What is the description of the formation of the thyroid hormones triiodothyronine (T3) and thyroxine (T4)?

From the Guidelines

The formation of thyroid hormones triiodothyronine (T3) and thyroxine (T4) involves a complex process of iodide uptake, organification, and coupling of iodinated tyrosines, as described in the context of thyroid function and disease 1. The process begins with the uptake of iodide from the bloodstream by thyroid follicular cells through the sodium-iodide symporter.

• Once inside the cell, iodide is oxidized to iodine by the enzyme thyroid peroxidase (TPO) in a process called organification.
• This activated iodine then attaches to tyrosine residues on thyroglobulin, a large glycoprotein synthesized within the thyroid follicular cells and stored in the colloid of thyroid follicles.
• The iodination of tyrosine creates monoiodotyrosine (MIT) and diiodotyrosine (DIT).
• These iodinated tyrosines then couple together through the action of TPO to form the active thyroid hormones - two DIT molecules combine to form T4 (containing four iodine atoms), while one MIT and one DIT combine to form T3 (containing three iodine atoms). The thyroglobulin with attached hormones is stored in the follicular lumen until needed.
• When thyroid hormone release is stimulated by thyroid-stimulating hormone (TSH), thyroglobulin is endocytosed back into the follicular cells, where proteolytic enzymes cleave the T3 and T4 from thyroglobulin, allowing them to be released into the bloodstream. In circulation, most thyroid hormones are bound to transport proteins, with only a small fraction existing in the free, active form that can enter cells and exert metabolic effects, as noted in the context of screening for thyroid dysfunction 1.

From the FDA Drug Label

Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

The formation of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) is not directly described in the provided text. However, it is mentioned that:

• T4 is converted to T3 through deiodination in peripheral tissues, with approximately 80% of circulating T3 derived from T4.
• The major pathway of thyroid hormone metabolism is through sequential deiodination.
• T4 is slowly eliminated and deiodinated to yield equal amounts of T3 and reverse T3 (rT3). 2

From the Research

Thyroid Hormone Formation

The formation of thyroid hormones, specifically triiodothyronine (T3) and thyroxine (T4), is a complex process that involves several steps and mechanisms.

• The process begins with iodine metabolism, which occurs in three sequential steps: active iodide transport into the thyroid, iodide oxidation, and subsequent iodination of tyrosyl residues of thyroglobulin (Tg) to produce idotyrosines monoidotyrosine (MIT) and diiodothyrosine (DIT) on Tg 3.
• Iodine oxidation is mediated by the thyroperoxidase enzyme (TPO), which is activated by Thyroid Stimulating Hormone (TSH) 3, 4.
• T4 and T3 are synthesized on Tg following MIT and DIT coupling reactions, and their production is highly regulated by a negative feedback interrelation between serum T4, T3, and TSH, as well as by the elevated iodine within the thyroid gland 3, 5.

Biosynthesis and Release

The biosynthesis and release of thyroid hormones involve the interaction of iodide, thyroglobulin (TG), hydrogen peroxide (H2O2), and thyroid peroxidase (TPO) at the apical plasma membrane of thyrocytes 4.

• The sodium/iodide symporter (NIS) plays a crucial role in the uptake of iodide by thyrocytes, and the iodination of tyrosyl residues of TG precedes thyroid hormone biosynthesis 4, 6.
• The production and release of T4 and T3 into the circulation are stimulated by TSH and inhibited by excess iodine, and the entire process is tightly regulated to maintain normal thyroid function 3, 6.

Regulation and Metabolism

The regulation and metabolism of thyroid hormones involve various mechanisms, including the conversion of T4 to T3 by iodothyronine deiodinases, and the transport of T3 out of cells by a specific, saturable, verapamil-inhibitable mechanism 5, 6.

• The intracellular concentration of T3 is determined by the rates of cellular uptake of T4 and T3, the rates of metabolic transformation, and the rate of T3 efflux 6.
• The function of thyroid hormone-binding proteins in plasma is to maintain an equilibrium between extracellular and cellular hormone pools, and certain proteins may serve specific transport functions 6.