View source for Hypothalamic–pituitary–thyroid axis

{{short description|Part of the neuroendocrine system}}
[[File:Thyroid system.svg|thumb|200px|right|Short overview of thyroid homeostasis.<ref>References used in overview figure are found in image article in Commons: [[:File:Thyroid system.png#References|References]].</ref>]]
The '''hypothalamic–pituitary–thyroid axis''' ('''HPT axis''' for short, a.k.a. thyroid homeostasis or thyrotropic feedback control) is part of the [[neuroendocrine system]] responsible for the regulation of [[metabolism]] and also responds to stress.
As its name suggests, it depends upon the [[hypothalamus]], the [[pituitary gland]], and the [[thyroid gland]].
The hypothalamus senses low circulating levels of thyroid hormone ([[Triiodothyronine]] (T3) and [[Thyroxine]] (T4)) and responds by releasing thyrotropin-releasing hormone (TRH). The TRH stimulates the anterior pituitary to produce thyroid-stimulating hormone (TSH). The TSH, in turn, stimulates the thyroid to produce thyroid hormone until levels in the blood return to normal. Thyroid hormone exerts negative feedback control over the hypothalamus as well as anterior pituitary, thus controlling the release of both TRH from hypothalamus and TSH from anterior pituitary gland.<ref>{{cite journal |vauthors=Dietrich JW, Landgrafe G, Fotiadou EH|title=TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis|year=2012|journal=Journal of Thyroid Research|volume=2012|pages=1–29|doi=10.1155/2012/351864|pmc=3544290|pmid=23365787|doi-access=free }}</ref>
The [[hypothalamic–pituitary–adrenal axis|HPA]], [[hypothalamic–pituitary–gonadal axis|HPG]], and HPT axes are three pathways in which the hypothalamus and pituitary direct neuroendocrine function.
==Physiology==
[[File:Thyrotropic feedback control.svg|thumb|200px|left|Thyrotropic feedback control on a more detailed and quantitative level.<ref>References used in detailed figure are found in image article in Commons: [[:File:Thyrotropic feedback control.svg#References|References]].</ref>]]
Thyroid homeostasis results from a multi-loop [[Feedback circuit|feedback system]] that is found in virtually all [[higher vertebrates]]. Proper function of thyrotropic feedback control is indispensable for [[Human development (biology)|growth]], [[Cellular differentiation|differentiation]], [[reproduction]] and [[intelligence]]. Very few animals (e.g. [[axolotl]]s and [[sloth]]s) have impaired thyroid homeostasis that exhibits a very low [[Setpoint (control system)|set-point]] that is assumed to underlie the [[Metabolism|metabolic]] and [[ontogenesis|ontogenetic]] anomalies of these animals.
The pituitary gland secretes [[thyrotropin]] (TSH; Thyroid Stimulating Hormone) that stimulates the thyroid to secrete [[thyroxine]] (T4) and, to a lesser degree, [[triiodothyronine]] (T3). The major portion of T3, however, is produced in peripheral organs, e.g. [[liver]], [[adipose tissue]], [[glia]] and [[skeletal muscle]] by deiodination from circulating T4. Deiodination is controlled by numerous [[hormone]]s and [[Nervous system|nerval signals]] including TSH, [[vasopressin]] and [[catecholamines]].
Both peripheral thyroid hormones (iodothyronines) inhibit thyrotropin secretion from the pituitary ([[negative feedback]]). Consequently, equilibrium concentrations for all hormones are attained.
TSH secretion is also controlled by [[thyrotropin releasing hormone]] (thyroliberin, TRH), whose secretion itself is again suppressed by plasma T4 and T3 in [[cerebrospinal fluid|CSF]] (long feedback, Fekete–Lechan loop).<ref name=LechanFekete2004>{{cite journal|last=Lechan|first=Ronald M.|author2=Fekete, C|title=Feedback regulation of thyrotropin-releasing hormone (TRH): mechanisms for the non-thyroidal illness syndrome|journal=[[Journal of Endocrinological Investigation]]|year=2004|volume=27|issue=6 Suppl|pages=105–19|pmid=15481810}}</ref> Additional feedback loops are ultrashort feedback control of TSH secretion (Brokken-Wiersinga-Prummel loop)<ref>{{cite journal|vauthors=Prummel MF, Brokken LJ, Wiersinga WM |doi=10.1089/thy.2004.14.825|pmid=15588378|title=Ultra short-loop feedback control of thyrotropin secretion|year=2004|journal=Thyroid|volume=14|issue=10|pages=825–9}}</ref> and linear feedback loops controlling [[plasma protein]] binding.
Recent research suggested the existence of an additional feedforward motif linking TSH release to deiodinase activity in humans.<ref>{{cite journal|vauthors=Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R |doi=10.1111/cen.12527|pmid=24953754|title=Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment|year=2014|journal=Clinical Endocrinology|volume=81|issue=6|pages=907–15|s2cid=19341039 |doi-access=free}}</ref><ref>{{cite journal|last1=Dietrich|first1=JW|last2=Midgley|first2=JE|last3=Larisch|first3=R|last4=Hoermann|first4=R|title=Of rats and men: thyroid homeostasis in rodents and human beings.|journal=The Lancet Diabetes & Endocrinology|date=December 2015|volume=3|issue=12|pages=932–933|doi=10.1016/S2213-8587(15)00421-0|pmid=26590684|doi-access=free}}<!--|access-date=24 November 2015--></ref><ref>{{cite journal|last1=Hoermann|first1=R|last2=Midgley|first2=JE|last3=Larisch|first3=R|last4=Dietrich|first4=JW|title=Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment.|journal=Frontiers in Endocrinology|date=2015|volume=6|pages=177|doi=10.3389/fendo.2015.00177|pmid=26635726|pmc=4653296|doi-access=free}}<!--|access-date=21 December 2015--></ref> The existence of this TSH-T3 shunt could explain why [[Sum activity of peripheral deiodinases|deiodinase activity]] is higher in hypothyroid patients and why a minor fraction of affected individuals may benefit from substitution therapy with T3.<ref>{{cite journal|vauthors=Hoermann R, Midgley JE, Larisch R, Dietrich JW |doi=10.1055/s-0034-1398616|pmid=25750078|title=Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects|year=2015|journal=Hormone and Metabolic Research|volume=47|issue=9|pages=674–80|s2cid=9824656 |url=https://zenodo.org/record/918309}}</ref>
Convergence of multiple afferent signals in the control of TSH release including but not limited to T3,<ref>{{cite journal|last1=Hoermann|first1=R|last2=Midgley|first2=JEM|last3=Dietrich|first3=JW|last4=Larisch|first4=R|title=Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients.|journal=Therapeutic Advances in Endocrinology and Metabolism|date=June 2017|volume=8|issue=6|pages=83–95|doi=10.1177/2042018817716401|pmid=28794850|pmc=5524252}}</ref> cytokines<ref>{{cite journal|last1=Fliers|first1=E|last2=Kalsbeek|first2=A|last3=Boelen|first3=A|title=Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis.|journal=European Journal of Endocrinology|date=November 2014|volume=171|issue=5|pages=R197–208|doi=10.1530/EJE-14-0285|pmid=25005935|url=https://pure.knaw.nl/ws/files/1060474/Fliers2014EurJEndocrinol.pdf|doi-access=free}}</ref><ref name="Chatzitomaris_2017"/> and TSH receptor antibodies<ref>{{cite journal|vauthors=Brokken LJ, Wiersinga WM, Prummel MF |doi=10.1210/jc.2003-030430|pmid=12970276|title=Thyrotropin receptor autoantibodies are associated with continued thyrotropin suppression in treated euthyroid Graves' disease patients|year=2003|journal=Journal of Clinical Endocrinology & Metabolism|volume=88|issue=9|pages=4135–4138|doi-access=free}}</ref> may be the reason for the observation that the relation between free T4 concentration and TSH levels deviates<ref>{{cite journal|vauthors=Hoermann R, Eckl W, Hoermann C, Larisch R |doi= 10.1530/EJE-10-0106|pmid=20299491|title=Complex relationship between free thyroxine and TSH in the regulation of thyroid function|year=2010|journal=[[European Journal of Endocrinology]]|volume=162|issue=6|pages=1123–9|doi-access=free}}</ref><ref>{{cite journal|vauthors=Clark PM, Holder RL, Haque SM, Hobbs FD, Roberts LM, Franklyn JA |doi= 10.1136/jclinpath-2011-200433|pmid=22287691|title=The relationship between serum TSH and free T4 in older people|year=2012|journal=Journal of Clinical Pathology|volume=65|issue=5|pages=463–5|s2cid= 43886378}}</ref><ref>{{cite journal|vauthors=Hoermann R, Midgley JE, Larisch R, Dietrich JW |doi= 10.1530/EJE-12-0819|pmid=23184912|title=Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?|year=2012|journal=European Journal of Endocrinology|volume=168|issue=2|pages=271–80|doi-access=free}}</ref><ref>{{cite journal|vauthors=Midgley JE, Hoermann R, Larisch R, Dietrich JW |doi=10.1136/jclinpath-2012-201213|pmid=23423518|title=Physiological states and functional relation between thyrotropin and free thyroxine in thyroid health and disease: In vivo and in silico data suggest a hierarchical model|year=2013|journal=Journal of Clinical Pathology|volume=66|issue=4|pages=335–42|s2cid=46291947 }}</ref> from a pure loglinear relation that has previously been proposed.<ref>{{cite journal|vauthors=Reichlin S, Utiger RD |pmid=4163614|year=1967|title=Regulation of the pituitary-thyroid axis in man: Relationship of TSH concentration to concentration of free and total thyroxine in plasma|volume=27|issue=2|pages=251–5|journal=The Journal of Clinical Endocrinology and Metabolism|doi=10.1210/jcem-27-2-251}}</ref> Recent research suggests that ghrelin also plays a role in the stimulation of T4 production and the subsequent suppression of TSH directly and by negative feedback.<ref>{{cite journal|vauthors=Kluge M et al. |year=2010|title=Ghrelin affects the hypothalamus–pituitary–thyroid axis in humans by increasing free thyroxine and decreasing TSH in plasma|volume=162|issue=6|pages=1059–1065|journal=European Journal of Endocrinology|doi=10.1530/EJE-10-0094|pmid=20423986 |s2cid=5237852 |doi-access=free}}</ref>
==Functional states of thyrotropic feedback control==
*[[Euthyroid]]ism: Normal thyroid function
*[[Hypothyroidism]]: Reduced thyroid function
**primary hypothyroidism: Feedback loop interrupted by low thyroid secretory capacity, e.g. after thyroid surgery or in case of [[autoimmune thyroiditis]]
**secondary hypothyroidism: Feedback loop interrupted on the level of pituitary, e.g. in anterior pituitary failure
**tertiary hypothyroidism: Lacking stimulation by TRH, e.g. in hypothalamic failure, [[Pickardt-Fahlbusch-Syndrome|Pickardt–Fahlbusch syndrome]] or [[euthyroid sick syndrome]].
*[[Hyperthyroidism]]: Inappropriately increased thyroid function
**primary hyperthyroidism: Inappropriate secretion of thyroid hormones, e.g. in case of [[Graves' disease]].
**secondary hyperthyroidism: Rare condition, e.g. in case of TSH producing [[pituitary adenoma]] or partial thyroid hormone resistance.
*[[Thyrotoxicosis]]: Over-supply with thyroid hormones, e.g. by overdosed exogenously levothyroxine supplementation.
*[[Low t3 syndrome|Low-T3 syndrome]] and high-T3 syndrome: Consequences of step-up hypodeiodination, e.g. in [[critical illness]] as an example for type 1 [[allostasis]],<ref>{{cite journal|vauthors=Liu S, Ren J, Zhao Y, Han G, Hong Z, Yan D, Chen J, Gu G, Wang G, Wang X, Fan C, Li J |pmid=22874844|year=2013|title=Nonthyroidal illness syndrome: Is it far away from Crohn's disease?|volume=47|issue=2|pages=153–9|doi=10.1097/MCG.0b013e318254ea8a|journal=Journal of Clinical Gastroenterology|s2cid=35344744 }}</ref> or hyperdeiodination, as in type 2 [[allostasis]], including [[posttraumatic stress disorder]].<ref name = "Chatzitomaris_2017">{{cite journal|last1=Chatzitomaris|first1=Apostolos|last2=Hoermann|first2=Rudolf|last3=Midgley|first3=John E.|last4=Hering|first4=Steffen|last5=Urban|first5=Aline|last6=Dietrich|first6=Barbara|last7=Abood|first7=Assjana|last8=Klein|first8=Harald H.|last9=Dietrich|first9=Johannes W.|title=Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming|journal=Frontiers in Endocrinology|date=20 July 2017|volume=8|pages=163|pmid=28775711|pmc=5517413|doi=10.3389/fendo.2017.00163|doi-access=free }}</ref>
*[[Thyroid hormone resistance|Resistance to thyroid hormone]]: Feedback loop interrupted on the level of pituitary thyroid hormone receptors.
==Diagnostics==
Standard procedures cover the determination of [[Blood serum|serum]] levels of the following hormones:
*[[Thyroid-stimulating hormone|TSH]] (thyrotropin, thyroid stimulating hormone)
*[[Free thyroxine|Free T4]]
*Free T3
For special conditions the following [[assay]]s and procedures may be required:
*Total T4
*Total T3
*[[Thyroxine-binding globulin|TBG]]
*[[TRH test]]
*[[Thyroid's secretory capacity|Thyroid's secretory capacity (GT)]]<ref name=dietrich2002>{{Cite book
|publisher = Logos-Verlag Berlin
|isbn = 978-3-89722-850-4
|location = Berlin, Germany
|title = Der Hypophysen-Schilddrüsen-Regelkreis
|author = Dietrich, J. W.
|date = 2002
|oclc = 50451543
|id = 3897228505
|ol = 24586469M
}}</ref>
*[[Sum activity of peripheral deiodinases|Sum activity of peripheral deiodinases (GD)]]<ref name=dietrich2002/>
*[[Thyroid function tests#TSH index|TSH Index (TSHI)]]<ref name=jostel2009>{{cite journal|vauthors=Jostel A, Ryder WD, Shalet SM |pmid=19226261|year=2009|title=The use of thyroid function tests in the diagnosis of hypopituitarism: Definition and evaluation of the TSH Index|volume=71|issue=4|pages=529–34|doi=10.1111/j.1365-2265.2009.03534.x|journal=Clinical Endocrinology|s2cid=10827131 }}</ref>
==See also==
* [[Thyroid function tests]]
* [[Hypothalamic–pituitary–adrenal axis]]
* [[Hypothalamic–pituitary–gonadal axis]]
* [[Hypothalamic–neurohypophyseal system]]
* [[SimThyr]], a free computer simulation for thyroid homeostasis in humans
==References==
{{reflist}}
==Further reading==
* {{cite journal | author = Dietrich J W, Tesche A, Pickardt C R, Mitzdorf U | year = 2004 | title = Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis | journal = [[Cybernetics and Systems]] | volume = 35 | issue = 4| pages = 315–331 | doi = 10.1080/01969720490443354 | s2cid = 13421388 }}
* {{cite journal | author = Gauna C, van den Berghe G H, van der Lely A J | year = 2005 | title = Pituitary Function During Severe and Life-threatening Illnesses | journal = [[Pituitary]] | volume = 8 | issue = 3–4| pages = 213–217 | doi = 10.1007/s11102-006-6043-3 | pmid = 16508715 | s2cid = 22305001 }}
* {{cite book |last1=Dietrich |first1=Johannes W. |last2=Midgley |first2=John E. M. |last3=Hoermann |first3=Rudolf |title=Homeostasis and allostasis of thyroid function |date=2018 |publisher=Frontiers Media SA |location=Lausanne |isbn=9782889455706}}
{{Endocrinology physiology}}
{{DEFAULTSORT:Hypothalamic-Pituitary-Thyroid Axis}}
[[Category:Hormones of the hypothalamus-pituitary-thyroid axis]]
[[Category:Biomedical cybernetics]]
[[Category:Human homeostasis]]
[[Category:Thyroid homeostasis| ]]