Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin
E. Dale Abel, … , Douglas Forrest, Fredric E. Wondisford
E. Dale Abel, … , Douglas Forrest, Fredric E. Wondisford
Published January 15, 1999
Citation Information: J Clin Invest. 1999;103(2):271-279. https://doi.org/10.1172/JCI5205.
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Article

Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin

Abstract

Patients with resistance to thyroid hormone (RTH) exhibit elevated thyroid hormone levels and inappropriate thyrotropin (thyroid-stimulating hormone, or TSH) production. The molecular basis of this disorder resides in the dominant inhibition of endogenous thyroid hormone receptors (TRs) by a mutant receptor. To determine the relative contributions of pituitary versus hypothalamic resistance to the dysregulated production of thyroid hormone in these patients, we developed a transgenic mouse model with pituitary-specific expression of a mutant TR (Δ337T). The equivalent mutation in humans is associated with severe generalized RTH. Transgenic mice developed profound pituitary resistance to thyroid hormone, as demonstrated by markedly elevated baseline and non–triodothyronine (T3)-suppressible serum TSH and pituitary TSH-β mRNA. Serum thyroxine (T4) levels were only marginally elevated in transgenic mice and thyrotropin-releasing hormone (TRH) gene expression in the paraventricular hypothalamus was downregulated. After TRH administration, T4 concentrations increased markedly in transgenic, but not in wild-type mice. Transgenic mice rendered hypothyroid exhibited a TSH response that was only 30% of the response observed in wild-type animals. These findings indicate that pituitary expression of this mutant TR impairs both T3-mediated suppression and T3-independent activation of TSH production in vivo. The discordance between basal TSH and T4 levels and the reversal with TRH administration demonstrates that resistance at the level of both the thyrotroph and the hypothalamic TRH neurons are required to elevate thyroid hormone levels in patients with RTH.

Authors

E. Dale Abel, Helen C. Kaulbach, Angel Campos-Barros, Rexford S. Ahima, Mary-Ellen Boers, Koshi Hashimoto, Douglas Forrest, Fredric E. Wondisford

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Effect of TRH administration. Serum T4 and TSH concentrations, before an...
Effect of TRH administration. Serum T4 and TSH concentrations, before and after the implantation of a 1-mg sustained release TRH pellet. Nineteen TG and 18 WT mice were studied. Basal T4 and TSH concentrations were obtained in all mice. To minimize the stress of repeated bleeding, and given the volume of serum required, TSH and T4 concentrations were obtained in a subset of mice (12 TG and 12 WT) at 6 h and 24 h. The remaining 7 TG and 6 WT mice were bled daily starting at 24 h for T4 only. Mice from both lines were studied, and combined data are shown. Note that TG and WT mice both show an initial T4 and TSH response to TRH, but the response is sustained beyond 24 h in TG mice at a time when values have returned to normal in WT animals. For T4 data: *P < 0.05, **P < 0.001, †P < 0.0001, TG vs WT. For TSH data: †P < 0.0001, TG vs. WT.