Hypothalamus‐Pituitary‐Thyroid Axis

Abstract

The hypothalamus-pituitary-thyroid (HPT) axis determines the set point of thyroid hormone (TH) production. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH), which acts at the thyroid to stimulate all steps of TH biosynthesis and secretion. The THs thyroxine (T4) and triiodothyronine (T3) control the secretion of TRH and TSH by negative feedback to maintain physiological levels of the main hormones of the HPT axis. Reduction of circulating TH levels due to primary thyroid failure results in increased TRH and TSH production, whereas the opposite occurs when circulating THs are in excess. Other neural, humoral, and local factors modulate the HPT axis and, in specific situations, determine alterations in the physiological function of the axis. The roles of THs are vital to nervous system development, linear growth, energetic metabolism, and thermogenesis. THs also regulate the hepatic metabolism of nutrients, fluid balance and the cardiovascular system. In cells, TH actions are mediated mainly by nuclear TH receptors (210), which modify gene expression. T3 is the preferred ligand of THR, whereas T4, the serum concentration of which is 100-fold higher than that of T3, undergoes extra-thyroidal conversion to T3. This conversion is catalyzed by 5'-deiodinases (D1 and D2), which are TH-activating enzymes. T4 can also be inactivated by conversion to reverse T3, which has very low affinity for THR, by 5-deiodinase (D3). The regulation of deiodinases, particularly D2, and TH transporters at the cell membrane control T3 availability, which is fundamental for TH action. © 2016 American Physiological Society. Compr Physiol 6:1387-1428, 2016.

Novel aspects of T3 actions on GH and TSH synthesis and secretion: physiological implications

“…Changes in the orientation, spacing and number of half-sites of TRE were also observed (Yen 2001, Ortiga-Carvalho et al 2016. In the rGh promoter, the sequences could be oriented as palindromes, or direct repeats separated by 4 nucleotides (Yen 2001, Cheng et al 2010.…”

“…The THRs are differentially expressed in most tissues. Thrb2 is highly expressed in the pituitary, paraventricular, ventromedial and arcuate nuclei of hypothalamus, inner ear and in some regions of the brain during development, while Thrb1 mRNA is mainly detected in the brain, skeletal muscle, liver and kidney of rats (Lazar 1993, Ortiga-Carvalho et al 2016. Mutations in THR isoforms are associated with different phenotypes according to tissue distribution of the mutated receptor (Mendoza & Hollenberg 2017).…”

“…Although the precise sequence of negative TREs (nTRE) has not been described yet (Ortiga-Carvalho et al 2016), previous studies demonstrated that they appear to be near the TSS of Cga/CGA and Tshb/TSHB genes of rats, mice and humans (Carr et al 1987, Shupnik 2000. However, recent studies have shown that the negative regulation of human TSHB gene exerted by T 3 is independent of nTRE (Matsushita et al 2007, Matsunaga et al 2015.…”

“…Considering that DIO2 is responsible for the intracellular generation of T 3 from T 4 and that T 3 is an important Gh and Tshb gene expression modulator (Ortiga-Carvalho et al 2016), our group attempted to investigate the repercussions of hypothyroidism and T 3 effects in the cytoskeleton of pituitary cells and the consequences to GH and TSH secretion (Silva et al 2006, Bargi-Souza et al 2013.…”

The Hypothyroid Brain

“…The thyroid, like other endocrine glands, is controlled by a classic feedback system, the hypothalamus-pituitary-thyroid axis [1,2] . And the hormone it produces, thyroid hormone (TH), plays a critical role in growth, development and cellular metabolism.…”