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Introduction
Growth hormone releasing factor (GRF) is a member of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily, and is the least conserved of the peptides among different species Hoyle (1998). GRF was originally isolated from human pancreatic endocrine tumors Ito et al (2001). As the name implies, GRF is released from the hypothalamus and binds to receptors in the anterior pituitary to induce the release of growth hormone Sherwood et al (2000), Ito et al (2001). Though this is a main GRF function, it is also found in ovaries, placenta, testis, gastrointestinal tract, and is secreted from lymphocytes Sherwood et al (2000).
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Ghrh
GHRH is well established as a hormone made in the brains of mammals. In humans, GHRH is a 44-amino-acid peptide (Fig. 1) that is released from nerve cells in brain and then binds to pituitary cells to release GH. In humans, GHRH is encoded by a single gene, with a GHRH-coding region that extends across exon 3 and part of exon 4 (Fig. 2). GHRH has a long evolutionary history in which GHRH shared a gene with PACAP until the appearance of mammals.
The distribution of GHRH is primarily in the brain, although it is reported to be present in the gut, gonads, placenta, pancreas and immune cells. There are both long and short versions of the GHRH receptor, which is the usual seven-transmembrane G protein-coupled receptor. The target organs for GHRH are primarily the pituitary and brain, although low levels of receptors are reported for the gonads, placenta, and kidney. The function of GHRH is to increase the synthesis and release of GH from somatotrophs in the pituitary, but also to stimulate these somatotroph cells for proliferation, differentiation, and growth. Centrally, GHRH is implicated in the control of food intake and enhancement of sleep. In the periphery, GHRH is reported to release insulin and to have a role in the gut, in reproduction, and in fetal growth.
Rare tumors that overexpress GHRH can occur in humans, especially in the pancreas, gastrointestinal tract, and lung. The symptoms in adults are typical of acromegaly with enlarged hands, feet, and jaw. Two such tumors were used for the first structural determination of human GHRH.
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Abstract
GHRH, a 44-amino acid peptide, is a member of a growing superfamily of brain–gut peptides. It is primarily expressed and secreted from the hypothalamic nerve terminals of the arcuate nucleus, and is carried to the anterior pituitary gland, where it stimulates the production and release of growth hormone (GH) secretion via binding to the growth hormone-releasing hormone receptor (GHRH-R). The N-terminal aa residue tyrosine and GHRH1–29 are important for biological activity. The synthesis and release of GHRH are regulated by transcriptional factors, sex hormones, aging, the negative feedback effect of GH, and diverse pathological conditions. GHRH is also involved in sleep and feeding regulation. Defects in GHRH/GHRH-R are implicated in abnormal GH production, causing dwarfism or acromegaly. One of the GHRH analogs has been used in diagnosis and treatment of children with idiopathic growth hormone deficiency.
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URL: https://www.sciencedirect.com/science/article/pii/B9780128010280001434
Growth Hormone-Releasing Hormone (GHRH)
Growth hormone-releasing hormone, also known as GH-releasing factor (GRF) is a 44-amino acid peptide produced in the ventromedial and arcuate nuclei of the hypothalamus. The stimulatory hypothalamic neuropeptide, GHRH was first originally isolated from extrahypothalamic/extrapituitary (pancreatic) tumor cells of a Turner׳s syndrome patient with acromegaly (Thorner et al., 1982). Studies in animal models and humans have unequivocally documented that GHRH as the primary GH pulse generator as well as exert a positive effect of somatotrope proliferation. Further studies have confirmed the direct relationship of GH pulsatile with increased concentration of GHRH in the portal blood (Burgess et al., 2002). The GHRH receptor (GHRH-R) present on the anterior pituitary somatotroph cells belongs to the family of the G protein-coupled receptors. Upon stimulation by GHRH results in the production cyclic adenosine monophosphate and this leads to increased GH synthesis and secretion. GH secretion is greater in the childhood and adolescence age range than in adulthood. This age related attenuation of GH secretion (somatopause) is due to diminished GHRH secretion and perhaps the pituitary responsiveness to GHRH remains intact. At all ages, the effect of GHRH on GH secretion is partially blocked by the administration of somatostatin which inhibits GH secretion and controls the GH pulse frequency (Backeljauw and Hwa, 2016).
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1 Growth Hormone-Releasing Hormone
Growth hormone-releasing hormone (GHRH) was originally isolated from ectopic tumors producing it (and thereby causing observable derangements in growth), rather than from the hypothalamus and its structure determined by two laboratories in 1982. GHRH is secreted by the arcuate nucleus of the hypothalamus and is derived from a 108 amino-acid pre-prohormone yielding either GHRH(1-44) shown in Figure 3-7 or GHRH(1-40), shortened at the carboxyl terminal. Both forms of GHRH are found in the human hypothalamus and since the full biological activity of GHRH lies in amino acid residues 1–29, the physiological differences between the two GHRH forms are likely minimal. Structurally, GHRH belongs to a family of proteins that includes secretin, glucagon, glucagon-like peptides (GLP-1 and GLP-2), and vasoactive intestinal peptide (VIP).
Following secretion from its neurons into the portal circulation, GHRH binds to its receptor, GHRH-R, a G-protein coupled receptor on the somatrophs of the anterior pituitary. Increased cyclic AMP production leads to the increased synthesis of GH. Cyclic AMP also stimulates the opening of Ca2+ and K+ ion channels, which play roles in the secretion of existing GH from the cell, in its characteristic pulsatile fashion. Phospholipid signaling may also be involved in the exocytosis associated with the release of GH by the somatotroph when stimulated by GHRH. In addition to its effect on GH secretion and synthesis by somatotrophs, GHRH stimulates proliferation of these cells through the activation of the MAP kinase pathway.
GHRH and/or its receptor also occur outside the central nervous system in such tissues as the pancreas where it stimulates insulin, glucagon and somatostatin release; in the gastrointestinal tract where it stimulates gastrin release and stimulates epithelial cell division; and in tumors of many types.
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VI.A Hormonal Feedback Regulation by the GH Axis
GH and IGF-I inhibit GHRH receptor mRNA expression (see Fig. 5). When GH signaling is disrupted, as demonstrated in two rodent models with GH receptor deficiencies, there is an increase in GHRH receptor mRNA expression. These findings suggest that GH negatively regulates GHRH receptor mRNA expression. When pituitary cells are treated with IGF-I, GHRH binding and GHRH-stimulated GH secretion are significantly reduced, indicating that IGF-I also negatively regulates the GHRH receptor.
GHRH-binding activity in the pituitary is significantly reduced following prolonged exposure to GHRH. This reduction in binding activity may arise from receptor desensitization and internalization. Receptor desensitization, or the process of attenuating the ability of GPCRs to activate heterotrimeric G-proteins, is often followed by receptor internalization. Currently, no studies with the cloned receptor have addressed GHRH receptor desensitization and internalization, but studies on the related receptors for secretin and glucagon have described receptor inactivation by these processes.
Whether homologous down-regulation of GHRH receptor mRNA expression occurs following prolonged ligand exposure is controversial. Whereas one study concluded that GHRH up-regulates receptor mRNA expression, another study found that GHRH down-regulates receptor expression. In yet another study, the inhibitory actions of GHRH on receptor expression were made evident only when SRIF was immunoneutralized, suggesting that homologous down-regulation of the GHRH receptor is obscured by the inhibitory effects of SRIF on receptor expression. Interestingly, GHRH has been localized to secretatory granules of somatotroph cells, suggesting a possible autocrine role for GHRH in perpetuating GH secretion and expediting receptor down-regulation.
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Growth hormone-releasing hormone and somatostatin
The growth hormone-releasing hormone neurons in ARC release the neuropeptide GHRH, which triggers secretion of the growth hormone (GH) from the pituitary gland (Mayo et al., 2000). GH, in turn, induces the hepatic expression of insulin-like growth factor 1 that controls bone epiphyses, muscle and adipose tissue development, growth plates development, and glucose homeostasis. In the human ARC-ME, GHRH neurons and the majority of somatostatin-immunoreactive neurons receive a dense innervation from substance P (SP) fibers indicating that substance P influences growth via action on GHRH and somatostatin neurons (Luu et al., 2020), which provide input to GHRH neurons. Such innervation may at least partially mediate the somatostatin effect on growth, in addition to the somatostatin effects on GH cells in PD. GHRH neurons are also approached by enkephalinergic axonal varicosities (Proudan et al., 2015), which may mediate the well-known modulatory effects on growth. Moreover, catecholaminergic, NPY-, and CRH-immunoreactive axon varicosities abut on the surface of the GHRH neurons and may represent the morphological substrate of the impact of stress (Peroski et al., 2016). Studies in humans have shown an increase in the number of GHRH neurons during prolonged illness prior to death (Goldstone et al., 2003).
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5.82.1.1.1 Functions of GHRH
GHRH is the central effector of the GH/insulin-like growth factor-I axis. GHRH stimulates GH synthesis and release and the proliferation and differentiation of pituitary somatotrophs, beginning in fetal life. In awake growing children, GHRH is secreted in a pulsatile manner about every 3 h and more frequently during sleep (Tapanainen et al., 1989). The pulsatile release of GHRH is age dependent and there is also a sexually dimorphic pattern, particularly at puberty when GHRH function becomes sexually dimorphic due to testosterone. GHRH actions in adult or aging animals become less responsive to testosterone and the feedback of GH on GHRH neurons also declines considerably with aging (Veldhuis et al., 1997). In aging, GHRH receptors diminish.
GH, which is stimulated by the pulsatile secretion of GHRH, is an anabolic hormone which promotes growth, stimulates protein synthesis, glycogenolysis, and lipolysis. Human GH is a single-chain polypeptide of 191 amino acids, with two disulfide bonds between Cys53 and Cys165 and between Cys182 and Cys182. The GH receptor belongs to the hematopoietin superfamily which includes receptors for erythropoietin, the interleukins, the interferons, and several white blood cell-stimulating factors. These receptors are glycoproteins with an extracellular N-terminus and a single transmembrane domain. Insulin growth factor (IGF)-I, which mediates some of GH's effects, is among one of 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 (Bertherat et al., 1995).
GHRH can also regulate sleep though its modulatory effect appears to be complex and related to age and sex (Mathias et al., 2007). Specifically, it can increase the duration of slow-wave sleep while at the same time inhibiting the secretion of ACTH and cortisol. GH-pulse frequency during sleep decreases in magnitude with aging and this appears to be correlated with shortened periods of sleep that are known to occur with senescence. GHRH can also affect food intake in a circadian-dependent manner which involves the suprachiasmatic nucleus (SCN) in some samples (Vaccarino et al., 1995). Interestingly, some recent evidence suggests that in women, pulsatile administration of GHRH impairs sleep (Mathias et al., 2007).
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GHRH Excess
Eutopic growth hormone-releasing hormone (GHRH) excess usually results in GH and prolactin-producing cell hyperplasia and rarely in adenoma formation. In a case report of congenital gigantism due to GH and prolactin-producing cell hyperplasia, high serum levels of GHRH were found. However, no evidence for a hypothalamic GHRH-producing tumor was found, which was suggestive for a congenital hypothalamic regulatory defect (Zimmerman et al., 1993). GHRH-secreting gangliocytomas within or in close proximity to the sella have also been reported in conjunction with gigantism (Scheithauer et al., 1986).
Ectopic GHRH-producing NETs are rare but well-known causes of acromegaly. Thus far, only two cases of acromegalic gigantism caused by ectopic GHRH secreting tumors have been described (Scheithauer et al., 1986).
Hereditary pituitary hyperplasia is described as a familial form of very early onset gigantism associated with abnormally high serum levels of GH and prolactin, but absence of radiological abnormalities in the pituitary area. It has been suggested that this condition results from embryonic pituitary maldevelopment with retention and expansion of the GH and prolactin-producing cells caused by paracrine or autocrine pituitary GHRH secretion during pituitary development (Glasker et al., 2011).
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1.2 Structure of GHRH-R
GHRH-R is a member of the class B GPCR subfamily. GHRH, a neuropeptide produced in the hypothalamus, regulates the secretion of GH by the pituitary through its binding to GHRH-R.
Like other class B GPCRs, GHRH-R consists of an extracellular domain (ECD) and a seven-transmembrane helix domain (Matsoukas & Spyroulias, 2017).
Pituitary type GHRH-R is a TM7 GPCR that, in rat and human, is 423 amino acids in length. The GHRH-R gene is localized to human chromosome 7p 14e15 and rat chromosome 4p24 and a member of the class B of GPCRs, which includes the secretin/glucagon/VIP/PACAP peptide receptors. Alternative splicing in GPCRs is one of many emerging mechanisms by which this class of receptors diversifies its activities (Fridlyand, Tamarina, Schally, & Philipson, 2016; Lin-Su & Wajnrajch, 2002). Characterization of the genomic sequence has revealed that the human GHRH-R gene consists of 13 exons and spans 15 kb (Fridlyand et al., 2016; Lin-Su & Wajnrajch, 2002).
The GHRH-R was initially cloned from human, rat, and mouse pituitary, and in these species the isolated cDNAs encode a 423-amino acid protein. The porcine receptor structured of 451-amino acid protein. There are several isoforms with differing carboxyl-terminal ends, presumably generated by alternative RNA processing, one of which corresponds to the 423-amino acid form. Bovine and ovine receptors have also been cloned. The ovine receptor has a 16-amino acid truncation at its carboxyl terminus, a characteristic shared with the caprine receptor (Mayo et al., 2003).
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