The Thyroid Gland and Its Iodothyronine Hormones Introduction The hormones associated with the thyroid gland are mainly the iodothyronines tri iodothyronine T3 and tetra iodothyronine T4 or thyroxine Being amines they have properties which allow them to span the two groups of hormones polypeptide protein and steroid Thyroid disorders are relatively common endocrine disorders second only to diabetes mellitus In addition of T3 and T4 a polypeptide hormone called calcitonin is synthesized by specific cells within the thyroid involved in calcium metabolism Embryological derivation general structure and histology Develops embryologically as an outgrowth of the developing floor of the pharynx around the fourth week of pregnancy In an adult the thyroid normally weighs approximately 15 20 g but when enlarged goiter is can be many times heavier weighing up to a few hundred grams Highly vascular with blood flow at 4 mL min g The superior thyroid arteries from the carotid The inferior thyroidal arteries from the subclavian Venous blood drains into the internal jugular and the left brachiocephalic vein cid 127 General structure called colloid Consists of single cell layers or balls of follicular cells or thyrocytes called follicles surrounding a central region filled with a yellow brown protein rich gel Between 30 and 40 follicles are grouped together by surrounding connective tissue to form lobules Each lobule has its own blood supply and can function independently Highly active follicles consist of thick columnar follicular cells while relatively inactive follicles have thinner more cuboidal follicular cells Interspersed between the follicles are small clumps of very different cells called parafollicular cells cid 127 Operate completely independently of the main thyroid Produce calcitonin Follicular cells thyrocytes produce iodothyronines Inner apical membrane facing the colloid is a site of much activity hormone synthesis and movement of synthesized hormone into out of the colloid cid 127 Well developed endoplasmic reticulum within the follicular cell and many mitochondria as well as an abundance of lysosomes filled with enzymes Synthesis storage and release of iodothyronines The iodothyronines are iodinated molecules The two main physiologically active thyroid hormones are T3 and T4 Seven distinct stages in iodothyronine synthesis Uptake of iodide into follicular cells Iodide has to move against an impressive electrochemical gradient in order to enter the follicular cells Sodium iodide symporter NIS in the basolateral membrane which transports two sodium and one iodide ions into the cell down the sodium gradient Energy to drive the symporter is provided by the sodium potassium ATPase which pumps three sodium ions out of the cell in exchange for two The Na I symporter is under the control of the anterior pituitary hormone thyrotrophin TSH which binds to its receptor and stimulates the second potassium ions messenger adenyl cyclase cAMP system Synthesis of thyroglobulin protein Synthesis is stimulated by TSH The follicular cell synthesizes a large glycoprotein homodimer called thyroglobulin which consists of two similar chains The glycoprotein is exported from the follicular cell into the lumen through the apical membrane Iodination and organification reactions forming mono and di iodotyrosines cid 127 Once iodide has been brought into the follicular cell it is transported through the apical membrane into the follicular lumen Pendrin transporter Along the apical membrane colloid border the inorganic iodide gets oxidized to a highly active short lived form known as reactive iodine Catalyzed by thyroidal peroxidase TPO in the presence of hydrogen peroxide Immediately gets organified by binding to positions 1 and 2 of certain tyrosine residues tyrosyls which are incorporated into the thyroglobulin 25 30 tyrosyls are iodinated Coupling reaction with the formation of tri and tetra iodothyronines T3 and T4 Still in the follicle lumen along the apical membrane the thyroglobulin undergoes a configurational change known as the coupling reaction Specific di iodotyrosyls link up with either mono or di iodotyrosyls to form tri and tetra iodothyronines A thyronine is the result of linkage between two tyrosyls Approximately 3 5 thyronines are formed on each thyroglobulin during normal conditions Storage in the follicle colloid The follicle lumen is filled with iodinated thyroglobulin protein which forms a yellowish thick gel like substance known as colloid Acts as a reservoir of iodothyronines cid 127 More of the thyronines synthesized in the thyroid are in the form of T4 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 T4 can be deiodinated to T3 which is much more biologically active in peripheral tissues Up to 3 months worth of iodothyronines are stored in the colloid Uptake from colloid and release into circulation cid 127 When the follicular cells are stimulated by TSH it is associated with the pinocytosis of colloid cid 127 Once the iodinated thyroglobulin is back in the follicular cell cytoplasm it is taken up by lysosomes Contain various enzymes including proteases and deiodinases which break down the thyroglobulin releasing iodine tyrosine and the thyronines The ratio of thyroidal T4 to T3 is usually of the order of 15 1 The iodothyronines T3 and T4 are secreted through the basolateral membranes into the general circulation via a transporter Peripheral conversions Thyroxine T4 plays a major role in acting as a prohormone in addition to its direct role as a hormone itself Numerous peripheral tissues contain deiodinases that deiodinate T4 into T3 by the removal of the iodine atom at position 3 A different deiodinase can act at the 5 position resulting in the biologically inactive reverse T3 rT3 The biological half life of T3 is approximately 15 hours compares with the 6 5 days for T4 Transport of iodothyronines in the blood Preferentially bind to plasma proteins Thyronine binding globulin TBG is specific for T3 and T4 About 80 of T3 and 70 of T4 Remainder bound to pre albumin or albumin Binding of hormone is in dynamic equilibrium small amount of free hormone is available to bind to receptors In pregnancy