For over fifty years, the management of growth disorders has centered on the growth hormone-insulin-like growth factor (GH-IGF) axis. Given limitations in the supply of pituitary-derived GH, endocrinologists focused on identification of patients with GH deficiency and replacement treatment with GH. When recombinant GH became available in the mid-1980’s, expanded indications for GH therapy were sought, such as Turner syndrome, small for gestational age (SGA) and idiopathic short stature, where the goal of treatment was not replacement of a deficiency in GH production, but, rather, an effort to overcome sluggish growth with super-physiological GH. More recently, the therapeutic armamentarium has been expanded by the use of IGF-I for patients with severe IGF deficiency, as is observed in GH resistant states.

Despite the great value of GH and/or IGF treatment in select cases of short stature, many forms of short stature are not characterized by deficiencies of either GH or IGF-I and respond only modestly (or not at all) to treatment with these agents. Additionally, GH must be administered by daily injection, while IGF-I, given its short half-life in serum, must be given at least twice per day. Adherence to these therapeutic regimens has proven to be problematic for many children.

As we look to the future of growth-promoting therapy, a number of new treatment modalities are worthy of consideration. These include a variety of long-acting GH preparations, oral GH secretagogue receptor agonists, and long-acting IGF-I preparations. For patients with skeletal dysplasias, most of which have proven to be relatively resistant to GH treatment, targeted therapy to the underlying growth plate abnormality holds great promise. For achondroplasia, the most common of the skeletal dysplasias, and where growth plate pathology is characterized by a constitutively hyperactive fibroblast growth factor receptor-3 (FGFR3), investigational therapies include tyrosine kinase inhibitors, soluble, competitive FGFR3, and stabilized analogs of C-natriuretic peptide, which can inhibit the FGFR3 pathway.