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Review
. 2020 Jul 3:11:616.
doi: 10.3389/fneur.2020.00616. eCollection 2020.

SeXX Matters in Multiple Sclerosis

Francesca Gilli  1 , Krista D DiSano  1 , Andrew R Pachner  1
Affiliations
Review

SeXX Matters in Multiple Sclerosis

Francesca Gilli et al. Front Neurol. .

Abstract

Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). An interesting feature that this debilitating disease shares with many other inflammatory disorders is that susceptibility is higher in females than in males, with the risk of MS being three times higher in women compared to men. Nonetheless, while men have a decreased risk of developing MS, many studies suggest that males have a worse clinical outcome. MS exhibits an apparent sexual dimorphism in both the immune response and the pathophysiology of the CNS damage, ultimately affecting disease susceptibility and progression differently. Overall, women are predisposed to higher rates of inflammatory relapses than men, but men are more likely to manifest signs of disease progression and worse CNS damage. The observed sexual dimorphism in MS may be due to sex hormones and sex chromosomes, acting in parallel or combination. In this review, we outline current knowledge on the sexual dimorphism in MS and discuss the interplay of sex chromosomes, sex hormones, and the immune system in driving MS disease susceptibility and progression.

Keywords: multiple sclerosis; neurodegeneration; sex chromosome; sex dimorphism; sex hormones.

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Figures

Figure 1
Figure 1
Mechanisms of sexual dimorphism that underlie sex differences in immune responses, ultimately affecting MS disease susceptibility and progression. Research regarding sex hormones has extensively been analyzed due to the pre-existing knowledge that hormone receptors affect immune cells. The three primary sex hormones that have been shown to affect the immune system are estrogen, progesterone, and testosterone. All of these hormones have also been shown to significantly affect both MS disease susceptibility and clinical outcome. Sex chromosome complement exerts its effect in promoting sexual dimorphism in MS independent of sex hormones. X-dosage compensation and escape from X-inactivation influence differential gene expression of innate and adaptive immune molecules. Y chromosome contributions include Y-linked potentially dysregulated immunity loci. Studies evaluating sexual dimorphism in immune responses focus on the interdependence of these factors, as well as their independent contributions.
Figure 2
Figure 2
Sex hormone production in men and women in relation to MS risk by sex. The average percentage of estrogen (pink) and testosterone (blue) production from birth to age 80 years is indicated for female and male healthy individuals, respectively. Aging curves for estrogen and testosterone show a striking similarity to the MS incidence and clinical course. Hormone-related physiological conditions in women such as puberty and menopause exert significant influence both on disease prevalence and clinical outcomes. On the other hand, men are diagnosed with MS more frequently after puberty, just as their testosterone levels begin to drop.
Figure 3
Figure 3
During pregnancy, it is evolutionarily advantageous for inflammatory immune responses that might lead to fetal rejection to be reduced and anti-inflammatory responses that promote the transfer of maternal antibodies to the fetus to be increased. Hormones modulate the immunological shift that occurs during pregnancy. Estrogens and progesterone increase throughout pregnancy and affect transcriptional signaling of inflammatory immune responses at the maternal-fetal interface and systemically. Levels of estrogen, progesterone, and human chorionic gonadotropin (hCG) throughout pregnancy are shown. Such alterations in the maternal hormonal and immune system ameliorate MS during pregnancy, especially during the third trimester, when hormones reach their peak. MS can flare up within a few months after giving birth.
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