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a Research Laboratory and Division of Rheumatology, Department of Internal Medicine–University of Genova, 16132 Genova, Italy b Laboratory NeuroEndocrinoImmunology, Department of Internal Medicine I, University Hospital, Regensburg, Germany
Key Words: anti-TNF-  therapy • adalimumab • biologic drugs • TNF- blockers • estrogens • androgens • sex hormones • rheumatoid arthritis • synovial fluid • macrophages
Address for correspondence: Maurizio Cutolo, Research Laboratory and Division of Rheumatology, Department of Internal Medicine–University of Genova, Viale Benedetto XV6, 16132, Genova, Italy. Voice: +39-010-353-7994; fax: +39-010-353-8885. e-mail: mcutolo{at}unige.it
Whenever serum estrogen concentrations are normal in rheumatoid arthritis (RA) patients, lower androgen concentrations (i.e., testosterone, androstenedione, and dehydroepiandrosterone sulfate [DHEAS]) are detected in the serum as well as in the synovial fluid of male and female RA patients. The presence in the RA synovial fluid of a significant altered sex hormone balance resulting in lower immunosuppressive androgens and higher immuno-enhancing estrogens, might determine a favorable condition for the development of the immunomediated RA synovitis. The inflammatory cytokines (i.e., TNF-
), particularly increased in RA synovitis, are able to markedly stimulate the aromatase activity in peripheral tissues and, therefore, induce the peripheral metabolism from androgens to estrogens. The effects of TNF blockers (and generally of anticytokine agents) on peripheral sex hormone levels seem exerted in a faster way at the level of the RA synovial tissue (before any influence on serum levels) where they seem to block the conversion from androgens (anti-inflammatory) to estrogens (proinflammatory) induced by aromatase. Therefore, the beneficial effects of restoring synovial androgens might be clinically more evident in male RA patients (as recently observed in ANTARES study) since they suffer more for the lack of androgens (anti-inflammatory) on account of the action of TNF- on peripheral hormonal conversion. However, therapy (3 months) with anti-TNF did not change serum levels of typical sex hormones in patients with RA, although baseline values were largely different from controls. In patients with at least long-standing RA, this indicates that alterations of serum sex hormones and altered activity of respective converting enzymes are imprinted for a long-lasting period over at least 12 weeks.
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