Syndrome of GH bioinactivity: myth or reality?

Short stature due to GH bioinactivity is characterized by lack of GH action in spite of high serum immunoassayable GH levels and low serum basal IGF-I values significantly increasing after a short-term exogenous GH administration. No clear data concerning the incidence, the diagnostic accuracy and the long-term growth response to GH therapy have been reported till now. Out of 700 short patients with a GH deficiency-like phenotype but normal GH secretion, we selected 12 prepubertal children (8 M, 4 F) showing normal/high serum peak GH levels measured by commercial kits (IFMA) in contrast with a reduced GH activity evaluated by Nb2 proliferation assay, and marked increase in serum IGF-I values during somatomedin generation test (0.1 IU/Kg/day per 4 days). The children’s mean chronological age was 10.59 yrs, bone age 7.75 yrs, height –2.74 SDS, and growth rate –2.13 SDS. In the same period, we evaluated 15 age-matched GHD prepubertal children (11 M, 4 F) with similar auxological criteria and complete GH deficiency (serum GH peak <5 ng/ml). The median area under the curve (AUC) of bioactivity/immunoactivity ratio was significantly lower in bioinactive than GHD children (6.30 vs. 32.3, p< 0.001) indicating a lower biological activity of GH. In the present research, we observed that substitutive GH therapy (0.23 mg/kg/week) induced a significant (p<0.001) increase in growth rate in both GHD and bioinactive patients during the first two years. Subsequently, only GHD children maintained the same growth velocity on the 3rd year of treatment. Both somatomedin generation test and Nb2 cell bioassay can identify the non-GHD children who would benefit from a long-term GH administration, but are not predictive of growth response to a long-term GH treatment. The waning effect observed after three years of substitutive therapy leads to hypothesize a partial GH insensitivity in children with reduced GH biological activity.