REVERSIBLE EFFECTS OF CESSATION AND RECOMMENCEMENT OF THYROXINE TREATMENT ON INSULIN-LIKE GROWTH-FACTORS (IGFS) AND IGF-BINDING PROTEINS INPATIENTS WITH TOTAL THYROIDECTOMY

There is a complex relationship between the thyroid and pituitary GH/i nsulin-like growth factor (IGF) axes. IGFs circulate in association wi th six specific high affinity binding proteins (IGFBPs) that modulate their bioactivity and bioavailability. Recent evidence suggests that g ene expression and circulating levels of IGFBPs are related to prevail ing thyroid hormone status. We have investigated the effects of both w ithdrawal and reinstitution of thyroid hormone replacement on circulat ing IGF and IGFBP levels in athyreotic patients (n = 10). The mean IGF -I concentration fell from a basal level of 191.8 +/- 12 mu g/L to a n adir of 136.4 +/- 17.8 mu g/L (P = 0. 026) 5 weeks after stopping T-4 treatment and returned to normal values 3 weeks after recommencement o f 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 mu g/L (P = 0.026) at 5 weeks. These changes paralleled the fall in free T-3 and free T-4. Similarly, IGFBP-1 levels fell after stopping T-4 treat ment from a basal level of 54.8 +/- 4.0 to 24.6 +/- 7.0 mu g/L (P = 0. 001) 5 weeks later. After T-4 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 T-3 (r = 0.488; P = 0/0037) and free T-4 (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 T-4 withdrawal wer e noted, and levels of IGFBP-1 did not exhibit the normal inverse rela tionship with circulating insulin levels. Levels of IGFBP-2, assessed by Western ligand blotting, increased during the development of hypoth yroidism, peaked 5 weeks after stopping T-4 replacement, and declined on reinstitution of replacement treatment. A further level of regulati on of the IGF-IGFBP axis is afforded by the presence of specific circu lating IGFBP proteases. Proteases directed against IGFBP-3 proteolytic ally cleave the major carrier BP in the circulation and reduce its bin ding affinity, possibly resulting in increased tissue IGF bioavailabil ity. Despite the marked reduction in circulating IGF levels and the ge neration of significant biochemical hypothyroidism, IGFBP-3 protease a ctivity was not apparent during the 10-week period of the study. We ha ve confirmed the intricate relationships between thyroid hormone statu s and circulating levels of IGFs and IGFBPs. During the genesis of hyp othyroidism, levels of IGF-I and -2 and IGFBP-1 and -3 fall, and level s of IGFBP-2 rise, but these changes are rapidly and completely revers ed by reinstitution of thyroid hormone replacement.