Growth Hormone Receptor Antagonists

Pegvisomant is the only member of a new class of drugs that was especially designed to block the GH receptor (GHR) and, therefore, GH action. In this review we will describe the structure and function of GH and its receptor with specific relevance to the discovery and development of GHR antagonists. With respect to clinical applications, we will first discuss the role of pegvisomant in the treatment of acromegaly. Thereafter, the potential role that pegvisomant might play in the treatment and prevention of late complications of diabetes mellitus and cancer will be discussed and compared with those of somatostatin analogs in these settings. GH is secreted by the somatotrophs of the anterior pituitary gland and acts on various tissues to promote growth and influence metabolism (1, 2). GH signal transduction begins with GH binding to a GHR on the plasma membrane (3). The cocrystal structure of the GH-GHR complex indicates that GH interacts with a preformed GHR dimer. This interaction is critical for GH-induced intracellular signal transduction (4). GH has two distinct domains (sites 1 and 2) that bind to the two identical GHRs at the cell surface. After initial, high affinity binding at site I, subsequent binding at site 2 produces functional receptor dimerization (Fig. 1A). After the GH/GHR interaction, a series of intracellular signaling systems are mobilized, ultimately resulting in the activation or inactivation of genes that are responsible for GH phenotypic effects (5). In humans and most mammals, the extracellular part of the GHR can be released from the cell surface by proteolytic cleavage, resulting in the generation of a serum GH-binding protein (6).