Thyroid hormones

Thyroid hormones are two hormones produced and released by the thyroid gland: triiodothyronine (T3) and thyroxine (T4). 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 (T4), 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 (three to four times more potent than T4) within cells by deiodinases (5′-deiodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). 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 98 million 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 (synergy with growth hormone) and neural maturation, and increase the body's sensitivity to catecholamines (such as norepinephrine and epinephrine) 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 (hypothyroidism). 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 (such as liotrix) and pure-T3 medications (INN: liothyronine). 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. These desiccated thyroid extract formulations predate the modern FDA drug approval process and have not undergone formal FDA review for safety and efficacy under current approval standards. 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

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