Adrenocorticotropic hormone

{{Short description|Pituitary hormone}} {{About|adrenocorticotropic hormone as a natural hormone|adrenocorticotropic hormone as a medication and diagnostic agent|Adrenocorticotropic hormone (medication)}} {{Use mdy dates|date=August 2017}} {{Infobox protein | Name = pro-opiomelanocortin | caption = | image = Pro-opiomelanocortin.png | width = 200px | HGNCid = 9201 | Symbol = POMC | AltSymbols = | EntrezGene = 5443 | OMIM = 176830 | RefSeq = NM_000939 | UniProt = P01189 | PDB = | ECnumber = | Chromosome = 2 | Arm = p | Band = 23 | LocusSupplementaryData = }} {{POMC}}

'''Adrenocorticotropic hormone''' ('''ACTH''';<ref>{{Cite encyclopedia |title=ACTH |encyclopedia=Henderson's Dictionary of Biological Terms |last=Lawrence |first=Eleanor |edition=10th |page=1 |isbn=0-470-21446-5}}</ref> also '''adrenocorticotropin''', '''corticotropin''') is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland.<ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA84|date=December 6, 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=84–}}</ref> It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with its precursor corticotropin-releasing hormone from the hypothalamus). Its principal effects are increased production and release of cortisol and androgens by the zona fasciculata and zona reticularis, respectively. ACTH is also related to the circadian rhythm in many organisms.<ref>{{cite journal | vauthors = Dibner C, Schibler U, Albrecht U | title = The mammalian circadian timing system: organization and coordination of central and peripheral clocks | journal = Annual Review of Physiology | volume = 72 | pages = 517–49 | year = 2010 | pmid = 20148687 | doi = 10.1146/annurev-physiol-021909-135821 | url = http://doc.rero.ch/record/17505/files/alb_mct.pdf | access-date = June 28, 2019 | archive-date = April 4, 2023 | archive-url = https://web.archive.org/web/20230404071830/https://doc.rero.ch/record/17505/files/alb_mct.pdf | url-status = live }}</ref>

Deficiency of ACTH is an indicator of secondary adrenal insufficiency (suppressed production of ACTH due to an impairment of the pituitary gland or hypothalamus, cf. hypopituitarism) or tertiary adrenal insufficiency (disease of the hypothalamus, with a decrease in the release of corticotropin releasing hormone (CRH)). Conversely, chronically elevated ACTH levels occur in primary adrenal insufficiency (e.g. Addison's disease) when adrenal gland production of cortisol is chronically deficient. In Cushing's disease, a pituitary tumor leads to excessive production of ACTH, which stimulates the adrenal cortex to produce high levels of cortisol.

== Production and regulation == POMC, ACTH and β-lipotropin are secreted from corticotropic cells in the anterior lobe (or adenohypophysis) of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus.<ref>{{cite web|title=Adrenocorticotropic Hormone (ACTH)|url=http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/acth.html|website=vivo.colostate.edu|url-status=dead|access-date=October 15, 2008|archive-date=May 22, 2023|archive-url=https://web.archive.org/web/20230522170645/http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/acth.html}}</ref> The pre-pro-opiomelanocortin (Pre-POMC) is the precursor of POMC, its cleavage forms POMC.<ref>{{Cite journal |last=Chen |first=Xuanyu |date=11 February 2024 |title=An analysis of POMC gene methylation and expression in patients with schizophrenia |journal=International Journal of Developmental Neuroscience |volume=84 |issue=3 |publisher=Wiley |pages=208–216 |doi=10.1002/jdn.10319 |pmid=38343101 |doi-access=free}}</ref> ACTH, on the other hand, is produced from the cleavage of POMC. The removal of the signal peptide during translation produces the 241-amino acid polypeptide POMC, which undergoes a series of post-translational modifications such as phosphorylation and glycosylation before it is proteolytically cleaved by endopeptidases to yield various polypeptide fragments with varying physiological activity. These fragments include:<ref>{{cite web|title=Pro-opiomelocortin precursor|url=https://www.uniprot.org/uniprot/P01189|access-date=April 8, 2013|website=UniProt|archive-date=July 16, 2024|archive-url=https://web.archive.org/web/20240716004206/https://www.uniprot.org/uniprot/P01189|url-status=live}}</ref> {| class="wikitable" |- ! polypeptide fragment !! alias !! abbreviation !! amino acid residues |- | NPP || |NPP | 27–102 |- | melanotropin gamma || || γ-MSH || 77–87 |- | potential peptide || || || 105–134 |- | corticotropin || adrenocorticotropic hormone || ACTH || 138–176 |- | melanotropin alpha || melanocyte-stimulating hormone || α-MSH || 138–150 |- | corticotropin-like intermediate peptide || || CLIP || 156–176 |- | lipotropin beta || || β-LPH || 179–267 |- | lipotropin gamma || || γ-LPH || 179–234 |- | melanotropin beta || || β-MSH || 217–234 |- | beta-endorphin || || || 237–267 |- | met-enkephalin || || || 237–241 |}

In order to regulate the secretion of ACTH, many substances secreted within this axis exhibit slow/intermediate and fast feedback-loop activity. Glucocorticoids secreted from the adrenal cortex work to inhibit CRH secretion by the hypothalamus, which in turn decreases anterior pituitary secretion of ACTH. Glucocorticoids may also inhibit the rates of POMC gene transcription and peptide synthesis. The latter is an example of a slow feedback loop, which works on the order of hours to days, whereas the former works on the order of minutes.

The half-life of ACTH in human blood is reported to be between ten and 30 minutes.<ref name="pmid14230021">{{cite journal | vauthors = Yalow RS, Glick SM, Roth J, Berson SA | title = Radioimmunoassay of human plasma ACTH | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 24 | issue = 11 | pages = 1219–25 | date = November 1964 | pmid = 14230021 | doi = 10.1210/jcem-24-11-1219 }}</ref><ref>{{cite book | vauthors = Patel K | title = Stability and Characterization of Protein and Peptide Drugs | chapter = Stability of Adrenocorticotropic Hormone (ACTH) and Pathways of Deamidation of Asparaginyl Residue in Hexapeptide Segments | series = Pharmaceutical Biotechnology | volume = 5 | pages = 201–20 | date = 1993 | pmid = 8019694 | doi = 10.1007/978-1-4899-1236-7_6 | isbn = 978-1-4899-1238-1 }}</ref><ref>{{cite journal | vauthors = Veldhuis JD, Iranmanesh A, Naftolowitz D, Tatham N, Cassidy F, Carroll BJ | title = Corticotropin secretory dynamics in humans under low glucocorticoid feedback | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 11 | pages = 5554–63 | date = November 2001 | pmid = 11701735 | doi = 10.1210/jcem.86.11.8046 | doi-access = free }}</ref>

== Structure == ACTH consists of 39 amino acids, the first 13 of which (counting from the N-terminus) may be cleaved to form α-melanocyte-stimulating hormones (α-MSH) (this common structure is responsible for excessively tanned skin in Addison's disease). After a short period of time, ACTH is cleaved into α-melanocyte-stimulating hormone (α-MSH) and CLIP, a peptide with unknown activity in humans.

In the human body, total weight ACTH is {{val|4540|ul=Da}}.<ref>[https://www.uniprot.org/uniprot/P01189 PROOPIOMELANOCORTIN; NCBI → POMC] {{Webarchive|url=https://web.archive.org/web/20240716004206/https://www.uniprot.org/uniprot/P01189 |date=July 16, 2024 }} Retrieved on September 28, 2009</ref>

== Function == ACTH stimulates secretion of glucocorticoid steroid hormones from adrenal cortex cells, especially in the zona fasciculata of the adrenal glands. ACTH acts by binding to cell surface ACTH receptors, which are located primarily on adrenocortical cells of the adrenal cortex. The ACTH receptor is a seven-membrane-spanning G protein-coupled receptor.<ref name="pmid8305507">{{cite journal | vauthors = Raikhinstein M, Zohar M, Hanukoglu I | title = cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1220 | issue = 3 | pages = 329–32 | date = February 1994 | pmid = 8305507 | doi = 10.1016/0167-4889(94)90157-0 | url = https://zenodo.org/record/890717 | access-date = June 28, 2019 | archive-date = September 13, 2017 | archive-url = https://web.archive.org/web/20170913183307/https://zenodo.org/record/890717 | url-status = live }}</ref> Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP<ref name="pmid2173715">{{cite journal | vauthors = Hanukoglu I, Feuchtwanger R, Hanukoglu A | title = Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells | journal = The Journal of Biological Chemistry | volume = 265 | issue = 33 | pages = 20602–8 | date = November 1990 | pmid = 2173715 | doi = 10.1016/S0021-9258(17)30545-8 | url = http://www.jbc.org/content/265/33/20602.full.pdf | doi-access = free | access-date = July 24, 2012 | archive-date = September 16, 2012 | archive-url = https://web.archive.org/web/20120916170728/http://www.jbc.org/content/265/33/20602.full.pdf | url-status = live }}</ref> and subsequent activation of protein kinase A.

ACTH influences steroid hormone secretion by both rapid short-term mechanisms that take place within minutes and slower long-term actions. The rapid actions of ACTH include stimulation of cholesterol delivery to the mitochondria where the P450scc enzyme is located. P450scc catalyzes the first step of steroidogenesis that is cleavage of the side-chain of cholesterol. ACTH also stimulates lipoprotein uptake into cortical cells. This increases the bioavailability of cholesterol in the cells of the adrenal cortex.

The long term actions of ACTH include stimulation of the transcription of the genes coding for steroidogenic enzymes, especially P450scc, steroid 11β-hydroxylase, and their associated electron transfer proteins.<ref name="pmid2173715" /> This effect is observed over several hours.<ref name="pmid2173715" />

In addition to steroidogenic enzymes, ACTH also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems.<ref name="pmid7504267">{{cite journal | vauthors = Raikhinstein M, Hanukoglu I | title = Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 22 | pages = 10509–13 | date = November 1993 | pmid = 7504267 | pmc = 47806 | doi = 10.1073/pnas.90.22.10509 | bibcode = 1993PNAS...9010509R | doi-access = free }}</ref> These actions are probably necessary to supply the enhanced energy needs of adrenocortical cells stimulated by ACTH.<ref name="pmid7504267" />

[[File:Blood values sorted by mass and molar concentration.png|thumb|center|800px|Reference ranges for blood tests, showing adrenocorticotropic hormone (green at left) among the hormones with smallest concentration in the blood]]

==ACTH receptors outside the adrenal gland== As indicated above, ACTH is a cleavage product of the pro-hormone, proopiomelanocortin (POMC), which also produces other hormones including α-MSH that stimulates the production of melanin. A family of related receptors mediates the actions of these hormones, the MCR, or melanocortin receptor family. These are mainly not associated with the pituitary-adrenal axis. MC2R is the ACTH receptor.<ref name="pmid15383650">{{cite journal | vauthors=Slominski A, Tobin DJ, Shibahara S, Wortsman J | title=Melanin pigmentation in mammalian skin and its hormonal regulation | journal= Physiological Reviews | volume=84 | issue=4 | pages=1155–1228 | year=2004 | doi= 10.1152/physrev.00044.2003 | pmid = 15383650}}</ref>

While it has a crucial function in regulating the adrenal glands, it is also expressed elsewhere in the body, specifically in the osteoblast, which is responsible for making new bone, a continual and highly regulated process in the bodies of air-breathing vertebrates.<ref name="pmid20392225">{{cite journal | vauthors = Isales CM, Zaidi M, Blair HC | title = ACTH is a novel regulator of bone mass | journal = Annals of the New York Academy of Sciences | volume = 1192 | issue = 1 | pages = 110–6 | date = March 2010 | pmid = 20392225 | doi = 10.1111/j.1749-6632.2009.05231.x | s2cid = 24378203 | bibcode = 2010NYASA1192..110I }}</ref> The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005.<ref name="pmid15804492">{{cite journal | vauthors = Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, Kang B, Xu J, Bollag RJ, Isales CM | display-authors = 6 | title = Multiple melanocortin receptors are expressed in bone cells | journal = Bone | volume = 36 | issue = 5 | pages = 820–31 | date = May 2005 | pmid = 15804492 | doi = 10.1016/j.bone.2005.01.020 }}</ref> Since that time, it has been demonstrated that the response of bone forming cells to ACTH includes production of VEGF, as it does in the adrenal. This response might be important in maintaining osteoblast survival under some conditions.<ref name="pmid20421485">{{cite journal | vauthors = Zaidi M, Sun L, Robinson LJ, Tourkova IL, Liu L, Wang Y, Zhu LL, Liu X, Li J, Peng Y, Yang G, Shi X, Levine A, Iqbal J, Yaroslavskiy BB, Isales C, Blair HC | display-authors = 6 | title = ACTH protects against glucocorticoid-induced osteonecrosis of bone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 19 | pages = 8782–7 | date = May 2010 | pmid = 20421485 | pmc = 2889316 | doi = 10.1073/pnas.0912176107 | bibcode = 2010PNAS..107.8782Z | doi-access = free }}</ref> If this is physiologically important, it probably functions in conditions with short-period or intermittent ACTH signaling, since with continual exposure of osteoblasts to ACTH, the effect was lost in a few hours.

== History == While working on her dissertation, Evelyn M. Anderson co-discovered ACTH with James Bertram Collip and David Landsborough Thomson and, in a paper published in 1933, explained its function in the body.<ref>{{cite journal | vauthors = Johnstone R | title = A sixty-year evolution of biochemistry at McGill University | journal = Scientia Canadensis | volume = 27 | pages = 27–84 | date = 2003 | pmid = 16116702 | doi = 10.7202/800458ar | url = http://www.erudit.org/revue/scientia/2003/v27/n/800458ar.pdf | doi-access = free | access-date = November 16, 2015 | archive-date = November 17, 2015 | archive-url = https://web.archive.org/web/20151117025730/http://www.erudit.org/revue/scientia/2003/v27/n/800458ar.pdf | url-status = live }}</ref><ref>{{cite journal | vauthors = Collip JB, Anderson E, Thomson DL |title=The adrenotropic hormone of the anterior pituitary lobe |journal=Lancet |volume=222 |issue=5737 |date=August 12, 1933 |pages=347–348 |doi=10.1016/S0140-6736(00)44463-6 }}</ref>

An active synthetic form of ACTH, consisting of the first 23 amino acids of native ACTH, was first made by Klaus Hofmann at the University of Pittsburgh.<ref>{{cite magazine |title=Simulated ACTH |magazine=Time|date=December 12, 1960 |url=http://www.time.com/time/magazine/article/0,9171,871916,00.html|archive-url=https://web.archive.org/web/20090906013356/http://www.time.com/time/magazine/article/0,9171,871916,00.html|url-status=dead|archive-date=September 6, 2009}}</ref>

== Associated conditions == * Diseases of the pituitary, the gland that produces, among others, the hormone ACTH * Hypopituitarism, the hyposecretion of ACTH in the pituitary, leading to secondary adrenal insufficiency (a form of hypocorticism) * Addison's disease, the primary adrenal insufficiency (another form of hypocorticism) * Cushing's syndrome, hypercorticism, one of the causes is hypersecretion of ACTH * Small cell carcinoma, a common cause of ACTH secreted ectopically * Congenital adrenal hyperplasia, diseases in the production of cortisol * Nelson's syndrome, the rapid enlargement of the ACTH producing pituitary after the removal of both adrenal glands * Adrenoleukodystrophy, can be accompanied by adrenal insufficiency * West syndrome ("infantile spasms"), a disease where ACTH is used as a therapy * Postorgasmic illness syndrome (POIS), through production of tyrosine hydroxylase and dopamine β-hydroxylase, which two enzymes comprise the biochemical mechanism by which norepinephrine and epinephrine are produced.{{Citation needed|date=August 2015}} * Critical illness-related corticosteroid insufficiency * DAVID syndrome, a genetic disorder that is characterized by adrenocorticotropic hormone deficiency combined with common variable immunodeficiency and hypogammaglobulinemia.

== See also ==

* Semax, a synthetic analogue fragment of adrenocorticotropic hormone

== References == {{reflist}}

== External links == * {{MeshName|Adrenocorticotropic+Hormone}}

{{Hormones}} {{Neuropeptides}} {{Orexigenics}} {{Melanocortin receptor modulators}} {{Authority control}}

{{DEFAULTSORT:Adrenocorticotropic Hormone}} Category:Anterior pituitary hormones Category:Peptide hormones Category:Melanocortin receptor agonists Category:World Anti-Doping Agency prohibited substances