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Submitted on December 29, 2008
Accepted on January 13, 2009
Division of Metabolism, Departments of Pediatrics, Medicine, and Physiology, Johns Hopkins University Medical School Baltimore, Maryland 21287, USA
* To whom correspondence should be addressed. E-mail: fwondisford{at}jhmi.edu.
Thyroid Hormone (TH) plays a critical role in development, growth and cellular metabolism. TH production is controlled by a complex mechanism of positive and negative regulation. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates thyrotropin (TSH) secretion from the anterior pituitary. TSH then initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit genes is inhibited at the transcriptional level by TH, which also inhibits post-translational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid (HPT) axis, TH negative feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant role for TRH in regulating the HPT axis and an unanticipated involvement of the thyroid hormone receptor (TR) ligand-dependent activation function (AF-2) domain in TH negative regulation. These results are summarized in the review.
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