Thyroid Gland, Hormones

and Antithyroid Drugs

Dr. Layla Borham

 Objectives
By the end of this lecture, the student will be able to:
• Know thyroid receptors, thyroid hormone release control,
thyroid hormone synthesis and storage
• Describe thyroid replacement therapy, initiation and
maintenance treatment
• Discuss antithyroid drugs: mechanism of action, uses,
kinetics and adverse effects
• Know different methods of the treatment of Grave's disease
(antithyroid drug, subtotal thyroidectomy and radioactive I)
• Management of thyroid Storm
Dr. Layla Borham
 Clinical Case
• A 72 year old man complains of tremor and inability to
concentrate. On exam, he has a heart rate of 100 beats per
minute. He has a swelling in his neck with many nodules, fine
tremors. His serum T4 is very high and TSH is very low. No
exophthalmos.

1. What is the diagnosis?

2. What treatments are likely to improve his symptoms?

3. Mention the indications of your answer.

 Thyroid Gland
Endocrine gland with three hormones released:

1. Thyroxine (T4) and triiodothyronine (T3), and

Calcitonin.

2. Thyroxine and triiodothyronine are important in:

• Growth, development.

• Maintaining normal body temperature.

• Energy metabolism regulation.

Dr. Layla Borham
 Thyroid Gland
Receptors:
1. Thyrotropin (TSH, a pituitary hormone protein)
modulates thyroid function by binding to TSH
receptors (TSH-R). Binds to target fixed cell surface
receptors.

2. TSH-R: localization and properties: basolateral

membrane of thyroid follicular cells.

Dr. Layla Borham

TSH (protein) stimulates specific fixed
cell membrane receptor on thyroid cell 
↑ adenylyl cyclase  ↑ cAMP (second
messenger)  ↑ RNA  ↑ the size,
vascularity and functions of thyroid
gland. Dr. Layla Borham
 Steps in Biosynthesis
 Iodide trapping

 Iodide Organification

1. Oxidation of iodide to iodine

2. Iodination of tyrosine

 Coupling (Formation of T4 and T3)

 Release of T4 and T3

Dr. Layla Borham

 Oxidation

Active uptake and

Sodium Iodide
concentration of
symporter NIS
inorganic iodide I-
A- Trapping (trapping) by thyroid
cells.
Active trapping (NIS) is
inhibited by:
- Monovalent chemical
group: perchlorate-,
nitrate-, and thiocyanate-.
compete with iodide I-.
- Anaerobic conditions
 depletion of ATP.
- Dinitrophenol 
uncoupling oxidative
phosphorylation  #
inorganic iodide synthesis of ATP.
- Digitalis  # ATPase
Organic iodine in food (I2), not  # utilization of ATP.
absorbed, in GIT  inorganic iodide I- Dr. Layla Borham
 B- Organification:
a- oxidation of inorganic
iodide (I-)  active
organic iodine (I2) by
peroxidase enzyme
which catalysis H2O2.

b- Iodination of
tyrosine. Elementary
iodine combines with
tyrosyl residue of
colloidal thyroglobulin
 mono- and di-
iododtyrosine (MIT and
DIT).

Dr. Layla Borham

 This process is blocked by
C- Coupling the Thionamides.
1- Coupling
of MIT and
DIT to form
T3 and T4.

2- Catalyzed
by peroxidase
enzyme

Dr. Layla Borham

 Storage and release
1. Storage of thyroglobulin with T3 and T4 extracellularly in the
colloid of thyroid follicles.
2. Endocytosis of TG under the control of TSH.
3. Proteolysis of TG by lysosomal enzymes.
4. MIT and DIT are retained inside the cell and deiodinated by
thyroid deiodinase enzyme  elementary iodine recycling
iodination of tyrosine. Congenital deficiency of deiodinase
enzyme  decrease availability of iodine  hypothyroidism.
5. Release of T3 and T4 under the control of TSH.
6. The major part of T3 and T4 are bound to plasma proteins mainly
thyroxin binding globulin (TBG). Dr. Layla Borham
1. Unbound T4 and T3
diffuse into the cell
2. Inside cell: T4
converted to T3.
3. T3 binds to a mobile
cytoplasmic receptor
 complex.

4. Complex is
transported to the cell
nucleus where T3
binds to a specific T3
nuclear receptor.
5. Increased DNA
transcription m
RNA and r RNA 
protein synthesis:
• increased Na/K
ATPase causes increas
ed ATP turnover,
increased oxygen
consumption
(calorigenic effect)
Dr. Layla Borham
 Hypothyroidism
I- Myxodema: Adult hypothyroidism: Types:
Type Origin Cause
Hashimoto's thyroiditis (an autoimmune disease) and
Thyroid
Primary radioiodine therapy for hyperthyroidism.
gland
TSH ↑ and T4 ↓.
Pituitary gland does not produce enough (TSH)
Caused by damage to the pituitary gland, as by a
tumor, radiation, or surgery to induce the thyroid gland
Pituitary
Secondary to produce enough T3 and T4.
gland
Secondary hypothyroidism accounts for less than 5%
or 10% of hypothyroidism cases.
TSH ↓ and T4 ↓.
Hypothalamus fails to produce sufficient thyrotropin-
Hypotha
Tertiary releasing hormone (TRH)
lamus
It accounts for less than 5% of hypothyroidism cases.
myxedema

Dr. Layla Borham

 Hypothyroidism
II- Cretinism: Childhood hypothyroidism, which leads to
retarded growth and mental retardation if not treated.

Causes:

• Idiopathic

• Hashimoto's thyroiditis

• Treatment of hyperthyroidism with radio-iodine, 131I.

Symptoms

weakness, shallow respiration, puffy face, frowsy hair.

Dr. Layla Borham
Cretinism

Dr. Layla Borham

 Hyperthyroidism: thyrotoxicosis
Causes:

1.Grave's disease: Exophthalmos.

2. Toxic nodular goiter: Thyroid nodules secreting
excess amounts of thyroid hormones. there is
no exophthalmos.
3. Thyroid storm: acute hyperthyroid crisis, which
can be deadly.
Dr. Layla Borham
 Grave's disease
• A malfunction in the body's immune system releases abnormal
auto-antibodies (Thyroid-stimulating immunoglobulin (TSI)
sometimes called (TSH receptor antibody) that mimic TSH and
activate the TSH-receptor, thereby stimulating thyroid hormone
synthesis and secretion, and thyroid growth.

• The same antibodies may also be involved in the eye changes seen
in Graves’ ophthalmopathy  Exophthalmos.

Diagnosis:

• TSH ↓, free T4 ↑, TSI positive result strongly supports the

diagnosis of Graves’ disease. Exophthalmos.
Dr. Layla Borham
Hyperthyroidism

Dr. Layla Borham

Dr. Layla Borham
Dr. Layla Borham
 Preparations
Synthetic:

1. Levothyroxine. l-thyroxin = T4.

2. Liothyronine. l-T3. Stronger, quicker onset (less

protein bound) and short duration of action than T4.

3. Liotrix. T4 + T3 (4:1).

4. Thyroglobulin.

5. Preparations of choice: synthetic levothyroxine

Dr. Layla Borham
 Preparations of choice: synthetic levothyroxine T4
Applications:
1. Thyroid replacement.
2. Suppression therapy.

Rationale:
1. Low-cost.
2. Stability.
3. Non-allergenic (no foreign protein).
4. Serum levels readily obtained.
5. Long half-life (seven days), supports once-daily dosing.
6. Since T4 is converted to T3 inside the cell, T4
administration produces both hormones.

Dr. Layla Borham

Liothyronine:
• More active than levothyroxine but not recommended because
of:
1. Shorter half-life (multiple dosing).
2. More costly.
3. Higher hormonal activity enhances cardiotoxicity (T3
contraindicated cardiac disease).
4. Most appropriate use: short-term TSH suppression and
emergency.
Therapeutic uses of thyroid hormones
1. Replacement therapy in hypothyroidism, e.g. myxoedema, and
critinism.
2. Simple non-toxic goiter.
3. Hypercholestrolemia. Dr. Layla Borham
Dr. Layla Borham
 Antithyroid Drugs
Purpose:

1. Reduction of thyroid activity.

2. Reduction of hormone effects.

• There are drugs inhibiting thyroid hormone

biosynthesis, either by inhibiting iodine uptake by
• Broccoli
the thyroid, or by inhibiting hormonal synthesis. • Cauliflower
Definition: "goitrogens" • Mustard Greens
• Radishes
1. Compounds that ↓ T3 and T4 secretion,  ↑ TSH. • Spinach
• Strawberries
2. Increased TSH levels  thyroid gland • Peaches
• Soy-Based Foods
enlargement (goiter). • Peanuts
Dr. Layla Borham
 Antithyroid drugs
Class Representative
propylthiouracil
methylthiouracil
Thionamides
methimazole
carbimazole
Iodides KI, NaI
131I
Radioactive iodine
β-adrenoceptor blockers propranolol

29
 Antithyroid Drugs
1. Thionamides. Inhibit organification of iodide. Has a
delayed effect.
2. Iodides. Temporarily (early on) inhibits proteolysis of
thyroglobulin, preventing freeing of thyroxin. Effect wears
off. Used to treat Thyroid Storm.
3. Radioactive iodine. 131I: Diffusely kills thyroid cells 
eventual and inevitable hypothyroidism.
4. -blockers. Reduction of sympathetic manifestations in
thyrotoxicosis.
Dr. Layla Borham
 Thionamides
1-
 blocking organification

2-Inhibit incorporation of
iodine into tyrosyl
residues of TG.

4-
3- Inhibit coupling of MIT
and DIT to form T3 and
T4, thus preventing
hormone synthesis. Dr. Layla Borham
 Thionamides
• Methimazole (MMI):
1. It is usually preferred over PTU because it reverses
hyperthyroidism and has fewer side effects.
2. It requires an average of six weeks to lower T4 levels to normal
and is often given before radioactive iodine treatment. It can be
taken once per day.
• Propylthiouracil (PTU):
1. PTU has more side effects.
2. Because of its potential for liver damage, it is used only when
MMI or carbimazole are not appropriate.
3. PTU must be taken two to three times per the day.
• Carbimazole: It is converted into MMI in the body.
Dr. Layla Borham
 Antithyroid Drugs During Pregnancy
1. PTU used to be the drug of choice during pregnancy because it
has a lower risk of causing birth defects (less free drug (more
protein-bound) is available to cross into the fetus).

2. But experts now recommend that PTU be given during the first
trimester only, because there have been rare cases of liver damage
in people taking PTU.

3. After the first trimester, women should switch to methimazole for

the rest of the pregnancy.

• For women who are nursing, methimazole is probably a better

choice than PTU (to avoid liver side effects)
Dr. Layla Borham
 Toxicity of thionamides
1. Allergy: most common: maculopapular pruritic rash. Most
serious potential reaction: agranulocytosis.
2. Increase size and vascularity of the thyroid  difficulty to
operate upon. (Use I- for 7-10 days before operation to
decrease size and vascularity of thyroid gland).
3. Large dose  hypothyroidism. Long-term use leads to
thyroid hyperplasia
4. Exophthalmos.
5. During pregnancy and lactation,  inhibit thyroid of the
baby  cretinism.
6. Loss or depigmentation of hair.
7. GIT disturbances.
8. Liver and kidney damage. Joint pain.
Dr. Layla Borham
 Uses of Thionamides
1. Drug of choice in mild hyperthyroidism. Moderate
hyperthyroidism is treated by subtotal thyroidectomy or
radioactive I131-

2. Temporary control in moderate and severe

hyperthyroidism.

– To prepare the patient for operation.

– Till the effect of I131- appears (3 months).

3. Propylthiouracil may be used in hyperthyroid storm

(crisis). Dr. Layla Borham
 Anion Inhibitors
Competitive inhibition:
• Perchlorate.

• Pertechnetate.

• Thiocyanate (also decrease organification).

– Blockade of thyroid gland reuptake of I- (competes with I-

reuptake, trapping, and storage by thyroid) in patients with

iodide-induced hyperthyroidism.

– Major clinical use: potassium perchlorate (not often used

because of the possibility of causing aplastic anemia
Dr. Layla Borham
Dr. Layla Borham
 Iodides
Actions on the thyroid: Rapid onset of effects = thyroidectomy.
1. Inhibit hormone release-- major action, perhaps by inhibition of
thyroglobulin proteolysis. Decreased release of T3 and T4.
2. Decreased thyroidal size and vascularity.
3. Inhibit organification.
4. Attenuate the effect of TSH on cAMP.
5. They may increase TSH. The antithyroid effect is maintained for
10-15 days  relapse of hyperthyroidism due to increase TSH 

paradoxical effect of iodide therapy.

Dr. Layla Borham

 Iodides
Clinical Considerations:
1. May be useful in short-term management of thyroid storm.
2. Maybe helpful in preoperative preparation for surgery (due
to reduction in gland vascularity, size, and fragility – used for 7-
10 days before operation).
3. Chronic iodide used in pregnancy iodide crosses the placenta
and may cause fetal goiter.
4. Iodide as monotherapy: not appropriate; iodide block lasts only
2-8 weeks; withdrawal at this time may exacerbate
thyrotoxicosis. It should be initiated only after thionamide
treatment Dr. Layla Borham
 Radioactive Iodine
131I is the radioactive isotope used for treating thyrotoxicosis.
Mechanism of Action:
1. Rapidly absorbed, concentrated in the thyroid.
2. Incorporated into thyroid follicles (trapping of 131I is increased by
circulating TSH).
3. Beta emission is the basis for therapeutic efficacy.
4. Thyroid parenchymal destruction occurs within a few weeks.
Therapeutic uses:
1.Treatment of hyperthyroidism (old patients, patients with cardiac
diseases, recurrence after subtotal thyroidectomy, and in failure of
medical antithyroid treatment). 2. Cancer thyroid. Dr. Layla Borham
 Radioactive Iodine
Therapeutic advantages for radioiodine:
1.Good efficacy.
2. Easy to administer.
3. Low expense.
Side effects:
1. Local pain and congestion.
2. Hypothyroidism.
3. Malignant changes after several years.
Contraindication:
1.131I: crosses placental barrier and excreted in breast milk.
2. Not used in childhood  hypothyroidism and malignant changes.
Dr. Layla Borham
 Propranolol

1. Reduction of sympathetic manifestations in thyrotoxicosis

2. Protects the heart from tachycardia, angina, and arrhythmia.
3. Propranolol:
• Passes BBB  # anxiety and tremors.
• Inhibits conversion of T4 to more active T3.
• Relieves temporarily thyrotoxic manifestations until control by
other measures. Dr. Layla Borham
 Thyroid Storm
Treatment:
1. Manage dehydration: IV glucose/Saline.

2. Glucocorticoids Corticosteroids are used only in severe

hyperthyroidis (to decrease peripheral conversion of T4 to T3.
This may also be useful in preventing relative adrenal
insufficiency due to hyperthyroidism).

3. Digitalis may be required to control elevated ventricular rates in

the presence of atrial fibrillation.

Dr. Layla Borham

 Thyroid Storm
Treatment:
1. Block hormone synthesis by large dose propylthiouracil (High-
dose propylthiouracil (PTU) is preferred because of its early
onset of action and capacity to inhibit peripheral conversion of
T4 to T3) followed by large doses of iodine, oral or parenteral;
sodium ipodate may be used instead of iodine.

2. Propranolol (adrenergic antagonist) important in the absence of

CHF.

3. Combination treatment with propylthiouracil, iodine,

dexamethasone is likely to result in serum T3 levels returning to

normal within one to two days. Dr. Layla Borham

 Graves’ Disease

• Reading Assignment:

http://www.thyroid.org/wp-
content/uploads/patients/brochures/Graves_brochur
e.pdf