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.

Ghrelin regulates proliferation and differentiation of osteoblastic cells

“…Previous reports have shown that both ghrelin and HEXA recognize with the same affinity the functional GHS-R1a receptor and that activation of this receptor stimulated an increase in [Ca 2+ ] i (intracellular calcium) and in IP 3 generation (Root & Root 2002). The effects of GHS on these second messengers correlate with their stimulatory effects on osteoblast proliferation since stimulation of the PI/ [Ca 2+ ] i signal pathways are generally associated with increased DNA and collagen synthesis (Yamaguchi et al 1988).…”

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

“…GRF is a C-terminal peptide of 40 to 44 amino acids (600). Administration of human GRF might be able to recover GH secretion pulses (601) and, therefore, the physiological actions of this pituitary hormone.…”

“…Its advantage over that of classical GRF is that it has been stabilized, and therefore it maintains its biological activity in plasma (600). Tesamorelin markedly increases levels of both GH and IGF-1 (618,620,621), thus resulting in the physiologic effects of these two anabolic agents.…”

Optimal Therapy of Growth Hormone Deficiency in the Child and Adolescent

“…Then GH release is stimulated by GH-releasing hormone (GHRH) from the hypothalamus and by gastric ghrelin during fasting. [13][14][15][16] Somatostatin 'tone' is interrupted occasionally, resulting in GH secretion into the bloodstream in a pulsatile fashion. Pulsatile GH secretion is considered important for many of the physiological effects of GH.…”