|Locus||Chr. 2 p23|
Adrenocorticotropic hormone (ACTH), also known as corticotropin (INN, BAN) (brand names Acortan, ACTH, Acthar, Acton, Cortigel, Trofocortina), is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland.
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 by the cortex of the adrenal gland. ACTH is also related to the circadian rhythm in many organisms. In addition to its endogenous role, ACTH is used clinically as a diagnostic agent in assessing adrenal function.
Deficiency of ACTH is a sign of secondary adrenal insufficiency (suppressed production of ACTH due to a 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 is the cause of elevated ACTH (from the anterior pituitary) and an excess of cortisol (hypercortisolism) – this constellation of signs and symptoms is known as Cushing's syndrome.
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. 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:
|polypeptide fragment||alias||abbreviation||amino acid residues|
|melanotropin alpha||melanocyte-stimulating hormone||α-MSH||138–150|
|corticotropin-like intermediate peptide||CLIP||156–176|
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.
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.
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. Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP 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. This effect is observed over several hours.
In addition to steroidogenic enzymes, ACTH also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems. These actions are probably necessary to supply the enhanced energy needs of adrenocortical cells stimulated by ACTH.
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. The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005. 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. 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.
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. 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, the gel became an extremely expensive pharmaceutical product after the acquisition of Questcor by Mallinckrodt Pharmaceuticals. Prices per vial have been as high as US$36,000. Acthar gel has been proposed as a therapy to treat refractory autoimmune diseases and refractory nephrotic syndrome due to a variety of glomerular diseases.
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.
- 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.
- Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 275–. ISBN 978-3-88763-075-1.
- 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.
- 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.
- 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.
- 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 . 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 . PMID 20421485.
- "Simulated ACTH". Time. December 12, 1960.
- "Pharma corp. hikes infant epilepsy drug price by 2,000%, from $33.05 per vial to $680 per vial". Retrieved 16 November 2015.
- Gettig J, Cummings JP, Matuszewski K (May 2009). "H.P. Acthar gel and cosyntropin review: clinical and financial implications". Pharmacy and Theraputics. 34 (5): 250–7. PMC . 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 . PMID 21448451.
- Johstone, Rose (2003). "A Sixty-Year Evolution of Biochemistry at McGill University" (PDF). Scientia Canadensis. 27: 27–83. doi:10.7202/800458ar.
- James B. Collip, Evelyn Anderson, D. L. Thomson (12 August 1933). "The adrenotropic hormone of the anterior pituitary lobe". Lancet. 222 (5737): 347–348. doi:10.1016/S0140-6736(00)44463-6.