The Growth Hormone Cascade: Progress and Long-Term Results of Growth Hormone Treatment in Growth Hormone Deficiency

Abstract

The growth hormone (GH) cascade and the remarkable advances over the past four decades in our knowledge of its components are considered. It is now over 40 years since human pituitary GH (pit-hGH) was purified and the first GH-deficient patient, a 17-year-old male, was successfully treated with pit-hGH. However, the shortage of pit-hGH limited its use and the dose, the biopotency of preparations varied, strict criteria of GH deficiency (GHD) were used for patient selection including peak plasma immunoreactive GH levels after provocative stimuli of <3.5–5 ng/ml, treatment was not infrequently interrupted, the mean age for initiating treatment was often late in childhood (12–13 years) and the growth deficiency severe (height –4 to –6 SDS), and finally pit-hGH therapy was often discontinued when girls attained a height of 5′ and boys 5′5′′. Nonetheless, the effects of pit-hGH were dramatic; the final height SDS increased in isolated GHD to about –2 SDS in boys and –2.5 to –3.0 SDS in girls, and in multiple pituitary hormone deficiencies to between –1 and –2 SDS. Between 1962 and 1985 when the Creutzfeldt-Jakob disease crisis struck, the number of GH-deficient patients treated with pit-hGH increased from about 150 to over 3,000. The advent of biosynthetic GH (rhGH) and its availability to treat large numbers of idiopathic GH-deficient children (the minimum prevalence rate of which in the USA and UK is between 1 in 3,400 and 4,000) dramatically changed this picture in 1985. It is estimated that more than 60,000 patients have been or are now on treatment. With rhGH treatment the attained mean adult height SDS is now about –1.0, and in our experience with the treatment of patients under 4 years of age, final height may exceed the target height. It is now recognized that (a) the replacement dose of rhGH ranges from 0.175 to 0.35 mg/kg/week and should be individualized; (b) dividing this dose into 6 or 7 daily subcutaneous injections is more effective than giving the same total dose in three weekly portions, and (c) final height correlates significantly with pretreatment chronologic age, height SDS and predicted adult height, duration of therapy, birth length, in some studies height SDS and age at start of puberty, weight, and serum GHBP (an indicator of GH receptor mass). Early recognition of GHD is essential for an optimal height outcome. rhGH treatment should not be delayed in children with documented GHD; the greater the height deficit, the lower the probability that target height will be reached. GHD needs to be detected earlier in children with organic hypopituitarism whether due to a developmental defect, neoplasm, radiation, head trauma, or a CNS infection. Early rhGH therapy in neonatal hypopituitarism has resulted in excellent growth responses. As the height prognosis in isolated GHD is not as good (especially in girls) as in GHD associated with gonadotropin deficiency, the use of LHRH agonists to delay puberty or potent aromatase inhibitors to delay skeletal maturation should be considered in selected patients with isolated GHD. When the growth response to rhGH is less than predicted, one must consider: (a) poor compliance; (b) improper preparation of rhGH for administration or faulty injection techniques; (c) the timing of administration; (d) the dose of glucocorticoid in the ACTH-deficient patient; (e) occult hypothyroidism; (f) inadequate nutrition; (g) a chronic illness; (h) neutralizing antibodies to rhGH, and (i) the wrong diagnosis. The major cause of mortality (unrelated to Creutzfeldt-Jakob disease or a CNS neoplasm) is adrenal crisis and hypoglycemia in children with both GH and ACTH deficiency. Major adverse effects of rhGH treatment in children are uncommon and include idiopathic intracranial hypertension, slipped capital femoral epiphysis, and acute pancreatitis. The rhGH is not an added risk for leukemia in the US and Europe in the absence of coexisting risk factors, nor is there a higher risk of recurrence of brain or other neoplasms. Even with the striking effects of rhGH on growth and body composition, there are important quality-of-life issues that need to be addressed. Finally, we need to consider the consequences of discontinuing treatment after adult height is achieved. We interpret the current weight of evidence to favor continued rhGH treatment at a much reduced dose and schedule of administration, with or without an interval of interrupted therapy (the latter has been useful in enabling the adolescent to make a personal judgment). Long-term monitoring including the determination of serial serum IGF-I levels is essential, for example, that the serum IGF-I does not exceed the normal range for age. The potential risk of excessive IGF-I on the growth of mutated cells merits vigilance. In any event, all GH-deficient patients should be reassessed for the presence of GHD as 25–65% of isolated GH-deficient patients have normal GH responses to provocative stimuli on retesting in adolescence and adulthood. New approaches to the treatment of GHD are discussed.