Skip to main content
Log in

The emerging role of peripheral corticotropin-releasing hormone (CRH)

  • Review Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Corticotropin-releasing hormone (CRH) is distributed in the brain and spinal cord and it has also been found in the myometrium, the endometrium, the placenta and diverse inflammatory sites. Traditionally, hypothalamic CRH has been considered to act indirectly in an anti-inflammatory fashion, since the end product of the hypothalamic-pituitary-adrenal axis is cortisol, a well-known anti-inflammatory compound. However, CRH produced at peripheral inflammatory sites may participate in an auto-/paracrine stimulation of inflammation. CRH in inflammatory sites seems to be involved in the activation of the Fas/Fas ligand system. Furthermore, locally produced embryonic and endometrial CRH plays a role in both the aseptic inflammatory process of implantation and the anti-rejection process that protects the fetus from the maternal immune system. There are two types of G protein-coupled CRH receptors, type 1 and 2. Pyrrolopyrimidine compounds, such as antalarmin, have been developed as CRH receptor antagonists. The systemic administration of antalarmin blocks pituitary CRH receptors and the CRH-induced secretion of adrenocorticotropin. Additonally, antalarmin has been shown to reduce the inflammatory-like reaction of the endometrium to the invading blastocyst, with a possible therapeutic potential as a non-steroidal inhibitor of pregnancy at its early stages.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chrousos G.P. The Hypothalamic-Pituitary-Adrenal axis and the immune/inflammatory reaction. N. Engl. J. Med. 1995, 332: 1351–1362.

    Article  CAS  PubMed  Google Scholar 

  2. Reichlin S. Neuroendocrine-immune interactions. N. Engl. J. Med. 1993, 329: 1246–1253.

    Article  CAS  PubMed  Google Scholar 

  3. Johnson H.M. Neuroendocrine peptide hormone regulation of immunity. In: Blalock J.E. ed. Neuroimmunoendocrinology. 2nd ed. Basel: Karger. 1992, 49–83.

    Chapter  Google Scholar 

  4. Rivier C., Brownstein M., Spiess J., et al. In vivo corticotropin-releasing factor-induced secretion of adrenocorticotropin, β-endorphin and corticosterone. Endocrinology 1982, 110: 272–278.

    Article  CAS  PubMed  Google Scholar 

  5. Vale W., Rivier C., Brown M.R., et al. Chemical and biological characterization of corticotropin releasing factor. Recent Prog. Horm. Res. 1983, 39: 245–270.

    CAS  PubMed  Google Scholar 

  6. Spiess J., Rivier J., Rivier C., Vale W. Primary structure of corticotropin-releasing factor from ovine hypothalamus. Proc. Natl. Acad. Sci. USA 1981, 78: 6517–6521.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Donaldson C.J., Sutton S.W., Perrin M.H., et al. Cloning and characterization of human urocortin. Endocrinology 1996, 137: 2167–2170.

    CAS  PubMed  Google Scholar 

  8. Shibahara S., Morimoto Y., Furutani Y., et al. Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene. EMBO J. 1983, 2:775–779.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Swanson L.W., Sawchenko P.E., Rivier J., Vale W.W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: An immunohistochemical study. Neuroendocrinology 1983, 36: 165–186.

    Article  CAS  PubMed  Google Scholar 

  10. Giraldi F.P., Cavagnini F. Corticotropin-releasing hormone is produced by rat corticotropes and modulates ACTH secretion in a paracrine/autocrine fashion. J. Clin. Invest. 1998, 101: 2478–2484.

    Article  CAS  PubMed Central  Google Scholar 

  11. Sawchenko P.E., Swanson L.W., Vale W.W. Corticotropinreleasing factors: Coexpression within distinct subsets of oxytocin-, vasopressin-, and neurotensin-immunoreactive neurons in the hypothalamus of the male rat. J. Neurosci. 1984, 4: 1118–1129.

    CAS  PubMed  Google Scholar 

  12. Schurmeyer T.H., Avgerinos P.C., Gold P.W., et al. Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and cortisol secretion. J. Clin. Endocrinol. Metab. 1984, 59: 1103–1108.

    Article  CAS  PubMed  Google Scholar 

  13. Conaglen J.V., Donld R.A., Espiner E.A., et al. The effect of ovine corticotropin-releasing factor on catecholamine, vasopressin, and aldosterone secretion in normal man. J. Clin. Endocrinol. Metab. 1984, 58: 463–466.

    Article  CAS  PubMed  Google Scholar 

  14. Pavlov E.P., Harman S.M., Chrousos G.P., et al. Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men. J. Clin. Endocrinol. Metab. 1986, 62: 767–772.

    Article  CAS  PubMed  Google Scholar 

  15. DeCherney G.S., DeBold C.R., Jackson R.V., et al. Diurnal variation in the response of plasma adrenocorticotropin and cortisol to intravenous ovine corticotropin-releasing hormone. J. Clin. Endocrinol. Metab. 1985, 61: 273–279.

    Article  CAS  PubMed  Google Scholar 

  16. Grino M., Chrousos G.P., Margioris A.N. The corticotropin releasing hormone gene is expressed in human placenta. Biochem. Biophys. Res. Commun. 1987, 148: 1208–1214.

    Article  CAS  PubMed  Google Scholar 

  17. Mastorakos G., Scopa C.D., Kao L.C., et al. Presence of immunoreactive corticotropin-releasing hormone in human endometrium. J. Clin. Endocrinol. Metab. 1996, 81: 1046–1050.

    CAS  PubMed  Google Scholar 

  18. Ferrari A., Petraglia F., Gurpide E. Corticotropin releasing factor decidualizes human endometrial stromal cells in vitro. Interaction with progestin. J. Steroid. Biochem. Mol. Biol. 1995, 54: 251–255.

    Article  CAS  PubMed  Google Scholar 

  19. Petraglia F., Tabanelli S., Galassi M.C., et al. Human decidua and in vitro decidualized endometrial stromal cells at term contain immunoreactive corticotropin-releasing factor (CRF) and CRF messenger ribonucleic acid. J. Clin. Endocrinol. Metab. 1992, 74: 1427–1431.

    CAS  PubMed  Google Scholar 

  20. Fabbri A., Tinajero J.C., Dufau M.L. Corticotropin-releasing factor is produced by rat Leydig cells and has a major local antireproductive role in the testis. Endocrinology 1990, 127: 1541–1543.

    Article  CAS  PubMed  Google Scholar 

  21. Ulisse S., Fabbri A., Dufau M.L. Corticotropin-releasing factor receptors and actions in rat Leydig cells. J. Biol. Chem. 1989, 264: 2156–2163.

    CAS  PubMed  Google Scholar 

  22. Mastorakos G., Webster E.L., Friedman T.C., Chrousos G.P. Immunoreactive corticotropin releasing hormone (CRH) and its binding sites in the rat ovary. J. Clin. Invest. 1993, 92: 961–968.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Mastorakos G., Scopa C.D., Vryonidou A., et al. Presence of immunoreactive corticotropin releasing hormone (CRH) in normal and polycystic human ovaries. J. Clin. Endocrinol. Metab. 1994, 79: 1191–1197.

    CAS  PubMed  Google Scholar 

  24. Mastorakos G., Scopa C.D., Friedman T.C., et al. Presence of immunoreactive corticotropin releasing hormone (CRH) in thyroid lesions. Am. J. Pathol. 1994, 145: 1159–1167.

    PubMed Central  PubMed  Google Scholar 

  25. Mastorakos G., Bouzas E.A., et al. Immune corticotropinreleasing hormone is present in the eyes of and promotes experimental autoimmune uveoretinitis in rodents. Endocrinology 1995, 136: 4650–4658.

    CAS  PubMed  Google Scholar 

  26. Sasaki A., Shinkawa O., Margioris A.N., et al. Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery. J. Clin. Endocrinol. Metab. 1987, 64: 224–229.

    Article  CAS  PubMed  Google Scholar 

  27. Jeske W., Soszynski P., Lukaszewicz E., et al. Enhancement of plasma corticotropin-releasing hormone in pregnancy-induced hypertension. Acta Endocrinol. 1990, 122: 711–714.

    CAS  PubMed  Google Scholar 

  28. Linton E.A., Wolfe C.D., Behan D.P., Lowry P.J. A specific carrier substance for human corticotropin releasing factor in late gestational maternal plasma which could mask the ACTH-releasing activity. Clin. Endocrinol. (Oxf) 1988, 28: 315–324.

    Article  CAS  Google Scholar 

  29. Chen R., Lewis K.A., Perrin M.H., Vale W.W. Expression cloning of a human corticotropin-releasing-factor receptor. Proc. Natl. Acad. Sci. USA 1993, 90: 8967–8971.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Vamvakopoulos N.C., Sioutopoulou T.O. Human corticotropin-releasing hormone receptor gene (CRHR) is located on the long arm of chromosome 17 (17q12-qter). Chromosome Res. 1994, 2: 471–473.

    Article  CAS  PubMed  Google Scholar 

  31. Slominski A., Wortsman J., Pisarchik A., et al. Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors. FASEB J. 2001, 15: 1678–1693.

    Article  CAS  PubMed  Google Scholar 

  32. Watanabe T., Orth D.N. Detailed kinetic analysis of adrenocorticotropin secretion by dispersed rat anterior pituitary cells in a microperfusion system: Effects of ovine corticotropin-releasing factor and arginine vasopressin. Endocrinology 1987, 121: 1133–1145.

    Article  CAS  PubMed  Google Scholar 

  33. Lundblad J.R., Roberts J.L. Regulation of proopiomelanocortin gene expression in pituitary. Endocr. Rev. 1988, 9: 135–158.

    Article  CAS  PubMed  Google Scholar 

  34. Wynn P.C., Harwood J.P., Catt K.J., Aguilera G. Regulation of corticotropin-releasing factor (CRF) receptors in the rat pituitary gland: Effect of adrenalectomy on CRF receptors and corticotropin responses. Endocrinology 1985, 116: 1653–1659.

    Article  CAS  PubMed  Google Scholar 

  35. Hauger R.L., Aguilera G. Regulation of pituitary corticotropin releasing hormone (CRH) receptors by CRH: Interaction with vasopressin. Endocrinology 1993, 133: 1708–1714.

    CAS  PubMed  Google Scholar 

  36. Paul W.E., Seder R.A. Lymphocyte responses and cytokines. Cell 1994, 76: 241–251.

    Article  CAS  PubMed  Google Scholar 

  37. Boumpas D.T., Chrousos G.P., Wilder R.I., Cupps T.R., Balow J.E. Glococorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann. Intern. Med. 1993, 119: 1198–1208.

    Article  CAS  PubMed  Google Scholar 

  38. Elenkov I.J., Webster E.L., Torpy D.J., Chrousos G.P. Stress, corticotropin releasing hormone, glucocorticoids, and the immune/inflammatory response: acute and chronic effects. Ann. NY Acad. Sci. 1999, 876: 1–13.

    Article  CAS  PubMed  Google Scholar 

  39. Mastorakos G., Weber J.S., Magiakou M.A., Gunn H., Chrousos G.P. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J. Clin. Endocrinol. Metab. 1994, 79: 934–939.

    CAS  PubMed  Google Scholar 

  40. Mastorakos G., Chrousos G.P., Weber J.S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J. Clin. Endocrinol. Metab. 1993, 77: 1690–1694.

    CAS  PubMed  Google Scholar 

  41. Gionis D., Ilias I., Moustaki M., et al. Hypothalamic-pituitary-adrenal axis & interleukin-6 activity in children with head trauma and syndrome of inappropriate secretion of antidiuretic hormone. J. Pediatr. Endocr. Metab. (in press.)

  42. Guillemin R., Rosenberg B. Humoral hypothalamic control of anterior pituitary: A study with combined tissue cultures. Endocrinology 1995, 57: 599–607.

    Article  Google Scholar 

  43. Kavelaars A., Berkenbosch F., Croiset G., Ballieux R.E., Heijnen C.J. Induction of beta-endorphin secretion by lymphocytes after subcutaneous administration of corticotropinreleasing hormone. Endocrinology 1990, 126: 759–764.

    Article  CAS  PubMed  Google Scholar 

  44. Karalis K., Sano H., Redwine J., Listwak S., Wilder R.L., Chrousos G.P. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science 1991, 254: 421–423.

    Article  CAS  PubMed  Google Scholar 

  45. Karalis K., Mastorakos G., Chrousos G.P., Tolis G. Somatostatin analogues suppress the inflammatory reaction in vivo. J. Clin. Invest. 1994, 93: 2000–2006.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Karalis K., Mastorakos G., Sano H., Wilder R.L., Chrousos G.P. Somatostatin may participate in the anti-inflammatory actions of glucocorticoids. Endocrinology 1995, 136: 4133–4138.

    CAS  PubMed  Google Scholar 

  47. Calogero A.E., Bernardini R., Margioris A.N, et al. Effects of serotonergic agonists ant antagonists on corticotropinreleasing hormone secretion by explanted rat hypothalami. Peptides 1989, 10: 189–200.

    Article  CAS  PubMed  Google Scholar 

  48. Suda T., Tomori N., Tozawa F., et al. Immunoreactive corticotropin and corticotropin-releasing factor in human hypothalamus, adrenal, lung cancer and pheochromocytoma. J. Clin. Endocrinol. Metab. 1984, 58: 919–924.

    Article  CAS  PubMed  Google Scholar 

  49. Crofford L.J., Sano H., Karalis K., et al. Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis. J. Clin. Invest. 1992, 90: 2555–2564.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Crofford L.J., Sano H., Karalis K., et al. Corticotropin-releasing hormone in synovial fluids and tissues of patients with rheumatoid arhtritis and osteoarthritis. J. Immunol. 1993, 151: 1–10.

    Google Scholar 

  51. Mastorakos G., Silver P.B., Bouzas E.A., Caspi R.R., Chan C.C., Chrousos G.P. Immunoreactive corticotropin releasing hormone in experimental uveitis. Inv. Ophthalmol. Vis. Sci. 1992, 33: 933.

    Google Scholar 

  52. Poulaki V., Mitsiades N., Mastorakos G., Caspi R.R., Chrousos G.P., Bouzas E. Fas/fas ligand-associated apoptosis in experimental autoimmune uveoretinitis in rodents: role of proinflammatory corticotropin-releasing hormone. Exp. Eye Res. 2001, 72: 623–629.

    Article  CAS  PubMed  Google Scholar 

  53. Scofitsch G., Hamill G.S., Jacobowitz D.M. Capsaicin depletes corticotropin-releasing factor-like immunoreactive neurons in the rat spinal cord and medulla oblongata. Neuroendocrinology 1984, 38: 514–517.

    Article  Google Scholar 

  54. Merchenthaler I., Hynes M.A., Vigh S., Schally A.V., Petrusz P. Immunocytochemical localization of corticotropin releasing factor (CRF) in the rat spinal cord. Brain Res. 1983, 275: 373–377.

    Article  CAS  PubMed  Google Scholar 

  55. Udelsman R., Harwood J.P., Millan M.A., et al. Functional corticotropin releasing factor receptors in the primate peripheral sympathetic nervous system. Nature 1986, 319: 147–150.

    Article  CAS  PubMed  Google Scholar 

  56. Ghizzoni L., Mastorakos G., Vottero A., et al. Corticotropinreleasing hormone (CRH) inhibits steroid biosynthesis by cultured human granulose-lutein cells in a CRH and interleukin-1 receptor-mediated fashion. J. Clin. Endocr. Metab. 1997, 138: 4806–4811.

    CAS  Google Scholar 

  57. Schulz D.W., Mansbach R.S., Sprouse J., et al. CP-I54,526: A potent and selective nonpeptide antagonist of corticotropin releasing factor receptors. Proc. Natl. Acad. Sci. USA 1996, 93: 10477–10482.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Webster E.L., Lewis D.B., Torpy D.J., Zachman E.K., Rice K.C., Chrousos G.P. In vivo characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: Suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 1996, 137: 5747–5750.

    CAS  PubMed  Google Scholar 

  59. Makrigiannakis A., Zoumakis E., Kalantaridou S., et al. Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance. Nature Immunology 2001, 2: 1018–1024.

    Article  CAS  PubMed  Google Scholar 

  60. Wintour E.M., Bell R.J., Carson R.S., et al. Effect of longterm infusion of CRF in the immature ovine fetus. J. Endocrinol. 1986, 111: 469–475.

    Article  CAS  PubMed  Google Scholar 

  61. Chan E.C., Falconer J., Madsen G., et al. A corticotropinreleasing hormone type I receptor antagonist delays parturition in sheep. Endocrinology 1998, 139: 3357–3360.

    Article  CAS  PubMed  Google Scholar 

  62. Bornstein S.R., Webster E.L., Torpy D.J., et al. Chronic effects of a nonpeptide corticotropin-releasing hormone type I receptor antagonist on pituitary adrenal function, body weight, and metabolic regulation. Endocrinology 1998, 139: 1546–1555.

    CAS  PubMed  Google Scholar 

  63. Wong M.L., Webster E.L., Spokes H., et al. Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitaryadrenal axis responses to acute immobilization stress. Life Sci. 1999, 65, PL53–58.

    Article  CAS  PubMed  Google Scholar 

  64. Habib K.E., Weld K.P., Rice K.C., et al. Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc. Natl Acad. Sci. USA 2000, 97: 6079–6084.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G. Mastorakos Dr.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ilias, I., Mastorakos, G. The emerging role of peripheral corticotropin-releasing hormone (CRH). J Endocrinol Invest 26, 364–371 (2003). https://doi.org/10.1007/BF03345186

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345186

Key-words

Navigation