Unique to Thyroid Hormones:

Thyroid hormones are iodinated amino acid

derivatives.

Thyroid Hormones

Iodine (I-): Thyroid hormones, precursors and

metabolites are the only iodine-containing
compounds in the body.
Long-term Storage: Thyroid stores sufficient
hormone precursor for several weeks of normal
secretion, which buffers against fluctuation in
available iodine supply

Thyroid Hormone Function

Regulates Basal Metabolic Rate
Increases body temperature
Increases O2 consumption
Stimulates protein, carbohydrate & fat metabolism
transcription of gene encoding Na/K ATPase, production
of mitochondria

Thyroid glandstructure & function

Normal gland weights ~20 g
Derived from embryonic endoderm
2 lobes joined by a thin isthmus

Required for proper neuronal development

In amphibians, it is the signal for metamorphosis

Slow Onset of Thyroid Hormone Action

Regulation of
Thyroid Hormone
T4 is the precursor for
the active thyroid
hormone T3

Somatostatin TRH

Slow action is consistent

with transcriptional
regulation
TSH (=Thyrotropin)

Target Cells:

T3

T4

Regulate DNA transcription

O2 and ATP consumption
temperature
basal metabolic rate

Thyroid Tissue

Inactive Follicles

Active Follicles

Composed of sacs called

follicles
colloid

Follicular cells are epithelial cells

that synthesize and secrete
thyroid hormones thyroxine (T4)
and triiodothyronine (T3)

colloid

Hormone precursors, coupled to

the protein thyroglobulin, are
stored in the jelly-like interior of
the follicle, a substance called the
colloid
Thyroid hormone precursors
stored in colloid

Upon stimulation by TSH, the follicular epithelial cells expand and actively
synthesize thyroid hormones.

Thyroid has a large reserve of hormone

Thyroid HormonesIodinated derivatives of Tyrosine

Precursors
(attached to thyroglobulin)

In the colloid, the thyroid stores

sufficient T3 and T4 precurors
for several weeks of thyroid
hormone usage

MIT

DIT

Thyroid hormones

T4

T3

Long-term storage capacity

protects the body from
deficiencies that might occur
due to fluctuations in available
iodine.
Antithyroid drugs, which target
the synthesis of thyroid
hormones, are slow to show
physiological effects because of
large storage reserve of
hormone precursor.

Thyroglobulin
660 kDa glycoprotein (2 identical subunits of 330
kDa)
~115 tyrosines; ~20 are iodinated
MIT, DIT, T3 and T4 residues are attached to
thyroglobulin inside the follicles (for storage)

Thyroid Follicular
Epithelial Cell

Follicle Lumen

Iodide uptake
Travel across epithelial cell
Iodination of tyrosines on
thyroglobulin
Coupling
Storage in colloid
Reuptake
Proteolysis & release

Hormones are released after thyroglobulin is

endocytosed and proteolyzed

Synthesis of Thyroid
Hormones

Iodide uptake
Follicle Lumen

Iodide supplied in diet

l-

Iodized salt, fish

Deficiency is endemic in
some areas

Uptake inhibited by
percholate (ClO4-) and
thiocyanide (SCN-)

Na+/Ico-transporter
Na+ & I-

CI-

Na+

IBasolateral
membrane

T3 T4

Na+

Cotransporter

I-

Coupling of MIT and DIT

Organification of iodide

Coupling is also catalyzed by

Thyroid Peroxidase at the
apical membrane of the
epithelial cell

Catalyzed by Thyroid Peroxidase

at the apical membrane of the
epithelial cell
Requires H2O2 (hydrogen
peroxide) as an oxidizing agent
Thyroid peroxidase oxidizes Iand iodinates tyrosine residues
of thyroglobulin

l-

Na+/I-

Oxidation of Iodide & Iodination of Thyroglobulin

MIT and DIT are formed,

attached to thyroglobulin

I-/Cl- Cotransporter

Iodide is concentrated into

the epithelial cell via the
Na+/I- cotransporter on
basolateral membrane
(Iodide Trap)

Thyroid follicular
epithelial cell

Apical
membrane

CI-

MIT

THYROGLOBULIN

I- + H2O2
Thyroid Peroxidase

Tyrosyl residue

While still attached to

thyroglobulin, two DITs are
coupled to form T4

MIT residue

or MIT & DIT are coupled to

form T3

T3 and T4, still attached to

thyroglobulin, are stored in the
colloid

I
Thyroid
Peroxidase

T4
residue

DIT residue

I
I

DIT
residue

Iodine Cycle

Endocytosis & Proteolysis

THYROGLOBULIN

Na+/I- cotransporter

Thyroglobulin is
endocytosed from the
colloid into the follicle
cell

Na+ & I-

Endocytic vesicles fuse

with lysozomes, and
proteolytically degrade
thyroglobulin
Free T4 and T3 are
released into the plasma
MIT & DIT are
deiodinated. Amino acids
and I- are reutilized

I-

H2O2 Thyroid Peroxidase

Tyrosyl residue

Deiodinases

I
I
I

MIT

I
I
Thyroxine (T4)

I
Thyroid
Peroxidase

Proteolysis

DIT

MIT residue

T4
residue

DIT residue

I
I

DIT
residue

Travel to target tissues

Most of the hormone synthesized and
released by thyroid is T4 (~20x more than T3)
T4 and T3 carried in plasma by thyroxine
binding globulin and albumin
Deiodinases convert T4
tissues

T3 in target

T3 is the active hormone, binds thyroid

hormone receptor and regulates transcription

Agents for treatment of hyperthyroid states

Thionamides (thioureylenes): Anti-thyroid drugs
containing thiocarbamide group
H
H3CH2CH2C

CH3

CH3
S

S
C

R
NH

N
COOC2H5

Propylthiouracil O

Methimazole

Carbimazole (UK)

Mechanism of action: Inhibit thyroid peroxidase

Radioactive iodine (131I): complete or partial

destruction of thyroid
High [iodide]: acute inhibition of iodide trap &
hormone release

Goiter:

Causes:
- Hashimotos disease (autoimmune)
- Iodide deficiency
- consumption of anti-thyroid compounds (cassava, brassica
(cauliflower, broccoli))
Agents for treatment of hypothyroid states:
- Synthetic T4 (&/or T3)
- Dietary iodide (to correct iodide deficiency)

stimulation of the thyroid causes

growth & enlargement of thyroid
gland (goiter)

Hyperthyroidism: Graves disease

An antibody mimics TSH &
stimulates thyroid
T3 & T4
The antibody is not subject to
feedback inhibition, so
continues to stimulate thyroid
& causes goiter

Hypothyroidism: Iodide deficiency

Low I- causes T3 & T4,
Lack of feedback inhibition
causes TSH
TSH stimulates thyroid,
causes goiter

Summary:

Thyroid hormones T3 & T4 stimulate basal metabolic rate, O2

consumption, temperature, also needed for normal neuronal development

Iodide trap: Na+/I- co-transporter takes up iodide into follicle cells

Thyroglobulin is synthesized in follicle cells, exported to colloid. Tyrosines

on thyroglobulin are iodinated (to MIT & DIT) and coupled (to T3 and T4),
stored in colloid, later endocytosed into follicle cell & proteolyzed

Thyroid hormone precursors are stored in colloid, so drugs that hormone

synthesis only slowly decrease T3 & T4

Thyroid hormone excess: warm, moist skin, restlessness, hyperactivity,

rapid pulse, appetite, GI motility, diarrhea, weight loss,
Graves disease (autoimmune; antibody mimics TSH)
Thyroid adenoma
Chronic ingestion of T3/T4 to lose weight

Thyroid hormone deficiency: dry, cool, puffy skin, myxedema, hair thinning,
appetite, weight, lethargy, weakness, sometimes goiter
Hashimotos disease (autoimmune destruction of thyroid)
Low dietary iodine
Ingestion of anti-thyroid compounds

Anti-thyroid drugs: thionamides (thiourylenes),

131I,

excess I-

Anti-thyroid drugs target hormone synthesis & release, not the thyroid hormone
receptor