Thyroid Hormones


  • Diseases of the thyroid gland are prevalent, and in this chapter, we deal with drug therapy used to mitigate these disorders.
  • We set the scene by briefly outlining the structure, regulation, and physiology of the thyroid, and highlight the most common abnormalities of thyroid function.
  • We then go on to consider the drugs that replace the thyroid hormones when these cease to function adequately, and the drugs that decrease thyroid function when this is excessive.

Synthesis Thyroid Hormones (Storage and Secretion)

  • The thyroid gland secretes three main hormones: thyroxine (T4), triiodothyronine (T3), and calcitonin. T4 and T3 are critically important for normal growth and development and energy metabolism.
  • Calcitonin is involved in the control of plasma Ca2+ and is dealt with in. The term thyroid hormone will be used here solely to refer to T4 and T3.
  • The functional unit of the thyroid is the follicle or acinus. Each follicle consists of a single layer of epithelial cells around a cavity, the follicle lumen, which is filled with a thick colloid containing thyroglobulin.
  • Thyroglobulin is a large glycoprotein, each molecule of which contains about 115 tyrosine residues. It is synthesized, glycosylated, and then secreted into the lumen of the follicle, where iodination of the tyrosine residues occurs.
  • Surrounding the follicles is a dense capillary network, and the rate of blood flow through the gland is very high in comparison with other tissues. The main steps in the synthesis, storage, and secretion of thyroid hormone are as follow:
  • Uptake of plasma iodide by the follicle cells.
  • Oxidation of iodide and iodination of tyrosine residues of thyroglobulin.
  • Secretion of thyroid hormone.
Thyroid Hormones
Fig.1: Thyroid Hormones (T3/T4) – Synthesis, Storage, and Secretion

Regulation of Thyroid Function

  • Thyrotrophin-releasing hormone (TRH), released from the hypothalamus in response to various stimuli, releases thyroid-stimulating hormone (TSH; thyrotropin) from the anterior pituitary as does the synthetic tripeptide protirelin (pyroglutamic-histidyl proline amide), which is used in this way for diagnostic purposes.
  • TSH acts on receptors on the membrane of thyroid follicle cells through a mechanism that involves cAMP and phosphatidylinositol 3-kinase. It controls all aspects of thyroid hormone synthesis, including:
  1. The uptake of iodide by follicle cells, by stimulating transcription of the iodide transporter genes; is the main mechanism by which it regulates thyroid function.
  2. The synthesis and secretion of thyroglobulin.
  3. The generation of H2O2 and the iodination of tyrosine.
  4. The endocytosis and proteolysis of thyroglobulin.
  5. The actual secretion of T3 and T4.
  6. The blood flow through the gland.
  • The thyroid-stimulating hormone also has a trophic action on the thyroid cells; it stimulates the transcription of the genes for thyroglobulin and thyroperoxidase, as well as the I transporters.
  • The production of TSH is also regulated by a negative feedback effect of thyroid hormones on the anterior pituitary gland, T3 being more active than T4 in this respect.
  • The peptide somatostatin also reduces basal TSH release.
  • The control of the secretion of TSH thus depends on a balance between the actions of T4 and TRH (and probably also somatostatin) on the pituitary, although even high concentrations of thyroid hormone do not inhibit TSH secretion.
  • The other main factor influencing thyroid function is the plasma iodide concentration. About 100 nmol of T4 is synthesized daily, necessitating uptake by the gland of approximately 500 nmol of iodide each day (equivalent to about 70 mg of iodine).
  • A reduced iodine intake, with reduced plasma iodide concentration, will result in a decrease in hormone production and an increase in TSH secretion. An increased plasma iodide has the opposite effect, although this may be modified by other factors.
  • The overall feedback mechanism responds to changes of iodide slowly over fairly long periods of days or weeks, because there is a large reserve capacity for the binding and uptake of iodide in the thyroid. The size and vascularity of the thyroid are reduced by an increase in plasma iodide.
  • Diets deficient in iodine eventually result in a continuous excessive compensatory secretion of TSH, and eventually in an increase in vascularity and (sometimes gross) hypertrophy of the gland. ‘Derbyshire neck’ was the name given to this condition is a part of the UK where sources of dietary iodine were once scarce.

Actions of The Thyroid Hormones

  • The physiological actions of the thyroid hormones fall into two categories: those affecting metabolism and those affecting growth and development.
  • The thyroid hormones produce a general increase in the metabolism of carbohydrates, fats, and proteins, and regulate these processes in most tissues, T3 being three to five times more active than T4 in this respect.
  • Although the thyroid hormones directly control the activity of some of the enzymes of carbohydrate metabolism, most effects are brought about in conjunction with other hormones, such as insulin, glucagon, glucocorticoids, and catecholamines.
  • There is an increase in oxygen consumption and heat production, which is manifested as an increase in the measured basal metabolic rate. This reflects the action of these hormones on tissues such as the heart, kidney, liver, and muscle, although not on others, such as the gonads, brain, or spleen.
  • The calorigenic action is important as part of the response to a cold environment.
  • Administration of thyroid hormone results in augmented cardiac rate and output and increased tendency to dysrhythmias such as atrial fibrillation.

Effects on Growth and Development:

  • The thyroid hormones have a critical effect on growth, partly by a direct action on cells and indirectly by influencing growth hormone production and potentiating its effects on its target tissues.
  • The hormones are important for a normal response to parathormone and calcitonin as well as for skeletal development; they are also essential for normal growth and maturation of the central nervous system.


  • While there is some evidence for non-genomic actions these hormones act mainly through a mechanism dependent on the occupation of a member of the nuclear receptor family, TR.
  • Two distinct genes, TRα and TRβ, code for several receptor isoforms that have distinct functions. T4 may be regarded as a prohormone because when it enters the cell, it is first converted to T3, which then binds with high affinity to a member of the TR family.
  • This interaction is likely to take place in the nucleus, where TR isoforms generally act as a repressor of target genes.
  • When T3 is bound, the receptors change conformation, the corepressor complex is released and a coactivator complex is recruited, which then activates transcription resulting in the generation of mRNA and protein synthesis.

Transport and Metabolism:

  • Both hormones are transported in the blood bound mainly to thyroxine-binding globulin (TBG). Plasma concentrations of these hormones can be measured by radioimmunoassay, and normally fall into the range 1 × 10-7 mol/l (T4) and 2 × 10-9 mol/l for T3.
  • Both are eventually metabolized in their target tissues by deiodination, deamination, decarboxylation, and conjugation with glucuronic and sulfuric acids.
  • The liver is a major site of metabolism, and the free and conjugated forms are excreted partly in the bile and partly in the urine. The metabolic clearance of T3 is 20 times faster than that of T4 (which is about 6 days).
  • The long half-life of T4 is a consequence of its strong binding to TBG.
  • Abnormalities in the metabolism of these hormones may occur naturally or be induced by drugs or heavy metals, and this may give rise to a variety of (uncommon) clinical conditions such as the low T3 syndrome.

Abnormalities of Thyroid Function:

  • Thyroid disorders are among the most common endocrine diseases, and subclinical thyroid disease is particularly prevalent in the middle-aged and elderly.
  • They are accompanied by many extrathyroidal symptoms, particularly in the heart and skin. One cause of organ dysfunction is thyroid cancer.
  • Depending on where it is located, this can affect all aspects of glandular function including iodide uptake, TSH expression, and thyroglobulin synthesis.
  • Many other thyroid disorders have an autoimmune basis; the ultimate reason for this is not clear, although it may be linked to polymorphisms in the PDS, TNF-α; or other genes. Regardless of causation, there are two principal manifestations of the disease.

Hyperthyroidism (Thyrotoxicosis):

  • In thyrotoxicosis, there is the excessive activity of the thyroid hormones, resulting in a high metabolic rate, an increase in skin temperature and sweating, and a marked sensitivity to heat.
  • Nervousness, tremor, tachycardia, heat sensitivity and increased appetite associated with loss of weight occur.
  • There are several types of hyperthyroidism, but only two are common: diffuse toxic goitre (also called Graves’ disease or exophthalmic goitre) and toxic nodular goitre.
  • Diffuse toxic goitre is an organ-specific autoimmune disease caused by thyroid-stimulating immunoglobulins directed at the TSH receptor.
  • Constitutively active mutations of the TRH receptor may also be involved. As it is indicated by the name, patients with exophthalmic goitre have protrusion of the eyeballs.
  • The pathogenesis of this condition is not fully understood, but it is thought to be caused by the presence of TSH receptor-like proteins in orbital tissues.
  • There is also enhanced sensitivity to catecholamines.
  • Toxic nodular goitre is caused by a benign neoplasm or adenoma and may develop in patients with long-standing simple goitre.
  • This condition does not usually have concomitant exophthalmos.
  • The antidysrhythmic drug amiodarone is rich in iodine and can cause either hyperthyroidism or hypothyroidism.
  • Some other iodine-containing drugs, such as iopanoic acid and its congeners, which are used as imaging agents used to visualise the gall bladder, may also interfere with thyroid function but may have some clinical utility in treating hyperthyroidism.

Simple, Non-Toxic Goitre:

  • A dietary deficiency of iodine, if prolonged, causes a rise in plasma TRH and eventually an increase in the size of the gland.
  • This condition is known as simple or non-toxic goitre. Another cause is the ingestion of goitrogens (e.g. from cassava root).
  • The enlarged thyroid usually manages to produce normal amounts of thyroid hormone, although if the iodine deficiency is very severe, hypothyroidism may supervene.


  • A decreased activity of the thyroid results in hypothyroidism, and in severe cases myxoedema. Once again, this disease is immunological in origin, and the manifestations include low metabolic rate, slow speech, deep hoarse voice, lethargy, bradycardia, sensitivity to cold, and mental impairment.
  • Patients also develop a characteristic thickening of the skin (caused by the subcutaneous deposition of glycosaminoglycans), which gives myxoedema its name.
  • Hashimoto’s thyroiditis, a chronic autoimmune disease in which there is an immune reaction against thyroglobulin or some other component of thyroid tissue, can lead to hypothyroidism and myxoedema.
  • Therapy of thyroid tumours with radioiodine (see below) is another cause of hypothyroidism.
  • Thyroid deficiency during development, caused by the congenital absence or incomplete development of the thyroid, which is the most prevalent endocrine disorder in the newborn (1 in 3000-4000 births) causes cretinism, characterised by gross retardation of growth and mental deficiency.
  • Pendred’s syndrome, an autosomal recessive disorder caused by mutations in the PDS transporter gene, may cause goitre as well as deafness and other symptoms.
Thyroid Hormones

Anti Thyroid Drugs

  • These are the drugs used as the treatment of hyperthyroidism. These drugs control the overproduction of thyroid hormones.


1. Goitrogens:

(a) Thiourea derivatives: Thiourial, Methyl thiouracil, Propylthiouracil, Methimazole and Carbimazole.

(b) Ionic Inhibition: Potassium thiocyanate, Potassium perchlorate.

2. Iodide:

Sodium Iodide, Potassium Iodide.

3. Radioactive iodine:

Iodine131, Iodine125.

4. Beta-Adreno receptor blockers:

Propranalol, Timolol

Thiourea Derivatives:

Mechanism of action:
  • Inhibits the oxidation of iodide to free iodine.
  • Prevents the combination of iodide with tyrosine.
  • Prevent the coupling reaction in the biosynthesis of thyroxine.
  • Inhibits peripheral conversion of T3 to T4.
  • Brings down BMP of- Grave’s disease and Thyrotoxicosis.
  • Patients just can avoid operation by recluse of these drugs.
  • Methyl thiouracil is more toxic compared to methimazole and carbimazole.
  • Methimazole is a less toxic and safe drugs use in the treatment of thyrotoxicosis.
  • Well absorbed within 20-30 min after oral administration.
  • 40-50% binds to plasma protein
  • Only a fraction is metabolised in the body
  • The rest is excreted in unchanged form.
  • They cross the placenta barrier and also excreted in milk.
Therapeutic Uses:
  • Hyperthyroidism
  • In the preparation of the patient for thyroid surgery.
  • Also use in children, pregnant and women with hyperthyroidism lead to Grave’s disease.
Adverse Effect:
  • Hypothyroidism, Goitre, skin rashes, arthralgia, agranulocytosis, leukopenia thrombocytopenia.

Propyl Thiouracil:

  • Idiosyncrasy, fever, transient- leukopenia, agranulocytosis.


  • Fever, bone marrow depression, leads to a blood disorder.

Ionic Inhibitors:

  • These drugs competitively inhibit the trapping of iodine by the thyroid gland.
  • This decreases the biosynthesis of the thyroid hormone.
Adverse Effect:
  • Gastric irritation, fever, skin rashes, agranulocytosis.


  • The iodide acts by decreasing the response of the thyroid gland to TSH.
  • Iodide inhibits the release of thyroid hormone and thus it is called thyroid constipation.
  • Shrinkage of the gland. The release of Iodine in the circulation is decreased and thus decreases the size of glands.

Lugal’s Solution:

  • Inhibits the release of thyroid hormones from the thyroid glands.

Other Action:

  • The secretion of thyroid hormones is decreased.
  • Reduction in basal metabolic rate.
  • The glands become less vascular and firm.
  • The acinar cell becomes small in size and collides content decrease.
Adverse Effect:
  • Iodism: characterised by skin rashes, Increase salivary secretion, Lacrimination, Acute hypersensitivity reaction, Cutaneous haemorrhage, angioedema.
Therapeutic Uses:
  • Preoperative to control hyperthyroidism in Grave’s disease.
  • Best control hyperthyroidism with propyl uracil, then iodine is given for 10 days before surgical operation.
Chronic Adverse Effect:
  • Increase salivation
  • The sourness of teeth and gums
  • Swelling of eyelids
  • Upper respiratory tract infection
  • Inflammation of pharynx and larynx.

Radio Isotopes:

  • Radioisotopes emit alpha and gamma rays which are having cytotoxic action on the thyroid gland and can be used for thyroid carcinoma.
Therapeutic Uses:
  • Highly effective in the treatment of hypothyroidism.
  • Especially in old patients where other hyperthyroidism drugs are contraindicated.
  • To diagnose any thyroid disorders.
  • Recurrent hyperthyroidism after any suitable antithyroid drug therapy.
Side Effects:
  • High incidence of delay hyperthyroidism.
  • Patients after 30 years- chances of cancer and potential damage of offspring.
Make sure you also check our other amazing Article on : Classification of Hormones
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