Corticotropin-releasing hormone explained

Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene. Its main function is the stimulation of the pituitary synthesis of adrenocorticotropic hormone (ACTH), as part of the hypothalamic–pituitary–adrenal axis (HPA axis).

Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 196-amino acid preprohormone. CRH is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress. Increased CRH production has been observed to be associated with Alzheimer's disease and major depression,^[1] and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.

In addition to being produced in the hypothalamus, CRH is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta, CRH is a marker that determines the length of gestation and the timing of parturition 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.^[2]

A recombinant version for diagnostics is called corticorelin (INN).

Actions and psychopharmacology

CRH is produced in response to stress, predominantly by parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and is released at the median eminence from neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal system. The portal system carries the CRH to the anterior lobe of the pituitary, where it stimulates corticotropes to secrete adrenocorticotropic hormone (ACTH) and other biologically-active substances (β-endorphin). ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids and DHEA.^[3]

In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention.^[4]

During chronic stress conditions such as post-traumatic stress disorder (PTSD), blood serum levels of CRH are decreased in combat veterans with PTSD compared to healthy individuals.^[5] It is believed that chronic stress enhances the negative feedback inhibition of the HPA axis, resulting in lower CRH levels and HPA function.^{[6] [7] [8]}

Abnormally high levels of CRH have been found in people with major depression,^[9] and in the cerebrospinal fluid of people who have committed suicide.^[10]

Corticotropin-releasing hormone has been shown to interact with its receptors, corticotropin-releasing hormone receptor 1 (CRFR1) and corticotropin-releasing hormone receptor 2 (CRFR2), in order to induce its effects.^{[11] [12] [13] [14]} Injection of CRH into the rodent paraventricular nucleus of the hypothalamus (PVN) can increase CRFR1 expression, with increased expression leading to depression-like behaviors.^[15] 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.^[16]

The CRH-1 receptor antagonist pexacerfont is currently under investigation for the treatment of generalized anxiety disorder.^[17] Another CRH-1 antagonist antalarmin has been researched in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out.

The activation of the CRH1 receptor has been linked with the euphoric feelings that accompany alcohol consumption. A CRH1 receptor antagonist developed by Pfizer, CP-154,526 is under investigation for the potential treatment of alcoholism.^{[18] [19]}

Increased CRH production has been observed to be associated with Alzheimer's disease.

Although one action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten the immune system's inflammation response, a process being investigated in multiple sclerosis research.^[20]

Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.

Alpha-helical CRH-(9–41) acts as a CRH antagonist.^[21]

Role in parturition

CRH is synthesized by the placenta and seems to determine the duration of pregnancy.^[22]

Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:^[23]

• Increases levels of dehydroepiandrosterone (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 by glucocorticoids and catecholamines, which increase prior to parturition lifting this progesterone block.^[24]

Structure

The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981.^[25] Its full sequence is:

• SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA

The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids.^[26]

• SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII

Role in non-mammalian vertebrates

In mammals, studies suggest that CRH has no significant thyrotropic 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 with TRH to control the hypothalamic–pituitary–thyroid axis (TRH has been found to be less potent than CRH in some species).^{[27] [28]}

See also

• Corticotropin-releasing hormone receptor
• ACTH
• Glucocorticoids
• Proopiomelanocortin
• Hypothalamic-pituitary-adrenal axis
• Cushing's syndrome
• Addison's disease

Further reading

• Florio P, Severi FM, Ciarmela P, Fiore G, Calonaci G, Merola A, De Felice C, Palumbo M, Petraglia F . Placental stress factors and maternal-fetal adaptive response: the corticotropin-releasing factor family . Endocrine . 19 . 1 . 91–102 . October 2002 . 12583606 . 10.1385/ENDO:19:1:91 . 39099605 .
• Florio P, Rossi M, Sigurdardottir M, Ciarmela P, Luisi S, Viganò P, Grasso D, Fiore G, Cobellis L, Di Blasio AM, Petraglia F . Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin A . Steroids . 68 . 10–13 . 801–807 . November 2003 . 14667971 . 10.1016/S0039-128X(03)00137-5 . 20953018 .
• Vamvakopoulos NC, Karl M, Mayol V, Gomez T, Stratakis CA, Margioris A, Chrousos GP . Structural analysis of the regulatory region of the human corticotropin releasing hormone gene . FEBS Letters . 267 . 1 . 1–5 . July 1990 . 2365075 . 10.1016/0014-5793(90)80272-K . 27597930 . free .
• Robinson BG, D'Angio LA, Pasieka KB, Majzoub JA . Preprocorticotropin releasing hormone: cDNA sequence and in vitro processing . Molecular and Cellular Endocrinology . 61 . 2 . 175–180 . February 1989 . 2783917 . 10.1016/0303-7207(89)90128-7 . 31350703 .
• Arbiser JL, Morton CC, Bruns GA, Majzoub JA . Human corticotropin releasing hormone gene is located on the long arm of chromosome 8 . Cytogenetics and Cell Genetics . 47 . 3 . 113–116 . 1988 . 3259914 . 10.1159/000132525 .
• Sasaki A, Tempst P, Liotta AS, Margioris AN, Hood LE, Kent SB, Sato S, Shinkawa O, Yoshinaga K, Krieger DT . Isolation and characterization of a corticotropin-releasing hormone-like peptide from human placenta . The Journal of Clinical Endocrinology and Metabolism . 67 . 4 . 768–773 . October 1988 . 3262120 . 10.1210/jcem-67-4-768 .
• Shibahara S, Morimoto Y, Furutani Y, Notake M, Takahashi H, Shimizu S, Horikawa S, Numa S . Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene . The EMBO Journal . 2 . 5 . 775–779 . 1984 . 6605851 . 555184 . 10.1002/j.1460-2075.1983.tb01499.x .
• Behan DP, Heinrichs SC, Troncoso JC, Liu XJ, Kawas CH, Ling N, De Souza EB . Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease . Nature . 378 . 6554 . 284–287 . November 1995 . 7477348 . 10.1038/378284a0 . 4305815 . 1995Natur.378..284B .
• Kawahito Y, Sano H, Mukai S, Asai K, Kimura S, Yamamura Y, Kato H, Chrousos GP, Wilder RL, Kondo M . Corticotropin releasing hormone in colonic mucosa in patients with ulcerative colitis . Gut . 37 . 4 . 544–551 . October 1995 . 7489943 . 1382908 . 10.1136/gut.37.4.544 .
• McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R . A placental clock controlling the length of human pregnancy . Nature Medicine . 1 . 5 . 460–463 . May 1995 . 7585095 . 10.1038/nm0595-460 . 27897688 .
• Slominski A, Ermak G, Hwang J, Chakraborty A, Mazurkiewicz JE, Mihm M . Proopiomelanocortin, corticotropin releasing hormone and corticotropin releasing hormone receptor genes are expressed in human skin . FEBS Letters . 374 . 1 . 113–116 . October 1995 . 7589495 . 10.1016/0014-5793(95)01090-2 . 37397132 . free .
• Sutton SW, Behan DP, Lahrichi SL, Kaiser R, Corrigan A, Lowry P, Potter E, Perrin MH, Rivier J, Vale WW . Ligand requirements of the human corticotropin-releasing factor-binding protein . Endocrinology . 136 . 3 . 1097–1102 . March 1995 . 7867564 . 10.1210/endo.136.3.7867564 .
• Vamvakopoulos NC, Chrousos GP . Structural organization of the 5' flanking region of the human corticotropin releasing hormone gene . DNA Sequence . 4 . 3 . 197–206 . 1994 . 8161822 . 10.3109/10425179309015632 .
• Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW . Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor . Endocrinology . 133 . 6 . 3058–3061 . December 1993 . 8243338 . 10.1210/endo.133.6.8243338 .
• Romier C, Bernassau JM, Cambillau C, Darbon H . Solution structure of human corticotropin releasing factor by 1H NMR and distance geometry with restrained molecular dynamics . Protein Engineering . 6 . 2 . 149–156 . February 1993 . 8386360 . 10.1093/protein/6.2.149 .
• Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA . Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach . Molecular Endocrinology . 11 . 7 . 980–985 . June 1997 . 9178757 . 10.1210/mend.11.7.9946 . free .
• Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, Blanquet V, Steckler T, Holsboer F, Wurst W . Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1 . Nature Genetics . 19 . 2 . 162–166 . June 1998 . 9620773 . 10.1038/520 . 20336316 .
• Perone MJ, Murray CA, Brown OA, Gibson S, White A, Linton EA, Perkins AV, Lowenstein PR, Castro MG . Procorticotrophin-releasing hormone: endoproteolytic processing and differential release of its derived peptides within AtT20 cells . Molecular and Cellular Endocrinology . 142 . 1–2 . 191–202 . July 1998 . 9783915 . 10.1016/S0303-7207(98)00104-X . 10621100 .
• Willenberg HS, Bornstein SR, Hiroi N, Päth G, Goretzki PE, Scherbaum WA, Chrousos GP . Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function . Molecular Psychiatry . 5 . 2 . 137–141 . March 2000 . 10822340 . 10.1038/sj.mp.4000720 . free .
• Saeed B, Fawcett M, Self C . Corticotropin-releasing hormone binding to the syncytiotrophoblast membranes . European Journal of Clinical Investigation . 31 . 2 . 125–130 . February 2001 . 11168450 . 10.1046/j.1365-2362.2001.00770.x . 42612842 .

Notes and References

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2. Web site: Entrez Gene: CRH corticotropin releasing hormone.
3. Web site: Corticotrophin-releasing hormone. 5 September 2012. Society for Endocrinology. 9 July 2013. https://web.archive.org/web/20161020174039/http://www.yourhormones.info/hormones/corticotrophinreleasing_hormone.aspx. 20 October 2016. dead.
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5. Ramos-Cejudo J, Genfi A, Abu-Amara D, Debure L, Qian M, Laska E, Siegel C, Milton N, Newman J, Blessing E, Li M, Etkin A, Marmar CR, Fossati S . CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans . Psychiatric Research and Clinical Practice . 3 . 4 . 153–162 . 2021 . 35211666 . 8764614 . 10.1176/appi.prcp.20210017 .
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