Current Insights into the Role of the Growth Hormone-Insulin-Like Growth Factor System in Short Children Born Small for Gestational Age

Abstract

Background: The reason for the insufficient catch-up growth seen in 10% of children born small for gestational age (SGA) is poorly understood. Disturbances in the growth hormone (GH) - insulin-like growth factor (IGF) axis might underlie this failure to show sufficient catch-up growth.

Conclusion: This review summarizes insights gained in the molecular and (epi) genetic mechanisms of the GH-IGF axis in short children born SGA. The most notable anomalies of the IGF system are the lowered IGF-I levels in both cord blood and the placenta, and the increased expression of IGF-binding proteins (IGFBP)-1 and IGFBP-2, which inhibit IGF-I, in the placenta of SGA neonates. These observations suggest a decreased bioactivity of IGF-I in utero. IGF-I levels remain reduced in SGA children with short stature, as well as IGFBP-3 and acid-labile subunit levels. Proteolysis of IGFBP-3 appears to be increased.

Keywords: Acid-labile subunit; Growth hormone; Insulin-like growth factor binding proteins; Small for gestational age; Ternary complex formation.

Fig. 1

Schematic view of the main components of the GH-IGF axis. GH releasing hormone (GHRH) is secreted in a pulsatile manner by the hypothalamus and stimulates the secretion of GH by the somatotrophic cells of the anterior pituitary. Somatostatin inhibits the release of GH. In the circulation, GH can be found free or bound to GH binding protein (not shown). Mutations in genes encoding GHRH, GHRH receptor (not shown), somatostatin receptor (not shown), GH, and GHR usually do not result in SGA birth. GH activates the GHR on the liver and various other target tissues. This may either result in direct, metabolic effects GH or indirect actions being mediated trough IGF-I. IGF-I can act in mainly an autocrine, paracrine, or endocrine fashion through binding to the IGF-IR which is expressed by nearly all cell types. IGF-II, which can also bind to the IGF-IR and at least in vitro, has similar effects as IGF-I, is not directly under the influence of GH. The IGFs exert negative feedback on GHRH and GH secretion and positive feedback on somatostatin release. The IGFs in the circulation are strongly bound to IGFBPs. This leaves a very small fraction of IGFs in the free unbound form. IGFBPs are important for the regulation of IGF bioavailability. Under normal circumstances IGFBP-3, mainly produced by the liver, is the most abundant IGFBP in the circulation. Together with an IGF and the ALS it forms a high molecular weight ternary complex that cannot pass the blood capillaries. ALS synthesis and release is GH-dependent. Most IGFBPs can also exert IGF-independent effects. At the tissue level, IGFs can be released from the IGFBPs by the action of various IGFBP proteases. GH, growth hormone; GHRH, GH releasing hormone; GHR, GH receptor; IGF, insulin-like growth factor; IGF-IR, IGF-I receptor; IGFBP, IGF-binding proteins; ALS, acid-labile subunit [96].

Fig. 2

Average distribution of IGFs among ternary and binary complexes and the unbound fraction in the circulation of healthy subjects. Stable ternary 150 kD complexes are formed by an IGF, IGFBP-3 (to a lesser extent also with IGFBP-5) and ALS. In addition, there are binary 40–50 kD complexes consisting of an IGF and an IGFBP with a relatively shorter half-life in the circulation. Only a very small fraction of the IGFs are present in the free unbound form. IGFs are released from the complexes by various types of IGFBP proteases (...) which include the (MMPs) PAPP-A2 and A. These proteases cleave IGFBP-3 and-5 (PAPP-A2) and IGFBP-2, -4, and -5 (PAPP-A) and are thought to play an important role in IGFBP proteolysis. STCs inhibit the proteolytic activities of PAPP-A and PAPP-A2, thereby resulting in decreased levels of free IGF-1 and, consequently, decreased IGF-1 signaling. MMP, matrix metalloproteinases; IGF, insulin-like growth factor; IGFBP, IGF-binding proteins; PAPP, pregnancy-associated plasma protein.

Fig. 3

Representative examples of the distribution of radioactivity among the various molecular weight size classes after (125I)-hIGF-I column chromatography of pooled normal serum (a) and a subject with severely reduced ternary complex formation (b). CPM, counts per minute; kD, kilo Dalton.