The Thyroid Gland

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 Introduction
• Thyroid gland primarily governs the rate at which metabolism
occurs in the individual
• It influences normal growth and development of the
individual.
• Essential for mental and psychological development in infancy
and early childhood.
• Though thyroid hormones are not very essential for immediate
maintenance of vital functions of life their deficiency causes
severe deficit in mental and physical growth and extreme
decrease in body metabolism.
• It also influences calcium metabolism by secreting calcitonin
from its parafollicular cells
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 Thyroid gland
• Thyroid is one of the largest of the endocrine glands
• Right & Left lobe connected by Isthmus
• Weighing 15-20 g in adults.
• Secretes T4, T3, and calcitonin
• About 93% of the metabolically active hormones
secreted by thyroid gland are thyroxine(T4) and 7% is
triiodothyronine(T3).
• Thyroid secretion is controlled primarily by thyroid
stimulating hormone (TSH).
• 4 para-thyroid glands are located posteriorly at each
pole of the gland
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Anatomy & Histology

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 Acini
• Thyroid gland is formed by aggregates of acini
or follicles.
• The follicles are spherical in shape and are
formed by a single layer of epithelial cells that
surrounds a central thick solution called colloid,
which is a viscous gel-like substance containing
thyroglobulin in it.
• The apical membrane of the follicular cells that
faces the colloid is covered with microvilli.
• The basal membrane of the follicular cells is in
close contact with the numerous capillaries
present in the interfollicular space
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• Parafollicular cells or C cells that
secrete calcitonin are present close to
follicles.
• Size of the follicle and the quantity of
colloid vary with the state of activity
of the gland.
• The follicles are large in size,
containing more colloid when the
gland is inactive
• In the active gland, follicles are small,
cells are columner, and colloid is
present in small quantity
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 Structure of thyroid follicular cells
Microvilli toward apical surface
The cells contain numerous granular ER,
lysosome, and Golgi complex
Function:
-Synthesize Thyroglobulin & store as
colloid
-Iodine trapping & transporting into
the colloid for hormone synthesis
-Remove thyroid hormones from
thyroglobulin & secret into
circulation

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 Formation & secretion of Thyroid
Hormones: Steps
Steps of Thyroid Hormone Synthesis
1. Formation of thyroglobulin
2. Iodide trapping
3. Oxidation of iodide into iodine
4. Organification/Iodination of Thyroglobulin
5. Coupling reaction
6. Proteolysis of thyroglobulin and secretion of
thyroid hormones

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Blood Thyroid cell: RMP -50mv Colloid

2 3
2

4
Iodotyrosine
dehalogenase

6 5
1

6 6

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 1) Formation of Thyroglobulin

• Thyroglobulin is a large glyco-protein

synthesized by the ER & golgi bodies of
thyroid cells and secreted into the follicles
• Each thyroglobulin contains about 70 tyrosine
amino acid which later combines with iodine
molecule during thyroid hormone synthesis

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 2) Iodide Trapping
• Thyroid cells RMP is -50mv
• I- is absorbed into the cell against electrical
gradient actively by Na+/I- Symporter or
NIS(iodide pump) located on basolateral side
• This pump co-transports 1 iodide ion along with 2
Na ion
• Energy for transporting iodide comes from Na K
ATPase pump
• This pump helps to concentrate iodide 30 times
that of blood (T/S Iodine ratio Normal 25-50:1)

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• I- diffuses passively into the colloid through
apical membrane down electrical gradient via
a chloride-iodide counter transporter called
PENDRIN
• Applied aspect of NIS
This pump is stimulated by TSH
Inhibited by: Monovalent anions
Eg: Chlorate, Thiocyanate, bi-iodate
: Metabolic poisons like cyanide
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 3) Oxidation of iodide into iodine

• Within the colloid I- immediately gets oxidized

to Iodine by thyroid peroxidase enzyme & its
accompanying H2O2 which makes it capable to
bind with tyrosine

This enzyme can be inhibited by anti-thyroid drugs like

thiouracil & carbimazole

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 4) Organification/Iodination of Thyroglobulin

• The binding of I with Thyroglobulin is

called organification of thyroglobulin
• I gets bound to ‘3’ position of tyrosine
(attached to thyroglobulin) forming
mono-iodo tyrosine (MIT)
• MIT is next iodinated at ‘5’ position to
form Di-iodo Tyrosine (DIT)

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 5) Coupling reaction
• These iodo tyrosine residues become
coupled with one another catalysed by
thyroid peroxidase
• DIT + DIT Thyroxine (T4) Major
product
• MIT + DIT Tri-iodo thyronine (T3)
• DIT + MIT Reverse T3 (inactive form)
• MIT DIT T3 & T4 are still in peptide linkage
with thyroglobulin which occurs as colloidal
aggregates within follicle
Coupling enzymes are competitively inhibited by anti
thyroid drugs 16
 6) Release of T3 & T4 into blood

• The colloid is ingested by the Thyroid cells via

pinocytosis with formation of reabsorbtion
lacunae
• Within the cell, the lysosomes contain protease
which break down the peptide bond to cause
liberation of T3 T4 MIT & DIT in the cytoplasm
• Iodinated T3 & T4 are de-iodinated by enzyme
iodotyrosine dehalogenase & the liberated I is
re-utilized
• About 90% is T4 and 10% is T3
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 Transport & Metabolism
• Transport of thyroid hormone is by thyroid
binding proteins:
Thyroid binding globulin
Thyroid binding pre-albumin
Albumin
• In the liver T4 & T3 are conjugated to form
sulphates & glucuronides which passes into
intestine via bile and excreted in stool
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 Regulation of Thyroid secretion
Exposure to cold,
Warmth, stress ,
Prolong anxiety or
1) TSH: Released from Ant anxiety
excitement

Pituitary
It not only increases the
secretion of thyroid
hormones but also
promotes the synthesis of 1

fresh thyroid hormones

2) Thyroid autoregulation
2

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 1) Thyroid stimulating Hormone: Effects

1. Increases I- trapping or uptake

2. Increases binding of I to tyrosine
3. Increases pinocytosis
4. Increases proteolysis of thyroglobulin
5. Increases synthesis of Thyroglobulin into colloid
6. Increases number & size of thyroid cells:
Hyperplasia & hypertrophy of Gland (GOITER)
7. Increases blood flow into thyroid

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 Control of TSH secretion
1) Hypothalamic control: By
Thyrotropin releasing
Hormone
2) Feedback control by T4:
Inverse relation exits
between TSH & T4
3) Measurement of plasma
TSH level is one of the
best test for Thyroid
functions

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 2) Thyroid autoregulation
1) Thyroid functions are controlled by intrinsic
control system within the gland
2) Role of Iodine in diet: Paradoxical effect
Small doses of I : normal thyroid function
High dosage of I : Decreases thyroid function
(Wolff chaikoff effect)
Reason: Organic Iodine affects the sensitivity of thyroid
response to TSH: Iodine deficiency increases the
sensitivity & iodine excess decreases the sensitivity
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 Action of high dose of Iodine
1) Prevent oxidation of I- to I
2) Prevent organification of tyrosine
3) Decrease proteolysis of Thyroglobulin
4) Decrease blood flow to Thyroid
5) Decrease TSH effect on Thyroid

These inhibitory effects due to i- excess last for only

1-2 weeks and wears of inspite of continued
therapy

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Mechanism of action of Thyroid Hormone

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• The Thyroid hormone act by increasing
transcription of large number of proteins
• This hormone activate nuclear receptors which
are attached to DNA genetic strands
• On binding with hormone the receptors are
activated & initiate transcription to form
messenger RNA
• These are translated to form various intracellular
proteins which cause the effects of thyroid
Hormone
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 Actions of Thyroid Hormone
1) Calorigenic action: Stimulate heat production
in the body secondary to stimulation of O2
consumption which increases the BMR
-Increase the activity of Na-k pump in almost
all tissues of the body
Hypothyroid patient: Hypersensitive to cold
temperature
Hyperthyroid patient: Hypersensitive to
warm temperature
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 2) Protein Metabolism
T4 in physiological • In Pharmacological doses cause
dose is anabolic ie protein catabolism leading to
increases protein negative Nitrogen balance
synthesis and • Catabolic effect in skeletal
positive Nitrogen muscle cause marked muscle
balance weakness and fatigue
(Thyrotoxic myopathy)
• Mobilization of bone protein
decreases bone mass & causes
osteoporosis

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 3) Carbohydrate metabolism
• In Physiological doses it produce 2 opposite
effect which balance each other
It can causes It can cause hyperglycemia by
hypoglycemia by -↑ glucose absorbtion in
increasing peripheral intestine
utilization of glucose like - ↑ glycogenolysis in liver
insulin -↑ Gluconeogenesis in liver
-↓ rate of secretion of Insulin

• In Pharmacological doses/hyperthyroid state it

precipitate Diabetes melitus
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 4) Lipid metabolism
• T4 decreases S cholesterol by increasing its
breakdown in liver & excretion in bile
• T4 decreases the stores of triglycerides &
phospho-lipids by increasing lipolysis

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 5) On CVS
• A combined effect of T4 & catecholamines cause
increase in HR ( Sleeping HR also ↑), increase in
force of myocardial contraction, rise in systolic BP
& decrease circulation time
• T4 increases body temperature which causes
vasodilatation & increase blood flow through skin
thus decreasing diastolic BP
• Decrease in circulation time increases the velocity
of blood flow causing inadequate tissue perfusion
(High output cardiac failure)
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 6) Nervous system
T4 is necessary for normal development & activity
in CNS (Critical period upto 1yr)
1) After Birth: deficiency causes
• Defective myelination in cortical neuron
• Branching & development of dendrites
decreases with abnormal synapse formation
• Reduction in vascular bed
All these causes Infantile brain & mental retardation

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2) In Adults: T4 deficiency In Adults : Excess T4
causes causes
• Loss of intellectual • Emotional instability ,
function anxiety
• Memory loss • Over excitability
• Slow speech • Insomnia
• Mental & Physical • Fine Tremors
lethargy

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 7) GIT
T4 causes modification of intestinal motility

• T4 deficiency decreases • T4 excess produce

intestinal motility thus diarrhoea due to
producing constipation increased intestinal
motility

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 8) On Gonads & Lactation
• Cretins show poor gonadal development with
absence of secondary sexual characters
• Hypothyroid Women: Menorrhagia
• Hyperthyroid Women: Scanty menstruation
• Fertility is also altered in case alteration of
thyroid activity
• T4 is essential for galactopoesis

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 9) Bone Marrow
• T4 deficiency leads to • T4 excess
anemia due to a) Stimulates
a) Decreased bone erythropoesis
marrow metabolism b) Increases production
which decreases of 2,3 DPG in RBC
erythropoesis
c) Shift O2 dissociation
b) Decreased curve to the right
absorbtion of vit B12
from GIT

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 10) On Growth & development
• T4 is important for normal body growth and
skeletal maturation because it increases
protein synthesis
• In cretins bone growth is slowed with delay in
epiphyseal closure
• T4 helps in tissue differentiation & maturation

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 11) Skin
• In hypothyroidism complexes of protein with
mucopolysaccharides, hyaluronic acid &
chondroitin sulphate are deposited under the
skin which retains water and NaCl.
• It causes dry coarse puffy appearance of skin:
Myxoedema
• It is a non pitting oedema

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 Anti thyroid drugs
• Reduction of the hyper-secretion of thyroid hormones
in hyper thyroidism can be achieved by drugs which act
in different ways on hormone synthesis & release
1) Inhibit I- trapping: Iodide uptake is blocked by
competitive inhibition by monovalent anions
eg Perchlorate, Thiocyanate.
2) Thiourylenes: They inhibit oxidation & organic binding
of iodine and also the coupling of iodotyrosine to
form T3 & T4 by blocking thyroid peroxidase &
coupling enzymes
eg Thiouracil & carbimazole
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3) Iodine or Iodide: high dose of iodine reduces
formation & release of thyroid hormone called
Wolff Chaikoff effect. (mechanism in previois
slide)
4) Beta adrenergic blockers: reduce the symptoms
of hyperthyroidism and are used during
preparation of patient before thyroidectomy
eg: Atenolol, propanolol
5) Radioactive I (131I) : To destroy overactive thyroid
tissue
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Applied aspects

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