Serum Insulin-Like Growth Factors and Insulin-Like Growth Factor-Binding Proteins: Clinical Implications (Beckman Conference‪)‬

It has been more than four decades since Salmon and Duaghaday (1) made the seminal observation that the action of growth hormone (GH)I on cartilage is mediated through a circulating factor absent in hypophysectomized animals. Over the ensuing years, discoveries concerning the identity of insulin-like growth factors (IGFs), their receptors, and various IGF-binding proteins (IGFBPs) and a host of tissue-specific IGFBP proteases have occupied investigators in several areas of endocrinology (2). The advent of recombinant peptide technology made possible preclinical research and clinical trials of GH as well as IGF-I, not only for various GH deficiency states but also for heart failure, neurological conditions, diabetes mellitus, muscle disorders, various catabolic states, stress syndromes, sarcopenia, and osteoporosis (3). At the same time, improved assay methodology has led to more widespread utilization of serum IGF-I as an indicator of GH status in both adults and children. More recently, serum IGF-I measurements have been studied in relation to the development and manifestation of chronic disease states. There is little doubt that the advances of the last decade are important for researchers and clinicians. GH replacement is now an approved and widely accepted therapy for GH deficiency (GHD) states. The use of serum IGF-I to monitor responsiveness in this condition is now common-place. The diagnosis of severe GHD is clinically straight-forward, but uncertainty remains regarding interpretation of serum IGF-I concentrations after midlife, where distinguishing between a "normal" age-related decline in IGF-I and GHD is more controversial. Although therapeutic trials with GH and/or IGF-I have been undertaken in several therapeutic venues, there is growing concern about possible adverse effects of these agents with respect to neoplasia, particularly if superphysiological IGF-I serum concentrations are achieved and maintained over decades. In this report, I will examine the clinical utility of IGF-I as a diagnostic tool with respect to chronic disorders, but in particular, osteoporosis and cancer. Throughout this review, the conundrum surrounding extrapolation of serum concentrations to tissue action will be examined.