Endocrine Block

Thyroid Hormones: Control Mechanism and Function

Dr Simon Harrison
[email protected]
Room S3-76

1
 Learning Objectives
• Explain how thyroid hormones are synthesized within the thyroid gland, including the
processes of iodine uptake, iodination of tyrosine residues in thyroglobulin by thyroid
peroxidase/ dual oxidase, and coupling to form T4 and T3.
• Describe the process of endocytosis by which thyroglobulin is retrieved from the follicle lumen
and processed to yield T3 and T4, which are secreted into the circulation.
• Diagram the hypothalamic-pituitary-thyroid axis to show how TSH regulates thyroid function
and how thyroid hormones feed back to regulate the axis
• Discuss the role of thyroid-binding proteins in the transport and stability of thyroid hormones,
and the role of peripheral deiodinases in the activation of T4 to T3 or inactivation to reverse T3.
Contrast the cellular location and function of the D1 and D2 deiodinases.
• Describe the mechanisms of thyroid hormone action, including the nature and location of the
thyroid hormone receptor and its ability to either repress or activate target gene transcription.
• Discuss the actions of thyroid hormone during development, especially on the central nervous
system (CNS) and skeleton, including the consequences of severe hypothyroidism.
• Describe the effects of thyroid hormone on basal metabolic rate and thermogenesis, on the
cardiovascular system (heart rate, cardiac output, systemic vascular resistance), and on other
organ systems (skin, skeletal muscle, digestive tract). 2

2
 Introduction
• The hypothalamus, pituitary and thyroid
gland make up the hypothalamic-
pituitary-thyroid axis
• The thyroid gland produces
tetraiodothyronine (T4, also called
thyroxine) and the more active
hormone triiodothyronine (T3).

• T4 and T3 are derived from the a.a. tyrosine and require iodine which is
incorporated into tyrosine molecules.
• Much of T3 is also made by peripheral conversion of T4 to T3.
• Thyroid hormone acts primarily through a nuclear receptor that regulates gene
transcription.
• T3 is critical for normal brain and bone development and has broad effects on
metabolism and cardiovascular function in adults. 3

3
 Basic Anatomy of the Thyroid gland
• The functional unit of the thyroid gland is the thyroid
follicle.
• The follicular lumen is filled with colloid (c),
composed of thyroglobulin, which contains 134
tyrosine molecules.
• This large (660 kDa) protein, is secreted into the
lumen and iodinated by the thyroid epithelial cells.
• The size of the epithelial cells and the amount of
colloid are dynamic and change with activity of the
gland.
• Scattered within the gland are parafollicular cells, or
C cells, which are the source of the polypeptide
hormone calcitonin.
4

Each thyroglobulin protein contains 134 tyrosine molecules. At an average level of

iodination, out of 134 tyrosine residues only 25–30 are iodinated, and only six to
eight of these form iodothyronines T4 and T3.

4
 Thyroid Hormone Synthesis: Step 1

• Thyroglobulin is synthesized in the

rough ER of the follicular epithelial
cells and packaged into secretory
granules in the Golgi.
• Secretory granules containing
thyroglobulin are secreted across
the apical membrane into the
follicular lumen.

5
 Thyroid Hormone Synthesis: Step 2
• Iodide is actively transported into the
gland by a sodium-iodide symporter
(NIS) located in the basolateral
membrane of thyroid epithelial cells
using the Na gradient set up by the
Na+,K+-ATPase.
• One iodide ion is transported uphill
against an iodide gradient while two
sodium ions move down their
electrochemical gradient from
extracellular fluid into the thyroid cell.
• Expression of the NIS gene is inhibited
by iodide and stimulated by TSH.

NIS is highly expressed in the thyroid gland but is also expressed at lower
levels in the placenta, salivary glands, and actively lactating breast.
A reduction in dietary iodide intake depletes the circulating iodide pool and
greatly enhances the activity of the iodide trap (NIS).

6
 Thyroid Hormone Synthesis: Step 2 (cont)
• After entering the epithelial cells,
iodide rapidly moves to the apical
membrane.
• From there, iodide is transported into
the lumen of the follicles by a
sodium-independent iodide/chloride
exchanger called pendrin.
• Iodide is immediately oxidized to I2
in the following reaction:
2I- + H2O2 = I2
• by thyroid peroxidase (TPO) and
H2O2 on the apical membrane and
incorporated into tyrosine residues
within thyroglobulin- a process
called Iodination or Organification 7

Pendrin is an Iodide/chloride electroneutral exchanger ( 1 Iodide enters the colloid phase

and 1 chloride ion enters the epithelial cell) located in the basal membrane.
Organification-defect is a condition where the thyroid is unable to covalently bind iodide to
colloid during the synthesis of thyroid hormones and is characterized by low levels ofT4
and T3.

7
 Thyroid Hormone Synthesis: Steps 3 & 4
• A single iodination forms a
monoiodotyrosine (MIT)
• A second iodination of the same tyrosine
residue produces diiodotyrosine (DIT).
• After iodination, two DIT molecules are
coupled to form one T4 molecule
• One MIT and one DIT are coupled to form
one T3 molecule.
• This latter process is called coupling
• This entire sequence of reactions is
catalyzed by thyroid peroxidase (TPO), an
enzyme complex that spans the apical
membrane.
• The immediate oxidant (electron acceptor) for the reaction is hydrogen peroxide
(H2O2) generated by dual oxidase enzymes. 8

Generation of H2O2 in the follicular lumen is catalyzed by dual oxidases

(DUOX1, DUOX2.

8
 Thyroid Hormone Synthesis: Step 5
• Of the 134 tyrosine molecules in thyroglobulin
25-30 are iodinated but only 6-8 form T4 and T3.
• Secretion of T4 and T3 into the bloodstream is
initiated by endocytosis of colloid from the
follicular lumen
• Endocytotic vesicles then fuse with lysosomes
and thyroglobulin is degraded
• MIT and DIT molecules, which are released
during proteolysis of thyroglobulin, are rapidly
deiodinated within the follicular cell by the
enzyme iodotyrosine deiodinase

• This deiodinase is specific for MIT and DIT and cannot break down T4 and T3. The
iodide from MIT and DIT degradation is recycled into synthesis of more T4 and T3.
9

T3 and T4 cross the membrane into the blood via monocarboxylate transporters
MCT8 and MCT10.

9
 Plasma binding of T3 and T4
• T4 and T3 are transported across the basal
membrane (via MCT8) and enter the blood.
• Secreted T4 and T3 circulate in the
bloodstream almost entirely bound to proteins.
• About 0.02% of total plasma T4 and 0.3% of
total plasma T3 exist in the free state.
• Free T3 is biologically active and mediates the
effects of thyroid hormone on peripheral tissues
in addition to exerting negative feedback on the
pituitary and hypothalamus.
• The major binding protein is thyroxine-binding globulin (TBG), which is
synthesized in the liver and binds one molecule of T4 or T3.
• About 70% of circulating T4 and T3 is bound to TBG; 10% to 15% is bound to
another specific thyroid-binding protein called transthyretin (TTR).
• Albumin binds 15% to 20%, and 3% is bound to lipoproteins. 10

MCT 8 is the monocarboxylate transporter 8 and a rare condition exists where

deficiency in this transporter due to genetic mutation leads to severe condition known
as Allan-Herndon-Dudley syndrome (AHDS). It is a rare genetic disorder that affects a
child's cognition, mobility and overall health. In individuals with AHDS, thyroid hormone is
unable to enter cells in the brain because of a defect in a thyroid hormone transporter
called MCT8.

10
 Transport of T3 and T4
• Ordinarily only alterations in TBG
concentration significantly affect total plasma
T4 and T3 levels.
• TBG maintains a large circulating reservoir of
T4 that buffers any acute changes in thyroid
gland function.
• Binding of plasma T4 and T3 to proteins
prevents loss of these small hormone
molecules in urine and thereby helps conserve
iodide.
• Half-life of T4 is approx. 5-7 days and T3, 1
day
• Transthyretin transports T4 in cerebrospinal
fluid and provides thyroid hormones to the
CNS. 11

The normal range of T4 is suggested to be 77–155 nmol/l, T3 to be 1.2–2.8

nmol/L and TSH to be 0.3–4 mU/l . The levels of hormones above or below
the normal range indicate hyperthyroidism or hypothyroidism.

11
 Peripheral conversion The primary product
of the thyroid gland is
The active form of thyroid hormone is T3 T4 (90%) with 10% T3

• T4 is converted to T3 by type 1
deiodinase (D1, Km of 1μM) in
tissues with high blood flow and
rapid exchange with plasma,
such as the liver and kidneys.
• This process supplies circulating
T3 for uptake by other tissues in
which local T3 generation is low
or absent.
• The brain maintains constant intracellular levels of T3 by a high-affinity
deiodinase called type 2 deiodinase (D2)
• D2 is expressed in glial cells of the CNS and has a very high affinity (Km
of 1 nM) and maintains intracellular concentrations of T3 even if T4 levels
fall e.g., due to hypothyroidism. Reverse T3 is inactive (Deiodinase type 3)
12

Peripheral conversion is essential to the thyroid axis. As 90% of

thyroid output is T4 (only 10% of output id T3) the throid axis depends
heavily on peripheral conversion of T4 to to the active form, T3.
D1 is also expressed in the thyroid (again, where T4 is abundant) and has
relatively low affinity (i.e., a Km of 1μM) for T4. Levels of D1 are
paradoxically increased in hyperthyroidism and contribute to the elevated
circulating T3 levels in this disease. D2 is also present in pituitary
thyrotropes. There, D2 acts as a “thyroid axis sensor” that mediates the
ability of circulating T4 to feed back. There is also an “inactivating”
deiodinase called type 3 deiodinase (D3). D3 is a high-affinity inner ring
deiodinase that converts T4 to the inactive rT3. Type 3 deiodinase is
increased during hyperthyroidism, which helps blunt overproduction of T4. All
forms of iodothyronines are eventually further deiodinated to noniodinated
thyronine. Expression of D2 is increased during hypothyroidism, which helps
maintain constant T3 levels in the brain.

12
 Cellular effects of Thyroid hormones
• Thyroid hormone acts on essentially all cells and
tissues. Imbalances in thyroid function constitute
some of the most common endocrine diseases.
• T4 enters target cells (via monocarboxylate
transporters), and is converted to T3 via Type 1
deiodinase (not CNS- type 2)
• T3 binds to the thyroid receptor hormone response
element (HRE) initiating mRNA transcription of
thyroid responsive genes and initiating protein
synthesis to affect cell function.
• Thyroid hormone has many direct actions, but it also
acts in more subtle ways to optimize the actions of
several other hormones and neurotransmitters.
13

Thyroid hormone has many direct actions, but it also acts in more subtle
ways to optimize the actions of several other hormones and
neurotransmitters.

13
 Cardiovascular effects of Thyroid hormones
• The cardiac inotropic effects of T3 are
both direct and indirect.
• The resting heart rate and stroke volume
are increased which increases cardiac
output. CO = SV x HR
• The speed and force of myocardial
contractions are enhanced (positive
chronotropic and inotropic effects)
• Diastolic relaxation time is shortened
(positive lusitropic effect).
• Systolic blood pressure is augmented and
diastolic blood pressure is decreased.
• Increased pulse pressure due to the increased stroke volume and
reduction in systemic vascular resistance secondary to blood vessel
dilation in skin, muscle, and heart. 14

Perhaps the most clinically important actions of thyroid hormone are those
on cardiovascular physiology. These effects in turn are partly due to the
increase in tissue production of heat and CO2 that thyroid hormone induces.
Thyroid hormone levels in the normal range are necessary for optimum
cardiac performance. A deficiency of thyroid hormone in humans reduces
stroke volume, left ventricular ejection fraction, cardiac output, and the
efficiency of cardiac function. Thyroid hormones stimulate catecholamine
release which underlies many of the thyroid hormone effects on the
cardiovascular system.

14
 Cardiovascular effects of Thyroid hormones
• Direct inotropic effects result from
increased α-myosin heavy chain
expression and inhibition of the plasma
membrane Na+/Ca2+ exchanger (NCX).
• Sarcoplasmic reticulum (SR) Ca2+-
ATPase (SERCA2) is increased by T3
and Phospholamban (PLB) is
decreased.
• As a result, sequestration of Ca by the SR
during diastole is enhanced and
relaxation time is shortened.
• Increased ryanodine receptors in the SR
increases Ca release from the SR during
systole.
15

The cardiac inotropic effects of T3 are both direct and indirect. The latter are
due primarily to enhanced responsiveness to catecholamines. Thyroid
hormones
are synergistic with catecholamines in increasing the metabolic rate, heat
production, heart rate, motor activity, and excitation of the CNS. T3 may
enhance sympathetic nervous system activity by increasing the number of β-
adrenergic receptors in heart muscle and the generation of intracellular
second messengers such as cyclic adenosine monophosphate (cAMP).

15
 Effects on BMR and Thermogenesis
• T3 increases glucose absorption from the GI tract and glucose turnover
(glucose uptake, oxidation, and synthesis).
• In adipose tissue, T3 increases synthesis of fatty acids and enhances lipolysis
• Protein turnover (release of muscle amino acids, protein degradation, protein
synthesis and urea formation) is also increased.
• T3 potentiates the stimulatory effects of epinephrine, norepinephrine, glucagon
cortisol, and growth hormone on gluconeogenesis, lipolysis, ketogenesis, and
proteolysis of the labile protein pool.
• Thyroid hormones stimulate thermogenesis by affecting both adenosine
triphosphate (ATP) utilization and the efficiency of ATP synthesis.
• ATP hydrolysis is upregulated including Na+,K+-ATPase and SERCA protein,
particularly in skeletal muscle, where calcium cycling between the cytoplasm
and sarcoplasmic reticulum uses ATP and generates heat.
16

Thyroid hormone also enhances the clearance of chylomicrons. Thus, lipid

turnover (free fatty acid release from adipose tissue and oxidation) is
augmented.
The overall metabolic effect of thyroid hormone has been aptly described as
accelerating the physiological response to starvation.

16
Respiratory and Skeletal Muscle Effects
• Respiratory effects stimulate O2 utilization and enhance O2 delivery.
• T3 increases the resting respiratory rate, minute ventilation, and
the ventilatory response to hypercapnia and hypoxia.
• These actions maintain a normal arterial PO2 when O2 utilization is
increased and a normal PCO2 when CO2 production is increased.
• Additionally, the hematocrit increases slightly to enhance O2-carrying
capacity. This increase results from stimulation of erythropoietin
production by the kidney.
• Gluconeogenesis and glycogenolysis are increased, whereas
glycogen and creatine phosphate are reduced by thyroid hormone

17

17
 Growth and Maturation
• A small amount of thyroid hormone crosses the placenta, and the fetal
thyroid axis becomes functional at mid-gestation.
• Thyroid hormone is extremely important for normal neurological
development and proper bone formation in the fetus.
• Thyroid hormone promotes linear bone growth, and maturation of the
epiphyseal bone centers.
• T3 enhances maturation and activity of chondrocytes. During linear
postnatal growth, T3 supports the actions of growth hormone, insulin-like
growth factor (IGF)-I, and other growth factors.
• T3 also supports normal adult bone remodelling.
• Tooth development and eruption depends on thyroid hormone, as does
the normal cycle of growth and maturation of the epidermis, its hair
follicles, and nails.
18

In infants, insufficient fetal thyroid hormone causes congenital

hypothyroidism, characterized by irreversible intellectual disability and short
stature.

18
 Effects on CNS and Reproductive Organs
• Thyroid hormone deficiency in utero and in early infancy inhibits growth of
the cerebral and cerebellar cortices, proliferation of axons and branching
of dendrites, synaptogenesis, myelination, and cell migration.
• This results in irreversible CNS impairment in utero
• Post partum, thyroid hormone also enhances wakefulness, alertness,
responsiveness to various stimuli, auditory sense, awareness of hunger,
memory, and learning capacity.
• Normal emotional responses depend on proper thyroid hormone
availability.
• Thyroid hormones are important in maintaining the normal ovarian cycle
of follicular development, maturation, and ovulation
• The testicular process of spermatogenesis, and maintenance of the
healthy pregnant state are all disrupted by significant deviations in thyroid
hormone levels from the normal range.
19

Thyroid hormone regulates the timing and pace of development of the CNS.
Irreversible CNS impairment results when neonatal thyroid hormone
deficiency is not recognized and treated promptly. Decreased thyroid
hormone levels reduce cell size, RNA and protein content, tubulin- and
microtubule associated protein, protein and lipid content of myelin, local
production of critical growth factors, and rates of protein synthesis.
Furthermore, the speed and amplitude of peripheral nerve reflexes are
increased by thyroid hormone, as is motility of the gastrointestinal tract.

19
 Thyroid Disorders: Hyperthyroidism
• Graves’ disease is the most common form of
hyperthyroidism.
• Graves’ disease is an autoimmune disorder in
which activating autoantibodies are produced
against the TSH receptor.
• It occurs most frequently between the ages of 20
and 50 and is 10 times more common in women
than in men.
• Hyperthyroidism driven by the antibody is often
accompanied by a diffuse goiter as a result of
hyperplasia and hypertrophy of the gland.
• The primary clinical state found in Graves’ disease
is thyrotoxicosis—the state of excessive thyroid
hormone in blood and tissues
20

In Graves’ disease the follicular epithelial cells become tall columnar cells, and
the colloid shows a scalloped periphery indicative of rapid turnover. The
autoantibody associated with Graves' disease — thyrotropin receptor antibody
(TRAb) — acts like the regulatory pituitary hormone. That means
that TRAb overrides the normal regulation of the thyroid, causing an overproduction
of thyroid hormones (hyperthyroidism).
Common signs and symptoms of Graves' disease include: Anxiety and irritability; A
fine tremor of the hands or fingers; Heat sensitivity and an increase in perspiration
or warm, moist skin; Weight loss, despite normal eating habits; Enlargement of the
thyroid gland (goiter); Change in menstrual cycles; Erectile dysfunction or reduced
libido; Frequent bowel movements; Bulging eyes (Graves' ophthalmopathy);
Fatigue; Thick, red skin usually on the shins or tops of the feet (Graves'
dermopathy); Rapid or irregular heartbeat (palpitations); Sleep disturbance

20
 Thyroid Disorders: Thyrotoxicosis
A patient with thyrotoxicosis presents with:
• large increase in metabolic rate leading to weight
loss despite increased food intake.
• Excess heat production, sweating, and greater
intake of water.
• Increased adrenergic activity produces a rapid heart
rate, muscle weakness, tremor, nervousness,
oligomenorrhea and a wide-eyed stare.
• Nervousness, emotional instability and difficulty
swallowing or breathing because of compression of
the esophagus or trachea by the enlarged thyroid
gland (goiter).
• The most common cardiovascular sign is sinus
tachycardia and increased CO.
21

Muscle weakness is caused by a loss of muscle mass as well as impaired

muscle function. Oligomenorrhea is a type of abnormal menstruation that
involves infrequent periods. Patients may regularly go for longer than 35 days
between periods. Exophthalmos is associated with Graves’ disease and is due to
the antibodies associated with the autoimmune disease itself rather than being
caused by the hyperthyroidism. Other hyperthyroid conditions such as Thyroiditis or
a pituitary adenoma are not associated with exophthalmos.

21
 Thyrotoxicosis Treatment
• Diagnose with thyroid function test. In thyrotoxicosis, serum levels of T3
and T4 are elevated and TSH levels low
• Anti-thyroid drugs: Drugs such as methimazole (Tapazole) and
propylthiouracil (PTU) block the thyroid from making hormones.
• Radioactive iodine by mouth: The overactive thyroid cells absorb the
radioactive iodine, which damages the cells.
• The thyroid gland shrinks and thyroid hormone levels are reduced, usually
leading to permanent destruction of the thyroid, which then causes
hypothyroidism.
• Surgery: Surgical removal of the thyroid gland (thyroidectomy). This will
correct hyperthyroidism, but it will usually cause hypothyroidism.
• Hypothyroidism from treatment can be treated with thyroid hormone drugs
to maintain appropriate hormone levels
22

Propylthiouracil and Methimazole are antithyroid agents which reduces the amount of
Thyroid hormones made by the gland.

22
 Thyroid Disorders: Hypothyroidism
• Primary hypothyroidism: T4 and T3 levels are
abnormally low and TSH is high.
• Secondary and tertiary hypothyroidism: both
thyroid hormones and TSH are low.
• Hypothyroidism in utero or early childhood leads to
congenital hypothyroidism (formerly known as
cretinism)
• Affected individuals have severe intellectual
disability, short stature with incomplete skeletal
development, coarse facial features, and a
protruding tongue.
• The image shows a normal 6-year-old child (left)
and a 17-year-old (right) in an area of endemic
hypothyroidism
• The main cause of endemic hypothyroidism in
children worldwide is iodide deficiency. 23

Hypothyroidism refers to insufficient production of thyroid hormones and can occur

as primary, secondary, or tertiary endocrine disease. The response of TSH levels
to synthetic TRH can be used to distinguish between pituitary and
hypothalamic disease. This tragic form of endemic hypothyroidism can be
prevented by public health programs that add iodide to table salt or provide yearly
injections of a slowly absorbed iodide preparation. Congenital causes of
neonatal/child hypothyroidism are less common causes of hypothyroidism. In most
cases the thyroid gland simply fails to develop. Early treatment (within few weeks
after birth) with supplement of iodide can revert back to normal growth of the
thyroid. Adding iodide to salt, a worldwide program begun in 1995, has
reduced endemic hypothyroidism in Africa.

23
 Hypothyroidism: Hashimoto’s disease
• Hypothyroidism in adults who are not iodide
deficient most often results from another
autoimmune disorder known as Hashimoto’s
disease (formerly called lymphocytic
thyroiditis).
• In contrast to the stimulatory effect of
autoantibodies seen in Graves’ disease,
thyroid autoantibodies in Hashimoto’s
disease (directed against thyroid peroxidase
(TPO), thyroglobulin) cause apoptosis of
thyroid cells and destruction of thyroid
follicles.
• This results in a great reduction in the
capacity for thyroid hormone secretion and
may include goiter, but not seen in all cases. 24

In this disease TSH levels will be elevated as The thyroid cannot make enough T4 and so
this stimulates secretion of TSH which drives hyperplasia leading to goiter.
It is likely that goiter will depend upon which element in thyroid function is the target of
the antibodies e.g. if TPO is the target, TSH and its receptor would be unaffected. So T4
would be low but TSH is high which could drive goiter formation

24
 Myxedema
• Myxedema is a severe hypothyroid state due to thyroid
failure
• Diagnosed with TSH and T4 tests
• Symptoms include reduced metabolic rate, dry skin,
sparse hair, hypothermia, swelling in face and legs,
goiter, low blood pressure and heart rate, confusion and
decreased breathing- opposite to hyperthyroidism.
• Accumulation of negatively charged polysaccharides in
connective tissue attracts water and sodium
• This leads to swelling of the face, tongue, lips and
periorbital edema.
• Non-pitting edema in lower extremities associated with
skin thickening and discoloration
• Treated with replacement T4
25

The clinical picture of hypothyroidism in adults is in many respects the exact

opposite of that seen in hyperthyroidism. The lower-than-normal metabolic
rate leads to weight gain without an appreciable increase in caloric intake.
The decreased thermogenesis lowers body temperature and causes
intolerance to cold, decreased sweating, and dry skin. Adrenergic activity is
decreased, and therefore bradycardia may occur. Movement, speech, and
thought are all slowed, and lethargy, sleepiness, and lowering of the upper
eyelids (ptosis) occur. Accumulation of negatively charged
mucopolysaccharides in connective tissues attracts sodium and fluid. The
resulting nonpitting myxedema produces puffy features, an enlarged tongue,
hoarseness, joint stiffness, effusions in the pleural, pericardial, and peritoneal
spaces, and pressure on peripheral and cranial nerves entrapped by excess
ground substance. Constipation, loss of hair, menstrual dysfunction, and
anemia are other signs. Severely advanced hypothyroidism can lead to a
myxedema crisis, which is a medical emergency.

25
 Myxedema Crisis
• Myxedema crisis occurs when the body can no longer tolerate the changes
caused by severe hypothyroidism which leads to decompensation and
requires immediate medical attention.
• Along with the signs and symptoms of severe hypothyroidism, symptoms of
myxedema crisis can include:
• decreased breathing (respiratory depression)
• lower than normal blood sodium levels (hyponatremia)
• hypothermia
• confusion or mental slowness
• shock
• low blood oxygen levels
• high blood carbon dioxide level
• Seizures and coma
• Myxedema crisis can cause death often due to complications from infection,
26
bleeding, or respiratory failure.

26
Summary of Hypo- and Hyper-thyroidism

27

27