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 66 216 386 256 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 ...
rect 66 332 342 374 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
rect 256 539 563 635 Thyroid hormones
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 substi ...
rect 399 716 591 750 Metabolism
desc bottom-left
Thyroid hormones are any
hormones produced and released by the
thyroid gland, namely
triiodothyronine (T
3) and thyroxine (T
4). They are
tyrosine-based hormones that are primarily responsible for regulation of
metabolism. T
3 and T
4 are partially composed of
iodine. A deficiency of iodine leads to decreased production of T
3 and T
4, enlarges the
thyroid tissue and will cause the disease known as
simple 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 ...
.
The major form of thyroid hormone in the blood is thyroxine (T
4), whose half-life of around one week is longer than that of T
3. In humans, the ratio of T
4 to T
3 released into the blood is approximately 14:1. T
4 is converted to the active T
3 (three to four times more potent than T
4) 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
deiodinase
Deiodinase (or "Monodeiodinase") is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.
Types
Types of deiodinases include:
Iodothyronine deiodinases catalyze release of iodine directly from the thyron ...
s (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
3-Iodothyronamine (T1AM) is an endogenous thyronamine. T1AM is a high-affinity ligand for the trace amine-associated receptor TAAR1 (TAR1, TA1), a recently discovered G protein-coupled receptor. T1AM is the most potent endogenous TAAR1 agonist yet ...
(T
1a) and
thyronamine
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:
* Thyronamin ...
(T
0a). All three isoforms of the deiodinases are
selenium-containing enzymes, thus dietary selenium is essential for T
3 production.
American chemist
Edward Calvin Kendall
Edward Calvin Kendall (March 8, 1886 – May 4, 1972) was an American chemist. In 1950, Kendall was awarded the Nobel Prize for Physiology or Medicine along with Swiss chemist Tadeusz Reichstein and Mayo Clinic physician Philip S. Hench, for the ...
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
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) 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 substi ...
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,
fat
In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food.
The term often refers specifically to triglycerides (triple est ...
, and
carbohydrate metabolism, affecting how human
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 ...
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:
* Thyronamin ...
function via some unknown mechanism to inhibit
neuronal 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 most ...
cycles of
mammals and the
moulting 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 lightweight ...
. 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 temperature ...
.
Medical use
Both T
3 and T
4 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 po ...
). They are both absorbed well by the stomach, so can be given orally.
Levothyroxine is the pharmaceutical name of the manufactured version of T
4, which is metabolised more slowly than T
3 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% T
3 and traces of
T2, T
1 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 T
3/T
4 in different ratios (such as
liotrix
Liotrix is a 4:1 mixture of thyroxine (T4) and triiodothyronine (T3) made synthetically. It is used to replenish thyroid hormones in thyroid deficiency and hypothyroidism. The only brand of liotrix available in the U.S. is Thyrolar, manufactured b ...
) and pure-T
3 medications (INN:
liothyronine
Liothyronine is a manufactured form of the thyroid hormone triiodothyronine (T3). It is most commonly used to treat hypothyroidism and myxedema coma. It can be taken by mouth or by injection into a vein.
Side effects may occur from excessive ...
).
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, 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
Sir Charles Robert Harington, KBE, FRS (1 August 1897 – 4 February 1972) was a chemist, best known for synthesising thyroxine.
Life
Although he was born and raised in Llanerfyl, north Wales. he was a member of the English aristocracy fro ...
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).
image:Liothyronine2DCSD.svg, (''S'')-triiodothyronine (T
3, also called
liothyronine
Liothyronine is a manufactured form of the thyroid hormone triiodothyronine (T3). It is most commonly used to treat hypothyroidism and myxedema coma. It can be taken by mouth or by injection into a vein.
Side effects may occur from excessive ...
).
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 T
4 only and is therefore largely ineffective for patients unable to convert T
4 to T
3. These patients may choose to take natural thyroid hormone, as it contains a mixture of T
4 and T
3,
["Consequences of Not Taking Thyroid Medications - Implications of Failing to Take Prescription Thyroid Drugs"](_blank)
Retrieved on 27 March 2009["Armour Thyroid"](_blank)
Retrieved on 1 April 2009["Nature-Throid"](_blank)
Retrieved on 1 April 2009
Retrieved on 27 March 2009 or alternatively supplement with a synthetic T
3 treatment.
[Liothyronine](_blank)
/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 thyroid gland and are regulated by TSH made by the thyrotrope
Thyrotropes (also called thyrotrophs) are endocrine cells in the anterior pituitary which produce thyroid stimulating hormone (TSH) in response to thyrotropin releasing hormone (TRH).Guyton, A.C. & Hall, J.E. (2006) ''Textbook of Medical Physiology ...
s 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) responsib ...
(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
Pendrin is an anion exchange protein that in humans is encoded by the ''SLC26A4'' gene (solute carrier family 26, member 4).
Pendrin was initially identified as a sodium-independent chloride-iodide exchanger with subsequent studies showing that i ...
.
# 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 Gs 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 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 r ...
, 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 (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 tyrosine residues, a small number of which (<20) are subject to iodination catalysed by thyroperoxidase
Thyroid peroxidase, also called thyroperoxidase (TPO) or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosin ...
. 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 (I—), 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. 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 ...
catalysed by the enzyme thyroperoxidase
Thyroid peroxidase, also called thyroperoxidase (TPO) or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosin ...
, tyrosine residues in the protein thyroglobulin are iodinated on their phenol rings, at one or both of the positions ''ortho'' to the phenolic hydroxyl group, yielding monoiodotyrosine
3-Iodotyrosine is an intermediate in the synthesis of thyroid hormones which is derived from iodination of tyrosine at the meta-position of the benzene ring. One unit can combine with diiodotyrosine to form triiodothyronine, as occurs in the col ...
(MIT) and diiodotyrosine
Diiodotyrosine (DIT) is a precursor in the production of thyroid hormone, and results from iodization of monoiodotyrosine at the other meta- position on the phenol ring.
Function
DIT is a modulator of the enzyme thyroid peroxidase (which is invo ...
(DIT), respectively. This introduces 1–2 atoms of the element iodine, 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 triiodothyronine:
* 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
A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding additi ...
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
Thyrotropin-releasing hormone (TRH) is released from hypothalamus by 6 – 8 weeks, and thyroid-stimulating hormone (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 triiodothyronine (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 thyroid-stimulating hormone, which causes the thyroid to enlarge (the resulting medical condition is called ''endemic colloid goitre''; see goitre). 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 is bound to transport proteins, 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 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. Th ...
.
Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone (TSH) that is present.
Membrane transport
Contrary to common belief, thyroid hormones cannot 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 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 intr ...
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
A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA ...
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 the ...
, 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: t ...
* Increases heart rate
* Increases ventilation rate
* Increases 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 ...
* Potentiates the effects of catecholamines (i.e. increases sympathetic activity)
* Potentiates brain development
* Thickens endometrium 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 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) responsib ...
(TBG). A related parameter is the free thyroxine index
Free may refer to:
Concept
* Freedom, having the ability to do something, without having to obey anyone/anything
* Freethought, a position that beliefs should be formed only on the basis of logic, reason, and empiricism
* Emancipate, to procure ...
, which is ''total T4'' multiplied by thyroid hormone uptake
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 ...
, which, in turn, is a measure of the unbound TBG.[Military Obstetrics & Gynecology > Thyroid Function Tests](_blank)
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 (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 po ...
(an example is Hashimoto's thyroiditis) 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. Introd ...
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, norepinephrine, and γ-aminobutyric acid (GABA) in the brain.
* 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 between ...
s 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. 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, 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 iodina ...
, 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 t ...
can reduce thyroid hormone production by interfering with iodine oxidation.
See also
* Goitre
* Graves–Basedow 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 ...
* Hashimoto's thyroiditis
* Hormone
* Polar T3 syndrome
* Thyroid gland
* Thyroid-stimulating hormone
* Thyronamine
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:
* Thyronamin ...
s, metabolites of the thyroid hormones that act at the trace amine-associated receptor TAAR1 (TAR1)
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