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Exploring the role of sex hormones and gender diversity in multiple sclerosis

Nature Reviews Neurology volume 21, pages 48–62 (2025)Cite this article

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Abstract

Sex and sex hormones are thought to influence multiple sclerosis (MS) through effects on inflammation, myelination and neurodegeneration, and exogenous hormones have been explored for their therapeutic potential. However, our understanding of how sex hormones influence MS disease processes and outcomes remains incomplete. Furthermore, our current knowledge is derived primarily from studies that focus exclusively on cisgender populations with exclusion of gender-diverse people. Gender-affirming hormone therapy comprising exogenous sex hormones or sex hormone blocking agents are commonly used by transgender and gender-diverse individuals, and it could influence MS risk and outcomes at various stages of disease. A better understanding of the impact and potential therapeutic effects of both endogenous and exogenous sex hormones in MS is needed to improve care and outcomes for cisgender individuals and, moreover, for gender-diverse populations wherein an evidence base does not exist. In this Perspective, we discuss the effects of endogenous and exogenous sex hormones in MS, including their potential therapeutic benefits, and examine both established sex-based dimorphisms and the potential for gender-diverse dimorphisms. We advocate for future research that includes gender-diverse people to enhance our knowledge of the interplay of sex and sex hormones in MS, leading to the development of more effective and inclusive treatment strategies and improvement of care for all individuals with MS.

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Fig. 1: Sex hormone receptors and the immune system.
Fig. 2: The neuroprotective role of sex hormone receptors in MS.
Fig. 3: Gender-affirming therapy.

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Authors and Affiliations

  1. Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia

    Cassie Nesbitt, Anneke Van Der Walt, Helmut Butzkueven & Vilija G. Jokubaitis

  2. Multiple Sclerosis and Neuroimmunology Clinic, Alfred Health, Melbourne, Victoria, Australia

    Cassie Nesbitt, Anneke Van Der Walt, Helmut Butzkueven & Vilija G. Jokubaitis

  3. Department of Neurology, Alfred Health, Melbourne, Victoria, Australia

    Cassie Nesbitt, Anneke Van Der Walt, Helmut Butzkueven & Vilija G. Jokubaitis

  4. Trans Health Research Group, Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia

    Ada S. Cheung

  5. Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia

    Ada S. Cheung

Authors
  1. Cassie Nesbitt
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  2. Anneke Van Der Walt
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  3. Helmut Butzkueven
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  4. Ada S. Cheung
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  5. Vilija G. Jokubaitis
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Contributions

C.N. researched data for the article. All authors contributed substantially to discussion of the content. C.N., A.S.C. and V.G.J. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Cassie Nesbitt or Vilija G. Jokubaitis.

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Competing interests

A.S.C. has received product from Besins Healthcare for investigator-initiated clinical studies using oestradiol and progesterone. No monetary support from Besins Healthcare has been received for any studies, and Besins Healthcare have had no input into study design, data analysis or writing of any manuscripts.

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Nature Reviews Neurology thanks Cole Harrington, Jorge Correale, Melinda Magyari and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Nesbitt, C., Van Der Walt, A., Butzkueven, H. et al. Exploring the role of sex hormones and gender diversity in multiple sclerosis. Nat Rev Neurol 21, 48–62 (2025). https://doi.org/10.1038/s41582-024-01042-x

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