Growth, IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis?

Intrauterine growth retardation (IUGR) is one of the major causes of short stature in childhood. Although postnatal catch-up growth occurs in the majority of IUGR children, approximately 20% of them remain permanently short. The mechanisms that allow catch-up growth or, on the contrary, prevent IUGR children from achieving a normal height are still unknown. Our aim was to investigate whether intrauterine reprogramming of hypothalamic-pituitary-adrenal axis may be involved in postnatal growth retardation of IUGR children through a modulation of the function of the IGF system. Anthropometry, IGF system assessment, cortisol measurement, and lipid profile evaluation were performed in 49 IUGR children. Children were subdivided into two groups according to their actual height corrected for midparental height: CG (catch-up growth) group, 19 children with corrected height >or=0 z-score; and NCG (noncatch-up growth) group, 30 subjects with corrected height <0 z-score. CG children showed significantly higher birth weight (p < 0.005) and body mass index (p < 0.05). No significant differences in IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, soluble IGF-II receptor levels (IGF2R), IGF-II/IGF2R ratio, and relative amounts of IGFBP-3 circulating forms were found between CG and NCG children. None of the IGF system-related variables correlated with anthropometric indices. NCG children showed significantly higher concentrations of cortisol (p < 0.005) and cortisol levels resulted inversely to birth weigh (r = -0.34, p < 0.05), birth length (r = -0.36, p < 0.05), and corrected height (r = -0.44, p < 0.01). Whereas total and HDL cholesterol concentrations were not significantly different in the two groups, LDL cholesterol levels were significantly higher in NCG children (p < 0.05), and five of 49 showed LDL cholesterol concentrations >3.4 mM (130 mg/dL). LDL cholesterol was inversely related to birth weight (r = -0.31, p < 0.05), corrected stature (r = -0.32, p < 0.05), and actual height (r = -0.31, p < 0.05) and directly related to the levels of IGF2R (r = 0.44, p < 0.01). Reanalysis of 15 of 30 IUGR newborns in whom we previously reported an inverse relationship between cord blood cortisol levels and first trimester length gain (r = -0.54, p < 0.005) showed that the relative amount of the IGFBP-3 18-kD fragment was related inversely to cortisol (r = -0.67, p < 0.01) and directly to early postnatal growth (r = 0.65, p < 0.05). Our results suggest that catch-up growth in IUGR children might be affected by intrauterine reprogramming of hypothalamic-pituitary-adrenal axis, which may result in a permanent modification of the neuroendocrine response to stress: children with increased cortisol secretion may be at higher risk of growth failure. During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and, therefore, reducing IGF bioavailability.