In response to comments from yesterday’s podcast and newsletter, I have prepared a more detailed analysis of the issues supporting gender-specific MS services. I hope this clarifies things better.
Historically, the clinical and epidemiological descriptions of MS have stressed differences between women and men with MS. This is often referred to as sexual dimorphism. MS is a disease that disproportionately affects women, with current prevalence estimates indicating a female-to-male ratio of approximately 3:1. This ratio has widened over the past century, largely attributed to environmental shifts—such as smoking, obesity, and vitamin D deficiency—that appear to impact female susceptibility more than male susceptibility. However, these changes in risk factors only explain a small proportion of the increased incidence and prevalence of MS in women. Consequently, the “typical” MS patient is often conceptualised as a young woman of childbearing age. This ‘heuristic’ has fundamentally shaped the design of clinical services, support networks, and therapeutic monitoring protocols in clinical practice.
However, this statistical predominance masks clinical reality: while women are more susceptible to acquiring the disease, men often experience a more severe, rapid, and neurodegenerative course. The “male paradox” in MS—lower susceptibility but higher severity—challenges the uniform application of clinical guidelines. Standardised care pathways, such as those outlined by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the American Academy of Neurology (AAN), largely advocate a generalised approach to pharmacological management and symptom monitoring, with sex-based differentiation primarily in reproductive safety.
I think it is time to challenge the “one-size-fits-all” model. There is data on genetic, hormonal, and immunological differences that warrant this. Alongside clinical registry data and emerging clinical pilots suggest that the care of women and men with MS differs sufficiently to warrant distinct service based on gender. Biological sex is not merely a demographic variable but a biological determinant of disease pathology, necessitating a shift from gender-neutral to gender-responsive care. This could be part of precision medicine, i.e., tailoring care to the individual.
Biological determinants
To determine whether clinical care pathways should diverge, one must first establish whether the underlying biological substrates of the disease differ significantly between the sexes.
While the HLA complex remains the main genetic risk locus for both sexes, sex-specific genetic factors modulate this risk. The “Four Core Genotypes” (FCG) mouse model aims to disentangle the effects of sex chromosomes from those of sex hormones. Utilising this model indicates that the sex chromosome exerts an independent effect on neurodegeneration; i.e., the presence of an XY chromosomal complement is associated with greater clinical severity and increased neuropathology compared to an XX complement, even when hormonal environments are controlled. This indicates that males may possess an intrinsic genetic vulnerability to neurodegenerative processes.
Specific gene polymorphisms exhibit sex-dependent risk profiles. An example is the galanin gene (GAL), which codes for a neuropeptide widely expressed in the brain and spinal cord. Variants in the GAL gene have been associated with MS susceptibility and delayed onset specifically in men, whereas in women these variants appear to influence disease progression rather than susceptibility. This implies that the genetic “motor” driving disease onset in men may differ from that in women. Whether different therapeutic targets are needed in men remains to be determined.
Neuroendocrine factors: oestrogens vs. androgens
Sex hormones—oestrogens and progestogens in females, and androgens in males—are immunomodulators that influence the blood-brain barrier (BBB) permeability, immune cell differentiation, and remyelination efficiency. Women possess a more robust adaptive immune system than men, characterised by stronger humoral (antibody-mediated) and Th1 (pro-inflammatory) responses. This evolutionary trait, while beneficial for fighting infection, may lower the threshold for developing autoimmune disease. Oestrogens typically enhance immune reactivity, which may contribute to the higher incidence of relapsing-remitting MS (RRMS) in women.
However, the role of oestrogens is biphasic and dose-dependent. At physiological levels present during the menstrual cycle, oestrogens may facilitate inflammation. Conversely, at the high concentrations observed during pregnancy (particularly oestriol), they exert immunosuppressive and neuroprotective effects, which are believed to be responsible for inducing temporary remission. In comparison, the postpartum period represents a withdrawal of this protection, leading to a rebound in relapse rates. The cessation of ovarian function at menopause is associated with an acceleration of disability accumulation, suggesting that oestrogens provide a “neuroprotective buffer” that delays the onset of secondary progression.
Testosterone acts as a natural immunosuppressant, suppressing Th1 differentiation and promoting a shift toward the anti-inflammatory Th2 phenotype. This mechanism may protect many men from developing MS. However, once the disease is established, men face a more rapid decline, which may be due to a failure of androgen-mediated repair.
Men with MS frequently exhibit lower testosterone levels than age-matched healthy controls. This hypogonadal state is not merely a comorbidity but appears to be a driver of pathology. Testosterone is essential for maintaining muscle mass, cognitive function, and synaptic plasticity. In the context of MS, low testosterone correlates with increased cognitive fatigue, reduced grey matter volume, and poorer functional outcomes. The vulnerability of male oligodendrocytes to oxidative stress and excitotoxicity, combined with lower levels of neuroprotective androgens, creates an environment for rapid neurodegeneration.
Neuropathology
While women tend to exhibit a disease course dominated by peripheral inflammation (relapses and gadolinium-enhancing lesions) during their reproductive years, men exhibit a predominance of neurodegenerative markers earlier in the disease course. Male patients accumulate “smouldering” or chronic active lesions—characterised by iron-laden rims of activated microglia—at a higher rate than women.
MRI studies demonstrate that men exhibit more rapid whole-brain and grey-matter atrophy, particularly in deep grey-matter structures such as the thalamus and cortex. This correlates with the faster cognitive decline observed in male cohorts.
Animal models suggest that remyelination efficiency is superior in females, potentially due to oestrogen’s influence on oligodendrocyte precursor cells. Male oligodendrocytes appear more vulnerable to metabolic stress, leading to permanent axonal loss rather than repair.
Prognostic disparities
Men are typically diagnosed at a later age than women and are significantly more likely to present with primary progressive MS (PPMS). Registry data indicate that while relapsing-remitting MS (RRMS) is the most common form for both sexes, the proportion of men with PPMS is significantly higher (approximately 22% vs. 8% in women). Even among those with relapse-onset disease, men convert to secondary progressive MS (SPMS) at a younger age and after a shorter disease duration than women.4
This diagnostic latency in men is multifactorial. Biologically, the higher threshold for inflammatory symptoms (relapses) in men may mask the disease until structural damage reaches a critical threshold. The perception of MS as a “woman’s disease” may delay clinical suspicion in men presenting with non-specific motor or cognitive symptoms, leading to diagnostic delays. Natural history studies confirm that male sex is an independent predictor of poor prognosis. Interestingly, the sex difference in relapse rates disappears after age 50—roughly the age of menopause.
Comorbidities
The comorbidity profile also differs, with some comorbidities affecting survival and disability differently. Men with MS have higher rates of cardiovascular and metabolic comorbidities, including diabetes, hypertension, and ischemic heart disease. These conditions act synergistically with MS pathology. Hypertension and diabetes impair microvascular perfusion in the CNS, reducing the metabolic reserve of neurons already under attack by the immune system. This double hit accelerates brain atrophy and disability worsening in men. Conversely, women with MS report higher rates of other autoimmune conditions (e.g., thyroid disease, psoriasis) and anxiety/depression. While these impact quality of life, they do not typically accelerate neurodegeneration at the same rate as vascular comorbidities.
Mortality and suicide risk
Mortality risks also differ significantly. While MS reduces life expectancy for all patients, the standardised mortality ratio (SMR) and suicide risk show profound gender imbalance. Men with MS have a higher rate of completed suicide compared to women, despite women reporting higher rates of suicidal ideation and attempts. This is likely due to the suicide methods chosen by men and the psychological strain of physical dependency, which conflicts with traditional masculine roles. The loss of physical autonomy strikes at the core of the male provider/protector role, creating a distinct psychological crisis for men that general depression screenings may not capture.
Caregivers
The experience of MS is not merely biological; it is also sociological. Gender norms influence how patients perceive their illness, how they seek help, and how their caregivers are burdened. Men with MS often face a crisis of masculinity. Traditional gender norms prioritise strength, independence, and emotional stoicism. MS, by its nature, enforces dependency and physical frailty. Research indicates that men are less likely to seek help, report symptoms later, and are less apt to adhere to treatment regimens compared to women. Men often minimise symptoms during clinical consultations to appear “strong” or to reassure their clinicians. This behaviour leads to the under-recognition of invisible symptoms like fatigue, depression, and sexual dysfunction. Men are significantly less likely to attend traditional support groups, which are often dominated by women and focus on emotional sharing. Studies suggest that men prefer action-oriented interventions—such as mentoring, physical reconditioning, or educational workshops—that allow them to retain a sense of agency and masculinity.
The burden of MS caregiving also splits along gender lines, creating distinct support needs for the partners of people with MS. Men caring for female partners often adopt a “stoic” approach, focusing on instrumental tasks (finances, logistics) while suppressing emotional distress. They are less likely to seek social support and may mask their burden until burnout occurs. Their mental health is strongly tied to their perception of “burden,” yet they receive few targeted interventions.
Women caring for male partners report lower mental health scores and higher overall burdens. This is partially explained by the intensity of care: female caregivers provide nearly twice as many hours of care per week (approx. 79 hours vs. 48 hours for men) and continue caregiving for longer durations. The physical demands of caring for a male partner (who may be larger and heavier) add physical strain, necessitating different support equipment and respite care services.
The gender-blind care model
Despite the overwhelming evidence of biological and clinical differences, current clinical practice guidelines remain largely gender-neutral regarding disease-modifying therapy (DMT) selection, monitoring, and holistic support.
The ECTRIMS/EAN and AAN guidelines provide recommendations for DMT usage based on disease activity (relapses and MRI activity). However, they do not stratify treatment algorithms by sex, except in the specific context of pregnancy and breastfeeding. The “Optimal Clinical Care Pathway” developed by the National Neurosciences Advisory Group (NNAG) emphasises timely diagnosis (within 12 weeks) and multidisciplinary team (MDT) access but does not specify distinct monitoring intervals or therapeutic targets for men versus women.
This neutrality assumes that DMTs work equally well in both sexes. However, post-hoc analyses of clinical trials suggest nuances. For instance, some data indicate that the efficacy of Interferon-beta may be linked to different cytokine pathways in men (IFN-gamma) versus women (IL-6). Furthermore, adherence patterns differ significantly, with men often exhibiting lower adherence to injectable therapies and a higher discontinuation rate due to perceived lack of efficacy or side effects.
Gaps in integrated care models
The current integrated care model focuses on coordinating services across neurology, rehabilitation, and primary care. While effective for general management, it fails to address gender-specific needs, resulting in significant gaps. Routine MS care rarely screens for hypogonadism (low testosterone) or prioritises erectile dysfunction (ED) as a primary medical concern, often delegating it to quality of life issues rather than viewing it as a symptom of neurogenic failure.
While pregnancy is well-managed, the menopausal transition is often overlooked. Symptoms of menopause (hot flashes, brain fog, fatigue) overlap with MS, leading to diagnostic confusion and potential mismanagement of DMTs during this window. There is often a lack of clarity on the safety of hormone replacement therapy (HRT) in women with MS.
Men are significantly less adherent to DMTs, often due to forgetfulness or a lack of perceived benefit. Women, conversely, are more proactive but face challenges with polypharmacy and side effect management. Uniform education strategies fail to address these distinct behavioural differences.
Women-specific care pathways
The argument for separate services for women is more advanced, driven by the sheer volume of female patients, the management of reproductive issues and the menopause. However, evidence suggests this pathway needs to expand beyond obstetrics and gynaecology to encompass the full life course.
This is the only area where a distinct pathway currently exists. Pre-conception counselling, DMT washout periods, and postpartum monitoring are standard practice. However, data indicate that even this is inconsistent, with variations in washout protocols and breastfeeding support. A formalised “Women’s Health in MS” pathway would try to standardise these protocols, ensuring that women on high-efficacy therapies can time pregnancies safely without risking rebound relapses.
Emerging evidence identifies menopause as a critical window of vulnerabilityfor women with MS. The decline in oestrogen is associated with increased disability progression and subjective worsening of symptoms. Studies show that after menopause, women experience a measurable decline in walking speed and dexterity, alongside increases in neurofilament light chain (NfL) levels, a biomarker of neuroaxonal damage.
Pilot clinics integrating gynaecological and neurological care have shown promise. These clinics help differentiate between hypo-oestrogenic symptoms and MS relapse, optimising the use of hormone replacement therapy (HRT), which is not contraindicated and may offer neuroprotective benefits. For example, a dedicated pathway would include routine screening for perimenopausal symptoms starting at age 45 to distinguish “brain fog” from MS cognitive decline. Frequent monitoring of bone density using DEXA scans, given the compounded risk of osteoporosis from corticosteroids, mobility loss, and menopause. The latter would include expert guidance on the interaction between HRT and DMTs.
Women with MS have altered risks for cervical and breast cancers, partly due to immunosuppressive therapies and lifestyle factors. Integrated pathways could ensure that cancer screening is accessible, particularly for women with physical disabilities who find standard gynaecological tables inaccessible—a significant barrier to care often ignored in general practice.
Men-specific care pathways
The evidence to support a male-specific pathway is grounded in the need for aggressive management of neurodegeneration, specific symptom control (sexual/urological), and culturally sensitive psychosocial support.
A pioneering pilot study at the National Hospital for Neurology and Neurosurgery (UCLH) tested a dedicated “Men’s Health” MS clinic. This service integrated neurology, urology, and psychology to address the specific needs of men. The clinic successfully captured symptoms that were underreported in standard reviews. The most frequent concerns were erectile dysfunction (ED), fatigue, mood management, and reduced libido. Notably, 67% of these concerns had been raised in previous general reviews but remained unaddressed. Following assessment, 56% of participants required referrals to specialist teams (andrology, vocational rehab) that they had not previously accessed, and 38% received direct symptom-management education. Post-clinic surveys indicated high satisfaction (54% found it helpful), suggesting that men are more willing to engage with healthcare when the environment is tailored to their specific concerns rather than a general “wellness” model.
Sexual dysfunction (SD) affects up to 90% of men with MS, compared to 80% of women, but the mechanics and implications differ. In men, ED is a direct marker of spinal cord pathology and often co-occurs with bladder dysfunction. Meta-analyses show a 3-fold higher risk of ED in men with MS compared to controls. This dysfunction is strongly linked to reduced quality of life and depression. Despite its prevalence, only about 20% of patients are asked about SD by their providers.
A separate pathway would prioritise early urological intervention, utilising phosphodiesterase inhibitors or intracavernosal injections not just for sexual satisfaction, but to improve adherence and mental health. Furthermore, men have higher rates of obstructive bladder symptoms (due to prostate enlargement overlapping with neurogenic bladder), necessitating specific urological surveillance to prevent renal damage.
One of the strongest arguments for a biological separation of care is the potential for sex-specific pharmacological intervention. Clinical trials have investigated testosterone replacement therapy (TRT) as a neuroprotective strategy in men with MS. A pilot study at UCLA involving men with RRMS demonstrated that daily testosterone gel treatment for 12 months improved cognitive performance and slowed brain atrophy by 67% compared with the pre-treatment phase. Testosterone appears to promote remyelination and reduce grey matter atrophy, addressing the specific “neurodegenerative disadvantage” men face. While not yet a standard of care, phase 2 trials of TRT are ongoing. If validated, this would necessitate a care pathway for men that includes routine gonadal profiling and TRT administration.
Lifestyle factors
Men with MS often exhibit different lifestyle risk profiles that require different targeted interventions. Programs like the “Pit Stop” initiatives in Australia have shown that men engage better with health screening when it is framed as mechanical maintenance, analogous to a car service, rather than medical care. Integrating this philosophy into MS care could improve engagement. Men incur higher indirect costs due to “presenteeism” (working while sick) and early retirement. Vocational rehabilitation tailored to male-dominated industries (which may be more physically demanding) is a critical component of a male-specific pathway to preserve economic independence.
Economic implications
The implementation of stratified pathways has economic implications. The cost of MS is driven largely by disability progression and lost productivity, both of which manifest differently by sex. Women generally incur higher direct medical costs due to longer life expectancy and higher utilisation of ambulatory care and complementary medicine. In comparison, men incur higher indirect costs related to productivity loss. Because men progress to disability milestones faster, their withdrawal from the workforce occurs earlier relative to their healthy peers, which represents a large economic loss.
A stratified approach that aggressively treats male neurodegeneration (perhaps with earlier high-efficacy therapies or in the future TRT) could delay workforce exit, yielding high economic returns. Similarly, optimising menopausal management in women could prevent the late-stage disability acceleration that drives long-term care costs in women.
Implementing separate pathways does not necessarily require the construction of new facilities. It implies a restructuring of existing resources—allocating “Men’s Health” clinic days or assigning specialised nurse practitioners to gender-specific comorbidities. The success of the UCLH pilot demonstrates that such interventions can be delivered within existing hospital infrastructure, thereby improving patient satisfaction. It will be important to assess if these results lead to better outcomes for men with MS.
Final thoughts
I have tried to make the case for gender-specific interventions based on biological, cultural, social and economic factors. Do you think the case is strong enough to set up gender-specific care pathways for people with MS? I do think that by having one gender-neutral MS service, the issues that women have seem to dominate. I have set up a short online survey to assess how gender-specific issues are being managed in current MS management and to explore the need for gender-specific interventions or care pathways.
If you have time, could you please take 3-4 minutes to complete the following short survey? Thank you.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.
