Endocrinology of cluster headache: Potential for therapeutic manipulation



Cluster headaches have always been among the most intriguing of the commonly recognized primary headache syndromes. This clinical interest is related to a number of factors, including the intense but short-lived nature of the pain, its sexual predilection, associated trigeminal autonomic dysfunction, and the remarkable circadian and circannual periodicity of cluster periods. Recent advances in neuroimaging and neuroendocrinology have shed light on the pivotal role of the hypothalamus in the biology of cluster headache. We discuss these revelations, along with current clinical observations in headache and sleep medicine.

References and Recommended Reading

  1. 1.
    Symonds C: A particular variety of headache. Brain 1956, 79:217–232.CrossRefPubMedGoogle Scholar
  2. 2.
    Headache Classification Subcommittee of the International Headache Society: The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004, 24(Suppl 1):9–160.Google Scholar
  3. 3.
    Hardebo JE: How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibers. Headache 1994, 34:125–131.CrossRefPubMedGoogle Scholar
  4. 4.
    Hannerz J: Orbital phlebography and signs of inflammation in episodic and chronic cluster headache. Headache 1991, 31:540–542.CrossRefPubMedGoogle Scholar
  5. 5.
    Hannerz J, Ericson K, Bergstrand G: Orbital phlebography in patients with cluster headaches. Cephalalgia 1987, 7:207–211.CrossRefPubMedGoogle Scholar
  6. 6.
    Remahl IN, Waldenlind E, Bratt J, Ekbom K: Cluster headache is not associated with signs of a systemic inflammation. Headache 2000, 40:276–280.CrossRefPubMedGoogle Scholar
  7. 7.
    Empl M, Fordeneuther S, Schwarz M, et al.: Soluble interleukin-2 receptors increase during active periods of cluster headache. Headache 2003, 43:63–68.CrossRefPubMedGoogle Scholar
  8. 8.
    Martelletti R, Stirpano G, DeStefano L, et al.: Defective expression of IL-2 receptors on peripheral blood lymphocytes from patients with cluster headache. Headache 1990, 30:228–231.CrossRefPubMedGoogle Scholar
  9. 9.
    Rasmussen BK: Epidemiology of cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford, UK: Oxford University Press; 1999:23–26.Google Scholar
  10. 10.
    Granella F: Case-control study on the epidemiology of cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford, UK: Oxford University Press; 1999:37–41.Google Scholar
  11. 11.
    Torelli P, Cologno D, Manzone GC: Gender ratio in cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford, UK: Oxford University Press; 1999:48–52.Google Scholar
  12. 12.
    Graham J, Rogado AZ: Some physical, physiological and psychological characteristics of patients with cluster headaches. In Background to Migraines. Third Migraine Symposium, Migraine Trust. London: William Heinemann; 1969:38–52.Google Scholar
  13. 13.
    Matharu MS, Cohen AP, McGonigle DJ, et al.: Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004, 44:747–761.CrossRefPubMedGoogle Scholar
  14. 14.
    Pringsheim T: Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can J Neurol Sci 2002, 29:33–40.PubMedGoogle Scholar
  15. 15.
    Stillman M: Testosterone replacement therapy for treatment of refractory cluster headache. Headache 2006, 46:925–933.CrossRefPubMedGoogle Scholar
  16. 16.
    Stewart P: The adrenal cortex. In Williams Textbook of Endocrinology, edn 10. Edited by Larsen R. Philadelphia: Saunders; 2003:501–505.Google Scholar
  17. 17.
    May A, Bahra, A, Buchelk C, et al.: PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 2000, 55:1328–1335.PubMedGoogle Scholar
  18. 18.
    Bussone G, Leone M, D’Amico D, et al.: Endocrinology of cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford, UK: Oxford, University Press; 1999:179–185.Google Scholar
  19. 19.
    Leone M, Bussone G: A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia 1993, 13:309–317.CrossRefPubMedGoogle Scholar
  20. 20.
    Sjaastad O, Salvesen R, Antonacci F: Headache research strategy. Cephalalgia 1987, 7:1–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Polleri A: Sex steroids and cluster headaches: hypotheses. Cephalalgia 1990, 10:183–187.CrossRefPubMedGoogle Scholar
  22. 22.
    Luboshitzky R, Lavi S, Lavie P: The association between melatonin and sleep stages in normal adults and hypogonadal men. Sleep 1999, 22:867–874.PubMedGoogle Scholar
  23. 23.
    Luboshitzky R, Herer P, Levi M, et al.: Relationship between rapid eye movement sleep and testosterone secretion in normal men. J Androl 1999, 20:731–737.PubMedGoogle Scholar
  24. 24.
    Luboshitzky R, Zabari Z, Shen-Orr Z, et al.: Disruption of the nocturnal testosterone rhythm by sleep fragmentation in normal men. J Clin Endocrinol Metab 2001, 86:1134–1139.CrossRefPubMedGoogle Scholar
  25. 25.
    Holland P, Goadsby PJ: The hypothalamic orexinergic system: pain and primary headaches. Headache 2007, 47:951–962.PubMedGoogle Scholar
  26. 26.
    Kudrow L: Plasma testosterone levels in cluster headache: preliminary results. Headache 1976, 16:28–31.CrossRefPubMedGoogle Scholar
  27. 27.
    Nelson R: Testosterone levels in cluster and non-cluster migrainous headache patients. Headache 1978, 18:265–267.CrossRefPubMedGoogle Scholar
  28. 28.
    Romiti A, Martelletti P, Gallo MF, Giacovazzo M: Low plasma testosterone levels in cluster headache. Cephalalgia 1983, 3:41–44.CrossRefPubMedGoogle Scholar
  29. 29.
    Murialdo G, Fanciullacci M, Nicolodi M, et al.: Cluster headache in the male: sex steroid pattern and gonadotropic response to luteinizing hormone releasing hormone. Cephalalgia 1989, 9:91–98.CrossRefPubMedGoogle Scholar
  30. 30.
    Facchinetti F, Nappi G, Cicolli C, et al.: Reduced testosterone levels in cluster headache: a stress-related phenomenon? Cephalalgia 1986, 6:29–34.CrossRefPubMedGoogle Scholar
  31. 31.
    Strittmatter M, Hamann GF, Grauer M, et al.: Altered activity of the sympathetic nervous system and changes in the balance of hypophyseal, pituitary and adrenal hormones in patients with cluster headache. Neuroreport 1996, 7:1229–1234.CrossRefPubMedGoogle Scholar
  32. 32.
    McCann SM, Haens G, Mastronardi C, et al.: Role of nitric oxide (NO) in control of LHRH release that mediates gonadotropin release and sexual behavior. Curr Pharm Des 2003, 9:381–390.CrossRefPubMedGoogle Scholar
  33. 33.
    Rettori V, Belova N, Dees WL, et al.: Role of nitric oxide in the control of luteinizing hormone-releasing hormone release in vivo and in vitro. Proc Natl Acad Sci U S A 1993, 90:10130–10134.CrossRefPubMedGoogle Scholar
  34. 34.
    Waldenlind E, Bussone G: Biochemistry, circannual and circadian rhythms, endocrinology, and immunology of cluster headaches. In The Headaches, edn 3. Edited by Olesen J, Goadsby PJ, Ramadan NM, et al.: Philadelphia: Lippincott Williams & Wilkins; 2005:759–762.Google Scholar
  35. 35.
    Chazot G, Claustrat B, Brun J, et al.: A chronobiological study of melatonin, cortisol, growth hormone, and prolactin secretion in cluster headache. Cephalalgia 1984, 4:213–220.CrossRefPubMedGoogle Scholar
  36. 36.
    Waldenlind E, Gustafsson SA, Ekbom K, Wetterberg L: Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987, 50:207–213.PubMedGoogle Scholar
  37. 37.
    Waldenlind E, Ekbom K, Wetterberg L, et al.: Lowered circannual urinary melatonin concentrations in episodic cluster headache. Cephalalgia 1994, 14:199–204.CrossRefPubMedGoogle Scholar
  38. 38.
    Frediani F, Amperti E, Leone M, et al.: Cluster headache patients’ responses to dexamethasone suppression test. Headache 1988, 28:130–132.CrossRefPubMedGoogle Scholar
  39. 39.
    Sandrini G, Ward TN: Acute treatment of cluster headache. In The Headaches, edn 3. Edited by Olesen J, Goadsby PJ, Ramadan NM, et al.: Philadelphia: Lippincott Williams & Wilkins; 2005:803–807.Google Scholar
  40. 40.
    Kudrow L: Cluster Headache. Mechanism and Management. Oxford, UK: Oxford University Press; 1980.Google Scholar
  41. 41.
    Couch JR, Ziegler DK: Prednisone therapy for cluster headache. Headache 1978, 18:219–221.CrossRefPubMedGoogle Scholar
  42. 42.
    Mir P, Alberca R, Navarro A, et al.: Prophylactic treatment of episodic cluster headache with intravenous bolus of methylprednisolone. Neurol Sci 2003, 24:318–321.CrossRefPubMedGoogle Scholar
  43. 43.
    Antonacci F, Costa A, Candeloro E, et al.: Single high-dose steroid treatment in episodic cluster headache. Cephalalgia 2005, 25:290–295.CrossRefGoogle Scholar
  44. 44.
    Ambrosini A, Vandanheede M, Rossi P, et al.: Suboccipital (greater occipital nerve) injection with long-acting steroids in cluster headache: a double-blind, placebo-controlled study. Pain 2005, 118:92–96.CrossRefPubMedGoogle Scholar
  45. 45.
    Shields KG, Levy MJ, Goadsby PJ: Alopecia and cutaneous atrophy after greater occipital nerve infiltration with corticosteroids. Neurology 2004, 63:2193–2194.PubMedGoogle Scholar
  46. 46.
    Klimek A: The use of testosterone in the treatment of cluster headache. Eur Neurol 1985, 24:53–56.CrossRefPubMedGoogle Scholar
  47. 47.
    Griffin JE, Wilson JD: Disorders of the testes and the male reproductive tract. In Williams Textbook of Endocrinology, edn 10. Edited by Larsen W. Philadelphia: Sauders; 2003:726–751.Google Scholar
  48. 48.
    Santen RJ: Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone secretion in men? J Clin Invest 1975, 56:1555–1563.CrossRefPubMedGoogle Scholar
  49. 49.
    Winters SJ, Troen P: Evidence for a role of endogenous estrogen in the hypothalamic control of gonadotropin secretion in men. J Clin Endocrinol Metab 1985, 61:842–845.PubMedCrossRefGoogle Scholar
  50. 50.
    Nicolodi M, Sicuteri F, Poggioni M: Hypothalamic modulation of nociception and reproduction in cluster headache. I. Therapeutic trials of leuprolide. Cephalalgia 1993, 13:253–257.CrossRefPubMedGoogle Scholar

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© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.T33, Cleveland Clinic FoundationClevelandUSA

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