Recombinant human insulin-like growth factor I (IGF-I): risks and benefits of normalizing blood IGF-I concentrations

Recombinant human (rh) insulin-like growth factor I (IGF-I) is being developed as a therapy for short stature caused by IGF deficiency (IGFD) and also for diabetes mellitus. To complement the human efficacy and safety data, a large amount of information is available regarding the pharmacology and toxicology of rhIGF-I in animals. This review summarizes the risks and benefits of normalizing blood IGF-I concentrations in IGFD, especially with regard to carcinogenicity, and compares and contrasts safety data for rhIGF-I, recombinant human growth hormone (rhGH), and insulin. A major difference between rhIGF-I and rhGH is that rhIGF-I (like insulin) has hypoglycaemic activity, whereas rhGH opposes insulin action and is diabetogenic. In most of their actions, GH and IGF-I are similar. IGF-I mediates most of the actions of GH, so the safety of rhGH and that of rhIGF-I also share many common features. In animals, the transgenic expression of hGH has been shown to act directly, by activating the prolactin receptor, to increase the incidence of mammary and prostate tumours. In comparison, the over-expression of IGF-I in animals or the administration of rhIGF-I does not have a carcinogenic effect. In formal toxicology and carcinogenicity studies, rhIGF-I has similar effects to insulin in that it can increase food intake, body size, and the growth rate of existing tumours. In animals and humans, IGFD has many long-term detrimental effects besides short stature: it increases the risk of diabetes, cardiovascular disease, and low bone mineral density. Therefore, a case can be made for replacement therapy with rhIGF-I to normalize blood IGF-I levels and reverse the detrimental effects of IGFD.