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  • Review Article
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Potential therapeutic applications of thyroid hormone analogs

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 632–640 (2007)Cite this article

Abstract

Thyroid hormone (T3 and T4) has many beneficial effects including enhancing cardiac function, promoting weight loss and reducing serum cholesterol. Excess thyroid hormone is, however, associated with unwanted effects on the heart, bone and skeletal muscle. We therefore need analogs that harness the beneficial effects of thyroid hormone without the untoward effects. Such work is largely based on understanding the cellular mechanisms of thyroid hormone action, specifically the crystal structure of the nuclear receptor proteins. In clinical studies, use of naturally occurring thyroid hormone analogs can suppress TSH levels in patients with thyroid cancer without producing tachycardia. Many thyromimetic compounds have been tested in animal models and shown to increase total body oxygen consumption, and to lower weight and serum cholesterol and triglyceride levels while having minor effects on heart rate. Alternatively, analogs that specifically enhance both systolic and diastolic function are potentially useful in the treatment of chronic congestive heart failure. In addition to analogs that are thyroid hormone receptor agonists, several compounds that are thyroid hormone receptor antagonists have been identified and tested. This Review discusses the potential application of thyroid hormone analogs (both agonists and antagonists) in a variety of human disease states.

Key Points

  • Thyroid hormone receptor agonists and antagonists can be used to harness the beneficial effects of naturally occurring hormones while minimizing adverse effects

  • Knowledge of the crystal structures of the hormone receptors has proved invaluable in designing effective analogs

  • Some analogs can increase total body oxygen consumption, lower weight and improve the lipid profile with only minor effects on heart rate

  • Other analogs can selectively enhance systolic and diastolic function to alleviate congestive heart failure

  • Analogs such as tetraiodothyroacetic acid can affect TSH release from the pituitary

  • Thyroid hormone antagonists might provide an acceptable alternative for conditions such as amiodarone-induced hyperthyroidism

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Figure 1: Structures of endogenous thyroid hormones (T4 and T3) and the most commonly studied thyroid hormone receptor agonists TRIAC, TETRAC, DITPA, DIMIT, GC-1, KB-141, SKF 94901 and antagonists DIBRT and NH-3
Figure 2: Relative biologic activity of KB-141 compared with T3 on heart rate, VO2, and serum cholesterol in cholesterol-fed rats13
Figure 3: Effects of thyroid hormones and their analogs on various organ systems

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Acknowledgements

This work was supported in part by an American Thyroid Association grant to S Danzi and NIH General Clinical Research Center MO1RR018535.

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Authors and Affiliations

  1. G Brenta is an Assistant Professor of Endocrinology at the School of Medicine of the Favaloro University of Buenos Aires and a staff member in the Department of Endocrinology and Metabolism, French Hospital, Buenos Aires, Argentina.,

    Gabriela Brenta

  2. S Danzi is an Assistant Professor of Medicine and I Klein is Associate Chairman in the Department of Medicine at North Shore University Hospital and the Feinstein Institute for Medical Research, New York; S Danzi is also Assistant Professor of Medicine and I Klein is Professor of Medicine in the Department of Medicine, and I Klein is Professor of Cell Biology in the Department of Cell Biology, Manhasset, New York University School of Medicine, New York, USA.,

    Sara Danzi & Irwin Klein

  3. S Danzi is also Assistant Professor of Medicine and I Klein is Professor of Medicine in the Department of Medicine, and I Klein is Professor of Cell Biology in the Department of Cell Biology, New York University School of Medicine, New York, USA.,

    Sara Danzi & Irwin Klein

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  1. Gabriela Brenta
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Correspondence to Irwin Klein.

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Competing interests

I Klein is a Consultant for King Pharmaceuticals, Roche Pharmaceuticals and Titan Pharmaceuticals; he has also received grant support from King Pharmaceuticals. The other authors declared no competing interests.

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Brenta, G., Danzi, S. & Klein, I. Potential therapeutic applications of thyroid hormone analogs. Nat Rev Endocrinol 3, 632–640 (2007). https://doi.org/10.1038/ncpendmet0590

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