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Sex-related factors in multiple sclerosis susceptibility and progression

Abstract

The pathogenesis of multiple sclerosis (MS) involves complex interactions between genetic susceptibility and environmental triggers. Clinical observations suggest that the study of sex differences might provide important insight into mechanisms of pathogenesis and progression of the disease in patients. MS occurs more frequently in women than in men, indicating that sex-related factors have an effect on an individual's susceptibility to developing the condition. These factors include hormonal, genetic and environmental influences, as well as gene–environment interactions and epigenetic mechanisms. Interestingly, women do not have a poorer prognosis than men with MS despite a higher incidence of the disease and more-robust immune responses, which suggests a mechanism of resilience. Furthermore, the state of pregnancy has a substantial effect on disease activity, characterized by a reduction in relapse rates during the third trimester but an increased relapse rate in the postpartum period. However, pregnancy has little effect on long-term disability in women with MS. The unravelling of the mechanisms underlying these clinical observations in the laboratory and application of the results to the clinical setting is a unique and potentially fruitful strategy to develop novel therapeutic approaches for MS.

Key Points

  • Women are at increased risk of developing multiple sclerosis (MS) but have a reduced relapse rate during pregnancy, indicating that sex-related factors are important in disease pathogenesis and activity

  • While women have a higher incidence of MS and a more robust immune response, male patients can demonstrate a more progressive disease course

  • The effects of sex-related factors on disease relapse should be considered separately from the effects on disease progression

  • Sex hormones and sex chromosomes can independently contribute to disease incidence and progression

  • Sex-related factors might exert different, even opposing, effects on the peripheral immune system and the CNS

  • The increasing difference in MS incidence between men and women is likely to be attributable to the interaction of sex-specific factors with autosomal genes, environmental factors and/or behavioural factors

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Acknowledgements

R. R. Voskuhl's research work was supported by the NIH (grants RO1 NS051591, R21 NS071210 and K24 NS062117); the National Multiple Sclerosis Society (grants RG3915, RG4033, RG4363); the Skirball Foundation; the Conrad Hilton Foundation; and the Sherak Family Fund. S. M. Gold's research work is supported by the European Union (grant RG268381) and a grant from the Hamburg Research and Science Foundation.

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R. R. Voskuhl and S. M. Gold contributed equally to researching data for the article, discussion of content, writing the article, and review and/or editing of the manuscript before submission.

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Correspondence to Rhonda R. Voskuhl.

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The University of California Los Angeles holds a use patent for oestriol for the treatment of multiple sclerosis: R. R. Voskuhl is an inventor of this treatment. Dr Voskuhl also provides consulting advice on treatments for multiple sclerosis to Adeona Pharmaceuticals with compensation capped at a maximum of $10,000 per year. S. M. Gold declares no competing interests.

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Voskuhl, R., Gold, S. Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 8, 255–263 (2012). https://doi.org/10.1038/nrneurol.2012.43

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