title: No effect of the PPAR-gamma agonist rosiglitazone on ACTH or cortisol secretion in Nelson's syndrome and Cushing's disease in vitro and in vivo.
abstract: OBJECTIVE
  Surgical tumor resection remains the primary treatment strategy in ACTH-secreting pituitary adenomas, i.e. Cushing's disease (CD) and Nelson's syndrome (NS). However, an effective long-term pharmacological regime is not available in patients with persistent ACTH-hypersecretion. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma) is abundantly expressed in most pituitary adenomas. First encouraging data reported that the PPAR-gamma ligand rosiglitazone antagonizes ACTH hypersecretion and exerts also antiproliferative effects in pituitary cell lines. Herein, we studied the potential therapeutical effects of rosiglitazone in patients with ACTH-secreting pituitary adenomas in vitro and in vivo.
  
  
  METHODS
  Seven patients with persistent ACTH-hypersecretion (3 with NS, 4 with persistent CD) were treated 5 months with rosiglitazone (4 - 16 mg/day). In vitro assays were performed in primary cell cultures obtained from eight additional patients with ACTH-secreting pituitary adenomas applying 80 microM rosiglitazone repeatedly over a time period of 14 days.
  
  
  RESULTS
  Our long-term clinical trial with the PPAR-gamma activator rosiglitazone showed no amelioration of clinical symptoms nor an inhibiting effect on ACTH-secretion in vivo. In vitro, rosiglitazone treatment led to a statistically significant decrease of ACTH levels in 2 out of 8 primary cell cultures after 14 days compared to untreated controls.
  
  
  CONCLUSIONS
  In contrast to the initially promising laboratory data gathered in pituitary cell line experiments and nude mice models, our experimental data obtained in primary human ACTH-expressing pituitary adenoma cell cultures as well as our clinical experience with a long-term rosiglitazone trial in approved antidiabetic doses support the recently reported disappointing reports on acute or short-term medical treatment of ACTH-hypersecretion with PPAR-gamma activators.
authors.affiliation: Department of Neurosurgery, University Hospital Erlangen, Germany. juergen.kreutzer@lrz.tum.de
authors.forename: J
authors.initials: J
authors.lastname: Kreutzer
authors.forename: I
authors.initials: I
authors.lastname: Jeske
authors.forename: B
authors.initials: B
authors.lastname: Hofmann
authors.forename: I
authors.initials: I
authors.lastname: Blumcke
authors.forename: R
authors.initials: R
authors.lastname: Fahlbusch
authors.forename: M
authors.initials: M
authors.lastname: Buchfelder
authors.forename: R
authors.initials: R
authors.lastname: Buslei
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000328:Adult; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009347:Nelson Syndrome / Q000097:blood* / Q000188:drug therapy; D047495:PPAR gamma / Q000819:agonists*; D047748:Pituitary ACTH Hypersecretion / Q000097:blood* / Q000188:drug therapy; D010911:Pituitary Neoplasms / Q000378:metabolism / Q000473:pathology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone