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Gene Review

CRH  -  corticotropin releasing hormone

Homo sapiens

Synonyms: CRF, CRH1, Corticoliberin, Corticotropin-releasing factor, Corticotropin-releasing hormone
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Disease relevance of CRH


Psychiatry related information on CRH

  • In the neurodegenerative disorder Alzheimer's disease (AD), levels of CRH are decreased [5].
  • CRH and BEND were markedly decreased in both AD and VAD patients, and BEND levels correlated negatively with degree of dementia within the patient population [6].
  • Preclinical data indicate that corticotropin-releasing hormone (CRH) has anxiogenic properties and a dysregulation in CRH systems has been suggested to play a role in a variety of stress-related psychiatric disorders, such as anxiety, depression, and eating disorders [7].
  • CRH may be involved in experimentally-occurring and perhaps in naturally-occurring panic attacks as well [8].
  • Moreover, acute psychological stress induces CRH-dependent mast cell degranulation [9].

High impact information on CRH


Chemical compound and disease context of CRH


Biological context of CRH

  • The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis [12].
  • AVP or angiotensin II (A-II), or their activated second messengers, also increase percentages of cells that bind CRH and store ACTH [20].
  • Using RT-PCR, mRNA expression of receptors for LIF, IL-6, and CRH, and the gp130 subunit, were all detected in fetal pituitaries of 18- and 31-wk gestation [21].
  • We wished to determine whether this immunoreactive substance is a product of CRH gene expression in the placenta [22].
  • The transfected rat POMC promoter -706/+64, fused to the luciferase reporter gene, was induced by LIF, which exerted strong (18-fold) synergy with CRH [23].

Anatomical context of CRH


Associations of CRH with chemical compounds

  • Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress [27].
  • Inhibition of ACTH secretion by ion channel blockers or corticosterone has potent inhibitory effects on percentages of CRH-bound cells [20].
  • Cold stress for 30 min also stimulates an increase in the percentage of immunoreactive corticotropes and cells that bind CRH or arginine vasopressin (AVP) [20].
  • The size of POMC mRNA did not change through the culture or after incubation with CRH or dexamethasone [1].
  • Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback [3].
  • Alanine substitutions of arginine 56 (R56A) and aspartic acid 62 (D62A) reduce the affinity for CRF by approximately 100-fold, while only marginally affecting the affinity for Ucn 1 [28].

Physical interactions of CRH

  • Previous studies using chimeric receptors between human CRFR1 and CRFR2 have identified three potentially important regions in the second and third extracellular domains of CRF receptor for the binding of rat/human CRF [29].
  • Urocortin has been found to bind with high affinity to CRF receptors [30].
  • CRF-BP binds human/rat CRF and urotensin-I with high affinity, sauvagine with moderate affinity, and ovine (o) CRF with low affinity [31].
  • Nuclear extracts were analyzed by electrophoretic mobility shift assay to determine NURR1 binding to the CRH promoter/enhancer [32].
  • Similarly, CRH pretreatment increased the percentage of corticotropes that bound AVP [33].

Enzymatic interactions of CRH

  • Plasma leptin levels were not affected by CRH infusion in either the controls or the patients despite clear-cut elevations in plasma ACTH and cortisol [34].
  • We hypothesize that GRK3 upregulation may be a cellular negative feedback process directed at maximizing CRF(1) receptor desensitization by heightening GRK3 phosphorylating capacity during prolonged exposure to high CRF [35].

Regulatory relationships of CRH

  • CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536 [24].
  • CRF-induced increments in ACTH and cortisol were much less, but the time course was similar and peak levels attained were still higher than those in normal subjects [36].
  • CRF and the non-mammalian-related peptide sauvagine bind to and activate CRF1 receptors with high affinity and equal potency [37].
  • The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated by brain-derived neurotrophic factor is enhanced by corticotropin releasing factor through the activation of a cAMP-dependent signaling pathway [38].
  • We have studied the involvement of intracellular calcium and calcium-dependent signaling in the NPY-induced CRF release in trophoblastic cells [39].

Other interactions of CRH


Analytical, diagnostic and therapeutic context of CRH

  • Furthermore the expression of CRH receptors was analyzed for the first time in pituitaries of suicide victims by in situ hybridization and quantitative PCR [44].
  • CRH (10-8 M) led to a moderate increase of cortisol release (145.7 +/- 20.0%) from cortical and chromaffin adrenal cells in co-culture [45].
  • We here describe the measurement of CRH-BP directly in plasma during human pregnancy using a radioimmunoassay that is not affected by the presence of the high plasma levels of CRH that occur at this time [46].
  • Purification by high performance liquid chromatography (HPLC) of stromal cell culture medium revealed a major peak of CRH immunoreactivity coeluting with the standard CRH(1-41), thus indicating the secretion of the mature peptide [47].
  • Using Northern blot analysis, we detected messenger RNA transcripts (2.7 kb) encoding the type-1 CRH receptor in total RNA extracted from midgestation human fetal adrenals, suggesting that the fetal adrenal cortex may be directly responsive to CRH [48].


  1. Effects of corticotropin-releasing hormone and dexamethasone on proopiomelanocortin messenger RNA level in human corticotroph adenoma cells in vitro. Suda, T., Tozawa, F., Yamada, M., Ushiyama, T., Tomori, N., Sumitomo, T., Nakagami, Y., Demura, H., Shizume, K. J. Clin. Invest. (1988) [Pubmed]
  2. Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro. Suda, T., Tozawa, F., Dobashi, I., Horiba, N., Ohmori, N., Yamakado, M., Yamada, M., Demura, H. J. Clin. Invest. (1993) [Pubmed]
  3. Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes. Zouboulis, C.C., Seltmann, H., Hiroi, N., Chen, W., Young, M., Oeff, M., Scherbaum, W.A., Orfanos, C.E., McCann, S.M., Bornstein, S.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  4. Corticotropin-releasing hormone modulates human trophoblast invasion through carcinoembryonic antigen-related cell adhesion molecule-1 regulation. Bamberger, A.M., Minas, V., Kalantaridou, S.N., Radde, J., Sadeghian, H., Löning, T., Charalampopoulos, I., Brümmer, J., Wagener, C., Bamberger, C.M., Schulte, H.M., Chrousos, G.P., Makrigiannakis, A. Am. J. Pathol. (2006) [Pubmed]
  5. Corticotropin-releasing hormone-mediated neuroprotection against oxidative stress is associated with the increased release of non-amyloidogenic amyloid beta precursor protein and with the suppression of nuclear factor-kappaB. Lezoualc'h, F., Engert, S., Berning, B., Behl, C. Mol. Endocrinol. (2000) [Pubmed]
  6. Cerebrospinal fluid neuropeptides in Alzheimer's disease and vascular dementia. Heilig, M., Sjögren, M., Blennow, K., Ekman, R., Wallin, A. Biol. Psychiatry (1995) [Pubmed]
  7. Corticotropin-releasing hormone receptor subtypes and emotion. Steckler, T., Holsboer, F. Biol. Psychiatry (1999) [Pubmed]
  8. Increased ACTH concentrations associated with cholecystokinin tetrapeptide-induced panic attacks in patients with panic disorder. Ströhle, A., Holsboer, F., Rupprecht, R. Neuropsychopharmacology (2000) [Pubmed]
  9. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Theoharides, T.C., Singh, L.K., Boucher, W., Pang, X., Letourneau, R., Webster, E., Chrousos, G. Endocrinology (1998) [Pubmed]
  10. Neuroendocrine-immune system interactions and autoimmunity. Wilder, R.L. Annu. Rev. Immunol. (1995) [Pubmed]
  11. The hypothalamus and hypertension. de Wardener, H.E. Physiol. Rev. (2001) [Pubmed]
  12. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Slominski, A., Wortsman, J., Luger, T., Paus, R., Solomon, S. Physiol. Rev. (2000) [Pubmed]
  13. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Timpl, P., Spanagel, R., Sillaber, I., Kresse, A., Reul, J.M., Stalla, G.K., Blanquet, V., Steckler, T., Holsboer, F., Wurst, W. Nat. Genet. (1998) [Pubmed]
  14. Suppression of alcohol-induced hypertension by dexamethasone. Randin, D., Vollenweider, P., Tappy, L., Jéquier, E., Nicod, P., Scherrer, U. N. Engl. J. Med. (1995) [Pubmed]
  15. Preeclampsia is associated with impaired regulation of the placental nitric oxide-cyclic guanosine monophosphate pathway by corticotropin-releasing hormone (CRH) and CRH-related peptides. Karteris, E., Vatish, M., Hillhouse, E.W., Grammatopoulos, D.K. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  16. Neuropeptides and human sleep. Steiger, A., Holsboer, F. Sleep. (1997) [Pubmed]
  17. Coupling of corticotropin-releasing hormone receptors to adenylyl cyclase in human Y-79 retinoblastoma cells. Olianas, M.C., Lampis, G., Onali, P. J. Neurochem. (1995) [Pubmed]
  18. Evidence that corticotropin-releasing hormone inhibits cell growth of human breast cancer cells via the activation of CRH-R1 receptor subtype. Graziani, G., Tentori, L., Muzi, A., Vergati, M., Tringali, G., Pozzoli, G., Navarra, P. Mol. Cell. Endocrinol. (2007) [Pubmed]
  19. Combined anterior pituitary function test using CRH, GRH, LH-RH, TRH and vasopressin in patients with non-functioning pituitary tumors. Hashimoto, K., Makino, S., Hirasawa, R., Takao, T., Kageyama, J., Ogasa, T., Ota, Z. Acta Med. Okayama (1990) [Pubmed]
  20. Structure-function correlates in the corticotropes of the anterior pituitary. Childs, G.V. Frontiers in neuroendocrinology. (1992) [Pubmed]
  21. Cytokine-dependent gp130 receptor subunit regulates human fetal pituitary adrenocorticotropin hormone and growth hormone secretion. Shimon, I., Yan, X., Ray, D.W., Melmed, S. J. Clin. Invest. (1997) [Pubmed]
  22. Characterization and gestational regulation of corticotropin-releasing hormone messenger RNA in human placenta. Frim, D.M., Emanuel, R.L., Robinson, B.G., Smas, C.M., Adler, G.K., Majzoub, J.A. J. Clin. Invest. (1988) [Pubmed]
  23. Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of STAT pathway. Ray, D.W., Ren, S.G., Melmed, S. J. Clin. Invest. (1996) [Pubmed]
  24. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. Cao, J., Papadopoulou, N., Kempuraj, D., Boucher, W.S., Sugimoto, K., Cetrulo, C.L., Theoharides, T.C. J. Immunol. (2005) [Pubmed]
  25. Corticotropin-releasing hormone signaling in synovial tissue from patients with early inflammatory arthritis is mediated by the type 1 alpha corticotropin-releasing hormone receptor. McEvoy, A.N., Bresnihan, B., FitzGerald, O., Murphy, E.P. Arthritis Rheum. (2001) [Pubmed]
  26. Urocortin, but not corticotropin-releasing hormone (CRH), activates the mitogen-activated protein kinase signal transduction pathway in human pregnant myometrium: an effect mediated via R1alpha and R2beta CRH receptor subtypes and stimulation of Gq-proteins. Grammatopoulos, D.K., Randeva, H.S., Levine, M.A., Katsanou, E.S., Hillhouse, E.W. Mol. Endocrinol. (2000) [Pubmed]
  27. Regulation of pituitary ACTH secretion during chronic stress. Aguilera, G. Frontiers in neuroendocrinology. (1994) [Pubmed]
  28. Residues of corticotropin releasing factor-binding protein (CRF-BP) that selectively abrogate binding to CRF but not to urocortin 1. Huising, M.O., Vaughan, J.M., Shah, S.H., Grillot, K.L., Donaldson, C.J., Rivier, J., Flik, G., Vale, W.W. J. Biol. Chem. (2008) [Pubmed]
  29. Localization of agonist- and antagonist-binding domains of human corticotropin-releasing factor receptors. Liaw, C.W., Grigoriadis, D.E., Lorang, M.T., De Souza, E.B., Maki, R.A. Mol. Endocrinol. (1997) [Pubmed]
  30. Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries. Muramatsu, Y., Sugino, N., Suzuki, T., Totsune, K., Takahashi, K., Tashiro, A., Hongo, M., Oki, Y., Sasano, H. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  31. Ligand requirements of the human corticotropin-releasing factor-binding protein. Sutton, S.W., Behan, D.P., Lahrichi, S.L., Kaiser, R., Corrigan, A., Lowry, P., Potter, E., Perrin, M.H., Rivier, J., Vale, W.W. Endocrinology (1995) [Pubmed]
  32. Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis. Murphy, E.P., McEvoy, A., Conneely, O.M., Bresnihan, B., FitzGerald, O. Arthritis Rheum. (2001) [Pubmed]
  33. Hypothalamic regulatory peptides and their receptors: cytochemical studies of their role in regulation at the adenohypophyseal level. Childs, G.V., Westlund, K.N., Tibolt, R.E., Lloyd, J.M. Journal of electron microscopy technique. (1991) [Pubmed]
  34. Plasma leptin levels do not change in patients with Cushing's disease shortly after correction of hypercortisolism. Cizza, G., Lotsikas, A.J., Licinio, J., Gold, P.W., Chrousos, G.P. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  35. GRK3 regulation during CRF- and urocortin-induced CRF1 receptor desensitization. Dautzenberg, F.M., Wille, S., Braun, S., Hauger, R.L. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  36. Pituitary microadenomas causing Cushing's disease respond to corticotropin-releasing factor. Orth, D.N., DeBold, C.R., DeCherney, G.S., Jackson, R.V., Alexander, A.N., Rivier, J., Rivier, C., Spiess, J., Vale, W. J. Clin. Endocrinol. Metab. (1982) [Pubmed]
  37. 125I-Tyro-sauvagine: a novel high affinity radioligand for the pharmacological and biochemical study of human corticotropin-releasing factor 2 alpha receptors. Grigoriadis, D.E., Liu, X.J., Vaughn, J., Palmer, S.F., True, C.D., Vale, W.W., Ling, N., De Souza, E.B. Mol. Pharmacol. (1996) [Pubmed]
  38. The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated by brain-derived neurotrophic factor is enhanced by corticotropin releasing factor through the activation of a cAMP-dependent signaling pathway. Traver, S., Marien, M., Martin, E., Hirsch, E.C., Michel, P.P. Mol. Pharmacol. (2006) [Pubmed]
  39. Characterization of neuropeptide Y-mediated corticotropin-releasing factor synthesis and release from human placental trophoblasts. Robidoux, J., Simoneau, L., St-Pierre, S., Masse, A., Lafond, J. Endocrinology (2000) [Pubmed]
  40. Corticotropin-releasing factor and neuropeptide Y: role in emotional integration. Heilig, M., Koob, G.F., Ekman, R., Britton, K.T. Trends Neurosci. (1994) [Pubmed]
  41. Corticotrophin-releasing factor receptors: from molecular biology to drug design. Chalmers, D.T., Lovenberg, T.W., Grigoriadis, D.E., Behan, D.P., De Souza, E.B. Trends Pharmacol. Sci. (1996) [Pubmed]
  42. The CRF peptide family and their receptors: yet more partners discovered. Dautzenberg, F.M., Hauger, R.L. Trends Pharmacol. Sci. (2002) [Pubmed]
  43. Multipoint linkage analysis of a candidate gene locus in rheumatoid arthritis demonstrates significant evidence of linkage and association with the corticotropin-releasing hormone genomic region. Fife, M.S., Fisher, S.A., John, S., Worthington, J., Shah, C.J., Ollier, W.E., Panayi, G.S., Lewis, C.M., Lanchbury, J.S. Arthritis Rheum. (2000) [Pubmed]
  44. Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls. Hiroi, N., Wong, M.L., Licinio, J., Park, C., Young, M., Gold, P.W., Chrousos, G.P., Bornstein, S.R. Mol. Psychiatry (2001) [Pubmed]
  45. Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function. Willenberg, H.S., Bornstein, S.R., Hiroi, N., Päth, G., Goretzki, P.E., Scherbaum, W.A., Chrousos, G.P. Mol. Psychiatry (2000) [Pubmed]
  46. Corticotropin releasing hormone-binding protein (CRH-BP): plasma levels decrease during the third trimester of normal human pregnancy. Linton, E.A., Perkins, A.V., Woods, R.J., Eben, F., Wolfe, C.D., Behan, D.P., Potter, E., Vale, W.W., Lowry, P.J. J. Clin. Endocrinol. Metab. (1993) [Pubmed]
  47. Expression of corticotropin-releasing hormone and its R1 receptor in human endometrial stromal cells. Di Blasio, A.M., Pecori Giraldi, F., Viganò, P., Petraglia, F., Vignali, M., Cavagnini, F. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  48. Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells. Smith, R., Mesiano, S., Chan, E.C., Brown, S., Jaffe, R.B. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
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