Children generally tolerate growth hormone treatment well. Adverse events are relatively rare and include pseudotumor cerebri, slipped capital femoral epiphysis, progression of scoliosis, edema, hyperglycemia, and increased risk of asphyxiation in severely obese patients with Prader-Willi syndrome and upper airway obstruction or sleep apnea. Patients with Turner syndrome have an increased risk of otitis media while taking GH. In children with GH deficiency, periodic evaluation of the other anterior pituitary hormones may reveal concurrent deficiencies, which also require treatment (ie, with hydrocortisone, levothyroxine, or gonadal hormones). Pancreatitis, gynecomastia, and nevus growth have occurred in patients receiving GH. Adults tend to have more adverse effects from GH therapy. Peripheral edema, myalgias, and arthralgias (especially in the hands and wrists) occur commonly but remit with dosage reduction. Carpal tunnel syndrome can occur. Growth hormone treatment increases the activity of cytochrome P450 isoforms, which may reduce the serum levels of drugs metabolized by that enzyme system (see Chapter 4). There has been no increased incidence of malignancy among patients receiving GH therapy, but such treatment is contraindicated in a patient with a known active malignancy. Proliferative retinopathy may rarely occur. Growth hormone treatment of critically ill patients appears to increase mortality. The long-term health effects of GH treatment in childhood are unknown. The results from the Safety and Appropriateness of GH in Europe (SAGHE) study are variable. A higher all-cause mortality (mostly due to cardiovascular disease) was found in the GH treatment group in the French arm of the study, but no long-term risks of GH treatment were observed in the study arm from another region of Europe.
A small number of children with growth failure have severe IGF-I deficiency that is not responsive to exogenous GH. Causes include mutations in the GH receptor and in the GH receptor signaling pathway, neutralizing antibodies to GH, and IGF-I gene defects. In 2005, the FDA approved two forms of recombinant human IGF-I (rhIGF-I) for treatment of severe IGF-I deficiency that is not responsive to GH: mecasermin and mecasermin rinfabate. Mecasermin is rhIGF-I alone, while mecasermin rinfabate is a complex of rhIGF-I and recombinant human insulin-like growth factor–binding protein-3 (rhIGFBP-3). This binding protein significantly increases the circulating half-life of rhIGF-I. Normally, the great majority of the circulating IGF-I is bound to IGFBP-3, which is produced principally by the liver under the control of GH. Due to a patent settlement, mecasermin rinfabate is not available for short stature-related indications. Mecasermin is administered subcutaneously twice daily at a recommended starting dosage of 0.04–0.08 mg/kg per dose and increased weekly up to a maximum twice-daily dosage of 0.12 mg/kg per dose.
The most important adverse effect observed with mecasermin is hypoglycemia. To avoid hypoglycemia, the prescribing instructions require consumption of a carbohydrate-containing meal or snack 20 minutes before or after mecasermin administration. Several patients have experienced intracranial hypertension, adenotonsillar hypertrophy, and asymptomatic elevation of liver enzymes.