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Testosterone metabolism and cyclosporin A treatment in rheumatoid arthritis.

Abstract
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.
AuthorsM Cutolo, M Giusti, B Villaggio, A Barone, S Accardo, A Sulli, O Granata, G Carruba, L Castagnetta
JournalBritish journal of rheumatology (Br J Rheumatol) Vol. 36 Issue 4 Pg. 433-9 (Apr 1997) ISSN: 0263-7103 [Print] England
PMID9159535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Androgens
  • Testosterone
  • Cyclosporine
Topics
  • Adult
  • Androgens (blood)
  • Arthritis, Rheumatoid (drug therapy, metabolism)
  • Cells, Cultured (metabolism)
  • Cyclosporine (therapeutic use)
  • Female
  • Follow-Up Studies
  • Humans
  • Macrophages (metabolism)
  • Male
  • Middle Aged
  • Synovial Fluid (cytology)
  • Testosterone (metabolism)

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