Thyroid Research Thyroid Research Archive Thyroid Hormone Secretion

Deficiency of thyrotropin-releasing hormone impairs the thyrotropin response to hypothyroidism

(July 2006)

The background of the study. Thyrotropin (TSH) secretion is stimulated by thyrotropin-releasing hormone (TRH) and inhibited by thyroxine (T4) and triiodothyronine (T3), the latter acting through nuclear T3 receptors (TR). In this study, the potency of these two regulatory mechanisms was evaluated in mice lacking TRH, in mice lacking TR, and in mice lacking both.

How the study was done. Mice lacking the TRH gene and the TR gene were mated to produce mice lacking both genes. Thus, there were four groups of mice: normal mice, TRH-deficient mice, TR-deficient mice, and TRH- and TR-deficient mice. All the mice were normal at birth and were viable thereafter, and their fertility was normal. Serum TSH and T4 were measured before and after induction of hypothyroidism with antithyroid drugs and treatment of hypothyroid mice with T3.

The results of the study. The TRH-deficient mice had slightly high serum immunoreactive TSH concentrations, and their serum T4 concentrations were low. In the TR-deficient mice, serum TSH and T4 concentrations were high. The TRH- and TR- deficient mice had slightly high serum TSH and low T4 concentrations, like the TRH-deficient mice. The biologic activity of serum TSH in the mice with TRH deficiency was low.

Hypothyroidism resulted in very low serum T4 concentrations in all groups, and very high serum TSH concentrations in normal mice and TR-deficient mice, moderately high concentrations in TRH-deficient mice, and only slight increases in the mice with both TRH and TR deficiency. When hypothyroid mice were treated with T3, their serum TSH concentrations progressively declined, but, as compared with wild-type mice, the decline was more rapid in the TRH-deficient mice and slower in the TR-deficient and the TRH- and TR-deficient mice, indicative of resistance to T3 action.

The conclusions of the study. TRH-deficient mice secrete TSH with decreased biologic activity and have hypothyroidism, and their ability to increase TSH secretion in response to hypothyroidism is poor, especially when there is concomitant thyroid hormone resistance.

The original article. Nikrodhanond AA, Ortiga-Carvalho TM, Shibusawa N, Hashimoto K. Liao XH, Refetoff S, Yamada M, Mori M, Wondisford FE. Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis. J Biol Chem 2006;281:5000-7.