title: Adrenocorticotrophic hormone (ACTH) responsiveness to ghrelin increases after 6 months of ketoconazole use in patients with Cushing's disease: comparison with GH-releasing peptide-6 (GHRP-6).
abstract: BACKGROUND
  In Cushing's disease (CD), adrenocorticotrophic hormone (ACTH)/cortisol responses to growth hormone secretagogues (GHS), such as ghrelin and GHRP-6, are exaggerated. The effect of clinical treatment of hypercortisolism with ketoconazole on ACTH secretion in CD is controversial. There are no studies evaluating ACTH/cortisol responses to GHS after prolonged ketoconazole use in these patients.
  
  
  OBJECTIVE
  To compare ghrelin- and GHRP-6-induced ACTH/cortisol release before and after ketoconazole treatment in patients with CD.
  
  
  METHODS
  Eight untreated patients with CD (BMI: 28.5 +/- 0.8 kg/m(2)) were evaluated before and after 3 and 6 months of ketoconazole treatment and compared with 11 controls (BMI: 25.0 +/- 0.8).
  
  
  RESULTS
  After ketoconazole use, mean urinary free cortisol values decreased significantly (before: 613.6 +/- 95.2 nmol/24 h; 3rd month: 170.0 +/- 27.9; 6th month: 107.9 +/- 30.1). The same was observed with basal serum cortisol (before: 612.5 +/- 69.0 nmol/l; 3rd month: 463.5 +/- 44.1; 6th month: 402.8 +/- 44.1) and ghrelin- and GHRP-6-stimulated peak cortisol levels (before: 1183.6 +/- 137.9 and 1045.7 +/- 132.4; 3rd month: 637.3 +/- 69.0 and 767.0 +/- 91.0; 6th month: 689.8 +/- 74.5 and 571.1 +/- 71.7 respectively). An increase in basal ACTH (before: 11.2 +/- 1.6 pmol/l; 6th month: 19.4 +/- 2.7) and in ghrelin-stimulated peak ACTH values occurred after 6 months (before: 59.8 +/- 15.4; 6th month: 112.0 +/- 11.2). GHRP-6-induced ACTH release also increased (before: 60.7 +/- 17.2; 6th month: 78.5 +/- 12.1), although not significantly.
  
  
  CONCLUSIONS
  The rise in basal ACTH levels during ketoconazole treatment in CD could be because of the activation of normal corticotrophs, which were earlier suppressed by hypercortisolism. The enhanced ACTH responses to ghrelin after ketoconazole in CD could also be due to activation of the hypothalamic-pituitary-adrenal axis and/or to an increase in GHS-receptors expression in the corticotroph adenoma, consequent to reductions in circulating glucocorticoids.
authors.affiliation: Division of Endocrinology, Universidade Federal de São Paulo, São Paulo, Brazil. dra.silviaregina@terra.com.br
authors.forename: Silvia R
authors.initials: SR
authors.lastname: Correa-Silva
authors.forename: Sérgio O
authors.initials: SO
authors.lastname: Nascif
authors.forename: Patrícia
authors.initials: P
authors.lastname: Molica
authors.forename: Larissa B P C
authors.initials: LB
authors.lastname: Sá
authors.forename: José G H
authors.initials: JG
authors.lastname: Vieira
authors.forename: Ana-Maria J
authors.initials: AM
authors.lastname: Lengyel
mesh_terms: D000236:Adenoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000652:urine; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000328:Adult; D003480:Cushing Syndrome / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D005260:Female; D054439:Ghrelin / Q000009:adverse effects / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000378:metabolism / Q000652:urine; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology*; D047748:Pituitary ACTH Hypersecretion / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism* / Q000652:urine; D010911:Pituitary Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000652:urine; D013997:Time Factors; D055815:Young Adult
chemical_list: D054439:Ghrelin; D006727:Hormone Antagonists; D009842:Oligopeptides; C041048:growth hormone releasing hexapeptide; D000324:Adrenocorticotropic Hormone; D007654:Ketoconazole; D006854:Hydrocortisone