Testosterone metabolism and cyclosporin A treatment in rheumatoid arthritis.
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.
Cutolo
M
M
Department of Internal Medicine, University of Genova, Italy.
Giusti
M
M
Villaggio
B
B
Barone
A
A
Accardo
S
S
Sulli
A
A
Granata
O
O
Carruba
G
G
Castagnetta
L
L
D000328:Adult; D000728:Androgens / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism*; D002478:Cells, Cultured / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013582:Synovial Fluid / Q000166:cytology; D013739:Testosterone / Q000378:metabolism*
D000728:Androgens; D013739:Testosterone; D016572:Cyclosporine