Abstract
Growth hormone secretion is classically modulated by two hypothalamic hormones, growth hormone-releasing hormone and somatostatin. A third pathway was proposed in the last decade, which involves the growth hormone secretagogues. Ghrelin is a novel acylated peptide which is produced mainly by the stomach. It is also synthesized in the hypothalamus and is present in several other tissues. This endogenous growth hormone secretagogue was discovered by reverse pharmacology when a group of synthetic growth hormone-releasing compounds was initially produced, leading to the isolation of an orphan receptor and, finally, to its endogenous ligand. Ghrelin binds to an active receptor to increase growth hormone release and food intake. It is still not known how hypothalamic and circulating ghrelin is involved in the control of growth hormone release. Endogenous ghrelin might act to amplify the basic pattern of growth hormone secretion, optimizing somatotroph responsiveness to growth hormone-releasing hormone. It may activate multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, since ghrelin has a greater ability to release growth hormone in vivo, its main site of action is the hypothalamus. In the current review we summarize the available data on the: a) discovery of this peptide, b) mechanisms of action of growth hormone secretagogues and ghrelin and possible physiological role on growth hormone modulation, and c) regulation of growth hormone release in man after intravenous administration of these peptides.
Highlights
In 1982, before the identification of growth hormone-releasing hormone (GHRH), Bowers et al [1] discovered a new group of synthetic substances with growth hormone (GH)-releasing ability
In the last decade several studies were performed with these growth hormone secretagogues (GHS), especially with GHRP6, and the results suggested a possible role for these peptides in GH modulation [3]
The discovery of ghrelin is an excellent example of reverse pharmacology, in which a new hormone was isolated starting from the chemical synthesis of compounds such as GHS, which led to the discovery of the endogenous orphan receptor and to the isolation of its natural ligand
Summary
In 1982, before the identification of growth hormone-releasing hormone (GHRH), Bowers et al [1] discovered a new group of synthetic substances with growth hormone (GH)-releasing ability (for a review, see Ref. 2). In the last decade several studies were performed with these growth hormone secretagogues (GHS), especially with GHRP6, and the results suggested a possible role for these peptides in GH modulation [3]. In the lit/lit mouse, which has a GHRH receptor mutation, GHS do not increase GH release, but there is an enhancement of hypothalamic cfos expression, which is a marker of neuronal activity [21].
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