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

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 dom inant inhibition of endogenous thyroid hormone receptors (TRs) by a mutant receptor. To determine the relative contributions of pituitary versus hypot halamic resistance to the dysregulated production of thyroid hormone in the se patients, we developed a transgenic mouse model with pituitary-specific expression of a mutant TR(Delta 337T). The equivalent mutation in humans is associated with severe generalized RTH. Transgenic mice developed profound pituitary resistance to thyroid hormone, as demonstrated by markedly eleva ted baseline and non-triodothyronine (T-3)-suppressible serum TSH and pitui tary TSH-beta mRNA. Serum thyroxine (T-4) levels were only marginally eleva ted in transgenic mice and thyrotropin-releasing hormone (TRH) gene express ion in the paraventricular hypothalamus was downregulated. After TRH admini stration, T-4 concentrations increased markedly in transgenic, but not in w ild-type mice. Transgenic mice rendered hypothyroid exhibited a TSH respons e that was only 30% of the response observed in wild-type animals. These fi ndings indicate that pituitary expression of this mutant TR impairs both T- 3-mediated suppression and T-3-independent activation of TSH production in vivo. The discordance between basal TSH and T-4 levels and the reversal wit h 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.