Impact of sex hormones on immune function and multiple sclerosis development

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting young people and leading to demyelination and neurodegeneration. The disease is clearly more common in women, in whom incidence has been rising. Gender differences include: earlier disease onset and more frequent relapses in women; and faster progression and worse outcomes in men. Hormone-related physiological conditions in women such as puberty, pregnancy, puerperium, and menopause also exert significant influence both on disease prevalence as well as on outcomes. Hormonal and/or genetic factors are therefore believed to be involved in regulating the course of disease. In this review, we discuss clinical evidence for the impact of sex hormones (estrogens, progesterone, prolactin, and testosterone) on MS and attempt to elucidate the hormonal and immunological mechanisms potentially underlying these changes. We also review current knowledge on the relationship between sex hormones and resident CNS cells and provide new insights in the context of MS. Understanding these molecular mechanisms may contribute to the development of new and safer treatments for both men and women.

Keywords: gender; multiple sclerosis; pregnancy; sex hormones.

Figure 1

Main differences in course of multiple sclerosis between women and men.

Figure 2

During pregnancy, influences from the placenta, the mother and the fetus condition placentation, regulating placental growth predisposing regulation of a Th2‐like anti‐inflammatory immune response. During this period, it is possible to observe a marked increase in the levels of estrogens, progesterone, glucocorticoids, and activated vitamin D coming from both the mother and the placenta. Taken together, these factors decrease maternal cellular immunity, evidenced by decreased number of multiple sclerosis exacerbations during pregnancy, particularly during the third trimester. B, B cells; DHEA, dehydroepiandrosterone; GM‐CSF, granulocyte–macrophage colony‐stimulating factor; IFN, interferon; LGL, large granular lymphocytes; M‐CSF, macrophage colony‐stimulating factor; MS, multiple sclerosis; MΦ, macrophages; NK, NK cells; T, T cells.

Figure 3

After childbirth, the protective influence of the placenta and the fetus is lost, and a pro‐inflammatory intrauterine environment prevails, determined mainly by maternal factors. A fall in the levels of estrogen, progesterone, glucocorticoids, and activated vitamin D is observed. Together these factors may condition an increase in the number of exacerbations observed during the postpartum period. PGs, Prostaglandins.

Figure 4

Effects of the female reproductive cycle on multiple sclerosis. Before puberty, multiple sclerosis (MS) prevalence is similar between boys and girls. After menarche, rates in girls are three times higher. During pregnancy, a decrease in relapse rates of approximately 70% is observed in the third trimester. After delivery, relapse rates increase to nearly three times higher than pre‐pregnancy levels during the first 3–6 months. Recent evidence suggests worsening of MS symptoms at menopause, and probably increased disease progression.