Thyroid hormone

The structural formula (left) and a space-filling model (right) of (S)-triiodothyronine (T3, also
called liothyronine in the pharmaceutical industry)

The structural formula (left) and a space-filling model (right) of (S)-thyroxine (T4.)

The thyroid hormones, triiodothyronine (T3) and its prohormone, thyroxine (T4), are tyrosinebasedhormones produced by the thyroid gland that are primarily responsible for regulation of
metabolism.Iodine is necessary for the production of T3 and T4. A deficiency of iodine leads to
decreased production of T3 and T4, enlarges the thyroid tissueand will cause the disease known
as simple goitre. The major form of thyroid hormone in the blood is thyroxine (T4), which has a
longer half-life than T3.[1] In humans, 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 bydecarboxylation and
deiodination to produceiodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the
deiodinases areselenium-containing enzymes, thus dietary selenium is essential for
T3 production.
Contents
[hide]

1 Function

2 Production
o 2.1 Central
o 2.2 Peripheral
o 2.3 Initiation of production in fetuses

3 Effect of iodine deficiency on thyroid hormone synthesis

4 Circulation and transport

o 4.1 Plasma transport
o 4.2 Membrane transport
o 4.3 Intracellular transport

5 Measurement

6 Effects of triiodothyronine

7 Medical use
o 7.1 Formulations

8 Related diseases

9 Anti-thyroid drugs

10 See also

11 References

12 External links

Function[edit]

The thyroid system of the thyroid hormones T3 andT4.[2]

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
neural 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 carbohydratemetabolism, 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, thethyronamines function via
some unknown mechanism to inhibitneuronal 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.

Production[edit]
Central[edit]

Synthesis of the thyroid hormones, as seen on an individual thyroid follicular cell:[3]

- Thyroglobulin is synthesized in the rough endoplasmic reticulum and follows the secretory
pathway to enter the colloid in the lumen of thethyroid follicle by exocytosis.
- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide (I) activelyinto 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.[4]
- In the colloid, iodide (I) is oxidized to iodine (I0) by an enzyme calledthyroid peroxidase.
- Iodine (I0) is very reactive and iodinates the thyroglobulin at tyrosylresidues in its protein chain
(in total containing approximately 120 tyrosyl residues).
- In conjugation, adjacent tyrosyl residues are paired together.
- Thyroglobulin binds the megalin receptor for endocytosis back into the follicular cell.
- Proteolysis by various proteases liberates thyroxine andtriiodothyronine molecules, which enter
the blood by largely unknown mechanisms.

Thyroid hormones (T4 and T3) are produced by thefollicular cells of the thyroid gland and are
regulated byTSH made by the thyrotropes of the anterior pituitarygland. The effects of T4 in vivo
are mediated via T3 (T4is 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.
The steps in this process are as follows:
1. 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.
2. I is moved across the apical membrane into the colloid of the follicle.
3. Thyroperoxidase oxidises two I to form I2. Iodide is non-reactive, and only the more
reactive iodine is required for the next step.
4. 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.
5. Iodinated Thyroglobulin binds megalin for endocytosis back into cell.
6. Thyroid-stimulating hormone (TSH) released from 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.
7. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal
enzymes cleave the T4 from the iodinated thyroglobulin.

8. These vesicles are then exocytosed, releasing the thyroid hormones.

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[edit]
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[edit]
Thyrotropin-releasing hormone (TRH) is released from hypothalamus by 6 8 weeks,
and thyroid-stimulating hormone(TSH) secretion from fetal pitutary is evident by 12 weeks of
gestation, and fetal production of thyroxine (T4) reaches a clinically significant level at 1820
weeks.[5] Fetal triiodothyronine (T3) remains low (less than 15 ng/dL) until 30 weeks of gestation,
and increases to 50 ng/dL at term.[5] Fetal self-sufficiency of thyroid hormones protects the fetus
against e.g. brain development abnormalities caused by maternal hypothyroidism.[6]
Effect of iodine deficiency on thyroid hormone synthesis[edit]
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 (the
resulting medical condition is called endemic colloid goiter; see 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.
Circulation and transport[edit]
Plasma transport[edit]
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.
Type

Percent

bound to thyroxine-binding globulin (TBG)

70%

bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA)

10-15%

albumin

15-20%

unbound T4 (fT4)

0.03%

unbound T3 (fT3)

0.3%

Despite being lipophilic, T3 and T4 cross the cell membrane via carrier-mediated transport, which
is ATP-dependent.[7] The thyroid hormones 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[edit]
Contrary to common belief, thyroid[8] hormones cannot traverse cell membranes in a passive
manner like other lipophilicsubstances. 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 genetic-regulated iodothyronine transportershave been identified in
humans. They guarantee that intracellular levels of thyroid hormones are higher than in blood
plasma or interstitial fluids.[9]

Intracellular transport[edit]
Little is known about intracellular kinetics of thyroid hormones. However, recently it could be
demonstrated that the crystallinCRYM binds 3,5,3-triiodothyronine in vivo.[10]
Measurement[edit]
Further information: Thyroid function tests
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.[11]
Effects of triiodothyronine[edit]
Effects of triiodothyronine (T3) which is the metabolically active form

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 (i.e. they have a catabolic action[12])

Medical use[edit]
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 levothyroxine sodium (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 andcalcitonin. 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.[13]
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[edit]
Today most patients are treated with levothyroxine, or a similar synthetic thyroid hormone.[14][15]
[16]
However, natural thyroid hormone supplements from the dried thyroids of animals are still
available.[16][17][18] Levothyroxine contains T4 only and is therefore largely ineffective for patients
unable to convert T4 to T3.[19] These patients may choose to take natural thyroid hormone as it
contains a mixture of T4 and T3,[16][20][21][22][23] or alternatively supplement with a synthetic T3
treatment.[24] In these cases, synthetic liothyronine is preferred due to the potential differences
between drug lots of natural thyroid products. Some natural thyroid hormone brands are F.D.A.
approved, but some are not.[25][26][27] Thyroid hormones are generally well tolerated.[15] 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.[15] 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.[16]
Related diseases[edit]
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.[28] Some research[29] has

shown that T3 is found in the junctions of synapses, and regulates the amounts and
activity of serotonin, norepinephrine, and -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.[30]
Anti-thyroid drugs[edit]
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 asgoitrin, methimazole, propylthiouracil can reduce
thyroid hormone production by interfering with iodine oxidation.[31]
See also[edit]

Goitre

Graves-Basedow disease

Hashimoto's thyroiditis

Hormone

Thyroid gland

Thyroid-stimulating hormone

Thyronamines, metabolites of the thyroid hormones that act at the trace amine-associated
receptor TAAR1 (TAR1)

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