Thyroid hormone

The thyroid hormones, thyroxine (T₄) and triiodothyronine (T₃), are tyrosine-based hormones produced by the thyroid gland. An important component in the synthesis is iodine. The major form of thyroid hormone in the blood is thyroxine (T₄). The ratio of T₄ to T₃ released in the blood is roughly 20 to 1. Thyroxine 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).

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Circulation

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, probably via amino acid importins, 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 the amount of thyroid-stimulating hormone (TSH) that is present.

Function

The thyronines act on the body to increase the basal metabolic rate, affect protein synthesis 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 vitamins metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.

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

Both excess and deficiency of thyroxine can cause disorders.

• Thyrotoxicosis or hyperthyroidism (more specifically 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.
• 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^[1]. Some research^[2] 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.

Medical use of thyroid hormones

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, the most commonly used synthetic thyroxine form, is a stereoisomer of physiological thyroxine, which is metabolised more slowly and hence usually only needs once-daily administration. Natural desiccated thyroid hormones, which are derived from pig thyroid glands, are a "natural" hypothyroid treatment containing 20% T₃ and traces of T₂, T₁ and calcitonin.

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.

Production of the thyroid hormones

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 'iodine trapping'and concentrated in the thyroid follicles. (If there is a deficiency of dietary iodine, the thyroid enlarges in an attempt to trap more iodine, resulting in goitre.) Via a reaction with the enzyme thyroperoxidase, iodine is covalently 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. Thyroxine is supposedly a prohormone and a reservoir for the most active and main thyroid hormone T₃. T₄ is converted as required in the tissues by deiodinases. 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.

Anti-thyroid drugs

Iodine uptake against a concentration gradient is mediated by a sodium iodine symporter. Perchlorate and thiocyanate are drugs that can compete with iodine at this point.

Effects of thyroxine

• Increases cardiac output
• Increases heart rate
• Increases ventilation rate
• Increases basal metabolic rate
• Potentiates brain development
• Thickens endometrium in females

References

1. ^ Kirkegaard C, Faber J (1998). "The role of thyroid hormones in depression.". Eur J Endocrinol 138 (1): 1-9. PMID 9461307.
2. ^ Dratman M, Gordon J (1996). "Thyroid hormones as neurotransmitters.". Thyroid 6 (6): 639-47. PMID 9001201.

See also

• 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