Growth hormone deficiency can have a genetic basis, be associated with midline developmental defect syndromes (eg, septo-optic dysplasia), or be acquired as a result of damage to the pituitary or hypothalamus by a traumatic event (including breech or traumatic delivery), intracranial tumors, infection, infiltrative or hemorrhagic processes, or irradiation. Neonates with isolated GH deficiency are typically of normal size at birth because prenatal growth is not GH-dependent. In contrast, IGF-I is essential for normal prenatal and postnatal growth. Through poorly understood mechanisms, IGF-I expression and postnatal growth become GH-dependent during the first year of life. In childhood, GH deficiency typically presents as short stature, often with mild adiposity. Another early sign of GH deficiency is hypoglycemia due to the loss of a counter-regulatory hormonal response of GH to hypoglycemia; young children are at risk for this condition due to high sensitivity to insulin. Criteria for diagnosis of GH deficiency usually include (1) a subnormal height velocity for age and (2) a subnormal serum GH response following provocative testing with at least two GH secretagogues. Clonidine (α2-adrenergic agonist), levodopa (dopaminergic agonist), and exercise are factors that increase GHRH levels. Arginine and insulin-induced hypoglycemia cause diminished SST, which increases GH release. The prevalence of GH deficiency is approximately 1:5000. If therapy with rhGH is initiated at an early age, many children with short stature due to GH deficiency will achieve an adult height within their midparental target height range.
In the past, it was believed that adults with GH deficiency do not exhibit a significant syndrome. However, more detailed studies suggest that adults with GH deficiency often have generalized obesity, reduced muscle mass, asthenia, diminished bone mineral density, dyslipidemia, and reduced cardiac output. Growth hormone-deficient adults who have been treated with GH experience reversal of many of these manifestations.
B. Growth Hormone Treatment of Pediatric Patients with Short Stature
Although the greatest improvement in growth occurs in patients with GH deficiency, exogenous GH has some effect on height in children with short stature caused by conditions other than GH deficiency. Growth hormone has been approved for several conditions (Table 37–4) and has been used experimentally or off-label in many others. Prader-Willi syndrome is an autosomal dominant genetic disease associated with growth failure, obesity, and carbohydrate intolerance. In children with Prader-Willi syndrome and growth failure, GH treatment decreases body fat and increases lean body mass, linear growth, and energy expenditure.
Growth hormone treatment has also been shown to have a strong beneficial effect on final height of girls with Turner syndrome (45 X karyotype and variants). In clinical trials, GH treatment has been shown to increase final height in girls with Turner syndrome by 10–15 cm (4–6 inches). Because girls with Turner syndrome also have either absent or rudimentary ovaries, GH must be judiciously combined with gonadal steroids to achieve maximal height. Other conditions of pediatric growth failure for which GH treatment is approved include chronic renal insufficiency pre-transplant and small-for-gestational-age at birth
TABLE 37–4 Clinical uses of recombinant human growth hormone.
in which the child’s height remains more than 2 standard deviations below normal at 2 years of age.