TESTOSTERONE-METABOLISM AND CYCLOSPORINE-A TREATMENT IN RHEUMATOID-ARTHRITIS

A constant dose-dependent side-effect in cyclosporin A (CSA)-treated p atients is the appearance of hypertrichosis; this occurs in both sexes and suggests an androgenizing activity. To determine the influence of CSA on peripheral androgen metabolism, we evaluated in rheumatoid art hritis (RA) patients treated with low-dose CSA (3.5 mg/kg/day), during a period of 12 months, plasma levels of testosterone (Tes) and of 5 a lpha-androstane-3 alpha, 17 beta-diol glucuronide (Adiol-G), an import ant peripheral Tes metabolite. Clinical and laboratory parameters of R A were also monitored. Furthermore, the metabolism of physiological co ncentrations of Tes (1 x 10(-8) M) was evaluated in primary cultures o f RA synovial macrophages (M phi) in the presence of CSA concentration s close to the pharmacological immunosuppressive doses (100-500 ng/ml) . At the final time of observation (12 months), a significant increase in the mean plasma Adiol-G level was observed in patients of both sex es. The increase was evident after 1 month of treatment in male patien ts (P < 0.01) and after 3 months in female patients (P < 0.05). Almost all the patients experienced the side-effect of a low-degree hypertri chosis after a mean period of 1-2 months. No significant correlations with the laboratory parameters of the disease were observed. Results f rom in vitro experiments on Tes metabolism by cultured synovial M phi showed at 24 and 48 h, ill the presence of CSA, a significantly (P < 0 .0001) greater formation of dihydrotestosterone and increased amounts of other Tes metabolites, including androstenedione, androsterone and epiandrosterone, when compared to untreated controls. In conclusion, t he appearance of a dose-related hypertrichosis and the increase in pla sma androgen metabolites (i.e. Adiol-G) in CSA-treated patients, as we ll as the hormonal metabolic effects on cultured synovial M phi, shoul d be regarded as possible markers of the influence of CSA on periphera l androgen metabolism at the level of target cells.