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)

Author(s)

Correa-Silva, Silvia R. ^[1] ; Nascif, Sergio O. ^[1] ; Molica, Patricia ^[1] ; Sa, Larissa B. P. C. ^[1] ; Vieira, Jose G. H. ^{[2, 1]} ; Lengyel, Ana-Maria J. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Div Endocrinol, Sao Paulo - Brazil

^[2] Fleury Inst, Sao Paulo - Brazil

• Document type: Journal article
• Source: CLINICAL ENDOCRINOLOGY; v. 72, n. 1, p. 70-75, JAN 2010.
• Web of Science Citations: 5

Abstract

P>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. Design/patients Eight untreated patients with CD (BMI: 28 center dot 5 +/- 0 center dot 8 kg/m2) were evaluated before and after 3 and 6 months of ketoconazole treatment and compared with 11 controls (BMI: 25 center dot 0 +/- 0 center dot 8). Results After ketoconazole use, mean urinary free cortisol values decreased significantly (before: 613 center dot 6 +/- 95 center dot 2 nmol/24 h; 3rd month: 170 center dot 0 +/- 27 center dot 9; 6th month: 107 center dot 9 +/- 30 center dot 1). The same was observed with basal serum cortisol (before: 612 center dot 5 +/- 69 center dot 0 nmol/l; 3rd month: 463 center dot 5 +/- 44 center dot 1; 6th month: 402 center dot 8 +/- 44 center dot 1) and ghrelin- and GHRP-6-stimulated peak cortisol levels (before: 1183 center dot 6 +/- 137 center dot 9 and 1045 center dot 7 +/- 132 center dot 4; 3rd month: 637 center dot 3 +/- 69 center dot 0 and 767 center dot 0 +/- 91 center dot 0; 6th month: 689 center dot 8 +/- 74 center dot 5 and 571 center dot 1 +/- 71 center dot 7 respectively). An increase in basal ACTH (before: 11 center dot 2 +/- 1 center dot 6 pmol/l; 6th month: 19 center dot 4 +/- 2 center dot 7) and in ghrelin-stimulated peak ACTH values occurred after 6 months (before: 59 center dot 8 +/- 15 center dot 4; 6th month: 112 center dot 0 +/- 11 center dot 2). GHRP-6-induced ACTH release also increased (before: 60 center dot 7 +/- 17 center dot 2; 6th month: 78 center dot 5 +/- 12 center dot 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. (AU)