Growth hormone excess and the development of growth hormone receptor antagonists

• Published in: Experimental physiology 2008-11, Vol.93 (11), p.1157-1169
• Main Authors: Higham, C. E., Trainer, P. J.
• Format: Article
• Language: English
• Subjects: Acromegaly - drug therapy; Acromegaly - metabolism; Animals; Antineoplastic Agents - therapeutic use; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Hormone Antagonists - adverse effects; Hormone Antagonists - therapeutic use; Human Growth Hormone - adverse effects; Human Growth Hormone - analogs & derivatives; Human Growth Hormone - antagonists & inhibitors; Human Growth Hormone - chemistry; Human Growth Hormone - genetics; Human Growth Hormone - metabolism; Human Growth Hormone - therapeutic use; Humans; Hypoglycemic Agents - therapeutic use; Models, Molecular; Mutation; Protein Binding; Protein Conformation; Protein Multimerization; Signal Transduction - drug effects
• ISSN: 0958-0670; 1469-445X
• DOI: 10.1113/expphysiol.2008.042515

In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH–GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor–GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH–IGF-I axis.