Gender Differences in Multiple Sclerosis: Induction of Estrogen Signaling in Male and Progesterone Signaling in Female Lesions

Abstract

The basis of gender differences in the prevalence and clinical progression of multiple sclerosis (MS) is not understood. Here, we identify gender-specific responses in steroid synthesis and signaling in the brains of MS patients as possible contributors to these differences. We investigated gene expression changes in these pathways and of inflammatory cytokines in MS lesions and normal-appearing white matter (NAWM) of male and female patients (n = 21) and control NAWM (n = 14) using quantitative polymerase chain reaction (25 MS lesions, 21 MS NAWM, and 14 control NAWM) and immunohistochemistry (3–4 sections per group). In MS lesions in males, there was local upregulation of aromatase (an enzyme involved in estrogen biosynthesis), estrogen receptor-β (ERβ), and tumor necrosis factor (TNF) mRNA; whereas in females, there was local upregulation of 3β-hydroxysteroid-dehydrogenase, a progesterone synthetic enzyme, and of progesterone receptor. Astrocytes in the rim and center of MS lesions were found to be the primary source of steroidogenic enzyme and receptor expression. Aromatase and ERoi mRNA levels were positively correlated with that of TNF in primary cultures of human microglia and astrocytes; TNF caused increased ERα, suggesting that inflammatory signals stimulate estrogen signaling in this cell type. Together, these findings suggest that there are gender differences in the CNS of MS patients that may affect lesion pathogenesis, that is, in males, estrogen synthesis and signaling are induced; whereas in females, progestogen synthesis and signaling are induced. These differences may represent contributing factors to gender differences in the prevalence and course of MS.

Gene expression, Multiple sclerosis, Neurosteroids, Postmortem human brain, Sex differences