Blunting of TSH response after repeated oral administration of TRH in normal and hypothyroid subjects.

Abstract

In euthyroid subjects, repeated oral doses of TRH produced a greater increase of plasma levels of thyroxine (T4) and triiodothyronine (T3) than did a single dose. The TSH response, in contrast, was diminished. To determine if this blunting of the response was mediated by a negative feedback mechanism, we compared the effects of single and repeated oral doses of TRH on TSH, T3, and T4 responses in euthyroid subjects and in patients with primary thyroid failure. Thirty-five euthyroid subjects were given 3 oral doses of 40 mg TRH over a period of 26 h. The mean TSH peak declined from 13.0 µU/ml after the 1st dose to 5,9 µU/ml after the 3rd dose (P < 0.0005). T4 concentrations increased from basal 7.5 to 10.2 µg/100 ml 3 h after the 3rd dose of TRH and T3 from 1.52 to 2.19 ng/ml. Repeated oral doses of TRH were also given to 9 patients with primary hypothyroidism and 9 patients after total thyroid ablation for thyroid carcinoma. The same significant blunting of the TSH response after the 3rd oral dose of TRH was observed in these 18 hypothyroid patients (98.2 µU/ml after the 1st dose and 43.7 µU/ml after the 3rd dose, P < 0.0005). No increase in T3 or T4 was detected in the 9 athyreotic patients. These findings do not support the suggestions of previous workers that the blunting of the TSH response is mediated only by a negative feedback mechanism. Our data in hypothyroid subjects clearly demonstrate that a decrease of the TSH response after repeated oral doses of TRH can occur without an increase in the levels of circulating thyroid hormones. Other mechanisms independent of the ordinary feedback regulation must therefore be considered: e.g. decrease of TRH receptors at the pituitary cells, pituitary depletion of TSH or a transitory disequilibrium between the release and the de novo synthesis or TSH suppression by “short loop” feedback mechanism. (J Clin Endocrinol Metab46: 260, 1978)