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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 (Delta337T). 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-beta 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.
AuthorsE D Abel, H C Kaulbach, A Campos-Barros, R S Ahima, M E Boers, K Hashimoto, D Forrest, F E Wondisford
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 103 Issue 2 Pg. 271-9 (Jan 1999) ISSN: 0021-9738 [Print] United States
PMID9916139 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Protein Precursors
  • RNA, Messenger
  • Receptors, Thyroid Hormone
  • Triiodothyronine
  • prepro-thyrotropin-releasing hormone
  • Thyrotropin-Releasing Hormone
  • Thyrotropin
  • Thyroxine
Topics
  • Animals
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Mutation (genetics)
  • Pituitary Gland (metabolism)
  • Protein Precursors (genetics)
  • RNA, Messenger (metabolism)
  • Receptors, Thyroid Hormone (genetics)
  • Thyroid Hormone Resistance Syndrome (genetics)
  • Thyrotropin (blood, metabolism)
  • Thyrotropin-Releasing Hormone (genetics)
  • Thyroxine (blood)
  • Triiodothyronine (pharmacology)

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