https://doi.org/10.4081/cc.2024.15775
Sex and gender differences in the epidemiology, clinical features, and pathophysiology of trigeminal autonomic cephalalgias
Submitted: 1 August 2024
Accepted: 30 August 2024
Published: 9 October 2024
Accepted: 30 August 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Emerging evidence suggests that primary headaches, classified as trigeminal autonomic cephalalgias (TACs), may exhibit sex and gender differences in clinical features, mechanisms, and treatment responses. While epidemiological and clinical gender-specific differences have been widely reported for cluster headache, limited evidence is available for other TACs. In this narrative review, we have analyzed the existing data on the influence of sex and gender on cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua. Given the role of calcitonin gene-related peptide (CGRP) in migraine and cluster headache, sex and gender differences in the levels and function of CGRP in preclinical models and patients are reported. Future studies are warranted to elucidate the role of sex and gender in the complex interplay of genetic and neurochemical factors in TACs.
Lieba-Samal D, Wober C. Sex hormones and primary headaches other than migraine. Curr Pain Headache Rep 2011;15:407-14.
DOI: https://doi.org/10.1007/s11916-011-0211-5
Haupt S, Carcel C, Norton R. Neglecting sex and gender in research is a public-health risk. Nature 2024;629:527-30.
DOI: https://doi.org/10.1038/d41586-024-01372-2
Ritz SA, Greaves L. Transcending the male-female binary in biomedical research: constellations, heterogeneity, and mechanism when considering sex and gender. Int J Environ Res Public Health 2022;19.
DOI: https://doi.org/10.3390/ijerph19074083
Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet 2020;396:565-82.
DOI: https://doi.org/10.1016/S0140-6736(20)31561-0
Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211.
DOI: https://doi.org/10.1177/0333102417738202
Katsarava Z, Obermann M, Yoon MS, Dommes P, Kuznetsova J, Weimar C, et al. Prevalence of cluster headache in a population-based sample in Germany. Cephalalgia 2007;27:1014-9.
DOI: https://doi.org/10.1111/j.1468-2982.2007.01380.x
Torelli P, Beghi E, Manzoni GC. Cluster headache prevalence in the Italian general population. Neurology 2005;64:469-74.
DOI: https://doi.org/10.1212/01.WNL.0000150901.47293.BC
Lupi C, Evangelista L, Favoni V, Granato A, Negro A, Pellesi L, et al. Rare primary headaches in Italian tertiary headache centres: three year nationwide retrospective data from the RegistRare Network. Cephalalgia 2018;38:1429-41.
DOI: https://doi.org/10.1177/0333102418768824
Petersen AS, Lund N, Goadsby PJ, Belin AC, Wang SJ, Fronczek R, et al. Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache. Lancet Neurol 2024;23:712-24.
DOI: https://doi.org/10.1016/S1474-4422(24)00143-1
Holle D, Obermann M. Rare primary headaches. Curr Opin Neurol 2014;27:332-6.
DOI: https://doi.org/10.1097/WCO.0000000000000089
Lainez MJ, Guillamon E. Cluster headache and other TACs: pathophysiology and neurostimulation options. Headache 2017;57:327-35.
DOI: https://doi.org/10.1111/head.12874
Lambru G, Matharu MS. Trigeminal autonomic cephalalgias: a review of recent diagnostic, therapeutic and pathophysiological developments. Ann Indian Acad Neurol 2012;15:S51-61.
DOI: https://doi.org/10.4103/0972-2327.100007
Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol 2009;8:755-64.
DOI: https://doi.org/10.1016/S1474-4422(09)70133-4
Casucci G, d'Onofrio F, Torelli P. Rare primary headaches: clinical insights. Neurol Sci 2004;25:S77-83.
DOI: https://doi.org/10.1007/s10072-004-0258-8
Henningsen MJ, Larsen JG, Karlsson WK, Christensen RH, Al-Khazali HM, Amin FM, et al. Epidemiology and clinical features of paroxysmal hemicrania: a systematic review and meta-analysis. Headache 2024;64:5-15.
DOI: https://doi.org/10.1111/head.14658
Prakash S, Patell R. Paroxysmal hemicrania: an update. Curr Pain Headache Rep 2014;18:407.
DOI: https://doi.org/10.1007/s11916-014-0407-6
Groenke BR, Daline IH, Nixdorf DR. SUNCT/SUNA: case series presenting in an orofacial pain clinic. Cephalalgia 2021;41:665-76.
DOI: https://doi.org/10.1177/0333102420977292
Kim BK, Cho SJ, Kim BS, Sohn JH, Kim SK, Cha MJ, et al. Comprehensive application of the international classification of headache disorders. Third Edition, Beta Version. J Korean Med Sci 2016;31:106-13.
DOI: https://doi.org/10.3346/jkms.2016.31.1.106
Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA)--a prospective clinical study of SUNCT and SUNA. Brain 2006;129:2746-60.
DOI: https://doi.org/10.1093/brain/awl202
Williams MH, Broadley SA. SUNCT and SUNA: clinical features and medical treatment. J Clin Neurosci 2008;15:526-34.
DOI: https://doi.org/10.1016/j.jocn.2006.09.006
Sjaastad O, Bakketeig LS. The rare, unilateral headaches. Vaga study of headache epidemiology. J Headache Pain 2007;8:19-27.
DOI: https://doi.org/10.1007/s10194-006-0292-4
Al-Khazali HM, Al-Khazali S, Iljazi A, Christensen RH, Ashina S, Lipton RB, et al. Prevalence and clinical features of hemicrania continua in clinic-based studies: A systematic review and meta-analysis. Cephalalgia 2023;43:3331024221131343.
DOI: https://doi.org/10.1177/03331024221131343
Bigal ME, Lipton RB. The differential diagnosis of chronic daily headaches: an algorithm-based approach. J Headache Pain 2007;8:263-72.
DOI: https://doi.org/10.1007/s10194-007-0418-3
Allena M, De Icco R, Sances G, Ahmad L, Putorti A, Pucci E, et al. Gender differences in the clinical presentation of cluster headache: a role for sexual hormones? Front Neurol 2019;10:1220.
DOI: https://doi.org/10.3389/fneur.2019.01220
Lund N, Barloese M, Petersen A, Haddock B, Jensen R. Chronobiology differs between men and women with cluster headache, clinical phenotype does not. Neurology 2017;88:1069-76.
DOI: https://doi.org/10.1212/WNL.0000000000003715
Lund NLT, Snoer AH, Jensen RH. The influence of lifestyle and gender on cluster headache. Curr Opin Neurol 2019;32:443-8.
DOI: https://doi.org/10.1097/WCO.0000000000000680
Ekbom K, Svensson DA, Traff H, Waldenlind E. Age at onset and sex ratio in cluster headache: observations over three decades. Cephalalgia 2002;22:94-100.
DOI: https://doi.org/10.1046/j.1468-2982.2002.00318.x
Fourier C, Ran C, Steinberg A, Sjostrand C, Waldenlind E, Belin AC. Sex differences in clinical features, treatment, and lifestyle factors in patients with cluster headache. Neurology 2023;100:e1207-e20.
DOI: https://doi.org/10.1212/WNL.0000000000201688
Manzoni GC, Micieli G, Granella F, Tassorelli C, Zanferrari C, Cavallini A. Cluster headache--course over ten years in 189 patients. Cephalalgia 1991;11:169-74.
DOI: https://doi.org/10.1046/j.1468-2982.1991.1104169.x
Lambru G, Stubberud A, Rantell K, Lagrata S, Tronvik E, Matharu MS. Medical treatment of SUNCT and SUNA: a prospective open-label study including single-arm meta-analysis. J Neurol Neurosurg Psychiatry 2021;92:233-41.
DOI: https://doi.org/10.1136/jnnp-2020-323999
Favoni V, Grimaldi D, Pierangeli G, Cortelli P, Cevoli S. SUNCT/SUNA and neurovascular compression: new cases and critical literature review. Cephalalgia 2013;33:1337-48.
DOI: https://doi.org/10.1177/0333102413494273
Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache 1989;29:648-56.
DOI: https://doi.org/10.1111/j.1526-4610.1989.hed2910648.x
Russell MB, Andersson PG, Thomsen LL, Iselius L. Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. J Med Genet 1995;32:954-6.
DOI: https://doi.org/10.1136/jmg.32.12.954
Pinessi L, Rainero I, Rivoiro C, Rubino E, Gallone S. Genetics of cluster headache: an update. J Headache Pain 2005;6:234-6.
DOI: https://doi.org/10.1007/s10194-005-0194-x
Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol 2004;3:279-83.
DOI: https://doi.org/10.1016/S1474-4422(04)00735-5
Katsarou MS, Papasavva M, Latsi R, Toliza I, Gkaros AP, Papakonstantinou S, et al. Population-based analysis of cluster headache-associated genetic polymorphisms. J Mol Neurosci 2018;65:367-76.
DOI: https://doi.org/10.1007/s12031-018-1103-5
Thompson MD, Xhaard H, Sakurai T, Rainero I, Kukkonen JP. OX1 and OX2 orexin/hypocretin receptor pharmacogenetics. Front Neurosci 2014;8:57.
DOI: https://doi.org/10.3389/fnins.2014.00057
Kuzawinska O, Lis K, Cudna A, Balkowiec-Iskra E. Gender differences in the neurochemical response of trigeminal ganglion neurons to peripheral inflammation in mice. Acta Neurobiol Exp (Wars) 2014;74:227-32.
DOI: https://doi.org/10.55782/ane-2014-1988
Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004;84:903-34.
DOI: https://doi.org/10.1152/physrev.00037.2003
Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 1995;60:119-23.
DOI: https://doi.org/10.1016/0304-3959(94)00097-X
Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994;117:427-34.
DOI: https://doi.org/10.1093/brain/117.3.427
Snoer A, Vollesen ALH, Beske RP, Guo S, Hoffmann J, Fahrenkrug J, et al. Calcitonin-gene related peptide and disease activity in cluster headache. Cephalalgia 2019;39:575-84.
DOI: https://doi.org/10.1177/0333102419837154
Goadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med 2019;381:132-41.
DOI: https://doi.org/10.1056/NEJMoa1813440
Peng KP, Burish MJ. Management of cluster headache: treatments and their mechanisms. Cephalalgia 2023;43:3331024231196808.
DOI: https://doi.org/10.1177/03331024231196808
A study comparing the efficacy and safety of fremanezumab (TEV-48125) for the prevention of chronic cluster headache (CCH). Available from: https://clinicaltrials.gov/ct2/show/NCT02964338
Eptinezumab in participants with episodic cluster headache (ALLEVIATE). Available from: https://classic.clinicaltrials.gov/ct2/show/NCT04688775
A 1-year trial to inform about long-term exposure to eptinezumab in participants with chronic cluster headache (cCH) (CHRONICLE). Available from: https://clinicaltrials.gov/study/NCT05064397
de Vries T, Boucherie DM, Chan KY, Rubio-Beltran E, Labastida-Ramirez A, Labruijere S, et al. Sex differences in CGRP-induced vasodilation of human middle meningeal arteries but not human coronary arteries: implications for migraine. Cephalalgia 2024;44:3331024241254088.
DOI: https://doi.org/10.1177/03331024241254088
Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 2017;57:47-55.
DOI: https://doi.org/10.1111/head.13081
Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, et al. Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol 2008;507:1277-99.
DOI: https://doi.org/10.1002/cne.21607
Tavares-Ferreira D, Shiers S, Ray PR, Wangzhou A, Jeevakumar V, Sankaranarayanan I, et al. Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors. Sci Transl Med 2022;14:eabj8186.
DOI: https://doi.org/10.1126/scitranslmed.abj8186
Stucky NL, Gregory E, Winter MK, He YY, Hamilton ES, McCarson KE, et al. Sex differences in behavior and expression of CGRP-related genes in a rodent model of chronic migraine. Headache 2011;51:674-92.
DOI: https://doi.org/10.1111/j.1526-4610.2011.01882.x
Porreca F, Dodick DW. Considering Patient Sex in Prescribing CGRP receptor antagonists for short-term treatment of migraine. JAMA Neurol 2023;80:885-6.
DOI: https://doi.org/10.1001/jamaneurol.2023.2335
De Logu F, Nassini R, Materazzi S, Carvalho Goncalves M, Nosi D, Rossi Degl'Innocenti D, et al. Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice. Nat Commun 2017;8:1887.
DOI: https://doi.org/10.1038/s41467-017-01739-2
Souza Monteiro de Araujo D, Nassini R, Geppetti P, De Logu F. TRPA1 as a therapeutic target for nociceptive pain. Expert Opin Ther Targets 2020;24:997-1008.
DOI: https://doi.org/10.1080/14728222.2020.1815191
Abdo H, Calvo-Enrique L, Lopez JM, Song J, Zhang MD, Usoskin D, et al. Specialized cutaneous Schwann cells initiate pain sensation. Science 2019;365:695-9.
DOI: https://doi.org/10.1126/science.aax6452
Messlinger K, Balcziak LK, Russo AF. Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators. J Neural Transm (Vienna) 2020;127:431-44.
DOI: https://doi.org/10.1007/s00702-020-02161-7
De Logu F, Nassini R, Hegron A, Landini L, Jensen DD, Latorre R, et al. Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice. Nat Commun 2022;13:646.
DOI: https://doi.org/10.1038/s41467-022-28204-z
Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology 2002;58:354-61.
DOI: https://doi.org/10.1212/WNL.58.3.354
van Vliet JA, Favier I, Helmerhorst FM, Haan J, Ferrari MD. Cluster headache in women: relation with menstruation, use of oral contraceptives, pregnancy, and menopause. J Neurol Neurosurg Psychiatry 2006;77:690-2.
DOI: https://doi.org/10.1136/jnnp.2005.081158
Ekbom K, Waldenlind E. Cluster headache in women: evidence of hypofertility(?) Headaches in relation to menstruation and pregnancy. Cephalalgia 1981;1:167-74.
DOI: https://doi.org/10.1046/j.1468-2982.1981.0103167.x
Stillman MJ. Testosterone replacement therapy for treatment refractory cluster headache. Headache 2006;46:925-33.
DOI: https://doi.org/10.1111/j.1526-4610.2006.00436.x
Leone M, Bussone G. A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia 1993;13:309-17.
DOI: https://doi.org/10.1046/j.1468-2982.1993.1305309.x
Prakash S, Shah ND. Pure menstrual hemicrania continua: does it exist? A case report. Cephalalgia 2010;30:631-3.
DOI: https://doi.org/10.1111/j.1468-2982.2009.01951.x
Broner SW, Sun-Edelstein C, Lay CL. Cluster headache in women. Curr Pain Headache Rep 2007;11:127-30.
DOI: https://doi.org/10.1007/s11916-007-0009-7
Louter MA, Wilbrink LA, Haan J, van Zwet EW, van Oosterhout WP, Zitman FG, et al. Cluster headache and depression. Neurology 2016;87:1899-906.
DOI: https://doi.org/10.1212/WNL.0000000000003282
Robbins MS. The psychiatric comorbidities of cluster headache. Curr Pain Headache Rep 2013;17:313.
DOI: https://doi.org/10.1007/s11916-012-0313-8
Rozen TD, Fishman RS. Female cluster headache in the United States of America: what are the gender differences? Results from the United States Cluster Headache Survey. J Neurol Sci 2012;317:17-28.
DOI: https://doi.org/10.1016/j.jns.2012.03.006
Chung PW, Lee MJ, Park JW, Sohn JH, Kim BK, Chu MK, et al. Differences of cluster headache on the basis of sex in the Korean cluster headache registry. Headache 2019;59:1722-30.
DOI: https://doi.org/10.1111/head.13637
Lund N, Petersen A, Snoer A, Jensen RH, Barloese M. Cluster headache is associated with unhealthy lifestyle and lifestyle-related comorbid diseases: results from the Danish Cluster Headache Survey. Cephalalgia 2019;39:254-63.
DOI: https://doi.org/10.1177/0333102418784751
Kudrow L, McGinty DJ, Phillips ER, Stevenson M. Sleep apnea in cluster headache. Cephalalgia 1984;4:33-8.
DOI: https://doi.org/10.1046/j.1468-2982.1984.0401033.x
Winsvold BS, Harder AVE, Ran C, Chalmer MA, Dalmasso MC, Ferkingstad E, et al. Cluster headache genomewide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. Ann Neurol 2023;94:713-26.
DOI: https://doi.org/10.1002/ana.26743
Shaefer JR, Khawaja SN, Bavia PF. Sex, gender, and orofacial pain. Dent Clin North Am 2018;62:665-82.
DOI: https://doi.org/10.1016/j.cden.2018.06.001
Genovese A, Taga A, Rausa F, Quintana S, Manzoni GC, Torelli P. Clinical features of cluster headache in relation to age of onset: results from a retrospective study of a large case series. Neurol Sci 2019;40:193-4.
DOI: https://doi.org/10.1007/s10072-019-03801-x
Manzoni GC, Micieli G, Granella F, Martignoni E, Farina S, Nappi G. Cluster headache in women: clinical findings and relationship with reproductive life. Cephalalgia 1988;8:37-44.
DOI: https://doi.org/10.1046/j.1468-2982.1988.0801037.x
Ornello R, Lambru G, Caponnetto V, Frattale I, Di Felice C, Pistoia F, et al. Efficacy and safety of greater occipital nerve block for the treatment of cluster headache: a systematic review and meta-analysis. Expert Rev Neurother 2020;20:1157-67.
DOI: https://doi.org/10.1080/14737175.2020.1809379
Pearson SM, Burish MJ, Shapiro RE, Yan Y, Schor LI. Effectiveness of oxygen and other acute treatments for cluster headache: results from the cluster headache questionnaire, an international survey. Headache 2019;59:235-49.
DOI: https://doi.org/10.1111/head.13473
Brandt RB, Doesborg PGG, Meilof R, de Coo IF, Bartels E, Ferrari MD, et al. Repeated greater occipital nerve injections with corticosteroids in medically intractable chronic cluster headache: a retrospective study. Neurol Sci 2022;43:1267-72.
DOI: https://doi.org/10.1007/s10072-021-05399-5
Rozen TD. Inhaled oxygen for cluster headache: efficacy, mechanism of action, utilization, and economics. Curr Pain Headache Rep 2012 Jan 29.
DOI: https://doi.org/10.1007/s11916-012-0246-2
Schurks M, Kurth T, de Jesus J, Jonjic M, Rosskopf D, Diener HC. Cluster headache: clinical presentation, lifestyle features, and medical treatment. Headache 2006;46:1246-54.
DOI: https://doi.org/10.1111/j.1526-4610.2006.00534.x
Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA 2009;302:2451-7.
DOI: https://doi.org/10.1001/jama.2009.1855
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Attorre S, Burgalassi A, Vigani G, De Cesaris F, Romozzi M, Iannone LF. Sex and gender differences in the epidemiology, clinical features, and pathophysiology of trigeminal autonomic cephalalgias. Confinia Cephalal [Internet]. 2024 Oct. 9 [cited 2025 Jan. 30];34(2). Available from: https://www.confiniacephalalgica.com/site/article/view/15775
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