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Human growth hormone (hGH, somatotrophin; Figure 8.11) is a polypeptide hormone synthesized in the anterior pituitary. It promotes normal body growth and lactation and influences various aspects of cellular metabolism.
Mature hGH contains 191 amino acid residues and displays a molecular mass of 22 kDa. It also contains two characteristic intra-chain disulphide linkages. hGH mRNA can also undergo alternate splicing, yielding a shortened GH molecule (20 kDa), which appears to display biological activities indistinguishable from the 22 kDa species.
hGH displays significant, although not absolute, species specificity. GHs isolated from other primates are the only preparations biologically active in humans (this precluded the earlier use of bovine/porcine preparations for medical use in humans).
Growth hormone synthesis and release from the pituitary is regulated by two hypothalamic factors: growth hormone releasing hormone (GHRH, also known as growth hormone releasing factor, GHRF, or somatorelin) and growth hormone release inhibiting hormone (GHRIH) or
HORMONES OF THERAPEUTIC INTEREST 325
Table 8.5. Some factors known to affect the rate of secretion of GH. Most of these factors influence GH release indirectly by affecting the rate and level of secretion of GHRH and/or GHRIH
Factors promoting increased GH secretion Factors promoting decreased GH secretion
Sleep Elevated blood glucose
Stress b-Adrenergic antagonists
Exercise b-Adrenergic agonists
Low blood glucose
Several amino acids
somatostatin (Table 8.5). Furthermore, while GH directly mediates some of its biological actions, its major influence on body growth is mediated indirectly via IGF-1, as discussed below. GHRH, GHRIH, GH and IGF-1 thus form a hormonal axis, as depicted in Figure 8.12.
Growth hormone releasing factor (GHRF) and inhibitory factor (GHRIF)
GHRF and GHRIF are peptides secreted by hypothalamic neurons termed ‘neuroendocrine transducers’ (the name is apt, as these interface between the nervous and endocrine systems). The factors that regulate their secretion are poorly understood but probably involve both nerve impulses originating from within the brain and feedback mechanisms, possibly involving pituitary hormones.
37, 40 and 44 amino acid GHRF variants have been identified. All can promote GH release from the pituitary, an activity which apparently resides in the first 29 amino acid residues of these molecules. Administration of GHRH to GH-deficient individuals generally promotes modest increases in GH secretion, thereby increasing growth rate.
Hypothalamic GHRIF is a cyclic 14 amino-acid peptide, although a 28 amino acid form is also found in some other tissues. GHRIF inhibits the release not only of GH but also of tyrotrophin and corticotrophin from the pituitary, and insulin and glucagon from the pancreas. It can also regulate the level of duodenal secretions.
The GH receptor
GH induces its characteristic biological effects by binding to a specific cell surface receptor. The human receptor is a single chain 620 amino acid transmembrane polypeptide. Sequence analysis indicates it is a member of the haemopoietic receptor superfamily (which includes receptors for several ILs, GM-CSF and EPO). X-ray crystallographic analysis shows that GH binds simultaneously to the extracellular domains of two receptor molecules, effectively promoting receptor dimerization (Figure 8.13). The exact molecular detail of the subsequent signal transduction events remain to be determined. However, ligand binding does induce receptor autophosphorylation, as well as phosphorylation of additional cellular substances and protein kinase C activation.
GHRH (+ ve) GHRIH (-ve)
Many growih-promoting effccts
Figure 8.12. Overview of the mechanisms by which GH induces its biological effects and how its secretion from the pituitary is regulated
Soluble GH-binding proteins (GHBPs) are also found in the circulation. In humans, these GHBPs are generated by enzymatic cleavage of the integral membrane receptor, releasing the GH-binding extracellular domain. In rodents, however, the GHBPs are derived from alternatively cleaved GH-receptor mRNA. The exact physiological role of these binding proteins remains to be elucidated. In serum, GH binds to two such GHBPs, an action which prolongs the hormone’s plasma half-life.