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Adrenocorticotropic hormone (ACTH), also known as corticotropin (INN, BAN) (brand names Acortan, ACTH, Acthar, Acton, Cortigel, Trofocortina),^[1]^[2] is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland.^[3] It 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. Primary adrenal insufficiency, also called Addison's disease, occurs when adrenal gland production of cortisol is chronically deficient, resulting in chronically elevated ACTH levels; when a pituitary tumor is the cause of elevated ACTH (from the anterior pituitary) this is known as Cushing's disease and the constellation of signs and symptoms of the excess cortisol (hypercortisolism) is known as Cushing's syndrome. Conversely, deficiency of ACTH is a cause of secondary adrenal insufficiency, often as a result of hypopituitarism. ACTH is also related to the circadian rhythm in many organisms.^[4]

In addition to its endogenous role, ACTH is used clinically as a diagnostic agent in assessing adrenal function.^[1]^[2]^[3]

Production and regulation

POMC, ACTH and β-lipotropin are secreted from corticotropes in the anterior lobe (or adenohypophysis) of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus.^[5] ACTH is synthesized from pre-pro-opiomelanocortin (pre-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:^[6]

polypeptide fragment	alias	abbreviation	amino acid residues
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 about ten minutes.^[7]

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 hormone (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.

Human ACTH has a molecular weight of 4,540 atomic mass units (Da).^[8]

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.^[9] Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP^[10] 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.^[10] This effect is observed over several hours.^[10]

In addition to steroidogenic enzymes, ACTH also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems.^[11] These actions are probably necessary to supply the enhanced energy needs of adrenocortical cells stimulated by ACTH.^[11]

Reference ranges for blood tests, showing adrenocorticotropic hormone (green at left) among the hormones with smallest concentration in the blood.

ACTH receptors outside of 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. While it has a crucial function in regulating the adrenal, 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.^[12] The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005.^[13] 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.^[14] 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.

Synthetic ACTH

An active synthetic form of ACTH, consisting of the first 24 amino acids of native ACTH, was first synthesized by Klaus Hofmann at the University of Pittsburgh.^[15] ACTH is available as a synthetic derivative in the forms of cosyntropin, tradename Cortrosyn, and Synacthen (synthetic ACTH). Synacthen is not FDA approved but is used in the UK and Australia to conduct the ACTH stimulation test.

ACTH was first synthesized as a replacement for Acthar Gel, a long-lasting animal product used to treat infantile spasms. Once relatively inexpensive, Acthar Gel is currently an extremely expensive pharmaceutical product. Prices per vial have been as high as $36,000.^[16]^[17] Acthar gel has been proposed as a therapy to treat refractory autoimmune diseases^[16] and refractory nephrotic syndrome due to a variety of glomerular diseases.^[18]

Discovery

While working on her dissertation, Evelyn M. Anderson co-discovered ACTH with J. B. Collip and D. L. Thomson and, in a paper published in 1933, explained its function in the body.^{[citation needed]}

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
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]}

References

^ ^a ^b Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 275–. ISBN 978-3-88763-075-1.
^ ^a ^b J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 316–. ISBN 978-1-4757-2085-3.
^ ^a ^b I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 84–. ISBN 978-94-011-4439-1.
^ Dibner C, Schibler U, Albrecht U (2010). "The mammalian circadian timing system: organization and coordination of central and peripheral clocks". Annual Review of Physiology 72: 517–49. doi:10.1146/annurev-physiol-021909-135821. PMID 20148687
^ "Adrenocorticotropic Hormone (ACTH)".
^ "Pro-opiomelocortin precursor". Retrieved 8 April 2013.
^ Yalow RS, Glick SM, Roth J, Berson SA (Nov 1964). "RADIOIMMUNOASSAY OF HUMAN PLASMA ACTH". The Journal of Clinical Endocrinology and Metabolism 24 (11): 1219–25. doi:10.1210/jcem-24-11-1219. PMID 14230021.
^ PROOPIOMELANOCORTIN; NCBI --> POMC Retrieved on September 28, 2009
^ Raikhinstein M, Zohar M, Hanukoglu I (Feb 1994). "cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor". Biochimica Et Biophysica Acta 1220 (3): 329–32. doi:10.1016/0167-4889(94)90157-0. PMID 8305507.
^ ^a ^b ^c Hanukoglu I, Feuchtwanger R, Hanukoglu A (Nov 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells" (PDF). The Journal of Biological Chemistry 265 (33): 20602–8. PMID 2173715.
^ ^a ^b Raikhinstein M, Hanukoglu I (Nov 1993). "Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells". Proceedings of the National Academy of Sciences of the United States of America 90 (22): 10509–13. Bibcode:1993PNAS...9010509R. doi:10.1073/pnas.90.22.10509. PMC 47806. PMID 7504267.
^ Isales CM, Zaidi M, Blair HC (Mar 2010). "ACTH is a novel regulator of bone mass". Annals of the New York Academy of Sciences 1192: 110–6. Bibcode:2010NYASA1192..110I. doi:10.1111/j.1749-6632.2009.05231.x. PMID 20392225.
^ Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, Kang B, Xu J, Bollag RJ, Isales CM (May 2005). "Multiple melanocortin receptors are expressed in bone cells". Bone 36 (5): 820–31. doi:10.1016/j.bone.2005.01.020. PMID 15804492.
^ 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 (May 2010). "ACTH protects against glucocorticoid-induced osteonecrosis of bone". Proceedings of the National Academy of Sciences of the United States of America 107 (19): 8782–7. Bibcode:2010PNAS..107.8782Z. doi:10.1073/pnas.0912176107. PMC 2889316. PMID 20421485.
^ "Simulated ACTH". Time. December 12, 1960.
^ ^a ^b Gettig J, Cummings JP, Matuszewski K (May 2009). "H.p. Acthar gel and cosyntropin review: clinical and financial implications". P & T 34 (5): 250–7. PMC 2697107. PMID 19561871.
^ Pollack A (2012-12-29). "Questcor Finds Profits, at $28,000 a Vial". New York Times.
^ Bomback AS, Tumlin JA, Baranski J, Bourdeau JE, Besarab A, Appel AS, Radhakrishnan J, Appel GB (2011). "Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel". Drug Design, Development and Therapy 5: 147–53. doi:10.2147/DDDT.S17521. PMC 3063118. PMID 21448451.

External links

* Adrenocorticotropic Hormone at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. コルチコトロピン-放出ホルモン（CRH）の生理学 physiology of corticotropin releasing hormone
2. コルチコトロピン-放出ホルモン（CRH）刺激試験 corticotropin releasing hormone stimulation test
3. 特発性膜性腎症の治療における代替剤 alternative agents in the treatment of idiopathic membranous nephropathy
4. 点頭てんかんのマネージメントおよび予後 management and prognosis of infantile spasms
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English Journal

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Matos G, Tenório NM, Bergamaschi CT, Campos RR, Cintra F, Tufik S, Andersen ML.SourceDepartamento de Psicobiologia - Universidade Federal de São Paulo, Brazil.
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Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling.

Li Q, Sullivan NR, McAllister CE, Van de Kar LD, Muma NA.SourceDepartment of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, United States.
Psychoneuroendocrinology.Psychoneuroendocrinology.2013 Jul;38(7):1145-57. doi: 10.1016/j.psyneuen.2012.11.005. Epub 2012 Dec 5.
A major problem with current anti-depressant therapy is that it takes on average 6-7 weeks for remission. Since desensitization of serotonin (5-HT)1A receptor signaling contributes to the anti-depressive response, acceleration of the desensitization may reduce this delay in response to antidepressan
PMID 23219224

Non-invasive evaluation of physiological stress in an iconic Australian marsupial: The Koala (Phascolarctos cinereus).

Narayan EJ, Webster K, Nicolson V, Mucci A, Hero JM.SourceEnvironmental Futures Centre, School of Environment, Griffith University, Gold Coast Campus, QLD 4222, Australia. Electronic address: e.narayan@ga.griffith.edu.au.
General and comparative endocrinology.Gen Comp Endocrinol.2013 Jun 15;187C:39-47. doi: 10.1016/j.ygcen.2013.03.021. Epub 2013 Apr 10.
Koalas (Phascolarctos cinereus) are the only extant representatives of Australia's unique marsupial family Phascolarctidae and were listed as nationally Vulnerable in 2012. Causes of mortality are diverse, although the disease chlamydiosis, dog attacks, collisions with cars, and loss of habitat repr
PMID 23583768

Japanese Journal

Remarkable Adrenocortical Hyperplasia in Adrenocorticotropin-dependent Cushing's Syndrome

Internal Medicine 54(21), 2783-2784, 2015
NAID 130005106607

Type 1 Diabetes Mellitus and Isolated Adrenocorticotropin Deficiency Manifested by Parkinsonism: A Case Report and Literature Review

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Related Pictures

★リンクテーブル★

リンク元	「副腎皮質刺激ホルモン」「adrenocorticotrophic hormone」

「副腎皮質刺激ホルモン」

pro-opiomelanocortin
Identifiers
Symbol	OMC
Entrez	5443
HUGO	9201
OMIM	176830
RefSeq	NM_000939
UniProt	P01189
Other data
Locus	Chr. 2 p23

　　[★]

英: adrenocorticotropic hormone (Z), ACTH
同: コルチコトロピン corticotropin、アドレノコルチコトロピン adrenocorticotropin
関: 副腎皮質ホルモン、ホルモン

分類

下垂体前葉ホルモン

性状

ペプチド

sysmehfrwgkpvgkkrrpvkvypngaedesaeafplef (39 aa)

region_name="ACTH_domain"

/note="Corticotropin ACTH domain; pfam00976"

/db_xref="CDD:144534"

産生組織

ACTH分泌細胞

標的組織

副腎皮質の索状層、網状層

作用

糖質コルチコイドと副腎アンドロジェンの産生を促す
メラニン細胞刺激作用(弱い、約1/30)　　→　アジソン病でATCHが過剰分泌される病態で色素沈着をきたす

(1-13位のアミノ酸はα-MSHに一致し、MSH様作用を併せ持つ

分泌の調整

副腎皮質刺激ホルモン放出ホルモン
ACTHの血中濃度は日内変動する(SP.891)

SP.890

（＋）

CRH、VP　→　細胞内Ca濃度↑　→　開口分泌
カテコラミン、アンジオテンシン　→　開口分泌

（－）

副腎皮質ホルモン　→　下垂体でACTH合成↓

分子機構 HBC 446

ACTHはエステラーゼを活性化して、副腎の細胞質中のコレステロールエステルをコレステロールに変換する。
ACTH依存性のsteroidogenic acute regulatory protein(StAR protein)がステロイドをミトコンドリア内膜にあるP450sccに運ぶのに重要である

臨床関連

ACTH高値

コルチゾール高値

コルチゾール低値

原発性副腎皮質不全
Nelson症候群
先天性副腎過形成

ACTH低値

基準値

4.4-52 pg/ml

「adrenocorticotrophic hormone」

　　[★] 副腎皮質刺激ホルモン

関: ACTH、adrenocorticotropic hormone、adrenocorticotropin、corticotrophin、corticotropin

[IndexNominum2000-1] Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 275–. ISBN 978-3-88763-075-1.

[Elks2014-2] J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 316–. ISBN 978-1-4757-2085-3.

[MortonHall2012-3] I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 84–. ISBN 978-94-011-4439-1.

[4] Dibner C, Schibler U, Albrecht U (2010). "The mammalian circadian timing system: organization and coordination of central and peripheral clocks". Annual Review of Physiology 72: 517–49. doi:10.1146/annurev-physiol-021909-135821. PMID 20148687

[5] "Adrenocorticotropic Hormone (ACTH)".

[6] "Pro-opiomelocortin precursor". Retrieved 8 April 2013.

[pmid14230021-7] Yalow RS, Glick SM, Roth J, Berson SA (Nov 1964). "RADIOIMMUNOASSAY OF HUMAN PLASMA ACTH". The Journal of Clinical Endocrinology and Metabolism 24 (11): 1219–25. doi:10.1210/jcem-24-11-1219. PMID 14230021.

[8] PROOPIOMELANOCORTIN; NCBI --> POMC Retrieved on September 28, 2009

[pmid8305507-9] Raikhinstein M, Zohar M, Hanukoglu I (Feb 1994). "cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor". Biochimica Et Biophysica Acta 1220 (3): 329–32. doi:10.1016/0167-4889(94)90157-0. PMID 8305507.

[pmid2173715-10] Hanukoglu I, Feuchtwanger R, Hanukoglu A (Nov 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells" (PDF). The Journal of Biological Chemistry 265 (33): 20602–8. PMID 2173715.

[pmid7504267-11] Raikhinstein M, Hanukoglu I (Nov 1993). "Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells". Proceedings of the National Academy of Sciences of the United States of America 90 (22): 10509–13. Bibcode:1993PNAS...9010509R. doi:10.1073/pnas.90.22.10509. PMC 47806. PMID 7504267.

[pmid20392225-12] Isales CM, Zaidi M, Blair HC (Mar 2010). "ACTH is a novel regulator of bone mass". Annals of the New York Academy of Sciences 1192: 110–6. Bibcode:2010NYASA1192..110I. doi:10.1111/j.1749-6632.2009.05231.x. PMID 20392225.

[pmid15804492-13] Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, Kang B, Xu J, Bollag RJ, Isales CM (May 2005). "Multiple melanocortin receptors are expressed in bone cells". Bone 36 (5): 820–31. doi:10.1016/j.bone.2005.01.020. PMID 15804492.

[pmid20421485-14] 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 (May 2010). "ACTH protects against glucocorticoid-induced osteonecrosis of bone". Proceedings of the National Academy of Sciences of the United States of America 107 (19): 8782–7. Bibcode:2010PNAS..107.8782Z. doi:10.1073/pnas.0912176107. PMC 2889316. PMID 20421485.

[15] "Simulated ACTH". Time. December 12, 1960.

[pmid19561871-16] Gettig J, Cummings JP, Matuszewski K (May 2009). "H.p. Acthar gel and cosyntropin review: clinical and financial implications". P & T 34 (5): 250–7. PMC 2697107. PMID 19561871.

[urlNY_Times_Advertisement-17] Pollack A (2012-12-29). "Questcor Finds Profits, at $28,000 a Vial". New York Times.

[pmid21448451-18] Bomback AS, Tumlin JA, Baranski J, Bourdeau JE, Besarab A, Appel AS, Radhakrishnan J, Appel GB (2011). "Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel". Drug Design, Development and Therapy 5: 147–53. doi:10.2147/DDDT.S17521. PMC 3063118. PMID 21448451.

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案内

案内

adrenocorticotropin