Thyroid Gland:

Location and Structure

The largest pure endocrine gland in the body,
located in the front of the neck, on the trachea
just below to the larynx.

Its two lobes are connected by a median tissue
mass called the isthmus.

Internally, it is composed of about 1 million of
round follicles. The walls of each follice are
formed by cuboidal and squamous epithelial
cells called follicle cells, which produce
thyroglobulin (glycoprotein).

The lumen of each follicle stores colloid, which
consists primarily of molecules of
thyroglobulin.

The follicular epithelium also consists of
parafollicular cells, a separate population of
endocrine cells that produce calcitonin, a
hormone involved in calcium homeostasis.
Thyroid hormones (THs)

The two THs contain iodine and are called thyroxin (or
T4) and triiodothyronine or (T3).

T4 and T3 have a very similar structure as each is made
up of two tyrosine amino acids linked together and
either 4 or 3 atoms of iodine, respectively.

T4 is the main hormone produced by the thyroid and T3
has most if not all of biological activity as all target
tissues rapidly convert T4 to T3.

Except for the adult brain, spleen, testes, and the
thyroid gland itself, THs affect all other types of cells in
the body where they stimulate activity of enzymes
especially those involved in glucose metabolism

Increase metabolic rate in target tissues, which increases
body heat production (calorigenic effect).

THs also are critically important for normal growth and
development of skeletal and nervous systems and
maturation of reproductive system.
Synthesis of thyroid hormones:

Formation and storage of thyroglobulin.

This process takes place in follicle cells and the final
product is packed into vesicles, their contents are
discharged into the lumen of the follicle and become
a major part of the colloid.

Iodide trapping and oxidation to iodine.

To produce functional iodinated hormones, follicle
cells accumulate iodide from the blood. A protein
pump (iodide trap), located on the basal surface of
follicle cells, actively transports iodide into follicle
cells where it is oxidized and converted to iodine (I).

Iodination.

Once formed, iodine is attached to tyrosine amino
acids which are part of the thyroglobulin.

Iodination of one tyrosine produces
monoiodotyrosine (MIT), iodination of two
tyrosines diiodotyrosine (DIT).

Coupling.

Then enzymes within the colloid link MITs and
DITs in a highly specific fashion, as a result two
DITs linked together result in T4 , while coupling of
MIT and DIT produce T3.

Coupling (cont.)
Interactions between two DITs are more frequent so
more thyroxin.
 At this point both thyroid hormones are still
attached to thyroglobulin molecules in the colloid.


Colloid endocytosis.

Colloid droplets containing iodinated thyroglobulin
are taken up by follicle cells by endocytosis. These
combine with lysosomes to form phagolysosomes.

Cleavage of the hormones for release.

Within the phagolysosomes, the hormones are
cleaved from the thyroglobulin by lysosomal
enzymes. The free hormones then diffuse through
the basal membrane out of the follicle cell and into
the blood stream.
Transport and regulation of release:

Most released T4 and T3 immediately bind to plasma
proteins, of which the most important is thyroxinbinding globulin (TBG) produced by the liver.

Binding proteins protect T4 and T3 from immediate
degeneration by plasma enzymes, also they allow T4 and
T3 to reach target tissues, often located a significant
distance away from the thyroid gland.

Decreasing blood levels of thyroxin trigger release of
TSH from the anterior pituitary, which stimulates the
thyroid gland to produce more thyroxin.
Actual transmission EM:
Pathology of the thyroid gland function:

Both hypo- and hyperactivity and of the thyroid gland
can cause severe metabolic disturbances.

In adults, hypothyroidism is referred to as


myxedema.
Symptoms:


Low metabolic rate, poor resistance to cold temperatures,
constipation, dry skin (especially facial), puffy eyes, lethargy
and mental sluggishness.
If hypothyroidism results from lack of iodine the thyroid
gland enlarges to form a goiter.

Severe hypothyroidism during the fetal
development and in infants is called cretinism.

Symptoms:
A short disproportionate body, a thick tongue and
neck, and mental retardation.
 The condition is preventable by thyroid hormone
replacement therapy. However, once developmental
abnormalities and mental retardation appear, they
are not reversible.

Hyperthyroidism:

The most common form of hyperthyroidism is Grave's disease, believed to
be an autoimmune disease.

The immune system produces antibodies that mimic TSH, which bind to
TSH receptors and permanently switch them on, resulting in continuous
release of thyroid hormones.

Typical symptoms include metabolic rate, sweating, rapid and irregular
heartbeat, nervousness, and weight loss despite adequate food intake.

Often, exophthalmos, or protrusion of the eyeballs, occurs caused by the
edema of tissues behind the eyes followed by fibrosis.

Treatments include surgical removal of the thyroid gland (very difficult due to
an extremely rich blood supply) or ingestion of radioactive iodine (131I),
which selectively destroys the most active thyroid cells.
Hyperthyroidism and Grave’s Disease
Comparative aspects of thyroid
function:

Originally, it is thought that animals secreted iodinated proteins as
a defense mechanism (panel A on fig. 8-3 Norris).


Iodinated molecules were secreted from all over the body, including the
mouth.
Iodinated proteins secreted in the mouth were ingested and digested. The
iodinated tyrosines and thyronines were absorbed.

Eventually, the secretion of iodinated proteins was
limited to the interior of the mouth (panel B).

Iodinated proteins are found in a great number of species,
including molluscs, arthropods and even some algae.

Cells secreting the iodinated proteins started to collect
together in the base of the mouth (panel C).

This arrangement is seen in the amphioxus.

Cells then congregated into open pits in the base of the
mouth (panel D).

Seen in the ammocetes larvae of the lamprey.

Finally, these pits were internalized and the cells began
secreting iodinated tyrosines and thyronines directly
into the blood (panel D).

This transformation is observed during the metamorphosis
of the lamprey larva into the adult form.
Pituitary control of thyroid function:



This seems to have evolved much later on.
There are no thyrotrophs in the agnathan
pituitary.
Thyrotrophs probably evolved later on, most
likely from gonadothrophs.
This is supported but the similarities in the hormone
structures between LH, FSH and TSH.
 In elasmobranchs, thyrotrophs are located adjacent
to the gonadotrophs.


Structurally, thyroptophs and gonadotrophs
resemble one-another closely.

TSH, LH, and FSH all feed back negatively on both
gonadotrophs and thyrotrophs in teleost fishes.

This doesn’t happen in mammals.

Teleostean gonadotropins have no effect on
mammalian thyrotrophs.

In non-mammalian vertebrates, there is a strong
interaction between the PRL axis and the
thyroid axis.

PRL antagonizes the response to thyroid hormones
in a number of species.
In amphibians, TRH does not seem to regulate TSH
secretion.
 Rather, it appears to stimulate PRL secretion.
 TRH levels are relatively high in the amphibian brain.


Agnathan fishes:
No true thyroid gland has been identified.
 However, there are follicle-like structures that
concentrate iodine.
 Thyroid hormones have been detected.
 No definitive functions have been ascribed to the
thyroid hormones.
 However, T4 levels have been shown to decrease
sharply in lampreys when the free-swimming, filterfeeding larva metamorphoses into the parasitic adult.
 Iodinated glycoproteins have been suggested to play a
similar role in metamorphosis in some inverts (e.g..
Cnidarians)


Chondricthyan fishes:

Very little is known about thyroid function in sharks
and rays.

However, they do have a well developed pituitary-thyroid
axis.
Distinct thyroid hormones are found.
 There are distinct thyroid cycles which coincide with
the reproductive cycle.



TH thought to be involved in promoting gonadal
maturation.
Thought to be involved in regulating metabolism
during migration.

In at least one species, increased TH induces migration.
Elevated TH levels seem to induce elevated O2
consumption during embryological development,
but the response is lost later in development.
 A number of inconclusive studies have attempted to
show positive TH control of O2 consumption, but
conclusive results have been elusive.
 However, another developmental role for TH has
been identified.


Development of neurosecretory activity in the
hypothalamus is accelerated by treatment with T3 and T4
in the oviparous dogfish.

Chondrostean fishes (sturgeons):

Preliminary evidence suggests that circulating TH
levels peak during spawning behaviour.


These elevated levels may also be associated with
migration.
Injection of TH can reverse the gonadal
degeneration seen in captive sturgeon.

This suggests a direct link between thyroid activity and
reproduction, but further studies need to be done.

Teleost fishes:
Thyroid tissue is found in diffusely distributed
follicles, spread throughout the head region (fig. 8-6).
 TRH and somatostatin are found in the hypothalamus
and appear to have the normal functional effects on
thyroid hormone secretion.


Exception is the salmonid fishes where TRH seems to
function as an inhibitory neurohormone.
T3 is the primary form that is secreted (unlike
mammals).
 Thyroid hormone seems to be involved in salt water
adaptation, regulation of migratory behaviour, and
metamorphosis (in fish with a distinct larval stage).


Sarcopterygean fishes:

T3 is involved in survival through a drought.
During aestivation, the metabolism all but stops and water
is conserved.
 During water deprivation, T3 levels drop significantly.
 When water is provided, T3 levels rise and metabolic rate
increases.


Amphibians:
Both T3 and T4 are present.
 Both are involved in regulation of reproduction and
metamorphosis.
 Both regulate moulting and general growth.
 During metamorphosis, TH influences gene activity
in the metamorphosing tissue.



T3 stimulates apoptosis in the tails of anurans.
T3 is also involved in modulating the water drive
seen in newts.

Thyroid function in reptiles:

Some reptiles have been shown to have circulating
MIT and DIT.


Isolated thyroid sections secrete MIT and DIT in
response to TSH in a turtle (Geochemys reevsii), a gecko
(Geckko gecko), and a snake (Elapha rachiata).
There are 5 major roles for thyroid hormones in
the reptiles.

Reproduction:
Thyroid function is positively correlated with a
number of reproductive events in lizards and turtles.
 Elevated thyroid activity (as assessed by histological
evaluation) is associated with spermatogenesis,
ovulation, and mating in a number of lizard species,
as well as at least one turtle and one snake species.
 In the lizard Lacerta vivipara thyroidectomy causes
premature ejection of most eggs and the remaining
retained eggs fail to develop.
 However, there is no evidence that thyroid function
is associated with gestation in live bearing lizards.


Temperature selection:
In snakes, thyroid function is greatest during warm
periods and lowest during hibernation (as seen in the
common Garter snake.
 In most temperate lizards, the relationship is the
same, high in warm seasons and low during cold
seasons.
 Artificially changing ambient temperature changes
thyroid function.


However, in a number of snakes and lizards, the
highest level of thyroid function is associated with
reproduction, not environmental temperature.

In lizards from tropical climates, environmental
temperature does not seem to have any effect on
thyroid function.

Injecting thyroid hormones has been shown to cause
selection of a warmer temperature.

Thyroid function and O2 consumption:
This relationship is temperature-dependent.
 In animals tested, manipulation of thyroid
hormones, TSH, or thyroidectomy have little effect
on O2 consumption at 20oC.
 However, if temperature is raised to 30oC, then O2
consumption is increased by eloevated thyroid
function.
 A similar effect is seen on reptile tissues in culture at
30oC.


Moulting:

Snakes and lizards respond in opposite ways.

In lizards, moulting is stimulated by increased
thyroid hormones and blocked by thyroidectomy.


Administration of PRL potentiates the stimulatory effect
of thyroid hormones.
In snakes, the situation is different. Thyroidectomy
increases the frequency of moulting and
administration of thyroid hormones stops moulting
completely.

Growth:

Some studies have suggested a possible link between
thyroid hormones and growth, but very few studies
have been done in this area.

More studies need to be performed before a positive
correlation can be established.

Thyroid function in birds:

The thyroid axis is well developed in birds and
emerges early in embryonic development.
For example, in domestic chickens, the thyroid responds
to inject TRH by day 6 of development.
 Plasma levels of thyroid hormones are detectable by day
13 and levels rise to a maximum by day 20.


Thyroid and reproduction.
Domestic birds require thyroid for gonadal
development.
 T4 is required for testicular development and
thyroidectomy or administration of goiterogenic
compounds will induce gonadal regression.
 However, in many wild species such treatment will
induce a precocious gonadal development.


Probably due to the breeding program for domesticated
birds.

Thermogenesis and O2 consumption:
Thyroid hormones are directly involved in cold
adaptation.
 As in mammals, thermogenesis is closely linked to
O2 consumption.
 Some wild birds exhibit elevated thyroid function
during late autumn and winter.
 Thyroidectomy of adult birds depress their ability to
generate heat.
 Treatment with thyroid hormones stimulates O2
consumption


Carbohydrate metabolism and growth.
Thyroid hormone elevation reduces the glycogen
stores in the liver, increases plasma free fatty acids
and causes hyperglycemia.
 There is evidence to suggest that there is a
significant interaction between thyroid hormones
and GH.

Release of GH is reduced when thyroid hormones are
elevated.
 Thyroidectomy causes depression of growth in birds.


Moulting
Thyroids hormones produce stimulatory effects on
skin and feathers, that are normally thought of as
being associated with moulting.
 Moulting is usually regulated along with
reproduction.
 Unlike lower vertebrates, thyroid hormones may act
in a permissive role in mouloting.


Migration:
Migratory birds seem to have more active thyroid
glands than non-migratory birds (within and
between species).
 May be involved in inducing elevated metabolic rates
associated with the strenuous act of migration.
