Comprehensive Physiology Wiley Online Library

Regulation and Actions of Corticotropin‐Releasing Hormone

Full Article on Wiley Online Library


The sections in this article are:

1 Corticotropin‐Releasing Hormone Expression
2 Corticotropin‐Releasing Hormone Receptors
3 Corticotropin‐Releasing Hormone‐Binding Protein
4 Corticotropin‐Releasing Hormone‐Like Molecules
5 Regulation of Corticotropin‐Releasing Hormone Expression
5.1 Corticotropin‐Releasing Hormone Gene Structure
5.2 Intracellular Second Messengers That Regulate Corticotropin‐Releasing Hormone Gene Expression
5.3 Extracellular Ligands That Regulate Corticotropin‐Releasing Hormone Expression and Release
6 Regulation of the Hypothalamic‐Pituitary‐Adrenal Axis
6.1 Role of Corticotropin‐Releasing Hormone in Stimulating Corticotropin Synthesis and Release
6.2 Other Corticotropin‐Releasing Factors
6.3 Role of Corticotropin‐Releasing Hormone in Circadian Rhythm Generation of the Hypothalamic‐Pituitary‐Adrenal Axis
6.4 Role of Corticotropin‐Releasing Hormone in Fetal Development
7 Role of Corticotropin‐Releasing Hormone in Responses to Physiological and Psychological Stressors
7.1 Acute Stressors
7.2 Chronic Stressors
8 Role of Corticotropin‐Releasing Hormone in Regulating Other Neuroendocrine Functions
8.1 Behavior
8.2 Appetite
8.3 Reproduction
8.4 Autonomic Function
9 Conclusion
Figure 1. Figure 1.

Postulated actions of central CRH. Corticotropin‐releasing hormone in the parvocellular neurons of the paraventricular nucleus of the hypothalamus (PVHpc) is a key component in the regulation of the HPA axis through stimulation of corticotropin production and/or secretion from the anterior pituitary. Vasopressin may also play a role in regulation of the axis. Other postulated central actions of hypothalamic CRH are control of sympathetic outflow, and inhibition of reproductive functions, growth, and appetite. In addition, CRH in the amygdala has been implicated in the behavioral response to stress.

Figure 2. Figure 2.

Comparison of the amino acid sequences of the mature peptides of mouse CRH (mCRH) and mouse urocortin (mUcn).

Figure 3. Figure 3.

Corticotropin‐releasing hormone‐deficient mice exhibit an abnormal, sexually dimorphic response to stress. Corticosterone measurements were taken by tail bleed 1 hr after lights on (pre‐stress), again following 20 min of restraint (restraint), and finally, 5 min after ether exposure with continued restraint (ether + restraint). Although the responses of CRH‐deficient (Ko) mice were significantly blunted as compared to wild‐type mice, CRH‐deficient females had a 9‐fold greater corticosterone response than CRH‐deficient males.

Reprinted from reference 132, with permission

Figure 1.

Postulated actions of central CRH. Corticotropin‐releasing hormone in the parvocellular neurons of the paraventricular nucleus of the hypothalamus (PVHpc) is a key component in the regulation of the HPA axis through stimulation of corticotropin production and/or secretion from the anterior pituitary. Vasopressin may also play a role in regulation of the axis. Other postulated central actions of hypothalamic CRH are control of sympathetic outflow, and inhibition of reproductive functions, growth, and appetite. In addition, CRH in the amygdala has been implicated in the behavioral response to stress.

Figure 2.

Comparison of the amino acid sequences of the mature peptides of mouse CRH (mCRH) and mouse urocortin (mUcn).

Figure 3.

Corticotropin‐releasing hormone‐deficient mice exhibit an abnormal, sexually dimorphic response to stress. Corticosterone measurements were taken by tail bleed 1 hr after lights on (pre‐stress), again following 20 min of restraint (restraint), and finally, 5 min after ether exposure with continued restraint (ether + restraint). Although the responses of CRH‐deficient (Ko) mice were significantly blunted as compared to wild‐type mice, CRH‐deficient females had a 9‐fold greater corticosterone response than CRH‐deficient males.

Reprinted from reference 132, with permission
 1. Addison, T. On the Constitutional and Local Effects of Disease of the Supra‐renal Capsules. London: Samuel Highley, 1855.
 2. Aguilera, G. Regulation of pituitary ACTH secretion during chronic stress. [Review] [1 refs]. Front Neuroendocrinol. 15: 321–350, 1994.
 3. Aguilera, G., J. P. Harwood, J. X. Wilson, J. Morell, J. H. Brown, K. J. Catt. Mechanisms of action of corticotropin‐releasing factor and other regulators of corticotropin release in rat pituitary cells. J. Biol. Chem. 258: 8039–8045, 1983.
 4. Ahima, R. S., D. Prabakaran, C. Mantzoros, D. Qu, B. Lowell, E. Maratos‐Flier, J. S. Flier. Role of leptin in the neuroendocrine response to fasting. Nature 382: 250–252, 1996.
 5. al Damluji, S. Adrenergic mechanisms in the control of corticotrophin secretion. J. Endocrinology. 119: 5–14, 1988.
 6. al Damluji, S., L. H. Rees. Effects of catecholamines on secretion of adrenocorticotrophic hormone (ACTH) in man. J. Clin. Pathol. 40: 1098–1107, 1987.
 7. al Damluji, S., Thomas, R., White, A., Besser, M. Vasopressin mediates alpha 1‐adrenergic stimulation of adrenocorticotropin secretion. Endocrinology 126: 1989–1995, 1990.
 8. Antoni, F. A. Receptors mediating the CRH effects of vasopressin and oxytocin. Ann. N.Y. Acad Sci. 512: 195–204, 1987.
 9. Antoni, F. A., Dayanithi, G. Guanosine 3': 5'cyclic monophosphate and activators of guanylate cyclase inhibit secretagogue‐induced corticotropin release by rat anterior pituitary cells. Biochem. Biophys. Res. Commun. 158: 824–830, 1989.
 10. Antoni, F. A., M. C. Holmes, J. Z. Kiss. Pituitary binding of vasopressin is altered by experimental manipulations of the hypothalamo‐pituitary‐adrenocortical axis in normal as well as homozygous (di/di) Brattleboro rats. Endocrinology 117: 1293–1299, 1985.
 11. Axelrod, J. Relationship between catecholamines and other hormones. [Review] [ refs]. Recent Prog. Horm. Res. 31: 1–35, 1975.
 12. Baertschi, A. J., M. A. Friedli. A novel type of vasopressin receptor on anterior pituitary corticotrophs. Endocrinology 116: 499–502, 1985.
 13. Banks, W. A., L. Ortiz, S. R. Plotkin, A. J. Kastin. Human interleukin. (IL) 1 alpha, murine IL‐1 alpha and murine IL‐1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. J. Pharmacol. Exp. Ther. 259: 988–996, 1991.
 14. Behan, D. P., D. E. Grigoriadis, T. Lovenberg, D. Chalmers, S. Heinrichs, C. Liaw, E. B. De Souza. Neurobiology of corticotropin releasing factor (CRF) receptors and CRF‐binding protein: implications for the treatment of CNS disorders [see comments]. [Review] [ refs]. Molecular Psychiatry 1: 265–277, 1996.
 15. Behan, D. P., O. Khongsaly, N. Ling, E. B. De Souza. Urocortin interaction with corticotropin‐releasing factor (CRF) binding protein (CRF‐BP): a novel mechanism for elevating “free” CRF levels in human brain. Brain Res. 725: 263–267, 1996.
 16. Berkenbosch, F., J. van Oers, A. del Rey, F. Tilders, H. Besedovsky. Corticotropin‐releasing factor‐producing neurons in the rat activated by interleukin‐1. Science 238: 524–526, 1987.
 17. Bernton, E. W., J. E. Beach, J. W. Holaday, R. C. Smallridge, H. G. Fein. Release of multiple hormones by a direct action of interleukin‐ 1 on pituitary cells. Science 238: 519–521, 1987.
 18. Berridge, C., A. Dunn. A corticotropin‐releasing factor antagonist reverses the stress‐induced changes of exploratory behavior in mice. Horm. Behav. 21: 393–401, 1987.
 19. Berridge, C., A. Dunn. CRF and restraint‐stress decrease exploratory behavior in hypophysectomized mice. Pharmacol. Biochem. Behav. 34: 517–519, 1989.
 20. Besedovsky, H., A. del Rey, E. Sorkin, C. A. Dinarello. Immunoregulatory feedback between interleukin‐1 and glucocorticoid hormones. Science 233: 652–654, 1986.
 21. Bittencourt, J. C., J. Vaughan, C. Arias, R. A. Rissman, W. W. Vale, P. E. Sawchenko. Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin‐containing projections with targets bearing type 2 CRF receptors. J. Comp. Neurol. 415: 285–312, 1999.
 22. Bjorklund, A., B. Falck, E. Rosengren. Monoamines in the pituitary gland of the pig. Life. Sci. 6: 2103–2110, 1967.
 23. Blumenfeld, Z., R. B. Jaffe. Hypophysiotropic and neuromodulatory regulation of adrenocorticotropin in the human fetal pituitary gland. J. Clin. Invest. 78: 288–294, 1986.
 24. Boyle, M., G. Yamamoto, M. Chen, J. Rivier, W. Vale. Interleukin 1 prevents loss of corticotropic responsiveness to beta‐adrenergic stimulation in vitro. Proc. Natl. Acad. Sci. U.S.A 85: 5556–5560, 1988.
 25. Bradbury, M. J., C. S. Cascio, K. A. Scribner, M. F. Dallman. Stress‐induced adrenocorticotropin secretion: diurnal responses and decreases during stress in the evening are not dependent on corticosterone. Endocrinology 128: 680–688, 1991.
 26. Britton, D., M. Varela, A. Garcia, M. Rosenthal. Dexamethasone suppresses pituitary‐adrenal but not behavioral effects of centrally administered CRF. Life Sci. 38: 211–216, 1986.
 27. Britton, K., G. Lee, R. Dana, S. Risch, G. Koob. Activating and ‘anxiogenic’ effects of corticotropin releasing factor are not inhibited by blockade of the pituitary‐adrenal system with dexamethasone. Life Sci. 39: 1281–1286, 1986.
 28. Britton, K., G. Lee, W. Vale, J. Rivier, G. Koob. Corticotropin releasing factor (CRF) receptor antagonist blocks activating and ‘anxiogenic’ actions of CRF in the rat. Brain Res. 369: 303–306, 1986.
 29. Britton, K., J. Morgan, J. Rivier, W. Vale, G. Koob. Chlordiazepoxide attenuates response suppression induced by corticotropin‐releasing factor in the conflict test. Psychopharmacology 86: 170–174, 1985.
 30. Brown, M., L. Fisher. Central nervous system effects of corticotropin releasing factor in the dog. Brain Res. 280: 75–79, 1983.
 31. Calogero, A. E. Neurotransmitter regulation of the hypothalamic corticotropin‐releasing hormone neuron. [Review] [ refs]. Ann. N.Y. Acad. Sci. 771: 31–40, 1995.
 32. Carryer, H. M., D. W. Sherrick, C. F. Gastineau. Occurence of allergic disease in patients with adrenal cortical hypofunction. JAMA 17: 1356–1360, 1960.
 33. Chang, C., R. Pearse II, S. O'Connell, M. Rosenfeld. Identification of a seven transmembrane helix receptor for corticotropin‐releasing factor and sauvagine in mammalian brain. Neuron 1187–1195, 1993.
 34. Chappell, P., M. Smith, C. Kilts, G. Bissette, J. Ritchie, C. Anderson, C. Nemeroff. Alterations in corticotropin‐releasing factor‐like immunoreactivity in discrete rat brain regions after acute and chronic stress. J. Neurosci. 6: 2908–2914, 1986.
 35. Chen, R., K. Lewis, M. Perrin, W. Vale. Expression cloning of a human corticotropin‐releasing factor receptor. Proc. Natl. Acad. Sci. U.S.A. 90: 8967–8971, 1993.
 36. Comb, M., N. C. Birnberg, A. Seasholtz, E. Herbert, H. M. Goodman. A cyclic AMP‐ and phorbol ester‐inducible DNA element. Nature 323: 353–356, 1986.
 37. Cryer, P. E., Glucose homeostasis and hypoglycemia. In: Textbook of Endocrinology, edited by J. D. Wilson and D. W. Foster. Philadelphia: W. B. Saunders, 1992: p. 1223–1254.
 38. Cuneo, R. C., J. H. Livesey, M. G. Nicholls, E. A. Espiner, R. A. Donald. Effects of alpha‐1 adrenergic blockade on the hormonal response to hypoglycaemic stress in normal man. Clin. Endocrinol. (Oxf.) 26: 1–8, 1987.
 39. Dallman, M. F., S. F. Akana, C. S. Cascio, D. N. Darlington, L. Jacobson, N. Levin. Regulation of ACTH Secretion: Variations on a Theme of B. Recent Prog. Horm. Res. 43: 113–173, 1987.
 40. Danaldson, C. J., S. W. Sutton, M. H. Perrin, A. Z. Corrigan, K. A. Lewis, J. E. Rivier, J. M. Vaughan, W. W. Vale. Cloning and characterization of human urocortin. Endocrinology 137: 38–96 1996.
 41. Darlington, D. N., G. Chew, T. Ha, L. C. Keil, M. F. Dallman. Corticosterone, but not glucose, treatment enables fasted adrenalectomized rats to survive moderate hemorrhage. Endocrinology 127: 766–772, 1990.
 42. Darlington, D. N., R. B. Neves, T. Ha, G. Chew, M. F. Dallman. Fed, but not fasted, adrenalectomized rats survive the stress of hemorrhage and hypovolemia. Endocrinology 127: 759–765, 1990.
 43. De Souza, E. B., T. R. Insel, M. H. Perrin, J. Rivier, W. W. Vale, M. J. Kuhar. Corticotropin‐releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study. J. Neurosci. 5: 3189–3203, 1985.
 44. DeBold, C. R., G. S. Decherney, R. V. Jackson, W. R. Sheldon, A. N. Alexander, D. P. Island, J. Rivier, W. Vale, D. N. Orth. Effect of synthetic ovine corticotropin‐releasing factor: prolonged duration of action and biphasic response of plasma adrenocorticotropin and cortisol. J. Clin. Endocrinol. Metab. 57: 294–298, 1983.
 45. DeBold, C. R., W. R. Sheldon, G. S. Decherney, R. V. Jackson, A. N. Alexander, W. Vale, J. Rivier, D. N. Orth. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin‐releasing factor. J. Clin. Invest. 73: 533–538, 1984.
 46. Decherney, G. S., C. R. DeBold, R. V. Jackson, W. R. Jr. Sheldon, T. C. Kamilaris, D. P. Island, D. N. Orth. Effect of ovine corticotropin‐releasing hormone administered during insulin‐induced hypoglycemia on plasma adrenocorticotropin and cortisol. J. Clin. Endocrinol. Metab. 64: 1211–1218, 1987.
 47. Deisseroth, K., E. K. Heist, R. W. Tsien. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392: 198–202, 1998.
 48. DeSouza, E., T. Insel. Corticotropin‐releasing factor (CRF) receptors in the rat central nervous system: autoradiographic localization studies. In: Corticotropin‐Releasing Factor: Basic and Clinical Studies of a Neuropeptide, edited by E. DeSouza and C. Nemeroff. Boca Raton: CRC Press, p. 69–90, 1990.
 49. Dunn, A., C. Berridge. Physiological and behavioral responses to corticotropin‐releasing factor admnistration: is CRF a mediator of anxiety or stress responses? Brain Res. Rev. 15: 71–100, 1990.
 50. Dunn, A. J., A. H. Swiergiel. Behavioral responses to stress are intact in CRF‐deficient mice. Brain Res. 845: 14–20, 1999.
 51. Ellis, M. J., R. S. Schmidli, R. A. Donald, J. H. Livesey, E. A. Espiner. Plasma corticotrophin‐releasing factor and vasopressin responses to hypoglycaemia in normal man. Clin. Endocrinol. (Oxf.) 32: 93–100, 1990.
 52. Emanuel, R. L., B. G. Robinson, E. W. Seely, S. W. Graves, I. Kohane, D. Saltzman, J. A. Majzoub. Corticotrophin releasing hormone levels in human plasma and amniotic fluid during gestation. Clin. Endocrino. 40: 257–262, 1994.
 53. Eskay, R. L., M. Grino, H. T. Chen. Interleukins, signal transduction, and the immune system‐ mediated stress response. Adv. Exp. Med. Biol. 274: 331–343, 1990.
 54. Evans, R. M. Molecular characterization of the glucocorticoid receptor. [Review] [ refs]. Recent Prog. Horm. Res. 45: 1–22, 1989.
 55. Fencl, M. D., R. J. Stillman, J. Cohen, D. Tulchinsky. Direct evidence of sudden rise in fetal corticoids late in human gestation. Nature 287: 225–226, 1980.
 56. Fisher, L. A. Central actions of corticotropin‐releasing factor on autonomic nervous activity and cardiovascular functioning. [Review] [ refs]. Ciba. Found. Symp. 172: 243–53, 1993.
 57. Frim, D. M., R. L. Emanuel, B. G. Robinson, C. M. Smas, G. K. Adler, J. A. Majzoub. Characterization and gestational regulation of corticotropin‐releasing hormone messenger RNA in human placenta. J. Clin. Invest. 82: 287–292, 1988.
 58. Frim, D. M., B. G. Robinson, K. B. Pasieka, J. A. Majzoub. Differential regulation of corticotropin‐releasing hormone mRNA in rat brain. Am. J. Physiol. 258 (Endocrinol. Metab. 21): E686–E692, 1990.
 59. Gaillard, R. C., D. Turnill, P. Sappino, A. F. Muller. Tumor necrosis factor alpha inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors. Endocrinology 127: 101–106, 1990.
 60. Gibbs, D. M., W. Vale, J. Rivier, S. S. Yen. Oxytocin potentiates the ACTH‐releasing activity of CRF but not vasopressin. Life. Sci. 34: 2245–2249, 1984.
 61. Giguere, V., F. Labrie. Vasopressin potentiates cyclic AMP accumulation and ACTH release induced by corticotropin‐releasing factor (CRF) in rat anterior pituitary cells in culture. Endocrinology 111: 1752–1754, 1982.
 62. Goland, R. S., S. L. Wardlaw, M. Blum, P. J. Tropper, R. I. Stark. Biologically active corticotropin‐releasing hormone in maternal and fetal plasma during pregnancy. Am. J. Obstet. Gynecol. 159: 884–890, 1988.
 63. Goland, R. S., S. L. Wardlaw, R. I. Stark, L. S. Brown Jr., A. G. Frantz. High levels of corticotropin‐releasing hormone immunoactivity in maternal and fetal plasma during pregnancy. J. Clin. Endocrinol. Metab. 63: 1199–1203, 1986.
 64. Guillaume, V., B. Conte‐Devolx, E. Magnan, F. Boudouresque, M. Grino, M. Cataldi, L. Muret, A. Priou, J. C. Figaroli, C. Oliver. Effect of chronic active immunization with antiarginine vasopressin on pituitary‐adrenal function in sheep. Endocrinology 130: 3007–3014, 1992.
 65. Guillemin, R., B. Rosenberg. Humoral hypothalamic control of anterior pituitay: a study with combined tissue cultures. Endocrinology 57: 599–607, 1955.
 66. Guillon, G., R. C. Gaillard, P. Kehrer, P. Schoenenberg, A. F. Muller, S. Jard. Vasopressin and angiotensin induce inositol lipid breakdown in rat adenohypophysial cells in primary culture. Regul. Pept. 18: 119–129, 1987.
 67. Hara, Y., Y. Ueta, T. Isse, N. Kabashima, I. Shibuya, Y. Hattori, H. Yamashita. Increase of urocortin‐like immunoreactivity in the rat hypothalamo‐neurohypophysial system after salt loading and hypophysectomy. Neuroscience Letters 227: 127–130, 1997a.
 68. Hara, Y., Y. Ueta, T. Isse, N. Kabashima, I. Shibuya, Y. Hattori, H. Yamashita. Increase of urocortin‐like immunoreactivity in the rat supraoptic nucleus after dehydration but not food deprivation. Neuroscience Letters 229: 65–68, 1997b.
 69. Harbuz, M., S. Lightman. Responses of hypothalamic and pituitary mRNA to physical and psychological stress in the rat. J. Endocrinol. 122: 705–711, 1989.
 70. Harris, G. Neural control of the pituitary gland. Physiol. Rev. 28, No. 2: 139–179, 1948.
 71. Heinrichs, S., F. Menzaghi, E. Pich, H. Baldwin, S. Rassnick, K. Britton, G. Koob. Anti‐stress action of a corticotropin‐releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity. Neuropsychopharmacology 11, No. 3: 179–186, 1994.
 72. Heinrichs, S., E. Pich, K. Miczek, K. Britton, G. Koob. Corticotropin‐releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action. Brain Res. 581: 190–197, 1992.
 73. Howlett, T. A., A. Grossman, L. McLoughlin, L. Perry, A. White, D. H. Coy, L. H. Rees, G. M. Besser. The effect of ovine corticotrophin‐releasing factor on the hormonal response to insulin‐induced hypoglycaemia. Clin. Endocrinol. (Oxf.) 30: 185–190, 1989.
 74. Imaki, T., J. Nahan, C. Rivier, P. Sawchenko, W. Vale. Differential regulation of corticotropin‐releasing factor mRNA in rat brain regions by glucocorticoids and stress. J. Neurosci. 11: 585–599, 1991.
 75. Jackson, R. V., A. J. Jackson, J. E. Grice, P. J. Penfold, M. B. Armour, A. W. Bachmann. Adrenaline infusion and adrenocorticotrophin (ACTH) and cortisol release in normotensive and hypertensive man. Clin Exp. Pharmacol. Physiol 14: 203–208, 1987.
 76. Japon, M. A., M. Rubinstein, M. J. Low. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J. Histochem. Cytochem. 42: 1117–1125, 1994.
 77. Jacobson, L. Glucocorticoid replacement, but not corticotropin‐releasing hormone deficiency, prevents adrenalectomy‐induced anorexia in mice. Endocrinology 140: 310–7, 1999.
 78. Jacobson, L., L. J. Muglia, S. C. Weninger, K. Pacák, J. A. Majzoub. CRH deficiency impairs but does not block pituitary‐adrenal responses to diverse stressors Neuroendocrinology 71: 79–87, 2000.
 79. Jeong, K. H., L. Jacobson, E. P. Widmaier, J. A. Majzoub. Normal suppression of the reproductive axis following stress in corticotropin‐releasing hormone‐deficient mice. Endocrinology 140: 1702–1708, 1999.
 80. Jeong, K. H., L. Jacobson, K. Pacák, E. P. Widmaier, D. S. Goldstein, J. A. Majzoub. Impaired basal and restraint‐induced epinephrine secretion in corticotropin‐releasing hormone‐deficient mice. Endocrinology 141: 256–263, 2000.
 81. Jezova, D., I. Skultetyova, D. I. Tokarev, P. Bakos, M. Vigas. Vasopressin and oxytocin in stress. Ann. N.Y. Acad. Sci. 771: 192–203, 1995.
 82. Jingami, H., N. Mizuno, H. Takahashi, S. Shibahara, Y. Furutani, H. Imura, S. Numa. Cloning and sequence analysis of cDNA for rat corticotropin‐releasing factor precursor. FEBS Letters 191: 63–66, 1985.
 83. Kalin, N., S. Shelton, G. Kraemer, W. McKinney. Corticotropin‐releasing factor administered intraventricularly to Rhesus monkeys. Peptides 4: 217–220, 1983.
 84. Kalin, N., J. Sherman, L. Takahashi. Antagonism of endogenous CRH systems attenuates stress‐induced freezing behavior in rats. Brain Res. 457: 130–135, 1988.
 85. Karalis, K., G. Goodwin, J. A. Majzoub. Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of human labor. Nat. Med. 2: 556–560, 1996.
 86. Karalis, K., H. Sano, J. Redwine, S. Listwak, R. L. Wilder, G. P. Chrousos. Autocrine or paracrine inflammatory actions of corticotropin‐releasing hormone in vivo. Science 254: 421–420, 1991.
 87. Karalis, K., G. Mastorakos, H. Sano, R. L. Wilder, G. P. Chrousos. Somatostatin may participate in the antiinflammatory actions of glucocorticoids. Endocrinology 136: 4133–4138, 1995.
 88. Karalis, K. P., E. Kontopoulos, L. J. Muglia, J. A. Majzoub. Corticotropin‐releasing hormone deficiency unmasks the proinflammatory effect of epinephrine. Proc. Natl. Acad. Sci. U.S.A. 96: 7093–7097, 1999.
 89. Karolyi, I. J., H. L. Burrows, T. M. Ramesh, M. Nakajima, J. S. Lesh, E. Seong, S. A. Camper, A. F. Seasholtz. Altered anxiety and weight gain in corticotropin‐releasing hormone‐binding protein‐deficient mice. Proc. Natl. Acad. Sci. U.S.A. 96: 11595–11600, 1999.
 90. Katsuura, G., A. Arimura, K. Koves, P. E. Gottschall. Involvement of organum vasculosum of lamina terminalis and preoptic area in interleukin 1 beta‐induced ACTH release. Am. J. Physiol. 258 (Endocrinol. Metab. 21): E163–E171, 1990.
 91. Katsuura, G., P. E. Gottschall, R. R. Dahl, A. Arimura. Adrenocorticotropin release induced by intracerebroventricular injection of recombinant human interleukin‐1 in rats: possible involvement of prostaglandin. Endocrinology 122: 1773–1779, 1988.
 92. Keegan, C. E., J. P. Herman, I. J. Karolyi, K. S. O'Shea, S. A. Camper, A. F. Seasholtz. Differential expression of corticotropin‐releasing hormone in developing mouse embryos and adult brain. Endocrinology 134: 2547–2555, 1994.
 93. Kehrer, P., D. Turnill, J. M. Dayer, A. F. Muller, R. C. Gaillard. Human recombinant interleukin‐1 beta and‐alpha, but not recombinant tumor necrosis factor alpha stimulate ACTH release from rat anterior pituitary cells in vitro in a prostaglandin E2 and cAMP independent manner. Neuroendocrinology 48: 160–166, 1988.
 94. Keller‐Wood, M., M. Dallman. Corticosteroid inhibition of ACTH secretion. Endocr. Rev. 5, No. 1: 1–24, 1984.
 95. Kiss, A., D. Jezova, G. Aguilera. Activity of the hypothalamic pituitary adrenal axis and sympathoadrenal system during food and water deprivation in the rat. Brain Res. 663: 84–92, 1994.
 96. Knapp, L. T., C. E. Keegan, A. F. Seasholtz, S. A. Camper. Corticotropin‐releasing hormone (Crh) maps to mouse chromosome 3. Mammalian Genome 4: 615–617, 1993.
 97. Koenig, J. I. Pituitary gland: neuropeptides, neurotransmitters and growth factors. Toxicol. Pathol. 17: 256–265, 1989.
 98. Korebrits, C., M. Ramirez, L. Watson, E. Brinkman, A. D. Bocking, J.R.G. Challis. Maternal corticotropin‐releasing hormone is increased with impending preterm birth. J. Clin. Endo. Metab. 83: 1585–1591, 1998.
 99. Korte, S., G. Korte‐Bouws, B. Bohus, G. Koob. Effect of corticotropin‐releasing factor antagonist on behavioral and neuroendocrine responses during exposure to defensive burying paradigm in rats. Physiol. Behav. 56, No.1: 115–120, 1994.
 100. Kovacs, K. J., P. E. Sawchenko. Regulation of stress‐induced transcriptional changes in the hypothalamic neurosecretory neurons. J. Molec. Neurosci. 7: 125–133, 1996.
 101. Kwak, S. P., M. I. Morano, E. A. Young, S. J. Watson, H. Akil. Diurnal CRH mRNA rhythm in the hypothalamus: decreased expression in the evening is not dependent on endogenous glucocorticoids. Neuroendocrinology 57: 96–105, 1993.
 102. Labrie, F., V. Giguere, L. Proulx, G. Lefevre. Interactions between CRF, epinephrine, vasopressin and glucocorticoids in the control of ACTH secretion. J. Steroid. Biochem. 20: 153–160, 1984.
 103. Larsen, P. J., M. S. Harbuz, D. S. Jessop, G. Aguilera, D. J. Eckland, S. L. Lightman. Evidence for arginine vasopressin as the primary activator of the HPA axis during adjuvant‐induced arthritis. Br. J. Pharmacol. 116: 2417–2424, 1995.
 104. Levin, N., M. Blum, J. L. Roberts. Modulation of basal and corticotropin‐releasing factor‐stimulated proopiomelanocortin gene expression by vasopressin in rat anterior pituitary. Endocrinology 125: 2957–2966, 1989.
 105. Lightman, S., W. Young. Corticotrophin‐releasing factor, vasopressin, and proopiomelanocortin mRNA responses to stress and opiates in the rat. J. Physiol. 403: 511–523, 1988.
 106. Lightman, S. L., W. S. Young. Influence of steroids on the hypothalamic corticotropin‐releasing factor and preproenkephalin mRNA responses to stress. Proc. Natl. Acad. Sci. U.S.A. 86: 4306–4310, 1989.
 107. Linton, E. A., D. P. Behan, P. W. Saphier, P.J. Lowry. Corticotropin‐releasing hormone (CRH)‐binding protein: reduction in the adrenocorticotropin‐releasing activity of placental but not hypothalamic CRH. J. Clin. Endocrinol. Metab. 70: 1574–1580, 1990.
 108. Loeffler, J. P., N. Kley, C. W. Pittius, V. Hollt. Calcium ion and cyclic adenosine 3',5'‐monophosphate regulate proopiomelanocortin messenger ribonucleic acid levels in rat intermediate and anterior pituitary lobes. Endocrinology 119: 2840–2847, 1986.
 109. Lovenberg, T., D. Chalmers, C. Liu, E. DeSouza. CRF2‐alpha and CRF2‐beta receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 136, No. 9: 4139–4142, 1995.
 110. Lovenberg, T., C. Liaw, D. Grigoriadis, W. Clevenger, D. Chalmers, E. DeSouza, T. Oltersdorf. Cloning and characterization of a functionally distinct corticotropin‐releasing factor receptor subtype from rat brain. Proc. Natl. Acad. Sci. U.S.A. 92: 836–840, 1995.
 111. Lowry, P. J., F. E. Estivariz, G. E. Gillies, A. C. Kruseman, E. A. Linton. CRF: its regulation of ACTH and proopiomelanocortin peptide release and its extra hypothalamic occurrence. Acta Endocrinol. Suppl. (Copenh.). 276: 56–62, 1986.
 112. Ludwig, D. S., K. G. Mountjoy, J. B. Tatro, J. A. Gillette, R. C. Frederich, J. S. Flier, E. Maratosflier. Melanin‐concentration hormone‐ a functional melanocortin antagonist in the hypothalamus. Am. J. Physiol. 274 (Endocrinol. Metab. 37): E627–E633, 1998.
 113. Luini, A., D. Lewis, S. Guild, D. Corda, J. Axelrod. Hormone secretagogues increase cytosolic calcium by increasing cAMP in corticotropin‐secreting cells. Proc. Natl. Acad. Sci. U.S.A. 82: 8034–8038, 1985.
 114. Magiakou, M. A., G. Mastorakos, D. Rabin, A. N. Margioris, B. Dubbert, A. E. Calogero, C. Tsigos, P. J. Munson, G.P. Chrousos. The maternal hypothalamic‐pituitary‐adrenal axis in the third trimester of human pregnancy. Clin. Endocrinol. 44: 419–428, 1996.
 115. Majzoub, J. A., R. Emanuel, G. Adler, C. Martinez, B. Robinson, G. Wittert. Second messenger regulation of mRNA for corticotropin‐releasing factor. [Review]. Ciba Foundation Symposium 172: 30–43; discuss, 1993.
 116. Majzoub, J. A., J. A. McGregor, C.J. Lockwood, R. Smith, M. S. Taggart, J. A Schulkin. Central theory of preterm labor: a putative role for corticotropin‐releasing hormone. Am. J. Obstet. Gyn. 180: 232–241, 1999.
 117. Makara, G., E. Stark, M. Karteszi, M. Palkovits, G. Rappay. Effects of paraventricular lesions on stimulated ACTH release and CRH in stalk‐median eminence of the rat. Am. J. Physiol. 240 (Endocrinol. Metab. 3): E441–E446, 1981.
 118. Makino, S., P. Gold, J. Schulkin. Corticosterone effects on corticotropin‐releasing hormone mRNA in the central nucleus of the amygdala and the parvocellular region of the paraventricular nucleus of the hypothalamus. Brain Res. 640: 105–112, 1994a.
 119. Makino, S., P. Gold, J. Schulkin. Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus. Brain Res. 657: 141–149, 1994b.
 120. Makino, S., M. A. Smith, P. W. Gold. Increased expression of corticotropin‐releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology 136: 3299–3309, 1995.
 121. Masuzawa, M., Y. Oki, M. Ozawa, F. Watanabe, T. Yoshimi. Corticotropin‐releasing factor but not urocortin is involved in adrenalectomy‐induced adrenocortiotropic release. J. Neuronendocrinol. 11: 71–74, 1999.
 122. Mason, J. A historical view of the stress field. Journal of Human Stress 1, No. 1: 6–12, 1975a.
 123. Mason, J. A historical view of the stress field, Part II. Journal of Human Stress 22–36, 1975b.
 124. Matta, S., J. Singh, R. Newton, B. M. Sharp. The adrenocorticotropin response to interleukin‐1 beta instilled into the rat median eminence depends on the local release of catecholamines. Endocrinology 127: 2175–2182, 1990.
 125. McCann, S. M., V. Rettori, L. Milenkovic, J. Jurcovicova, M. C. Gonzalez. Role of monokines in control of anterior pituitary hormone release. Adv. Exp. Med. Biol. 274: 315–329, 1990.
 126. Michie, H. R., J. A. Majzoub, S. T. O'Dwyer, A. Revhaug, D. W. Wilmore. Both cyclooxygenase‐dependent and cyclooxygenase‐independent pathways mediate the neuroendocrine response in humans. Surgery. 108: 254–9, discuss, 1990.
 127. Michie, H. R., K. R. Manogue, D. R. Spriggs, A. Revhaug, S. ODwyer, C. A. Dinarello, A. Cerami, S. M. Wolff, D. W. Wilmore. Detection of circulating tumor necrosis factor after endotoxin administration. N. Engl. J. Med. 318: 1481–1486, 1988.
 128. Michie, H. R., D. R. Spriggs, K. R. Manogue, M. L. Sherman, A. Revhaug, S. T. ODwyer, K. Arthur, C. A. Dinarello, A. Cerami, S. M. Wolff, et Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings. Surgery, 104: 280–286, 1988.
 129. Milsom, S. R., R. A. Donald, E. A. Espiner, M. G. Nicholls, J. H. Livesey. The effect of peripheral catecholamine concentrations on the pituitary‐adrenal response to corticotrophin releasing factor in man. Clin. Endocrinol. (Oxf.) 25: 241–246, 1986.
 130. Moreau, J. L., G. Kilpatrick, F. Jenck. Urocortin, a novel neuropeptide with anxiogenic‐like properties. Neuroreport. 8: 1697–1701, 1997.
 131. Morley, J., A. Levine. Corticotropin releasing factor, grooming, and ingestive behavior. Life Sci. 31: 1459–1464, 1982.
 132. Muglia, L., L. Jacobson, P. Dikkes, J. A. Majzoub. Corticotropin‐releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 373: 427–432, 1995.
 133. Muglia, L. J., D. S. Bae, T. T. Brown, S. K. Vogt, J. G. Alvarez, M. E. Sunday, J. A. Majzoub. Proliferation and differentiation defects during lung development in corticotropin‐releasing hormone deficient mice. Am. J. Resp. Cell. and Mol. Biol. 20: 181–188, 1999.
 134. Muglia, L. J., L. Jacobson, S. C. Weninger, C. E. Luedke, D. S. Bae, K. H. Jeong, J. A. Majzoub. Impaired diurnal adrenal rhythmicity restored by constant infusion of corticotropin‐releasing hormone in corticotropin‐releasing hormone‐deficient mice. J. Clin. Invest. 99: 2923–2929, 1997.
 135. Muglia, L J, Jacobson L, Luedke, C E, Vogt, S K, Schaefer, M L, Dikkes P, Fukuda S, Saiki Y, Suda T, Majzoub, J A. Corticotropin‐releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency, J. Clin. Invest. 2000 (in press).
 136. Munck, A., P. M. Guyre, N. J. Holbrook. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr. Rev. 5: 25–44, 1984.
 137. Nabel, E. G., W. S. Colucci, L. S. Lilly, S. S. Cutler, J. A. Majzoub, S. M. St. John, V. J. Dzau, M. A. Creager. Relationship of cardiac chamber volume to baroreflex activity in normal humans. J. Clin. Endocrinol. Metab. 65: 475–481, 1987.
 138. Naitoh, Y., J. Fukata, T. Tominaga, Y. Nakai, S. Tamai, K. Mori, H. Imura. Interleukin‐6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely moving rats. Biochem. Biophys. Res. Commun. 155: 1459–1463, 1988.
 139. Nakamura, H., S. Motoyoshi, T. Kadokawa. Antiinflammatory action of interleukin 1 through the pituitary‐adrenal axis in rats. Eur. J. Pharmacol. 151: 67–73, 1988.
 140. Navarra, P., S. Tsagarakis, M. S. Faria, L. H. Rees, G. M. Besser, A. B. Grossman. Interleukins‐1 and‐6 stimulate the release of corticotropin‐ releasing hormone‐41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology 128: 37–44, 1991.
 141. Nemeroff, C. The role of corticotropin‐releasing factor in the pathogenesis of major depression. Pharmacopsychiatry 21: 76–82 1988.
 142. Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308: 693–698, 1984.
 143. Owens, M. J., C. B. Nemeroff. Preclinical and clinical studies with corticotropin‐releasing factor: implications for affective disorders. Psychopharmacol. Bull. 24: 355–359, 1988.
 144. Page, S. R., V. T. Ang, R. Jackson, A. White, S. S. Nussey, J. S. Jenkins. The effect of oxytocin infusion on adenohypophyseal function in man. Clin. Endocrinol. (Oxf.). 32: 307–313, 1990.
 145. Parkes, D. G., J. Vaughan, J. Rivier, W. Vale, C. N. May. Cardiac inotropic actions of urocortin in conscious sheep. Am. J. Physiol. 272: t–22, 1997.
 146. Perrin, M., C. Donaldson, R. Chen, A. Blount, T. Berggren, L. Bilezikjian, P. Sawchenko, W. Vale. Identification of a second corticotropin‐releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc. Natl. Acad. Sci. U.S.A. 92: 2969–2973, 1995.
 147. Perrin, M., C. Donaldson, R. Chen, K. Lewis, W. Vale. Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor. Endocrinology 133: 3058–3061, 1993.
 148. Petraglia, F., P. Florio, R. Gallo, T. Simoncini, M. Saviozzi, A. M. Di Blasio, J. Vaughan, W. Vale. Human placenta and fetal membranes express human urocortin mRNA and peptide. J. Clin. Endocrinol. Metab. 81: 3807–3810, 1996.
 149. Pitts, A. F., M. A. Preston, R. S. Jaeckle, W. Meller, R. G. Kathol. Simulated acute hemorrhage through lower body negative pressure as an activator of the hypothalamic‐pituitary‐adrenal axis. Horm. Metab. Res. 22: 436–443, 1990.
 150. Plotsky, P. M. Hypophysiotropic regulation of stress‐induced ACTH secretion. Adv. Exp. Med. Biol. 245: 65–81, 1988.
 151. Plotsky, P. M., T. O. Bruhn, W. Vale. Evidence for multifactor regulation of the adrenocorticotropin secretory response to hemodynamic stimuli. Endocrinology 116: 633–639, 1985.
 152. Potter, E., D. Behan, E. Linton, P. Lowry, P. Sawchenko, W. Vale. The central distribution of a corticotropin‐releasing factor (CRF)‐binding protein predicts multiple sites and modes of interaction with CRF. Proc. Natl. Acad. Sci. U.S.A. 89: 4192–4196, 1992.
 153. Potter, E., D. P. Behan, W. H. Fischer, E. A. Linton, P. J. Lowry, W. W. Vale. Cloning and characterization of the cDNAs for human and rat corticotropin releasing factor‐binding proteins. Nature 349: 423–426, 1991.
 154. Potter, E., S. Sutton, C. Donaldson, R. Chen, M. Perrin, K. Lewis, P. Sawchenko, W. Vale. Distribution of corticotropin‐releasing factor receptor mRNA expression in the rat brain and pituitary. Proc. Natl. Acad. Sci. U.S.A. 91: 8777–8781, 1994.
 155. Raff, H., D. C. Merrill, M. M. Skelton, M. S. Brownfield, A. W. Cowley, Jr.. Control of adrenocorticotropin secretion and adrenocortical sensitivity in neurohypophysectomized conscious dogs: effects of acute and chronic vasopressin replacement. Endocrinology 122: 1410–1418, 1988.
 156. Reichlin, S. Neuroendocrine‐immune interactions. N. Engl. J. Med. 329: 1246–1253, 1993.
 157. Reisine, T., G. Rougon, J. Barbet. Liposome delivery of cyclic AMP‐dependent protein kinase inhibitor into intact cells: specific blockade of cyclic AMP‐mediated adrenocorticotropin release from mouse anterior pituitary tumor cells. J. Cell. Biol. 102: 1630–1637, 1986.
 158. Reisine, T., G. Rougon, J. Barbet, H. U. Affolter. Corticotropin‐releasing factor‐induced adrenocorticotropin hormone release and synthesis is blocked by incorporation of the inhibitor of cyclic AMP‐dependent protein kinase into anterior pituitary tumor cells by liposomes. Proc. Natl. Acad. Sci. U.S.A 82: 8261–8265, 1985.
 159. Riegel, A. T., J. Remenick, R. G. Wolford, D. S. Berard, G. L. Hager. A novel transcriptional activator (PO‐B) binds between the TATA box and cap site of the pro‐opiomelanocortin gene. Nucleic Acids Res. 18: 4513–4521, 1990.
 160. Riley, S. C., J. C. Walton, J. M. Herlick, J. R. Challis. The localization and distribution of corticotropin‐releasing hormone in the human placenta and fetal membranes throughout gestation. J. Clin. Endocrinol. Metab. 72: 1001–1007, 1991.
 161. Rivest, S. C. Rivier. Influence of the paraventricular nucleus of the hypothalamus in the alteration of neuroendocrine functions induced by intermittent footshock or interleukin. Endocrinology 129: 2049–2057, 1991.
 162. Rivest, S., C. Rivier. The role of corticotropin‐releasing factor and interleukin‐1 in the regulation of neurons controlling reproductive functions. [Review] [ refs]. Endocr. Rev. 16: 177–199, 1995.
 163. Rivier, C., M. Brownstein, J. Spiess, J. Rivier, W. Vale. In vivo corticotropin‐releasing factor‐induced secretion of adrenocorticotropin, beta‐endorphin, and corticosterone. Endocrinology 110: 272–278, 1982.
 164. Rivier, C., J. Rivier, W. Vale. Stress‐induced inhibition of reproductive functions: role of endogenous corticotropin‐releasing factor. Science 231: 607–609, 1986.
 165. Rivier, C., W. Vale. Influence of the frequency of ovine corticotropin‐releasing factor administration on adrenocorticotropin and corticosterone secretion in the rat. Endocrinology 113: 1422–1426, 1983.
 166. Rivier, C., W. Vale. Influence of corticotropin‐releasing factor on reproductive functions in the rat. Endocrinology 114: 914–921, 1984.
 167. Rivier, C., W. Vale. Effects of corticotropin‐releasing factor, neurohypophyseal peptides, and catecholamines on pituitary function. Fed. Proc. 44: 189–195, 1985.
 168. Rivier, C., W. Vale. Stimulatory effect of interleukin‐1 on adrenocorticotropin secretion in the rat: is it modulated by prostaglandins. Endocrinology 129: 384–388, 1991.
 169. Rivier, C. L., P. M. Plotsky. Mediation by corticotropin releasing factor (CRF) of adenohypophysial hormone secretion. Annu. Rev. Physiol. 48: 475–494, 1986.
 170. Rivier, J., C. Rivier, W. Vale. Synthetic competitive antagonists of corticotropin‐releasing factor: effect on ACTH secretion in the rat. Science 224: 889–891, 1984.
 171. Robinson, B. G., R. L. Emanuel, D. M. Frim, J. A. Majzoub. Glucocorticoid stimulates expression of corticotropin‐releasing hormone gene in human placenta. Proc. Natl. Acad. Sci. U.S.A. 85: 5244–5248, 1988.
 172. Roche, P. J., R. J. Crawford, R. T. Fernley, G. W. Tregear, J. P. Coghlan. Nucleotide sequence of the gene coding for ovine corticotropin‐releasing factor and regulation of its mRNA levels by glucocorticoids. Gene 71: 421–431, 1988.
 173. Romero, L. M., P. M. Plotsky, R. M. Sapolsky. Patterns of adrenocorticotropin secretagog release with hypoglycemia, novelty, and restraint after colchicine blockade of axonal transport. Endocrinology 132: 199–204, 1993.
 174. Rosen, L. B., J. A. Majzoub, G. K. Adler. Effects of glucocorticoid on corticotropin‐releasing hormone gene regulation by second messenger pathways in NPLC and AtT‐20 cells. Endocrinology 130: 2237–2244, 1992.
 175. Saavedra, J. M., M. Palkovits, J. S. Kizer, M. Brownstein, J. A. Zivin. Distribution of biogenic amines and related enzymes in the rat pituitary gland. J. Neurochem. 25: 257–260, 1975.
 176. Saffran, M., A. Schally, B. Benfey. Stimulation of the release of corticotropin from the adenohypophysis by a neurohypophysial factor. Endocrinology 57: 439–444, 1955.
 177. Sapolsky, R., C. Rivier, G. Yamamoto, P. Plotsky, W. Vale. Interleukin‐1 stimulates the secretion of hypothalamic corticotropin‐ releasing factor. Science 238: 522–524, 1987.
 178. Sawchenko, P. E., L. W. Swanson, W. W. Vale. Co‐expression of corticotropin‐releasing factor and vasopressin immunoreactivity in parvocellular neurosecretory neurons of the adrenalectomized rat. Proc. Natl. Acad. Sci. U.S.A. 81: 1883–1887, 1984.
 179. Schafer, M., S. A. Mousa, C. Stein. Corticotropin‐releasing factor in antinociception and inflammation. [Review] [ refs]. Eur. J. Pharmacol. 323: 1–10, 1997.
 180. Schulte, H. M., G. P. Chrousos, P. W. Gold, J. D. Booth, E. H. Oldfield, G. B. J. Cutler, D. L. Loriaux. Continuous administration of synthetic ovine corticotropin‐releasing factor in man. Physiological and pathophysiological implications. J. Clin. Invest. 75: 1781–1785, 1985.
 181. Schulz, D. W., R. S. Mansbach, J. Sprouse, J. P. Braselton, J. Collins, M. Corman, A. Dunaiskis, S. Faraci, A. W. Schmidt, T. Seeger, P. Seymour, F. D. Tingley, E. N. Winston, Y. L. Chen, J. Heym. CP‐154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors. Proc. Natl. Acad. Sci. U.S.A. 93: 10477–10482, 1996.
 182. Schwartz, L. B. Understanding human parturition. Lancet 350: 1792–1793, 1997.
 183. Seasholtz, A. F., R. C. Thompson. J. O. Douglass. Identification of a cyclic adenosine monophosphate‐responsive element in the rat corticotropin‐releasing hormone gene. Mol. Endocrinol. 2: 1311–1319, 1988.
 184. Selye, H. A syndrome produced by diverse nocous agents. Nature 138: 32 1936a.
 185. Selye, H. Thymus and adrenals in the response of the organism to injuries and intoxications. Br. J. Exper. Pathol. 17: 234–248, 1936b.
 186. Selye, H. Confusion and controversy in the stress field. Journal of Human Stress 37–44, 1975.
 187. Sharp, B. M., S. G. Matta, P. K. Peterson, R. Newton, C. Chao, K. Mcallen. Tumor necrosis factor‐alpha is a potent ACTH secretagogue: comparison to interleukin‐1 beta. Endocrinology 124: 3131–3133, 1989.
 188. Shibahara, S., Y. Morimoto, Y. Furutani, M. Notake, H. Takahashi, S. Shimizu, S. Horikawa, S. Numa. Isolation and sequence analysis of the human corticotropin‐releasing factor precursor gene. EMBO Journal 2: 775–779, 1983.
 189. Sobel, D. O. Characterization of 12‐O‐tetradecanoyl‐phorbol‐13 acetate mediated ACTH release. Endocr. Res. 14: 149–163, 1988.
 190. Spengler, D., R. Rupprecht, L. P. Van, F. Holsboer. Identification and characterization of a 3',5'‐cyclic adenosine monophosphate‐responsive element in the human corticotropin‐releasing hormone gene promoter. Mol. Endocrinol. 6: 1931–1941, 1992.
 191. Spina, M., E. Merlo‐Pich, R. K. Chan, A. M. Basso, J. Rivier, W. Vale, G. F. Koob. Appetite‐suppressing effects of urocortin, a CRF‐related neuropeptide. Science 273: 1561–1564, 1996.
 192. Spinedi, E., A. Negro‐Vilar. Arginine vasopressin and adrenocorticotropin release: correlation between binding characteristics and biological activity in anterior pituitary dispersed cells. Endocrinology 114: 2247–2251, 1984.
 193. Stenzel‐Poore, M., S. Heinrichs, S. Rivest, G. Koob, W. Vale. Overproduction of corticotropin‐releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J. Neurosci. 14: 2579–2584, 1994.
 194. Stenzel, P., R. Kesterson, W. Yeung, R. Cone, M. Rittenberg, M. Stenzel‐Poore. Identification of a novel murine receptor for corticotropin‐releasing hormone expressed in the heart. Mol. Endocrinol. 9: 637–645, 1995.
 195. Suda, T., Y. Nakano, F. Tozawa, T. Sumitomo, Y. Sato, M. Yamada, H. Demura. The role of corticotropin‐releasing factor and vasopressin in hypoglycemia‐induced proopiomelanocortin gene expression in the rat anterior pituitary gland. Brain Res. 579: 303–308, 1992.
 196. Suda, T., F. Tozawa, T. Ushiyama, N. Tomori, T. Sumitomo, Y. Nakagami, M. Yamada, H. Demura, K. Shizume. Effects of protein kinase‐C‐related adrenocorticotropin secretagogues and interleukin‐1 on proopiomelanocortin gene expression in rat anterior pituitary cells. Endocrinology 124: 1444–1449, 1989.
 197. Sutton, R., G. Koob, M. Le Moal, J. Rivier, W. Vale. Corticotropin releasing factor produces behavioural activation in rats. Nature 297: 331–333, 1982.
 198. Swerdlow, N., M. Geyer, W. Vale, G. Koob. Corticotropin‐releasing factor potentiates acousttic startle in rats: blockade by chlordiazepoxide. Psychopharmacology 88: 147–152, 1986.
 199. Swerdlow, N. R., K. T. Britton, G. F. Koob. Potentiation of acoustic startle by corticotropin‐releasing factor (CRF) and by fear are both reversed by alpha‐helical CRF (9–41). Neuropsychopharmacology 2: 285–292, 1989.
 200. Tazi, A., N. Swerdlow, M. LeMoal, J. Rivier, W. Vale, G. Koob. Behavioral activation by CRF: evidence for the involvement of the ventral forebrain. Life Sci. 41: 41–49, 1987.
 201. Tilders, F. J., R. H. DeRijk, A. M. Van Dam, V. A. Vincent, K. Schotanus, J. H. Persoons. Activation of the hypothalamus‐pituitary‐adrenal axis by bacterial endotoxins: routes and intermediate signals. [Review] [ refs]. Psychoneuroendocrinology 19: 209–232, 1994.
 202. Todd, K., S. L. Lightman. Vasopressin activation of phosphatidylinositol metabolism in rat anterior pituitary in vitro and its modification by changes in the hypothalamo‐pituitary‐adrenal axis. Neuroendocrinology 45: 212–218, 1987.
 203. Tomori, N., T. Suda, Y. Nakagami, F. Tozawa, T. Sumitomo, T. Ushiyama, H. Demura, K. Shizume. Adrenergic modulation of adrenocorticotropin responses to insulin‐induced hypoglycemia and corticotropin‐releasing hormone. J. Clin. Endocrinol. Metab. 68: 87–93, 1989.
 204. Udelsman, R., J. Ramp, W. T. Gallucci, A. Gordon, E. Lipford, J. A. Norton, D. L. Loriaux, G. P. Chrousos. Adaptation during surgical stress. A reevaluation of the role of glucocorticoids. J. Clin. Invest. 77: 1377–1381, 1986.
 205. Uehara, A., P. E. Gottschall, R. R. Dahl, A. Arimura. Interleukin‐1 stimulates ACTH release by an indirect action which requires endogenous corticotropin releasing factor. Endocrinology 121: 1580–1582, 1987a.
 206. Uehara, A., P. E. Gottschall, R. R. Dahl, A. Arimura. Stimulation of ACTH release by human interleukin‐1 beta, but not by interleukin‐1 alpha, in conscious, freely‐moving rats. Biochem. Biophys. Res. Commun. 146: 1286–1290, 1987b.
 207. Vale, W., J. Spiess, C. Rivier, J. Rivier. Characterization of a 41‐residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta‐endorphin. Science 213: 1394–1397, 1981.
 208. Vamvakopoulos, N. C., M. Karl, V. Mayol, T. Gomez, C. A. Stratakis, A. Margioris, G. P. Chrousos. Structural analysis of the regulatory region of the human corticotropin releasing hormone gene. FEBS. Lett. 267: 1–5, 1990.
 209. Van, L. P. Phorbolester stimulates the activity of human corticotropin‐releasing hormone gene promoter via 3',5'‐cyclic adenosine monophosphate response element in transiently transfected chicken macrophages. Endocrinology 132: 30–34, 1993.
 210. Vankelecom, H., P. Carmeliet, H. Heremans, J. Van Damme, R. Dijkmans, A. Billiau, C. Denef. Interferon‐gamma inhibits stimulated adrenocorticotropin, prolactin, and growth hormone secretion in normal rat anterior pituitary cell cultures. Endocrinology 126: 2919–2926, 1990.
 211. Vaughan, J., C. Donaldson, J. Bittencort, M. Perrin, K. Lewis, S. Sutton, R. Chan, A. Turnbull, D. Lovejoy, C. Rivier, J. Rivier, P. Sawchenko, W. Vale. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin‐releasing factor. Nature 378: 287–292, 1995.
 212. Wand, G. S., V. May, B. A. Eipper. Comparison of acute and chronic secretagogue regulation of proadrenocorticotropin/endorphin synthesis, secretion, and messenger ribonucleic acid production in primary cultures of rat anterior pituitary. Endocrinology 123: 1153–1161, 1988.
 213. Watabe, T., K. Tanaka, M. Kumagae, S. Itoh, F. Takeda, K. Morio, M. Hasegawa, T. Horiuchi, S. Miyabe, N. Shimizu. Hormonal responses to insulin‐induced hypoglycemia in man. J. Clin. Endocrinol. Metab. 65: 1187–1191, 1987.
 214. Watanabe, T., A. Morimoto, Y. Sakata, N. Murakami. ACTH response induced by interleukin‐1 is mediated by CRF secretion stimulated by hypothalamic PGE. Experientia 46: 481–484, 1990.
 215. Watanabe, T., Y. Oki, D. N. Orth. Kinetic actions and interactions of arginine vasopressin, angiotensin‐ II, and oxytocin on adrenocorticotropin secretion by rat anterior pituitary cells in the microperifusion system. Endocrinology 125: 1921–1931, 1989.
 216. Watanabe, T., D. N. Orth. Detailed kinetic analysis of adrenocorticotropin secretion by dispersed rat anterior pituitary cells in a microperifusion system: effects of ovine corticotropin‐releasing factor and arginine vasopressin. Endocrinology 121: 1133–1145, 1987.
 217. Watts, A. G., L. W. Swanson. Diurnal variations in the content of preprocorticotropin‐releasing hormone messenger ribonucleic acids in the hypothalamic paraventricular nucleus of rats of both sexes as measured by in situ hybridization. Endocrinology 125: 1734–1738, 1989.
 218. Weninger, S. C., L. J. Muglia, L. Jacobson, J. A. Majzoub. CRH‐deficient mice have a normal anorectic response to chronic stress. Regul. Pept. 84: 69–74, 1999.
 219. Weninger, S. C., A. J. Dunn, L. J. Muglia, P. Dikkes, K. A. Miczek, A. H. Swiergiel, C. W. Berridge, J. A. Majzoub. Stress‐induced behaviors require the corticotropin‐releasing hormone (CRH) receptor, but not CRH. Proc. Natl. Acad. Sci. U.S.A. 96: 8283–8288, 1999.
 220. Weninger, S. C., L. L. Peters, J. A. Majzoub. Urocortin expression in the Edinger‐Westphal nucleus is up‐regulated by stress and corticotropin‐releasing hormone deficiency. Endocrinology 141: 256–263, 2000.
 221. Whitnall, M. H. Stress selectively activates the vasopressin‐containing subset of corticotropin‐releasing hormone neurons. Neuroendocrinology 50: 702–707, 1989.
 222. Whitnall, M.H. Regulation of the hypothalamic corticotropin‐releasing hormone neurosecretory system. Prog. Neurobiol. 40: 573–629, 1993.
 223. Wong, M., J. Licinio, K. Pasternak, P. Gold. Localization of corticotropin‐releasing hormone (CRH) receptor mRNA in adult rat brain by in situ hybridization histochemistry. Endocrinology 135, No.5: 2275–2278, 1994.
 224. Wong, M.L., A. al‐Shekhlee, P. B. Bongiorno, A. Esposito, P. Khatri, E. M. Sternberg, P. W. Gold, J. Licinio. Localization of urocortin messenger RNA in rat brain and pituitary [see comments]. Molecular. Psychiatry 1: 307–312, 1996.
 225. Wyllie, A.H., J. F. Kerr, A. R. Currie. Cellular events in the adrenal cortex following ACTH deprivation. J. Pathol. 106: ix 1972.
 226. Wyllie, A.H., J. F. Kerr, I. A. Macaskill, A. R. Currie. Adrenocortical cell deletion: the role of ACTH. J. Pathol. 111: 85–94, 1973.
 227. Yaswen, L., N. Diehl, M. B. Brennan, U. Hochgeschwender. Obesity in the mouse model of pro‐opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 9: 1066–1070, 1999.
 228. Young, E.A., H. Akil. Corticotropin‐releasing factor stimulation of adrenocorticotropin and beta‐endorphin release: effects of acute and chronic stress. Endocrinology 117: 23–30, 1985.
 229. Zhao, L., C. Donalsdon, G. Smith, W. Vale. The structures of the mouse and human urocortin genes (Ucn and UCN). Genomics 50: 23–33, 1998.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Stacie C. Weninger, Joseph A. Majzoub. Regulation and Actions of Corticotropin‐Releasing Hormone. Compr Physiol 2011, Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms: 103-124. First published in print 2001. doi: 10.1002/cphy.cp070406