The effects of thyroid hormone on insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) expression in the neonatal rat: Prolonged high expression of IGFBP-2 in methimazole-induced congenital hypothyroidism

In the rat a developmental switch in the serum insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) profile takes place during the first 3 postnatal weeks. The fetal expression pattern of high IGF-II and IGFBP-2 is replaced by the adult pattern of low levels of IGF-II and IGFBP-2 and high levels of IGF-I and IGFBP-3. The regulatory mechanisms mediating these changes are unknown, but may include perinatal changes in endocrine function. To study the effects of thyroid function and the perinatal thyroid secretory burst on IGF and IGFBP expression, we established a rat model of congenital hypothyroidism, leading to marked postnatal growth retardation during the perinatal period. The hypothyroid animals lacked the steep rise in serum IGF-I levels normally occurring during the third week of life, showing only a modest rise to approximately 50% of control levels. The pattern of serum IGF-II decline in hypothyroid animals was slightly different from that in controls, with lower IGF-II levels during the second week of life and a slower decline down to the very low final levels. The hypothyroid pups continued to express high levels of IGFBP-2 up to the age of 19 days, while the control animals, after a slow initial decline, showed an abrupt fall of IGFBP-2 serum levels during the third week of life. Liver IGFBP-2 mRNA levels reflected the serum changes, with elevated IGFBP-2 mRNA in hypothyroid animals. The expression of other IGFBPs did not differ from that in the control group. At the age of 18 days, serum GH levels in the hypothyroid animals were approximately one third of control GH levels, which suggests a role for GH as a possible mediator of thyroid hormone actions on the IGF system. The changes in growth parameters and in the IGF and IGFBP profile of hypothyroid pups could be abolished by thyroid hormone replacement from birth. We conclude that thyroid hormone is, directly or indirectly, essential for some of the neonatal changes in IGF and IGFBP profiles.