Clinical Pharmacology of Human Growth Hormone and its Secretagogues

Abstract

The regulation of the synthesis and secretion of human growth hormone (hGH), its biologic activity, and its therapeutic use are reviewed. Both the production and secretion of GH are stimulated by hypothalamic GH-releasing hormone (GHRH) and by the endogenous GH secretagogue (GHS) ghrelin, a product of the oxyntic cells located within the fundus of the stomach. Ghrelin and GHRH act synergistically to stimulate GH secretion when administered in vivo, but they act additively when incubated with somatotrophs in vitro. Ghrelin is also found within the hypothalamic arcuate nucleus where it may enhance the release of GHRH and impair that of somatostatin (SRIH) thus contributing to its synergism with GHRH; ghrelin is an orexigenic peptide as well as a GHS and appears to play an important role in energy metabolism. SRIH inhibits the secretion but not the synthesis of GH and more effectively that stimulated by GHRH than that by ghrelin. The action of GH is mediated by the GH receptor, a straight chain protein of 620 amino acids with extracellular, transmembrane and cytoplasmic domains. GH has two specific receptor binding sites, (I, II) that bind sequentially to similar acceptor sequences of two GHRs. Activation of the GHR signal transduction pathway begins with attachment of two Janus kinase 2 (JAK2) molecules to the intracellular domains of the GHRs leading to phosphorylation of the tyrosine residues of JAK2 and the GHRs; thereafter the signal transduction and activators of transcription (STAT) and Ras mitogen-activated-protein kinase pathways are enhanced. GHRH, SRIH, and ghrelin act through G-protein coupled receptors (GPCR); GHRH activates adenylyl cyclase, cyclic AMP, and protein kinase A pathways, while ghrelin stimulates phospholipase C activity leading to production of inositol 1,4,5-trisphophate and diacylglycerol, increase in cytosolic calcium levels, and GH release; SRIH acts though an inhibitory GPCR to prevent depolarization of the somatotroph thus blocking GH secretion. GH has long been used to stimulate linear growth in children with GH deficiency (GHD); it has also been demonstrated to be effective in adults with GHD. The availability of large quantities of recombinant hGH has broadly increased the number of children with short stature being treated with this agent--not always with marked effectiveness. Synthesis of the GHR antagonist pegvisomant has provided another agent with which to treat patients with acromegaly. GHRH also enhances linear growth rate effectively in children with GHD but is less effective than hGH. The discovery of peptidyl and non-peptidyl GH secretagogues (that preceded and led to the identification of ghrelin itself) presents yet other agents for stimulation of endogenous GH secretion that have been useful in diagnostic studies for GHD and for its treatment in small groups of subjects. It is likely that hGH and its secretagoguess will become of increasing clinical usefulness in future decades.

Growth Hormone Secretory Status Evaluated by Growth Hormone Peak after Two Pharmacological Growth Hormone Release Stimuli Did Not Significantly Influence the Two-Year Catch-Up Growth Induced by Growth Hormone Therapy in 318 Prepubertal Short Children with Idiopathic Growth Retardation

“…However, they are used for the diagnosis of GHD and for deciding on GH therapy since no better alternatives are currently available for the evaluation of GH secretion in clinical practice [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. …”

“…The use of GH release stimuli in these children has long been a matter of debate since they are known to be unphysiological, irreproducible and potentially dangerous for children; however, clinicians continue to use them since no better alternatives are currently available for the evaluation of GH secretion [1,2,3,4,6,7,8,9,10,11,12,13,14,15]. In addition, GH serum measurements vary according to the immunoassays used [1,16,17].…”

Up-regulation of High Voltage-activated Ca2+ Channels in GC Somatotropes After Long-term Exposure to Ghrelin and Growth Hormone Releasing Peptide-6

“…Growth hormone (GH) release is primarily under the regulation of two hypothalamic neuropeptides, GH releasing hormone (GHRH) and somatotropin releaseinhibiting factor (SRIF; somatostatin), the former stimulating and the latter inhibiting the secretion of GH (Frohman et al 1992;Hartman et al 1993;BluetPajot et al 2001;Root and Root 2002). GHRH appears to bind to specific receptors on the plasma membrane of somatotropes, resulting in the stimulation of adenylyl cyclase activity and consequent generation of cAMP (Bilezikjian and Vale 1983;Frohman et al 1992;Wong et al 1995;Malagon et al 2003).…”

“…In addition to GHRH, a group of synthetic GHreleasing oligopeptides (GHRP) also known as GH secretagogues (GHS) are able to stimulate GH secretion (Chen 2000;Root and Root 2002;Smith 2005). GH-releasing peptide-6 (GHRP-6) is the most representative of these compounds (Bowers et al 1984;Chen 2000;Root and Root 2002;Smith 2005).…”

“…GH-releasing peptide-6 (GHRP-6) is the most representative of these compounds (Bowers et al 1984;Chen 2000;Root and Root 2002;Smith 2005). Research on the mechanism for GHS induction of GH release led to the discovery of the GHS receptor (GHS-R) and later to ghrelin, the endogenous ligand for the GHS-R (Kojima et al 1999;Chen 2000;Root and Root 2002;Smith 2005).…”