## 3 Role of Sex Hormones and Chromosomes  
Sex hormones have been extensively studied in the past decade. Gender bias is described only in people with MS with an onset during the reproductive age, and there is evidence that the age at menarche may be related to the age at the disease onset [17]. Indeed, early menarche has been associated with an increased risk of developing MS [17]. The possible role of hormones is further supported by the evidence for an effect of pregnancy on MS activity. Studies report a 70% decrease in relapse rates during the third trimester compared with pre-pregnancy levels and increased relapse rates 3-6 months after delivery to levels almost three times higher than pre-pregnancy ones [17]. The effects of pregnancy on disability progression in MS remain controversial. In a cohort of 2466 patients followed for 10 years, more pregnancies were independently associated with lower disability scores [18]. However, although some studies show that women with MS who have been pregnant have less progression of disability and propose that these effects might even be cumulative, other studies have shown no effect on permanent disability scores [19]. Because of the presence of hormone receptors on immune cells, sex hormones, such as estrogens, progesterone, androgens can influence different aspects of the immune system, potentially modulating the risk, activity, and progression of MS (Figure 1) [20]. Figure 1: Sex differences in the oral–gut–brain axis in people with MS. Sex hormones, such as estrogens (E1, E2, E3), progesterone (PG) in females, androgens in males, can influence different aspects of the immune system, potentially modulating the risk, activity, and progression of MS. In females (right side of the figure), the influence of sex hormones on the immune system can be considered proinflammatory (see balance). In contrast, in males (left side of the figure), the influence of sex hormones shifts the balance versus an immunomodulatory effect. Further, sex hormones have been demonstrated to influence gut microbiota composition. Dysbiotic gut bacteria can lead to systemic inflammation and contribute to neuroinflammation and demyelination through the oral–gut–brain axis, anatomically sustained by the vagus nerve (see arrow in the figure). At the same time, oral bacteria can contribute to neuroinflammation via the trigeminal nerve (see arrow). Created with BioRender.com. Estrogen receptors (\(\alpha\) and \(\beta\) coded by the genes ESR1 and ESR2) are expressed at different levels on peripheral blood mononucleated cells (PBMCs). B cells express the highest levels of ESR1 RNA while CD+T cells, CD+T cells, natural killer (NK) cells, and plasmacytoid dendritic cells (DCs) express intermediate levels. Monocytes have the lowest levels of ESR1 RNA. ESR2 RNA is expressed at the highest levels in B cells and plasmacytoid DCs and at low levels in other cell types [21]. To further complicate the picture, the expression of estrogen receptors on different immune cells varies based on the sex and life period. Monocytes in premenopausal women contain lower amounts of ESR1 RNA than monocytes isolated from males and postmenopausal women, suggesting that higher estradiol levels correlate with reduced ESR1 expression. In contrast, ESR1 and ESR2 RNA levels did not differ in male and female B and T lymphocytes or plasmacytoid DCs, or in lymphocytes of pre- and postmenopausal women [21]. The effect of estrogens on the immune system depends on the estrogen type and its levels. Endogenous estrogens produced in female mammals include estrone (E1), 17\(\beta\)-estradiol (E2), and estriol (E3, produced only in pregnancy). E2 is the predominant form in premenopausal women.