Thyroid Gland –

Normal Function
 Objectives

Describe
– Synthesis, storage and secretion
– Transport in blood
– Mechanism of action
– Actions
– Regulation of secretion
of thyroid hormones
 Thyroid Hormones

1 “Thyroid hormones”
• Thyroxine
• Triiodothyronine
Synthesised and secreted by follicular cells

2. Calcitonin
Secreted by parafollicular cells
Thyroxine and triiodothyronine

Tetraiodo thyronine’
T4
Thyroxine

Triiodo thyronine’
T3
Reverse T3
Functional unit
Follicular cells:
cuboidal or
columnar
Colloid:
content varies –
high/low

These depend on the

degree of activity of
the gland
 Synthesis of thyroid hormones

Made of two iodinated tyrosine molecules

• Iodine obtained from blood
• Proteins containing tyrosine produced
• Iodine combines with tyrosine in the protein
• Two iodinated tyrosine molecules coupled (while still in
the protein molecule)
• The coupled tyrosine is broken off from the protein and
secreted
 Iodine “trapping”

Na+-I- pump
• Follicular cell basal cell membrane has Na+-I- transport
system
• Symport
• Active
• Activity of the pump varies – inversely with the
availability of iodine
• May be blocked by other anions (has been used to reduce
thyroid hormone sysnthesis)
 Iodine oxidation

I- need to be converted to iodine before they can be

incorporated into tyrosine residues
•I- that is pumped into the follicular cell moves from the
basal membrane towards the apical (luminal) membrane
•At the luminal membrane it is oxidised to I2 by thyroid
peroxidase
•Thyroid peroxidase is an enzyme associated with the apical
membrane of follicular cells
 Thyroglobulin synthesis

A protein called thyroglobulin is produced by

follicular cells
•Through the same process as for any other protein
•Thyroglobulin contains tyrosine residues
•After synthesis, thyroglobulin containing vesicles are
transported towards the apical membrane
 Iodination of tyrosine

Both I2 and thyroglobulin reach the apical

membrane where iodination of tyrosine takes place
•Catalysed by thyroid peroxidase
•Iodine combines with tyrosine residues while they are still
part of the thyroglobulin protein
•Each tyrosine residue may combine with one or two iodine
atoms
•Tyrosine + one iodine atom = monoiodo tyrosine (MIT)
•Tyrosine + two iodine atoms = diiodo tyrosine (DIT)
 Coupling of iodinated tyrosine

The iodinated tyrosine molecules are coupled

together – at the membrane
•Catalysed by thyroid peroxidase
•Two tyrosine molecules join together
 Coupling of iodinated tyrosine

The iodinated tyrosine molecules are coupled

together – at the membrane
Possible combinations:
DIT + MIT – results in triiodothyronine (T3)
DIT + DIT – results in tetraiodothyronine (T4)
•More T4 than T3 formed
•Thyronines are still part of the thyroglubulin molecule
•Some MIT and DIT remain left without being coupled
 Thyroid peroxidase

• Catalyses three steps in the synthesis of thyroid hormone

• Inhibition of the enzyme will markedly reduce thyroid
hormone production
• This is used pharmacologically when there is a need to
reduce thyroid hormone secretion
 Release of thyroglobulin into the colloid

After coupling occurs, thyroglobulin chains enter

the colloid
•T4 and T3 attached to thyroglobulin
•Some DIT and MIT remain in the protein chain without
being coupled
 Secretion of thyroid hormones

• Thyroglobulin from the colloid is taken back into the

follicular cell by endocytosis
• T4 and T3 are broken off from the thyroglobulin chain by
lysosomal enzymes. Any DIT and MIT are also cleaved
from thyroglobulin
• The T4 and T3 thus released diffuses out of the cell into
blood along a concentration gradient
• DIT and MIT released are deiodinated (a deiodinase
enzyme) resulting in iodine and tyrosine, both of which
are reused by the cell
 Transport of thyroid hormones

T4 and T3 are lipid soluble substances

Carried in blood mostly bound to protein
– Protein bound fraction
– Free fraction (biologically active)
 Transport of thyroid hormones

Specific carrier protein – thyroxine binding globulin - TBG

(not the same as thyroglobulin), binds both T4 and T3

Non specific carrier protein –

• albumin
• pre-albumin (transthyretin)
 Transport of thyroid hormones

Biological
Protein bound Free
Activity
(including negative
feedback)

An increase or a decrease in protein bound form only

does not result in hyper or hypo function.
 Biological Effect of thyroid hormones

Quantity –
T4 is secreted and found in blood in larger quantities

Protein binding –
T4 is more extensively bound to proteins (99% of total)

Activity –
T3 is more potent at target tissues
 Mechanism of action of thyroid hormones

Mechanism of action
– Bind to nuclear receptors
– T3 has greater affinity than T4 – it is T3 that mostly
binds to the receptor
 Mechanism of action of thyroid hormones

Mechanism of action

T4 is converted to T3 in the cell

– Deiodinase enzyme acts on T4
– T3 is formed
– Some reverse T3 which is inactive is also formed (rT3
formation increases in some disease conditions)
 Mechanism of action of thyroid hormones

T3 + Nuclear receptor complex binds to DNA

• Modulates DNA transcription
• Results in changes in protein synthesis
Effects of thyroxine have a slow onset
Receptor is a hormone-sensitive nuclear transcription factor
Almost all cells are influenced by thyroid hormones
Different types of receptors in different tissues – may
account for the many different actions of the hormone
 Actions of thyroid hormones

1. Energy metabolism
Thyroid hormones raise the Basal Metabolic Rate and
tend to:
– Increase O2 consumption
– Increase Body temperature

The increase in the metabolic rate is mainly due to an

increase in Na+K+ ATPase activity
 Actions of thyroid hormones
2. Effect on metabolism
Normal amounts of thyroid hormones help to maintain all
metabolic processes

Excess thyroid hormones favours

• Gluconeogenesis, increased glucose absorption
• Lipolysis, lowering of cholesterol
• Proteolysis
• Conversion of carotene to vitamin A
 Actions of thyroid hormones
2. Effect on metabolism
Excess tends to result in
• Loss of weight
• Increased blood glucose levels

Acts synergistically with glucagon, catecholamines,

growth hormone and cortisol in many actions on
metabolism
 Actions of thyroid hormones

3. Effect on cardiovascular function

Effects occur through two mechanisms
Direct – effect on beta receptors:
– upregulate beta receptors
– increase cardiac muscle metabolism
 Actions of thyroid hormones

3. Effect on cardiovascular function

Indirect – due to increased body metabolism

– Increased oxygen demand
– Increased heat production

Effects: Increase in heart rate, increase in cardiac

output, vasodilatation, increase in blood
pressure
 Actions of thyroid hormones

4. Effect on growth
Affects both physical and mental growth

Somatic growth –
– Facilitate bone growth
– Accelerates appearance of ossification centres and
epiphyseal fusion
 Actions of thyroid hormones

4. Effect on growth

Cerebral growth –
– Facilitates neural maturation and metabolism
– Facilitates CNS myelination
Of particular importance during CNS maturation age (up
to about 2 years of age)
 Actions of thyroid hormones

5. Effect on the autonomic nervous system

Increases the expression of beta receptors
Acts synergistically with adrenaline
 Regulation of secretion
Temperature

Hypothalamus
Dopamine
TRH
Somatostatin

T3 Anterior pituitary

TSH
Free
T4, T3
Thyroid

T4 T3