HORMONES SECRETED BY THYROID GLAND
• Thyroxine ( T4 )
• Triiodothyronine ( T3 )
• Calcitonin - interfollicular c cells
• The thyroid gland secretes 3 hormones – thyroxine (T4),
triiodothyronine (T3) and calcitonin.
• T3 and T4 are produced by the thyroid follicles under the
influence of TSH secreted by the pituitary gland.
• Calcitonin is produced by the parafollicular ‘C’ cells. It is
important for calcium metabolism and is considered along
SYNTHESIS OF THYROID HORMONES
1. IODIDE UPTAKE
2. OXIDATION AND IODINATION
4. STORAGE AND RELEASE
5. PERIPHERAL CONVERSION OF T4 TO T3
• The thyroid cells have an active transport process (Na+: I¯
symporter or NIS)
• To concentrate iodide ion - pumps dietary I - into the cell
• This trapping is stimulated by TSH
• Rate –limiting step in thyroid hormone synthesis
• Iodide trapped by follicular cells is carried across the apical
membrane by another transporter termed ‘pendrin’.
• Oxidized by the membrane bound thyroid peroxidase
enzyme with the help of H2O2 form iodinium (I+) ions
• These forms of iodine combine with tyrosil residues of
• To form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
• MIT +DIT = T3 (Tri-iodothyronine)
• DIT + DIT = T4 (Thyroxin)
• All attached to thyroglobulin and stored in the colloid
• This process is stimulated by TSH
STORAGE AND RELEASE
• Thyroglobulin containing iodinated tyrosil and thyronil residues
is transported to the interior of the follicles by endocytosis
and broken down by lysosomal proteases.
• The T4 and T3 so released is secreted into circulation while
MIT and DIT residues are deiodinated and the iodide
released is reutilized.
• The uptake of colloid and proteolysis are
stimulated by TSH
• Normal human thyroid secretes 60–90 μg of T4
and 10–30 μg of T3 daily.
PERIPHERAL CONVERSION OF T4 TO T3
• Peripheral tissues, especially liver and kidney, convert
T4 to T3.
• About 1/3 of T4 secreted by thyroid undergoes this change
and most of the T3 in plasma is derived from liver.
• Target tissues take up T3 from circulation for their
metabolic need, except brain and pituitary which take up
T4 and convert it to T3 within their own cells.
ABSORPTION, TRANSPORT, METABOLISM AND EXCRETION
• Oral bioavailability of l-thyroxine is ~ 75%, but severe hypothyroidism can
reduce oral absorption.
• It should be administered in empty stomach to avoid interference by food.
• Sucralfate, iron, calcium and proton pump inhibitors also reduce l-thyroxine
• Thyroid hormones are avidly bound to plasma proteins—only 0.03–0.08% of
T4 and 0.2–0.5% of T3 are in the free form.
• Binding occurs to 3 plasma proteins. In the order of affinity for T4, these are:
(i.) Thyroxine binding globulin (TBG)
(ii.) Thyroxine binding prealbumin
• Only the free hormone is available for action as well as for metabolism
• Metabolic inactivation of T4 and T3 occurs by deiodination and
glucuronide /sulfate conjugation of the hormones.
• CYP3A4 inducers like rifampin, phenytoin and carbamazepine accelerate
metabolism of T4; dose of l-thyroxine may need enhancement.
• Liver is the primary site (also salivary glands and kidneys). The conjugates
are excreted in bile.
• Plasma t½ of T4 is 6–7 days, while that of T3 is 1–2 days.
Relation between T4 and T3
• secretion of T4 more than T3, but in iodine deficient state T4 is reduced.
• T4 is 15 times more tightly bound to plasma proteins While T3 is more tightly bound to
the nuclear receptor .
• T3 is 5 times more potent and acts faster acting while T4 less potent and slow acting.
• Peak effect of T3 comes in 1–2 days while T4 takes 6–8 days.
• About 1/3 of T4 is converted to T3 in the thyroid cells, liver and kidney by type 1
deiodinase (D1) and released into circulation. In addition, T3 is generated within the
target cells (skeletal muscle, heart, brain, pituitary) by another type (D2) of deiodinase.
• Thus, it may be concluded that T3 is the active hormone, while T4 is mainly a transport
form; functions as a prohormone of T3.
• Due to the fast action T3 is preferred in emergency (myxoedema coma) while due to the
long acting T4 is preferred for long treatment required (hypothyroidism)
1.) Growth and development
• T4 and T3 are essential for normal growth and
• Congenital deficiency of T4 and T3 resulting in cretinism
emphasizes their importance.
• T4 and T3 indirectly enhance lipolysis by potentiating the
action of catecholamines and other lipolytic hormones
• Plasma free fatty acid levels are elevated.
• Thus, hyperthyroidism is characterized by
• LDL levels in blood are reduced.
• Heart rate, contractility and output are increased resulting
in a fast, bounding pulse.
• BP, specially systolic, is often raised.
• Muscles are flabby and weak in myxoedema, while
thyrotoxicosis produces increased muscle tone, tremor and
weakness due to myopathy.
• Propulsive activity of gut is increased by T3/T4.
• Hypothyroid patients are often constipated, while diarrhoea
is common in hyperthyroidism.
1. Cretinism –
• It is due to failure of thyroid development or a
defect in hormone synthesis or due to extreme
iodine deficiency .
• It is usually detected during infancy or childhood.
• Treatment with thyroxine (8–12 μg/kg) daily should
be started as early as possible, because mental
retardation that has already ensued is only partially
2. Adult hypothyroidism
• This is one of the commonest endocrine disorders
• CAUSES - thyroiditis, thyroidectomy, severe iodine deficiency, or
may be idiopathic.
• Important drugs that can cause hypothyroidism are 131I, lithium and
• Treatment with T4 - start with a low dose—50 μg of l thyroxine daily
and increase every 2–3 weeks to an optimum of 100–200 μg/day
(adjusted by clinical response and serum TSH levels).
3. Myxoedema coma
• It is an emergency; characterized by progressive mental
deterioration due to acute hypothyroidism.
• More common in old age associated with CAD may lead to
angina and MI
• Rapid thyroid replacement is crucial.
• Though liothyronine (T3) acts faster, its use is attended by
higher risk of cardiac arrhythmias, angina, etc.
• Drug of choice is l-thyroxine (T4) 200– 500 μg i.v. followed
by 100 μg i.v. OD till oral therapy can be instituted.
4. Nontoxic goiter
• Iodine deficiency which may be accentuated by factors present in
water excess calcium), food or milk (goitrin, thiocyanates).
• A defect in hormone synthesis may be responsible for sporadic
• In both types, deficient production of thyroid hormone leads to
excess TSH → thyroid enlarges.
• Treatment with T4
• Endemic goiter due to iodine deficiency is preventable by ensuring
daily ingestion of 150–200 μg of iodine.
• This is best achieved by iodizing edible salt.
DRUGS IN HYPERTHYROIDISM
1.) Inhibit hormone synthesis (Antithyroid drugs)
Thioamides- e.g- Propylthiouracil, Carbimazole, Methimazole
2.) Inhibit iodide trapping (ionic inhibitors)
Thiocynates, perchlorates, nitrates
3.) Inhibit hormone release
Iodine, iodides of Na and K
4.) Destroy thyroid tissue
• Thioamides inhibits the enzyme thyroid peroxidase
• Some report suggested that coupling reaction more sensitive
• Thioamides do not affect on other process but Propylthiouracil
also inhibits the peripheral conversion of t4 to t3 by D1 and
5DI but not D2 (Brain, pituitary, hypothalamus, thyroid, brown
fat, skeletal muscle)
• All antithyroid drugs are quickly absorbed orally.
• Widely distributed and conc. In thyroid glands, Peak conc. Of
Propylthiouracil is achieved in 1 hr.
• Plasma half-life is shorter (75 min) but effect is longer due to the
accumulation ( longer intrathyroid half life ).
• Carbimazole convert into active metabolite methimazole which contribute
longer action and 10 time more potent.
• Cross the Placenta and secrete in milk (avoid in pregnancy and lactation) but
Propylthiouracil less cross placenta & less secrete in milk (can be used if
necessary) and strongly bound to the plasma protein.
• Metabolized in liver and excreted in urine also secrete in milk.
1.) Antithyroid drugs control thyrotoxicosis in both Graves’ disease
and toxic nodular goiter.(with propranolol not in CHF, Asthma)
2. For the preparation of pt for surgery of thyroid gland.
Advantages of antithyroid drugs over surgery are:-
• No surgical risk,
• No scar
• no chances of injury to parathyroid glands or recurrent laryngeal
• Hypothyroidism, if induced, is reversible.
• Disadvantages are:
• (a) Prolonged treatment is needed.
• (b) relapse rate is high.
• (c) Drug toxicity.
Oral dose schedule
• Propylthiouracil- 50-150 mg TDS followed by maintenance dose 25-59
• Carbimazole- 5-15 mg TDS initially followed by maintenance dose 2.5-
• Methimazole- 5-15 mg TDS initially followed by maintenance dose 2.5-
10mg BD or OD
• Hypothyroidism and goiter can occur due to overtreatment, but is
reversible on stopping the drug.
• Important side effects are: g.i.t intolerance, skin rashes and joint
• Loss or graying of hair, loss of taste, fever and liver damage are
• A rare but serious adverse effect is agranulocytosis (1 in 500 to 1000
• It is mostly reversible.
• Certain monovalent anions inhibit iodide trapping by NIS
• Perchlorate is 10 times more potent than thiocyanate in blocking NIS,
while nitrate is very weak.
• They are toxic and not clinically used now.
• Thiocyanates: can cause liver, kidney, bone marrow and brain toxicity.
• Perchlorates: produce rashes, fever, aplastic anaemia, agranulocytosis.
IODIDES & IODINE
• Oldest and fast acting agents for earlier control the
• Require for synthesis also for the inhibition of thyroid
At low dose it stimulate the synthesis & at much higher
dose inhibits the release of thyroid hormone.
• by inhibiting thyroglobulin proteolysis.
• Excess iodide inhibits its own transport into thyroid cells by
interfering with expression of NIS on the cell membrane.
• AT higher conc. It reduced the thyroid blood flow(use for
preoperative preparation surgery and Thyrotoxicosis)
• Some time acute inhibition of iodination of tyrosine resulting in
reduced T3/T4 synthesis (Wolff-Chaikoff effect).