Growth Hormone Releasing Hormone (GHRH)
The existence of growth hormone-releasing hormone (GHRH) was postulated following identification that hypothalamic extracts stimulate growth hormone (GH) release (Schally et al. 1965) and that hypothalamic lesions in rats caused a reduction in linear growth and reduced pituitary weight (Reichlin 1961). Pituitary extracts from these rats had a marked reduction in capacity to stimulate growth, suggesting that loss of hypothalamic control of the pituitary gland might contribute to reduced pituitary GH production. Subsequent observations confirmed the release of GH soon following electrical stimulation of the ventromedial hypothalamic nucleus (VMH) and thus provided an added premise that a potent hypothalamic GH-stimulating factor may selectively enhance pituitary GH production and release (Frohman et al. 1968).
Initial attempts to isolate and purify hypothalamic GHRH remained only partially successful (Frohman et al. 1980), primarily due to difficulties in confirming the bioactivity of GHRH preparations as a consequence of contamination with somatostatin (a potent inhibitor of GH release (Steyn et al. 2016)). An opportunity to isolate and purify GHRH presented itself in 1980, wherein a 21-year-old patient with suspected acromegaly was treated at St. Bartholomew’s Hospital (London, England). Initially diagnosed with acromegaly due to a suspected pituitary tumor, it was soon discovered that the patient had somatotroph hyperplasia due to extrinsic stimulation of a GH-promoting factor (Thorner 1999). A large islet-cell tumor was detected in the tail of her pancreas, and surgical resection of this mass resulted in a recovery from acromegaly. Closer examination of this tumor found no traces of GH, insulin, or other growth factors, therefore excluding the tumor as a direct source for factors that cause acromegaly. Rather, this tumor contained high GHRH activity, providing a suitable source of peptide for the eventual isolation, purification, and sequencing of human GHRH (Thorner 1999).
The GHRH Gene and Peptide Structure
GHRH is a peptide hormone that is structurally related to the family of brain-gut peptides. This family includes glucagon, glucagon-like peptide I (GLP-1), vasoactive intestinal polypeptide (VIP), secretin, gastric-inhibitory peptide (GIP), and pituitary adenylyl cyclase-activating peptide (PACAP). The GHRH gene was first identified and characterized from human mRNA, extracted from the same human pancreatic tumor from which it was isolated (Gubler et al. 1983; Mayo et al. 1983). Human Ghrh is localized to chromosome 20 and includes five exons spanning ~10–18 kb of genomic DNA. Placental and hypothalamic Ghrh cDNA share exons 2 and 5, with distinct mRNA generated from the placenta and hypothalamus following splicing of tissue-specific exon-1, and common exons 2–5. These mRNAs code an identical GHRH precursor protein. The GHRH precursor protein contains 108 amino acids, which is processed into a 40- or 44-amino acid peptide (Lin-Su and Wajnrajch 2002).
Localization and Action of GHRH
GHRH is dominantly expressed within hypothalamic neurons specific to the arcuate nucleus (Steyn et al. 2016). These neurons project from the ARC to innervate the median eminence (ME), where GHRH is released into vasculature of the pituitary portal system. From here, GHRH is transported to the somatotrophs within the anterior pituitary gland where GH production and release is stimulated. Contribution of the role of GHRH in regulating the patterned release of GH has been reviewed extensively (Steyn 2015). Briefly, episodic GH secretion is the product of combined feedback between stimulatory GHRH-expressing neurons and inhibitory somatostatin-expressing neurons. Low peripheral levels of GH promote the activation of GHRH-expressing neurons and the release and transport of GHRH to the anterior pituitary gland. Stimulation of GH release from somatotrophs initiates the activation of somatostatin-expressing neurons (a process called negative feedback). Somatostatin neurons directly inhibit GHRH-neuron activity, while somatostatin release and transport to the anterior pituitary gland inhibits GHRH-induced GH release. The release of GH is closely entrained to sleep and calorie supply (Steyn 2015; Steyn et al. 2016), and thus neuronal populations that normally engage hypothalamic control of food intake may directly or indirectly modulate the activity of hypothalamic GHRH-expressing neurons. The activity of these neurons is further shaped by feedback of peripheral factors, including liver derived insulin-like growth factor 1 (IGF-1) and insulin, that prime the extent and patterned release of GHRH and thus GHRH-mediated GH secretion (Steyn et al. 2016).
Subsets of non-endocrine GHRH-expressing neurons (i.e., neurons that do not regulate GH release via the pituitary portal system) are located within the ventromedial nucleus, around the infundibular nucleus, the periventricular zone of the hypothalamus, and in the amygdala ((Lin-Su and Wajnrajch 2002). Extensive expression of GHRH outside of the hypothalamus suggests that GHRH may play additional physiological roles, with some observations suggesting that GHRH may be important in the regulation of sleep and food intake (Lin-Su and Wajnrajch 2002). For example, GHRH is thought to regulate deep non-REM sleep, acting independent of GH (Obal and Krueger 2004). Outside of the central nervous system (CNS), Ghrh is expressed in numerous tissues, including the heart, skeletal muscle, intestines, adipose, liver, lungs, pancreas, adrenal glands, ovary, and testes. Within the placenta, GHRH is thought to regulate fetal pituitary GH production (Margioris et al. 1990). Within ovaries and testes, GHRH is thought to regulate steroidogenesis (Lin-Su and Wajnrajch 2002).
GHRH Signaling in Somatotrophs
GH production is mediated via the Gα subunit of the GHRH-R. As a GS-coupled receptor, binding of the GHRH-R catalyzes the binding of guanosine 5′triphosphate (GTP) to the α-subunit of the receptor. This stimulates membrane-bound adenylyl cyclase (AC) to generate cyclic adenosine monophosphate (cAMP). A rise in intracellular cAMP leads to an increase in the activity of protein kinase A (PKA) and the phosphorylation of cAMP-responsive element binding protein (CREB). Together with its coactivators, p300 and CREB-binding protein (CBP), phosphorylated CREB stimulates the de novo production of GH following transcription of pituitary Gh. This cascade of events also promotes transcription of Ghrh-r and thus restoration of GHRH-R to the cell surface, a critical component of the short-loop regulation of GHRH-mediated GH release. Regulation of Gh and Ghrh-r transcription requires pituitary specific Pit-1, a prototypic Pit-Oct-Unc (POU) domain protein.
GH release is mediated via the Gβ and Gγ GHRH-R subunits. Binding of the βγ-subunits of the GHRH-R stimulates phospholipase C (PLC), inducing the production of diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 initiates the release of intracellular calcium (from ER stores). The resulting increase in intracellular calcium promotes vesicle fusion and the release of stored GH. Some calcium influx may also occur in response to a cAMP-induced opening of sodium channels, a process mediated by phosphatidylinositol 4,5-bisphosphate (PIP2, a minor phospholipid component of the cell membrane). Importantly, GHRH excess or deficiency contributes to pituitary somatotroph hyperplasia or hypoplasia, respectively. Thus, while modulating GH production and release, GHRH also regulates somatotroph proliferation and growth (Lin-Su and Wajnrajch 2002).
GHRH in Health and Disease
Mutations in Ghrh are very rare, and diseases associated with GHRH more commonly occur as a consequence of excess GHRH production or following the loss of GHRH-R function. Excess GHRH production leads to GH excess and acromegaly. GHRH excess is often associated with hypothalamic tumors, including gliomas and gangliocitomas. Extrahypothalamic GHRH-producing tumors may result in excess GH production and acromegaly (as was demonstrated during the discovery of human GHRH (Thorner 1999)). While GHRH is present in several tumors types, including carcinoid and pancreatic cell tumors, small-cell lung cancers, adrenal adenomas, and pheochromocytomas, the release of GHRH may not always be sufficient to cause GH excess or somatotroph hypertrophy (Doga et al. 2001).
Loss of GHRH function, as might occur following mutation of the GHRH-R, results in GH deficiency. In instances where GH deficiency occurs, independent of loss of GHRH function, therapies that modulate GHRH signaling may be effective in restoring GH release. Indeed, GHRH treatment in many children with idiopathic GH deficiency results in a very robust increase in GH release. While pharmacological use of GHRH to treat GH deficiency is of clinical benefit, current treatment strategies to recover GH deficiency favor the use of recombinant human GH. A recent review on the use of recombinant human GH (rhGH) to treat GH deficiency found this safe practice however recommended ongoing monitoring of rhGH use for approved interventions only (Allen et al. 2016). It was advised that rhGH use not be recommended for performance enhancement, antiaging, or other illicit uses. In this instance, strategies that seek to enhance endogenous GH release to slow aging processes may offer renewed opportunities to advance GHRH-directed treatments. For example, 20 weeks of GHRH treatment improved cognitive function in healthy adults and adults with mild cognitive impairment (Baker et al. 2012). Potential treatment effects of GHRH on cognitive decline and function are still under investigation and may offer a promising avenue to slow the effects of age on the brain. Other potential treatments using GHRH, or that target the GHRH-R, include treatments for cancer (Schally et al. 2008), heart disease (Kanashiro-Takeuchi et al. 2015), and some metabolic diseases including dyslipidemia as a consequence of type-1 diabetes (Romero et al. 2016). These therapeutic investigations reflect the wide range of tissues that express Ghrh and its receptor.
GHRH is a peptide hormone originally identified as a potent hypothalamic-derived factor that stimulates the production and release of GH while promoting the differentiation and growth of somatotrophs within the anterior pituitary gland. Within somatotrophs, GHRH binds the GHRH-R, a G protein-coupled receptor, to induce a series of downstream signaling processes that mediate hormone release and gene transcription. While uncommon, loss of GHRH function results in GH deficiency. Excess GHRH production (usually as a consequence of an extrahypothalamic GHRH-producing tumor) may cause GH excess and acromegaly. More recent interest in GHRH includes the potential use of GHRH to slow cognitive decline with old age, as well as therapeutic intervention or treatment for a range of diseases, including certain cancers, heart disease, and metabolic disorders. Potential therapeutic use of GHRH reflects the wide distribution of Ghrh and Ghrh-r in tissues outside of the CNS, including the pancreas, heart, and adipose tissue.
Related Molecules to Link
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