensitivity to subclinical changes. To provide a more comprehensive assessment of females with MS across menopause, Silverman et al. recently conducted a longitudinal study using the Multiple Sclerosis Functional Composite (MSFC), which evaluates cognitive, fine motor, and walking tasks. The authors also measured serum neurofilament light chain (sNfL) levels to assess neuronal injury. This study showed that menopause reflects inflection points in MSFC worsening and an increase in serum neurofilament levels, indicating that it may represent a turning point in the accumulation of neuronal injury and functional decline in MS [8].

Consistent with these findings, postmenopausal women exhibit increased MRI markers of neurodegeneration, as demonstrated by studies linking menopause to greater brain and spinal cord atrophy [9–11]. From a biological perspective, a recent study has investigated the association of menopausal hormone levels (estradiol, follicle-stimulating hormone, and luteinizing hormone) with progression-related biomarkers of MS, including sNfL and glial fibrillary acidic protein (sGFAP). The study has shown that low estradiol levels are associated with more pronounced brain atrophy and higher sGFAP levels, and thus, advanced astrogliosis, which is likely related to the more rapid progression of MS after menopause. However, in this study, 1 year of menopausal hormone therapy (MHT) did not significantly alter sGFAP or sNfL levels, suggesting that hormonal shifts associated with menopause may represent only one of several biological factors contributing to disease progression [12].

1.2. Reproductive ageing vs. chronological ageing in MS

Reproductive and chronological aging may have synergistic and cumulative effects on disease progression. Reproductive aging, which is characterized by hormonal shifts, primarily affects the immune system through estrogen decline. This leads to increased levels of proinflammatory cytokines, reduced CD4⁺ T cells, altered T-cell responses, and an inverted CD4/CD8 ratio, which is a hallmark of aging associated with oxidative stress [2]. Additionally, a decline in estrogen and progesterone levels is associated with a reduction in their neuroprotective effects on the central nervous system (CNS). Preclinical studies have extensively shown that estrogen reduces oxidative stress and inflammation, whereas progesterone has complementary neuroprotective effects, including myelin repair and anti-inflammatory actions in the CNS [13]. In contrast, chronological aging induces immunosenescence, which is characterized by a reduction in immune function and an imbalance between the pro- and anti-inflammatory responses. This is accompanied by a chronic inflammatory state marked by the persistent production of proinflammatory mediators, referred to as ‘inflammageing,’ which increases the risk of age-related morbidity and mortality. Therefore, both immunosenescence and inflammaging processes may be at least partially responsible for the transition from a high-grade to a low-grade inflammatory state, along with a parallel accelerated neurodegenerative process observed in aging patients with MS [14]. As these mechanisms surpass the compensatory reserves of the CNS, the impact of aging becomes more pronounced. Moreover, as in healthy aging, iron is released, and its extracellular accumulation enhances oxidative stress, further accelerating CNS neurodegeneration and contributing to disability progression in patients with MS. This process, combined with a higher prevalence of comorbidities, contributes to accelerated brain atrophy in aging patients with MS, reflecting an additive relationship between natural aging and MS-associated pathological changes [14]. In this context, aging is a critical factor influencing MS outcomes and progression [15]. Furthermore, the gradual accumulation of physical and cognitive disabilities in patients with MS is driven by smoldering pathological processes. From the earliest stages of the disease, these processes tend to worsen over time within the biological continuum of MS. In this context, it is plausible that menopausal transition may accelerate a range of smoldering pathological mechanisms, potentially exacerbating disability progression across the MS spectrum. Recently, a large study of 1,210 female patients with MS, with a mean follow-up duration of 17 years, highlighted the influence of sex hormone-related factors on the overall risk and timing of progression, independent of relapse activity (PIRA). This study found that patients who were menopausal at the time of diagnosis experienced a shorter time to the first PIRA event, suggesting that menopause may act as an accelerator of MS progression within the complex interplay of aging [16].

Finally, it is worth noting that the postmenopausal period increases susceptibility to various comorbidities, including osteoporosis, depression, cancer, and cardiovascular disease, making this phase more vulnerable, exacerbating frailty, compromising brain health, and potentially worsening the MS trajectory [3]. Moreover, several menopausal symptoms, such as fatigue, brain fog, mood swings, and urinary and sexual dysfunction, may contribute to the perceived worsening of function during this transition, as demonstrated by Bove et al., who reported a deterioration in patient-reported severity scores across seven functional areas based on the MS Rating Scale. Thus, menopausal and MS symptoms may overlap, complicating their recognition and exerting an amplified detrimental effect on patients’ quality of life (QoL), with multifaceted implications for their overall well-being [17].

1.3. MHT and MS

Currently, the use of MHT is recommended for treating menopausal symptoms, with both dosage and duration tailored to the individual [18]. MHT typically consists of estrogen, such as estradiol, paired with a progestogen. Despite the known immunomodulatory effects of estrogen, the direct influence of MHT on MS outcomes remains unclear. Recently, a Danish registry study found no benefit of MHT in MS relapse or progression. However, the small number of females receiving MHT and the limited use of high-efficacy therapies in the examined cohort precluded definitive conclusions [19]. MHT has proven to be useful in alleviating many menopausal symptoms, with a reasonably good safety profile and positive effects on health-related QoL in symptomatic females with menopause [18]. It has also recently been reported that MHT use, particularly when initiated in females younger than 60 years and/or at or near the onset of menopause, is associated with a significant reduction in all-cause mortality and cardiovascular disease [18], as well as beneficial effects against brain damage. However, careful consideration is needed for patients with MS, as their MHT risk profile may differ from that of the general population owing to their history of disease-modifying treatments and related risks.

1.4. Conclusion and future directions

In conclusion, the challenge remains in interpreting the intricate interaction between menopause, aging, and immunosenescence, as well as their influence on smoldering MS and disease progression. The difficulty persists in distinguishing the specific contributions of each factor from their combined synergistic and cumulative effects on disease trajectory. Preclinical studies have extensively explored the roles of estrogen and progesterone in menopause, particularly their effects on brain function, cardiovascular health, and metabolism. However, clinical data remain limited, and large-scale studies are essential to determine the true impact of hormonal changes in a condition as complex as MS. Further research is urgently needed to explore both natural and iatrogenic or surgical menopause. Additionally, dedicated studies are required to define the impact of MHT on disease outcomes and brain health from both clinical and biological perspectives. Ultimately, the goal is to develop a more refined understanding of the factors that modulate MS progression during menopausal transition. This knowledge will pave the way for more effective interventions to improve QoL for female patients with MS in this critical life stage. By addressing these research gaps, we can move closer to personalized medical approaches that consider the unique biological and clinical profiles of each individual [20], thereby optimizing treatment and management strategies.

Article highlights

• Both reproductive and chronological aging may impact the MS trajectory.

• Menopause could accelerate neurodegeneration and disability in MS.

• Further research is needed to explore both natural and iatrogenic menopause.

• Understanding how menopause interacts with MS, considering aging, inflammation, and comorbidities, is essential.

• Dedicated studies are needed to assess the impact of MHT on MS and brain health.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Lorefice L and Ferraro E: drafting and critical revision of the manuscript