Ghrelin, hypothalamus-pituitary-adrenal (HPA) axis and Cushing's syndrome.

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS. Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts pleiotropic actions that are explained by the widespread distribution of ghrelin and GHS-R expression. Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a. However, GHS-R subtypes are likely to exist; they also bind unacylated ghrelin that is, in fact, the most abundant circulating form and exerts some biological actions. Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction. The role of glucocorticoids on ghrelin synthesis and secretion is still unclear although morning ghrelin levels have been found reduced in some patients with Cushing's syndrome; this, however, would simply reflect its negative association to body mass. Ghrelin, like synthetic GHS, stimulates ACTH and cortisol secretion in normal subjects and this effect is generally sensitive to the negative glucocorticoid feedback. It is remarkable that, despite hypercortisolism, ghrelin as well as synthetic GHS display marked increase in their stimulatory effect on ACTH and cortisol secretion in patients with Cushing's disease. This is even more intriguing considering that the GH response to ghrelin and GHS is markedly reduced by glucocorticoid excess. It has been demonstrated that the ACTH-releasing effect of ghrelin and GHS is purely mediated at the central level in physiological conditions; its enhancement in the presence of ACTH-secreting tumours is, instead, likely to reflect direct action on GHS receptors present on the neoplastic tissues. In fact, peculiar ACTH hyperresponsiveness to ghrelin and GHS has been observed also in ectopic ACTH-secreting tumours.