Reversible effects of cessation and recommencement of thyroxine treatment on insulin-like growth factors (IGFs) and IGF-binding proteins in patients with total thyroidectomy.

Abstract

There is a complex relationship between the thyroid and pituitary GH/insulin-like growth factor (IGF) axes. IGFs circulate in association with six specific high affinity binding proteins (IGFBPs) that modulate their bioactivity and bioavailability. Recent evidence suggests that gene expression and circulating levels of IGFBPs are related to prevailing thyroid hormone status. We have investigated the effects of both withdrawal and reinstitution of thyroid hormone replacement on circulating IGF and IGFBP levels in athyreotic patients (n = 10). The mean IGF-I concentration fell from a basal level of 191.8 +/- 12 micrograms/L to a nadir of 136.4 +/- 17.8 micrograms/L (P = 0.026) 5 weeks after stopping T4 treatment and returned to normal values 3 weeks after recommencement of replacement treatment. The fall in IGF-II levels followed a similar pattern from a basal mean level of 649 +/- 33.7 to 547 +/- 42.7 micrograms/L (P = 0.026) at 5 weeks. These changes paralleled the fall in free T3 and free T4. Similarly, IGFBP-1 levels fell after stopping T4 treatment from a basal level of 54.8 +/- 4.0 to 24.6 +/- 7.0 micrograms/L (P = 0.001) 5 weeks later. After T4 treatment was restarted, IGFBP-1 levels rose and were not significantly different from basal values by week 8. There were strong positive correlations between paired data sets for IGFBP-1 and free T3 (r = 0.488; P = 0/0037) and free T4 (r = 0.56; P = 0.0006), and a strong negative correlation with TSH (r = -0.515; P = 0.0001). Insulin is known to be important in the regulation of IGFBP-1, but no changes in fasting insulin levels during T4 withdrawal were noted, and levels of IGFBP-1 did not exhibit the normal inverse relationship with circulating insulin levels. Levels of IGFBP-2, assessed by Western ligand blotting, increased during the development of hypothyroidism, peaked 5 weeks after stopping T4 replacement, and declined on reinstitution of replacement treatment. A further level of regulation of the IGF-IGFBP axis is afforded by the presence of specific circulating IGFBP proteases. Proteases directed against IGFBP-3 proteolytically cleave the major carrier BP in the circulation and reduce its binding affinity, possibly resulting in increased tissue IGF bioavailability. Despite the marked reduction in circulating IGF levels and the generation of significant biochemical hypothyroidism, IGFBP-3 protease activity was not apparent during the 10-week period of the study.(ABSTRACT TRUNCATED AT 400 WORDS)