Recombinant human insulin-like growth factor I (rhIGF-I) and rhIGF-I/rhIGF-binding-protein-3: new growth treatment options?

INSULIN-LIKE GROWTH FACTOR I (IGF-I) AND GROWTH he 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). Hepatic IGF-I circulates almost entirely ( 99%) bound to IGF-binding proteins (IGFBPs). The IGFBPs are a family of six tructurally related proteins with a high affinity for binding IGF. The principal BP, IGFBP-3, which binds 75% to 90% of irculating IGF-I, is a large ternary complex consisting of IGFBP-3, acid labile subunit (ALS), and IGF molecules. ALS and GFBP-3 are produced in the liver as a direct effect of GH. The ALS stabilizes the IGF–IGFBP-3 complex, reduces the passage f IGF-I to the extravascular compartment, and extends its half-life. The remainder of bound IGF-I is mostly with IGFBP-1 nd IGFBP-2. IGFBP-1 concentrations are controlled by nutritional status as reflected in insulin levels, with the highest GFBP-1 concentrations found in the fasting, hypoinsulinemic state. Similarly, circulating concentration of IGFBP-2 is under egative control by GH directly, independently of IGF-I, and is elevated with GH deficiency or resistance; the positive effect f IGF-I on IGFBP-2 results in further elevation when patients who are GH receptor deficient (GHRD, Laron syndrome) are reated with IGF-I. The IGFBPs modulate IGF action by controlling storage and release of IGF-I in the circulation and nfluencing its binding to its receptor, facilitating storage of IGF-I in extracellular matrices, and they also exert independent ctions. IGF-I binds to the type 1 IGF receptor with high affinity and to the structurally similar insulin receptor with an affinity hat is approximately 100-fold less that of insulin. Because IGF-I is present in the circulation at molar concentrations that are 000 times those of insulin, even a small insulin-like effect of IGF-I as a result of its binding to the insulin receptor could be ore important than that of insulin itself, were it not for the IGFBPs that control the availability and activity of IGF-I, and dapt to changing energy status. The importance of IGF-I in normal intrauterine growth in humans has been demonstrated in a patient with a homozygous artial deletion of the IGF-I gene, in a patient with mutation of the IGF-I gene resulting in high circulating levels of an neffective IGF-I, and in patients with mutations of the IGF-I receptor, who all had severe intrauterine growth retardation. ntrauterine IGF-I synthesis, however, does not appear to be GH dependent because most patients with genetically determined evere IGF-I deficiency have normal or only minimally reduced intrauterine growth. Standard deviation score (SDS) for length eclines rapidly after birth in these conditions, demonstrating the immediate need for GH-stimulated IGF-I synthesis for ostnatal growth. Growth velocity in the absence of GH is typically half normal, but it has been reported to be normal or upranormal despite absence of GH in some hypothalamic conditions characterized by hyperphagia, with obesity or rapid weight ain. A similar phenomenon was described in a placebo-controlled study of rhIGF-I treatment of patients with severe IGF-I eficiency from GHRD, in which 3 of the 9 placebo-treated subjects grew over the -month study period at an accelerated rate comparable with that of the rhIGF-I–treated ubjects, attributed to improved nutrition in the investigative milieu.