Recombinant Human Insulin-Like Growth Factor-1 Treatment: Prime Time or Timeout? [Commentary on “Recombinant Human Insulin Like Growth Factor-1 Treatment: Ready for Prime Time” by Bright GM, Mendoza JR, Rosenfeld RG, Endocrinol Metab Clin N Am 2009; 38:625–38]

The paper by Bright et al. is an effort to authenticate the recently introduced designation of " primary insulin-like growth factor-1 deficiency (IGFD) " and it's treatment with recombinant human insulin-like growth factor-1 (rhIGF-1). The concept of " primary IGFD " is supported by comparison to states of hormone deficiency that occur despite adequate stimulation to the target gland, such as primary hypothyroidism and primary hypocortisolism. This is a specious argument. These designations of primary abnormality are not diagnoses but provisional diagnostic categories. While primary hypothyroidism is used as a broad categorization, diagnosis requires, at the very least, differentiation between congenital and acquired, both of which include a wide range of specific diagnoses which have prognostic and therapeutic importance. Similarly, we rarely, if ever, speak of primary hypocortisolism, because of the very limited information or therapeutic guidance conveyed by a categorization that encompasses various forms of congenital adrenal hyperplasia, autoimmune and infectious Addison disease, adrenal leukodystrophy, and congenital adrenal unresponsiveness. These authors, however, are suggesting that " primary IGFD " is a viable specific diagnosis applicable to a substantial proportion of children with idiopathic short stature (ISS). Were this proposal validated, the market for recombinant insulin-like growth factor-1 (rhIGF-1) would be greatly expanded beyond the rare conditions resulting in growth hormone (GH) insensitivity for which rhIGF-1 was approved by the US Food and Drug Administration (FDA) [1]. It makes no more sense to refer to GH insensitivity or resistance as " primary IGFD " than it would to refer to GH deficiency (GHD) as " secondary IGFD " [2]. The problem with this designation as a useful diagnostic entity is seen in the vast differences among the conditions subsumed, from GH receptor and IGF-1 gene mutations, and including acid labile subunit (ALS) mutation as one of the molecular defects listed in Box 1 as causing " primary IGFD. " Because ALS is needed to stabilize the complex of IGF-1 and IGFBP3 in the circulation, its absence results in extremely low circulating IGF-1 and IGFBP3 levels. However, there is no impairment of IGF-1 synthesis in any tissue, making the assignment of ALS mutation as a cause of " primary IGFD " irrational. That the ALS deficiency has no effect on paracrine/autocrine IGF-1 synthesis or effect is the likely explanation for no-to-modest effect on growth in individuals with ALS deficiency [3, 4]. The notion of " primary IGFD " is further advanced …