Selenium and the Thyroid Gland

More Good News for Clinicians

Anne Drutel; Françoise Archambeaud; Philippe Caron

Disclosures

Clin Endocrinol. 2013;78(2):155-164. 

In This Article

Essential Role of Selenium in the Physiology of the Thyroid

Selenium: Its Role in the Synthesis of Thyroid Hormones

Synthesis of thyroid hormones requires iodination of thyroglobulin at the apical pole, in the follicular lumen under the action of thyroperoxidase (TPO) and in the presence of hydrogen peroxide (H2O2) (Fig. 1). Synthesis of H2O2, potentially dangerous for thyrocytes, is regulated by TSH via a complex system of second messengers[12] and appears to be the step that limits thyroid hormone synthesis when sufficient iodine is available. This organization enables the H2O2 formed at the surface of thyrocytes to be rapidly used for iodination reactions, while the intracellular H2O2 is degraded by antioxidant enzymes such as GPXs, TRs and catalases.[12]

Figure 1.

Role of specific selenoproteins in the synthesis of thyroid hormones in humans (adapted from Beckett GJ and Arthur JR).

Role of GPX3 In human thyrocytes, GPX3 (extracellular or plasmatic GPx) is one of the selenoproteins that is the most expressed and consequently, it contributes to the high selenium content of the thyroid.[10] It appears to be a direct regulator of thyroid hormone synthesis.

In the absence of TSH, GPX3 secretion at the apical pole of the thyrocyte decreases the amount of H2O2 available for iodination reactions. Conversely, in the presence of TSH, which is responsible for increased calcium ionophore levels, the decrease in GPX3 at the apical pole results in more H2O2 being available for TPO. GPX3 concentrations thus increase within the thyrocytes, thereby increasing the protection against oxidative stress induced by the synthesis of thyroid hormones (Fig. 1).[5]

Role of the Deiodinases Only D1 and D2 have been identified in human thyrocytes.[13] The expression of deiodinases in different tissues varies depending on the species, which makes it difficult to extrapolate the results of animal studies to humans. While less expressed than GPX3, D1 and D2 are responsible for the local activation of thyroid hormones. Although many mechanisms regulate the synthesis of deiodinases (TSH, thyroid hormones, cyclic AMP), selenium content also directly affects their activity,[14,15] and therefore, indirectly affects T3 synthesis. Selenium distribution in tissues is variable and selenoprotein synthesis is priortorized based on sources. Deiodinases appear to occupy a special place in the hierarchy in cases of selenium deficiencies thanks to the existence of a selenium accumulation and/or redistribution system in the thyroid gland.[16] More specifically, D2 and D3 appear to be more readily preserved than D1, but with organ-dependant particularities.[17,18]

Several mechanisms appear to be implicated in the maintenance of the synthesis of various selenoproteins in cases of deficient intake. So far, two distinct types of stem-loop structures (SECIS) have been identified in the 3′ region of mRNA encoding selenoproteins, with each very probably displaying different features at the time of translation of specific mRNA.[19] Although no particular affinities have been identified in vivo between the SBP2-binding protein (indispensible to translation) and either of the two SECIS variants, special interactions have been identified between SBP2 and the SECIS structures of GPX4 or selenoprotein P.[20] Furthermore, mRNAs encoding selenoproteins have different half-lives, particularly in cases of selenium deficiency.[21]

Finally, variable and relative contents of selenoproteins in cells and tissues also contribute to hierarchizing synthesis: deiodinases expressed at very low concentrations may recruit and use the selenium released during turnover of the selenoproteins present in much higher concentrations such as GPX1 or selenoprotein P. These two selenoproteins therefore represent a stock of accessible selenium in cases where intake is reduced.[25]

Selenium as an Antioxidant

Selenoproteins play a role in the regulation of the immune system. The role GPXs play in the maintenance of cell integrity and protein iodination has been clearly demonstrated, namely through the use of thyrocyte cultures of animal origin.

In pigs, selenium deficiency causing a decrease in intracellular GPX activity leads to cytoplasmic iodination of proteins following exposure to H2O2, whereas when sufficient selenium is available, iodination is limited to the apical pole of the thyrocytes.[12] Thus, alteration of the defence mechanisms used to fight the oxidative stress related to selenium deficiency results in aberrant iodination of certain proteins leading to cell apoptosis or the exposure of unusual epitopes possibly recognized by the immune system. In cultures of human thyroid follicles, apoptosis is induced by high doses of d' H2O2, iodine or TGF-β. Preincubation with low doses of selenium increases GPX activity and reduces cell death.[22]

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