THE GROWTH-HORMONE CASCADE - PROGRESS AND LONG-TERM RESULTS OF GROWTH-HORMONE TREATMENT IN GROWTH-HORMONE DEFICIENCY

The growth hormone (GH) cascade and the remarkable advances over the p ast 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 successful ly treated with pit-hGH. However, the shortage of pit-hGH limited its use and the dose, the biopotency of preparations varied, strict criter ia of GH deficiency (GHD) were used for patient selection including pe ak plasma immunoreactive GH levels after provocative stimuli of less-t han 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 p it-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 defi ciencies to between -1 and -2 SDS. Between 1962 and 1985 when the Creu tzfeldt-Jakob disease crisis struck, the number of GH-deficient patien ts treated with pit-hGH increased from about 150 to over 3,000. The ad vent of biosynthetic GH (rhGH) and its availability to treat large num bers 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) dramatical ly 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 a ttained 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 replaceme nt dose of rhGH ranges from 0.175 to 0.35 mg/kg/week and should be ind ividualized, (b) dividing this dose into 6 or 7 daily subcutaneous inj ections is more effective than giving the same total dose in three wee kly portions, and (c) final height correlates significantly with pretr eatment chronologic age, height SDS and predicted adult height, durati on of therapy, birth length, in some studies height SDS and age at sta rt of puberty, weight, and serum GHBP (an indicator of GH receptor mas s). Early recognition of GHD is essential for an optimal height outcom e. rhGH treatment should not be delayed in children with documented GH D; the greater the height deficit, the lower the probability that targ et height will be reached. GHD needs to be detected earlier in childre n with organic hypopituitarism whether due to a developmental defect, neoplasm, radiation, head trauma, or a CNS infection. Early rhGH thera py in neonatal hypopituitarism has resulted in excellent growth respon ses. As the height prognosis in isolated GHD is not as good (especiall y in girls) as in GHD associated with gonadotropin deficiency, the use of LHRH agonists to delay puberty or potent aromatase inhibitors to d elay skeletal maturation should be considered in selected patients wit h isolated GHD. When the growth response to rhGH is less than predicte d, one must consider: (a) poor compliance; (b) improper preparation of rhGH for administration or faulty injection techniques; (c) the timin g of administration; (d) the dose of glucocorticoid in the ACTH-defici ent patient; (e) occult hypothyroidism; (f) inadequate nutrition; (g) a chronic illness; (h) neutralizing antibodies to rhGH, and (i) the wr ong 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 r hGH treatment in children are uncommon and include idiopathic intracra nial hypertension, slipped capital femoral epiphysis, and acute pancre atitis. The rhGH is not an added risk for leukemia in the US and Europ e in the absence of coexisting risk factors, nor is there a higher ris k of recurrence of brain or other neoplasms. Even with the striking ef fects of rhGH on growth and body composition, there are important qual ity-of-life issues that need to be addressed. Finally, we need to cons ider the consequences of discontinuing treatment after adult height is achieved. We interpret the current weight of evidence to favor contin ued rhGH treatment at a much reduced dose and schedule of administrati on, 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 excee d the normal range for age. The potential risk of excessive IGF-I on t he growth of mutated cells merits vigilance. In any event, all GH-defi cient patients should be reassessed for the presence of GHD as 25-65% of isolated GH-deficient patients have normal GH responses to provocat ive stimuli on retesting in adolescence and adulthood. New approaches to the treatment of GHD are discussed.