Long-Term Safety of Growth Hormone Therapy: Still a Controversial Issue

Substantial experimental evidence supports the involvement of growth hormone (GH) and, especially, its main effector insulin-like growth factor-I (IGF-I) in the development, growth, and dissemination of several types of cancer (Cianfarani and Rossi, 1997; Holly et al., 1999, Renehan et al., 2004; Clayton et al., 2011). However, although the data from in vitro and in vivo studies are robust, the evidence in humans is weak (Clayton et al., 2011). Growth hormone extracted from human pituitaries (hGH) became available for therapy of GH deficient children in early 1960s. In 1985, following the reports of an association of this treatment with the occurrence of Creutzeldt–Jakob disease, human GH was banned and replaced by recombinant hGH (rhGH). Since then, due to the unlimited supply of this molecule, the indications for rhGH have greatly expanded worldwide, now including childhood and adult GH deficiency, Turner syndrome, chronic renal failure, small for gestational age (SGA), Prader–Willi syndrome, Noonan syndrome, SHOX deficiency, idiopathic short stature (ISS), and AIDS wasting. Despite a so long time of use in so many different clinical conditions, rhGH has rarely been associated with the occurrence of serious side effects. However, longitudinal studies aimed at evaluating the health of adult subjects treated with rhGH during childhood are few and often not independent of Pharmaceutical Companies. Nevertheless, an association of hGH or rhGH treatment with a higher incidence of cancer (Swerdlow et al., 2002) and type 2 diabetes (Cutfield et al., 2000; Child et al., 2011) has been reported. The recent publication of two studies stemming from SAGhE (Safety and Appropriateness of GH treatments in Europe) European consortium, which was started in 2009 and includes eight countries (France, Sweden, Belgium, the Netherlands, Switzerland, Germany, United Kingdom, and Italy), has generated confusion and controversy rather than shedding light on this delicate matter (Carel et al., 2012; Sävendahl et al., 2012). The French study reported a significant increase in both allcause mortality and specific mortality for bone tumors or cerebral hemorrhage in a cohort of about 6500 young adult subjects treated with rhGH during childhood for GH deficiency, SGA, or ISS (Table 1). On the basis of these findings, in 2010 the EMA’s Committee for Medicinal Products for Human Use (CHMP) launched a warning aimed at narrowing the dose range used in the different indications approved in Europe and started a review of all available data to Long-term safety of growth hormone therapy: still a controversial issue