A constant dose-dependent side-effect in
cyclosporin A (CSA)-treated patients 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 arthritis (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 5alpha-androstane-3alpha, 17beta-diol
glucuronide (Adiol-G), an important peripheral
Tes metabolite. Clinical and laboratory parameters of RA were also monitored. Furthermore, the metabolism of physiological concentrations of
Tes (1 x 10(-8) M) was evaluated in primary cultures of RA synovial macrophages (M phi) in the presence of CSA concentrations 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 sexes. The increase was evident after 1 month of treatment in male patients (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
hypertrichosis after a mean period of 1-2 months. No significant correlations with the laboratory parameters of the disease were observed. Results from in vitro experiments on
Tes metabolism by cultured synovial M phi showed at 24 and 48 h, in 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, the appearance of a dose-related
hypertrichosis and the increase in plasma
androgen metabolites (i.e. Adiol-G) in CSA-treated patients, as well as the hormonal metabolic effects on cultured synovial M phi, should be regarded as possible markers of the influence of CSA on peripheral
androgen metabolism at the level of target cells.