A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis
The female predominance in several autoimmune diseases suggests a role for sex steroid hormones in disease susceptibility. We therefore investigated to what extent sex hormones would influence immune responsiveness. We analyzed T helper type 1 (TH1) and type 2 cytokine patterns, chemokine receptor expression (n = 2 x 10), and Ig levels (n = 2 x 25) in transsexual men and women before and after 4 months of cross-sex hormone administration. Antithyroperoxidase levels were compared between 186 transsexual males (treated >5 yr with estrogens) and 186 male controls. In men, estrogens plus antiandrogens increased free cortisol levels in 24-h urine samples, decreased natural killer cell numbers, and slightly inhibited the mitogen-induced interferon-gamma/interleukin-4 ratio, but up-regulated the expression of TH1-associated chemokine receptors, CCR1, CXCR3, and CCR5. Conversely, in women, androgens slightly decreased free cortisol levels in 24-h urine samples and enhanced the mitogen-induced interferon-gamma/interleukin-4 ratio and tumor necrosis factor-alpha production. At the single cell level no TH 1/TH2 shifts were found. Remarkably, up-regulation of TH1 cytokines was accompanied by down-regulation of CCR1, CXCR3, and CCR5 expression. Neither CD4+ lymphocyte numbers nor IgG, IgM, and antithyroperoxidase levels, although higher in women then in men, were affected by cross-sex hormonal treatment. These results demonstrate that the capacity to develop a TH1 phenotype of peripheral blood lymphocytes is stimulated by androgens and is slightly inhibited by estrogens. These changes may be direct or indirect through the effects on other hormones.