Download the cells responsible for synthesis of thyroid hormones

The microscopic structure of the thyroid is quite distinctive. Thyroid
epithelial cells - the cells responsible for synthesis of thyroid hormones are arranged in spheres called thyroid follicles. Follicles are filled with
colloid, a proteinaceous depot of thyroid hormone precursor. In the low
(left) and high-magnification (right) images of a cat thyroid below, follicles
are cut in cross section at different levels, appearing as roughly circular
forms of varying size.
In standard histologic preps such as these, colloid stains pink.
In addition to thyroid epithelial cells, the thyroid gland houses one other
important endocrine cell.
Nestled in spaces between thyroid follicles are parafollicular or C cells,
which secrete the hormone calcitonin.
The structure of a parathyroid gland is distinctly different from a thyroid
gland. The cells that synthesize and secrete parathyroid hormone are
arranged in rather dense cords or nests around abundant capillaries. The
image below shows a section of a feline parathyroid gland on the left,
associated with thyroid gland (note the follicles) on the right.
Chemistry of Thyroid Hormones
Thyroid hormones are derivatives of tyrosine
bound covalently to iodine.
The two principal thyroid hormones are:
thyroxine (known as T4 or L-3,5,3',5'-tetraiodothyronine) and
triiodotyronine (T3 or L-3,5,3'-triiodothyronine).
Thyroid hormones are basically two tyrosines linked together
with the critical addition of iodine at three or four positions
on the aromatic rings. The number and position of the
iodines is important.
Several other iodinated molecules are generated that have
little or no biological activity; so called "reverse T3" (3,3',5'T3) is such an example.
A large majority of the thyroid hormone
secreted from the thyroid gland is T4, but T3
is the considerably more active hormone.
Although some T3 is also secreted, the bulk of
the T3 is derived by deiodination of T4 in
peripheral tissues, especially liver and kidney.
Deiodination of T4 also yields reverse T3, a
molecule with no known metabolic activity.
Thyroid hormones are poorly soluble in water,
and more than 99% of the T3 and T4
circulating in blood is bound to carrier
proteins.
The principle carrier of thyroid hormones is
thyroxine-binding globulin, a glycoprotein
synthesized in the liver.
Two other carriers of import are transthyrein and
albumin.
Carrier proteins allow maintenance of a stable pool of
thyroid hormones from which the active, free hormones
are released for uptake by target cells.
Synthesis and Secretion of Thyroid Hormones
Thyroid hormones are synthesized by mechanisms
fundamentally different from what is seen in other endocrine
systems.
Thyroid follicles serve as both factory and warehouse for
production of thyroid hormones.
Constructing Thyroid Hormones
The entire synthetic process occurs in 3 major
steps,
Production and accumulation of the raw
materials
Synthesis of the hormones on a backbone or
scaffold precursor
Release of the free hormones from the
scaffold and secretion into blood
thyroid hormones calls for 2 principle raw materials:
Tyrosines are provided from a large
glycoprotein scaffold called
thyroglobulin, which is synthesized by
thyroid epithelial cells and secreted into
the lumen of the follicle - colloid is
essentially a pool of thyroglobulin.
A molecule of thyroglobulin contains
134 tyrosines, although only a handful
of these are actually used to
synthesize T4 and T3.
The recipe for making thyroid hormones calls for 2
principle raw materials:
Iodine, or more accurately iodide (I-), is
avidly taken up from blood by thyroid
epithelial cells, which have on their outer
plasma membrane a sodium-iodide
symporter or "iodine trap".
Once inside the cell, iodide is
transported into the lumen of the follicle
along with thyroglobulin.
Synthesis of thyroid hormones is conducted by the enzyme
thyroid peroxidase, an integral membrane protein present
in the apical (colloid-facing) plasma membrane of thyroid
epithelial cells. Thyroid peroxidase catalyzes two
sequential reactions:
Iodination of tyrosines on thyroglobulin (also known as
"organification of iodide").
Synthesis of thyroxine or triiodothyronine from two
iodotyrosines.
Through the action of
thyroid peroxidase, thyroid
hormones accumulate in
colloid, on the surface of
thyroid epithelial cells.
Remember that hormone is
still tied up in molecules of
thyroglobulin - the task
remaining is to liberate it
from the scaffold and
secrete free hormone into
blood.
Thyroid hormones are excised from their
thyroglobulin scaffold by digestion in
lysosomes of thyroid epithelial cells.
This final act in thyroid hormone
synthesis proceeds in the following
steps:
Thyroid epithelial cells ingest colloid by endocytosis
from their apical borders - that colloid contains
thyroglobulin decorated with thyroid hormone.
Colloid-laden endosomes fuse with
lysosomes, which contain hydrolytic
enzymes that digest thyroglobluin,
thereby liberating free thyroid hormones.
Finally, free thyroid hormones diffuse
out of lysosomes, through the basal
plasma membrane of the cell, and into
blood where they quickly bind to carrier
proteins for transport to target cells.
Control of Thyroid Hormone Synthesis and
Secretion
Each of the processes described above
appears to be stimulated by TSH from the
anterior pituitary gland.
Binding of TSH to its receptors on thyroid
epithelial cells stimulates synthesis of the
iodine transporter, thyroid peroxidase and
thyroglobulin.
Control of Thyroid Hormone Synthesis and
Secretion
The magnitude of the TSH signal also sets the
rate of endocytosis of colloid - high
concentrations of TSH lead to faster rates of
endocytosis, and hence, thyroid hormone
release into the circulation.
Conversely, when TSH levels are low, rates of
thyroid hormone synthesis and release
diminish.
Control of Thyroid Hormone Synthesis and
Secretion
The thyroid gland is part of the hypothalamicpituitary-thyroid axis, and control of thyroid
hormone secretion is exerted by classical negative
feedback, as depicted on previous slide. TRH from
the hypothalamus stimulates TSH from the pituitary,
which stimulates thyroid hormone release.
As blood concentrations of thyroid hormones
increase, they inhibit both TSH and TRH, leading to
"shutdown" of thyroid epithelial cells.
Later, when blood levels of thyroid hormone have
decayed, the negative feedback signal fades, and
the system wakes up again.
Control of Thyroid Hormone Synthesis and
Secretion
A # of other factors influence TH secretion.
In rodents and young children, exposure to a
cold environment triggers TRH secretion,
leading to enhanced thyroid hormone release.
This makes sense considering the known
ability of thyroid hormones to spark body heat
production.
Mechanism of Action and Physiologic Effects of
Thyroid Hormones
Thyroid Hormone Receptors and Mechanism of
Action
Receptors for thyroid hormones are intracellular
DNA-binding proteins that function as hormoneresponsive transcription factors, like receptors for
steroid hormones.
Thyroid hormones enter cells through membrane
transporter proteins. A number of PM transporters
have been identified, some of which require ATP
hydrolysis; the relative importance of different
carrier systems is not yet clear and may differ
among tissues.
Mechanism of Action and Physiologic Effects of
Thyroid Hormones
Once inside the nucleus, the hormone binds its
receptor, and the hormone-receptor complex
interacts with specific sequences of DNA in the
promoters of responsive genes. The effect of
receptor binding to DNA is to modulate gene
expression, either by stimulating or inhibiting
transcription of specific genes.
TREs-thyorid hormone response elements
Thyroid Hormone Receptors
Receptors for thyroid hormones are members of a
large family of nuclear receptors that include those
of the steroid hormones. They function as hormoneactivated transcription factors and thereby act by
modulating gene expression. In contrast to steroid
hormone receptors, thyroid hormone receptors bind
DNA in the absence of hormone, usually leading to
transcriptional repression.
Hormone binding is associated with a
conformational change in the receptor that causes it
to function as a transcriptional activator.
Receptor Structure
Mammalian thyroid hormone receptors are encoded by
2 genes, designated alpha and beta. Further, the primary
transcript for each gene can be alternatively spliced,
generating different alpha and beta receptor isoforms.
Currently, four different thyroid hormone receptors are
recognized: alpha-1, alpha-2, beta-1 and beta-2.
Like other members of the nuclear receptor superfamily,
thyroid hormone receptors encapsulate three functional
domains:
TRa1
TRb1
TRa2
TRb2
Receptor Structure
Like other members of the nuclear receptor superfamily,
thyroid hormone receptors encapsulate 3 functional
domains:
A transactivation domain (TAD) at the N terminus that
interacts with other transcription factors to form complexes
that repress or activate transcription. There is considerable
divergence in sequence of the TADS of alpha and beta
isoforms and between the two beta isoforms of the receptor.
A DNA-binding domain that binds to sequences of promoter
DNA known as hormone response elements (TRE).
A ligand-binding and dimerization domain at the carboxyterminus.
The DNA-binding domains of the different receptor
isoforms are very similar, but there is considerable
divergence among transactivation and ligandbinding domains. Most notably, the alpha-2 isoform
has a unique carboxy-terminus and does not bind
triiodothyronine (T3).
The different forms of thyroid receptors have
patterns of expression that vary by tissue and
by developmental stage.
For example, almost all tissues express the
alpha-1, alpha-2 and beta-1 isoforms, but
beta-2 is synthesized almost exclusively in
hypothalamus, anterior pituitary and
developing ear.
Receptor a1 is the first isoform expressed in
the conceptus, and there is a profound
increase in expression of b receptors in brain
shortly after birth. Interestingly, the b receptor
preferentially activates expression from
several genes known to be important in brain
development (e.g. myelin basic protein), and
upregulation of this particular receptor may
thus be critical to the well known effects of
THs on development of the fetal and neonatal
brain.
The presence of multiple forms of the
thyroid hormone receptor, with tissue
and stage-dependent differences in their
expression, suggests an extraordinary
level of complexity in the physiologic
effects of thyroid hormone.
Interaction of Thyroid Hormone Receptors
with DNA
Thyroid hormone receptors bind to short,
repeated sequences of DNA called thyroid or
T3 response elements (TREs), a type of
hormone response element.
A TRE is composed of two AGGTCA "half
sites" separated by four nucleotides. The half
sites of a TRE can be arranged as direct
repeats, pallindromes or inverted repeats.
Interaction of Thyroid Hormone Receptors with DNA
The DNA-binding domain of the receptor contains
two sets of four cysteine residues, and each set
chelates a zinc ion, forming loops known as "zinc
fingers".
A part of the first zinc finger interacts directly with
nucleotides in the major groove of TRE DNA, while
residues in the second finger interact with
nucleotides in the minor groove of the TRE.
Thus, the zinc fingers mediate specificity in binding
to TREs.
Thyroid hormone receptors can bind to a TRE
as monomers, as homodimers or as
heterodimers with the retinoid X receptor
(RXR), another member of the nuclear
receptor superfamily that binds 9-cis retinoic
acid.
The heterodimer affords the highest
affinity binding, and is thought to
represent the major functional form
of the receptor.
Thyroid hormone receptors bind to TRE DNA
regardless of whether they are occupied by T3.
However, the biological effects of TRE binding by
the unoccupied versus the occupied receptor are
dramatically different. In general, binding of thyroid
hormone receptor alone to DNA leads to repression
of transcription, whereas binding of the thyroid
hormone-receptor complex activates transcription.
Ligand-free state: The transactivation domain of the
T3-free receptor, as a heterodimer with RXR,
assumes a conformation that promotes interaction
with a group of transcriptional corepressor
molecules. A part of this corepressor complex has
histone deacetylase activity (HDA), which is
associated with formation of a compact, "turned-off"
conformation of chromatin. The net effect of
recruiting these types of transcription factors is to
repress transcription from affected genes.
Ligand-bound state: Binding of T3 to its receptor induces a
conformational change in the receptor that makes it
incompetent to bind the corepressor complex, but competent
to bind a group of coactivator proteins. The coactivator
complex contains histone transacetylase (HAT) activity,
which imposes an open configuration on adjacent chromatin.
The coactivator complex associated with the T3-bound
receptor functions to activate transcription from linked
genes.
A growing number of specific proteins have been
identified as members of the corepressor and
coactivator complexes described.
It should also be mentioned that there are several
exceptions to the scheme described above.
As mentioned, the alpha-2 receptor is unable to bind
T3 and acts as similarly to a dominant-negative
mutant of the receptor, but its carboxy-terminus can
be differentially phosphorylated, which affects DNA
binding and dimerization.
Also, the beta-2 isoform apparently fails to function
as a repressor in the absence of T3.
Disorders of Thyroid Hormone Receptors
A number of humans with a syndrome of thyroid
hormone resistance have been identified, and found
to have mutations in the receptor b gene which
abolish ligand binding. Clinicially, such individuals
show a type of hypothyroidism characterized by
goiter, elevated serum concentrations of T3 and
thyroxine and normal or elevated serum
concentrations of TSH.
More than half of affected children show attentiondeficit disorder, which is intriguing considering the
role of thyroid hormones in brain development. In
most affected families, this disorder is transmitted
as a dominant trait, which suggests that the mutant
receptors act in a dominant negative manner.
Disorders of Thyroid Hormone Receptors
Mice with targeted deletions in TR genes have
provided additional understanding of the possible
roles of different forms of TH receptors.
Knockout mice that are unable to produce the a1
receptor showed subnormal body temperature and
mild abnormalities in cardiac function.
Other mice which lack expression of both a
isoforms are severely hypothyroid and died within
the first few weeks of life.
Mice with disruptions of the entire b gene exhibited
elevated TSH levels and deafness, while mice with
mutations that disrupted only b2 expression had
elevated TSH, but normal hearing.
Such experiments are beginning to allow
determination of which functions of the different
receptor isoforms are redundant and which are not.
Inactivating mutations in thyroid hormone receptors
do not produce a syndrome analogous to the lack of
thyroid hormones.
This is the case even in mice with targeted deletions
in both alpha and beta receptor genes. The most
likely explanation for the relative mild effects of
receptor deficiency is that responsive genes are left
in a "neutral" state, rather than being chronically
suppressed as happens with hormone deficiency.
Physiologic Effects of Thyroid Hormones
It is likely that all cells in the body are targets
for thyroid hormones. While not strictly
necessary for life, thyroid hormones have
profound effects on many "big time"
physiologic processes, such as
development, growth and
metabolism.
Many of the effects of thyroid hormone have
been delineated by study of deficiency and
excess states
Metabolism: Thyroid hormones stimulate
diverse metabolic activities most
tissues, leading to an increase in basal
metabolic rate. One consequence of this
activity is to increase body heat
production, which seems to result, at
least in part, from increased oxygen
consumption and rates of ATP
hydrolysis.
By way of analogy, the action of thyroid
hormones is akin to blowing on a
smouldering fire.
A few examples of specific metabolic effects of thyroid
hormones include:
Lipid metabolism: Increased thyroid hormone
levels stimulate fat mobilization, leading to
increased concentrations of fatty acids in
plasma. They also enhance oxidation of fatty
acids in many tissues. Finally, plasma
concentrations of cholesterol and
triglycerides are inversely correlated with
thyroid hormone levels - one diagnostic
indication of hypothyroidism is increased
blood cholesterol concentration.
Carbohydrate metabolism: Thyroid hormones
stimulate almost all aspects of carbohydrate
metabolism, including enhancement of
insulin-dependent entry of glucose into cells
and increased gluconeogenesis and
glycogenolysis to generate free glucose.
Growth: Thyroid hormones are clearly
necessary for normal growth in children
and young animals, as evidenced by the
growth-retardation observed in thyroid
deficiency. Not surprisingly, the growthpromoting effect of thyroid hormones is
intimately intertwined with that of GH, a
clear indication that complex
physiologic processes like growth
depend upon multiple endocrine
controls.
Development: A classical experiment in
endocrinology was the demonstration that
tadpoles deprived of thyroid hormone failed
to undergo metamorphosis into frogs. Of
critical importance in mammals is the fact that
normal levels of thyroid hormone are
essential to the development of the fetal and
neonatal brain.
Other Effects: As mentioned above, there do not
seem to be organs and tissues that are not affected
by thyroid hormones.
A few additional, well-documented effects of thyroid
hormones include:
Cardiovascular system: Thyroid hormones
increases heart rate, cardiac contractility and
cardiac output. They also promote vasodilation,
which leads to enhanced blood flow to many organs.
Central nervous system: Both decreased and
increased concentrations of thyroid hormones lead
to alterations in mental state. Too little thyroid
hormone, and the individual tends to feel mentally
sluggish, while too much induces anxiety and
nervousness.
Other Effects: As mentioned above, there do not
seem to be organs and tissues that are not affected
by thyroid hormones.
Reproductive system: Normal
reproductive behavior and
physiology is dependent on having
essentially normal levels of thyroid
hormone. Hypothyroidism in
particular is commonly associated
with infertility.
Thyroid Disease States
Disease is associated with both inadequate
production and overproduction of thyroid
hormones.
Both types of disease are relatively common
afflictions of man and animals.
Thyroid Disease States
Hypothyroidism is the result from any
condition that results in TH deficiency.
Two well-known examples include:
Iodine deficiency: Iodide is absolutely
necessary for production of thyroid
hormones; without adequate I intake, TH
cannot be synthesized. Historically, this
problem was seen particularly in areas with Ideficient soils, and frank I deficiency has been
virtually eliminated by I supplementation of
salt.
Thyroid Disease States
Hypothyroidism is the result from any
condition that results in TH deficiency.
Two well-known examples include:
Primary thyroid disease: Inflammatory
diseases of the thyroid that destroy parts of
the gland are clearly an important cause of
hypothyroidism.
Endemic goiter
The term endemic goiter is a descriptive diagnosis and
reserved for a disorder characterized by enlargement of
the thyroid gland in a significantly large fraction of a
population group, and is generally considered to be due
to insufficient iodine in the daily diet. Since nontoxic
goiter also exists when there is abundant iodine in the
diet, the distinction between endemic and nonendemic
goiter is necessarily arbitrary. Endemic goiter may be
said to exist in a population when more than 5% of the
preadolescent (at 6-12) school-age children have
enlarged thyroid glands, as assessed by the clinical
criterion of the thyroid lobes being each larger than the
distal phalanx of the subject's thumb.
Most of the significantly mountainous districts in the world
have been or still are endemic goiter regions.
The disease may be seen throughout the Andes, in the whole
sweep of the Himalayas, in the Alps where iodide prophylaxis
has not yet reached the entire population, in Greece and the
Middle Eastern countries, in many foci in the People's
Republic of China, and in the highlands of New Guinea.
There are or were also important endemics in
nonmountainous regions, as for example, the belt
extending from the Cameroon grasslands across
northern Zaire and the Central African Republic to
the borders of Uganda and Rwanda, Holland, Central
Europe and the interior of Brazil. An endemic existed
in the Great Lakes region in North America two
generations ago.
Measurements have indicated that these regions
have in common a low concentration of
environmental iodine. The iodine content of the
drinking water is low, as is the quantity of iodide
excreted each day by residents of these districts.
Causes
Iodine Deficiency
The arguments supporting I deficiency as the cause
of endemic goiter are 4:
(1)the close association between a low iodine
content in food and water and the appearance of
the disease in the population;
(2) the sharp reduction in incidence when I is added
to the diet;
(3) the demonstration that the metabolism of I by
patients with endemic goiter fits the pattern that
would be expected from I deficiency and is
reversed by I repletion.
(4) Finally, I deficiency causes changes in the
thyroid glands of animals that are similar to those
seen in humans
Common symptoms of hypothyroidism
arising after early childhood include
lethargy
fatigue,
cold-intolerance,
weakness,
hair loss
and reproductive failure.
If these signs are severe, the clinical
condition is called myxedema.
In the case of iodide deficiency, the thyroid
becomes inordinantly large and is called a
goiter.
The most severe and devestating form of
hypothyroidism is seen in young children with
congenital thyroid deficiency. If that condition
is not corrected by supplemental therapy
soon after birth, the child will suffer from
cretinism, a form of irreversible growth and
mental retardation.
Myxedematous endemic
cretinism in the Democratic
Republic of Congo.
Four inhabitants aged 15-20
years : a normal male and
three females with severe
longstanding hypothyroidism
with dwarfism, retarded sexual
development, puffy features,
dry skin and hair and severe
mental retardation.
Very common in Ziare
Most cases of hypothyroidism are readily
treated by oral administration of synthetic
thyroid hormone. In times past, consumption
of dessicated animal thyroid gland was used
for the same purpose.
cretinism
Hyperthyroidism results from excess secretion of
thyroid hormones.
In most species, this condition is less common than
hypothyroidism.
In humans the most common form of
hyperthyroidism is Graves disease, an immune
disease in which autoantibodies bind to and activate
the TSH receptor, leading to continual stimulation of
thyroid hormone synthesis.
Another interesting, but rare cause of
hyperthyroidism is so-called hamburger
thyrotoxicosis.
Cretinism is a condition of
severely stunted physical
and mental growth due to
untreated congenital
deficiency of thyroid
hormones (hypothyroidism).
Common signs of hyperthyroidism are basically the
opposite of those seen in hypothyroidism, and
include
nervousness,
insomnia,
high heart rate,
eye disease and
anxiety.
Graves disease is commonly treated with antithyroid drugs (e.g. propylthiourea, methimazole),
which suppress synthesis of thyroid hormones
primarily by interfering with iodination of
thyroglobulin by thyroid peroxidase.
Hamburger Thyrotoxicosis
Thyroid hormones are orally active, which means that
consumption of thyroid gland tissue can cause
thyrotoxicosis, a type of hyperthyroidism.
Several outbreaks of thyrotoxicosis have been attributed to a
practice, now banned in the US, called "gullet trimming",
where meat in the neck region of slaughtered animals is
ground into hamburger. Because thyroid glands are reddish
in color and located in the neck, it's not unusual for gullet
trimmers to get thyroid glands into hamburger or sausage.
People, and presumably pets, that eat such hamburger can
get dose of thyroid hormone
A report by Hedberg and
colleagues (1987) on this topic
is one of several in the
literature. They described an
outbreak of thyrotoxicosis in
Minnesota and South Dakota
that was traced to thyroidcontaminated hamburger.
A total of 121 cases were
identified in nine counties, with
the highest incidence in the
county having offending
slaughter plants. The patients
complained of sleeplessness,
nervousness, headache, fatique,
excessive sweating and weight
loss.
The graph below shows serum concentrations of
thyroxine and thyroid-stimulating hormone in a
volunteer that consumed a well-cooked, 227 g
hamburger (admittedly, a large meal) prepared from
the contaminated meat. Note how TSH levels were
suppressed during the time when thyroxine (T4)
concentrations were elevated.