GROWTH HORMONE SECRETION : ITS REGULATION A N D THE INFLUENCE OF NUTRITIONAL FACTORS (original) (raw)
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Factors Regulating Growth Hormone Secretion in Humans
Endocrinology and Metabolism Clinics of North America, 2007
Growth hormone (GH) secretion is pulsatile in nature in all species. The periodic pattern of GH release plays an important role in transmitting the GH message in a tissue-specific manner. For example, only pulsatile GH can normalize muscle and cartilage insulin-like growth factor (IGF)-1 mRNA levels [1] and only the continuous component of GH's secretory profile induces hepatic mRNAs for certain cytochrome P-450 enzymes [2]. The question of what regulates the pulsatile GH secretion pattern is an issue of not only theoretical interest but of considerable practical importance for designing different GH therapies for a variety of human diseases. GH synthesis and secretion are regulated primarily by the hypothalamic neuropeptides growth hormone-releasing hormone (GH-RH) and somatotropin release-inhibiting factor (somatostatin [SRIF]). Similar to other endocrine systems, the end product of GH's action, IGF-1, exerts a negative feedback effect on GH secretion. The amount of GH secreted and the pattern of its release is also subject to the nutritional state and to nutrients themselves and to the prevailing gonadal steroid milieu. Additionally, the recently discovered gastric hormone, ghrelin, may play a role. All these factors interact with each other in a precise and coordinated manner and the interplay between them is necessarily complex. This article provides a brief introductory overview of the different regulators of GH secretion and concentrates primarily on human studies.
Hypothalamic and hypophyseal regulation of growth hormone secretion
Cellular and molecular neurobiology, 1998
1. Regulation of pulsatile secretion of growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their operation are growth hormone releasing hormone (GHRH) synthetized mostly in arcuate nucleus (ARC) neurons, and somatostatin (SRIH), synthetized both in hypothalamus periventricular (PVe) and ARC neurons. 2. Neurons synthetizing both peptides can inhibit each other in a reciprocal manner. Other neuropeptides synthetized in ARC neurons, such as galanin, or in ARC interneurons, such as neuropeptide Y (NPY), are able to modulate synthesis and release of GHRH and SRIH into the hypothalamohypophyseal portal system. 3. In addition, the hitherto uncharacterized endogenous ligand of the recently cloned growth hormone releasing peptide receptor, expressed mostly in the ARC, triggers GH release, presumably by actions on ARC interneurons. 4. Thyroid, gonadal, and adrenal steroid hormones also affect the GHRH-SRIH balance; a differential distribution of sex ster...
Neuroendocrine Control of Growth Hormone Secretion
Acta Paediatrica, 1989
The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to the discovery of five separate SS receptor genes encoding a family of G protein-coupled SS receptors, which are widely expressed in the pituitary, brain, and the periphery, and to the synthesis of analogs with subtype specificity. Better understanding of the function of GHRH, SS, and their receptors and, hence, of neural regulation of GH secretion in health and disease has been achieved with the discovery of a new class of fairly specific, orally active, small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane domain receptors, whose natural ligands are not yet known.
Journal of Clinical Investigation, 1996
The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr 1 , D-Arg 2)GHRH(1-29)NH 2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 g/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline or GHRH-Ant 400 g/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion.
Growth Hormone Secretion: Molecular and Cellular Mechanisms and In Vivo Approaches
Growth hormone (GH) release is under the direct control of hypothalamic releasing hormones, some being also produced peripherally. The role of these hypothalamic factors has been understood by in vitro studies together with such in vivo approaches as stalk sectioning. Secretion of GH is stimulated by GH-releasing hormone (GHRH) and ghrelin (acting via the GH secretagogue [GHS] receptor [GHSR]), and inhibited by somatostatin (SRIF). Other peptides/proteins influence GH secretion, at least in some species. The cellular mechanism by which the releasing hormones affect GH secretion from the somatotrope requires specific signal transduction systems (cAMP and/or calcium influx and/or mobilization of intracellular calcium) and/ or tyrosine kinase(s) and/or nitric oxide (NO)/cGMP. At the subcellular level, GH release (at least in response to GHS) is accomplished by the following. The GH-containing secretory granules are moved close to the cell surface. There is then transient fusion of the secretory granules with the fusion pores in the multiple secretory pits in the somatotrope cell surface. Exp
Growth hormone-releasing hormone: Extrapituitary effects in physiology and pathology
Cell Cycle, 2010
The existence of growth hormone-releasing hormone (GHRH) was first suggested in 1961, 1 but the breakthrough for the identification of this hormone was provided by the demonstration of the ectopic production of GHRH by carcinoid and pancreatic tumors. The 44-amino-acid forms of GHRH were then first isolated and characterized from human pancreatic tumors that caused acromegaly 3 and GHRH was only subsequently identified from human and animal hypothalami. GHRH belongs to a family of related peptides that includes vasoactive intestinal peptide (VIP), pituitary adenylate cyclaseactivating peptide (PACAP), secretin, glucagon, glucagon-like peptides-1 and -2, and gastric inhibitory peptide. 3 Peptides in this family act to stimulate the intracellular accumulation of cAMP with the resultant activation of protein kinase A. 5,6 The full intrinsic biological activity of GHRH is retained by the *Correspondence to: Andrew V. Schally;
Neuroendocrine regulation of growth hormone
European Journal of Endocrinology, 1995
This short review is focused on the neuroendocrine regulation of growth hormone (GH) pulsatile secretory pattern and GH gene expression. The neuronal network involved in the central control of GH includes extrahypothalamic neurons such as the noradrenergic and cholinergic systems, which regulate the two antagonistic neurohormonal systems: somatostatin (SRIH) and GH-releasing hormone (GHRH). Intrahypothalamic Proopiomelanocortin- and Galanin-containing interneurons also participate in the regulation of SRIH and GHRH neuronal activity, which also is dependent on sex steroids and GH and/or insulin-like growth factor I (IGF-I) feedback. cAMP (controlled mainly by GHRH and SRIH), thyroid and glucocorticoid hormones. IGF-I and activin are among the factors that regulate GH gene expression at the transcriptional level and may play a role in somatotroph differentiation and proliferation during ontogeny as well as physiological and pathological states such as acromegaly.
The Journal of Clinical Endocrinology & Metabolism, 2001
GH-releasing peptides (GHRPs) are synthetic peptides that bind to specific receptors and thereby stimulate the secretion of pituitary GH. In vivo it is uncertain whether these peptides act directly on somatotroph cells or indirectly via release of GHRH from the hypothalamus. In this study we compared the pituitary hormone response to GHRP-2 in 11 individuals with isolated GH deficiency (GHD) due to a homozygous mutation of the GHRH receptor (GHRH-R) gene and in 8 normal unrelated controls. Basal serum GH levels were lower in the GHD group compared with controls [0.11 Ϯ 0.11 (range, Ͻ0.04 to 0.38) vs. 0.59 Ϯ 0.76 g/L (range, 0.04-2.12 g/L); P ϭ 0.052]. After GHRP-2 administration there was a 4.5-fold increase in serum GH relative to baseline values in the GHD group (0.49 Ϯ 0.41 vs. 0.11 Ϯ 0.11 g/L; P ϭ 0.002), which was significantly less than the 79-fold increase in the control group (46.8 Ϯ 17.6 vs. 0.59 Ϯ 0.76 g/L; P ϭ 0.008). Basal and post-GHRP-2 serum levels of ACTH, cortisol, and PRL were similar in both groups. Basal levels of serum TSH were significantly higher in the GHD group than in the control group (3.23 Ϯ 2.21 vs. 1.37 Ϯ 0.34 IU/mL; P ϭ 0.003). TSH levels in both groups did not change after GHRP-2 administration. These results suggest that an intact GHRH signaling system is not an absolute requirement for GHRP-2 action on GH secretion and that GHRP-2 has a GHRH-independent effect on pituitary somatotroph cells.