title: Estrogen metabolism and autoimmunity.
abstract: Epidemiological and experimental immunological evidence suggest that estrogens enhance the humoral immune response, and at the same time, seem to play important roles in pathophysiology of autoimmune rheumatic diseases. Estrogens in human subjects are generally considered as enhancers of cell proliferation (anti-apoptotic), however, rather than through their serum levels (that may exert opposite dose-related effects), they play important roles through their peripheral metabolites especially in autoimmune rheumatic diseases. Several investigations strongly support an accelerated aromatase-mediated peripheral metabolic conversion of upstream androgen precursors to estrogen metabolites in peripheral tissues affected by immune/inflammatory reactions, both, in male and female patients. In RA synovial tissue, biological effects of these metabolites as a consequence of altered peripheral sex hormone synthesis (intracrine, e.g., at the level of macrophages and fibroblasts) mainly results in stimulation of cell proliferation and cytokine production (i.e. TNF). It was shown that RA synovial cells mainly produce the cell proproliferative 16alpha-hydroxyestrone which, in addition to 16alpha-hydroxy-17beta-estradiol, is the downstream estrogen metabolite that interferes with monocyte proliferation. Therefore, a preponderance of 16alpha-hydroxylated estrogens is an unfavorable sign, at least, in synovial inflammation and possibly related synovial tissue hyperplasia. Interestingly, urinary concentration and total urinary loss of 2-hydroxyestrogens was found 10 times higher in healthy subjects compared to RA or SLE patients irrespective of prior prednisolone treatment or sex. The intracrine synthesis of active estrogen metabolites at the level of cells involved in the immune response (e.g. macrophages and fibroblasts) represents a common pathway that characterizes a similar final immune reactivity in both male and female patients.
authors.affiliation: Research Laboratory and Academic Unit of Clinical Rheumatology, Dept. Internal Medicine, University of Genova Italy, Viale Benedetto XV, 6-16132 Genova, Italy. mcutolo@unige.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cutolo
authors.forename: Alberto
authors.initials: A
authors.lastname: Sulli
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004967:Estrogens / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D004967:Estrogens