Abstract
For decades, glucocorticoid therapy has been a well-recognized abortive treatment for cluster headaches. However, the role of steroid hormones, including both glucocorticoids and sex steroids, in the pathophysiology and therapy of cluster headaches has been a topic of much debate and speculation. Current research now points to the importance of cortisol and testosterone in the pathogenesis of cluster headaches, and they appear to be linked mechanistically to another hormone, melatonin. Melatonin, unlike cortisol or testosterone, is not a product of the hypothalamic pituitary axis but of the retinohypothalamic pineal axis, and is the major biomarker of circadian rhythms. The regulation of steroids and melatonin in the pathogenesis of cluster headaches in turn depends on the sympathetic nervous system. Accumulated evidence suggests sympathetic dysfunction —embodied in the Horner sign so commonly seen in the cluster headache—as a necessary ingredient in the inception of the cluster headache. Sympathetic dysfunction now is thought to be associated with the hypercortisolism, hypotestosteronism, and lower-than-normal melatonin levels in the active cluster patient. Future research may hold the key to a fuller explanation of the complex interaction of hormonal systems in the cluster headache.
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References and Recommended Reading
Symonds C: A particular variety of headache. Brain 1956, 79:217–232.
Headache Classification Subcommittee of the International Headache Society: The International Classification of Headache Disorders, edn 2. Cephalalgia 2004, 24(suppl 1):9–160. Along with the text commentary, this is essential reading for headache clinicians and researchers alike. This classification helps define inclusion criteria in any study of cluster headaches.
Hardebo JE: How cluster headache is explained as an intracavernous infiammatory process lesioning sympathetic fibers. Headache 1994, 34:125–131.
Hannerz J: Orbital phlebography and signs of infiammation in episodic and chronic cluster headache. Headache 1991, 31:540–542.
Hannerz J, Ericson K, Bergstrand G: Orbital phlebography in patients with cluster headaches. Cephalalgia 1987, 7:207–211.
Remahl IN, Waldenlind E, Bratt J, Ekbom K: Cluster headache is not associated with signs of a systemic infiammation. Headache 2000, 40:276–280.
Empl M, Fordeneuther S, Schwarz M, et al.: Soluble interleukin-2 receptors increase during active periods of cluster headache. Headache 2003, 43:63–68. Draws together evidence of immune activation and cytokine release, subsequent hypothalamic-pituitary-adrenal activation, and cortisol release with the induction of pain in the setting of a cluster headache.
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.
Rasmussen BK: Epidemiology of cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford: Oxford University Press; 1999:23–26.
Granella F: Case-control study on the epidemiology of cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford: Oxford University Press; 1999:37–41.
Torelli P, Cologno D, Manzone GC: Gender ration in cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford: Oxford University Press; 1999:48–52.
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.
Pringsheim T: Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can J Neurol Sci 2002, 29:33–40. Up-to-date review of the neuroendocrine and circadian functions of the hypothalamus in cluster headache. It also presents evidence regarding the sympathetic dysfunction.
Stewart P: The adrenal cortex. In Williams Textbook of Endocrinology, edn 10. Edited by Larsen R. Philadelphia: Saunders; 2003:501–505.
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. Seminal article describing the hypothalamic locus of metabolic activity in the patient with cluster headache.
Bussone G, Leone M: Endocrinology of cluster headache. In Cluster Headache and Related Conditions. Edited by Olesen J, Goadsby P. Oxford: Oxford University Press; 1999:179–185.
Leone M, Bussone G: A review of hormonal findings in cluster headache: evidence for hypothalamic involvement. Cephalalgia 1993, 13:309–317.
Sjaastad O, Salvesen R, Antonacci F: Headache research strategy. Cephalalgia 1987, 7:1–6.
Polleri A: Sex steroids and cluster headaches: hypotheses. Cephalalgia 1990, 10:183–187.
Luboshitzky R, Lavi S, Lavie P: The association between melatonin and sleep stages in normal adults and hypogonadal men. Sleep 1999, 22:867–874.
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.
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. One of a series of articles from a laboratory that has studied the relationship of testosterone to melatonin in non-cluster males who have normal and abnormal gonadotropic function. As yet, no studies have been performed on patients with cluster headache.
Kudrow L: Plasma testosterone levels in cluster headache: preliminary results. Headache 1976, 16:28–31.
Nelson R: Testosterone levels in cluster and non-cluster migrainous headache patients. Headache 1978, 18:265–267.
Romiti A, Martelletti P, Gallo MF, Giacovazzo M: Low plasma testosterone levels in cluster headache. Cephalalgia 1983, 3:41–44.
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.
Facchinetti F, Nappi G, Cicolli C, et al.: Reduced testosterone levels in cluster headache: A stress-related phenomenon? Cephalalgia 1986, 6:29–34.
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. One of the early articles to draw the complete picture of adrenergic dysfunction and specific neuroendocrine disorders.
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.
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 1993, 90:10130–10134.
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.
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.
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.
Waldenlind E, Ekbom K, Wetterberg L, et al.: Lowered circannual urinary melatonin concentrations in episodic cluster headache. Cephalalgia 1994, 14:199–204.
Leone M, Maltempo M, Gritti A, Bussone G: The insulin tolerance test and ovine corticotrophin-releasing-hormone test in episodic cluster headache II: comparison with low back pain patients. Cephalalgia 1994, 14:357–364.
Frediani F, Amperti E, Leone M, et al.: Cluster headache patients’ responses to dexamethasone suppression test. Headache 1988, 28:130–132.
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.
Kudrow L: Cluster Headache. Mechanism and Management. Oxford: Oxford University Press; 1980.
Couch JR, Ziegler DK: Prednisone therapy for cluster headache. Headache 1978, 18:219–221.
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.
Antonacci F, Costa A, Candeloro E, et al.: Single high-dose steroid treatment in episodic cluster headache. Cephalalgia 2005, 25:290–295.
Ambrosini A, Vandanheede M, Rossi P, et al.: Suboccipital (greater occipital nerve) injection with long-acting steroids in cluster headache: a double-blind, placebocontrolled study. Pain 2005, 118:92–96.
Shields KG, Levy MJ, Goadsby PJ: Alopecia and cutaneous atrophy after greater occipital nerve infiltration with corticosteroids. Neurology 2004, 63:2193–2194.
Klimek A: The use of testosterone in the treatment of cluster headache. Eur Neurol 1985, 24:53–56.
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Stillman, M. Steroid hormones in cluster headaches. Current Science Inc 10, 147–152 (2006). https://doi.org/10.1007/s11916-006-0027-x
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DOI: https://doi.org/10.1007/s11916-006-0027-x