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.

Dihydrotestosterone Inhibits Tumor Necrosis Factor .ALPHA. Induced Interleukin-1.ALPHA. mRNA Expression in Rheumatoid Fibroblast-Like Synovial Cells

“…In women, serum testosterone is 0.78Ϯ 0.27 normal women and 0.20Ϯ0.06 nmol/l in RA patients, respectively. 20) RT-PCR analysis indicated that TNFa induced IL-1a mRNA expression in these primary synovial cells, and DHT significantly inhibited the IL-1a mRNA inducing activity of TNFa (Fig. 1).…”

Cyclosporin A Production from Tolipocladium inflatum

“…• Causes metabolic alterations in liver, muscle and adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance [19] • Acute kidney injury • Hyperlipidemia (especially hypertriglyceridemia) • Hypertension • Gastrointestinal upset and headaches [20] • Hypertrichosis [21] • Increase testosterone level [22] • Gingival overgrowth [23] …”

Recent Advances in Neuro-Endocrine-Immune Interactions in the Pathophysiology of Rheumatoid Arthritis

“…This suppression of B cell function seems to be indirect effect via decreased IL-6 production by monocytes. Testosterone at physiological concentrations inhibits IL-1 production in synovial macrophages [16], and inhibits G-CSF and M-CSF productions by synovial cells [17], indicating the concept of immnosuppressive and antiinflammatory functions of androgens.…”