Journal article
Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin
The Journal of clinical investigation, Vol.103(2), pp.271-279
01/15/1999
DOI: 10.1172/JCI5205
PMCID: PMC407884
PMID: 9916139
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 (T
3
)-suppressible serum TSH and pituitary TSH-β mRNA. Serum thyroxine (T
4
) levels were only marginally elevated in transgenic mice and thyrotropin-releasing hormone (TRH) gene expression in the paraventricular hypothalamus was downregulated. After TRH administration, T
4
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 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 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.
Details
- Title: Subtitle
- Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin
- Creators
- E. Dale Abel - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USAHelen C Kaulbach - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USAAngel Campos-Barros - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USARexford S Ahima - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USAMary-Ellen Boers - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USAKoshi Hashimoto - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USADouglas Forrest - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USAFredric E Wondisford - Thyroid Unit and Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.103(2), pp.271-279
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI5205
- PMID
- 9916139
- PMCID
- PMC407884
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 01/15/1999
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024551602771
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