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.
|
