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 depressi...