THYROID HORMONES

Dr. Umrana MirzaRef: Harper 25th edition

Objectives:1.Name the different tyrosine derived thyroid hormones and list the steps of their synthesis explaining the role of iodine2.Describe the mechanism of storage,secretion,transport,degradation and excretion of tyrosine derived thyroid hormones.3.List their metabolic effects.

Thyroid gland is located on either sides of the trachea just belowthe larynx.The tyrosine derived hormones secreted by thyroid gland are1. Tri-iodothyronine(T3) and

2. Tetra-iodothyronine or thyroxine ( T4)

These hormones are necessary for the proper functioning ofalmost all the systems and biological processes. Synthesis of thyroid hormone requiresIodine: is a trace element, requirement is 150 to 200µgm/ day.Sources-drinking water, fish, cereals, vegetables and iodinated salt. Thyroglobulin: is a complex glycosylated protein ( 500 a.a),synthesized by thyroid follicular cells. It has 115 tyrosine residues.Amino acid-Tyrosine in thyroglobulin

SynthesisFirst step: Uptake and concentration of iodine by thyroid gland by anActive process linked to Na+/ K+ ATP ase pump. This step is stimulated by TSH and is inhibited by high concentration of iodine inthyroid gland.

Second step: iodine is than oxidized to active iodine. Thyroid gland is the only organ which can perform this function.This step is stimulated by TSH. Require Thyroperoxidase as enzyme and NADPH ascoenzyme. Thyroperoxidase

Iodine- Active iodine+ H2o2 O2

NADPH + H+

.

Third step: iodination of tyrosine.iodination of tyrosine takes place in the intact thyroglobulin molecule in thefollicular space. Third position of aromatic ring is iodinated first to form MIT,Than the 5th position to form DIT.Fourth step: Coupling of iodotyrosyls. DIT + DIT T4

DIT + MIT T3

 Under normal conditions 99% of the hormone produced bythyroid gland is T4

3,5,3’,5’ Tetraiodothyronine

3,5,3’ Tri-iodothyronine

Step-1 Uptake and concentration of iodine

Step-2Activationof iodine

Step-3Iodination of tyrosine

Step-4Coupling ofiodotyrosyls

Thyroid follicular cell

Follicular space

Storage and secretion: Synthesized thyroid hormone is stored as

colloid in thyroid acini. When stimulated by TSH the thyroglobulin is

taken from the acinar colloid back into the cell by pinocytosis.

The hormone is than released by hydrolysis by specific proteases in lysosomes.

T4 is than released into the blood stream. T3 is produced from T4 by deiodination at

5‘position in the peripheral tissues. The MIT and DIT that are not utilized are

deiodinated by deiodinase and the released iodine is reutilized.

Thyroid cell

Follicular

space

Blood

Transport Thyroid hormone is lipophilic, therefore it is

transported bound to proteins such as• thyroxine binding globulin(TBG),• thyroid binding pre-albumin(TBPA) and• albumin. 1/2 to 2/3rd of T4 and T3 bind with TBG & TBPA.

Bound form is biologically inactive. Free fraction is only 0.03%, which is biologically active.

T4 concentration is 70 times greater than T3 concentration in blood, but T3 is biologically more active.

RegulationFree form of T3 and T4 inhibits the secretion

of TSH by negative feedback mechanism.

Degradation and ExcretionThyroid hormones are degraded in peripheral tissues by total deiodinationand inactivation. First it is deiodinated and decarboxylated, followed by glucuronidation andsulfation in the liver and made hydrophilic and therefore excreted in bile reabsorbed from the gut reaches kidney and is excreted as glucuronideConjugate in urine.

Mechanism of ActionGroup-I hormoneT3 and T4 bind to specific nuclear receptors.T3 has more affinity to bind with nuclear receptors and hence biologicallymore active.Transported to the nucleus and binds with thyroid responsive element in theDNA increases rate of transcription produces biochemical effect.

Biochemical Functions(metabolic effects)

1. Thyroid hormone stimulates the metabolic activity and increases the oxygen consumption in most of the tissues of the body.

2. Promote protein synthesis by acting at the transcriptional level.

3. Promotes intestinal absorption of glucose and its utilization.4. Increases glycogenolysis & gluconeogenesis with an overall

effect of increasing blood glucose level hyperglycemia.5. Lipid turn over and utilization are stimulated by T3 & T4.

Hence hypothyroidism is associated with elevated cholesterol level.

6. Regulates water and electrolyte metabolism.