Diagnosis of growth hormone (GH) deficiency and the use of GH in children with growth disorders

(1) Diagnosis of GH deficiency must be based on auxological as well as biochemical evidence. Clinically, several combinations of height and growth deficit may be used as auxological criteria: (a) severe growth retardation (HSDS < - 3); (b) moderate growth retardation (HSDS < - 2) and decreased growth rate (< 25th percentile); (c) severely decreased growth rate (< 5th percentile), or (d) decreased growth rate following cranial irradiation. Biochemically, two separate pathological provocative tests are required with peak GH responses below a well-characterized cut-off value corresponding to the specific provocative stimulus and GH assay used in each clinic. At present, auxological criteria, provocative testing (peak GH < 10 ng/ml) combined with IGF-I and IGFBP-3 determination is recommended for the initial diagnosis. However, provocative testing is unphysiological and we still lack international standardization of GH assays and definition of proper cut-off limits for the provocation test. However, IGF-I and IGFBP-3 levels < - 2 SD below the sex- and age-related mean for healthy children predict GHD to a high degree if other diseases (e.g. malnutrition) are excluded. (2) GHD: GH therapy is safe in children with GHD at a conventional starting dose of 2 IU/m2/day, and significantly improves final height in the majority of these children. Individual dosaging is important, but no consensus exists on how to monitor treatment in GHD children. Nevertheless, GH therapy should be considered in adulthood due to its metabolic effects after a thorough re-evaluation of GH secretory capacity with ITT after a GH withdrawal period. GH replacement therapy should be reinstituted only if peak GH response to ITT is < 9 mIU/l (3 ng/ml). In GHD adults significantly lower GH doses are required compared with what is commonly used in childhood, and the doses should be decreased with increasing age according to the IGF-I levels. (3) CRF: GH therapy can so far be regarded as safe in children with CRF before renal transplantation, and a dose of 4 IU/m2/day will significantly improve growth in these children. Renal allograft recipients have a marked increase in growth velocity, but this indication has not been registered yet. Preliminary data clearly suggest an increased final height, however, further studies are required. (4) IUGR: Children with short stature due to IUGR may benefit from GH in supraphysiological doses (3-6 IU/m2/day) in terms of short-term growth during childhood and possibly improvement of final height. However, no studies exist on GH treatment until final height in these conditions, and therefore GH treatment in IUGR is still to be considered as an experimental option. (5) TS: The partial GH resistance in TS can be overcome by supraphysiological doses of GH (approx. 4 IU/m2/day). Consequently, in many TS patients, growth is improved during GH treatment and it appears to increase final height, although the results of pending worldwide meta-analyses are awaited. (6) ISS: The available studies which have evaluated final height outcome following GH therapy question the general use of GH in these conditions, but clearly some children benefit from therapy and it therefore remains a future option to optimize prediction of which ISS children may eventually benefit from GH therapy. At present there are sufficient data available to exclude ISS as a future registered indication for GH therapy. (7) Future studies of new indications such as skeletal dysplasias, osteogenesis imperfecta, Prader-Willi syndrome, Down syndrome, Noonan syndrome, glucocorticoid-induced growth failure, and post-renal transplantation should primarily be based on large multicentre trials. Adverse events should be followed closely, reported to central independent registers. However, at present, only voluntary reports of side effects to the pharmaceutical companies is functional. Special attention should be paid to the high-dose regimens for nonconventional GH treatment for which we have limited long-term safety data.