Thyroxine (T₄)

Triiodothyronine (T₃)

Thyroxine (T₄)

Triiodothyronine (T₃)

The thyroid hormones, thyroxine (T₄) and triiodothyronine (T₃), are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. Iodine is important for the production of T₃ and T₄. A deficiency of iodine leads to decreased production of T₃ and T₄, enlarges the thyroid tissue and will cause the disease known as goitre. The major form of thyroid hormone in the blood is thyroxine (T₄), which has a longer half-life than T₃. The ratio of T₄ to T₃ released into the blood is roughly 20 to 1. T₄ is converted to the active T₃ (three to four times more potent than T₄) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T₁a) and thyronamine (T₀a).

Circulation and transport[link]

Plasma transport[link]

Most of the thyroid hormone circulating in the blood is bound to transport proteins. Only a very small fraction of the circulating hormone is free (unbound) and biologically active, hence measuring concentrations of free thyroid hormones is of great diagnostic value.

When thyroid hormone is bound, it is not active, so the amount of free T₃/T₄ is what is important. For this reason, measuring total thyroxine in the blood can be misleading.

T₃ and T₄ cross the cell membrane easily as they are lipophilic molecules, and function via a well-studied set of nuclear receptors in the nucleus of the cell, the thyroid hormone receptors.

T₁a and T₀a are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor TAAR1 (TAR1, TA1), a G-protein-coupled receptor located in the cell membrane.

Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone (TSH) that is present.

Membrane transport[link]

Contrary to common belief, thyroid hormones can not traverse cell membranes in a passive manner like other lipophilic substances. The iodine in o-position makes the phenolic OH-group more acidic, resulting in a negative charge at physiolocical pH. However, at least 10 different active, energy dependent and genetic regulated iodothyronine transporters have been identified in humans. They guarantee that intracellular levels of thyroid hormones are higher than in blood plasma or interstitial fluids.^[1]

Intracellular transport[link]

Little is known about intracellular kinetics of thyroid hormones. However, recently it could be demonstrated that the crystallin CRYM binds 3,5,3′-triiodothyronine in vivo.^[2]

Function[link]

The thyroid system of the thyroid hormones T3 and T4.^[3]

The thyronines 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 neuronal maturation, and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness. The 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 hormone leads 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.

Related diseases[link]

Both excess and deficiency of thyroxine can cause disorders.

• Hyperthyroidism (an example is Graves Disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men. Thyrotoxicosis is often used interchangeably with hyperthyroidism, but there are subtle differences. Although thyrotoxicosis also refers to an increase in circulating thyroid hormones, it can be caused by the intake of thyroxine tablets or by an over-active thyroid, whereas hyperthyroidism refers solely to an over-active thyroid.
• Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.
• Clinical depression can sometimes be caused by hypothyroidism.^[4] Some research^[5] has shown that T₃ is found in the junctions of synapses, and regulates the amounts and activity of serotonin, norepinephrine, and Gamma-aminobutyric acid (GABA) in the brain.

Preterm births can suffer neurodevelopmental disorders due to lack of maternal thyroid hormones, at a time when their own thyroid is unable to meet their postnatal needs.^[6]

Measurement[link]

Thyroxine and triiodothyronine can be measured as free thyroxine and free triiodothyronine, which are indicators of thyroxine and triiodothyronine activities in the body. They can also be measured as total thyroxine and total triiodothyronine, which also depend on the thyroxine and triiodothyronine that is bound to thyroxine-binding globulin. A related parameter is the free thyroxine index, which is total thyroxine multiplied by thyroid hormone uptake, which, in turn, is a measure of the unbound thyroxine-binding globulins.^[7]

Medical use of thyroid hormones[link]

Both T₃ and T₄ are used to treat thyroid hormone deficiency (hypothyroidism). They are both absorbed well by the gut, so can be given orally. Levothyroxine is the pharmaceutical name (INN) of physiological thyroxine (T₄), which is metabolised more slowly than T₃ and hence usually only needs 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 is usually the first course of treatment tried. Some patients feel they do better on desiccated thyroid hormones, however, this is based on anecdotal evidence and no clinical trials have shown any benefit over the biosynthetic forms.^[8]

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, useful in preventing damage during ischemic shock.

Synthetic thyroxine was first successfully produced by Charles Robert Harington and George Barger in 1926.

Formulations[link]

Today most patients are treated with levothyroxine, or a similar synthetic thyroid hormone.^[9][10][11] However, natural thyroid hormone supplements from the dried thyroids of animals are still available.^[11] Natural thyroid hormones have become less popular, due to evidence that varying hormone concentrations in the thyroids of animals before they are slaughtered leads to inconsistent potency and stability.^[12][13] Levothyroxine contains T4 only and is therefore largely ineffective for patients unable to convert T4 to T3.^[14] These patients may choose to take natural thyroid hormone as it contains a mixture of T4 and T3,^{[11][15][16][17][18]} or alternatively supplement with a synthetic T3 treatment.^[19] In these cases, synthetic liothyronine is preferred due to the potential differences between drug lots of natural thyroid products. Also it would be counterintuitive to supplement with a T4/T3 combination if the patient cannot convert T4 to T3. Some natural thyroid hormone brands are F.D.A. approved, but some are not.^[20][21][22] Thyroid hormones are generally well tolerated.^[10] Thyroid hormones are usually not dangerous for pregnant women or nursing mothers, but should be given under a doctor's supervision. In fact, if a woman who is hypothyroid is left untreated, her baby is at a higher risk for birth defects. When pregnant, a woman with a low functioning thyroid will also need to increase her dosage of thyroid hormone.^[10] One exception is that thyroid hormones may aggravate heart conditions, especially in older patients; therefore, doctors may start these patients on a lower dose & work up to avoid risk of heart attack.^[11]

Production of the thyroid hormones[link]

Central[link]

Synthesis of the thyroid hormones, as seen on an individual thyroid follicular cell:^[23]
- Thyroglobulin is synthesized in the rough endoplasmic reticulum and follows the secretory pathway to enter the colloid in the lumen of the thyroid follicle by exocytosis.
- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide (I^-) actively into the cell, which previously has crossed the endothelium by largely unknown mechanisms.
- This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin, in a purportedly passive manner.^[24]
- In the colloid, iodide (I^-) is oxidized to iodine (I⁰) by an enzyme called thyroid peroxidase.
- Iodine (I⁰) is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain (in total containing approximately 120 tyrosyl residues).
- In conjugation, adjacent tyrosyl residues are paired together.
- The entire complex re-enters the follicular cell by endocytosis.
- Proteolysis by various proteases liberates thyroxine and triiodothyronine molecules, which enter the blood by largely unknown mechanisms.

Thyroid hormones (T₄ and T₃) are produced by the follicular cells of the thyroid gland and are regulated by TSH made by the thyrotrophs of the anterior pituitary gland. Because the effects of T₄ in vivo are mediated via T₃ (T₄ is converted to T₃ in target tissues), T₃ is 3- to 5- fold more active than T₄.

Thyroxine (3,5,3',5'-tetraiodothyronine) is produced by follicular cells of the thyroid gland. It is produced as the precursor thyroglobulin (this is not the same as TBG), which is cleaved by enzymes to produce active T₄.

Thyroxine is produced by attaching iodine atoms to the ring structures of tyrosine molecules. Thyroxine (T₄) contains four iodine atoms. Triiodothyronine (T₃) is identical to T₄, but it has one less iodine atom per molecule.

Iodide is actively absorbed from the bloodstream by a process called iodide trapping. In this process, 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. Via a reaction with the enzyme thyroperoxidase, iodine is bound to tyrosine residues in the thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). Linking two moieties of DIT produces thyroxine. Combining one particle of MIT and one particle of DIT produces triiodothyronine.

• DIT + MIT → r-T₃ (biologically inactive)
• MIT + DIT → triiodothyronine (usually referred to as T₃)
• DIT + DIT → thyroxine (referred to as T₄)

Proteases digest iodinated thyroglobulin, releasing the hormones T₄ and T₃, the biologically active agents central to metabolic regulation.

Peripheral[link]

Thyroxine is believed to be a prohormone and a reservoir for the most active and main thyroid hormone T₃. T₄ is converted as required in the tissues by iodothyronine deiodinase. Deficiency of deiodinase can mimic an iodine deficiency. T₃ is more active than T₄ and is the final form of the hormone, though it is present in less quantity than T₄.

Initiation of production in fetuses[link]

Thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) start being secreted from the fetal hypothalamus and pituitary at 18-20 weeks of gestation, and fetal production of thyroxine (T₄) reach a clinically significant level at 18–20 weeks.^[25] Fetal triiodothyronine (T₃) remains low (less than 15 ng/dL) until 30 weeks of gestation, and increases to 50 ng/dL at term.^[25] Fetal self-sufficiency of thyroid hormones protects the fetus against e.g. brain development abnormalities caused by maternal hypothyroidism.^[26]

Effect of iodine deficiency on thyroid hormone synthesis[link]

If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormone. The lack of thyroid hormone will lead to decreased negative feedback on the pituitary, leading to increased production of thyroid-stimulating hormone, which causes the thyroid to enlarge (goiter)endemic colloid goiter. This has the effect of increasing the thyroid's ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone.

Anti-thyroid drugs[link]

Iodine uptake against a concentration gradient is mediated by a sodium-iodine symporter and is linked to a sodium-potassium ATPase. Perchlorate and thiocyanate are drugs that can compete with iodine at this point. Compounds such as goitrin can reduce thyroid hormone production by interfering with iodine oxidation.^[27]

Effects of thyroxine[link]

• Increases cardiac output
• Increases heart rate
• Increases ventilation rate
• Increases basal metabolic rate
• Potentiates the effects of catecholamines (i.e. increases sympathetic activity)
• Potentiates brain development
• Thickens endometrium in females
• increase metabolism of proteins and carbohydrates

Herbs[link]

There are no herbs (plant chemicals) that contain thyroid hormone.^[15][28] Therefore, while there are some herbs that may provide some help for a sluggish thyroid (i.e. if the thyroid is producing a low amount of thyroid hormone, but has not stopped completely),^[29] myxedema requires treatment with synthetic or desiccated natural thyroid hormones.^[28][30] However, there are many edible plants that have high concentrations of iodine (e.g., seaweed and kelp). Iodine is an irreplaceable precursor to the biosynthesis of thyroid hormones.

See also[link]

• Hormone
• Thyroid gland
• Thyroid-stimulating hormone
• Thyronamines, metabolites of the thyroid hormones that act at the trace amine-associated receptor TAAR1 (TAR1)
• Goitre
• Graves-Basedow disease

References[link]

External links[link]

• Find TH response elements in DNA sequences.
• Triiodothyronine bound to proteins in the PDB
• Thyroxine bound to proteins in the PDB

Thyroid hormone treatment in thyroid disease

• Thyroid Hormone Treatment Brochure by the American Thyroid Association
• Elaborate article about the use of thyroid drugs Written by an MD
• What is the "Best" Thyroid Drug? Is it Synthroid, Unithroid, Armour, Thyrolar, or Something Else? Article by health activist and patient advocate Mary Shomon
• Thyroid Disease Manager Collection of elaborate medical articles on thyroid disease, including information on thyroid hormones
• Stop the thyroid madness Collection of references to articles comparing different treatment methods of hypothyroidism