Special ArticleUpdate of guidelines for the use of growth hormone in children: the Lawson Wilkins pediatric endocrinology society drug and therapeutics committee
Section snippets
FDA-approved uses of GH
Recombinant human GH has replaced human pituitary-derived GH, which should no longer be used because of the risk of contamination with the Jakob Creutzfeld prion. By 1995, the Food and Drug Administration (FDA) had approved GH therapy for short stature in the following conditions for which efficacy has been shown and much experience has been gained:
- 1.
Growth hormone deficiency (GHD)/insufficiency
- 2.
Chronic renal insufficiency pretransplantation
- 3.
Turner syndrome
Since 1995, the FDA has approved GH for
Diagnosis of GHD
The diagnoses of Turner syndrome, PWS, chronic renal insufficiency, and SGA are generally straightforward based on genetic testing, renal function, and/or birth data coupled with auxology. However, considerable variability exists in the diagnosis of GH deficiency, which remains a clinical challenge.3., 4. This is related to the continuum between severe GHD and normality, marked variability in GH assays, arbitrary “cut-offs” conventionally used to define GH deficiency on the basis of GH
Adult GHD
The approval for adult GHD is based on evidence that GH can reverse some of the abnormalities in body composition (increased total body fat, decreased lean body mass) and elevation in serum cholesterol seen in adult GHD. Subsequent studies have demonstrated improvements in bone mineral density, cardiac function, and quality of life in adult patients with GHD treated with GH.9., 10., 11., 12., 13.
AIDS wasting
GH is approved for adults (but not children) with AIDS wasting.14 Recently a multicenter study was launched under the auspices of the Pediatric AIDS Clinical Trials Group to determine the efficacy and safety of GH in children with HIV.
Prader-Willi syndrome
Studies of four years' duration have demonstrated GH-induced alterations in body composition (decreased body fat and increased lean body mass) and increased linear growth in children with PWS.15., 16., 17., 18., 19. Many of these children appear to have GHD, although this should be interpreted in the context of the patients' body mass index because short, nonobese children with PWS may not have biochemical evidence of GHD. Dosages used have varied in different studies. Higher doses may be
Sustained postnatal growth failure in children who have been SGA
Studies up to six years in duration have demonstrated that GH treatment of children with sustained postnatal growth failure secondary to intrauterine growth restriction (used synonymously with SGA in this communication) increases growth rate and stature.20., 21., 22., 23., 24. Although extensive adult height data have not yet been reported, a recent randomized study looking at the effect of GH therapy for 2.7±0.6 years on short adolescents born SGA demonstrated an increase in near adult height
Idiopathic short stature
GH was recently approved by the FDA for children with idiopathic short stature who are >2.25 SD below the mean in height and who are unlikely to catch up in height. The predicted adult heights of children in this group were <63 inches for boys and <59 inches for girls. This approval is based on one randomized placebo controlled study and a second dose–response study in children with idiopathic short stature demonstrating an increase adult height or predicted adult height of from 1.5 to 3 inches.
Investigational uses of GH
Recent studies have suggested a potential role for GH therapy in a variety of additional conditions. A placebo-controlled study demonstrated a reduction in disease-related symptoms in adults with Crohn's disease.26 Another study demonstrated an anabolic effect of GH in children with glucocorticoid-dependent Crohn's disease.27 Uncontrolled studies have demonstrated short-term improvements in growth velocity in children with glucocorticoid-induced suppression of growth in other disorders, but no
Safety issues
The safety of GH therapy was evaluated in a Growth Hormone Research Society consensus conference published in 2001 and endorsed by the Lawson Wilkins Pediatric Endocrine Society.37 A review of the safety of childhood GH therapy was recently published.38 Established and potential side effects of GH are listed in Table I. Overall, adverse effects of GH therapy occur in fewer than 3% of treated children compared with ∼10% of adults.
“Benign” increased intracranial pressure (pseudotumor cerebri) may
Growth hormone products
Multiple preparations of GH are available. Overall, there are no observable differences in the results obtained among the different preparations as long as the regimen follows currently approved daily injections. Many of the products are available in a variety of injection devices that are meant to make administration more appealing and easier. At this time, there is no evidence that clinical outcome differs among the various injection systems, although there may be patient and parent
Dosing of GH
Children with GHD may be treated once magnetic resonance imaging or computed tomography has excluded an intracranial mass lesion. GH should be administered subcutaneously on a daily basis and the dosage of GH should be expressed in μg (or mg)/kg/day. GH is routinely used in the range of 25-50 μg/kg/day in prepubertal children. A dose-response relationship in terms of height velocity in the first two years of treatment has been clearly demonstrated within this range. In prepubertal males with GHD
Recommendations for monitoring and dose adjustments
The routine follow-up of pediatric patients receiving GH should be performed by a pediatric endocrinologist in partnership with the pediatrician or primary care physician. Children should be evaluated every 3 to 6 months. Increase in height and height velocity are the most important indicators of response to GH. For comparative purposes, data should be expressed as the increase in (or Δ) height SDS for age and sex.
Adequate response to childhood GH therapy is shown by an increase in linear
Transition from pediatric to adult use of GH
Often idiopathic GHD does not persist into adult life, whereas organic GHD usually does. GH has major metabolic actions, which are important for body composition, bone mineral density, and general health in adults as well as in children. Therefore, repeat screening for GHD63 is advisable after GHD children reach adult height. Such testing should be undertaken after an interval of 1 to 3 months off GH therapy. Because the criteria for adult GHD are more stringent (peak GH <5 ng/mL) than for
Conclusions
Recombinant human GH is an important pharmacologic agent to stimulate linear growth and improve body composition in children with GHD and to increase linear growth in children with chronic renal failure, Turner syndrome, PWS, and those with postnatal growth failure secondary to having been born SGA. Side effects are uncommon and often reversible with discontinuation of GH or a reduction in dose. Although recently approved by the FDA for severe idiopathic short stature, the impact of GH
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