Effects of chronic administration of PPAR-gamma 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 thiazolidinediones may be effective as therapy for Cushing's disease (CD).


METHODS
Rosiglitazone (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/24 h, 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.
Endocrinology Unit, Department of Medical and Surgical Sciences, University of Milan, Istituto Policlinico San Donato, San Donato Milanese, Milan, Italy. bruno.ambrosi@unimi.it
Bruno
B
Ambrosi
Chiara
C
Dall'Asta
Salvatore
S
Cannavo
Rossella
R
Libe
Teresa
T
Vigo
Paolo
P
Epaminonda
Iacopo
I
Chiodini
Stefano
S
Ferrero
Francesco
F
Trimarchi
Maura
M
Arosio
Paolo
P
Beck-Peccoz
D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D003480:Cushing Syndrome / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D008875:Middle Aged; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects; D014157:Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome
D007004:Hypoglycemic Agents; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone