Dose-response relationship between thyroid hormone and growth velocity in cynomolgus monkeys

To investigate the dose-response relationship between thyroid hormone and linear growth, we studied 10 castrated prepubertal cynomolgus monkeys. Hypothyroidism was induced by administration of methimazole (0.0125% in drinking water) and was confirmed by high serum TSH levels (greater than 40 mU/L) in all animals. Subsequently, each animal received 1, 2, 4, or 8 micrograms/kg.day T4, im, for 9 weeks. The sequence of T4 doses was random, and 6 weeks elapsed between successive T4 doses. Serum T4, T3, TSH, and insulin-like growth factor I (IGF-I) levels and lower leg length were measured every 3 weeks. Methimazole administration decreased thyroid hormone and IGF-I levels and lower leg growth rate. With increasing doses of exogenous T4, serum T4, T3, and IGF-I as well as lower leg growth rate increased significantly. Animals not given T4 had a 65% decrease in lower leg growth rate (P less than 0.01). Animals given 4 and 8 micrograms/kg.day T4 had 56% and 73% increases, respectively, in lower leg growth rate compared to baseline (P less than 0.05 and P less than 0.01, respectively). Lower leg growth rate correlated better with serum T3 (r = 0.50; P less than 0.001) than with serum T4 (r = 0.29; P less than 0.05). Lower leg growth rate also correlated with serum IGF-I levels (r = 0.53; P less than 0.001). Serum IGF-I correlated with serum T3 (r = 0.47; P less than 0.001), but not with serum T4. We conclude that increased serum T4 and T3 levels cause progressive increases in growth velocity and IGF-I levels over a range from moderate hypothyroidism to moderate hyperthyroidism. Growth velocity and IGF-I levels correlated more strongly with the serum T3 than with the serum T4 level.