Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 196-amino acid preprohormone. CRH is secreted by theparaventricular nucleus (PVN) of thehypothalamus in response tostress. Increased CRH production has been observed to be associated withAlzheimer's disease andmajor depression,[6] and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences includinghypoglycemia.[5]
In addition to the hypothalamus, CRH is produced by neurons in other brain regions, including theneocortex,limbic system andbrainstem.[7] In theolivocerebellar tract, CRH is expressed in neurons that send theiraxons from theinferior olivary complex to thecerebellar cortex.[8] CRH is also synthesized in peripheral tissues, such asT lymphocytes, and it is highly expressed in theplacenta, where it regulates the length ofgestation and the timing ofparturition and delivery. A rapid increase in circulating levels of CRH occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, CRH may act as a trigger for parturition.[5]
In the short term, CRH can suppressappetite, increase subjective feelings ofanxiety, and perform other functions like boostingattention.[10]
During chronic stress conditions such aspost-traumatic stress disorder (PTSD),blood serum levels of CRH are decreased in combat veterans with PTSD compared to healthy individuals.[11] It is believed that chronic stress enhances the negative feedback inhibition of the HPA axis, resulting in lower CRH levels and HPA function.[12][13][14]
Corticotropin-releasing hormone has been shown tointeract with its receptors,corticotropin-releasing hormone receptor 1 (CRFR1) andcorticotropin-releasing hormone receptor 2 (CRFR2), in order to induce its effects.[17][18][19][20] Injection of CRH into the rodent paraventricular nucleus of the hypothalamus (PVN) can increase CRFR1 expression, with increased expression leading to depression-like behaviors.[21] Sex differences have also been observed with respect to both CRH and the receptors that it interacts with. CRFR1 has been shown to exist at higher levels in the female nucleus accumbens, olfactory tubercle, and rostral anteroventral periventricular nucleus (AVPV) when compared to males, while male voles show increased levels of CRFR2 in the bed nucleus of the stria terminalis compared to females.[22]
The CRH-1 receptor antagonistpexacerfont is currently under investigation for the treatment ofgeneralized anxiety disorder.[23] Another CRH-1 antagonistantalarmin has been researched[citation needed] in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out.
Although one action of CRH isimmunosuppression via the action of cortisol, CRH itself can actually heighten the immune system'sinflammation response, a process being investigated inmultiple sclerosis research.[26]
Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences includinghypoglycemia.[5]
Alpha-helical CRH-(9–41) acts as a CRH antagonist.[27]
CRH is synthesized by theplacenta and seems to determine the duration ofpregnancy.[28]
Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:[29]
Increases levels ofdehydroepiandrosterone (DHEA) directly by action on the fetal adrenal gland, and indirectly via the mother's pituitary gland. DHEA has a role in preparing for and stimulating cervical contractions.
Increases prostaglandin availability in uteroplacental tissues. Prostaglandins activate cervical contractions.
Prior to parturition it may have a role inhibiting contractions, through increasing cAMP levels in the myometrium.
In culture, trophoblast CRH is inhibited by progesterone, which remains high throughout pregnancy. Its release is stimulated byglucocorticoids and catecholamines, which increase prior to parturition lifting this progesterone block.[30]
In mammals, studies suggest that CRH has no significantthyrotropic effect. However, in representatives of all non-mammalian vertebrates, it has been found that, in addition to its corticotropic function, CRH has a potent thyrotropic function, acting withTRH to control thehypothalamic–pituitary–thyroid axis (TRH has been found to be less potent than CRH in some species).[33][34]
^abcRaadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJ, Tilders FJ, Swaab DF (September 1995). "Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression".The American Journal of Psychiatry.152 (9):1372–1376.doi:10.1176/ajp.152.9.1372.PMID7653697.
^Powers RE, DeSouza EB, Walker LC, Price DL, Vale WW, Young WS 3rd (1987). "Corticotropin-releasing factor as a transmitter in the human olivocerebellar pathway".Brain Research.415 (2):347–352.doi:10.1016/0006-8993(87)90218-6.PMID2886191.
^Galard R, Catalán R, Castellanos JM, Gallart JM (March 2002). "Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test".Biological Psychiatry.51 (6):463–468.doi:10.1016/s0006-3223(01)01273-2.PMID11922880.S2CID23478346.
^Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, et al. (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin".Neuropharmacology.36 (10):1439–1446.doi:10.1016/S0028-3908(97)00098-1.PMID9423932.S2CID6235036.
^Ramot A, Jiang Z, Tian JB, Nahum T, Kuperman Y, Justice N, et al. (March 2017). "Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress".Nature Neuroscience.20 (3):385–388.doi:10.1038/nn.4491.PMID28135239.S2CID5017743.
^Bale TL, Vale WW (10 February 2004). "CRF and CRF receptors: role in stress responsivity and other behaviors".Annual Review of Pharmacology and Toxicology.44 (1):525–557.doi:10.1146/annurev.pharmtox.44.101802.121410.PMID14744257.
^Santos J, Saunders PR, Hanssen NP, Yang PC, Yates D, Groot JA, et al. (August 1999). "Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat".The American Journal of Physiology.277 (2):G391 –G399.doi:10.1152/ajpgi.1999.277.2.G391.PMID10444454.S2CID4457633.
^Lye S, Challis JR (2001). "Chapter 12: Parturition". In Bocking AD, Harding R (eds.).Fetal growth and development. Cambridge, UK: Cambridge University Press. pp. 241–266.ISBN978-0-521-64543-0.
^Jones SA, Brooks AN, Challis JR (April 1989). "Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta".The Journal of Clinical Endocrinology and Metabolism.68 (4):825–830.doi:10.1210/jcem-68-4-825.PMID2537843.
^Vale W, Spiess J, Rivier C, Rivier J (September 1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin".Science.213 (4514):1394–1397.Bibcode:1981Sci...213.1394V.doi:10.1126/science.6267699.PMID6267699.
^Chrousos GP, Schuermeyer TH, Doppman J, Oldfield EH, Schulte HM, Gold PW, et al. (March 1985). "NIH conference. Clinical applications of corticotropin-releasing factor".Annals of Internal Medicine.102 (3):344–358.doi:10.7326/0003-4819-102-3-344.PMID2982307.
^De Groef B, Van der Geyten S, Darras VM, Kühn ER (March 2006). "Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates".General and Comparative Endocrinology.146 (1):62–68.doi:10.1016/j.ygcen.2005.10.014.PMID16337947.
Florio P, Severi FM, Ciarmela P, Fiore G, Calonaci G, Merola A, et al. (October 2002). "Placental stress factors and maternal-fetal adaptive response: the corticotropin-releasing factor family".Endocrine.19 (1):91–102.doi:10.1385/ENDO:19:1:91.PMID12583606.S2CID39099605.
Florio P, Rossi M, Sigurdardottir M, Ciarmela P, Luisi S, Viganò P, et al. (November 2003). "Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin A".Steroids.68 (10–13):801–807.doi:10.1016/S0039-128X(03)00137-5.PMID14667971.S2CID20953018.
Arbiser JL, Morton CC, Bruns GA, Majzoub JA (1988). "Human corticotropin releasing hormone gene is located on the long arm of chromosome 8".Cytogenetics and Cell Genetics.47 (3):113–116.doi:10.1159/000132525.PMID3259914.
Sasaki A, Tempst P, Liotta AS, Margioris AN, Hood LE, Kent SB, et al. (October 1988). "Isolation and characterization of a corticotropin-releasing hormone-like peptide from human placenta".The Journal of Clinical Endocrinology and Metabolism.67 (4):768–773.doi:10.1210/jcem-67-4-768.PMID3262120.
McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R (May 1995). "A placental clock controlling the length of human pregnancy".Nature Medicine.1 (5):460–463.doi:10.1038/nm0595-460.PMID7585095.S2CID27897688.
Sutton SW, Behan DP, Lahrichi SL, Kaiser R, Corrigan A, Lowry P, et al. (March 1995). "Ligand requirements of the human corticotropin-releasing factor-binding protein".Endocrinology.136 (3):1097–1102.doi:10.1210/endo.136.3.7867564.PMID7867564.
Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW (December 1993). "Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor".Endocrinology.133 (6):3058–3061.doi:10.1210/endo.133.6.8243338.PMID8243338.
Romier C, Bernassau JM, Cambillau C, Darbon H (February 1993). "Solution structure of human corticotropin releasing factor by 1H NMR and distance geometry with restrained molecular dynamics".Protein Engineering.6 (2):149–156.doi:10.1093/protein/6.2.149.PMID8386360.
Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, et al. (June 1998). "Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1".Nature Genetics.19 (2):162–166.doi:10.1038/520.PMID9620773.S2CID20336316.
Perone MJ, Murray CA, Brown OA, Gibson S, White A, Linton EA, et al. (July 1998). "Procorticotrophin-releasing hormone: endoproteolytic processing and differential release of its derived peptides within AtT20 cells".Molecular and Cellular Endocrinology.142 (1–2):191–202.doi:10.1016/S0303-7207(98)00104-X.PMID9783915.S2CID10621100.
Saeed B, Fawcett M, Self C (February 2001). "Corticotropin-releasing hormone binding to the syncytiotrophoblast membranes".European Journal of Clinical Investigation.31 (2):125–130.doi:10.1046/j.1365-2362.2001.00770.x.PMID11168450.S2CID42612842.
1go9: MONITORING THE STRUCTURAL CONSEQUENCES OF PHE12-->D-PHE12 AND LEU15-->AIB15 SUBSTITUTION IN H/R CORTICOTROPIN RELEASING HORMONE: IMPLICATIONS FOR DESIGN OF CRH ANTAGONISTS.
1goe: MONITORING THE STRUCTURAL CONSEQUENCES OF PHE12-->D-PHE12 AND LEU15-->AIB15 SUBSTITUTION IN H/R CORTICOTROPIN RELEASING HORMONE: IMPLICATIONS FOR DESIGN OF CRH ANTAGONISTS.
Media related toCorticotropin releasing hormone at Wikimedia Commons
