Sex Differences in Multiple Sclerosis Mechanisms

Multiple sclerosis (MS) exhibits a striking sexual dimorphism: women are three times more likely to develop the disease, yet men who do manifest MS often experience more rapid disability accumulation and greater neurodegeneration. Underlying mechanisms span immunological, hormonal and chromosomal factors. Inflammation predominates in women, with a higher frequency of acute relapses driven by adaptive immune cells, whereas men show an enhanced propensity for chronic lesion expansion, iron accumulation and accelerated grey matter atrophy. Oestrogens and androgens modulate immune cell phenotype and central nervous system resilience, while the complement of X and Y chromosomes influences gene expression in microglia and T lymphocytes. Differences in remyelination efficiency, oxidative stress susceptibility and neurotrophic factor production further contribute to divergent trajectories. Recognition of these sex-specific pathways is essential for the development of tailored neuroprotective and immunomodulatory strategies.

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Sex Differences in Multiple Sclerosis Mechanisms publication trend

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Technical terms

Demyelination: Loss of the myelin sheath insulating nerve fibres, leading to impaired nerve conduction.

Microglia: Resident immune cells of the central nervous system that mediate inflammatory and repair processes.

Th17 cells: A subset of CD4+ T lymphocytes characterised by interleukin-17 production and potent inflammatory capacity.

Remyelination: The process by which oligodendrocyte progenitors restore myelin sheaths around demyelinated axons.

Sex chromosome complement: The combination of X and Y chromosomes that influences gene expression beyond hormonal effects.

References

1. Male Sex Is Independently Associated with Faster Disability Accumulation in Relapse-Onset MS but Not in Primary Progressive MS. PLOS ONE (2015).
2. Sex differences in brain atrophy in multiple sclerosis. Biology of Sex Differences (2020).
3. Potential biological contributers to the sex difference in multiple sclerosis progression. Frontiers in Immunology (2023).
4. Progressive Injury in Chronic Multiple Sclerosis Lesions Is Gender-Specific: A DTI Study. PLOS ONE (2016).
5. Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity. Cell Reports (2021).
6. Hormonal Therapies in Multiple Sclerosis: a Review of Clinical Data. Current Neurology and Neuroscience Reports (2023).
7. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. Journal of Neuroinflammation (2008).