Hormonal Influences on Headache

  • E. Anne MacGregor
  • Astrid Gendolla
Reference work entry


Specific hormonal events during the reproductive years have a profound influence on migraine in women. Onset of migraine is usually postmenarche, during the teens, and early 20s. Migraine prevalence peaks during the early 40s and improves postmenopause. During the reproductive years, migraine is three times more prevalent in women than in men. This is generally considered to be the result of female sex hormones on migraine. Menstruation is a significant migraine trigger with more than 50% of women reporting an association. Attacks are most likely to occur during the 2 days before menstruation and the first 3 days of bleeding. Menstrual attacks are almost invariably without aura, even in women who have attacks with aura at other times of the cycle. The majority of attacks can be controlled with symptomatic treatment alone. However, since they are more severe, of longer duration, and more disabling than non-menstrual attacks, targeted prophylaxis may be necessary. Recognition of menstrual migraine as a specific entity has resulted in improved diagnosis and increased research into the condition. However, our understanding of the pathophysiology and the consequent development of effective management strategies remain limited. Clinical and research data support an association between attacks of migraine without aura and “withdrawal” of endogenous or exogenous estrogen, following a period of estrogen priming. Estrogen “withdrawal” migraine can be prevented by maintaining constant levels of estrogen, with or without suppression of the natural menstrual cycle. Further research is necessary to identify if estrogen “withdrawal” is a primary or secondary mechanism. Other mechanisms have also been implicated, particularly prostaglandin release as occurs during migraine associated with dysmenorrhea. Perimenstrual prophylaxis with triptans has shown efficacy. Limited research suggests that high levels of estrogen, such as that occur during pregnancy, with use of combined hormonal contraceptives, and with estrogen replacement therapy, can trigger migraine with aura. The pathophysiology of this effect is poorly understood. Genetic susceptibility is a recognized factor in the development of both migraine with and without aura and research for genes involved in hormonal pathways is ongoing.


Menstrual Cycle Migraine With Aura International Headache Society Migraine Without Aura Menstrual Migraine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aegidius K, Zwart J-A, Hagen K, Stovner L (2009) The effect of pregnancy and parity on headache prevalence: the head-HUNT study. Headache 49:851–859PubMedGoogle Scholar
  2. Aloisi A (2003) Gonadal hormones and sex differences in pain reactivity. Clin J Pain 19:168–174PubMedGoogle Scholar
  3. Archer DF (2006) Menstrual-cycle-related symptoms: a review of the rationale for continuous use of oral contraceptives. Contraception 74:359–366PubMedGoogle Scholar
  4. Beckham JC, Krug LM, Penzien DB, Johnson CA, Mosley TH, Meeks GR, Pbert LA, Prather RC (1992) The relationship of ovarian steroids, headache activity and menstrual distress: a pilot study with female migraineurs. Headache 32:292–297PubMedGoogle Scholar
  5. Benedetto C (1989) Eicosanoids in primary dysmenorrhea, endometriosis and menstrual migraine. Gynecol Endocrinol 3:71–94PubMedGoogle Scholar
  6. Berman NE, Puri V, Chandrala S, Puri S, Macgregor R, Liverman CS, Klein RM (2006) Serotonin in trigeminal Ganglia of female rodents: relevance to menstrual migraine. Headache 46:1230–1245PubMedGoogle Scholar
  7. Bickerstaff ER (1975) Neurological complications of oral contraceptives. Oxford University Press, OxfordGoogle Scholar
  8. Bille B (1962) Migraine in school children. Acta Paediatr Scand 51:1–151Google Scholar
  9. Brandes JL, Smith T, Diamond M, Ames MH (2007) Open-label, long-term tolerability of naratriptan for short-term prevention of menstrually related migraine. Headache 47:886–894PubMedGoogle Scholar
  10. Brandes JL, Poole A, Kallela M, Schreiber CP, MacGregor EA, Silberstein SD, Tobin J, Shaw R (2009) Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks. Cephalalgia 29:1133–1148PubMedGoogle Scholar
  11. Calhoun AH (2004) A novel specific prophylaxis for menstrual-associated migraine. South Med J 97:819–822PubMedGoogle Scholar
  12. Calhoun A, Ford S (2008) Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache J Head Face Pain 48:1186–1193Google Scholar
  13. Carlson LA, Ekelund LG, Oro L (1968) Clinical and metabolic effects of different doses of prostaglandin E1 in man. Prostaglandin and related factors. Acta Med Scand 183:423–430PubMedGoogle Scholar
  14. Chan W (1983) Prostaglandins and nonsteroidal antiinflammatory drugs in dysmenorrhoea. Annu Rev Pharmacol Toxicol 23:131–149PubMedGoogle Scholar
  15. Chancellor AM, Wroe SJ, Cull RE (1990) Migraine occurring for the first time in pregnancy. Headache 30:224–227PubMedGoogle Scholar
  16. Colson NJ, Lea RA, Quinlan S, Griffiths LR (2006) The role of vascular and hormonal genes in migraine susceptibility. Mol Genet Metab 88:107–113PubMedGoogle Scholar
  17. Colson NJ, Fernandez F, Lea RA, Griffiths LR (2007) The search for migraine genes: an overview of current knowledge. Cell Mol Life Sci 64:331–344PubMedGoogle Scholar
  18. Couturier EG, Bomhof MA, Neven AK, van Duijn NP (2003) Menstrual migraine in a representative Dutch population sample: prevalence, disability and treatment. Cephalalgia 23:302–308PubMedGoogle Scholar
  19. Crawford M, Lehman L, Slater S, Kabbouche M, Lecates S, Segers A, Manning P, Powers S, Hershey A (2009) Menstrual migraine in adolescents. Headache J Head Face Pain 49:341–347Google Scholar
  20. 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 15:140–144PubMedGoogle Scholar
  21. de Lignieres B, Vincens M, Mauvais-Jarvis P, Mas JL, Touboul PJ, Bousser MG (1986) Prevention of menstrual migraine by percutaneous oestradiol. Br Med J (Clin Res Ed) 293:1540Google Scholar
  22. Dennerstein L, Morse C, Burrows G, Oats J, Brown J, Smith M (1988) Menstrual migraine: a double-blind trial of percutaneous estradiol. Gynecol Endocrinol 2:113–120PubMedGoogle Scholar
  23. Downie J, Poyser N, Wonderlich M (1974) Levels of prostaglandins in human endometrium during normal menstrual cycle. J Physiol 236:465–472PubMedGoogle Scholar
  24. Dowson AJ, Kilminster SG, Salt R, Clark M, Bundy MJ (2005) Disability associated with headaches occurring inside and outside the menstrual period in those with migraine: a general practice study. Headache 45:274–282PubMedGoogle Scholar
  25. Dzoljic E, Sipetic S, Vlajinac H, Marinkovic J, Brzakovic B, Pokrajac M, Kostic V (2002) Prevalence of menstrually related migraine and nonmigraine primary headache in female students of Belgrade University. Headache 42:185–193PubMedGoogle Scholar
  26. Epstein MT, Hockaday JM, Hockaday TD (1975) Migraine and reproductive hormones throughout the menstrual cycle. Lancet 1:543–548PubMedGoogle Scholar
  27. Facchinetti F, Martignoni E, Fioroni L, Sances G, Genazzani AR (1990) Opioid control of the hypothalamus-pituitary-adrenal axis cyclically fails in menstrual migraine. Cephalalgia 10:51–56PubMedGoogle Scholar
  28. Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S (2008) Symptoms in the menopausal transition: hormone and behavioral correlates. Obstet Gynecol 111:127–136PubMedGoogle Scholar
  29. 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 33:385–389PubMedGoogle Scholar
  30. Granella F, Sances G, Pucci E, Nappi RE, Ghiotto N, Napp G (2000) Migraine with aura and reproductive life events: a case control study. Cephalalgia 20:701–707PubMedGoogle Scholar
  31. 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 24:707–716PubMedGoogle Scholar
  32. Gray L (1941) The use of progesterone in nervous tension states. South Med J 34:1004–1005Google Scholar
  33. Guidotti M, Mauri M, Barrila C, Guidotti F, Belloni C (2007) Frovatriptan vs. transdermal oestrogens or naproxen sodium for the prophylaxis of menstrual migraine. J Headache Pain 8:283–288PubMedGoogle Scholar
  34. Headache Classification Committee of the International Headache Society (1988) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8:1–96Google Scholar
  35. Headache Classification Subcommittee of the International Headache Society (IHS) (2004) The international classification of headache disorders (2nd edition). Cephalalgia 24:1–160Google Scholar
  36. Holdaway IM, Parr CE, France J (1991) Treatment of a patient with severe menstrual migraine using the depot LHRH analogue Zoladex. Aust NZ J Obstet Gynaecol 31:164–165Google Scholar
  37. Horrobin D (1977) Prostaglandins and migraine. Headache 16:113–116Google Scholar
  38. Irwin J, Morse E, Riddick D (1981) Dysmenorrhoea induced by autologous transfusion. Obstet Gynecol 58:286–290PubMedGoogle Scholar
  39. Johannes CB, Linet MS, Stewart WF, Celentano DD, Lipton RB, Szklo M (1995) Relationship of headache to phase of the menstrual cycle among young women: a daily diary study. Neurology 45:1076–1082PubMedGoogle Scholar
  40. Johnson R, Hornabrook R, Lambie D (1986) Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neurol Scand 73:490–492PubMedGoogle Scholar
  41. LaGuardia KD, Fisher AC, Bainbridge JD, LoCoco JM, Friedman AJ (2005) Suppression of estrogen-withdrawal headache with extended transdermal contraception. Fertil Steril 83:1875–1877PubMedGoogle Scholar
  42. Lichten EM, Lichten JB, Whitty A, Pieper D (1996) The confirmation of a biochemical marker for women's hormonal migraine: the depo-estradiol challenge test. Headache 36:367–371PubMedGoogle Scholar
  43. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF (2007) Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 68:343–349PubMedGoogle Scholar
  44. MacGregor A (1999) Estrogen replacement and migraine aura. Headache 39:674–678PubMedGoogle Scholar
  45. MacGregor EA (2007) Menstrual migraine: a clinical review. J Fam Plann Reprod Health Care 33(1):36–47PubMedGoogle Scholar
  46. MacGregor EA, Hackshaw A (2002) Prevention of migraine in the pill-free interval of combined oral contraceptives: a double-blind, placebo-controlled pilot study using natural oestrogen supplements. J Fam Plann Reprod Health Care 28:27–31PubMedGoogle Scholar
  47. MacGregor EA, Hackshaw A (2004) Prevalence of migraine on each day of the natural menstrual cycle. Neurology 63:351–353PubMedGoogle Scholar
  48. MacGregor EA, Chia H, Vohrah RC, Wilkinson M (1990) Migraine and menstruation: a pilot study. Cephalalgia 10:305–310PubMedGoogle Scholar
  49. MacGregor EA, Igarashi H, Wilkinson M (1997) Headaches and hormones: subjective versus objective assessment. Headache Q 8:126–136Google Scholar
  50. MacGregor EA, Brandes J, Eikermann A, Giammarco R (2004) Impact of migraine on patients and their families: the Migraine and Zolmitriptan Evaluation (MAZE) survey – Phase III. Curr Med Res Opin 20:1143–1150PubMedGoogle Scholar
  51. MacGregor EA, Frith A, Ellis J, Aspinall L (2005) Predicting menstrual migraine with a home-use fertility monitor. Neurology 64:561–563PubMedGoogle Scholar
  52. MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A (2006a) Prevention of menstrual attacks of migraine: a double-blind placebo-controlled crossover study. Neurology 67:2159–2163PubMedGoogle Scholar
  53. MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A (2006b) Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology 67:2154–2158PubMedGoogle Scholar
  54. MacGregor EA, Brandes JL, Silberstein S, Jeka S, Czapinski P, Shaw B, Pawsey S (2009) Safety and tolerability of short-term preventive frovatriptan: a combined analysis. Headache 49:1298–1314PubMedGoogle Scholar
  55. MacGregor E, Pawsey S, Campbell J, Hu X (2010a) Safety and tolerability of Frovatriptan in the acute treatment of migraine and prevention of menstrual migraine. Gend Med 7(2)88–108PubMedGoogle Scholar
  56. MacGregor E, Victor T, Hu X, Xiang Q, Puenpatom R, Chen W, Campbell J (2010b) 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(4):528–538PubMedGoogle Scholar
  57. Mannix LK (2008) Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt) 17:879–891Google Scholar
  58. Mannix LK, Savani N, Landy S, Valade D, Shackelford S, Ames MH, Jones MW (2007) Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache 47:1037–1049PubMedGoogle Scholar
  59. Martin VT, Behbehani M (2006) Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis – part I. Headache 46:3–23PubMedGoogle Scholar
  60. Martin V, Wernke S, Mandell K, Zoma W, Bean J, Pinney S, Liu J, Ramadan N, Rebar R (2003) Medical oophorectomy with and without estrogen add-back therapy in the prevention of migraine headache. Headache 43:309–321PubMedGoogle Scholar
  61. Martin VT, Lee J, Behbehani MM (2007) Sensitization of the trigeminal sensory system during different stages of the rat estrous cycle: implications for menstrual migraine. Headache 47:552–563PubMedGoogle Scholar
  62. Mattsson P (2003) Hormonal factors in migraine: a population-based study of women aged 40 to 74 years. Headache 43:27–35PubMedGoogle Scholar
  63. McEwan B (2002) Estrogen actions throughout the brain. Recent Prog Horm Res 57:357–384Google Scholar
  64. Melhado E, Maciel JA Jr, Guerreiro CA (2005) Headaches during pregnancy in women with a prior history of menstrual headaches. Arq Neuropsiquiatr 63:934–940PubMedGoogle Scholar
  65. Moschiano F, Allais G, Grazzi L, Usai S, Benedetto C, D'Amico D, Roncolato M, Bussone G (2005) Naratriptan in the short-term prophylaxis of pure menstrual migraine. Neurol Sci 26(Suppl 2):s162–s166PubMedGoogle Scholar
  66. Murray SC, Muse KN (1997) Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and 'add-back' therapy. Fertil Steril 67:390–393PubMedGoogle Scholar
  67. Nagel-Leiby S, Welch KM, Grunfeld S, D'Andrea G (1990) Ovarian steroid levels in migraine with and without aura. Cephalalgia 10:147–152PubMedGoogle Scholar
  68. Neri I, Granella F, Nappi R, Manzoni GC, Facchinetti F, Genazzani AR (1993) Characteristics of headache at menopause: a clinico-epidemiologic study. Maturitas 17:31–37PubMedGoogle Scholar
  69. Newman LC, Lipton RB, Lay CL, Solomon S (1998) A pilot study of oral sumatriptan as intermittent prophylaxis of menstruation-related migraine. Neurology 51:307–309PubMedGoogle Scholar
  70. Newman L, Mannix LK, Landy S, Silberstein S, Lipton RB, Putnam DG, Watson C, Jobsis M, Batenhorst A, O'Quinn S (2001) Naratriptan as short-term prophylaxis of menstrually associated migraine: a randomized, double-blind, placebo-controlled study. Headache 41:248–256PubMedGoogle Scholar
  71. North American Menopause Society (2010) Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 17:242–255Google Scholar
  72. Oldenhave A, Jaszmann LJ, Everaerd WT, Haspels AA (1993) Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age. Am J Obstet Gynecol 168:765–771PubMedGoogle Scholar
  73. Owens P (1984) Prostaglandin synthetase inhibitors in the treatment of primary dysmenorrhoea: outcome trials reviewed. Am J Obstet Gynecol 148:96Google Scholar
  74. Pfaffenrath V (1993) Efficacy and safety of percutaneous estradiol vs. placebo in menstrual migraine. Cephalalgia 13:244Google Scholar
  75. Pinkerman B, Holroyd KA (2010) Menstrual and nonmenstrual migraines differ in women with menstrually-related migraine. Cephalalgia 30(10):1187–1194PubMedGoogle Scholar
  76. Pradalier A, Clapin A, Dry J (1988) Treatment review: non-steroidal anti-inflammatory drugs in the treatment and long-term prevention of migraine attacks. Headache 28:550–557PubMedGoogle Scholar
  77. Pradalier A, Vincent D, Beaulieu P, Baudesson G, Launey J-M (1994) Correlation between estradiol plasma level and therapeutic effect on menstrual migraine. In: Rose F (ed) New advances in headache research. Smith-Gordon, London, pp 129–132Google Scholar
  78. Sances G, Martignoni E, Fioroni L, Blandini F, Facchinetti F, Nappi G (1990) Naproxen sodium in menstrual migraine prophylaxis: a double-blind placebo controlled study. Headache 30:705–709PubMedGoogle Scholar
  79. Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N, Polatti F, Nappi G (2003) Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia 23:197–205PubMedGoogle Scholar
  80. Sarrel PM (1999) The differential effects of oestrogens and progestins on vascular tone. Hum Reprod Update 5:205–209PubMedGoogle Scholar
  81. Scharff L, Marcus DA, Turk DC (1997) Headache during pregnancy and in the postpartum: a prospective study. Headache 37:203–210PubMedGoogle Scholar
  82. Silberstein SD, Elkind AH, Schreiber C, Keywood C (2004) A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology 63:261–269PubMedGoogle Scholar
  83. Silberstein SD, Berner T, Tobin J, Xiang Q, Campbell JC (2009) Scheduled short-term prevention with frovatriptan for migraine occurring exclusively in association with menstruation. Headache 49:1283–1297PubMedGoogle Scholar
  84. Singh I, Singh I (1947) Progesterone in the treatment of migraine. Lancet i:745–747Google Scholar
  85. Smits MG, van der Meer YG, Pfeil JP, Rijnierse JJ, Vos AJ (1994) Perimenstrual migraine: effect of Estraderm TTS and the value of contingent negative variation and exteroceptive temporalis muscle suppression test. Headache 34:103–106PubMedGoogle Scholar
  86. Somerville BW (1971) The role of progesterone in menstrual migraine. Neurology 21:853–859PubMedGoogle Scholar
  87. Somerville BW (1972a) The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355–365PubMedGoogle Scholar
  88. Somerville BW (1972b) The influence of progesterone and estradiol upon migraine. Headache 12:93–102PubMedGoogle Scholar
  89. Somerville BW (1975a) Estrogen-withdrawal migraine II. Attempted prophylaxis by continuous estradiol administration. Neurology 25:245–250PubMedGoogle Scholar
  90. Somerville BW (1975b) Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology 25:239–244PubMedGoogle Scholar
  91. Stein G, Morton J, Marsh A, Collins W, Branch C, Desaga U, Ebeling J (1984) Headaches after childbirth. Acta Neurol Scand 69:74–79PubMedGoogle Scholar
  92. Steiner TJ, Scher AI, Stewart WF, Kolodner K, Liberman J, Lipton RB (2003) The prevalence and disability burden of adult migraine in England and their relationships to age, gender and ethnicity. Cephalalgia 23:519–527PubMedGoogle Scholar
  93. Stewart WF, Linet MS, Celentano DD, Van Natta M, Ziegler D (1991) Age- and sex-specific incidence rates of migraine with and without visual aura. Am J Epidemiol 134:1111–1120PubMedGoogle Scholar
  94. Stewart WF, Lipton RB, Celentano DD, Reed ML (1992) Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA 267:64–69PubMedGoogle Scholar
  95. Stewart WF, Lipton RB, Chee E, Sawyer J, Silberstein SD (2000) Menstrual cycle and headache in a population sample of migraineurs. Neurology 55:1517–1523PubMedGoogle Scholar
  96. Stewart WF, Wood C, Reed ML, Roy J, Lipton RB (2008) Cumulative lifetime migraine incidence in women and men. Cephalalgia 28:1170–1178PubMedGoogle Scholar
  97. Stoffel-Wagner B (1993) Neurosteroid biosynthesis in the human brain and its clinical implications. Ann NY Acad Sci 1007:64–78Google Scholar
  98. Tuchman MM, Hee A, Emeribe U, Silberstein S (2008) Oral zolmitriptan in the short-term prevention of menstrual migraine: a randomized, placebo-controlled study. CNS Drugs 22:877–886PubMedGoogle Scholar
  99. Wang SJ, Fuh JL, Lu SR, Juang KD, Wang PH (2003) Migraine prevalence during menopausal transition. Headache 43:470–478PubMedGoogle Scholar
  100. Welch KM, Brandes JL, Berman NE (2006) Mismatch in how oestrogen modulates molecular and neuronal function may explain menstrual migraine. Neurol Sci 27(Suppl 2):S190–S192PubMedGoogle Scholar
  101. Wober C, Brannath W, Schmidt K, Kapitan M, Rudel E, Wessely P, Wober-Bingol C (2007) Prospective analysis of factors related to migraine attacks: the PAMINA study. Cephalalgia 27:304–314PubMedGoogle Scholar
  102. World Health Organization (2009) Medical eligibility criteria for contraceptive use. WHO, GenevaGoogle Scholar
  103. Wright G, Patel M (1986) Focal migraine and pregnancy. BMJ 293:1557–1558PubMedGoogle Scholar

Copyright information

© Lifting The Burden 2011

Authors and Affiliations

  1. 1.The City of London Migraine ClinicLondonUK
  2. 2.Regionales Schmerzzentrum EssenEssenGermany

Personalised recommendations