Thyroid hormones
Thyroid hormones are two hormones produced and released by
the thyroid gland: triiodothyronine (T3) and thyroxine (T4). They are
tyrosine-based hormones that are primarily responsible for regulation of
metabolism. T3 and T4 are partially composed of iodine, which is derived from
food American chemist Edward Calvin Kendall was responsible for the isolation
of thyroxine in 1915. Levothyroxine, a synthetic derivative of Thyroxine, is on
the World Health Organization's List of Essential Medicines.
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 by deiodinases (5′-deiodinase). These are further processed by
decarboxylation and deiodination to produce iodothyronamine (T1a) and
thyronamine (T0a). All three isoforms of the deiodinases are
selenium-containing enzymes, thus dietary selenium is essential for T3
production. Calcitonin, a peptide hormone produced and secreted by the thyroid,
is usually not included in the meaning of "thyroid hormone".
Thyroid hormones are one of the factors responsible for the
modulation of energy expenditure. This is achieved through several mechanisms,
such as mitochondrial biogenesis and adaptive thermogenesis.
Central metabolism
- Thyroglobulin is synthesized in the rough endoplasmic
reticulum and follows the secretory pathway to enter the colloid in the lumen
of the thyroid follicle by exocytosis.
- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide
(I−) actively into the cell, which previously has crossed the endothelium by
largely unknown mechanisms.
- This iodide enters the follicular lumen from the cytoplasm
by the transporter pendrin, in a purportedly passive manner.
- In the colloid, iodide (I−) is oxidized to iodine (I0) by
an enzyme called thyroid peroxidase.
- Iodine (I0) is very reactive and iodinates the
thyroglobulin at tyrosyl residues in its protein chain (in total containing
approximately 120 tyrosyl residues).
- In conjugation, adjacent tyrosyl residues are paired
together.
- Thyroglobulin re-enters the follicular cell by
endocytosis.
- Proteolysis by various proteases liberates thyroxine and
triiodothyronine molecules
- Efflux of thyroxine and triiodothyronine from follicular
cells, which appears to be largely through monocarboxylate transporter 8 (MCT
8) and 10, and entry into the blood.
Thyroid hormones (T4 and T3) are produced by thyroid
epithelial cells (a.k.a. thyroid follicular cells) and are regulated by
thyroid-stimulating hormone (TSH) made by the thyrotropes of the anterior
pituitary 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 more active than T4. T4,
thyroxine (3,5,3′,5′-tetraiodothyronine), is produced by follicular cells of
the thyroid gland. It is produced from the precursor thyroglobulin (this is not
the same as thyroxine-binding globulin [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. This is called iodide trapping.[36]
Sodium is cotransported with iodide from the basolateral side of the membrane
into the cell,[clarification needed] and then concentrated in the thyroid
follicles to about thirty times its concentration in the blood.
I− is moved across the apical membrane into the colloid of
the follicle by pendrin. Hydrogen peroxide is also introduced into the follicle
by the action of DUX (Dual Oxidase).
Iodide is non-reactive, and the reactive I2 species is
required for the next step. Thyroid peroxidase (TPO) reduces hydrogen peroxide
to water by transferring one electron from two I− atoms that react to form I2.
Iodine (I2) is converted into HOI, by hydration with water.
Both I2 and HOI iodinate specific tyrosyl residues of the thyroglobulin within
the colloid to form 3-monoiodityrosyl (MIT-yl) and 3,5-diiodityrosyl (DIT-yl)
residues—introducting iodine atoms at one or both locations ortho to the
hydroxyls of tyrosine. The thyroglobulin was synthesised in the ER of the
follicular cell and secreted into the colloid.
TPO also converts tyrosyl, MIT-yl, and DIT-yl residues into
their free radical forms. These forms attack other MIT-yl and DIT-yl residues.
When a DIT-yl radical attacks a DIT, T4-yl (peptidic T4) is formed. When a
MIT-yl radical attacks a DIT, T3-yl is formed. Other reactions are possible,
but do not form physiologically active products.
Iodinated thyroglobulin binds megalin for endocytosis back
into the cell.
TSH released from the anterior pituitary (a.k.a. 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 any MIT, DIT, T3, T4 as well as
the inactive analogues from the iodinated thyroglobulin.
The thyroid hormones cross the follicular cell membrane
towards the blood vessels by monocarboxylate transporter 8 (MCT 8) and 10 which
play major roles in the efflux of the thyroid hormones from thyroid cells.
Thyroglobulin (Tg) is a 660 kDa, 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.[48] The thyroglobulin protein accounts for approximately half of the
protein content of the thyroid gland.[49] Each thyroglobulin molecule contains
approximately 100–120 tyrosine residues, a small number (<20) of which 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 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).
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 metabolism
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,[56] 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 gestational weeks, and thyroid-stimulating hormone (TSH)
secretion from the fetal pituitary gland is evident by 12 gestational weeks;
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, for example,
neurodevelopmental abnormalities caused by maternal hypothyroidism
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:
|
Type |
Percent |
|
bound to thyroxine-binding globulin (TBG) |
70% |
|
bound to transthyretin or
"thyroxine-binding prealbumin" (TTR or TBPA) |
10–15% |
|
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
Membrane
transport
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 or
interstitial fluids.
Mechanism of action
The thyroid hormones function via a well-studied set of
nuclear receptors, termed the thyroid hormone receptors. 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, activating transcription of the gene.
Functions of Thyroid Hormones
Thyroid hormones act on nearly every cell in the
body. They act to
·
increase the basal
metabolic rate
·
affect protein synthesis
·
help regulate long bone
growth in synergy with growth hormone
·
effect neural maturation
·
increase the body's
sensitivity to catecholamines (such as norepinephrine and epinephrine) by
permissiveness, especially under cold exposure.
·
essential to proper
development and differentiation of all cells of the human body.
·
These hormones also
regulate protein, fat, and carbohydrate metabolism, affecting how human cells
use energetic compounds.
·
They stimulate vitamin metabolism.
·
Thyroid hormones lead to
heat generation in humans.
Functions of triiodothyronine
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
·
Increases catabolism of
proteins and carbohydrates.
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