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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: 28.5 +/- 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.

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.To compare ghrelin- and GHRP-6-induced ACTH/cortisol release before and after ketoconazole treatment in patients with CD.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).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.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.