Growth hormone receptor modulators.

Growth hormone (GH) regulates somatic growth, substrate metabolism and body composition. Its actions are elaborated through the GH receptor (GHR). GHR signalling involves the role of at least three major pathways, STATs, MAPK, and PI3-kinase/Akt. GH receptor function can be modulated by changes to the ligand, to the receptor or by factors regulating signal transduction. Insights on the physico-chemical basis of the binding of GH to its receptor and the stoichiometry required for activation of the GH receptor-dimer has led to the development of novel GH agonists and antagonists. Owing to the fact that GH has short half-life, several approaches have been taken to create long-acting GHR agonists. This includes the pegylation, sustained release formulations, and ligand-receptor fusion proteins. Pegylation of a GH analogue (pegvisomant) which binds but not activate signal transduction forms the basis of a new successful approach to the treatment of acromegaly. GH receptors can be regulated at a number of levels, by modifying receptor expression, surface availability and signalling. Insulin, thyroid hormones and sex hormones are among hormones that modulate GHR through some of these mechanisms. Estrogens inhibit GH signalling by stimulating the expression of SOCS proteins which are negative regulators of cytokine receptor signalling. This review of GHR modulators will cover the effects of ligand modification, and of factors regulating receptor expression and signalling.