File:Thyroid_system.svg, upright=1.5, The

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The ...

system of the thyroid hormones T₃ and T₄ rect 376 268 820 433

Thyroid-stimulating hormone Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism ...

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Thyrotropin-releasing hormone Thyrotropin-releasing hormone (TRH) is a hypophysiotropic hormone produced by neurons in the hypothalamus that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary. TRH has been used clinicall ...

rect 297 168 502 200

Hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

rect 66 216 386 256

Anterior pituitary gland A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...

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Negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

rect 308 436 510 475

Thyroid gland The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

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Thyroid hormones File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 386 ...

rect 357 827 569 856

Catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a su ...

rect 399 716 591 750

Metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...

desc bottom-left Thyroid hormones are any

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

s produced and released by the

thyroid gland The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

, namely

triiodothyronine Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. Production of T3 and its prohormone thyrox ...

(T₃) and thyroxine (T₄). They are

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...

-based hormones that are primarily responsible for regulation of

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...

. T₃ and T₄ are partially composed of

iodine Iodine is a chemical element with the Symbol (chemistry), symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , ...

. A deficiency of iodine leads to decreased production of T₃ and T₄, enlarges the thyroid tissue and will cause 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 Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

by deiodinases (5′-deiodinase). These are further processed by

decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

and deiodination to produce iodothyronamine (T₁a) and thyronamine (T₀a). All three isoforms of the deiodinases are

selenium Selenium is a chemical element with the symbol Se and atomic number 34. It is a nonmetal (more rarely considered a metalloid) with properties that are intermediate between the elements above and below in the periodic table, sulfur and tellurium, ...

-containing enzymes, thus dietary selenium is essential for T₃ production. 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 The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

Function

The thyroid hormones act on nearly every cell in the body. It acts to increase the

basal metabolic rate Basal metabolic rate (BMR) is the rate of energy expenditure per unit time by endothermic animals at rest. It is reported in energy units per unit time ranging from watt (joule/second) to ml O2/min or joule per hour per kg body mass J/(h·kg). P ...

, affect

protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...

, help regulate long bone growth (synergy with

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...

) and neural maturation, and increase the body's sensitivity to

catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a su ...

s (such as

adrenaline Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands an ...

) by permissiveness. The thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

, fat, and

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...

, affecting how human

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 Thyronamine refers both to a molecule, and to derivatives of that molecule: a family of decarboxylated and deiodinated metabolites of the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3). Types The group includes: * Thyronamine ...

function via some unknown mechanism to inhibit

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

al activity; this plays an important role in the

hibernation Hibernation is a state of minimal activity and metabolic depression undergone by some animal species. Hibernation is a seasonal heterothermy characterized by low body-temperature, slow breathing and heart-rate, and low metabolic rate. It mos ...

cycles of

mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

and the

moulting In biology, moulting (British English), or molting (American English), also known as sloughing, shedding, or in many invertebrates, ecdysis, is the manner in which an animal routinely casts off a part of its body (often, but not always, an outer ...

behaviour of

birds Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

. One effect of administering the thyronamines is a severe drop in

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...

Medical use

Both T₃ and T₄ are used to treat thyroid hormone deficiency (

hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as ...

). They are both absorbed well by the stomach, so can be given orally. Levothyroxine is the pharmaceutical name of the manufactured version of T₄, which is metabolised more slowly than T₃ and hence usually only needs once-daily administration.

Natural desiccated thyroid hormones Desiccated thyroid, also known as thyroid extract, is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism. It is less preferred than levothyroxine. It is taken by mouth. Maximal effects may take u ...

are derived from pig thyroid glands, and are a "natural" hypothyroid treatment containing 20% T₃ and traces of T₂, T₁ and

calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates. in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the ...

. 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 feel they do better on desiccated thyroid hormones; however, this is based on anecdotal evidence and clinical trials have not shown any benefit over the 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 Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe ...

, which causes the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

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 George Barger FRS FRSE FCS LLD (4 April 1878 – 5 January 1939) was a British chemist. Life He was born to an English mother, Eleanor Higginbotham, and Gerrit Barger, a Dutch engineer in Manchester, England. He was educated at Utrecht and T ...

in 1926.

Formulations

Structure of (''S'')-thyroxine (T₄). (''S'')-triiodothyronine (T₃, also called liothyronine). Most people are treated with levothyroxine, or a similar synthetic thyroid hormone.Robert Lloyd Segal, MD Endocrinologist Different polymorphs of the compound have different solubilities and potencies. Additionally, natural thyroid hormone supplements from the dried thyroids of animals are still 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,"Consequences of Not Taking Thyroid Medications - Implications of Failing to Take Prescription Thyroid Drugs"
Retrieved on 27 March 2009"Armour Thyroid"
Retrieved on 1 April 2009"Nature-Throid"
Retrieved on 1 April 2009
Retrieved on 27 March 2009 or alternatively supplement with a synthetic T₃ treatment.Liothyronine
/ref> In these cases, synthetic liothyronine is preferred due to the potential differences between the natural thyroid products. Some studies show that the mixed therapy is beneficial to all patients, but the addition of lyothyronine contains additional side effects and the medication should be evaluated on an individual basis. Some natural thyroid hormone brands are FDA approved, but some are not.
, Retrieved on 27 March 2009
, Retrieved on 1 April 2009 Thyroid hormones are generally well tolerated. 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. One exception is that thyroid hormones may aggravate heart conditions, especially in older patients; therefore, doctors may start these patients on a lower dose and work up to a larger one to avoid risk of heart attack.

Thyroid metabolism

Central

Thyroid hormones (T₄ and T₃) are produced by the follicular cells of the

gland and are regulated by TSH made by the thyrotropes of the

anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...

gland. The effects of T₄ in vivo are mediated via T₃ (T₄ is converted to T₃ in target tissues). T₃ is three to five times as 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

thyroxine-binding globulin Thyroxine-binding globulin (TBG) is a globulin protein that in humans is encoded by the ''SERPINA7'' gene. TBG binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) respon ...

(TBG)), which is cleaved by enzymes to produce active T₄. The steps in this process are as follows: # 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. # I⁻ is moved across the apical membrane into the colloid of the follicle by pendrin . # Thyroperoxidase oxidizes two I⁻ to form I₂. Iodide is non-reactive, and only the more reactive iodine is required for the next step. # The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid. # Iodinated Thyroglobulin binds megalin for endocytosis back into cell. # Thyroid-stimulating hormone (TSH) released from the anterior pituitary (also known as the adenohypophysis) binds the TSH receptor (a G_s protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid. # The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T₄ from the iodinated thyroglobulin. # The thyroid hormones cross the follicular cell membrane towards the blood vessels by an unknown mechanism. Text books have stated that

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical ...

is the main means of transport, but recent studies indicate that monocarboxylate transporter (MCT) 8 and 10 play major roles in the efflux of the thyroid hormones from the thyroid cells. Thyroglobulin (Tg) is a 660

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

, dimeric

produced by the follicular cells of the thyroid and used entirely within the

gland. Thyroxine is produced by attaching iodine atoms to the ring structures of this protein's

residues; thyroxine (T₄) contains four iodine atoms, while triiodothyronine (T₃), 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

residues, a small number of which (<20) 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 In chemistry, a bicyclic molecule () is a molecule that features two joined rings. Bicyclic structures occur widely, for example in many biologically important molecules like α-thujene and camphor. A bicyclic compound can be carbocyclic (all ...

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 (experimentally observed to be on the order of 5–6 molecules of either T₄ or T₃ per original molecule of thyroglobulin). More specifically, the monatomic anionic form of iodine,

iodide An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. In everyday life, iodide is most commonly encountered as a component of iodized salt, which many governments mandate. Worldwide, iodine de ...

(I^—), is actively absorbed from the bloodstream by a process called iodide trapping. In this process,

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

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. Then, in the first

reaction Reaction may refer to a process or to a response to an action, event, or exposure: Physics and chemistry *Chemical reaction *Nuclear reaction * Reaction (physics), as defined by Newton's third law *Chain reaction (disambiguation). Biology and m ...

catalysed by the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

thyroperoxidase,

residues in the protein thyroglobulin are iodinated on their

phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it r ...

rings, at one or both of the positions ''ortho'' to the phenolic

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

, yielding monoiodotyrosine (MIT) and diiodotyrosine (DIT), respectively. This introduces 1–2

atom Every atom is composed of a nucleus and one or more electrons bound to the nucleus. The nucleus is made of one or more protons and a number of neutrons. Only the most common variety of hydrogen has no neutrons. Every solid, liquid, gas, a ...

s of the element

, covalently bound, per tyrosine residue. The further coupling together of two fully iodinated tyrosine residues, also catalysed by thyroperoxidase, yields the peptidic (still peptide-bound) precursor of thyroxine, and coupling one molecule of MIT and one molecule of DIT yields the comparable precursor of

: * peptidic MIT + peptidic DIT → peptidic triiodothyronine (eventually released as triiodothyronine, T₃) * 2 peptidic DITs → peptidic thyroxine (eventually released as thyroxine, T₄) (Coupling of DIT to MIT in the opposite order yields a substance, r-T₃, which is biologically inactive.) Hydrolysis (cleavage to individual amino acids) 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.

Peripheral

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 hypothyroidism due to iodine deficiency. T₃ is more active than T₄, though it is present in less quantity than T₄.

Initiation of production in fetuses

(TRH) is released from hypothalamus by 6 – 8 weeks, and

thyroid-stimulating hormone Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism ...

(TSH) secretion from fetal pituitary is evident by 12 weeks of gestation, and fetal production of thyroxine (T₄) reaches a clinically significant level at 18–20 weeks. Fetal

(T₃) remains low (less than 15 ng/dL) until 30 weeks of gestation, and increases to 50 ng/dL at term. Fetal self-sufficiency of thyroid hormones protects the fetus against e.g. brain development abnormalities caused by maternal hypothyroidism.

Iodine deficiency

If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormones. The lack of thyroid hormones will lead to decreased

negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

on the pituitary, leading to increased production of

, which causes the thyroid to enlarge (the resulting medical condition is called ''endemic colloid goitre''; see

goitre A goitre, or goiter, is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly. Worldwide, over 90% of goitre cases are caused by iodine deficiency. The term is ...

). 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.

Circulation and transport

Plasma transport

Most of the thyroid hormone circulating in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

is bound to

transport protein A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

s, and only a very small fraction is unbound and biologically active. Therefore, measuring concentrations of free thyroid hormones is important for diagnosis, while measuring total levels can be misleading. Thyroid hormone in the blood is usually distributed as follows: Despite being lipophilic, T₃ and T₄ cross the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

via carrier-mediated transport, which is ATP-dependent. T₁a and T₀a are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor (TAR1, TA1), a

G-protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

located in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

. Another critical diagnostic tool is measurement of the amount of

(TSH) that is present.

Membrane transport

Contrary to common belief, thyroid hormones cannot traverse

s in a passive manner like other

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

substances. The iodine in ''o''-position makes the phenolic OH-group more acidic, resulting in a negative charge at physiological pH. However, at least 10 different active, energy-dependent and genetically regulated iodothyronine transporters have been identified in humans. They guarantee that intracellular levels of thyroid hormones are higher than in

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...

or interstitial fluids.

Intracellular transport

Little is known about intracellular kinetics of thyroid hormones. However, recently it could be demonstrated that the

crystallin In anatomy, a crystallin is a water-soluble structural protein found in the lens and the cornea of the eye accounting for the transparency of the structure. It has also been identified in other places such as the heart, and in aggressive breast c ...

CRYM Mu-crystallin homolog also known as NADP-regulated thyroid-hormone-binding protein (THBP) is a protein that in humans is encoded by the ''CRYM'' gene. Multiple alternatively spliced transcript variants have been found for this gene. Function ...

binds 3,5,3′-triiodothyronine in vivo.

Mechanism of action

The thyroid hormones function via a well-studied set of

nuclear receptors In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of specif ...

, termed the

thyroid hormone receptor The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have ...

s. These receptors, together with corepressor molecules, bind DNA regions called thyroid hormone response elements (TREs) near genes. This receptor-corepressor-DNA complex can block gene transcription. Triiodothyronine (T₃), which is the active form of thyroxine (T₄), goes on to bind to receptors. The deiodinase catalyzed reaction removes an iodine atom from the 5′ position of the outer aromatic ring of thyroxine's (T₄) structure. When triiodothyronine (T₃) binds a receptor, it induces a conformational change in the receptor, displacing the corepressor from the complex. This leads to recruitment of coactivator proteins and

RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens th ...

, activating transcription of the gene. Although this general functional model has considerable experimental support, there remain many open questions. More recently genetic evidence has been obtained for a second mechanism of thyroid hormone action involving one of the same nuclear receptors, TRβ, acting rapidly in the cytoplasm through the

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

. This mechanism is conserved in all mammals but not fish or amphibians, and regulates brain development and adult metabolism. The mechanism itself parallels the actions of the nuclear receptor in the nucleus: in the absence of hormone, TRβ binds to PI3K and inhibits its activity, but when hormone binds the complex dissociates, PI3K activity increases, and the hormone bound receptor diffuses into the nucleus.

Thyroxine, iodine and apoptosis

Thyroxine and iodine stimulate the spectacular apoptosis of the cells of the larval gills, tail and fins in amphibian metamorphosis, and stimulate the evolution of their nervous system transforming the aquatic, vegetarian tadpole into the terrestrial, carnivorous frog. In fact, amphibian frog ''Xenopus laevis'' serves as an ideal model system for the study of the mechanisms of apoptosis.

Effects of triiodothyronine

Effects of triiodothyronine (T₃) which is the metabolically active form: * Increases

cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: th ...

* Increases heart rate * Increases ventilation rate * Increases

* Potentiates the effects of catecholamines (i.e. increases sympathetic activity) * Potentiates brain development * Thickens

endometrium The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer ...

in females * Increases catabolism of proteins and carbohydrates

Measurement

Further information: Thyroid function tests Triiodothyronine (T₃) and thyroxine (T₄) can be measured as ''free T₃'' and ''free T₄'', which are indicators of their activities in the body. They can also be measured as ''total T₃'' and ''total T₄'', which depend on the amount that is bound to

(TBG). A related parameter is the free thyroxine index, which is ''total T₄'' multiplied by thyroid hormone uptake, which, in turn, is a measure of the unbound TBG.Military Obstetrics & Gynecology > Thyroid Function Tests
In turn citing: Operational Medicine 2001, Health Care in Military Settings, NAVMED P-5139, 1 May 2001, Bureau of Medicine and Surgery, Department of the Navy, 2300 E Street NW, Washington, D.C., 20372-5300 Additionally, thyroid disorders can be detected prenatally using advanced imaging techniques and testing fetal hormone levels.

Related diseases

Both excess and deficiency of thyroxine can cause disorders. *

Hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidis ...

(an example is

Graves' disease Graves' disease (german: Morbus Basedow), also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyro ...

) 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 Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as ...

(an example is

Hashimoto's thyroiditis Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enlarg ...

) is the case where there is a deficiency of thyroxine, triiodothyronine, or both. *

Clinical depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

can sometimes be caused by hypothyroidism. Some research has shown that T₃ is found in the junctions of

synapses In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses fr ...

, and regulates the amounts and activity of

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

, and γ-aminobutyric acid (GABA) in the

. * Hair loss can sometimes be attributed to a malfunction of T₃ and T₄. Normal hair growth cycle may be affected disrupting the hair growth. *Both thyroid excess and deficiency can cause cardiovascular disorders or make preexisting conditions worse. The link between excess and deficiency of thyroid hormone on conditions like arrhythmias, heart failure, and atherosclerotic vascular diseases, have been established for nearly 200 years.

Preterm birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...

s can suffer

neurodevelopmental disorder Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmenta ...

s due to lack of maternal thyroid hormones, at a time when their own thyroid is unable to meet their postnatal needs. Also in normal pregnancies, adequate levels of maternal thyroid hormone are vital in order to ensure thyroid hormone availability for the foetus and its developing brain. Congenital hypothyroidism occurs in every 1 in 1600–3400 newborns with most being born asymptomatic and developing related symptoms weeks after birth.

Anti-thyroid drugs

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 Goitrin is a sulfur-containing oxazolidine, a cyclic thiocarbamate, that reduces the production of thyroid hormones such as thyroxine. It is found in cruciferous vegetables such as cabbage, brussels sprouts and rapeseed oil, and is formed by the ...

carbimazole Carbimazole (brand names Neo-Mercazole, Anti-Thyrox, etc.) is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodin ...

methimazole Thiamazole, also known as methimazole, is a medication used to treat hyperthyroidism. This includes Graves disease, toxic multinodular goiter, and thyrotoxic crisis. It is taken by mouth. Full effects may take a few weeks to occur. Common s ...

propylthiouracil Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. In a thyrotoxic crisis it is generally more effective than methimazole. Otherwise it is ...

can reduce thyroid hormone production by interfering with iodine oxidation.

References

External links

Find TH response elements in DNA sequences.

Triiodothyronine bound to proteins
in the PDB
Thyroxine bound to proteins
in the PDB * T₄ a
Lab Tests Online
Thyroid hormone treatment in

thyroid disease Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning ...

Thyroid Hormone Treatment
Brochure by the American Thyroid Association
Elaborate article about the use of thyroid drugs
Written by an MD
Thyroid Disease Manager
Collection of elaborate medical articles on thyroid disease, including information on thyroid hormones {{Authority control Iodinated tyrosine derivatives Hormones of the thyroid gland Thyroid hormone receptor agonists Thyroid Hormones of the hypothalamus-pituitary-thyroid axis Halogen-containing natural products Iodine-containing natural products