Age-Related Change in Pituitary Threshold for TSH Release During Thyroxine Replacement Therapy for Cretinism

Abstract

Nine patients with athyrotic or ectopic cretinism ages 6 mo.-17 yrs-were studied to examine the relation between age and the quantities of oral L-thyroxine (T4) adequate to restore TSH hypersecretion to normal levels by feedback control. All but one patient had very low levels of endogenous T4 (below 1.0 mug/100 ml) before treatment. However, based on clinical signs and serum T4-1 values, all were judged to be euthyroid or sub-clinically hyperthyroid by L-T4 replacement during the observation period. L-T4 dosage was increased or decreased by 25 or 50 mug/day at 2-12 mo. intervals, and the TSH response to exogenous thyrotropin-releasing hormone (TRH) was tested sequentially at each dose of L-T4 until a normal or slightly suppressed TSH response was obtained The L-T4 dosage which was associated with normal TSH responsiveness to TRH (the adequate L-T4 dose) was high in infancy (10 mug/kg/day), decreasing with age to a level of 3-4 mug/kg/day in pubertal children (correlation coefficient r=-0.820, P less than 0.01). The adequate L-T4 dose observed between 4 and 12 yrs of age was lower than the usually recommended dose (4-6 vs. 7-8 mug/kg/day). On these L-T4 doses, serum T4I concentrations were significantly higher in patients under 5 yrs of age than in older patients (8.3+/-1.5 vs. 6.5+/-0.7 mug/100 ml, P less than 0.02). Serum triiodothyronine (T3) values were also elevated in young children, decreasing with age to the normal range. TSH responses to TRH were completely suppressed at the serum T4-I levels of 9 mug/100 ml and T3 of 250 ng/100 ml or less in 7 patients over 4 yrs of age, but not in 2 younger patients. Although the number of patients examined was limited, these results suggest that the pituitary threshold for feedback regulation of TSH secretion by T4 decreases with age in children with cretinism and the usually recommended replacement doses of L-T4 between 4 and 12 yrs of age are probably overestimated.