THYROID

HORMONES
 Thyroid gland

 One of largest pure endocrine glands in the

body ( 20gms).
 Its size depends on:
1. age … age   size.
2. sex … female > male.
3. physiological condition … (pregnancy, lactation)

 Site:
Located in the neck just below the larynx, on
either
side of & anterior to the trachea.
Thyroid gland … (Continued)
 Thyroid gland

 Thyroid gland is well vascularized (rich in

blood
supply).
 Formed of 2 lobes (Rt & Lt), that are
connected by a band of tissue called
“isthmus”.
Thyroid gland structure
 The Thyroid Gland
Gland is composed of hollow spheres, called colloid follicles.

Squamous epithelial cells, cuboidal cells (follicle cells)

Colloid fills the follicle cavities

Follicle cells produce thyroglobulinI ---- Tg
Structure of thyroid follicle -
Euthyroid follicle

Colloid Basal membrane of epithelial

(glycoprotei cells
n) Apical membrane of epithelial
cells

Thyroid C-
cell

Capillary
(Rich blood
supply)

Cuboidal epithelial
cells
Basemen
t
membran
e
Thyroglobulin (Tg) is a 660 kDa,dimeric protein produced
by the follicular cells of the thyroid and used entirely within
the thyroid gland. Thyroglobulin protein accounts for
approximately half of the protein content of the thyroid
.gland
Each thyroglobulin molecule contains approximately 100-
120 tyrosyl (Tyrosine) residues. However, because only a
small number (>20) of these tyrosine residues are subject
to iodination by thyroperoxidase in the follicular colloid,
each Tg molecule is only able to form very small amounts
of thyroid hormone (5-6 molecules of either T4 and T3)
Thyroid gland secretions
● 2 important thyroid hormones:
● Thyroxine (T4) or tetraiodothyronine
● Triiodothyronine (T3)

- Secreted by Follicular cells.

- Having significant effect on metabolic
rate of the body.
● Calcitonin

- Secreted by Parafollicular cells.

- Important hormone for Ca2+
metabolism & homeostasis.
Thyroid hormones derived from
two iodinated tyrosine
molecules
Thyroid hormones
 Amount secreted:

- Thyroxine (T4) or tetraiodothyronine …90%

- Triiodothyronine (T3) …10%
 Almost all T4 is converted to T3 in
tissues.

T4 T3
T4 T4
Capillary Reverse T3
(Rich blood
supply)
Target
cell
Thyroid hormones … (continued)
 T3 is the active form of T4.
 T3  3-5 times > potent
(active/important) than T4 in tissue, but is
present in much smaller quantities in
blood, & persists for a much shorter time
than does T4.
 T3 has great affinity to nuclear
receptors than T4.

 Reverse T3 (RT3) is inactive.

 Synthesis
of
thyroid hormones
How thyroid hormones are synthesized?
 T3 & T4 are synthesized in the colloid by:

1. Iodine formation
2. Thyroglobulin formation
3. Iodination
4. Condensation (coupling)
5. Thyroid hormones secretion
6. Deiodination
How thyroid hormones are synthesized?
1. Iodine formation:
 Iodine (Io) is a raw material essential for THs synthesis.
 Found in food, e.g. salt, & sea food, in the form of “iodide
(I-)”.
 120-150 µg of I- is needed daily to maintain normal
thyroid fx in adults (or 1mg/wk).
 Iodide (I-) actively transported (trap) into the follicle (90 –
95%).
 (I-) conc in thyroid cells is 30X its conc in blood.
 (I-) secreted into colloid along concentration gradient.
 Thyroid Peroxidase enzyme found near apex of follicular
cells oxidize iodide (I-) to iodine (Io).
 Active transport of iodine (ATPase
dependent) against electrical and
chemical gradient - concentration of
iodine 30-50 times that of the circulation
 How thyroid hormones are synthesized?

2. Thyroglobulin formation:
 Thyroglobulin is a glycoprotein, made up of 2
subunits, & has a MW of 660kDa.

 Synthesized in the thyroid cells following entry

amino acids from ECF.

 Secreted into colloid by exocytosis of granules

that also contain thyroid Peroxidase.
How thyroid hormones are synthesized?
3. Iodination:

 Iodine attach to tyrosine within thyroglobulin

chain.
 Iodinase enzyme is found in the apical
membrane  Colloid  start iodination process.
4. Condensation (coupling):
Thyroid Peroxidase cleaves off MIT or DIT and Couples it
to Acceptor DIT residues on TG,

 Three combinations can occur:

 DIT + DIT coupling gives T4,
 MIT + DIT coupling gives T3,
 DIT + MIT gives r T3 (inactive hormone)
Major coupling reaction is formation of T4,

- Not all DIT & MIT  thyroid hormones.

- Only 25% of DIT & MIT give rise to thyroid hormones.

- T3 can also be formed by de-iodination (removing 1

iodine atom) of T4 by deiodinase enzyme.
 Incorporation of iodine onto tyrosine
residues on the thyroglobulin molecule

Tyrosine
iodinase
 5. Thyroid hormones secretion:

 After formation of THs, they remain bound to

thyroglobulin in the colloid until secreted.

 Hormones are surrounded in colloid by acid pool, then

converted into ‘colloid droplet’.

 TSH stimulates endocytosis of thyroglobulin into the

follicular cell.

 Lysozome enzymes hydrolyze peptide bonds & release

T3 & T4 from thyroglobulin.

 T3 & T4 will be discharged freely & secreted into the

capillaries (blood), attaching to TBG.
6. Deiodination:

 Inside follicular cells, DIT & MIT forms NOT

secreted into the blood will be deiodinized to (Io)
& tyrosine.

 Deiodized tyrosine will be recycled back to

synthesize New MIT & DIT.
How is T4 utilized in peripheral tissues?
(Production of T3 in peripheral tissues)
T4: Pro-hormone produced by Thyroid gland •
Biologically active Thyroid hormone is T3 •
Liver and Kidneys have De-Iodinase that De- •
iodinate T4 to produce about two-thirds of T3 in
plasma
De-Iodinase that catalyses conversion of T4 to T3 •
requires trace element Selenium, because it contains
”a specific Amino Acid called “Seleno-Cysteine
type III De-Iodinase that does not require Selenium, •
 Transfer
of
thyroid hormones
in blood
Transfer of thyroid hormones in blood
 Almost all THs are carried in the blood, mostly in
an
inactive form, bound to 3 different types of
proteins:

a. Thyroxine binding globulin … 80%

b. Thyroxine binding pre-albumin …  10%
c. Plasma albumin (serum albumin) …  10%

N.B. T4 has greater affinity to bind proteins than

T3.

 Only very little T3 (0.25-0.3%) & T4 (0.03%) are

carried
Regulation of Thyroid Hormone
Levels

• Thyroid hormone synthesis and secretion is

regulated by two main mechanisms:
- an “autoregulation” mechanism, which
reflects the available levels of iodine
- regulation by the hypothalamus and
anterior pituitary
Autoregulation of Thyroid Hormone
Production
• The rate of iodine uptake and incorporation
into thyroglobulin is influenced by the amount
of iodide available:
- low iodide levels increase iodine transport
into follicular cells
- high iodide levels decrease iodine transport
into follicular cells
Thus, there is negative feedback regulation of
iodide transport by iodide.
 Action of TSH on the Thyroid
• TSH acts on follicular cells of the thyroid to
- increase iodide transport into follicular cells
- increase production and iodination of
thyroglobulin
- increase endocytosis of colloid from lumen into
follicular cells -
I +Na +K +Na

gene
ATP
follicle colloid droplet thyroglobulin I
-

cell

endocytosis

thyroglobulin thyroglobulin
iodination
+
I I
-

T3 T4
Mechanism of Action of TSH
• TSH binds to a plasma membrane-bound, G
protein-coupled receptor on thyroid follicle cells.
• Specifically, it activates a Gs-coupled receptor,
resulting in increased cAMP production and PKA
activation.
Adenylyl
TSH Cyclase

Gsa
ATP cyclic AMP
Follicle cell

Protein kinase
A
Regulation of TSH Release from
the Anterior Pituitary
• TSH release is influenced by hypothalamic TRH,
and by thyroid hormones themselves.
• Thyroid hormones exert negative feedback on
TSH release at the level of the anterior pituitary.
- inhibition of TSH synthesis
- decrease in pituitary receptors for TRH
hypothalamus

+ TRH
TRH receptor
-
-
pituitary
TSH synthesis
T3/T4
 Influence of TRH on TSH Release
• Thyrotropin-releasing hormone (TRH) is a
hypothalamic releasing factor which travels through
the pituitary portal system to act on anterior
pituitary thyrotroph cells.
• TRH acts through G protein-coupled receptors,
activating the IP3 (Ca2+) and DAG (PKC) pathways
to cause increased production and release of TSH.

IP3 Calcium
G protein-
coupled
TRH receptor Phospholipase
C calmodulin

DAG PKC
.Thyroid hormones also inhibit TRH synthesis •
Negative Feedback Actions of Thyroid
Hormones on TSH Synthesis and Release

TRH synthesis
hypothalamus

+ TRH -
TRH receptor -
T3/T4
-
pituitary
TSH synthesis

TSH binds

Thyroid gland
follicle cell receptors
 Thyroid
hormones
mechanism of
action
Thyroid
hormones
metabolism
Metabolism of thyroid hormones
• T3 and T4 undergo deiodination, deamination, decarboxylation and
conjugation.
• Deiodination is the major pathway (75% metabolism of T4)
• Deiodination of T4 is responsible for most of the T3 formed.
• Deiodinases: present in thyroid gland and peripheral tissues.
• Iodotyrosine deiodinase in the thyroid gland
• Iodothyronine deiodinases in peripheral tissues like liver, kidney
brain, anterior pituitary, and thyroid.
• 2 different Iodothyronine deiodinases that catalyzes
monodeiodonation on the phenolic (outer) or tyrosyl (inner) ring
giving rise to T3 and rT3 respectively.
• Oxidative deaminase and transaminase converts it into products
like pyruvic acid and acetic acid derivatives
In addition to deiodination, iodothyronines are
metabolized by conjugation of the phenolic hydroxyl
group with sulfate or glucuronic acid. Sulfation and
glucuronidation are so-called phase II detoxification
reactions, the general purpose of which is to
increase the water-solubility of the substrates and,
thus, to facilitate their biliary and/or urinary
Glucuronidation
.clearance is catalyzed by UDP-
glucuronyltransferases (UGTs) that utilize
UDP-glucuronic acid (UDPGA) as
Cofactor and sulfation is catalyzed by
Sulfotransferases
 Functions
of
thyroid hormones
Actions of Thyroid Hormones
• The thyroid hormones act on nearly every
cell in the body.
• They act to increase the basal metabolic
rate
• affect protein synthesis
• help regulate long bone growth (synergy
with growth hormone) and neural
maturation
• and increase the body's sensitivity to
catecholamines (such as adrenaline) by
permissiveness.
Actions of Thyroid Hormone
• Required for GH and prolactin production and secretion
• Required for GH action
• Increases intestinal glucose absorption
(glucose transporter)
• Increases mitochondrial oxidative phosphorylation (ATP
production)
• Increases activity of adrenal medulla (glucose
production)
• Induces enzyme synthesis
• Result: stimulation of growth of tissues and increased
metabolic rate. Increased heat production (calorigenic
effect)
 Hormones

Hormone Function Stimulated by

T3/T4 h metabolic rate i metabolic

h protein synthesis rate
h energy production T3/T4
Most important h TSH
hormone in day today
regulation of
metabolic rate
Thyroid Hormones

Hormones Function Stimulated by

T3/T4 h metabolism i metabolism
Calcitonin i blood calcium h blood Ca
concentration levels
i the reabsorption of
Ca and Ph from
bones to blood
Calcitonin “tones”
down serum Ca
levels
Effects of Thyroid Hormone on Nutrient
Sources
• Effects on protein synthesis and degradation:
-at low thyroid hormone levels there will be
increased protein synthesis (low metabolic rate;
growth)
-at high thyroid hormone levels there will be
increased protein degradation (high metabolic
rate; energy)
• Effects on carbohydrates:
-low doses of thyroid hormone increase
glycogen synthesis (low metabolic rate;
storage of energy)
- high doses increase glycogen breakdown (high
metabolic rate; glucose production)
One Major Target Gene of T3: The Na+/K+
ATPase Pump
• Pumps sodium and potassium across cell membranes
to maintain resting membrane potential
• Activity of the Na+/K+ pump uses up energy, in the form
of ATP
• About 1/3rd of all ATP in the body is used by the Na +/K+
ATPase
• T3 increases the synthesis of Na+/K+ pumps, markedly
increasing ATP consumption.
• T3 also acts on mitochondria to increase ATP synthesis
• The resulting increased metabolic rate increases
thermogenesis (heat production).
 Abnormal
thyroid hormones
secretions
Hyperthyroidism
Definition
• increase T3/T4 in blood
Pathophysiology
• Primary hyperthyroidism
– Problem with thyroid gland  T3/T4
• Secondary hyperthyroidism
– Problem with pituitary gland  T3/T4
– Pituitary  TSH  T3/T4
– TSH  thyroid growth  goiter
 I: Hyperthyroidism … ‘Grave’s disease’

 90% of hyperthyoidism is due to “Grave’s disease”.

 GD is an autoimmune disease  the body produces
antibodies to the receptor for thyroid-stimulating hormone
 Symptoms of GD:
Exophthalmous,
- Lid lag,
- Anxiety & restlessness.
- Sleeplessness.
-  appetite,  weight & diarrhea.
- Intolerance to heat.

 Treatment:
- drugs to  iodination process, such as PTU
‘Propylthiouracil’; MMI
‘methylmercaptoimidazole’.
 II: Hypothyroidism
Adult (Myxedema)
 Hypothyroidism in adults   THs.
 Could be:
primary hypothyroidism … (disease is in the
gland)
- autoimmune disease such as “Hashimoto’s
thyroiditis”.
- lack of iodine.
- absence of deiodination enzyme.
 T3 & T4  reflex  TSH.
2ry hypothyroidism … (disease is higher up)
 TRH   TSH   T3 & T4.
II: Hypothyroidism (myxedema) … cont.

 If No Iodine   T3 & T4   TRH   TSH

 growth (size) of the gland  simple
goiter.
How goiter ‘swollen neck’ is formed?
With lack of iodine …

Hypothalamu
TR
s
+
H
Anterio
r
pituitar
TSH y +
NO or low Thyroi Lack of
feedback iodine
d
inhibition
gland
Poo +++
r
Low T3 or T4 ­ Growth of
release the gland
 II: Hypothyroidism (myxedema) … cont.

 If there is absence of deiodinase enzyme


NO recycle synthesis of DIT & MIT 
accumulate.

 DIT & MIT will not be used for new THs

formation
  THs.
 II: Hypothyroidism (myxedema) … cont.

 Symptoms of Hypothyroidism:
- Decreased metabolic rate.
- Slow heart rate & pulse.
- Slow muscle contractions
-  appetite,  weight gain, & constipation.
- Prolonged sleep, & dizziness.
- Coarse skin.
- Slow thinking, lethargy, & mask face.
- Intolerence to cold ( ability to adapt cold).
- Myxoedema  swollen & puffy appearance of
body,
due to deposition of protein-carbohydrate
complexes
‘mucopolysaccharides’ & fluid in subcutaneous
 II: Hypothyroidism
Children (Cretinism)

 Hypothyroidism in children  THs.

• Hypothyroid from end of 1st trimester to 6
months
postnatally, or in the 1st few years of life.
 T3 & T4  reflex  TSH.
 Additional Signs & Symptoms:
- Severe mental retardation.
- Short stature (due to  growth of bones, muscle,
&
brain).
 Treatment: Thyroxine.