Editing Thyroid (section)

== Function ==
[[File:Thyroid system.svg|thumb|upright=1.25|The [[thyroid hormone]]s [[triiodothyronine|T<sub>3</sub>]] and [[thyroxine|T<sub>4</sub>]] have a number of metabolic, cardiovascular and developmental effects on the body. The production is stimulated by release of thyroid stimulating hormone (TSH), which in turn depends on release of thyrotropin releasing hormone (TRH). Every downstream hormone has [[negative feedback]] and decreases the level of the hormone that stimulates its release.|alt=Diagram explaining the relationship between the thyroid hormones T<sub>3</sub> and T<sub>4</sub>, thyroid stimulating hormone (TSH), and thyrotropin releasing hormone (TRH)]]

===Thyroid hormones===
{{Main|Thyroid hormones}}

The primary function of the thyroid is the production of the iodine-containing [[thyroid hormones]], [[triiodothyronine]] (T<sub>3</sub>) and [[thyroxine]] or tetraiodothyronine (T<sub>4</sub>) and the [[peptide hormone]] [[calcitonin]].{{sfn|Davidson's|2010|p=736}} The thyroid hormones are created from [[iodine]] and [[tyrosine]]. T<sub>3</sub> is so named because it contains three atoms of iodine per molecule and T<sub>4</sub> contains four atoms of iodine per molecule.{{sfn|Guyton & Hall|2011|p=909}} The thyroid hormones have a wide range of effects on the human body. These include:

* '''Metabolic.'''<!--Metabolic--> The thyroid hormones increase the [[basal metabolic rate]] and have effects on almost all body tissues.{{sfn|Guyton & Hall|2011|p=934}} Appetite, the absorption of substances, and gut motility are all influenced by thyroid hormones.{{sfn|Guyton & Hall|2011|p=937}} They increase the absorption in the gut, [[gluconeogenesis|generation]], [[glucose uptake|uptake by cells]], and [[glycolysis|breakdown]] of glucose.{{sfn|Guyton & Hall|2011|p=936}} They stimulate the [[lipolysis|breakdown of fats]], and increase the number of [[free fatty acid]]s.{{sfn|Guyton & Hall|2011|p=936}} Despite increasing free fatty acids, thyroid hormones decrease [[cholesterol]] levels, perhaps by increasing the rate of secretion of cholesterol in [[bile]].{{sfn|Guyton & Hall|2011|p=936}} 
* '''Cardiovascular.''' <!--Cardiovascular-->The hormones increase the rate and strength of the heartbeat. They increase the rate of breathing, intake and consumption of oxygen, and increase the activity of [[mitochondria]].{{sfn|Guyton & Hall|2011|p=937}} Combined, these factors increase blood flow and the body's temperature.{{sfn|Guyton & Hall|2011|p=937}} 
* '''Developmental.'''<!--In development--> Thyroid hormones are important for normal development.{{sfn|Guyton & Hall|2011|p=936}} They increase the growth rate of young people,{{sfn|Guyton & Hall|2011|p=935-6}} and cells of the developing brain are a major target for the thyroid hormones T<sub>3</sub> and T<sub>4</sub>. Thyroid hormones play a particularly crucial role in brain maturation during fetal development and first few years of postnatal life{{sfn|Guyton & Hall|2011|p=936}}
* <!--Other-->The thyroid hormones also play a role in maintaining normal sexual function, sleep, and thought patterns. Increased levels are associated with increased speed of thought generation but decreased focus.{{sfn|Guyton & Hall|2011|p=937}} Sexual function, including libido and the maintenance of a normal [[menstrual cycle]], are influenced by thyroid hormones.{{sfn|Guyton & Hall|2011|p=937}}

After secretion, only a very small proportion of the thyroid hormones travel freely in the blood. Most are bound to [[thyroxine-binding globulin]] (about 70%), [[transthyretin]] (10%), and [[serum albumin|albumin]] (15%).{{sfn|Greenspan's|2011|p=169}} Only the 0.03% of T<sub>4</sub> and 0.3% of T<sub>3</sub> traveling freely have hormonal activity.<ref name=bowen>{{cite web| vauthors = Bowen R |title=Thyroid Hormone Receptors|url=http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/thyroid/receptors.html|website=Colorado State University|access-date=22 February 2015|date=2000|archive-url=https://web.archive.org/web/20110927050157/http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/thyroid/receptors.html|archive-date=27 September 2011|url-status=dead}}</ref> In addition, up to 85% of the T<sub>3</sub> in blood is produced following conversion from T<sub>4</sub> by [[iodothyronine deiodinase]]s in organs around the body.{{sfn|Davidson's|2010|p=736}}

Thyroid hormones act by crossing the [[cell membrane]] and binding to [[intracellular receptor|intracellular]] [[nuclear receptor|nuclear]] [[thyroid hormone receptor]]s [[thyroid hormone receptor#Isoforms|TR-α<sub>1</sub>, TR-α<sub>2</sub>, TR-β<sub>1</sub>, and TR-β<sub>2</sub>]], which bind with [[hormone response element]]s and [[transcription factor]]s to modulate [[DNA transcription]].<ref name=bowen />{{sfn|Greenspan's|2011|p=178}} In addition to these actions on DNA, the thyroid hormones also act within the cell membrane or within cytoplasm via reactions with [[enzyme]]s, including [[Plasma membrane Ca2+ ATPase|calcium ATPase]], [[adenylyl cyclase]], and [[glucose transporter]]s.{{sfn|Greenspan's|2011|p=179}}

===Hormone production===
[[File:Thyroid hormone synthesis.png|thumb|upright=2|Synthesis of the [[thyroid hormone]]s, as seen on an individual [[thyroid follicular cell]]:<ref name="Elsevier/Saunders">{{cite book|title=Medical Physiology: A Cellular And Molecular Approaoch|vauthors=Boron WF, Boulpaep E|publisher=Elsevier/Saunders|year=2003|isbn=978-1-4160-2328-9|page=1300|chapter=Chapter 48: "synthesis of thyroid hormones"}}</ref>
<br>- [[Thyroglobulin]] is synthesized in the [[rough endoplasmic reticulum]] and follows the [[secretory pathway]] to enter the colloid in the lumen of the [[thyroid follicle]] by [[exocytosis]].
<br>- Meanwhile, a [[sodium-iodide symporter|sodium-iodide (Na/I) symporter]] pumps iodide (I<sup>−</sup>) [[active transport|actively]] into the cell, which previously has crossed the [[endothelium]] by largely unknown mechanisms. 
<br>- This iodide enters the follicular lumen from the cytoplasm by the transporter [[pendrin]], in a purportedly [[passive transport|passive]] manner.
<br>- In the colloid, iodide (I<sup>−</sup>) is [[Redox|oxidized]] to iodine (I<sup>0</sup>) by an enzyme called [[thyroid peroxidase]].
<br>- Iodine (I<sup>0</sup>) is very reactive and iodinates the thyroglobulin at [[Tyrosine|tyrosyl]] residues in its protein chain (in total containing approximately 120 tyrosyl residues).
<br>- In ''conjugation'', adjacent tyrosyl residues are paired together.
<br>- The entire complex re-enters the follicular cell by [[endocytosis]].
<br>- [[Proteolysis]] by various [[protease]]s liberates [[thyroxine]] and [[triiodothyronine]] molecules, which enters the blood by largely unknown mechanisms.
]]

The thyroid hormones are created from [[thyroglobulin]]. This is a [[protein]] within the colloid in the [[follicular lumen]] that is originally created within the [[rough endoplasmic reticulum]] of follicular cells and then transported into the follicular lumen. Thyroglobulin contains 123 units of [[tyrosine]], which reacts with iodine within the follicular lumen.<ref name="ACBianco">{{cite journal | vauthors = Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR | title = Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases | journal = Endocrine Reviews | volume = 23 | issue = 1 | pages = 38–89 | date = February 2002 | pmid = 11844744 | doi = 10.1210/edrv.23.1.0455 | doi-access = free }}</ref>

[[Iodine]] is essential for the production of the thyroid hormones. Iodine (I<sup>0</sup>) travels in the blood as [[iodide]] (I<sup>−</sup>), which is taken up into the follicular cells by a [[sodium-iodide symporter]]. This is an [[ion channel]] on the cell membrane which in the same action transports two sodium ions and an iodide ion into the cell.<ref name=williams>{{cite book| vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM |title=Williams Textbook of Endocrinology |url= https://archive.org/details/williamstextbook00melm_993 |url-access=limited|date=2011|publisher=Saunders|page=[https://archive.org/details/williamstextbook00melm_993/page/n336 331]|isbn=978-1-4377-0324-5|edition=12th}}</ref> Iodide then travels from within the cell into the lumen, through the action of [[pendrin]], an iodide-chloride [[antiporter]]. In the follicular lumen, the iodide is then [[oxidation|oxidized]] to iodine. This makes it more reactive,<ref name="Elsevier/Saunders"/> and the iodine is attached to the active tyrosine units in thyroglobulin by the enzyme [[thyroid peroxidase]]. This forms the precursors of thyroid hormones [[monoiodotyrosine]] (MIT), and [[diiodotyrosine]] (DIT).<ref name=boron />

When the follicular cells are stimulated by [[thyroid-stimulating hormone]], the follicular cells reabsorb thyroglobulin from the follicular lumen. The iodinated tyrosines are cleaved, forming the thyroid hormones T<sub>4</sub>, T<sub>3</sub>, DIT, MIT, and traces of [[reverse triiodothyronine]]. T<sub>3</sub> and T<sub>4</sub> are released into the blood. The hormones secreted from the gland are about 80–90% T<sub>4</sub> and about 10–20% T<sub>3</sub>.<ref name="endocrine">[http://www.endocrineweb.com/thyfunction.html How Your Thyroid Works: A Delicate Feedback Mechanism]. Updated 2009-05-21.</ref><ref name="percent">[https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.chapter.235 The thyroid gland] in ''Endocrinology: An Integrated Approach'' by Stephen Nussey and Saffron Whitehead (2001) Published by BIOS Scientific Publishers Ltd. {{ISBN|1-85996-252-1}}</ref> [[Deiodinase|Deiodinase enzymes]] in peripheral tissues remove the iodine from MIT and DIT and convert T<sub>4</sub> to T<sub>3</sub> and RT<sub>3.</sub> <ref name="ACBianco" /> This is a major source of both RT<sub>3</sub> (95%) and T<sub>3</sub> (87%) in peripheral tissues.<ref>{{Cite book|title=Ganong's review of medical physiology Edition 25}}</ref>

===Regulation===

The production of thyroxine and triiodothyronine is primarily regulated by thyroid-stimulating hormone (TSH), released by the [[anterior pituitary]] gland. TSH release in turn is stimulated by [[thyrotropin releasing hormone]] (TRH), released in a pulsatile manner from the [[hypothalamus]].{{sfn|Greenspan's|2011|p=174}} The thyroid hormones provide [[negative feedback]] to the [[thyrotrope]]s TSH and TRH: when the thyroid hormones are high, TSH production is suppressed. This negative feedback also occurs when levels of TSH are high, causing TRH production to be suppressed.{{sfn|Greenspan's|2011|p=177}}

TRH is secreted at an increased rate in situations such as cold exposure in order to stimulate [[thermogenesis]].{{sfn|Guyton & Hall|2011|p=896}} In addition to being suppressed by the presence of thyroid hormones, TSH production is blunted by [[dopamine]], [[somatostatin]], and [[glucocorticoid]]s.{{sfn|Harrison's|2011|pp=2215}}

===Calcitonin===
{{Main|Calcitonin}}
The thyroid gland also produces the hormone [[calcitonin]], which helps regulate blood [[calcium metabolism|calcium]] levels. Parafollicular cells produce calcitonin in response to [[hypercalcemia|high blood calcium]]. Calcitonin decreases the release of calcium from bone, by decreasing the activity of [[osteoclast]]s, cells which break down bone. Bone is constantly reabsorbed by osteoclasts and created by [[osteoblast]]s, so calcitonin effectively stimulates movement of calcium into [[bone]]. The effects of calcitonin are opposite those of the [[parathyroid hormone]] (PTH) produced in the parathyroid glands. However, calcitonin seems far less essential than PTH, since calcium metabolism remains clinically normal after removal of the thyroid ([[thyroidectomy]]), but not the [[parathyroid gland]]s.{{sfn|Guyton & Hall|2011|pp=988–9}}