Foundation: endocrine

system - thyroid and

parathyroid hormones
ME-SEM1 2014
9:15 10.15 am.
Tuesday 30 December 2014
Venue 4.02.

Prof Peter Barling

peter_barling@imu.edu.my
2776
Ext
DID: 0327317285
MOB: 0128398749

Word of advice
This set of powerpoint slides is far more
extensive than can be covered during the
lecture.
Only some will be used.
You are encouraged to look at all of them as the
main means of undertaking your subsequent
self-learning and understanding of this topic.
What you will have to recall for any test or
exam will be clearly explained during the
lecture.

Objectives of this lecture:

To introduce you to the thyroid
hormones and parathyroid hormone.
You will receive a very brief introduction
to common diseases of the thyroid or of
calcium homeostasis.
This will only brush the surface of the
knowledge you will acquire during the
organ-specific modules which follow
later.

Learning objectives
1. To describe the structure of the
thyroid gland and parathyroids.
2. To describe the

structures
biosynthesis
transport
actions
physiological effects
regulation of secretion

of the thyroid hormones and

parathyroid hormone.

Thyroid gland

This lies in the anterior neck,

overlying the trachea just
inferior to the larynx.
Consists of two lateral lobes,
connected by a medial tissue
mass called the isthmus.
Receives its rich blood supply
through the inferior and
superior thyroid arteries,
which arise from the
external carotid &
subclavian arteries
The thyroid two important
hormones: thyroxine and
tri-iodothyronine.

Thyroid gland - histology

Composed of spherical
structures (follicles).
Follicles: formed by
cuboidal (or squamous)
follicle epithelial
cells
Follicle cells : produce
the glycoprotein
thyroglobulin
Thyroglobulin is
stored in the
follicles

Thyroid Follicles

 Parafollicular cells
are also located in the
follicular epithelium
They secrete another
hormone calcitonin.
Calcitonin : inhibits
bone resorption &
release of ionic Ca
from the bony matrix.
It has only a minor
endocrine function in
adult humans.

Thyroid hormones
Derivatives of the amino acid
tyrosine.
Consists of two major types:
Thyroxine (T4) has 4 iodine
atoms
Triiodothyronine (T3) - has 3
iodine atoms
Both synthesised from 2
iodotyrosine amino acids linked
together

T4 : the major thyroid hormone

secreted by the thyroid follicles.
T3 : formed mainly at the target
tissues by conversion of T4 to T3.
T3 I is the actual functional
thyroid hormone and its
precursor is T4.

Biosynthesis of the thyroid

hormones
1. Formation of thyroglobulin
synthesised on the ribosomes & then
transported to the Golgi apparatus, where
sugar residues are attached & the molecules
packed into vesicles.
protein-containing vesicles move to the apex of
the follicle cell, where their contents are
discharged into the lumen, to become part of
the storage colloid.

Iodine is essential for

thyroid hormone production
The thyroid hormones are unique biological
molecules in incorporating iodine in their
structure.
Adequate iodine intake (diet, water) is required
for normal thyroid hormone production.
Major sources of iodine:
- iodized salt
- iodated bread
- dairy products
- shellfish
Minimum requirement: 100 micrograms/day
Can be monitored by measuring iodide daily
secretion in urine (iodide in = iodide out)

Iodine attachment to thyrogobulin

Follicle cells actively accumulate iodide (I-) from the

blood.
Inside the cells, iodides are oxidised to iodine
Iodine enters the follicle lumen & attaches to the
tyrosine amino acids of thyroglobulin, forming part of
the thyroglobulin colloid.
Attachment of 2 iodines to a tyrosine diiodotyrosine
(DIT)
Attachment of 1 iodine to a tyrosine
monoiodotyrosine (MIT)

Coupling
-

Enzymes within the colloid link DIT and MIT together

At this stage, the hormones are still
2 linked DITs T4
part of the thyroglobulin colloid
1 MIT & 1 DIT T3

Auto-regulation 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.

Cleavage of the hormones for release

Follicle cells reclaim iodinated thyroglobulin by
endocytosis & combine it with lysosomes.
The hormones are cleaved out of the colloid by lysosomal
enzymes and diffuse from the follicle cells into the
bloodstream.
About 10% of the T4 is converted to T3 before secretion.

The thyroid gland is unique because of its

ability to concentrate iodide and to store and
slowly release its hormones.
The amount of stored iodine as thyroglobulin
colloid remains relatively constant & is sufficient
to provide normal levels of hormone release for
over 3 months

Transport of thyroid hormones

in plasma
T3 and T4 are not water-soluble and when
they are released from the thyroid gland they
are bound to three binding proteins
present in human plasma.
These are:
1. thyroxine-binding prealbumin
(TBPA)
2. thyroxine-binding globulin (TBG)
3. plasma albumin
70-75% of T4 is bound to TBG
15-20% is bound to TBPA
5-10% is bound to albumin.

Control of thyroid secretion

The highest level of control is in the hypothalamus
This releases TRH (thyrotropin-releasing hormone)
TRH regulates the release of TSH (thyroid
stimulating
hormone) from the anterior pituitary gland.
T3 and T4, in turn feed back on the hypothalamus and
the
anterior pituitary gland when there is sufficient thyroid
hormone available .
This negative feedback decreases the secretion of
TRH and TSH.

Mechanism of action of thyroid

hormone T3

Biological outcomes of the

actions of thyroid hormones
Thyroid hormones are essential for
normal growth of tissues, especially
the nervous system.
Lack of thyroid hormone during
development results in short stature and
mental deficits (cretinism).
Thyroid hormone stimulates basal
metabolic rate and thereby increases
heat production (a calorigenic effect)

Actions of thyroid hormone (T3)

on body systems
Required for GH (and prolactin)
production, secretion and action
Increases intestinal glucose reabsorption
(glucose transporter)
Increases mitochondrial size, number,
key enzymes and rate of oxidative
phosphorylation (ATP production)
Increases activity of adrenal medulla and
induces sympathetic receptors,
speeding heart rate
Induces enzyme synthesis
Result: stimulation of growth of
tissues and increased metabolic
rate.

A major target gene of T3: the

Na+/K+ ATPase pump
Pumps sodium and potassium across cell
membranes to maintain the 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).

Thyroid hormone: key

points
Held in storage
Metabolised from an inactive (T4) to an active (T3)
form
Acts on mitochondria, thereby increasing ATP
production
Bound to receptors activating genes that control
energy utilization and tissue development
Exerts a calorigenic effect

Effects of thyroid hormone

on the cardiovascular
system

Increase heart rate

Increase force of cardiac contractions
Increase stroke volume
Increase cardiac output
Up-regulates catecholamine
receptors

Hypothyroidism

May result from :

1.
2.
3.
4.

thyroid gland defect

deficits of TSH or TRH release
surgical removal of thyroid gland
deficiency in dietary iodine

Symptoms:
Low BMR, feeling chilled, constipation, thick, dry skin &
puffy eyes, edema, lethargy & mental sluggishness
if it is due to a lack of iodine, the thyroid gland enlarges
from increased TSH secretion
goitre

GOITRE

Hyperthyroidism
The most common hyperthyroid pathology
causing this is Grave disease.
Grave disease is an autoimmune disease
caused by abnormal antibodies that act against
the TSH receptorof the follicle cell membrane
which then behaves as if TSH levels were very
high
Symptoms : BMR, >> perspiration, rapid,
irregular heartbeat, nervousness, weight loss &
exophthalmos protusion of the eyeballs.

Exophthalmos protusion of the eyeballs due to

hyperthyrodism

Parathyroid hormone

Embedded in the posterior aspect of the thyroid

gland.
Usually there are four of these glands.
Important in enhancing plasma ionised calcium
levels in the blood.
Release is triggered by falling blood [Ca ++] level &
inhibited by hypercalcelmia.
Effects of PTH:
1.
2.
3.

Bones - activation of osteoclasts to digest the bony matrix

& release of Ca & phosphate to the blood.
Kidneys - reabsorption of Ca ( retention of phosphate)
Intestinal mucosal cells - Ca absorption (enhanced
indirectly by PTHs effect on vit D activation).

At the end of this lecture,

you should understand:
Why and how ionized calcium is regulated
very closely
How parathyroid hormone acts and is
regulated
A little about the role of vitamin D in
regulating calcium absorption and turnover
A little about the physiological effects of
hypercalcaemia and hypocalcaemia and
some disorders of calcium homeostasis

DAILY CALCIUM FLUX RATES

DIETARY INTAKE
0.5 - 1.0 g

GUT

controlled

BLOOD

0.3 g
net
0.3-0.4 g

0.3 g

FECAL EGESTION
0.2 - 0.6 g

0.25 2.0 g

URINARY EXCRETION
0.1 - 0.4 g

BONE

1300 g
1300total
g

redily
exchangable
bone
mineral

slowly
exchangable
bone
mineral

Total body calcium:

99% (1300 g) in bone
0.3% in muscle
0.7% in extracellular fluids
0.05% in plasma

Turnover of calcium in bone

Tetracycline labelling:
long bones - 5 - 11% per year
ribs
- 14 - 44% per year
skull
- very low turnover
Calcium kinetic analysis:
Overall
6 - 25% per year, or
0.25 - 2 g/day

Calcium in plasma:

2.3 - 2.6 mM
* 35-50% bound to albumin
* 50-50% ionized (i.e. Ca++)
* 5-10% organic complexes, e.g.
citrate
oxalate

Variation in plasma Ca

++

Ionized calcium is maintained at a

constant level: 1.03 1.23 mM
18% overall variation

DAILY CALCIUM FLUX RATES

DIETARY INTAKE
0.5 - 1.0 g

GUT

controlled

BLOOD

0.3 g
net
0.3-0.4 g

0.3 g

FECAL EGESTION
0.2 - 0.6 g

0.25 2.0 g

URINARY EXCRETION
0.1 - 0.4 g

BONE

1300 g
1300total
g

redily
exchangable
bone
mineral

slowly
exchangable
bone
mineral

Yellow arrows = osteoclast-induced pits

Activation of osteoclastogenesis
by
PTH or PTHrP

The role of the

extracellular calcium
sensing receptor in PTH
secretion and action

The calcium-sensing
receptor (CaSR)

A G-protein coupled receptor which responds

to an increase in the extracellular
concentration of calcium ions.
In parathyroid gland cells, activation of the
calcium-sensing receptor on th surface by an
increase in extracellular ionised calcium
initiates an intracellular cascade which causes
activation of a Gq G protein, which
stimulates the phospholipase C pathway,
which inhibits the release of parathyroid
hormone (PTH).

Hyperparathyroidism
Primary - tumour (usually
adenoma) of parathyroid glands
Hypercalcemia of malignancy generation of PTH-related peptide
by tumours, e.g. lung carcinoma,
some breast tumours etc
Secondary chronic renal disease
pseudohypoparathyroidism
rickets and osteomalacia

Primary
hyperparathyroidism
Ca++ elevated - dehydration
Bone disease apparent in
advanced cases - osteitis
fibrosa cystica: bone pain,
demineralization, cysts
Treated by removal of 1 or
more of the 4 parathyroids

Hypocalcaemia &
hypoparathroidism

Defective synthesis or secretion of

parathyroid hormone (PTH).
Sometimes inappropriate
activation or antibody-stimulation
of calcium-sensing receptor.
End-organ resistance to PTH.
Result: severe hypocalcemia seizures, stridor, prolonged QT
interval (heart) and tetany.
Can often be treated
effectively with vitamin D.

Summary - parathyroid
hormone (PTH)

Produced by the parathyroid glands

A peptide with 84 amino acid residues
The first 30 or so are essential for its
biological effects
A central mediator of calcium homeostasis
it increases ionised calcium levels
Acts on bone to increase osteoclastic bone
resorption and on the kidneys to inhibit
calcium excretion by enhancing the renal
resorption of Ca2+ from 99% to 99.9% .

Review questions
1. Distinguish between T3 and T4 in terms
of their structure and biological activity.
2. Explain how the secretion of thyroid
hormones is regulated.
3. What are the effects of thyroid
hormones on protein, carbohydrate and
lipid metabolism?
4. Explain the role of parathyroid hormone
(PTH) in regulating calcium balance in
the blood.

References
1. Marieb, EN. Human Anatomy &
Physiology. Chapter 17. The Endocrine
System.
2. Johnson LR. Essential Medical
Physiology. Chapter 39: Thyroid Gland