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Menstrual migraine: what it is and does it matter?

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Abstract

The diagnostic criteria of menstrual migraine (MM), migraine related to menstruation and pure menstrual migraine, are placed in the appendix of the International Classification of Headache Disorders and are still primarily considered as research criteria that need validation. Although there is a great wealth of knowledge about the neurobiological processes underlying MM and its symptoms, the mechanisms by which an attack starts during the menstrual cycle remain baffling, and the disease is still undertreated. In this narrative review, we aim to summarize recent data on pathophysiology, epidemiology, burden of disease and treatment of MM. The vast majority of the literature focuses on the relationship between MM and hormonal factors. The role of falling in estrogen levels is believed to increase the susceptibility of blood vessels to prostaglandins, which have been implicated in neurogenic inflammation. Moreover, fluctuations of ovarian steroid hormone levels modulate calcitonin gene-related peptide in the trigeminovascular system. In addition, it has been observed that gonadal hormones modulate cortical spreading depression susceptibility in animal models. Sex hormone influences on MM affect not only the frequency and severity of headache attack but also its treatment. Understanding the mechanisms that contribute to neuroendocrine vulnerability in some women and some menstrual cycles may yield possible marker of the disease opening treatment options specifically targeting MM. An increased interest for future research on the subject will further elucidate how to manage this debilitating type of migraine.

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References

  1. Headache Classification Committee of the International Headache Society (IHS) (2018) The international classification of headache disorders, 3rd edition. Cephalalgia 38:1–211

    Google Scholar 

  2. Couturier EG, Bomhof MA, Neven AK, van Duijn NP (2003) Menstrual migraine in a representative Dutch population sample: prevalence, disability and treatment. Cephalalgia 23:302–308

    CAS  PubMed  Google Scholar 

  3. Granella F, Sances G, Allais G, Nappi RE, Tirelli A, Benedetto C, Brundu B, Facchinetti F, Nappi G (2004) Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia 24:707–716

    CAS  PubMed  Google Scholar 

  4. MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A (2006) Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology 67:2154–2158

    CAS  PubMed  Google Scholar 

  5. MacGregor EA, Victor TW, Hu X, Xiang Q, Puenpatom RA, Chen W, Campbell JC (2010) Characteristics of menstrual vs nonmenstrual migraine: a post hoc, within-woman analysis of the usual-care phase of a nonrandomized menstrual migraine clinical trial. Headache 50:528–538

    PubMed  Google Scholar 

  6. Pinkerman B, Holroyd K (2010) Menstrual and nonmenstrual migraines differ in women with menstrually-related migraine. Cephalalgia 30:1187–1194

    PubMed  Google Scholar 

  7. Vetvik KG, Benth JŠ, MacGregor EA, Lundqvist C, Russell MB (2015) Menstrual versus non-menstrual attacks of migraine without aura in women with and without menstrual migraine. Cephalalgia 35:1261–1268

    PubMed  Google Scholar 

  8. Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain (1988) Headache classification committee of the International Headache Society. Cephalalgia 8(Suppl 7):1–96

    Google Scholar 

  9. Headache Classification Subcommittee of the International Headache Society (2004) The international classification of headache disorders: 2nd edition. Cephalalgia 24(Suppl 1):9–160

    Google Scholar 

  10. Headache Classification Committee of the International Headache Society (IHS) (2013) The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:629–808

    Google Scholar 

  11. Somerville BW (1972) The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355–365

    CAS  PubMed  Google Scholar 

  12. Epstein MT, Hockaday JM, Hockaday TD (1975) Migraine and reproductive hormones throughout the menstrual cycle. Lancet 1:543–548

    CAS  PubMed  Google Scholar 

  13. Horth CE, Wainscott G, Neylan C, Wilkinson MI (1975) Proceedings: progesterone, oestradiol and aldosterone levels in plasma during the menstrual cycle of women suffering from migraine. J Endocrinol 65:24P–25P

    CAS  PubMed  Google Scholar 

  14. Martin VT, Wernke S, Mandell K, Ramadan N, Kao L, Bean J, Liu J, Zoma W, Rebar R (2005) Defining the relationship between ovarian hormones and migraine headache. Headache 45:1190–1201

    PubMed  Google Scholar 

  15. MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A (2006) Prevention of menstrual attacks of migraine: a double-blind placebo-controlled crossover study. Neurology 67:2159–2163

    CAS  PubMed  Google Scholar 

  16. Pavlović JM, Allshouse AA, Santoro NF, Crawford SL, Thurston RC, Neal-Perry GS, Lipton RB, Derby CA (2016) Sex hormones in women with and without migraine: evidence of migraine-specific hormone profiles. Neurology 5(87):49–56

    Google Scholar 

  17. Hassan S, Muere A, Einstein G (2014) Ovarian hormones and chronic pain: a comprehensive review. Pain 155:2448–2460

    CAS  PubMed  Google Scholar 

  18. Downie J, Poyser NL, Wunderlich M (1974) Levels of prostaglandins in human endometrium during the normal menstrual cycle. J Physiol 236:465–472

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Moskowitz MA (1984) The neurobiology of vascular head pain. Ann Neurol 16:157–168

    CAS  PubMed  Google Scholar 

  20. Ho TW, Edvinsson L, Goadsby PJ (2010) CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 6:573–582

    CAS  PubMed  Google Scholar 

  21. Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14:1289–1303

    CAS  PubMed  Google Scholar 

  22. Russell FA, King R, Smillie SJ, Kodji X, Brain SD (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94:1099–1142

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Antonova M, Wienecke T, Olesen J, Ashina M (2013) Prostaglandins in migraine: update. Curr Opin Neurol 26:269–275

    CAS  PubMed  Google Scholar 

  24. Matsuda M, Huh Y, Ji RR (2019) Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J Anesth 33:131–139

    PubMed  Google Scholar 

  25. Stevenson JC, Macdonald DW, Warren RC, Booker MW, Whitehead MI (1986) Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed) 293:1329–1330

    CAS  Google Scholar 

  26. Yallampalli C, Chauhan M, Thota CS, Kondapaka S, Wimalawansa SJ (2002) Calcitonin gene-related peptide in pregnancy and its emerging receptor heterogeneity. Trends Endocrinol Metab 13:263–269

    CAS  PubMed  Google Scholar 

  27. Valdemarsson S, Edvinsson L, Hedner P, Ekman R (1990) Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Investig 50:385–388

    CAS  Google Scholar 

  28. Gupta P, Harte A, Sturdee DW, Sharma A, Barnett AH, Kumar S, Mc Ternan PG (2008) Effects of menopausal status on circulating calcitonin gene-related peptide and adipokines: implications for insulin resistance and cardiovascular risks. Climacteric 11:364–372

    CAS  PubMed  Google Scholar 

  29. Gupta S, Villalon CM, Mehrotra S, De Vries R, Garrelds IM, Pramod R, Saxena PR, MaassenVanDenBrink A (2007) Female sex hormones and rat dural vasodilatation to CGRP, periarterial electrical stimulation and capsaicin. Headache 47:225–235

    PubMed  Google Scholar 

  30. Gupta S, Mehrotra S, Villalón C, De Vries R, Garrelds I, Saxena P, Vandenbrink AM (2007) Effects of female sex hormones on responses to CGRP, acetylcholine, and 5-HT in rat isolated arteries. Headache 47:564–575

    PubMed  Google Scholar 

  31. Ibrahimi K, van Oosterhout WP, van Dorp W, Danser AH, Garrelds IM, Kushner SA, Lesaffre EM, Terwindt GM, Ferrari MD, van den Meiracker AH, MaassenVanDenBrink A (2015) Reduced trigeminovascular cyclicity in patients with menstrually related migraine. Neurology 84:125–131

    PubMed  Google Scholar 

  32. Sandweiss AJ, Cottier KE, McIntosh MI, Dussor G, Davis TP, Vanderah TW, Largent-Milnes TM (2017) 17-β-Estradiol induces spreading depression and pain behavior in alert female rats. Oncotarget 8:114109–114122

    PubMed  PubMed Central  Google Scholar 

  33. Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, Ferrari MD, van den Maagdenberg Arn MJM, Moskowitz MA, Ayata C (2009) Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Investig 119:99–109

    CAS  PubMed  Google Scholar 

  34. Chauvel V, Multon S, Schoenen J (2018) Estrogen-dependent effects of 5-hydroxytryptophan on cortical spreading depression in rat: modelling the serotonin-ovarian hormone interaction in migraine aura. Cephalalgia 38:427–436

    PubMed  Google Scholar 

  35. Borsook D, Erpelding N, Lebel A, Linnman C, Veggeberg R, Grant PE, Buettner C, Becerra L, Burstein R (2014) Sex and the migraine brain. Neurobiol Dis 68:200–214

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Amandusson A, Hermanson O, Blomqvist A (1995) Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat. Neurosci Lett 196:25–28

    CAS  PubMed  Google Scholar 

  37. Shughrue PJ, Bushnell CD, Dorsa DM (1992) Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous cycle: a comparison with ovariectomized females and intact males. Endocrinology 131:381–388

    CAS  PubMed  Google Scholar 

  38. Amandusson A, Blomqvist A (2013) Estrogenic influences in pain processing. Front Neuroendocrinol 34:329–349

    CAS  PubMed  Google Scholar 

  39. Sutherland HG, Champion M, Plays A, Stuart S, Haupt LM, Frith A, MacGregor EA, Griffiths LR (2017) Investigation of polymorphisms in genes involved in estrogen metabolism in menstrual migraine. Gene 5(607):36–40

    Google Scholar 

  40. Rodriguez-Acevedo AJ, Smith RA, Roy B, Sutherland H, Lea RA, Frith A, MacGregor EA, Griffiths LR (2014) Genetic association and gene expression studies suggest that genetic variants in the SYNE1 and TNF genes are related to menstrual migraine. J Headache Pain 14(15):62

    Google Scholar 

  41. Pollock CE, Sutherland HG, Maher BH, Lea RA, Haupt LM, Frith A, MacGregor EA, Griffiths LR (2018) The NRP1 migraine risk variant shows evidence of association with menstrual migraine. J Headache Pain 19:31

    PubMed  PubMed Central  Google Scholar 

  42. MacGregor EA, Chia H, Vohrah RC, Wilkinson M (1990) Migraine and menstruation: a pilot study. Cephalalgia 10:305–310

    CAS  PubMed  Google Scholar 

  43. Granella F, Sances G, Zanferrari C, Costa A, Martignoni E, Manzoni GC (1993) Migraine without aura and reproductive life events: a clinical epidemiological study in 1300 women. Headache 33:385–389

    CAS  PubMed  Google Scholar 

  44. Cupini LM, Matteis M, Troisi E, Calabresi P, Bernardi G, Silvestrini M (1995) Sex-hormone-related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura. Cephalalgia 15:140–144

    CAS  PubMed  Google Scholar 

  45. Vetvik KG, MacGregor EA, Lundqvist C, Russell MB (2010) Self-reported menstrual migraine in the general population. J Headache Pain 11:87–92

    PubMed  PubMed Central  Google Scholar 

  46. Vetvik KG, Macgregor EA, Lundqvist C, Russell MB (2014) Prevalence of menstrual migraine: a population-based study. Cephalalgia 34:280–288

    PubMed  Google Scholar 

  47. Pavlović JM, Stewart WF, Bruce CA, Gorman JA, Sun H, Buse DC, Lipton RB (2015) Burden of migraine related to menses: results from the AMPP study. J Headache Pain 16:24

    PubMed  PubMed Central  Google Scholar 

  48. Güven B, Güven H, Çomoğlu S (2017) Clinical characteristics of menstrually related and non-menstrual migraine. Acta Neurol Belg 117:671–676

    PubMed  Google Scholar 

  49. Melhado EM, Thiers Rister HL, Belitardo GA, de Oliveira DR, Buttarello A, Belucio IS, Oliveira Marcos JM, Tonhá Xavier ML, Prieto Peres MF (2019) Allodynia in menstrually related migraine: Score Assessment by Allodynia Symptom Checklist (ASC-12). Headache. https://doi.org/10.1111/head.13677(Epub ahead of print)

    Article  PubMed  Google Scholar 

  50. Ferreira KS, Guilherme G, Faria VR, Borges LM, Uchiyama AA (2017) Women living together have a higher frequency of menstrual migraine. Headache 57:135–142

    PubMed  Google Scholar 

  51. Petrovski BÉ, Vetvik KG, Lundqvist C, Eberhard-Gran M (2018) Characteristics of menstrual versus non-menstrual migraine during pregnancy: a longitudinal population-based study. J Headache Pain 19:27

    PubMed  PubMed Central  Google Scholar 

  52. Wang SJ, Fuh JL, Lu SR, Juang KD, Wang PH (2003) Migraine prevalence during menopausal transition. Headache 43:470–478

    PubMed  Google Scholar 

  53. Nierenburg Hdel C, Ailani J, Malloy M, Siavoshi S, Hu NN, Yusuf N (2015) Systematic review of preventive and acute treatment of menstrual migraine. Headache 55:1052–1071

    PubMed  Google Scholar 

  54. Bigal M, Sheftell F, Tepper S, Tepper D, Ho TW, Rapoport A (2008) A randomized double-blind study comparing rizatriptan, dexamethasone, and the combination of both in the acute treatment of menstrually related migraine. Headache 48:1286–1293

    PubMed  Google Scholar 

  55. Allais G, Rolando S, Schiapparelli P, Airola G, Borgogno P, Mana O, Benedetto C (2013) Frovatriptan plus dexketoprofen in the treatment of menstrually related migraine: an open study. Neurol Sci 34:S179–S181

    PubMed  Google Scholar 

  56. Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T (2009) Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ 339:b3914

    PubMed  PubMed Central  Google Scholar 

  57. Carlton C, Banks M, Sundararajan S (2018) Oral contraceptives and ischemic stroke risk. Stroke 49:e157–e159

    PubMed  Google Scholar 

  58. Sacco S, Merki-Feld GS, Ægidius KL, Bitzer J, Canonico M, Kurth T, Lampl C, Lidegaard Ø, MacGregor EA, MaassenVanDenBrink A, Mitsikostas DD, Nappi RE, Ntaios G, Sandset PM, Martelletti M, European Headache Federation (EHF), the European Society of Contraception, and Reproductive Health (ESC) (2017) Hormonal contraceptives and risk of ischemic stroke in women with migraine: a consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC). J Headache Pain 18:108

    PubMed  PubMed Central  Google Scholar 

  59. Warhurst S, Rofe CJ, Brew BJ, Bateson D, McGeechan K, Merki-Field GS, Garrick R, Tomlinson SE (2018) Effectiveness of the progestin-only pill for migraine treatment in women: a systematic review and meta-analysis. Cephalalgia 38:754–764

    PubMed  Google Scholar 

  60. Burke BE, Olson RD, Cusack BJ (2002) Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother 56:283–288

    CAS  PubMed  Google Scholar 

  61. Ferrante F, Fusco E, Calabresi P, Cupini LM (2004) Phyto-oestrogens in the prophylaxis of menstrual migraine. Clin Neuropharmacol 27:137–140

    CAS  PubMed  Google Scholar 

  62. Grazzi L, Egeo G, Calhoun AH, McClure CK, Liebler E, Barbanti P (2016) Non-invasive vagus nerve stimulation (nVNS) as mini-prophylaxis for menstrual/menstrually related migraine: an open-label study. J Headache Pain 17:91

    PubMed  PubMed Central  Google Scholar 

  63. Coffee AL, Sulak PJ, Hill AJ, Hansen DJ, Kuehl TJ, Clark JW (2014) Extended cycle combined oral contraceptives and prophylactic frovatriptan during the hormone-free interval in women with menstrual-related migraines. J Womens Health (Larchmt) 23:310–317

    Google Scholar 

  64. Dima L, Bălan A, Moga MA, Dinu CG, Dimienescu OG, Varga I, Neculau AE (2019) Botulinum toxin a valuable prophylactic agent for migraines and a possible future option for the prevention of hormonal variations-triggered migraines. Toxins (Basel) 11(8):E465. https://doi.org/10.3390/toxins11080465

    Article  CAS  Google Scholar 

  65. Ho TW, Ho AP, Ge YJ, Assaid C, Gottwald R, MacGregor EA, Mannix LK, van Oosterhout WP, Koppenhaver J, Lines C, Ferrari MD, Michelson D (2016) Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine. Cephalalgia 36:148–161

    PubMed  Google Scholar 

  66. Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA (2017) A controlled trial of erenumab for episodic migraine. N Engl J Med 377:2123–2132

    CAS  PubMed  Google Scholar 

  67. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR (2018) Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol 75:1080–1088

    PubMed  PubMed Central  Google Scholar 

  68. Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E (2018) Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA 319:1999–2008

    CAS  PubMed  Google Scholar 

  69. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J, for the ALD403 study investigators (2014) Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 13:1100–1107

    CAS  PubMed  Google Scholar 

  70. Do TP, Guo S, Ashina M (2019) Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain 20:37. https://doi.org/10.1186/s10194-019-0974-3

    Article  PubMed  PubMed Central  Google Scholar 

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Category 1, (a) conception and design: LMC, IC, PS; (b) acquisition of data: LMC, IC, PS; (c) analysis and interpretation of data: LMC, IC, PS. Category 2, (a) drafting the manuscript: LMC, IC, PS; (b) revising it for intellectual content: LMC, IC, PS. Category 3, (a) final approval of the completed manuscript: LMC, IC, PS.

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Correspondence to Letizia Maria Cupini.

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Cupini, L.M., Corbelli, I. & Sarchelli, P. Menstrual migraine: what it is and does it matter?. J Neurol 268, 2355–2363 (2021). https://doi.org/10.1007/s00415-020-09726-2

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