Decreased serum insulin-like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease

To determine whether chronic hypoxemia results in alterations in endocrine function that may contribute to growth failure, we measured growth hormone (GH), somatomedins (insulin-like growth factors I and II, IGF-I and IGF-2), hepatic growth hormone receptors, and circulating IGF-binding proteins IGFBP-3 and IGFBP-2 in 12 newborn lambs with surgically created pulmonic stenosis and atrial septal defect, and in 10 controls. During chronic hypoxemia (oxygen saturation of 60-74% for 2 wk), weight gain was 60% of control (hypoxemic, 135±20 vs. control, 216±26 g/d, P < 0.02). IGF-I was decreased by 43% (hypoxemic 253.6±29.3 SE vs. control 448.0±75.5 ng/ml, P = 0.01), whereas GH was unchanged (19.9±5.1 vs. 11.9±3.0 ng/ml, NS). The increase in IGF-1 was associated with a decrease in IGFBP-3 (hypoxemic, 5.09±1.25 vs. control, 11.2±1.08 arbitrary absorbency units per mm (Au · mm), P <0.01), and increase in IGFBP-2 (0.47±0.03 vs. 0.19±0.13 Au · mm, P < 0.05), but no significant downregulation of hepatic GH receptors (hypoxemic, 106.1±20.1 vs. control, 147.3±25.9 fmol/mg, NS). Thus, chronic hypoxemia in the newborn is associated with a decrease in IGF-I and IGFBP-3 in the face of normal GH. This suggests peripheral GH unresponsiveness, similar to protein-calorie malnutrition or GH receptor deficiency dwarfism, but mediated at a level distal to the hepatic GH receptor.