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THYROID HORMONE
Dr. Ayisha Qureshi
MBBS, Mphil.
THE THYROID
GLAND
- The thyroid gland is the
largest of the endocrine
glands & is located at the
base of the neck
immediately below the
Larynx on each side of &
anterior to the Trachea.
- The thyroid gland consists
of two lobes of endocrine
tissue (lying on either side
of trachea) joined in the
middle by a narrow portion
of the gland called, the
Isthmus.
- In a normal adult male, it
weighs 15-20 g but is
capable of enormous
growth, sometimes
achieving a weight of
several hundred grams.
LOCATION OF THE THYROID GLAND
THYROID GLAND
The thyroid gland consists of 2 types of
cells:
1. Follicular cells: These are more
abundant, and the major secretory cells.
They secrete Thyroid hormone.
2. Parafollicular cells or C-cells: These
are fewer in number & interspersed.
They secrete calcitonin.
THYROID GLAND AS A
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).
Each follicle is a closed
structure filled with a
glycoprotein colloid called
Thyroglobulin.
There are about 3 million
follicles in an adult human
thyroid gland.
THE THYROID HORMONE
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
THYROID HORMONES
• About 93% of secreted hormone is T4,
while 7% is T3. However, almost all of the
T4 is ultimately converted into 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!
THYROID HORMONE
BIOSYNTHESIS:
1. INGESTION OF IODINE
• 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!
• 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.
2. IODIDE TRAPPING
• This is done with the help of an electrogenic “Iodide pump”
located in the thyroid cell membrane.
The Iodide pump is a Sodium Iodide Symporter (NIS) & is present in
the follicular cell basolateral membrane.
↓
This pump transfers 2 Na ions with each Iodide ion.
(Under normal circumstances, iodine is 25-50 times more
concentrated in the cytosol of Thyroid follicular cells than in the
blood plasma. Iodine moves into the thyroid cells against a steep
concentration gradient!)
↓
Na/ K pump then extrudes 3 Na ions in exchange for 2 K ions to
maintain the electrochemical gradient for Na.
NOTE: Other ions as percholate & thiocyanate compete for binding
sites on the symporter and can block the uptake of iodide.
3. THYROGLOBULIN 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. And is
synthesized in the Thyroid follicular cells.
• Tyrosine becomes incorporated into Thyroglobulin while it is
being formed.
• Once produced, the tyrosine-containing thyroglobulin is
exported from the follicular cells into the colloid by exocytosis.
• For hormone synthesis to take place, Iodine must also be
delivered to the follicular lumen.
• The Iodine that has entered into the follicular cell from the
blood stream diffuses across the follicular cell & exits it to
enter the colloid of the Follicle. This is done with the help of a
transporter protein called Pendrin.
4. OXIDATION OF THE IODIDE ION
• Iodide ion is oxidized to form either
nascent iodine (I°) or I3− .
• This oxidation is catalyzed by the enzyme
thyroid peroxidase and its accompanying
hydrogen peroxidase.
• These enzymes are located in the apical
membrane of the cell or attached to it.
5. ORGANIFICATION
•
Addition of iodine molecules to tyrosine
residues in the thyroglobulin is called
Organification of thyroglobulin.
• This reaction is catalyzed by the enzyme
Iodinase.
• Tyrosine + 1 Iodine = Monoiodotyrosine
(MIT)
• Tyrosine + 2 Iodines = Di-iodotyrosine
(DIT)
6. 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!
This mature hormone is formed while being a part of
Thyroglobulin molecule, & remains a part of this
large storage molecule till the
stimulus for
secretion arrives.
7. STORAGE
In normal individuals, approximately 30% of
the mass of thyroid gland is thyroglobulin,
which is about 2-3 months supply of
hormone.
8. SECRETION
• Before their release, T4 & T3 are still bound with
the thyroglobulin molecule.
• 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”.
• The endocytic vesicles fuse with the lysosomes.
• Lysosomes release enzymes that split off the
biologically active hormones: T3 & T4, as well as
the inactive iodotyrosines, MIT & DIT.
• The thyroid hormones being very lipophilic, pass
freely through the outer membrane of the
follicular cells & into the blood!
9. 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.
MECHANISM OF ACTION
M.O.A
• Thyroid hormone receptors are members
of a large family of nuclear hormone
receptors
Location: Thyroid hormone receptors are
either attached to the DNA genetic strand
or located in close proximity to them.
M.O.A
The receptor usually forms a heterodimer with retinoid X receptor (RXR) at
specific thyroid hormone receptor elements (THR) on the DNA.
↓
The thyroid hormone receptor binds to the response elements in the absence
of the hormone.
↓
When the thyroid hormone becomes available, the receptor becomes activated
& initiates the transcription process.
↓
Large number of mRNA are formed
↓
Within minutes or hours: RNA translation on the cytoplasmic ribosomes takes
place
↓
Hundreds of new intracellular proteins are formed
↓
Most of the actions are exerted through these proteins
ACTIONS OF THYROID
HORMONE
1. GENES
•
Thyroid hormone increases the transcription of large
number of genes.
↓
Thus, in all cells of the body, there is increased production
of:
1. Protein enzymes
2. Structural proteins
3. Transport proteins
4. Other substances
↓
Net result: there is generalized increase in functional
activity throughout the body!
2. GROWTH & MATURATION
• It stimulates growth of the skeletal system by affecting
bone maturation.
• It stimulates normal synthesis & secretion of the GH.
• It is essential for the normal growth of the children.
• It stimulates & promotes normal growth & development
of the brain during the perinatal period (nerve
myelination & brain vascularity).
• Its deficiency during postnatal period can lead to
irreversible mental & physical retardation in infants & a
small sized brain.
• In the adult, it has excitatory effects on the nervous
system.
3. AUTONOMIC NERVOUS SYSTEM
• Interactions b/w thyroid hormone & ANS are
important throughout life.
• ↑ secretion of thyroid hormone exaggerates
many responses of the sympathetic neurons.
• It ↑ the number of receptors for epinephrine &
NE (beta- adrenergic receptors) in the
myocardium & other tissues.
• Thus, many symptoms of hyperthyroidism
resemble sympathetic nervous system.
4. Carbohydrate metabolism
It stimulates all aspects of carbohydrate
metabolism:
1. ↑ hepatic glucose production
2.↑ gluconeogenesis
3.↑ glycogenolysis
4.The plasma glucose levels remain normal
provided the pancreas respond by ↑ Insulin
secretion.
5. LIPIDS
• It stimulates lipid mobilization from fat stores
of the body.
• ↑ Lipogenesis
• ↑ Lipolysis (to provide glycerol for
gluconeogenesis)
• Increased levels of TH shift the balance in
favor of lipolysis, mobilizing fat stores.
• ↑ secretion of cholesterol into bile, thus
decreasing the cholesterol levels in the
blood.
6. PROTEIN METABOLISM
• ↑ Proteolysis (to provide the amino acids
for gluconeogenesis)
• ↑ Protein synthesis
Usually the Proteolysis outweighs the
protein synthesis and there is a net increase
in Protein catbolism.
7. BASAL METABOLIC RATE
• BMR is highly sensitive to thyroid status.
HYPOthyroidism decreases BMR &
HYPERthyroidism increases BMR.
• TH is “calorigenic” which means that it promoted
heat production.
• It is not surprising that one of the classical signs of
hypothyroidism is decreased tolerance to cold,
whereas excessive heat production & sweating
are seen in hyperthyroidism.
8. HEART
•
•
•
Blood Flow & Cardiac Output:
Increased BMR
↓
Increased & more rapid oxygen consumption by the tissues
↓
Greater than normal metabolic end products
↓
Vasodilatation in most tissues
↓
Increased blood flow
↓
Increased cardiac output
Increased Heart Rate
Heart Strength:
Small increase in thyroid hormone secretion: Increase in heart strength
due to increased enzymatic activity (as occurs in mild fevers during
exercise)
Large increase in thyroid hormone secretion: heart strength becomes
depressed b/c of long term protein metabolism
Some severely Thyrotoxic patients die of severe cardiac decompensation (due to myocardial
failure b/c of increased cardiac output causing increased cardiac load)
9. RESPIRATION
Increased rate of metabolism
↓
Increased utilization of oxygen
+
Increased formation of carbon dioxide
↓
Increased rate & depth of Respiration
10. GASTROINTESTINAL TRACT
• Increased appetite
• Increased food intake
• Increased GI motility
• Increased GI secretions
SO, Hypothyroidism causes:__________
& Hyperthyroidism causes: __________
11. SLEEP
Increased thyroid hormone secretion
↓
Exhaustive effect on the musculature & CNS
↓
Constant tiredness
BUT, b/c of the excitable effects on
synapses, IT IS DIFFICULT TO SLEEP
12. Effect on Other Endocrine Glands
Increased rate of secretion of thyroid hormones
↓
Increases the need of the tissues for the hormones
↓
Increases the rate of secretion of various hormones
• For normal sexual development and function,
thyroid hormone production needs to be normal.
CONTROL & DIAGNOSIS
THYROID HORMONE
SECRETION
THYROID STIMULATING HORMONE
(TSH)/ THYROTROPIN
• Is a glycoprotein with a mw of 28, 000 and secreted by the
anterior pituitary.
• Main function: It increases the secretion of both T3 & T4by the
thyroid gland.
• Mechanism of Action:
TSH + TSH receptors on the thyroid follicular cell membrane
↓
Adenylyl cyclase is stimulated
↓
ATP→ cAMP
↓
Protein kinase A is activated
↓
Multiple phosphorylations throughout the cell
↓
1. Immediate increase in thyroid hormone secretion
2. Stimulates growth of the thyroid glandular tissue
THYROID STIMULATING
HORMONE
EFFECTS ON THE THYROID GLAND:
1. Increased proteolysis of the Thyroglobulin already
stored in the follicular cells
2. Increased activity of the “Iodide pump”
3. Stimulates Organification
4. Increased size & secretory activity of the thyroid cells
5. Increased number of the Thyroid cells (with change
into columnar from cuboidal)
IN SUMMARY: TSH increases all the known secretory
activities of the thyroid gland!
MOST IMPORTANT IS PROTEOLYSIS WHICH CAUSES
RELEASE OF THE TH INTO THE BLOOD STREAM
WITHIN 30 MINUTES!
• ANTERIOR PITUITARY SECRETION OF
TSH IS REGULATED BY
THYROTROPIN-RELEASING HORMONE
FROM THE HYPOTHALAMUS
THYROTROPIN RELEASING
HORMONE (TRH)
• A tripeptide amide (pyroglutamyl-histidyl-proline-amide)
• Secreted by the nerve endings in the median eminence
of hypothalamus
Mechanism of secretion:
TRH + TRH receptor in the pituitary cell membrane
↓
Phospholipase C second messenger system activated
↓
TSH released
HYPOTHALAMIC-HYPOPHYSIAL
PITUITARY AXIS
Hypothalamus
↓
TRH
↓
Hypothalamic-Hypophysial portal blood system
↓
Anterior pituitary
↓
TSH
↓
Thyroid gland
↓
Tri-iodothyronine & Thyroxine Secretion
HypothalamicHypophysial Feedback
System
IF TYROID
HORMONE
DEFICIENT, THEN
THE SECRETION
IS STIMULATED
THROUGH THIS
FEEDBACK
SYSTEM!
&
VICE VERSA!