Ghrelin Is No Longer Able to Stimulate Growth Hormone Secretion in Patients with Cushing’s Syndrome but Instead Induces Exaggerated Corticotropin and Cortisol Responses

Growth and growth hormone (GH) secretion are blunted or severely impeded in chronic hypercortisolism and in patients with Cushing’s syndrome. A mechanistic explanation for the effect however has yet to be provided. On the other hand, several properties of ghrelin, a new peptide recently identified as the endogenous ligand of the GH secretagogue receptor, are still largely unknown. The two aims of this study were to observe whether ghrelin-mediated GH secretion was altered, and to characterize the corticotropin (ACTH) and cortisol response to this new stimulus in patients with Cushing’s disease. Ten patients with active Cushing’s disease (6 harboring microadenomas and 4 with macroadenomas) and 10 sex- and age-matched controls were studied. Ghrelin was administered at a dose of 1 µg/kg i.v. and GH, ACTH and cortisol analyzed in duplicate. In control women, ghrelin induced GH secretion to levels of 74.4 ± 12.8 µg/l, while chronic hypercortisolism severely reduced the ghrelin-mediated GH release in all patients with Cushing’s disease (peak values 17.7 ± 5.2 µg/l). The slightly, but significantly higher adiposity of patients vs. controls may have contributed to the effect, since a significant negative correlation (r = 0.639) was found between the amplitude of the GH peak and body mass index. In control women, ghrelin increased ACTH and cortisol levels, with peaks at 57.4 ± 19.0 ng/l and 162 ± 16 µg/l, respectively. This secretion was enhanced in Cushing’s syndrome patients, with ACTH and cortisol values of 380.7 ± 109.8 ng/l and 338 ± 81 µg/l respectively, both significantly higher than in controls. In conclusion, ghrelin-induced GH secretion was severely blunted in patients with active Cushing’s syndrome, in addition to a remarkable hyper-response in ACTH and cortisol secretion. These findings could have implications for the understanding of the physiology and physiopathology of interactions between GH and ACTH regulation.