Background: Hypoxia represents a main risk factor for acquired brain injuries and neurological disabilities in premature and full-term infants. Stabilization of hypoxia-inducible transcription factors (HIF) is one of the most important adaptive mechanism modulating the degree of hypoxic-ischemic brain lesions due to cellular adaptation to reduced oxygen concentrations. Additionally, neuro-protective effects of GH and GH-induced neurotrophic factors are evident as shown by previous in vitro studies.
Hypothesis: GH treatment prevents hypoxia-induced disturbances of the GH/IGF1 axis mediating protective effects under global hypoxia during early brain development.
Methods: At postnatal day 7 (P7) 180 mice were randomized into treatment groups of eight animals and exposed to normoxia or hypoxia (8% O2) for 6 h using an INVIVO2400 hypoxia workstation (Baker Ruskinn). Within 30 min after re-oxygenation and once daily for three consecutive days, mice were injected (i.p.) with 104 000 μg/kg hGH (Genotropin, Pfizer). Body weight and length as well as mGH and IGF1 plasma concentrations were monitored.
Results: Mice treated with 10250 μg/kg hGH gained 72% less weight (P<0.0001) until P10 and were significantly shorter than non- or sham-treated mice. Growth retardation persisted until P21 in mice dosed with 10 and 50 μg/kg hGH and were correlated to significantly decreased mGH and IGF1 plasma concentrations. Hypoxia-exposed non- and sham-treated animals gained significantly less weight (P<0.0001) between P7 and P10 than normoxic litter mates. Simultaneously, exposure to hypoxia significantly decreased plasma mGH (P<0.05) and IGF1 levels (P<0.05) for at least 1 week. Notably, treatment with 1 000 and 4 000 μg/kg hGH restored hypoxia-induced disturbances of the GH/IGF1 axis compensating hypoxia-associated growth deficiency in neonatal mice.
Conclusions: Our data clearly indicate that GH treatment stabilizes the somatotropic axis after perinatal systemic hypoxia preventing hypoxia-induced disturbances of the GH-/IGF1 system. Furthermore, demonstrating GH-dose-dependent and hypoxia-induced effects on GH regulation, our present study extends present knowledge on GH regulation during early development serving as a promising basis for further research on neuro-protective mechanisms of the immature rodent brain.
Funding: This study was supported by an unrestricted grant from Pfizer (WI178424).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology