Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Article Article has an altmetric score of 3

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

  • Text
  • PDF
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

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Effect of T3 administration on serum T4, TSH concentrations, and pituita...
Effect of T3 administration on serum T4, TSH concentrations, and pituitary TSH-β mRNA. (a) Total T4 concentrations (line 1) obtained at weekly intervals during the administration of pharmacological doses of T3 for 3 weeks. The hatched line represents the limit of detection of the T4 RIA. Mice with homozygous allelic expression of the transgene (TG homo; n = 5) were compared with TG mice harboring one transgenic allele (TG hetero; n = 13) and WT mice (n = 21). TSH concentrations were determined at baseline and at the end of 3 weeks in 11 heterozygous TG mice and 8 WT mice. Note that T4 and TSH are undetectable in WT mice after 3 weeks. In contrast, TG mice reveal only partial suppression of T4 and lack of suppression of TSH, indicating pituitary resistance. For the T4 data: ¥¥P < 0.01 and ††P< 0.0001, TG homo vs. TG hetero; ¥P < 0.01, †P< 0.001, *P < 0.0001, TG homo and hetero vs. WT. For TSH data: ¥P < 0.01, basal vs. treated WT. (b) Comparison of T4 concentrations before and after the administration of T3 in line 1 and line 2 TG mice. Note that despite basal thyroid hormone concentrations in line 2 that were similar to those of WT mice, T4 concentrations in line 2 are only partially suppressed to a level that is similar to that observed in line 1. TSH concentrations in line 2 mice were also partially suppressed to levels that were equivalent to untreated WT mice (44 ng/ml) after 3 weeks of T3 administration (data not shown). *P < 0.0001 compared with T3 treated values in lines 1 and 2. (c) TSH-β mRNA expression in pituitaries of T3 treated mice from both lines. Total RNA from pooled pituitaries (six mice per group) was analyzed by Northern blotting. The blots were initially hybridized with the mouse TSH-β cDNA and then with cyclophillin. Densitometry was used to determine mRNA abundance and cyclophyllin expression used to adjust the TSH-β message for differences in loading. TSH mRNA abundance is expressed in arbitrary OD units with WT basal expression normalized to 100. Note complete suppression of TSH-β message in WT mice, lack of suppression in line 1 mice, and partial suppression in line 2 mice. T3, triiodothyronine.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 1 policy sources
30 readers on Mendeley
See more details