General Background on the Hypothalamic-Pituitary-Thyroid (HPT) Axis

Abstract

This article reviews the thyroid system, mainly from a mammalian standpoint. However, the thyroid system is highly conserved among vertebrate species, so the general information on thyroid hormone production and feedback through the hypothalamic-pituitary-thyroid (HPT) axis should be considered for all vertebrates, while species-specific differences are highlighted in the individual articles. This background article begins by outlining the HPT axis with its components and functions. For example, it describes the thyroid gland, its structure and development, how thyroid hormones are synthesized and regulated, the role of iodine in thyroid hormone synthesis, and finally how the thyroid hormones are released from the thyroid gland. It then progresses to detail areas within the thyroid system where disruption could occur or is already known to occur. It describes how thyroid hormone is transported in the serum and into the tissues on a cellular level, and how thyroid hormone is metabolized. There is an in-depth description of the alpha and beta thyroid hormone receptors and their functions, including how they are regulated, and what has been learned from the receptor knockout mouse models. The nongenomic actions of thyroid hormone are also described, such as in glucose uptake, mitochondrial effects, and its role in actin polymerization and vesicular recycling. The article discusses the concept of compensation within the HPT axis and how this fits into the paradigms that exist in thyroid toxicology/endocrinology. There is a section on thyroid hormone and its role in mammalian development: specifically, how it affects brain development when there is disruption to the maternal, the fetal, the newborn (congenital), or the infant thyroid system. Thyroid function during pregnancy is critical to normal development of the fetus, and several spontaneous mutant mouse lines are described that provide research tools to understand the mechanisms of thyroid hormone during mammalian brain development. Overall this article provides a basic understanding of the thyroid system and its components. The complexity of the thyroid system is clearly demonstrated, as are new areas of research on thyroid hormone physiology and thyroid hormone action developing within the field of thyroid endocrinology. This review provides the background necessary to review the current assays and endpoints described in the following articles for rodents, fishes, amphibians, and birds.

Bioconcentration and metabolism of decabromodiphenyl ether (BDE-209) result in thyroid endocrine disruption in zebrafish larvae

“…Significant transcriptional up-regulation of Pax8 and Nkx2.1a was observed, suggesting that thyroid growth and development were promoted to compensate for the depressed T4 levels. As thyroid transcription factors, Nkx2.1a (TTF1) and Pax8 regulate the expression of NIS and TG in the thyroid system (Kambe et al, 1996;Zoeller et al, 2007), the increased gene transcription of NIS and TG observed in the present study may be controlled by Nkx2.1a and Pax8 to compensate for the reduced T4 levels. A significant up-regulation in transcription of these genes has also been reported in DE-71 exposure to zebrafish larvae concomitant with decreased T4 levels (Yu et al, 2010).…”

Exposure to DE-71 alters thyroid hormone levels and gene transcription in the hypothalamic–pituitary–thyroid axis of zebrafish larvae

“…In the present study, the transcription of slc5a5 and TG genes was significantly upregulated. The transcription of the NIS gene is regulated by thyroid transcription factor (TTF-1, TTF-2) and Pax8, and stimulated by TSH (Zoeller et al, 2007a). Thus, TSH enhances the ability of the thyroid gland to trap iodide.…”

“…In the present study, exposure to DE-71 significantly upregulated the transcription of CRH and TSH␤ genes. Some reports suggest that THs modulate the expression of TRH and TSH in mammals via a negative feedback mechanism (Elsalini and Rohr, 2003;Zoeller et al, 2007a;Manchado et al, 2008;Chiamolera and Wondisford, 2009). Probably, the modulation of transcription of CRH and TSH genes is influenced by the TH levels.…”

“…The products of sodium/iodide symporter (NIS), TG, and TPO genes are known to be involved in TH synthesis (Zoeller et al, 2007a;Manchado et al, 2008). In zebrafish, the slc5a5 gene (encoding a sodium/iodide symporter) is expressed in the thyroid and its product is responsible for iodine uptake from the bloodstream (Porazzi et al, 2009).…”

Variation in adrenal and thyroid hormones with life-history stage in juvenile northern elephant seals (Mirounga angustirostris)

“…Thyroid hormones help regulate metabolic rate by altering expression of membrane ion pumps and can increase glucose oxidation rates in some species (Atkinson et al, 2011). Thyroid hormones can increase the metabolic clearance of cortisol (Thompson, 2007), as well as inducing the release of cortisol at inflammation sites (Zoeller et al, 2007). Under conditions of chronic stress, cortisol promotes the expression of deiodonase enzymes that produce rT3 from T4 (Helmreich and Tylee, 2011).…”