Clinical Information

Insulin-like growth factor 1 (IGF1) is a 70-amino acid polypeptide (molecular weight 7.6 kDa; Uniprot Accession P05019 [aa 49-118]). IGF1 is a member of a family of closely related growth factors with high homology to insulin that signal through a corresponding group of highly homologous tyrosine kinase receptors. IGF1 is produced by many tissues, with the liver being the main source of circulating IGF1. IGF1 is the major mediator of the anabolic and growth-promoting effects of growth hormone (GH). IGF1 is transported by IGF-binding proteins, in particular IGF-binding protein 3 (IGFBP3), which also controls its bioavailability and half-life. Noncomplexed IGF1 and IGFBP3 have short half-lives (t1/2) of 10 minutes and 30 to 90 minutes, respectively, while the IGFBP3/IGF1 complex is cleared with a much slower t1/2 of 12 hours.

The secretion patterns of IGF1 and IGFBP3 mimic each other, their respective syntheses being controlled by GH. Unlike GH secretion, which is pulsatile and demonstrates significant diurnal variation, IGF1 and IGFBP3 levels show only minor fluctuations. IGF1 and IGFBP3 serum levels, therefore, represent a stable and integrated measurement of GH production and tissue effect.

Low IGF1 and IGFBP3 levels are observed in GH deficiency or GH resistance. If acquired in childhood, these conditions result in short stature.

Childhood GH deficiency can be an isolated abnormality or associated with deficiencies of other pituitary hormones. Some of the latter cases may be due to pituitary or hypothalamic tumors or result from either cranial radiation or intrathecal chemotherapy for childhood malignancies.

Most GH resistance in childhood is mild-to-moderate, with causes ranging from poor nutrition to severe systemic illness (eg, kidney failure). These individuals may have IGF1 and IGFBP3 levels within the reference range. Severe childhood GH resistance is rare and usually due to defects of the GH-receptor, its downstream signaling cascades, or deleterious variants in IGF1, its binding proteins, or its receptor signaling cascades.

Both GH deficiency and mild-to-moderate GH resistance can be treated with recombinant human GH (rhGH) injections, while severe resistance will usually not respond to GH. However, such patients might respond to recombinant IGF1 therapy, unless the underlying defect is in the IGF1 receptor or its downstream signaling systems.

The exact prevalence and causes of adult GH resistance are uncertain, but adult GH deficiency is seen mainly in patients with pituitary tumors. It is associated with decreased muscle bulk and increased cardiovascular morbidity and mortality, but replacement therapy remains controversial.

Elevated serum IGF1 and IGFBP3 levels often indicate either a sustained overproduction of GH or excessive rhGH therapy. Endogenous GH excess is caused mostly by GH-secreting pituitary adenomas, resulting in gigantism if acquired before epiphyseal closure and in acromegaly thereafter. Both conditions are associated with generalized organomegaly, hypertension, diabetes, cardiomyopathy, osteoarthritis, compression neuropathies, a mild increase in cancer risk (breast, colon, prostate, lung), and diminished longevity. It is plausible, but unproven, that long-term rhGH overtreatment may result in similar adverse outcomes.

Malnutrition results in low serum IGF1 concentrations, which recover with restoration of adequate nutrition.