Endocrine and Non-Endocrine Activities of Growth Hormone Secretagogues in Humans

Ghigo, Ezio; Arvat, Emanuela; Broglio, Fabio; Giordano, Roberta; Gianotti, Laura; Muccioli, Giampiero; Papotti, Mauro; Graziani, Andrea; Bisi, G; Deghenghi, Romano; Camanni, F.

doi:10.1159/000053156

Cited by 46 publications

(23 citation statements)

References 42 publications

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“…This fact, in view of the known functional interactions between GHRPs and GHRH, reinforces the proposition that SSIW disinhibits hypothalamic GHRH neurons, allowing a synergy of the exogenously administered GHRP with endogenously released GHRH (31,56). Since, reportedly, GHRPs promptly stimulate hypothalamic GHRH neurons (11, 57, 58), the biological effects of the endogenous GHRH release following SSIW could be further magni®ed.…”

Section: Discussionsupporting

confidence: 66%

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide

Rigamonti

Cavallera

Bonomo³

et al. 2001

European Journal of Endocrinology

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Objective: Evidence has been presented that in both animals and humans the rebound secretion of growth hormone (GH) following withdrawal of an infusion of somatostatin (SS) is due to the functional activation of the hypothalamic GH-releasing hormone (GHRH) neurons of the recipient organism. Based on this premise, this study has sought to assess the existence of functional interactions between endogenous GHRH released by a SS infusion withdrawal (SSIW) and growth hormone-releasing peptides (GHRPs), a class of compounds allegedly acting via GHRH. Methods: Five young dogs (3 to 4 years old, 2 male and 3 female) were administered, on different occasions, three consecutive intravenous boli of physiological saline (0.1 ml/kg), or GHRH (2 mg/kg), or EP92632 (125 mg/kg), a GHRP compound, or GHRH plus EP92632 at the end of three cycles of 1-h SS infusions (8 mg/(kgÂh)) or during a 6-h infusion of saline. Results: Under saline infusion (SALI), plasma GH levels were unaltered, whereas each SSIW cycle was followed by similar GH secretory episodes. Administration of the ®rst GHRH bolus under SALI induced a rise in plasma GH concentrations slightly higher than that induced by the ®rst cycle of SSIW, but the GH response to the second and third GHRH boli was similar to that after SSIW. Following SSIW, the response to the ®rst bolus of GHRH was higher than that during SALI, but the second and third cycles of SSIW induced GH responses similar to those evoked by the GHRH bolus. During SALI, administration of the ®rst bolus of EP92632 induced a rise in plasma GH which was higher than that induced by the ®rst GHRH bolus, the second bolus elicited a GH peak of lesser amplitude and there was a partial restoration of the GH response to the third peptide bolus. SSIW strikingly enhanced the GH release to the ®rst EP92632 bolus, a pattern also present, although to a lesser extent, with the second and third cycles of SSIW. Under SALI, combined administration of GHRH and EP92632 had a synergistic effect on GH release, but a progressive reduction was present in the GH response to the second and third GHRH plus EP92632 boli. SSIW increased only weakly the GH response to the ®rst co-administration of the peptides over that present after administration of EP92632 alone, and did not induce a GH response higher than that present during SALI when the second bolus of the peptides was administered; after the third SSIW a GH rise higher than that present during SALI was elicited by the combined administration of the peptides. Conclusions: (i) the uniformity of the GH rebound responses to multiple cycles of SSIW may indicate that the latter activate a physiological mechanism which mimics that normally controlling GH pulse generation; (ii) EP92632 elicits, under our experimental conditions, a plasma GH rise higher than that induced by GHRH; (iii) SSIW enhances the GH response to EP92639 alone, to an extent reminiscent of that following combined administration of GHRH and EP92632. This pattern reinforces the view that SSIW elicits release of end...

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Section: Discussionsupporting

confidence: 66%

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide

Rigamonti

Cavallera

Bonomo³

et al. 2001

European Journal of Endocrinology

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“…Lower levels of binding were observed, on the other hand, in adipose tissue, veins, uterus, skin and lymphnode, while negligible binding was found in parathyroid glands, pancreas, placenta, mammary gland, prostate, salivary gland, stomach, colon, and spleen. These findings indicate that GHS have widely spread receptors in some (but not all) peripheral endocrine and nonendocrine human tissues which could mediate effects other than classical endocrine and central activities (33). Evidence has been provided that treatment with peptidyl GHS exerts cardiovascular activities.…”

Section: Discussionmentioning

confidence: 95%

Growth Hormone Secretagogue Binding Sites in Peripheral Human Tissues1

Papotti¹,

Ghè²,

Cassoni³

et al. 2000

The Journal of Clinical Endocrinology &Amp; Metabolism

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130

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The family of GH secretagogues (GHS) includes peptidyl (hexarelin) and nonpeptidyl (MK 0677) molecules possessing specific receptors in the brain, pituitary, and thyroid. GHS receptor subtypes have also been identified in the heart; and a gastric-derived peptide, named ghrelin, has recently been proposed as a natural ligand. Our aim was to investigate the presence of GHS receptors in a wide range of human tissues, by radioreceptor assay with [125 I]Tyr-Ala-hexarelin. GHS receptors were detected mainly in the myocardium, but they were also present (in order of decreasing binding activity) in adrenal, gonads, arteries, lung, liver, skeletal muscle, kidney, pituitary, thyroid, adipose tissue, veins, uterus, skin, and lymphnode. In contrast, negligible binding was found in parathyroid, pancreas, placenta, mammary gland, prostate, salivary gland, stomach, colon, and spleen. Hexarelin, MK 0677, and human ghrelin completely displaced the radioligand from binding sites of endocrine tissues, but MK 0677 and ghrelin were less potent than hexarelin. In nonendocrine tissues, both MK 0677 and ghrelin were inactive in displacement of [125 I]Tyr-Alahexarelin, whereas hexarelin was as active as a displacing agent in endocrine tissues. This study provides the first detailed analysis of the tissue localization of GHS receptors and suggests that a still unknown receptor subtype, specific for peptidyl GHS, may exist in the heart and in other tissues. (J Clin Endocrinol Metab 85: 3803-3807, 2000) G H SECRETAGOGUES (GHS) are synthetic, peptidyl [GH-releasing peptides (GHRPs)], and nonpeptidyl molecules that possess strong, dose-dependent, and reproducible GH-releasing activity in vivo in several species and in man. They are active by the iv, sc, intranasal route and even after oral administration (1-3). Both peptidyl and nonpeptidyl compounds also possess significant PRL-and ACTH/cortisol-releasing effect (4, 5). The neuroendocrine activities of GHRPs are mediated by specific receptors, which have originally been identified in the pituitary and the hypothalamus in humans (6), as well as in rats (7, 8), using radiolabeled peptidyl ([ 125 I]Tyr-Ala-hexarelin) or radiolabeled nonpeptidyl GHS ([ 35 S]MK 0677). A specific animal and human GHS receptor has recently been cloned (9). It is encoded by a rare messenger RNA (mRNA) with a predicted open reading frame of 366 amino acids with a transmembrane topology typified by the Gprotein-coupled receptor family. Receptor transcripts are expressed in the pituitary and the hypothalamus (4, 9), and their sequence shows partial homology with the neurotensin receptor and other orphan receptors, such as GPR38, GPR39, and FM-3 (10, 11).The hypothalamus and the pituitary gland display the highest specific GHS binding in humans and in animals (6 -9), though a high level of specific binding has also been found in other areas of the central nervous system, such as the cerebral (but not cerebellar) cortex, hippocampus, medulla oblongata, choroid plexuses, thalamus, striatum, and substantia nigr...

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“…GH is controlled by many factors, in particular by two hypothalamic neuropeptides; GH release is stimulated by hypothalamic GH-releasing hormone (GHRH) and inhibited by somatostatin (5,165). Recently, however, a third independent pathway regulating GH release has been identified from studies of GH secretagogues (GHSs) (26,66,87,126,222). GHSs are synthetic compounds that are potent stimulators of GH release, working through a G protein-coupled receptor (GPCR), the GHS-receptor (GHS-R) (111,138,186).…”

Section: Introductionmentioning

confidence: 99%

Ghrelin: Structure and Function

Kojima

Kangawa²

2005

Physiological Reviews

1,621

1,176

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Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it “ghrelin,” after a word root (“ghre”) in Proto-Indo-European languages meaning “grow.” Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

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Endocrine and Non-Endocrine Activities of Growth Hormone Secretagogues in Humans

Cited by 46 publications

References 42 publications

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide

Growth Hormone Secretagogue Binding Sites in Peripheral Human Tissues1

Ghrelin: Structure and Function

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