Physiology of Thyroid Gland Department of physiology

Dr.Hanan Altaee

After studying this lecture, you should be able to:

1. Describe the structure of the thyroid gland and how it relates to its function.
2. Define the chemical nature of the thyroid hormones and how they are
synthesized.
3. Understand the critical role of iodine in the thyroid gland and how its
transport is controlled.
4. Describe the role of protein binding in the transport of thyroid hormones and
peripheral metabolism.
5. Identify the role of the hypothalamus and pituitary in regulating thyroid
function.
6. Define the effects of the thyroid hormones in homeostasis and development.
7. Understand the basis of conditions where thyroid function is abnormal and
how they can be treated.

THYROID GLAND:

Thyroid is an endocrine gland situated at the root of the neck on either side of the
trachea (figure 1).It develops from an evagination of the floor of the pharynx, and a
thyroglossal duct marking the path of the thyroid from the tongue to the neck
sometimes persists in the adult.

It has two lobes, which are connected in the middle by an isthmus. It weighs
about 20 to 40 g in adults. Thyroid is larger in females than in males. The structure
and the function of the thyroid gland change in different stages of the sexual cycle
in females. Its function increases slightly during pregnancy and lactation and
decreases during menopause.
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 Figure (1): Demonstrating anatomy of thyroid gland

Histology OF Thyroid gland:

Thyroid gland is composed of large number of closed follicles. These follicles are
lined with cuboidal epithelial cells, which are called the follicular cells. Follicular
cavity is filled with a colloidal substance which is secreted by the follicular cells.
The major constituent of colloid is the large glycoprotein called thyroglobulin.
Follicular cells also secrete tetraiodothyronine (T4 or thyroxin) and tri-
iodothyronine (T3).Thyroid secretion is controlled primarily by thyroid-stimulating
hormone (TSH) secreted by the anterior pituitary gland. In between the follicles,
the parafollicular cells are present; these cells secrete calcitonin (figure
2).Thyroid gland has very rich blood supply.
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Figure2: Demonstrating histology of thyroid gland.

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 Chemistry

Both T4 and T3 are iodine-containing derivatives of amino acid tyrosine.

The potency of T3 is four times more than that of T4. Duration of T4 action is four
times more than T3 action. This is because of the difference in the affinity of these
hormones to plasma proteins. T3 has less affinity for plasma proteins and combines
loosely with them, so that it is released quickly.T4 has more affinity and strongly
binds with plasma proteins, so that it is released slowly. T4 has a long half-life of 7
days. Half-life of T3 is less than 24 hours.

Plasma Level

Total T3 = 0.15 μg/dL

Total T4 = 8 μg/dL.

Hormones of thyroid gland

Thyroid gland secretes three hormones:

1. Tetraiodothyronine or T4 (thyroxine) it forms about 93% of the total secretion

2. Tri-iodothyronine or T3 is only 7% to 10% of total secretion.

3. Calcitonin.

Synthesis of thyroid hormones

Synthesis of thyroid hormones takes place in thyroglobulin, present in follicular

cavity. Iodine and tyrosine are essential for the formation of thyroid hormones.
Iodine is consumed through diet. It is converted into iodide and absorbed from GI
tract. Tyrosine is also consumed through diet and is absorbed from the GI tract. For
the synthesis of normal quantities of thyroid hormones, approximately 1 mg of
iodine is required per week or about 50 mg per year. To prevent iodine deficiency,
common table salt is iodized with one part of sodium iodide to every 100,000 parts
of sodium chloride. The principal organs that take up circulating Iodide are the
thyroid, which uses it to make thyroid hormones, and the kidneys, which excrete it
in the urine.
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 Stages of synthesis of thyroid hormones (6 steps):

1. Thyroglobulin Synthesis

Endoplasmic reticulum and Golgi apparatus in the follicular cells of thyroid gland
synthesize and secrete thyroglobulin continuously. Thyroglobulin molecule is a
large glycoprotein containing 140 molecules of amino acid tyrosine. After
synthesis, thyroglobulin is stored in the follicle.

2. Iodide Trapping

Iodide is actively transported from blood into follicular cell, against

electrochemical gradient. This process is called iodide trapping .The salivary
glands, the gastric mucosa, the placenta, the ciliary body of the eye, the choroid
plexus, the mammary glands, and certain cancers derived from these tissues also
can transport iodide against a concentration gradient. Iodide is transported into the
follicular cell along with sodium by sodium-iodide pump )symporter(, which is
also called iodide pump. Normally, iodide is 30 times more concentrated in the
thyroid gland than in the blood. However, during hyperactivity of the thyroid
gland, the concentration of iodide increases 200 times more.

3. Oxidation of Iodide

Iodide must be oxidized to elementary iodine. The oxidation occurs in the presence
of thyroid peroxidase. Absence or inactivity of this enzyme stops the synthesis of
thyroid hormones.

4. Transport of Iodine into Follicular Cavity: From the follicular cells, iodine is
transported into the follicular cavity by an iodide-chloride pump called pendrin.

Combination of iodine with tyrosine is known as iodination. First, iodine is

transported from follicular cells into the follicular cavity, where it binds with
thyroglobulin. This process is called organification of thyroglobulin. Then, iodine
(I) combines with tyrosine. Iodination process is accelerated by the enzyme
iodinase, which is secreted by follicular cells. Iodination of tyrosine occurs in
several stages.Tyrosine is iodized first into monoiodotyrosine (MIT) and later into
di-iodotyrosine (DIT). MIT and DIT are called the iodotyrosine residues.
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6. Coupling Reactions
 Iodotyrosine residues get coupled with one another. The coupling occurs in
different configurations, to give rise to different thyroid hormones. Coupling
reactions are:

Tyrosine + I = Monoiodotyrosine (MIT)

MIT + I = Di-iodotyrosine (DIT)

DIT + MIT = Tri-iodothyronine (T3)

MIT + DIT = Reverse T3

DIT + DIT = Tetraiodothyronine or Thyroxine (T4). (Figure 3 )

After synthesis, the thyroid hormones remain in the form of vesicles within
thyroglobulin and are stored for long period. When there is a need for thyroid
hormone secretion, colloid is internalized by the thyrocytes by endocytosis, and
directed toward lysosomal degradation. Thus, the peptide bonds of thyroglobulin
are hydrolyzed and free T4 and T3 are discharged into cytosol and thence to the
capillaries .In combination with thyroglobulin, the thyroid hormones can be stored
for several months. Thyroid gland is unique in this, as it is the only endocrine
gland that can store its hormones for a long period of about 4 months. So, when the
synthesis of thyroid hormone stops, the signs and symptoms of deficiency do not
appear for about 4 months.
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 Figure3: Steps of Thyroid hormone synthesis.

Thyroid hormones are transported in the blood by three types of proteins:

1. Thyroxine-binding globulin (TBG), mainly T4

2. Thyroxine-binding prealbumin (TBPA)

3. Albumin. Mainly T3

Most of the Thyroxine Secreted by the Thyroid Is Converted to

Triiodothyronine. Before acting on the genes to increase genetic transcription.
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Intracellular thyroid hormone receptors have a very high affinity for T3.
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 Consequently, more than 90 per cent of the thyroid hormone molecules that bind
with the receptors are T3.

Metabolism of Thyroid Hormones

Degradation of thyroid hormones occurs in muscles, liver and kidney by

deiodination process.

Sequence of Events of thyroid hormone action: Thyroid hormones enter the

nucleus of cell and bind with thyroid hormone receptors (TR), and form the
hormone-receptor complex. This complex activates the ribosomes to synthesize the
new proteins. New proteins are involved in many activities including the
enzymatic actions.

Regulation of secretion of thyroid hormones

Secretion of thyroid hormones is controlled by anterior pituitary and hypothalamus

through feedback mechanism. Many factors are involved in the regulation of
thyroid secretion.

Thyroid-stimulating Hormone

Thyroid-stimulating hormone (TSH) secreted by anterior pituitary is the major

factor regulating the synthesis and release of thyroid hormones. It is also necessary
for the growth and the secretory activity of the thyroid gland. Thus, TSH
influences every stage of formation and release of thyroid hormones.

Chemistry

Thyroid-stimulating hormone is a peptide hormone with one α-chain and one β-

chain. Half-life of TSH is about 60 minutes. The normal plasma level of TSH is
approximately 2 U/mL.

Actions of Thyroid-stimulating Hormone

Thyroid-stimulating hormone increases:

1. The number of follicular cells of thyroid.

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2. The development of thyroid follicles.

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 3. Size and secretory activity of follicular cells.

4. Iodide pump and iodide trapping in follicular cells.

5. Thyroglobulin secretion into follicles.

6. Iodination of tyrosine and coupling to form the hormones.

7. Proteolysis of the thyroglobulin, by which release of hormone is enhanced and

colloidal substance, is decreased.

Immediate effect of TSH is proteolysis of the thyroglobulin, by which thyroxine is

released within 30 minutes. Effect of TSH on other stages in thyroxine synthesis
takes place after some hours, days or weeks.

Mode of Action of TSH

TSH acts through cyclic AMP mechanism.

Role of hypothalamus

Hypothalamus regulates thyroid secretion by controlling TSH secretion through

thyrotropic-releasing hormone (TRH). From hypothalamus, TRH is transported
through the hypothalamo-hypophyseal portal vessels to the anterior pituitary;
where it causes the release of TSH.

Feedback control:

Thyroid hormones regulate their own secretion through negative feedback control,
by inhibiting the release of TRH from hypothalamus and TSH from anterior
pituitary (figure 4).
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 Figure (4):Factors regulating thyroid hormone secretion.

Functions of thyroid hormones

The actions of thyroid hormones are:

1. Action on basal metabolic rate (BMR): Thyroxin increases the metabolic

activities in most of the body tissues, except brain, retina, spleen, testes, uterus
lymph nodes, anterior pituitary and lungs. It increases BMR by increasing the
oxygen consumption of the tissues. The action that increases the BMR is called
calorigenic action.This action is brought about by increase mitochondrial and Na+-
k+ ATPase activities.

BMR: is the quantity of energy production at rest (physical and mental)

during optimal temperature, measured 12 hours after last meal.

In hyperthyroidism, BMR increases by about 60%to 100% above the normal level
and in hypothyroidism itfalls by 20% to 40% below the normal level.

2. Action on protein metabolism:

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 Thyroid hormone increases the synthesis of proteins in the cells, by the following
ways:

 Increasing the Translation of RNA.

 Increasing the Transcription of DNA to RNA.
 Increasing the Activity of Mitochondria and increase the production of ATP.
 Increasing the Activity of Cellular Enzymes.

This action is when thyroid hormone is within physiological limits .But if we have
increase in the level of thyroid hormone this will be converted to catabolic action
and causes protein break down especially in muscles and causes muscle weakness
(Thyrotoxic myopathy). Conversely, lack of Thyroid hormone causes muscles to
become sluggish, and relax slowly after contraction.

3. Action on carbohydrate metabolism:

Thyroxine:

 Increases the absorption of glucose from GI tract.

 Enhances the glucose uptake by the cells, by accelerating the transport of
glucose through the cell membrane.
 Increases the breakdown of glycogen into glucose.
 Accelerates gluconeogenesis.

4. Action on fat metabolism:

Thyroxine decreases the fat storage by mobilizing it from adipose tissues and fat
depots. The mobilized fat is converted into free fatty acid and transported by blood.
Thus, thyroxine increases the free fatty acid level in blood.

5. Action on plasma and liver fats:

Even though there is an increase in the blood level of free fatty acids, thyroxine
specifically decreases the cholesterol, phospholipids and triglyceride levels in
plasma. So, in hyposecretion of thyroxine, the cholesterol level in plasma
increases, resulting in atherosclerosis. Thyroxine also increases deposition of fats
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in the liver, leading to fatty liver.

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 Thyroxine decreases plasma cholesterol level by increasing its excretion from liver
cells into bile, and then it is excreted through the feces. A possible mechanism for
the increased cholesterol secretion is that thyroid hormone induces increased
numbers of low-density lipoprotein receptors on the liver cells, leading to rapid
removal of low-density lipoproteins from the plasma by the liver and subsequent
secretion of cholesterol in these lipoproteins by the liver cells.

6. Action on vitamin metabolism

Thyroxine increases the formation of many enzymes. Since vitamins form essential
parts of the enzymes, itis believed that the vitamins may be utilized during the
formation of the enzymes. Hence, vitamin deficiency is possible during
hypersecretion of thyroxine.

7. Action on body temperature

Thyroid hormone increases the heat production in the body, by accelerating

various cellular metabolic processes and increasing BMR. It is called thyroid
hormone induced thermogenesis. During hypersecretion of thyroxine, the body
temperature increases greatly, resulting in excess sweating.

8. Action on growth:

In humans, the effect of thyroid hormone on growth is manifest mainly in growing

children. In those who are hypothyroid, the rate of growth is greatly retarded.In
those who are hyperthyroid, excessive skeletal growth often occurs, causing the
child to become considerably taller at an earlier age. However, the bones also
mature more rapidly and the epiphyses close at an early age, so that the duration of
growth and the eventual height of the adult may actually be shortened.

An important effect of thyroid hormone is to promote growth and development of

the brain during fetal life and for the first few years of postnatal life. If the fetus
does not secrete sufficient quantities of thyroid hormone, growth and maturation of
the brain both before birth and afterward are greatly retarded, and the brain
remains smaller than normal. Without specific thyroid therapy within days or
weeks after birth, the child without a thyroid gland will remain mentally deficient
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throughout life.
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 9. Action on body weight: Thyroxin is essential for maintaining the body weight.
Increase in thyroxine secretion decreases the body weight and fat storage. Decrease
in thyroxine secretion increases the body weight because of fat deposition.

10. Action on blood

Thyroxine accelerates erythropoietic activity and increases blood volume. It is one

of the important general factors necessary for erythropoiesis. Polycythemia is
common in hyperthyroidism.

11. Action on cardiovascular system:

Thyroxine increases the overall activity of cardiovascular system.

 On Heart Rate

Thyroxine acts directly on heart and increases the heart rate (β1 receptor
stimulation). It is an important clinical investigation for diagnosis of
hypothyroidism and hyperthyroidism.

 On the Force of Contraction of the Heart :

Due to its effect on enzymatic activity, thyroxine generally increases the force
of contraction of the heart. But in hyperthyroidism or in thyrotoxicosis, the heart
may become weak due to excess activity and protein catabolism. So, the patient
may die of cardiac decompensation. Cardiac decompensation refers to failure of
the heart to maintain adequate circulation associated with dyspnea, venous
engorgement (veins overfilled withblood) and edema.

 On Blood Vessels:

Thyroxine causes vasodilatation by increasing the metabolic activities.

 On Arterial Blood Pressure:

Because of increase in rate and force of contraction of the heart, increase in
blood volume and blood flow by the influence of thyroxine, cardiac output
increases. This in turn, increases the blood pressure. But, generally, the mean
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arterial pressure usually remains about normal after administration of thyroid

hormone. Because of increased blood flow through the tissues between heart
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 beats, the pulse pressure is often increased, with the systolic pressure elevated
in hyperthyroidism 10 to 15 mm Hg and the diastolic pressure reduced a
corresponding amount.

12. Action on respiration

Thyroxine increases the rate and force of respiration indirectly. The

increased metabolic rate (caused by thyroxine) increases the demand for oxygen
and formation of excess carbon dioxide. These two factors stimulate the respiratory
centers to increase the rate and force of respiration.

13. Action on gastrointestinal tract

Generally, thyroxine increases the appetite and food intake. It also increases
the secretions and movements of GI tract. So, hypersecretion of thyroxine causes
diarrhea and the lack of thyroxine causes constipation.

14. Action on central nervous system

Thyroxine is very essential for the development and maintenance of normal

function of central nervous system (CNS).

 On Development of Central Nervous System: Thyroxine is important

development of synapses and myelination of the axons.
 On the Normal Function of Central Nervous System

The cerebral blood flow, O2 consumption and glucose are not affected by thyroid
hormones, but some of the thyroid effects on the brain are due to increased
responsiveness to catecholamine with consequent increase in activation of the
reticular activating system.

15. Action on skeletal muscle

Thyroxine is essential for the normal activity of skeletal muscles. Slight increase in
thyroxine level makes the muscles to work with more vigor. But, hypersecretion of
thyroxine causes weakness of the muscles due to catabolism of proteins. This
condition is called thyrotoxic myopathy. The muscles relax very slowly after the
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contraction. Hyperthyroidism also causes fine muscular tremor. Tremor occurs at

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 the frequency of 10 to 15 times per second. It is due to the thyroxine-induced
excess neuronal activity. The lack of thyroxine makes the muscles more sluggish.

16. Action on sleep

Normal thyroxine level is necessary to maintain normal sleep pattern.

Hypersecretion of thyroxine causes excessive stimulation of the muscles and
central nervous system. So, the person feels tired, exhausted and feels like
sleeping. But, the person cannot sleep because of the stimulatory effect of
thyroxine on neurons. On the other hand, hyposecretion of thyroxine causes
somnolenc, with sleep sometimes lasting 12 to 14 hours a day.

17. Action on sexual function

Normal thyroxine level is essential for normal sexual function. In men,

hypothyroidism leads to complete loss of libido (sexual drive) and hyperthyroidism
leads to impotence.

In women, hypothyroidism causes menorrhagia and polymenorrhea . In some

women, it causes irregular menstruation and occasionally amenorrhea.
Hyperthyroidism in women leads to oligomenorrhea and sometimes amenorrhea.
https://www.mdpi.com/1422-0067/23/5/2708

18. Action on other endocrine glands: Because of its metabolic effects,

thyroxine increases the demand for secretion by other endocrine glands.

THYROID FUNCTION TESTS

Functional status of thyroid gland is assessed by the following tests:

1. Measurement of plasma level of T3 and T4.

2. Measurement of TRH and TSH: There is almost total absence of these two
hormones in hyperthyroidism. It is because of negative feedback mechanism, by
the increased level of thyroid hormones. Measurement of TSH has become the
principal test for the evaluation of thyroid function in most circumstances

3. Measurement of basal metabolic rate: In hyperthyroidism, basal metabolic rate is

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increased by about 30% to 60%. Basal metabolic rate is decreased in

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hypothyroidism by 20% to 40%.

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