thyroid hormones

Thyroid hormones act on nearly every cell in the body. They act to increase the basal metabolic rate, affect protein synthesis, help regulate long bone growth (synergy with growth hormone) and neural maturation, and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness.{{cite book | vauthors = Shahid MA, Ashraf MA, Sharma S | chapter = Physiology, Thyroid Hormone |date=2022 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK500006/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29763182 |access-date=2022-08-18 }} Thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.

Thyroid hormones lead to heat generation in humans. However, the thyronamines function via some unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals and the moulting behaviour of birds. One effect of administering the thyronamines is a severe drop in body temperature.

{{anchor|replacement}}Both T₃ and T₄ are used to treat thyroid hormone deficiency (hypothyroidism). They are both absorbed well by the stomach, so can be given orally. Levothyroxine is the chemical name of the manufactured version of T₄, which is metabolised more slowly than T₃ and hence usually only needs once-daily administration. Natural desiccated thyroid hormones are derived from pig thyroid glands, and are a "natural" hypothyroid treatment containing 20% T₃ and traces of T₂, T₁ and calcitonin.

Also available are synthetic combinations of T₃/T₄ in different ratios (such as liotrix) and pure-T₃ medications (INN: liothyronine).

Levothyroxine Sodium is usually the first course of treatment tried. Some patients feel they do better on desiccated thyroid hormones; however, this is based on anecdotal evidence and clinical trials have not shown any benefit over the biosynthetic forms.{{cite journal | vauthors = Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L | title = Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 7 | pages = 2592–2599 | date = July 2006 | pmid = 16670166 | doi = 10.1210/jc.2006-0448 | doi-access = free }} Thyroid tablets are reported to have different effects, which can be attributed to the difference in torsional angles surrounding the reactive site of the molecule.{{cite journal | vauthors = Schweizer U, Steegborn C | title = Thyroid hormones--From Crystal Packing to Activity to Reactivity | journal = Angewandte Chemie | volume = 54 | issue = 44 | pages = 12856–12858 | date = October 2015 | pmid = 26358899 | doi = 10.1002/anie.201506919 }}

Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia, which causes the brain to enter a protective cycle, useful in preventing damage during ischemic shock.

Synthetic thyroxine was first successfully produced by Charles Robert Harington and George Barger in 1926.

image:Levothyroxine2DCSD.svg

image:Liothyronine2DCSD.svg)]]

Most people are treated with levothyroxine, or a similar synthetic thyroid hormone.Robert Lloyd Segal, MD Endocrinologist{{cite web | url = http://www.medicinenet.com/levothyroxine_sodium/article.htm | title = preferred thyroid hormone --Levothyroxine Sodium (Synthroid, Levoxyl, Levothroid, Unithroid) | work = MedicineNet.com | access-date = 27 March 2009 }}{{cite web | url = http://www.medicinenet.com/hypothyroidism/page5.htm#toc7at | title = Hypothyroidism Causes, Symptoms, Diagnosis, Treatment Information Produced by Medical Doctors | work = MedicineNet.com | access-date = 27 March 2009 }} Different polymorphs of the compound have different solubilities and potencies.{{cite journal | vauthors = Mondal S, Mugesh G | title = Structure Elucidation and Characterization of Different Thyroxine Polymorphs | journal = Angewandte Chemie | volume = 54 | issue = 37 | pages = 10833–10837 | date = September 2015 | pmid = 26213168 | doi = 10.1002/anie.201505281 }} Additionally, natural thyroid hormone supplements from the dried thyroids of animals are still available.{{cite journal | vauthors = Cooper DS | title = Thyroid hormone treatment: new insights into an old therapy | journal = JAMA | volume = 261 | issue = 18 | pages = 2694–2695 | date = May 1989 | pmid = 2709547 | doi = 10.1001/jama.1989.03420180118042 }}{{cite journal |vauthors=Clyde PW, Harari AE, Mohamed Shakir KM |title=Synthetic Thyroxine vs Desiccated Thyroid -Reply (citing Cooper, DS, above) |journal=JAMA: The Journal of the American Medical Association |year=2004 |volume=291 |issue=12 |page=1445 |doi=10.1001/jama.291.12.1445-b }} Levothyroxine contains T₄ only and is therefore largely ineffective for patients unable to convert T₄ to T₃.{{cite journal | vauthors = Wiersinga WM | title = Thyroid hormone replacement therapy | journal = Hormone Research | volume = 56 Suppl 1 | issue = Suppl 1 | pages = 74–81 | year = 2001 | pmid = 11786691 | doi = 10.1159/000048140 | s2cid = 46756918 }} These patients may choose to take natural thyroid hormone, as it contains a mixture of T₄ and T₃,[http://thyroid.about.com/od/thyroiddrugstreatments/a/refusingmeds.htm "Consequences of Not Taking Thyroid Medications - Implications of Failing to Take Prescription Thyroid Drugs"] {{Webarchive|url=https://web.archive.org/web/20090216030136/http://thyroid.about.com/od/thyroiddrugstreatments/a/refusingmeds.htm |date=16 February 2009 }}, Retrieved on 27 March 2009[http://www.armourthyroid.com/ "Armour Thyroid"], Retrieved on 1 April 2009[http://www.nature-throid.com/ "Nature-Throid"], Retrieved on 1 April 2009[http://thyroid.about.com/b/2008/09/10/armour-thyroid-shortages-worsening-what-can-thyroid-patients-do.htm "Armour Thyroid Shortages Worsening: What Can Thyroid Patients Do?"] {{Webarchive|url=https://web.archive.org/web/20090303160034/http://thyroid.about.com/b/2008/09/10/armour-thyroid-shortages-worsening-what-can-thyroid-patients-do.htm |date=3 March 2009 }}, Retrieved on 27 March 2009 or alternatively supplement with a synthetic T₃ treatment.[https://web.archive.org/web/20100628160635/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000685 Liothyronine] In these cases, synthetic liothyronine is preferred due to the potential differences between the natural thyroid products. Some studies show that the mixed therapy is beneficial to all patients, but the addition of lyothyronine contains additional side effects and the medication should be evaluated on an individual basis.{{cite journal | vauthors = Escobar-Morreale HF, Botella-Carretero JI, Morreale de Escobar G | title = Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 29 | issue = 1 | pages = 57–75 | date = January 2015 | pmid = 25617173 | doi = 10.1016/j.beem.2014.10.004 | hdl-access = free | hdl = 10261/124621 }} Some natural thyroid hormone brands are FDA approved, but some are not.[http://www.usdoctor.com/thyroid.htm "Thyroid Information"] {{Webarchive|url=https://web.archive.org/web/20120227144308/http://www.usdoctor.com/thyroid.htm |date=27 February 2012 }}, Retrieved on 27 March 2009{{cite journal | vauthors = Eliason BC, Doenier JA, Nuhlicek DN | title = Desiccated thyroid in a nutritional supplement | journal = The Journal of Family Practice | volume = 38 | issue = 3 | pages = 287–288 | date = March 1994 | pmid = 8126411 }}[http://drugs.emedtv.com/nature-throid/nature-throid.html "Nature-Throid"] {{Webarchive|url=https://web.archive.org/web/20090215200438/http://drugs.emedtv.com/nature-throid/nature-throid.html |date=15 February 2009 }}, Retrieved on 1 April 2009 Thyroid hormones are generally well tolerated. Thyroid hormones are usually not dangerous for pregnant women or nursing mothers, but should be given under a doctor's supervision. In fact, if a woman who is hypothyroid is left untreated, her baby is at a higher risk for birth defects. When pregnant, a woman with a low-functioning thyroid will also need to increase her dosage of thyroid hormone. One exception is that thyroid hormones may aggravate heart conditions, especially in older patients; therefore, doctors may start these patients on a lower dose and work up to a larger one to avoid risk of heart attack.

{{anchor|synthesis}}

File:Thyroid hormone synthesis.png:Chapter 49, "Synthesis of Thyroid Hormones" in: {{cite book |author1=Walter F. Boron |author2=Emile L. Boulpaep |title=Medical Physiology |edition= 2nd|publisher=Elsevier/Saunders |year=2012 |isbn=9781437717532}}{{page needed|date=April 2016}}{{page needed|date=April 2016}}

- 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.

- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide (I⁻) actively into the cell, which previously has crossed the endothelium by largely unknown mechanisms.

- This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin, in a purportedly passive manner.

- In the colloid, iodide (I⁻) is oxidized to iodine (I⁰) by an enzyme called thyroid peroxidase.

- Iodine (I⁰) is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain (in total containing approximately 120 tyrosyl residues).

- In conjugation, adjacent tyrosyl residues are paired together.

- Thyroglobulin re-enters the follicular cell by endocytosis.

- Proteolysis by various proteases liberates thyroxine and triiodothyronine molecules

- Efflux of thyroxine and triiodothyronine from follicular cells, which appears to be largely through monocarboxylate transporter (MCT) 8 and 10, and entry into the blood.

]]

Thyroid hormones (T₄ and T₃) are produced by the follicular cells of the thyroid gland and are regulated by TSH made by the thyrotropes of the anterior pituitary gland. The effects of T₄ in vivo are mediated via T₃ (T₄ is converted to T₃ in target tissues). T₃ is three to five times more active than T₄.

T₄, Thyroxine (3,5,3′,5′-tetraiodothyronine), is produced by follicular cells of the thyroid gland. It is produced from the precursor thyroglobulin (this is not the same as thyroxine-binding globulin (TBG)), which is cleaved by enzymes to produce active T₄.{{cite book | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK28/ | title=Endocrinology: An Integrated Approach | chapter=The thyroid gland | date=28 March 2024 | publisher=BIOS Scientific Publishers }}

The steps in this process are as follows:

1. The Na⁺/I⁻ symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion. This is a secondary active transporter that utilises the concentration gradient of Na⁺ to move I⁻ against its concentration gradient. This is called iodide trapping.{{cite journal | vauthors = Ahad F, Ganie SA | title = Iodine, Iodine metabolism and Iodine deficiency disorders revisited | journal = Indian Journal of Endocrinology and Metabolism | volume = 14 | issue = 1 | pages = 13–17 | date = January 2010 | pmid = 21448409 | pmc = 3063534 }} Sodium is cotransported with iodide from the basolateral side of the membrane into the cell,{{clarify|date=April 2016}} and then concentrated in the thyroid follicles to about thirty times its concentration in the blood.{{cite journal | vauthors = Nilsson M | title = Iodide handling by the thyroid epithelial cell | journal = Experimental and Clinical Endocrinology & Diabetes | volume = 109 | issue = 1 | pages = 13–17 | date = 2001 | pmid = 11573132 | doi = 10.1055/s-2001-11014 | s2cid = 37723663 }}{{cite journal | vauthors = Martín M, Salleron L, Peyret V, Geysels RC, Darrouzet E, Lindenthal S, Bernal Barquero CE, Masini-Repiso AM, Pourcher T, Nicola JP | title = The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane | journal = FASEB Journal | volume = 35 | issue = 8 | pages = e21681 | date = August 2021 | pmid = 34196428 | doi = 10.1096/fj.202100303R | s2cid = 235698589 | doi-access = free }}
2. I⁻ is moved across the apical membrane into the colloid of the follicle by pendrin.
3. Thyroperoxidase (TPO) oxidizes two I⁻ to form I₂. Iodide is non-reactive, and only the more reactive iodine is required for the next step.
4. Iodine is converted into HOI,{{cite journal | vauthors = Kessler J, Obinger C, Eales G | title = Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis | journal = Thyroid | volume = 18 | issue = 7 | pages = 769–74 | date = Jul 2008 | pmid = 18631006 | doi = 10.1089/thy.2007.0310 }} which iodinates the tyrosyl residues of the thyroglobulin within the colloid to form 3-monoiodityrosyl (MIT-yl) and 3,5-diiodityrosyl (DIT-yl) residues – introducting iodine atoms at one or both locations ortho to the hydroxyls of tyrosine.{{cite journal | vauthors = Ahad F, Ganie SA | title = Iodine, Iodine metabolism and Iodine deficiency disorders revisited | journal = Indian Journal of Endocrinology and Metabolism | volume = 14 | issue = 1 | pages = 13–17 | date = January 2010 | pmid = 21448409 | pmc = 3063534 }} The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.
5. TPO also converts tyrosyl, MIT-yl, and DIT-yl residues into their free radical forms. These forms attack other MIT-yl and DIT-yl residues. When a DIT-yl radical attacks a DIT, T₄-yl (peptidic T₄) is formed. When a MIT-yl radical attacks a DIT, T₃-yl is formed. Other reactions are possible, but do not form physiologically active products.{{cite book | vauthors = Rousset B, Dupuy C, Miot F, Dumont J | chapter = Chapter 2 Thyroid Hormone Synthesis And Secretion |date=2000 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK285550/ |title = Endotext | veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G |place=South Dartmouth (MA) |publisher=MDText.com, Inc. |pmid=25905405 |access-date=2022-11-23 }}{{cite journal | vauthors = Li D, Zhang Y, Fan Z, Chen J, Yu J | title = Coupling of chromophores with exactly opposite luminescence behaviours in mesostructured organosilicas for high-efficiency multicolour emission | journal = Chemical Science | volume = 6 | issue = 11 | pages = 6097–6101 | date = November 2015 | pmid = 30090223 | pmc = 6054107 | doi = 10.1039/c5sc02044a }}{{cite journal | vauthors = den Hartog MT, Sijmons CC, Bakker O, Ris-Stalpers C, de Vijlder JJ | title = Importance of the content and localization of tyrosine residues for thyroxine formation within the N-terminal part of human thyroglobulin | journal = European Journal of Endocrinology | volume = 132 | issue = 5 | pages = 611–617 | date = May 1995 | pmid = 7749504 | doi = 10.1530/eje.0.1320611 }}
6. Iodinated Thyroglobulin binds megalin for endocytosis back into cell.
7. Thyroid-stimulating hormone (TSH) released from the anterior pituitary (also known as the adenohypophysis) binds the TSH receptor (a G_s protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.
8. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave any MIT, DIT, T₃, T₄ as well as the inactive analogues from the iodinated thyroglobulin.{{cite journal | vauthors = Darragh AJ, Moughan PJ | title = The effect of hydrolysis time on amino acid analysis | journal = Journal of AOAC International | volume = 88 | issue = 3 | pages = 888–893 | date = 2005 | pmid = 16001867 | doi = 10.1093/jaoac/88.3.888 | doi-access = free }}{{cite journal | vauthors = Jim S, Jones V, Copley MS, Ambrose SH, Evershed RP | title = Effects of hydrolysis on the delta13C values of individual amino acids derived from polypeptides and proteins | journal = Rapid Communications in Mass Spectrometry | volume = 17 | issue = 20 | pages = 2283–2289 | date = 2003 | pmid = 14558127 | doi = 10.1002/rcm.1177 }}
9. The thyroid hormones cross the follicular cell membrane towards the blood vessels by an unknown mechanism. Text books have stated that diffusion is the main means of transport,{{cite book|title=Human Anatomy & Physiology, Sixth Edition|publisher=Benjamin Cummings|date=2 May 2003|isbn=978-0805354621|url-access=registration|url=https://archive.org/details/humananatomyphys0006mari}} but recent studies indicate that monocarboxylate transporter (MCT) 8 and 10 play major roles in the efflux of the thyroid hormones from the thyroid cells.{{cite journal | vauthors = Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ | title = Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10 | journal = Molecular Endocrinology | volume = 22 | issue = 6 | pages = 1357–1369 | date = June 2008 | pmid = 18337592 | pmc = 5419535 | doi = 10.1210/me.2007-0112 }}{{cite journal | vauthors = Brix K, Führer D, Biebermann H | title = Molecules important for thyroid hormone synthesis and action - known facts and future perspectives | journal = Thyroid Research | volume = 4 Suppl 1 | issue = Suppl 1 | pages = S9 | date = August 2011 | pmid = 21835056 | pmc = 3155115 | doi = 10.1186/1756-6614-4-S1-S9 | doi-access = free }}

Thyroglobulin (Tg) is a 660 kDa, dimeric protein produced by the follicular cells of the thyroid and used entirely within the thyroid gland.{{Cite book|title=Diagnostic Immunohistochemistry| vauthors = Dabbs DJ |publisher=Elsevier|year=2019|pages=345–389}} Thyroxine is produced by attaching iodine atoms to the ring structures of this protein's tyrosine residues; thyroxine (T₄) contains four iodine atoms, while triiodothyronine (T₃), otherwise identical to T₄, has one less iodine atom per molecule.{{cite journal | vauthors = Izumi M, Larsen PR | title = Triiodothyronine, thyroxine, and iodine in purified thyroglobulin from patients with Graves' disease | journal = The Journal of Clinical Investigation | volume = 59 | issue = 6 | pages = 1105–1112 | date = June 1977 | pmid = 577211 | pmc = 372323 | doi = 10.1172/JCI108734 }} The thyroglobulin protein accounts for approximately half of the protein content of the thyroid gland.{{cite journal | vauthors = Zhang X, Malik B, Young C, Zhang H, Larkin D, Liao XH, Refetoff S, Liu M, Arvan P | title = Maintaining the thyroid gland in mutant thyroglobulin-induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood | journal = The Journal of Biological Chemistry | volume = 298 | issue = 7 | pages = 102066 | date = July 2022 | pmid = 35618019 | pmc = 9213252 | doi = 10.1016/j.jbc.2022.102066 | doi-access = free }} Each thyroglobulin molecule contains approximately 100–120 tyrosine residues, a small number of which (<20) are subject to iodination catalysed by thyroperoxidase.{{cite book | author = Boron, W.F. | title = Medical Physiology: A Cellular And Molecular Approach | publisher = Elsevier/Saunders | year = 2003 | isbn = 1416023283 }} The same enzyme then catalyses "coupling" of one modified tyrosine with another, via a free-radical-mediated reaction, and when these iodinated bicyclic molecules are released by hydrolysis of the protein, T₃ and T₄ are the result.{{cite journal | vauthors = Marmelstein AM, Lobba MJ, Mogilevsky CS, Maza JC, Brauer DD, Francis MB | title = Tyrosinase-Mediated Oxidative Coupling of Tyrosine Tags on Peptides and Proteins | journal = Journal of the American Chemical Society | volume = 142 | issue = 11 | pages = 5078–5086 | date = March 2020 | pmid = 32093466 | doi = 10.1021/jacs.9b12002 | bibcode = 2020JAChS.142.5078M | url = https://figshare.com/articles/journal_contribution/11942070 }} Therefore, each thyroglobulin protein molecule ultimately yields very small amounts of thyroid hormone (experimentally observed to be on the order of 5–6 molecules of either T₄ or T₃ per original molecule of thyroglobulin).

Hydrolysis (cleavage to individual amino acids) of the modified protein by proteases then liberates T₃ and T₄, as well as the non-coupled tyrosine derivatives MIT and DIT. The hormones T₄ and T₃ are the biologically active agents central to metabolic regulation.{{cite journal | vauthors = Brent GA | title = Mechanisms of thyroid hormone action | journal = The Journal of Clinical Investigation | volume = 122 | issue = 9 | pages = 3035–3043 | date = September 2012 | pmid = 22945636 | pmc = 3433956 | doi = 10.1172/JCI60047 }}

Thyroxine is believed to be a prohormone and a reservoir for the most active and main thyroid hormone T₃.{{cite journal | vauthors = Kansagra SM, McCudden CR, Willis MS |title=The Challenges and Complexities of Thyroid Hormone Replacement|journal=Laboratory Medicine|date=June 2010|volume=41|issue=6|pages=338–348|doi=10.1309/LMB39TH2FZGNDGIM|doi-access=free}} T₄ is converted as required in the tissues by iodothyronine deiodinase.{{cite journal | vauthors = St Germain DL, Galton VA, Hernandez A | title = Minireview: Defining the roles of the iodothyronine deiodinases: current concepts and challenges | journal = Endocrinology | volume = 150 | issue = 3 | pages = 1097–1107 | date = March 2009 | pmid = 19179439 | pmc = 2654746 | doi = 10.1210/en.2008-1588 }} Deficiency of deiodinase can mimic hypothyroidism due to iodine deficiency.{{cite book | veditors = Wass JA, Stewart PM |title=Oxford Textbook of Endocrinology and Diabetes|date=2011|publisher=Oxford University Press|location=Oxford|isbn=978-0-19-923529-2|page=565|edition= 2nd}} T₃ is more active than T₄,{{cite book| veditors = Wass JA, Stewart PM |title=Oxford Textbook of Endocrinology and diabetes|date=2011|publisher=Oxford University Press|location=Oxford|isbn=978-0-19-923529-2|page=18|edition= 2nd}} though it is present in less quantity than T₄.

Thyrotropin-releasing hormone (TRH) is released from hypothalamus by 6 – 8 weeks, and thyroid-stimulating hormone (TSH) secretion from fetal pituitary is evident by 12 weeks of gestation, and fetal production of thyroxine (T₄) reaches a clinically significant level at 18–20 weeks.{{cite book | vauthors = Eugster EA, Pescovitz OH |title=Pediatric endocrinology: mechanisms, manifestations and management |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2004 |pages= 493 (Table 33-3) |isbn=978-0-7817-4059-3 }} Fetal triiodothyronine (T₃) remains low (less than 15 ng/dL) until 30 weeks of gestation, and increases to 50 ng/dL at term. Fetal self-sufficiency of thyroid hormones protects the fetus against e.g. brain development abnormalities caused by maternal hypothyroidism.{{cite journal | vauthors = Zoeller RT | title = Transplacental thyroxine and fetal brain development | journal = The Journal of Clinical Investigation | volume = 111 | issue = 7 | pages = 954–957 | date = April 2003 | pmid = 12671044 | pmc = 152596 | doi = 10.1172/JCI18236 }}

If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormones.{{cite journal | vauthors = Zimmermann MB, Boelaert K | title = Iodine deficiency and thyroid disorders | journal = The Lancet. Diabetes & Endocrinology | volume = 3 | issue = 4 | pages = 286–295 | date = April 2015 | pmid = 25591468 | doi = 10.1016/S2213-8587(14)70225-6 }} The lack of thyroid hormones will lead to decreased negative feedback on the pituitary, leading to increased production of thyroid-stimulating hormone, which causes the thyroid to enlarge (the resulting medical condition is called endemic colloid goitre; see goitre).{{Cite book|title=Henry's clinical diagnosis and management by laboratory methods |isbn=9780323413152|edition= 23rd |location=St. Louis, Mo. | publisher = Elsevier Health Sciences |oclc=949280055| vauthors = McPherson RA, Pincus MR |date = 5 April 2017}} This has the effect of increasing the thyroid's ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone.{{cite journal | vauthors = Bähre M, Hilgers R, Lindemann C, Emrich D | title = Physiological aspects of the thyroid trapping function and its suppression in iodine deficiency using 99mTc pertechnetate | journal = Acta Endocrinologica | volume = 115 | issue = 2 | pages = 175–182 | date = June 1987 | pmid = 3037834 | doi = 10.1530/acta.0.1150175 }}

Most of the thyroid hormone circulating in the blood is bound to transport proteins, and only a very small fraction is unbound and biologically active. Therefore, measuring concentrations of free thyroid hormones is important for diagnosis, while measuring total levels can be misleading.

Thyroid hormone in the blood is usually distributed as follows:{{Citation needed|date=March 2020}}

Despite being lipophilic, T₃ and T₄ cross the cell membrane via carrier-mediated transport, which is ATP-dependent.{{cite journal | vauthors = Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ | title = Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability | journal = Endocrine Reviews | volume = 22 | issue = 4 | pages = 451–476 | date = August 2001 | pmid = 11493579 | doi = 10.1210/edrv.22.4.0435 | hdl-access = free | doi-access = free | hdl = 1765/9707 }}

T₁a and T₀a are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor {{Gene|TAAR1}} (TAR1, TA1), a G-protein-coupled receptor located in the cytoplasm.

Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone (TSH) that is present.

Contrary to common belief, thyroid hormones cannot traverse cell membranes in a passive manner like other lipophilic substances. The iodine in o-position makes the phenolic OH-group more acidic, resulting in a negative charge at physiological pH. However, at least 10 different active, energy-dependent and genetically regulated iodothyronine transporters have been identified in humans. They guarantee that intracellular levels of thyroid hormones are higher than in blood plasma or interstitial fluids.{{cite journal | vauthors = Dietrich JW, Brisseau K, Boehm BO | title = [Absorption, transport and bio-availability of iodothyronines] | journal = Deutsche Medizinische Wochenschrift | volume = 133 | issue = 31–32 | pages = 1644–1648 | date = August 2008 | pmid = 18651367 | doi = 10.1055/s-0028-1082780 }}

Little is known about intracellular kinetics of thyroid hormones. However, recently it could be demonstrated that the crystallin CRYM binds 3,5,3′-triiodothyronine in vivo.{{cite journal | vauthors = Suzuki S, Suzuki N, Mori J, Oshima A, Usami S, Hashizume K | title = micro-Crystallin as an intracellular 3,5,3'-triiodothyronine holder in vivo | journal = Molecular Endocrinology | volume = 21 | issue = 4 | pages = 885–894 | date = April 2007 | pmid = 17264173 | doi = 10.1210/me.2006-0403 | doi-access = free }}

{{Main|Thyroid hormone receptor}}

The thyroid hormones function via a well-studied set of nuclear receptors, termed the thyroid hormone receptors. These receptors, together with corepressor molecules, bind DNA regions called thyroid hormone response elements (TREs) near genes. This receptor-corepressor-DNA complex can block gene transcription. Triiodothyronine (T₃), which is the active form of thyroxine (T₄), goes on to bind to receptors. The deiodinase catalyzed reaction removes an iodine atom from the 5′ position of the outer aromatic ring of thyroxine's (T₄) structure.{{cite journal | vauthors = Mullur R, Liu YY, Brent GA | title = Thyroid hormone regulation of metabolism | journal = Physiological Reviews | volume = 94 | issue = 2 | pages = 355–382 | date = April 2014 | pmid = 24692351 | pmc = 4044302 | doi = 10.1152/physrev.00030.2013 }} When triiodothyronine (T₃) binds a receptor, it induces a conformational change in the receptor, displacing the corepressor from the complex. This leads to recruitment of coactivator proteins and RNA polymerase, activating transcription of the gene.{{cite journal | vauthors = Wu Y, Koenig RJ | title = Gene regulation by thyroid hormone | journal = Trends in Endocrinology and Metabolism | volume = 11 | issue = 6 | pages = 207–211 | date = August 2000 | pmid = 10878749 | doi = 10.1016/s1043-2760(00)00263-0 | s2cid = 44602986 }} Although this general functional model has considerable experimental support, there remain many open questions.{{cite journal | vauthors = Ayers S, Switnicki MP, Angajala A, Lammel J, Arumanayagam AS, Webb P | title = Genome-wide binding patterns of thyroid hormone receptor beta | journal = PLOS ONE | volume = 9 | issue = 2 | pages = e81186 | year = 2014 | pmid = 24558356 | pmc = 3928038 | doi = 10.1371/journal.pone.0081186 | doi-access = free | bibcode = 2014PLoSO...981186A }}

More recently genetic evidence has been obtained for a second mechanism of thyroid hormone action involving one of the same nuclear receptors, TRβ, acting rapidly in the cytoplasm through the PI3K.{{cite journal | vauthors = Martin NP, Marron Fernandez de Velasco E, Mizuno F, Scappini EL, Gloss B, Erxleben C, Williams JG, Stapleton HM, Gentile S, Armstrong DL | title = A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo | journal = Endocrinology | volume = 155 | issue = 9 | pages = 3713–3724 | date = September 2014 | pmid = 24932806 | pmc = 4138568 | doi = 10.1210/en.2013-2058 }}{{cite journal | vauthors = Hönes GS, Rakov H, Logan J, Liao XH, Werbenko E, Pollard AS, Præstholm SM, Siersbæk MS, Rijntjes E, Gassen J, Latteyer S, Engels K, Strucksberg KH, Kleinbongard P, Zwanziger D, Rozman J, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Klein-Hitpass L, Köhrle J, Armstrong DL, Grøntved L, Bassett JH, Williams GR, Refetoff S, Führer D, Moeller LC | title = Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 52 | pages = E11323–E11332 | date = December 2017 | pmid = 29229863 | pmc = 5748168 | doi = 10.1073/pnas.1706801115 | doi-access = free | bibcode = 2017PNAS..11411323H }} This mechanism is conserved in all mammals but not fish or amphibians, and regulates brain development and adult metabolism. The mechanism itself parallels the actions of the nuclear receptor in the nucleus: in the absence of hormone, TRβ binds to PI3K and inhibits its activity, but when hormone binds the complex dissociates, PI3K activity increases, and the hormone bound receptor diffuses into the nucleus.

Thyroxine and iodine stimulate the apoptosis of the cells of the larval gills, tail and fins in amphibian metamorphosis, and stimulate the evolution of their nervous system transforming the aquatic, vegetarian tadpole into the terrestrial, carnivorous frog. In fact, amphibian frog Xenopus laevis serves as an ideal model system for the study of the mechanisms of apoptosis.{{cite journal | vauthors = Jewhurst K, Levin M, McLaughlin KA | title = Optogenetic Control of Apoptosis in Targeted Tissues of Xenopus laevis Embryos | journal = Journal of Cell Death | volume = 7 | pages = 25–31 | year = 2014 | pmid = 25374461 | pmc = 4213186 | doi = 10.4137/JCD.S18368 }}{{Cite journal |author=Venturi, Sebastiano |title=Evolutionary Significance of Iodine |journal=Current Chemical Biology |volume=5 |pages=155–162 |year=2011 |issn=1872-3136 |doi=10.2174/187231311796765012 |issue=3|doi-broken-date=29 January 2025 }}{{Cite journal | vauthors = Venturi S, Venturi M |title=Iodine, PUFAs and Iodolipids in Health and Disease: An Evolutionary Perspective |journal=Human Evolution |volume= 29 |issue= 1–3 |pages=185–205 |year=2014 }}{{cite journal | vauthors = Tamura K, Takayama S, Ishii T, Mawaribuchi S, Takamatsu N, Ito M | title = Apoptosis and differentiation of Xenopus tail-derived myoblasts by thyroid hormone | journal = Journal of Molecular Endocrinology | volume = 54 | issue = 3 | pages = 185–192 | date = June 2015 | pmid = 25791374 | doi = 10.1530/JME-14-0327 | doi-access = free }}

Effects of triiodothyronine (T₃) which is the metabolically active form:

• Increases cardiac output
• Increases heart rate
• Increases ventilation rate
• Increases basal metabolic rate
• Potentiates the effects of catecholamines (i.e. increases sympathetic activity)
• Potentiates brain development
• Thickens endometrium in females
• Increases catabolism of proteins and carbohydrates{{cite journal | vauthors = Gelfand RA, Hutchinson-Williams KA, Bonde AA, Castellino P, Sherwin RS | title = Catabolic effects of thyroid hormone excess: the contribution of adrenergic activity to hypermetabolism and protein breakdown | journal = Metabolism | volume = 36 | issue = 6 | pages = 562–569 | date = June 1987 | pmid = 2884552 | doi = 10.1016/0026-0495(87)90168-5 }}

Further information: Thyroid function tests

Triiodothyronine (T₃) and thyroxine (T₄) can be measured as free T₃ and free T₄, which are indicators of their activities in the body.{{cite journal | vauthors = Stockigt JR | title = Case finding and screening strategies for thyroid dysfunction | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 315 | issue = 1–2 | pages = 111–124 | date = January 2002 | pmid = 11728414 | doi = 10.1016/s0009-8981(01)00715-x }} They can also be measured as total T₃ and total T₄, which depend on the amount that is bound to thyroxine-binding globulin (TBG). A related parameter is the free thyroxine index, which is total T₄ multiplied by thyroid hormone uptake, which, in turn, is a measure of the unbound TBG.[http://www.brooksidepress.org/Products/Military_OBGYN/Lab/ThyroidFunctionTests.htm Military Obstetrics & Gynecology > Thyroid Function Tests] In turn citing: Operational Medicine 2001, Health Care in Military Settings, NAVMED P-5139, 1 May 2001, Bureau of Medicine and Surgery, Department of the Navy, 2300 E Street NW, Washington, D.C., 20372-5300 Additionally, thyroid disorders can be detected prenatally using advanced imaging techniques and testing fetal hormone levels.{{cite journal | vauthors = Polak M, Luton D | title = Fetal thyroïdology | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 28 | issue = 2 | pages = 161–173 | date = March 2014 | pmid = 24629859 | doi = 10.1016/j.beem.2013.04.013 }}

Both excess and deficiency of thyroxine can cause disorders.

• Hyperthyroidism (an example is Graves' disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men. Thyrotoxicosis is often used interchangeably with hyperthyroidism, but there are subtle differences. Although thyrotoxicosis also refers to an increase in circulating thyroid hormones, it can be caused by the intake of thyroxine tablets or by an over-active thyroid, whereas hyperthyroidism refers solely to an over-active thyroid.
• Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a deficiency of thyroxine, triiodothyronine, or both.
• Clinical depression can sometimes be caused by hypothyroidism.{{cite journal | vauthors = Kirkegaard C, Faber J | title = The role of thyroid hormones in depression | journal = European Journal of Endocrinology | volume = 138 | issue = 1 | pages = 1–9 | date = January 1998 | pmid = 9461307 | doi = 10.1530/eje.0.1380001 | doi-access = free }} Some research{{cite journal | vauthors = Dratman MB, Gordon JT | title = Thyroid hormones as neurotransmitters | journal = Thyroid | volume = 6 | issue = 6 | pages = 639–647 | date = December 1996 | pmid = 9001201 | doi = 10.1089/thy.1996.6.639 }} has shown that T₃ is found in the junctions of synapses, and regulates the amounts and activity of serotonin, norepinephrine, and γ-aminobutyric acid (GABA) in the brain.
• Hair loss can sometimes be attributed to a malfunction of T₃ and T₄. Normal hair growth cycle may be affected disrupting the hair growth.
• Both thyroid excess and deficiency can cause cardiovascular disorders or make preexisting conditions worse.{{cite journal | vauthors = Cappola AR, Desai AS, Medici M, Cooper LS, Egan D, Sopko G, Fishman GI, Goldman S, Cooper DS, Mora S, Kudenchuk PJ, Hollenberg AN, McDonald CL, Ladenson PW | title = Thyroid and Cardiovascular Disease: Research Agenda for Enhancing Knowledge, Prevention, and Treatment | journal = Circulation | volume = 139 | issue = 25 | pages = 2892–2909 | date = June 2019 | pmid = 31081673 | pmc = 6851449 | doi = 10.1161/CIRCULATIONAHA.118.036859 | doi-access = free }} The link between excess and deficiency of thyroid hormone on conditions like arrhythmias, heart failure, and atherosclerotic vascular diseases, have been established for nearly 200 years.Parry CH. Elements of Pathology and Therapeutics, Being the Outlines of a Work. Bath, England: R. Cruttwell, 1815.
• Abnormal thyroid function—hypo- and hyperthyroidism—can manifest as myopathy with symptoms of exercise-induced muscle fatigue, cramping, muscle pain and may include proximal weakness or muscle hypertrophy (particularly of the calves).{{Cite web |title=Myopathies associated with thyroid disease |url=https://www.medlink.com/articles/myopathies-associated-with-thyroid-disease |access-date=2023-06-09 |website=MedLink Neurology |language=en}}{{cite journal | vauthors = Rodolico C, Bonanno C, Pugliese A, Nicocia G, Benvenga S, Toscano A | title = Endocrine myopathies: clinical and histopathological features of the major forms | journal = Acta Myologica | volume = 39 | issue = 3 | pages = 130–135 | date = September 2020 | pmid = 33305169 | pmc = 7711326 | doi = 10.36185/2532-1900-017 }} Prolonged hypo- and hyperthyroid myopathy leads to atrophy of type II (fast-twitch/glycolytic) muscle fibres, and a predominance of type I (slow-twitch/oxidative) muscle fibres.{{cite journal | vauthors = Celsing F, Blomstrand E, Melichna J, Terrados N, Clausen N, Lins PE, Jansson E | title = Effect of hyperthyroidism on fibre-type composition, fibre area, glycogen content and enzyme activity in human skeletal muscle | journal = Clinical Physiology | volume = 6 | issue = 2 | pages = 171–181 | date = April 1986 | pmid = 2937605 | doi = 10.1111/j.1475-097x.1986.tb00066.x }}{{cite journal | vauthors = Sharma V, Borah P, Basumatary LJ, Das M, Goswami M, Kayal AK | title = Myopathies of endocrine disorders: A prospective clinical and biochemical study | journal = Annals of Indian Academy of Neurology | volume = 17 | issue = 3 | pages = 298–302 | date = July 2014 | pmid = 25221399 | pmc = 4162016 | doi = 10.4103/0972-2327.138505 | doi-access = free }} Muscle biopsy shows abnormal muscle glycogen: high accumulation in hypothyroidism and low accumulation in hyperthyroidism.{{cite book | vauthors = Fariduddin MM, Bansal N | chapter = Hypothyroid Myopathy |date=2023 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK519513/ | title = StatPearls |access-date=2023-06-09 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30137798 }}{{cite journal | vauthors = Dimitriadis GD, Leighton B, Parry-Billings M, West D, Newsholme EA | title = Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat | journal = The Biochemical Journal | volume = 257 | issue = 2 | pages = 369–373 | date = January 1989 | pmid = 2649073 | pmc = 1135589 | doi = 10.1042/bj2570369 }} Myopathy associated with hypothyroidism includes Kocher-Debre-Semelaigne syndrome (childhood-onset), Hoffman syndrome (adult-onset), myasthenic syndrome, and atrophic form. Myopathy associated with hyperthyroidism includes thyrotoxic myopathy, thyrotoxic periodic paralysis, and Graves' ophthalmopathy. In Graves' ophthalmopathy, the proptosis is secondary to extraocular muscle (EOM) enlargement and gross expansion of orbital fat.{{cite book | vauthors = Chea P, Rutan E, Kousoubris PD, Freitag SK | chapter = 39 - Thyroid-Associated Orbitopathy |date=2019-01-01 | chapter-url=https://www.sciencedirect.com/science/article/pii/B9780323445498000390 |title =Neuroradiology |pages=302–307 | veditors = Small JE, Noujaim DL, Ginat DT, Kelly HR |access-date=2023-06-09 |place=Philadelphia |publisher=Elsevier |language=en |isbn=978-0-323-44549-8 }}

Preterm births can suffer neurodevelopmental disorders due to lack of maternal thyroid hormones, at a time when their own thyroid is unable to meet their postnatal needs.{{cite journal | vauthors = Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM | title = Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity | journal = Cerebral Cortex | volume = 20 | issue = 6 | pages = 1462–1475 | date = June 2010 | pmid = 19812240 | pmc = 2871377 | doi = 10.1093/cercor/bhp212 }} Also in normal pregnancies, adequate levels of maternal thyroid hormone are vital in order to ensure thyroid hormone availability for the foetus and its developing brain.{{cite journal | vauthors = Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T, Tiemeier H, Peeters RP | title = Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study | journal = The Lancet. Diabetes & Endocrinology | volume = 4 | issue = 1 | pages = 35–43 | date = January 2016 | pmid = 26497402 | doi = 10.1016/s2213-8587(15)00327-7 | hdl-access = free | hdl = 1765/79096 }} Congenital hypothyroidism occurs in every 1 in 1600–3400 newborns with most being born asymptomatic and developing related symptoms weeks after birth.{{cite journal | vauthors = Szinnai G | title = Genetics of normal and abnormal thyroid development in humans | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 28 | issue = 2 | pages = 133–150 | date = March 2014 | pmid = 24629857 | doi = 10.1016/j.beem.2013.08.005 }}

Iodine uptake against a concentration gradient is mediated by a sodium–iodine symporter and is linked to a sodium-potassium ATPase. Perchlorate and thiocyanate are drugs that can compete with iodine at this point. Compounds such as goitrin, carbimazole, methimazole, propylthiouracil can reduce thyroid hormone production by interfering with iodine oxidation.{{cite journal | vauthors = Spiegel C, Bestetti GE, Rossi GL, Blum JW | title = Normal circulating triiodothyronine concentrations are maintained despite severe hypothyroidism in growing pigs fed rapeseed presscake meal | journal = The Journal of Nutrition | volume = 123 | issue = 9 | pages = 1554–1561 | date = September 1993 | pmid = 8360780 | doi = 10.1093/jn/123.9.1554 | doi-access = free }}

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