The thyroid is controlled by a classic hypothalamic-pituitary axis (Fig. 3.1).¹ The hypothalamic tripeptide thyrotropin-releasing hormone (TRH) stimulates the production and secretion of the glycoprotein hormone TSH in the pituitary. TSH is formed of an α and a β subunit; the α subunit is common to the glycoproteins TSH, follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin.

On thyroid follicular cells, TSH binds to the TSH receptor, a G protein-coupled transmembrane receptor, which is expressed at the basolateral membrane (Fig. 3.2).² TSH binding results in stimulation of cell growth, cell differentiation, and thyroid hormone synthesis. Activation of the TSH receptor leads primarily to coupling with the stimulatory G protein Gs_α and subsequent activation of adenylyl cyclase. This, in turn, leads to an increase in intracellular cyclic AMP, phosphorylation of protein kinase A, and activation of numerous cytosolic and nuclear target proteins. At high doses of TSH, the TSH receptor also couples to G_q/11 and thereby activates the phospholipase C-dependent inositol phosphate Ca²⁺/diacylglycerol pathway. This results in an increase in hydrogen peroxide (H₂O₂) generation and iodination.

After synthesis of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3) (Fig. 3.3), a process that is discussed in more detail below, they are secreted into the bloodstream. In the serum, most T4 and T3 are protein bound to thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin, and only a minute fraction is present as free hormone.³ Thyroid hormones enter peripheral cells, a process that is at least partially mediated by amino acid channels.⁴ In the cytosol, T4 is either 5′-deiodinated by deiodinase I or II, resulting in formation of the more active T3, or is inactivated to rT3 by deiodination of the inner ring (Fig. 3.3).⁵ Thyroid hormone action is primarily mediated by two nuclear receptors, TRα and TRβ, which regulate the transcription of numerous genes.⁶ In addition, several nongenomic actions are mediated by thyroid hormones. T3 exerts a negative feedback on TRH and TSH secretion (Fig. 3.1).

Thyroid hormone synthesis requires several biochemical steps within thyroid follicular cells and the follicular lumen, the functional unit of the thyroid.⁷,⁸,⁹ Iodide is actively transported into thyroid follicular cells by the sodium-iodide symporter (NIS) at the basolateral membrane (Fig. 3.4).¹⁰ This transport requires an electrochemical gradient, which is generated by the Na, K-ATPase. Iodide then reaches the apical membrane. At the apical membrane, iodide is released into the follicular lumen. This efflux occurs, at least in part, through the anion transporter pendrin (PDS/SLC26A4).¹¹ Once iodide reaches the follicular lumen, it is oxidized by the enzyme thyroperoxidase (TPO).⁷ The oxidation of iodide by TPO requires the presence of H₂O₂. H₂O₂ production is catalyzed by the dual oxidase 2 (DUOX2), an enzyme that requires a specific maturation factor, DUOXA2, to reach the apical membrane.¹²,¹³ The follicular lumen is filled with colloid, which consists largely of thyroglobulin (TG).¹² TG serves as matrix for the synthesis of T4 and T3. In a first step, TPO iodinates selected tyrosyl residues on TG, thereby generating monoiodotyrosine (MIT) and diiodotyrosine (DIT) (organification reaction). In a second step, iodotyrosines are coupled by TPO to form T4 and T3 (coupling reaction). To release thyroid hormones, TG is internalized into the follicular cell by micro- or macropinocytosis and digested in lysosomes. T4 (˜80%) and T3 (˜20%) are subsequently released into the blood stream, in part through the thyroid hormone-transporting channel monocarboxylate transporter 8 (MCT8).¹³ To recycle iodide, which is a scarce micronutrient in many parts of the world,¹⁴,¹⁵ MIT and DIT are deiodinated by a recently cloned iodotyrosine dehalogenase, DEHAL1.¹⁶ After deiodination, the released iodide is recycled into the follicular lumen and reused for hormone synthesis (Fig. 3.4).