Partial restoration of GH responsiveness to ghrelin in Cushing's disease after 6 months of ketoconazole treatment: comparison with GHRP-6 and GHRH

Abstract

Objective: In Cushing's disease (CD), GH responsiveness to several stimuli, including ghrelin, GHRP-6, and GHRH, is blunted. Recovery of GH secretion after remission of hypercortisolism after transsphenoidal surgery, radiotherapy, or adrenalectomy is controversial. There are no studies evaluating the effect of primary clinical treatment with ketoconazole on GH secretion in CD. The aim of this study is to compare ghrelin-, GHRP-6-, and GHRH-induced GH release before and after ketoconazole in CD. Design: GH responses to ghrelin, GHRP-6, and GHRH of eight untreated patients with CD (mean age: 33.8G3.1 years; body mass index: 28.5G0.8 kg/m 2 ) were evaluated before and after 3 and 6 months of ketoconazole treatment, and compared with 11 controls (32.1G2.5; 25.0G0.8). Methods: Serum GH was measured by an immunofluorometric assay and urinary free cortisol (UFC) by liquid chromatography and tandem mass spectrometry. Results: After ketoconazole use, mean UFC decreased significantly (before: 222.4G35.0 mg/24 h; third month: 61.6G10.1; sixth month: 39.1G10.9). Ghrelin-induced GH secretion increased significantly after 6 months (peak before: 6.8G2.3 mg/l; sixth month: 16.0G3.6), but remained lower than that of controls (54.1G11.2). GH release after GHRP-6 increased, although not significantly, while GH responsiveness to GHRH was unchanged. Conclusions: Ghrelin-induced GH release increases significantly after 6 months of ketoconazole treatment in CD. This could suggest that a decrease in cortisol levels during this time period can partially restore glucocorticoid-induced GH suppression in CD. GH-releasing mechanisms stimulated by ghrelin/GHS could be more sensitive, as no changes in GHRH-induced GH release were observed.