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Sex-linked Disorders01:43

Sex-linked Disorders

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Like autosomes, sex chromosomes contain a variety of genes necessary for normal body function. When a mutation in one of these genes results in biological deficits, the disorder is considered sex-linked.
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Multiple sclerosis lesions exhibit sex-specific steroid changes.

Sabina Luchetti1, Matthew R J Mason1, Philippe Liere2

  • 1Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Meibergdreef 47, Amsterdam 1105BA, the Netherlands.

Neurobiology of Disease
|July 24, 2025
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Summary

Hormonal differences in multiple sclerosis (MS) lesions show increased neuroactive steroid production in females and altered androgen levels, potentially explaining sex-based disease progression. Steroids also impacted glial cell responses in vitro.

Keywords:
AllopregnanoloneAstrocytesGC/MSMicrogliaMultiple sclerosisNeurosteroids

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Area of Science:

  • Neuroimmunology
  • Endocrinology
  • Multiple Sclerosis Pathogenesis

Background:

  • Sex differences in multiple sclerosis (MS) susceptibility and progression suggest hormonal involvement.
  • Previous findings indicated differential steroidogenic enzyme expression in MS lesions between sexes.

Purpose of the Study:

  • To measure steroid levels in active, inactive, and remyelinating MS lesions and control white matter.
  • To investigate the in vitro effects of sex hormones on glial cells from MS patients.

Main Methods:

  • Gas chromatography-mass spectrometry (GC/MS) was used to quantify steroid levels in MS lesions and control white matter.
  • Gene expression of steroid receptors and enzymes was analyzed.
  • In vitro studies assessed the impact of estradiol (E2), progesterone, and testosterone on primary microglia and astrocytes.

Main Results:

  • Female MS lesions showed increased allopregnanolone and reduced testosterone metabolites and dehydroepiandrosterone (DHEA).
  • Male MS lesions had minimal steroid changes, with a slight increase in 5α-DHDOC.
  • Remyelinating lesions showed no steroid level differences, but females had higher steroid receptor and AKR1C3 gene expression.
  • In vitro, sex hormones beneficially modulated cytokine and neuroprotective gene expression in glial cells under inflammatory conditions.

Conclusions:

  • Sex-specific alterations in steroid levels and metabolism in MS lesions may contribute to disease progression differences.
  • Hormonal influences on glial cell responses could play a role in MS pathogenesis and lesion resolution.
  • Further research into hormonal therapies for MS is warranted.