Endocrine Activities of Ghrelin, a Natural Growth Hormone Secretagogue (GHS), in Humans: Comparison and Interactions with Hexarelin, a Nonnatural Peptidyl GHS, and GH-Releasing Hormone 1 (original) (raw)
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An endogenous ligand for the GH secretagogue-receptor (GHSreceptor) has recently been isolated, from both the rat and the human stomach, and named ghrelin. It is a 28-amino-acid peptide showing a unique structure with an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. In fact, it has been demonstrated that ghrelin specifically stimulates GH secretion from both rat pituitary cells in culture and rats in vivo. The aim of the present study was to test the GH-releasing activity of ghrelin in humans and to compare it with that of GHRH and hexarelin (HEX), a nonnatural peptidyl GHS, which possesses strong GH-releasing activity but also significantly stimulates PRL, ACTH, and cortisol secretion. To clarify the mechanisms of action underlying the GH-releasing activity of ghrelin in humans, its interaction with GHRH and HEX was also studied. Seven normal young volunteers (7 men; 24 -32 yr old; body mass index, 20 -24 kg/m 2 ) were studied. All subjects underwent the administration of ghrelin, HEX, and GHRH-29 (1.0 g/kg iv at 0 min) as well as placebo (2 mL isotonic saline iv at 0 min). Six subjects also underwent the combined administration of ghrelin and GHRH or HEX. Blood samples were taken every 15 min from Ϫ15 up to ϩ180 min. GH levels were assayed at each time point in all sessions; PRL, ACTH, cortisol, and aldosterone levels were also assayed after administration of ghrelin and/or HEX.
Ghrelin in the Regulation of GH Secretion and Other Pituitary Hormones
Growth Hormone Related Diseases and Therapy, 2011
Ghrelin, a 28 amino acid octanoylated peptide predominantly produced by the stomach, was discovered to be the natural ligand of the type 1a growth hormone (GH) secretagogue receptor (GHS-R1a). Thus, it was considered as a natural GHS additional to growth hormone-releasing hormone (GHRH), although later on ghrelin has mostly been considered a major orexigenic factor. Ghrelin activity at the pituitary level is not fully specific for GH, because it also includes stimulatory effects on both the lactotroph and corticotroph system. In fact, ghrelin in humans significantly stimulates prolactin (PRL) secretion, independently of both gender and age and probably involving a direct action on somatomammotroph cells, and possesses an acute stimulatory effect on the activity of the hypothalamus-pituitary-adrenal axis, which is similar to that of the opioid antagonist naloxone, arginine-vasopressin (AVP) and even corticotropin-releasing hormone (CRH). Finally, ghrelin plays a relevant role in the modulation of the hypothalamus-pituitary-gonadal axis function, with a predominantly central nervous system (CNS)-mediated inhibitory effect upon the gonadotropin pulsatility both in animals and in humans.
Effect of ghrelin on regulation of growth hormone release: A review
The occurrence of ghrelin indicates that GH release from the pituitary may be regulated not only by hypothalamic growth hormone releasing hormone (GHRH), but also by ghrelin, a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR). Objective: To review the role of ghrelin as a stimulant for the secretion of GH and GHRH. Methodology: We searched the following electronic databases: The Cochrane Library, MEDLINE, PubMed, Science Citation Index, BIOSIS, EMBASE, and CINAHL. The references of all identified studies were inspected for further randomized controlled trials. No language restrictions were applied. Results: The ghrelin receptor growth hormone secretagogue receptor-1 (GHSR-1) is found in several neuronal subtypes in the arcuate nucleus. In the presence of SS, the percent increase in GH released with human ghrelin plus GHRH was greater than that by either human ghrelin or GHRH alone. Conclusion: Ghrelin increases GH release and can be used as an adjunctive treatment. Reported adverse events were infrequent, mild, and transient. Future trials should report clinical as well as physiological outcomes. The role of ghrelin in the regulation of GH and its clinical implications needs further assessment.
Ghrelin-induced growth hormone secretion in humans
European Journal of Endocrinology, 2000
Ghrelin is a novel growth hormone (GH) releaser acylated peptide that has recently been purified from stomach, and which potently binds to the GH secretagogue receptor. Ghrelin releases GH in vitro and in vivo in animal models, however its actions, potency and specificity in humans are unknown. In the present study, 12 healthy subjects were studied: 6 underwent four tests with ghrelin administered i.v. at the dose of 0 (placebo), 0.25, 0.5 and 1 microg/kg which corresponds to 0, 18, 37 and 75 microg total dose. A further 6 volunteers underwent two tests on different days with ghrelin at the dose of 3.3 or 6.6 microg/kg which corresponds to 250 microg and 500 microg total dose. Ghrelin-mediated GH secretion showed a dose-response curve, in which 1 microg/kg was the minimally effective dose in some individuals, but not as a group. On the contrary, the total doses of 250 microg and 500 microg elicited a powerful GH secretion, with a mean peak of 69.8+/-9.2 microg/l and 90.9+/-16.9 micr...
Ghrelin and Growth Hormone Secretagogues, Physiological and Pharmacological Aspect
Current Drug Discovery Technologies, 2009
The first "growth hormone secretagogues" (GHSs) were discovered by Bowers et al. in 1977. In 1996 the GHSs receptor (GHS-R 1a) was cloned. The endogenous ligand for this receptor, ghrelin, was not identified until 1999. Synthetic molecules termed GHSs are substances that stimulate growth hormone (GH) release, via a separate pathway distinct from GH releasing hormone (GHRH)/somatostatin. Ghrelin displays strong GH-releasing activity through the activation of the GHS-R 1a. Apart from stimulating GH secretion, ghrelin and many synthetic GHSs: 1) stimulate prolactin and ACTH secretion; 2) negatively influence the pituitary-gonadal axis; 3) stimulate appetite and positive energy balance; 4) modulate pancreatic endocrine function and affect glucose levels; 5) have cardiovascular actions. The control of ghrelin secretion is not well established at present, although nutrition is an important regulator. Investigators have exploited the ability of GHSs and ghrelin to release GH by mechanisms different from GHRH as a diagnostic tool, which is the present main clinical use of some GHSs. As an alternative to GH, GH deficient conditions could be treated with any substance which would release endogenous GH, such as synthetic GHSs. It is likely that GHSs, acting as either agonists or antagonists on different pathophysiological processes, might have some other clinical impact and therapeutic potential. At least theoretically ghrelin receptor antagonists could be anti-obesity drugs, as blockers of the orexigenic signal from the gastrointestinal tract to the brain. Inverse agonists of the ghrelin receptor, by blocking the constitutive receptor activity, might lower the set-point for hunger between meals.
Endocrinology, 2005
Ghrelin was purified from rat stomach as an endogenous ligand for the GH secretagogue (GHS) receptor. As a GHS, ghrelin stimulates GH release, but it also has additional activities, including stimulation of appetite and weight gain. Plasma GH and ghrelin secretory patterns appear unrelated, whereas many studies have correlated ghrelin variations with food intake episodes. To evaluate the role of endogenous ghrelin, GH secretion and food intake were monitored in male rats infused sc (6 g/h during 10 h) or intracerebroventricularly (5 g/h during 48 h) with BIM-28163, a full competitive antagonist of the GHS-R1a receptor. Subcutaneous BIM-28163 infusion significantly decreased GH area under the curve during a 6-h sampling period by 54% and peak amplitude by 46%. Twelve hours after the end of treatment these parameters returned to normal. Central treatment was similarly effective (؊37 and ؊42% for area under the curve and ؊44 and ؊49% for peak amplitude on the first and second days of infusion, respectively). Neither peripheral nor central BIM-28163 injection modified GH peak number, GH nadir, or IGF-I levels. In this protocol, food intake is not strongly modified and water intake is unchanged.
Ghrelin: Ghrelin as a Regulatory Peptide in Growth Hormone Secretion
Background: Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of growth hormone (GH). It is a first hormone linking gastrointestinal-pituitary axis. Objective: This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Observation: Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS–GHS receptor signalling system in the regulation of GH secretion. Conclusion: Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH. Keywords : Ghrelin, Growth Hormone, Ghrelin-Pituitary-Gh Axis Linkage System
Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations
Nutrition Metabolism and Cardiovascular Diseases, 2005
Background: Growing evidence indicates that the administration of large amounts of ghrelin to humans increases circulating concentrations of several pituitary and adrenal hormones, induces hyperglycemia and reduces serum insulin concentrations. At present, it is not known whether physiological increments in plasma ghrelin concentrations affect glucose kinetics or hormone concentrations in humans. Methods and results: We compared the effects of two-and three-fold increments in plasma ghrelin concentrations in eight healthy subjects during a 2 h intravenous infusion of 7.5 (GHRE7.5), 15 (GHRE15) pmol kg ÿ1 min ÿ1 acylated human ghrelin or placebo (PL), in a randomized double-blind study. Compared with PL (146G24 pM) plasma ghrelin concentrations increased at 120 min (p!0.001) about two-fold after GHRE7.5 (300G35 pM) and three-fold after GHRE15 (494G30 pM). GHRE15 significantly increased circulating concentrations of NEFA, GH, ACTH, epinephrine, and prolactin (p!0.01). GHRELIN7.5 significantly (p!0.01) increased only serum GH concentrations. Neither ghrelin infusions changed glucose flux or circulating concentrations of glucose, insulin, C-peptide, glucagon, IGF-1, cortisol and norepinephrine. Conclusions: GH secretion is the only response that is stimulated by physiological increments in plasma ghrelin concentrations; about three-fold increases in plasma Nutrition, Metabolism & Cardiovascular Diseases (2005) 15, 410e417 www.elsevier.com/locate/nmcd ghrelin concentrations are required to elicit the responses of epinephrine, prolactin, ACTH and NEFA. ª