Sex Hormones as Key Modulators of the Immune Response in Multiple Sclerosis: A Review

Abstract

Background: A variety of autoimmune diseases, including MS, amplify sex-based physiological differences in immunological responsiveness. Female MS patients experience pathophysiological changes during reproductive phases (pregnancy and menopause). Sex hormones can act on immune cells, potentially enabling them to modify MS risk, activity, and progression, and to play a role in treatment.

Methods: Scientific papers (published between 1998 and 2021) were selected through PubMed, Google Scholar, and Web of Science literature repositories. The search was limited to publications analyzing the hormonal profile of male and female MS patients during different life phases, in particular focusing on sex hormone treatment.

Results: Both men and women with MS have lower testosterone levels compared to healthy controls. The levels of estrogens and progesterone increase during pregnancy and then rapidly decrease after delivery, possibly mediating an immune-stabilizing process. The literature examined herein evidences the neuroprotective effect of testosterone and estrogens in MS, supporting further examinations of their potential therapeutic uses.

Conclusions: A correlation has been identified between sex hormones and MS clinical activity. The combination of disease-modifying therapies with estrogen or estrogen plus a progestin receptor modulator promoting myelin repair might represent an important strategy for MS treatment in the future.

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

Figure 1

(A) Main differences in the immune response between men and women. Blue arrows represent the trend in the men while violet arrows represent the trend in the women. Innate immune cell number and activity differ between males and females. Males present a higher number of natural killer cells compared to females, while phagocytic activity of neutrophils and macrophages is higher in females [4]. Additionally, antigen-presenting cells (APCs) are more efficient in females than males [4]. Sex hormones and an XY karyotype also influence adaptive immunity. Differences between the two sexes are present in B lymphocytes, CD4+, and CD8+ T lymphocytes. For example, females present with a higher CD4+ T lymphocytes count and a higher CD4/CD8 ratio compared to males of the same age, while males exhibit a higher CD8+ T lymphocytes count [4]. Women show higher numbers of activated CD4+ and CD8+ T lymphocytes and a higher number of proliferating T lymphocytes compared to men. Furthermore, women show higher levels of immunoglobulins and higher numbers of B lymphocytes compared to men [4]. (B) Some examples of immune modulation by sex hormones. Classic hormone-receptor transduction is a multi-step process where receptor dimerization, ligand binding, cofactor interaction, and DNA binding take place. Once the ligand is bound, the receptor-ligand complex migrates into the nucleus to specific DNA binding sites, regulating transcription. Androgen receptors (AR) are expressed in various organs, as well as the cells of the immune system, indicating their involvement in immunity. Estrogenic receptors (ERs) regulate pathways of both innate and adaptive immune systems, while concurrently regulating immune cell development and function, explaining, in part, the differences between the innate pathway responses in the two sexes. Changes of circulating estrogen levels can affect progenitors and mature cells of the innate and adaptive immune system, regulating the number and the specific biological functions of the cells (neutrophils chemiotaxis, infiltration, and cytokine production, macrophage chemiotaxis, phagocytic activity and cytokine production, natural killer (NK) cell cytotoxicity, dendritic cell differentiation, and cytokine expression).

Figure 2

Summary of the effects of the hormonal changes on the prevalence, relapse, and progression of the multiple sclerosis (MS) during the different life phases. Before puberty (age 10 years), MS prevalence is similar between male and females. After menarche, in line with the increase of the estrogens level, prevalence in girls is three times higher. During the fertile age, female predominance remains and relapses are shown in both sexes, but during pregnancy, a significant decrease in female relapse rates (about 70%) is observed, especially in the third trimester. After delivery during the puerperium, relapse rates increase to three times higher than pre-pregnancy levels. Worsening of symptoms and progression of MS have been shown in menopause.