Thyroid Gland:

1
Thyroid Gland

• Location and Structure

2

• 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).

3

• 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.

4
(No Transcript)
5
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.

6

• 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.

7
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.

8

• 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).

9

• 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).

10

• 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.

11
(No Transcript)
12

• 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.

13

• Colloid endocytosis.
• Colloid droplets containing iodinated
  thyroglobulin are taken up by follicle cells by
  endocytosis. These combine with lysosomes to
  form phagolysosomes.

14

• 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.

15
(No Transcript)
16
Transport and regulation of release

• Most released T4 and T3 immediately bind to
  plasma proteins, of which the most important is
  thyroxin-binding 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.

17
(No Transcript)
18
Actual transmission EM
19
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.

20

• 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.

21
(No Transcript)
22
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.

23
Hyperthyroidism and Graves Disease
24
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.

25

• 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.

26

• Cells secreting the iodinated proteins started to
  collect together in the base of the mouth (panel
  C).
• This arrangement is seen in the amphioxus.

27

• Cells then congregated into open pits in the base
  of the mouth (panel D).
• Seen in the ammocetes larvae of the lamprey.

28

• 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.

29
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.

30

• 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 doesnt happen in mammals.
• Teleostean gonadotropins have no effect on
  mammalian thyrotrophs.

31

• 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.

32

• 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,
  filter-feeding larva metamorphoses into the
  parasitic adult.
• Iodinated glycoproteins have been suggested to
  play a similar role in metamorphosis in some
  inverts (e.g.. Cnidarians)

33

• 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.

34

• 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.

35

• 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.

36

• 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).

37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40

• 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.

41

• 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.

42
(No Transcript)
43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48

• 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.

49

• 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.

50

• 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.

51

• 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.

52

• 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.

53

• 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.

54

• 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.

55

• 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.

56

• 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.

57

• 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

58

• 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.

59

• 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.

60

• 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.