Thyroid hormones


Thyroid hormones are two hormones produced and released by the thyroid gland: triiodothyronine and thyroxine. They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, which is derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue, and causes the disease known as simple goitre.
The major form of thyroid hormone in the blood is thyroxine, whose half-life of around one week is longer than that of T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 within cells by deiodinases. These are further processed by decarboxylation and deiodination to produce iodothyronamine and thyronamine. All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production. Calcitonin, a peptide hormone produced and secreted by the thyroid, is usually not included in the meaning of "thyroid hormone".
Thyroid hormones are one of the factors responsible for the modulation of energy expenditure. This is achieved through several mechanisms, such as mitochondrial biogenesis and adaptive thermogenesis.
American chemist Edward Calvin Kendall was responsible for the isolation of thyroxine in 1915. In 2020, levothyroxine, a manufactured form of thyroxine, was the second most commonly prescribed medication in the United States, with more than 98million prescriptions. Levothyroxine is on the World Health Organization's List of Essential Medicines.

Function

Thyroid hormones act on nearly every cell in the body. They act to increase the basal metabolic rate, affect protein synthesis, help regulate long bone growth and neural maturation, and increase the body's sensitivity to catecholamines by permissiveness, especially under cold exposure. Thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.
Thyroid hormones lead to heat generation in humans. However, the thyronamines function via some unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals and the moulting behaviour of birds. One effect of administering the thyronamines is a severe drop in body temperature.

Medical use

Both T3 and T4 are used to treat thyroid hormone deficiency. They are both absorbed well by the stomach, so they can be given orally. Levothyroxine is the chemical name of the manufactured version of T4, which is metabolised more slowly than T3 and hence usually needs only once-daily administration. Natural desiccated thyroid hormones are derived from pig thyroid glands, and are a "natural" hypothyroid treatment containing 20% T3 and traces of T2, T1 and calcitonin.
Also available are synthetic combinations of T3/T4 in different ratios and pure-T3 medications. Levothyroxine sodium is usually the first course of treatment tried. Some patients report better outcomes with desiccated thyroid hormone; however, this is based on anecdotal evidence, and clinical trials have not shown any benefit over biosynthetic forms. Thyroid tablets are reported to have different effects, which can be attributed to the difference in torsional angles surrounding the reactive site of the molecule.
Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia, which causes the brain to enter a protective cycle and can be useful in preventing damage during ischemic shock. Synthetic thyroxine was first successfully produced by Charles Robert Harington and George Barger in 1926.

Formulations

Most people are treated with levothyroxine, or a similar synthetic thyroid hormone. Different polymorphs of the compound have different solubilities and potencies. Additionally, natural thyroid hormone supplements from the dried thyroids of animals are available. Levothyroxine contains T4 only and is therefore largely ineffective for patients unable to convert T4 to T3. These patients may choose to take natural thyroid hormone, as it contains a mixture of T4 and T3, or alternatively supplement with a synthetic T3 treatment. In these cases, synthetic liothyronine is preferred due to the potential differences between the natural thyroid products. Some studies show that mixed therapy is beneficial to all patients, but the addition of lyothyronine causes side effects, so the medication should be evaluated on an individual basis. Some natural thyroid hormone brands are FDA-approved, but others are not. Thyroid hormones are generally well tolerated. Thyroid hormones are usually not dangerous for pregnant women or nursing mothers, but should be given under a physician's supervision. In fact, if a pregnant woman with hypothyroidism is left untreated, her fetus is at a higher risk for congenital disabilities relative to the norm. When pregnant, a woman with a low-functioning thyroid will also need to increase her dosage of thyroid hormone. One exception is that thyroid hormones may aggravate heart conditions, especially in older patients; therefore, physicians may start these patients on a lower dose and work up to a larger one to avoid the risk of a heart attack.

Thyroid metabolism

Central

Thyroid hormones are produced by thyroid epithelial cells and are regulated by thyroid-stimulating hormone made by the thyrotropes of the anterior pituitary gland. The effects of T4 in vivo are mediated via T3. T3 is three to five times more active than T4. T4, thyroxine, is produced by follicular cells of the thyroid gland. It is produced from the precursor thyroglobulin, which is cleaved by enzymes to produce active T4.
The steps in this process are as follows:
  1. The Na+/I− symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I− against its concentration gradient. This is called iodide trapping. Sodium is cotransported with iodide from the basolateral side of the membrane into the cell, and then concentrated in the thyroid follicles to about thirty times its concentration in the blood.
  2. I− is moved across the apical membrane into the colloid of the follicle by pendrin. Hydrogen peroxide is also introduced into the follicle by the action of DUX.
  3. Iodide is non-reactive, and the reactive I2 species is required for the next step. Thyroperoxidase reduces hydrogen peroxide to water by transferring one electron from two I− atoms that react to form I2.
  4. Iodine is converted into HOI, by hydration with water. Both I2 and HOI iodinate specific tyrosyl residues of the thyroglobulin within the colloid to form 3-monoiodityrosyl and 3,5-diiodityrosyl residues—introducting iodine atoms at one or both locations ortho to the hydroxyls of tyrosine. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.
  5. TPO also converts tyrosyl, MIT-yl, and DIT-yl residues into their free radical forms. These forms attack other MIT-yl and DIT-yl residues. When a DIT-yl radical attacks a DIT, T4-yl is formed. When a MIT-yl radical attacks a DIT, T3-yl is formed. Other reactions are possible, but do not form physiologically active products.
  6. Iodinated thyroglobulin binds megalin for endocytosis back into the cell.
  7. TSH released from the anterior pituitary binds the TSH receptor on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.
  8. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave any MIT, DIT, T3, T4 as well as the inactive analogues from the iodinated thyroglobulin.
  9. The thyroid hormones cross the follicular cell membrane towards the blood vessels by an unknown mechanism. Textbooks have stated that diffusion is the main means of transport, but recent studies indicate that monocarboxylate transporter 8 and 10 play major roles in the efflux of the thyroid hormones from thyroid cells.
Thyroglobulin is a 660 kDa, dimeric protein produced by the follicular cells of the thyroid and used entirely within the thyroid gland. Thyroxine is produced by attaching iodine atoms to the ring structures of this protein's tyrosine residues; thyroxine contains four iodine atoms, while triiodothyronine, otherwise identical to T4, has one less iodine atom per molecule. The thyroglobulin protein accounts for approximately half of the protein content of the thyroid gland. Each thyroglobulin molecule contains approximately 100–120 tyrosine residues, a small number of which are subject to iodination catalysed by thyroperoxidase. The same enzyme then catalyses "coupling" of one modified tyrosine with another, via a free-radical-mediated reaction, and when these iodinated bicyclic molecules are released by hydrolysis of the protein, T3 and T4 are the result. Therefore, each thyroglobulin protein molecule ultimately yields very small amounts of thyroid hormone.
Hydrolysis of the modified protein by proteases then liberates T3 and T4, as well as the non-coupled tyrosine derivatives MIT and DIT. The hormones T4 and T3 are the biologically active agents central to metabolic regulation.