Growth Hormone-Releasing Peptides (GHRP) were discovered by C.Y. Bowers and his group in 1976. Experimenting with the metenkephalin molecule they identified through theoretic low-energy conformational calculations, computer modelling, and structural modification a series of small peptides that are able to stimulate GH secretion. At that time these compounds were not considered to be endogenous releasing peptides. In the early eighties the first highly potent GHRP-6 (hexapeptide) was developed. This compound increases GH secretion acting both at the hypothalamic and pituitary level. Subsequent studies into the nature and activity of GHRP-6 and its follow-up compounds has led to a number of findings which are relevant to clinical practice. In retrospect it is interesting to note that GHRPs were constructed well before the isolation and characterization of Growth Hormone Releasing Hormone (GHRH) in 1982. For many years it was thought that the pulsatile secretion of GH by the pituitary somatotrophs was controlled by only two antagonistic hypothalamic peptides: somatostatin which inhibits GH release and GHRH which stimulates GH release. Both peptides had been purified and well characterized, while their specific receptors have been cloned.
Both GHRH and somatostatin receptors belong to the family of seven transmembrane receptors coupled to a heterotrimeric GTP-binding protein. The somatostatin receptor is coupled to a Gi protein and its activation inhibits adenylate cyclase. On the other hand, the GHRH receptor is coupled to a Gs protein and its activation stimulates adenylate cyclase activity leading to increased intracellular cycUc AMP levels. The discovery of the GHRPs has led to the hypothesis of a third endocrine pathway controlling GH secretion, and indeed human GHRP receptors eventually have been cloned in the anterior pituitary and hypothalamus. GHRP pituitary action is mediated via a phosphoinositol-protein kinase-C intracellular pathway, while its hypothalamic action is not yet firmly established.
The latter might involve the release of endogenous GHRH as well as inhibition of somatostatin release and/or the action of an as yet unknown hypothalamic factor. In addition the episodic, pulsatile nature of GH secretion is shown, as well as its binding to a specific GH-binding protein within the circulation (GHBP). Finally it is indicated that most of the biological effects of GH are mediated via peripherally formed growth factors, the most important being Insulin-hke Growth Factor-I (IGF-I). Over the last twenty years a great number of peptidyl and non-peptidyl GH secretagogues have been developed. The GHRPs which were initially designed as effective releasers of GH in animals and man had to be administered intravenously or subcutaneously, but subsequently also intranasally and orally active compounds became available. Among these, the non-peptidyl GHRPs (L-692429, L-692585, MK-677) have already been studied extensively in man. More recently, a number of cyclic peptides, as well as penta-, tetra-, and pseudotripeptides have also been synthesized and tested in animals. GH is currently used extensively in the treatment of GH-deficient children, as well as in GH-deficient adults. GH is administered once daily, and therefore does not mimic the normal pulsatile release pattern of GH. Also synthetic IGF-I is available for clinical studies, but a potential disadvantage of its use is the occurrence of hypoglycemia.
In theory both the GHRPs and GHRH would be attractive alternatives for GH and IGF-I in the activation of the GH/IGF-I-axis in patients with absolute or relative (aging, catabolism, bums) GH-deficiency, as long as somatotroph activity is intact. Theoretically an orally active GH secretagogue induces a GH secretory pattern which is close to the physiological GH secretion, inducing IGF-I levels within normal limits. Therefore such an oral compound would have major advantages above GH and IGF-I with regard to tolerability, compliance and the incidence of adverse effects. These aspects will be extensively discussed throughout this article.
One other aspect of the GHRPs should be mentioned in this Introduction as well. Although GHRPs were initially based on an opioid peptide structure, they are devoid of opioid activity. Still their GH-releasing activity is not in all instances specific. GH secretagogues also have a stimulatory effect on Prolactin (PRL), Adrenocorticotropin (ACTH) and Cortisol secretion both in animals and in man. The mechanism underlying the PRL releasing activity is unclear. A hypothalamus-mediated effect has not been demonstrated, while a direct stimulation of pituitary somatomammotrope cells has been hypothesized. Clinical effects of chronic elevated PRL levels during treatment with GH secretagogues might therefore include mastopathy, galactorrhea, and/or a loss of libido. The stimulatory effect of GHRPs on the activity of the hypothalamo-pituitary-adrenal axis in man might be even more cumbersome. The acute ACTH and Cortisol response after the start of GHRP's administration seems to be mediated via the hypothalamus, as it is lost after cutting the pituitary stalk. A major unknown factor is whether the stimulatory effect of GHRPs in man will eventually be lost during prolonged administration, but even a minor activation of the hypothalamo-pituitary-adrenal axis would on clinical grounds be unacceptable, as adverse effects in many organ systems have to be expected.
The characterization and availability of the GHRPs is one of the most exciting developments in experimental and clinical neuroendocrinology. Apart from their potential use in diagnosis and therapy of disease, they have given new insight into the physiology and pathophysiology of GH secretion.
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1. Enhancement of hormone release
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