THYROID HORMONE

biochemistry
 THYROID GLAND
Two lobes connected by isthamus
On ventral aspect of trachea just below larynx
Vascularised by sup- & inf- thyroid artey
The thyroid gland consists of 2 types of cells:
1. Follicular cells: are the major secretory cells
releasing thyroid hormones &
2. Parafollicular cells or C-cells: are fewer in
number, interspersed & secrete calcitonin
 FUNCTIONAL UNIT
The functional unit of the Thyroid Gland is a
Follicle which is composed of cuboidal epithelial
(follicular) cells arranged around hollow vesicles
of various shapes (size: 0.02-0.3 mm in
diameter). Arrangement is such that each
follicular epithelial cell lies adjacent to a
capillary!
Each follicle is a closed structure filled with a
glycoprotein colloid called as Thyroglobulin.
There are about 3 million follicles in an adult
human thyroid gland.
• Normally, the thyroid gland secretes 80–
100 g T4 and approximately 5g T3 per
day. The additional 22–25g T3 “produced”
daily is the result of the deiodination of the
5-carbon of T4 in peripheral tissues.
• T3 is believed to be the predominant
biologically active form of thyroid hormone
in the body.
TRH (hypothalamus)
a tripeptide, all components are
essential.
Regulates TSH secretion from
thyrotrophs.
also regulates sec- of other Ant- pit
hormones.
Play an imp- role in post
translational pro- cessing of oligo-
sec moiety of TSH.
It is resistant to intestinal peptidase
action.
Its effects are mediated by
membrane receptor coupled to
phospholipase C as a second
messenger.
TSH(thyrotropin)
a glycoprotein, sec- by Ant- pit. (thyrotroph)
• Its secretion is regulated by a balance
b/w TRH & -ve feedback of T3 & T4.
• It stimulates all phases of thyroid
hormone synthesis.
• Also increases the blood flow of the
gland, hypertrophy & hyperplasia.
• It binds to its specific receptor on acinar
cells → ↑cAMP and Ca level
Normal = 1ng/ml
• the TSH receptor which is
located on the basal surface of
the thyroid follicular cell
 THYROID HORMONES
• The Thyroid gland secretes 2 major hormones:
1. Thyroxine or T4 having 4 atoms of Iodine &
2. Triiodothyronine or T3 having 3 atoms of Iodine
It also secretes:
3. Calcitonin which is an important hormone for calcium
metabolism
 THYROID HORMONES
• About 93% of secreted hormone is T4, while
7% is T3. However, almost all T4 is
ultimately converted in to T3.
• The functions of the 2 hormones are the
SAME but they differ in rapidity & intensity
of action.
• T3 is about 4 times as potent as T4, but is
present in blood in much smaller
quantities & for a much shorter time!
Synthesis of the thyroid hormones (T3 and T4)
 BIOSYNTHESIS OF THYROID
HORMONE
POINTS TO REMEMBER:
1. Iodine in large amounts is required for thyroid hormone
synthesis. This is acquired through diet & THERE IS
NO OTHER USE OF THIS ELEMENT IN THE BODY!
2. The hormones are synthesized in the follicular epithelial
lumen & then stored in the follicular cell!
3. The hormone is thus doubly secreted: once from the
follicular cell as thyroglobulin into the follicular lumen,
then reuptaken by the follicular cells where
thyroglobulin is degraded & the released T3 & T4 are
then secreted into the blood.
4. Thyroxine, the major secretory product, is not the
biologically active form but must be transformed to T3
at extrathyroidal sites.
 INGESTION OF IODINE

• 50 mg of Iodine is required each year OR

1 mg/week.
• To prevent deficiency, common table salt
is iodized with about 1 part sodium iodide
to every 100,000 parts sodium chloride.
• Ingested iodide is absorbed from the GIT.
 IODINE TRAPPING
Under normal circumstances, iodine is 25-50 times
more concentrated in the cytosol of Thyroid
follicular cells than in the blood plasma
↓
Thus, iodine moves into the thyroid cells against a
steep concentration gradient!
↓
This is done with the help of an elctrogenic “Iodide
pump” located in the thyroid cell membrane.
 IODIDE PUMP
The Iodide pump is a Sodium Iodide Symporter.
↓
This pump, thus, transfers 2 Na ions with each
Iodide ion.
↓
Na pump then extrudes 3 Na ions in exchange for
2 K ions to maintain the electrochemical gradient
for Na.
 THYROGLOBULIN SYNTHESIS
• It is the other substance needed for thyroid hormone
synthesis.
• It is the matrix for thyroid hormone synthesis & is the
form in which the hormone is stored in the gland.
• It is a large glycoprotein with a m.w of 660,000 Da.
Synthesized on ribosomes
↓
Glycosylated in the ER
↓
Packaged in the secretory vesicles
THYROGLOBULIN SYNTHESIS

Tyrosine becomes incorporated into

Thyroglobulin while it is being formed
↓
Iodination to form the mature hormone will
not take place until the thyroglobulin is not
secreted into the lumen of the follicle.
 Transport of Iodine into the
follicular lumen!

• For hormone synthesis to take place, Iodine

must be delivered to the follicular lumen.
• The Iodine that has entered into the follicular
lumen from the blood stream diffuses across
the follicular cuboidal cell & exits it to enter
the colloid of the Follicle!
 POINTS TO REMEMBER:

• Tyrosine-containing Thyroglobulin is
exported from the follicular cells into the
colloid by exocytosis.

• Iodine is transferred into the Colloid!

OXIDATION OF THE IODIDE ION
• Iodide ion is oxidized to form either
nascent iodine (I°) or I3− .
• This oxidation is then promoted by the
enzyme thyroperoxidase/ peroxidase and
its accompanying hydrogen peroxidase.
• These enzymes are located in the apical
membrane of the cell or attached to it.
 ORGANIFICATION
• Addition of iodine molecules to tyrosine
residues in the thyroglobulin is called
Organification of thyroglobulin. This
reaction is catalyzed by the enzyme
Iodinase.
1. Attachment of 1 Iodine to tyrosine yields
MONOIODOTYROSINE (MIT)
2. Attachment of 2 Iodines to tyrosine yield
DI-IODOTYROSINE (DIT)
 ORGANIFICATION

• Tyrosine + 1 Iodine = Monoiodotyrosine

(MIT)
• Tyrosine + 2 Iodines = Di-iodotyrosine
(DIT)
 COUPLING
• It is the combination or coupling of 2
molecules of iodinated tyrosine molecules
to form thyroid hormone:

- DIT + DIT = Thyroxine (T4)

- DIT + MIT = Tri-iodothyronine (T3)

COUPLING DOES NOT OCCUR B/W 2 MIT

MOLECULES!
 COUPLING

This mature hormone is formed while a part

of Thyroglobulin molecule, & remains a
part of this large storage molecule till the
stimulus for secretion arrives.
 STORAGE

In normal individuals, approximately 30% of

the mass of thyroid gland is thyroglobulin,
which is about 2-3 months supply of
hormone.
 SECRETION
• For secretion to occur, thyroglobulin must be brought back
into follicular cells by a process of endocytosis.
• Pseudopodia reach out form the follicular cells to engulf
chunks of thyroglobulin, which are taken up in endocytic
vesicles- this is also called “BITING OFF”.
↓
On appropriate stimulation for thyroid secretion, the follicular
cells internalize a portion of thyroglobulin- hormone
complex by phagocytozing a piece of colloid
 SECRETION
The endocytic vesicles fuse with the lysosomes
↓
Lysosomes release enzymes that split off the
biologically active hormones: T3 & T4, as well as
the inactive iodotyrosine, MIT & DIT.
↓
The thyroid hormones being very lipophilic, pass
freely through the outer membrane of the follicular
cells & into the blood!
 FATE OF MIT & DIT
The MIT & DIT are of no endocrine value.
↓
The follicular cells contain an enzyme
(deiodinase) that will swiftly remove the
Iodine from MIT & DIT, allowing the freed
Iodine to be recycled for synthesis of more
hormone
PASSAGE THROUGH BLOOD
This highly lipophilic thyroid hormone molecule
binds with several plasma proteins.
• The binding proteins are:
1. Thyroxine binding globulin (TBG)
2. Transthyretin (TTR)
3. Albumin
The majority (70%) bind to TBG, a plasma protein
that selectively binds only Thyroid hormone.
Less than 0.1% of T4 and less than 1% of T3 is in
the unbound (free) form.
 POINT TO REMEMBER:
• T3 is about 4 times more potent than T4 in its
biological activity.
• Most of the hormone released by the thyroid
gland is T4.
• Most of the T4 is converted to T3, or activated,
by being stripped of one of its iodines outside of
thyroid gland, primarily in the liver & kidneys.
• T3 is the major biologically active form of thyroid
hormone at the cellular level, even though the
thyroid gland secretes mostly T4.
 METABOLISM
• Thyroxine half-life: 6.2 days
• Tri-iodothyronine: 1 day
• Prolonged latent period for Thyroxine:
action starts to show almost 2-3 days after
release & may persist for as long as 6
weeks to 12 months.
• Tri-iodothyronine: 6- 12 hours & maximal
cellular activity occurs within 2-3 days.
 Effects of Thyroid Hormone on The Liver
• affect carbohydrate and lipid metabolism
• increases glycolysis and cholesterol synthesis
• increases the conversion of cholesterol to bile salts.
Through its action of increasing the sensitivity of the
hepatocyte to the gluconeogenic and glycogenolytic
actions of epinephrine,
• T3 indirectly increases hepatic glucose production
(permissive or facilitatory action). Because of its ability to
sensitize the adipocyte to the lipolytic action of
epinephrine,
• T3 increases the flow of fatty acids to the liver and
thereby indirectly increases hepatic triacylglycerol
synthesis. The concurrent increase in the flow of glycerol
to the liver (as a result of increased lipolysis) further
enhances hepatic gluconeogenesis.
 Effects of Thyroid Hormone on The Adipocyte

• T3 has an amplifying or facilitatory effect on the lipolytic

action of epinephrine on the fat cell.
• Yet thyroid hormone has a bipolar effect on lipid storage,
because it increases the availability of glucose to the fat
cell, which serves as a precursor for fatty acid and
glycerol 3-phosphate synthesis.
• The major determinant of the rate of lipogenesis,
however, is not T3, but rather the amount of glucose and
insulin available to the adipocyte for triacylglycerol
synthesis
 Effects of Thyroid Hormone on
Muscle
• In physiologic concentrations, T3 increases glucose
uptake by muscle cells. It also stimulates protein
synthesis, and, therefore, growth of muscle, through its
stimulatory actions on gene expression.
• In physiologic concentrations, thyroid hormone
sensitizes the muscle cell to the glycogenolytic actions of
epinephrine.
• Glycolysis in muscle is increased by this action of T3.
 Effects of Thyroid Hormone on The
Pancreas

• Thyroid hormone increases the sensitivity

of the cells of the pancreas to those
stimuli that normally promote insulin
release and is required for optimal insulin
secretion.
 Calorigenic action
• Thyroid hormone participates in this acute response by
sensitizing the sympathetic nervous system to the
stimulatory effect of cold exposure. The ability of T3 to
increase heat production is related to its effects on the
pathways of fuel oxidation, which both generate ATP and
release energy as heat.
• The effects of T3 on the sympathetic nervous system
increase the release of norepinephrine. Norepinephrine
stimulates the uncoupling protein thermogenin in brown
adipose tissue (BAT), resulting in increased heat
production from the uncoupling of oxidative
phosphorylation
 Goiter

• swelling in neck due to thyroid hypertrophy

• both hypo- and hyperthyroidism
 Thyroid Dysfunctions

• cretinism
- congential absence of T3 and T4 or
chronic iodine deficiency during
childhood

- retarded growth

- sluggish movements

- mental deficiencies
• adult hypothyroidism
- low rate of metabolism and lethargy

- decreased body temp

- decreased heart rate

- outer skin becomes scaley

- myxodema – swelling of sub-cu

connective tissues
• adult hyperthyroidism

- Grave’s Disease

- tall stature, hyperactivity

- high rate of metabolism

- high body temp

- high heart rate

 Exophthalmus

- edematous swelling at the rear of eye socket