Decreased GH secretion and enhanced ACTH and cortisol release after ghrelin administration in Cushing’s disease: Comparison with GH-releasing peptide-6 (GHRP-6) and GHRH

Abstract

GH responsiveness to GH secretagogues (GHS) is blunted in Cushing's disease (CD), while ACTH/cortisol responses are enhanced, by mechanisms still unclear. Ghrelin, the endogenous ligand for GHS-receptors (GHS-R), increases GH, ACTH, cortisol and glucose levels in humans. This study evaluated the GH, ACTH, cortisol and glucose-releasing effects of ghrelin in CD in comparison with GHRP-6. GHRH-induced GH release was also studied. Ten patients with CD (BMI 26.9+/-1.0 kg/m(2)) and ten controls (BMI 24.4+/-1.1 kg/m(2)) received ghrelin (1 microg/kg), GHRP-6 (1 microg/kg) and GHRH (100 microg) separately. GH, ACTH, cortisol and glucose levels were measured. In CD ghrelin-induced GH (microg/L; mean +/- SE) release (peak: 7.2+/-3.0) was higher than seen with GHRP-6 (2.7+/-1.0) and GHRH (0.7+/-0.2), but lower than in controls (ghrelin: 58.3+/-12.1; GHRP-6: 22.9+/-4.8; GHRH: 11.3+/-3.7). In controls ACTH (pg/mL) release after ghrelin (79.2+/-26.8) was higher than after GHRP-6 (23.6+/-5.7). In CD these responses (ghrelin: 192+/-43; GHRP-6: 185+/-56) were similar, and enhanced compared to controls. The same was observed with cortisol. Glucose levels failed to increase after ghrelin in CD, differently than in controls. Our data suggests that hypothalamic and pituitary pathways of GH release activated by ghrelin, GHRP-6 and GHRH are deranged in chronic hypercortisolism. The increased ACTH/cortisol responses to ghrelin and GHRP-6 in CD could be mediated by overexpression of GHS-R in ACTH-secreting adenomas. Hypercortisolism apparently impairs the ability of ghrelin to increase glucose levels.

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

“…In our patients with CD GH responses to ghrelin, GHRP-6, and GHRH were blunted, confirming earlier reports by us and others (10,14,15). GH responsiveness to ghrelin was higher in CD and also in controls, which is probably due to the greater potency of this peptide compared to GHRP-6 and GHRH.…”

“…It is well known that glucocorticoid excess impairs GH secretion (10). It has been previously shown that GH responses to several stimuli, including ghrelin, GHRP-6, and GHRH, are severely blunted in patients with Cushing's disease (CD) (10)(11)(12)(13)(14)(15).…”

“…It has been previously shown that GH responses to several stimuli, including ghrelin, GHRP-6, and GHRH, are severely blunted in patients with Cushing's disease (CD) (10)(11)(12)(13)(14)(15). The mechanisms involved in the inhibitory effect of longterm endogenous glucocorticoid excess on GH secretion are as yet unclear.…”

“…Patients with CD have an increased ACTH and cortisol responsiveness to ghrelin and GHRP-6 compared to normal subjects (10). This could be due to direct effect of these peptides on GHS-R (growth hormone secretagogue receptor) in the corticotroph adenoma (18), while in normal subjects a hypothalamic site of action has been suggested (19).…”

Association between tumoral GH-releasing peptide receptor type 1a mRNA expression and in vivo response to GH-releasing peptide-6 in ACTH-dependent Cushing's syndrome patients

“…Series reported to date have shown ACTH and cortisol-positive responses in patients harboring Cushing's disease (CD) (1)(2)(3)(4)(5)(6)(7)(8), and attenuated or negative responses in patients harboring ectopic ACTH syndrome (EAS) and adrenal cortisol-producing adenomas (1). Such responses have been attributed to the expression of the GH-releasing peptide receptor type 1a (GHS-1a) in corticotrophic tumors (9,10), but there is no study correlating the in vivo response to the pattern of receptor expression.…”