Recombinant Human Insulin-Like Growth Factor I (rhIGF-I) and rhIGF-I/rhIGF-Binding-Protein-3: New Growth Treatment Options?

The growth effect that gives growth hormone (GH) its name is the result of GH stimulation of IGF-I production in the liver (endocrine IGF-I) and peripheral tissues, particularly bone and muscle (autocrine/paracrine IGF-I).¹ Hepatic IGF-I circulates almost entirely (>99%) bound to IGF-binding proteins (IGFBPs). The IGFBPs are a family of six structurally related proteins with a high affinity for binding IGF. The principal BP, IGFBP-3, which binds 75% to 90% of circulating IGF-I, is a large ternary complex consisting of IGFBP-3, acid labile subunit (ALS), and IGF molecules. ALS and IGFBP-3 are produced in the liver as a direct effect of GH. The ALS stabilizes the IGF–IGFBP-3 complex, reduces the passage of IGF-I to the extravascular compartment, and extends its half-life.² The remainder of bound IGF-I is mostly with IGFBP-1 and IGFBP-2. IGFBP-1 concentrations are controlled by nutritional status as reflected in insulin levels, with the highest IGFBP-1 concentrations found in the fasting, hypoinsulinemic state.³ Similarly, circulating concentration of IGFBP-2 is under negative control by GH directly, independently of IGF-I, and is elevated with GH deficiency or resistance; the positive effect of IGF-I on IGFBP-2 results in further elevation when patients who are GH receptor deficient (GHRD, Laron syndrome) are treated with IGF-I. The IGFBPs modulate IGF action by controlling storage and release of IGF-I in the circulation and influencing its binding to its receptor, facilitating storage of IGF-I in extracellular matrices, and they also exert independent actions.³

Abbreviations: ALS, Acid labile subunit, GH, Growth hormone, GHD, GH deficient, GHRD, GH receptor deficient, IGFBP, IGF-binding proteins, IGF-I, Insulin-like growth factor I, rhIGF-I, Recombinant IGF-I, SDS, Standard deviation score, FDA, US Food and Drug Administration