Effects of chronic administration of PPAR-γ ligand rosiglitazone in Cushing's disease

Objective: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidine-diones may be effective as therapy for Cushing's disease (CD). Patients and methods: Rosiglitazonc (8 mg/day) was administered to 14 patients with active CD (13 women. one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. Results: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238 +/- 211 vs 154 +/- 40 nmol/24h, P < 0.03), but not for ACTH (15.9 +/- 3.7 vs 7.9 +/- 0.9 pmol/l) and F levels (531 +/- 73 vs 344 +/- 58 nmol/l). Two of six cases. followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. Conclusions: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD. at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.