Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Hormonal influences in migraine — interactions of oestrogen, oxytocin and CGRP

Nature Reviews Neurology volume 17, pages 621–633 (2021)Cite this article

Subjects

Abstract

Migraine is ranked as the second highest cause of disability worldwide and the first among women aged 15–49 years. Overall, the incidence of migraine is threefold higher among women than men, though the frequency and severity of attacks varies during puberty, the menstrual cycle, pregnancy, the postpartum period and menopause. Reproductive hormones are clearly a key influence in the susceptibility of women to migraine. A fall in plasma oestrogen levels can trigger attacks of migraine without aura, whereas higher oestrogen levels seem to be protective. The basis of these effects is unknown. In this Review, we discuss what is known about sex hormones and their receptors in migraine-related areas in the CNS and the peripheral trigeminovascular pathway. We consider the actions of oestrogen via its multiple receptor subtypes and the involvement of oxytocin, which has been shown to prevent migraine attacks. We also discuss possible interactions of these hormones with the calcitonin gene-related peptide (CGRP) system in light of the success of anti-CGRP treatments. We propose a simple model to explain the hormone withdrawal trigger in menstrual migraine, which could provide a foundation for improved management and therapy for hormone-related migraine in women.

Key points

  • All three oestrogen receptor subtypes are widely expressed throughout migraine-related pain and nociceptive pathways in the CNS and in the peripheral trigeminal ganglia.

  • Central and peripheral regions related to migraine co-express oestrogen receptors with calcitonin gene-related peptide (CGRP), CGRP receptors, oxytocin and/or oxytocin receptors, suggesting functional interactions.

  • Hormonal fluctuations in women are thought to influence oscillating migraine neural networks and alter the threshold for a migraine attack and influence its intensity and/or duration.

  • Oestrogen-regulated oxytocin could be a factor in menstrual and other hormone-related migraine attacks.

  • We suggest a model to explain the oestrogen withdrawal theory of menstrual migraine, in which oestrogen regulates the balance of pro-migraine factors, such as CGRP, and anti-migraine factors, such as oxytocin, within the trigeminal ganglion.

  • Development of selective oestrogen agonists or oxytocin agonists could be a strategy to improve the treatment of hormone-related migraine in women.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Fluctuations in the incidence of migraine and hormone blood levels over the menstrual cycle.
Fig. 2: Localization of signalling molecules and receptors in migraine-related regions.
Fig. 3: Localization of oestrogen receptors, oxytocin receptors, CGRP and CGRP receptors in cells of the trigeminal ganglia.
Fig. 4: Oxytocin pathways.
Fig. 5: Theory of hormonal balance in the trigeminal ganglion and the impact of hormone withdrawal in menstrual migraine.

Similar content being viewed by others

Article 13 January 2022

Michel D. Ferrari, Peter J. Goadsby, … David W. Dodick

References

  1. GBD. 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1545–1602 (2016).

    Article  Google Scholar 

  2. Vetvik, K. G. & MacGregor, E. A. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol. 16, 76–87 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Lipton, R. B. et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 68, 343–349 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Lipton, R. B. et al. Identifying natural subgroups of migraine based on comorbidity and concomitant condition profiles: results of the chronic migraine epidemiology and outcomes (CaMEO) Study. Headache 58, 933–947 (2018).

    Article  PubMed  Google Scholar 

  5. Gazerani, P. & Cairns, B. E. Sex-specific pharmacotherapy for migraine: a narrative review. Front. Neurosci. 14, 222 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bolay, H. et al. Gender influences headache characteristics with increasing age in migraine patients. Cephalalgia 35, 792–800 (2015).

    Article  PubMed  Google Scholar 

  7. Steiner, T. J., Stovner, L. J., Vos, T., Jensen, R. & Katsarava, Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? J. Headache Pain 19, 17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 17, 954–976 (2018).

    Article  Google Scholar 

  9. Steiner, T. J. et al. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J. Headache Pain 21, 137 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Edvinsson, L., Haanes, K. A., Warfvinge, K. & Krause, D. N. CGRP as the target of new migraine therapies — successful translation from bench to clinic. Nat. Rev. Neurol. 14, 338–350 (2018). Review of the role of CGRP in migraine and the successful development of migraine-specific therapies that block CGRP (antibodies and receptor antagonists).

    Article  CAS  PubMed  Google Scholar 

  11. Haanes, K. A. & Edvinsson, L. Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs 33, 525–537 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Maasumi, K., Tepper, S. J. & Kriegler, J. S. Menstrual migraine and treatment options: review. Headache 57, 194–208 (2017).

    Article  PubMed  Google Scholar 

  13. Borsook, D. et al. Sex and the migraine brain. Neurobiol. Dis. 68, 200–214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Faubion, S. S., Batur, P. & Calhoun, A. H. Migraine throughout the female reproductive life cycle. Mayo Clin. Proc. 93, 639–645 (2018).

    Article  PubMed  Google Scholar 

  15. Gupta, S. et al. Potential role of female sex hormones in the pathophysiology of migraine. Pharmacol. Ther. 113, 321–340 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Petrovski, B. E., Vetvik, K. G., Lundqvist, C. & Eberhard-Gran, M. Characteristics of menstrual versus non-menstrual migraine during pregnancy: a longitudinal population-based study. J. Headache Pain 19, 27 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  17. MacGregor, E. A. & Hackshaw, A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology 63, 351–353 (2004).

    Article  PubMed  Google Scholar 

  18. Sacco, S. & Ripa, P. Migraine in pregnancy. J. Headache Pain 16, A24 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  19. MacGregor, E. A. Menstrual and perimenopausal migraine: a narrative review. Maturitas 142, 24–30 (2020).

    Article  CAS  PubMed  Google Scholar 

  20. Delaruelle, Z. et al. Male and female sex hormones in primary headaches. J. Headache Pain 19, 117 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Reading through the history of migraine. In: Migraine Matters. https://www.migraine-matters.com/reading-through-the-history-of-migraines/ (2016).

  22. Critchley, M. F. & Fergusonritchley, F. R. Migrane. Lancet 221, 123–126 (1933).

    Article  Google Scholar 

  23. Vetvik, K. G. & MacGregor, E. A. Menstrual migraine: a distinct disorder needing greater recognition. Lancet Neurol. 20, 304–315 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Martin, V. T. & Lipton, R. B. Epidemiology and biology of menstrual migraine. Headache 48 (Suppl. 3), S124–130 (2008).

    Article  PubMed  Google Scholar 

  25. Somerville, B. W. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22, 355–365 (1972). The classic study of the relationship between oestrogen levels and menstrual migraine that formed the basis of the oestrogen withdrawal theory.

    Article  CAS  PubMed  Google Scholar 

  26. MacGregor, E. A. Oestrogen and attacks of migraine with and without aura. Lancet Neurol. 3, 354–361 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Warnock, J. K., Cohen, L. J., Blumenthal, H. & Hammond, J. E. Hormone-related migraine headaches and mood disorders: treatment with estrogen stabilization. Pharmacotherapy 37, 120–128 (2017).

    Article  PubMed  Google Scholar 

  28. MacGregor, E. A. Migraine, menopause and hormone replacement therapy. Post. Reprod. Health 24, 11–18 (2018).

    Article  PubMed  Google Scholar 

  29. Merki-Feld, G. S., Caveng, N., Speiermann, G. & MacGregor, E. A. Migraine start, course and features over the cycle of combined hormonal contraceptive users with menstrual migraine - temporal relation to bleeding and hormone withdrawal: a prospective diary-based study. J. Headache Pain 21, 81 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pavlovic, J. M. Evaluation and management of migraine in midlife women. Menopause 25, 927–929 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gupta, S., McCarson, K. E., Welch, K. M. & Berman, N. E. Mechanisms of pain modulation by sex hormones in migraine. Headache 51, 905–922 (2011).

    Article  PubMed  Google Scholar 

  32. Somerville, B. W. The influence of progesterone and estradiol upon migraine. Headache 12, 93–102 (1972).

    Article  CAS  PubMed  Google Scholar 

  33. Kim, M. J. et al. Progesterone produces antinociceptive and neuroprotective effects in rats with microinjected lysophosphatidic acid in the trigeminal nerve root. Mol. Pain 8, 16 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Warhurst, S. et al. Effectiveness of the progestin-only pill for migraine treatment in women: a systematic review and meta-analysis. Cephalalgia 38, 754–764 (2018).

    Article  PubMed  Google Scholar 

  35. Pogatzki-Zahn, E. M. et al. Progesterone relates to enhanced incisional acute pain and pinprick hyperalgesia in the luteal phase of female volunteers. Pain 160, 1781–1793 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Guennoun, R. et al. Progesterone and allopregnanolone in the central nervous system: response to injury and implication for neuroprotection. J. Steroid Biochem. Mol. Biol. 146, 48–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Labastida-Ramirez, A., Rubio-Beltran, E., Villalon, C. M. & MaassenVanDenBrink, A. Gender aspects of CGRP in migraine. Cephalalgia 39, 435–444 (2019).

    Article  PubMed  Google Scholar 

  38. Hornung, R. S. et al. Progesterone and allopregnanolone rapidly attenuate estrogen-associated mechanical allodynia in rats with persistent temporomandibular joint inflammation. Front. Integr. Neurosci. 14, 26 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Colciago, A., Bonalume, V., Melfi, V. & Magnaghi, V. Genomic and non-genomic action of neurosteroids in the peripheral nervous system. Front. Neurosci. 14, 796 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rustichelli, C. et al. Serum levels of allopregnanolone, progesterone and testosterone in menstrually-related and postmenopausal migraine: a cross-sectional study. Cephalalgia 40, 1355–1362 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Coronel, M. F., Labombarda, F. & Gonzalez, S. L. Neuroactive steroids, nociception and neuropathic pain: a flashback to go forward. Steroids 110, 77–87 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Cutrer, F. M. & Moskowitz, M. A. Wolff Award 1996. The actions of valproate and neurosteroids in a model of trigeminal pain. Headache 36, 579–585 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Hayasaki, H. et al. A local GABAergic system within rat trigeminal ganglion cells. Eur. J. Neurosci. 23, 745–757 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Schaeffer, V., Meyer, L., Patte-Mensah, C. & Mensah-Nyagan, A. G. Progress in dorsal root ganglion neurosteroidogenic activity: basic evidence and pathophysiological correlation. Prog. Neurobiol. 92, 33–41 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Tzabazis, A. et al. Oxytocin and migraine headache. Headache 57 (Suppl. 2), 64–75 (2017). This paper describes seminal clinical studies demonstrating that oxytocin, given intranasally, provides acute relief of migraine symptoms and also reports preclinical data indicating a role of oxytocin in the trigeminal pathway.

    Article  PubMed  Google Scholar 

  46. Phillips, W. J., Ostrovsky, O., Galli, R. L. & Dickey, S. Relief of acute migraine headache with intravenous oxytocin: report of two cases. J. Pain Palliat. Care Pharmacother. 20, 25–28 (2006).

    PubMed  Google Scholar 

  47. Amico, J. A., Seif, S. M. & Robinson, A. G. Oxytocin in human plasma: correlation with neurophysin and stimulation with estrogen. J. Clin. Endocrinol. Metab. 52, 988–993 (1981).

    Article  CAS  PubMed  Google Scholar 

  48. Young, L. J., Muns, S., Wang, Z. & Insel, T. R. Changes in oxytocin receptor mRNA in rat brain during pregnancy and the effects of estrogen and interleukin-6. J. Neuroendocrinol. 9, 859–865 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Welsh, T. et al. Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium. J. Endocrinol. 212, 227–238 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Murata, T., Narita, K. & Ichimaru, T. Rat uterine oxytocin receptor and estrogen receptor alpha and beta mRNA levels are regulated by estrogen through multiple estrogen receptors. J. Reprod. Dev. 60, 55–61 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Miller, F. D., Ozimek, G., Milner, R. J. & Bloom, F. E. Regulation of neuronal oxytocin mRNA by ovarian steroids in the mature and developing hypothalamus. Proc. Natl Acad. Sci. USA 86, 2468–2472 (1989). A classic study that first showed that oxytocin gene expression in the hypothalamus (rat) is regulated by ovarian hormones, with increases at puberty and during lactation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dale, H. H. On some physiological actions of ergot. J. Physiol. 34, 163–206 (1906).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Du Vigneaud, V., Ressler, C. & Trippett, S. The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J. Biol. Chem. 205, 949–957 (1953).

    Article  CAS  Google Scholar 

  54. Uvnas-Moberg, K. et al. Maternal plasma levels of oxytocin during physiological childbirth - a systematic review with implications for uterine contractions and central actions of oxytocin. BMC Pregnancy Childbirth 19, 285 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Jirikowski, G. F. Diversity of central oxytocinergic projections. Cell Tissue Res. 375, 41–48 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Eliava, M. et al. A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron 89, 1291–1304 (2016). In this study, individual hypothalamic oxytocin neurons were shown to suppress nociception via two pathways: direct inhibitory projections to spinal sensory neurons and stimulation of oxytocin release into the blood.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jurek, B. & Neumann, I. D. The oxytocin receptor: from intracellular signaling to behavior. Physiol. Rev. 98, 1805–1908 (2018).

    Article  CAS  PubMed  Google Scholar 

  58. Carter, C. S. et al. Is oxytocin “Nature’s medicine”? Pharmacol. Rev. 72, 829–861 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Poisbeau, P., Grinevich, V. & Charlet, A. Oxytocin signaling in pain: cellular, circuit, system, and behavioral levels. Curr. Top. Behav. Neurosci. 35, 193–211 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. de Geest, K., Thiery, M., Piron-Possuyt, G. & Vanden Driessche, R. Plasma oxytocin in human pregnancy and parturition. J. Perinat. Med. 13, 3–13 (1985).

    Article  PubMed  Google Scholar 

  61. Murata, T., Narita, K., Honda, K. & Higuchi, T. Changes of receptor mRNAs for oxytocin and estrogen during the estrous cycle in rat uterus. J. Vet. Med. Sci. 65, 707–712 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Amico, J. A., Seif, S. M. & Robinson, A. G. Elevation of oxytocin and the oxytocin-associated neurophysin in the plasma of normal women during midcycle. J. Clin. Endocrinol. Metab. 53, 1229–1232 (1981).

    Article  CAS  PubMed  Google Scholar 

  63. Engel, S., Klusmann, H., Ditzen, B., Knaevelsrud, C. & Schumacher, S. Menstrual cycle-related fluctuations in oxytocin concentrations: a systematic review and meta-analysis. Front. Neuroendocrinol. 52, 144–155 (2019). This study demonstrates the fluctuation of oxytocin blood levels over the human menstrual cycle, indicating a sharp drop at the time of menstruation.

    Article  CAS  PubMed  Google Scholar 

  64. Warfvinge, K. et al. Oxytocin as a regulatory neuropeptide in the trigeminovascular system: localization, expression and function of oxytocin and oxytocin receptors. Cephalalgia 40, 1283–1295 (2020).

    Article  PubMed  Google Scholar 

  65. Tzabazis, A. et al. Oxytocin receptor: expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders. Cephalalgia 36, 943–950 (2016).

    Article  PubMed  Google Scholar 

  66. Garcia-Boll, E., Martinez-Lorenzana, G., Condes-Lara, M. & Gonzalez-Hernandez, A. Oxytocin inhibits the rat medullary dorsal horn Sp5c/C1 nociceptive transmission through OT but not V1A receptors. Neuropharmacology 129, 109–117 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Warfvinge, K., Krause, D. & Edvinsson, L. The distribution of oxytocin and the oxytocin receptor in brain: relation to regions active in migraine. J. Headache Pain 21, 10 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lagunas, N. et al. Estrogen receptor beta and G protein-coupled estrogen receptor 1 are involved in the acute estrogenic regulation of arginine-vasopressin immunoreactive levels in the supraoptic and paraventricular hypothalamic nuclei of female rats. Brain Res. 1712, 93–100 (2019).

    Article  CAS  PubMed  Google Scholar 

  69. Dayanithi, G. et al. Vasopressin and oxytocin in sensory neurones: expression, exocytotic release and regulation by lactation. Sci. Rep. 8, 13084 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Juif, P. E. & Poisbeau, P. Neurohormonal effects of oxytocin and vasopressin receptor agonists on spinal pain processing in male rats. Pain 154, 1449–1456 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. DiCarlo, L. M., Vied, C. & Nowakowski, R. S. The stability of the transcriptome during the estrous cycle in four regions of the mouse brain. J. Comp. Neurol. 525, 3360–3387 (2017).

    Article  CAS  PubMed  Google Scholar 

  72. Franchimont, P. et al. Prolactin levels during the menstrual cycle. Clin. Endocrinol. 5, 643–650 (1976).

    Article  CAS  Google Scholar 

  73. Chen, Y., Navratilova, E., Dodick, D. W. & Porreca, F. An emerging role for prolactin in female-selective pain. Trends Neurosci. 43, 635–648 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Avona, A. et al. Meningeal CGRP-prolactin interaction evokes female-specific migraine behavior. Ann. Neurol. 89, 1129–1144 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Porkka-Heiskanen, T., Kalinchuk, A., Alanko, L., Huhtaniemi, I. & Stenberg, D. Orexin A and B levels in the hypothalamus of female rats: the effects of the estrous cycle and age. Eur. J. Endocrinol. 150, 737–742 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Strother, L. C., Srikiatkhachorn, A. & Supronsinchai, W. Targeted orexin and hypothalamic neuropeptides for migraine. Neurotherapeutics 15, 377–390 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Holland, P. & Goadsby, P. J. The hypothalamic orexinergic system: pain and primary headaches. Headache 47, 951–962 (2007).

    Article  PubMed  Google Scholar 

  78. Edvinsson, J. C. A. et al. The fifth cranial nerve in headaches. J. Headache Pain 21, 65 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Messlinger, K. & Russo, A. F. Current understanding of trigeminal ganglion structure and function in headache. Cephalalgia 39, 1661–1674 (2019).

    Article  PubMed  Google Scholar 

  80. Dodick, D. W. A phase-by-phase review of migraine pathophysiology. Headache 58 (Suppl. 1), 4–16 (2018).

    Article  PubMed  Google Scholar 

  81. Pietrobon, D. & Moskowitz, M. A. Pathophysiology of migraine. Annu. Rev. Physiol. 75, 365–391 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Edvinsson, L. Tracing neural connections to pain pathways with relevance to primary headaches. Cephalalgia 31, 737–747 (2011).

    Article  PubMed  Google Scholar 

  83. Liu, Y., Broman, J. & Edvinsson, L. Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res. 1208, 103–110 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Liu, Y., Broman, J., Zhang, M. & Edvinsson, L. Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats. Cephalalgia 29, 935–948 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Noseda, R. & Burstein, R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain https://doi.org/10.1016/j.pain.2013.07.021 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  86. May, A. Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol. Sci. 38, 125–130 (2017).

    Article  PubMed  Google Scholar 

  87. May, A. & Burstein, R. Hypothalamic regulation of headache and migraine. Cephalalgia 39, 1710–1719 (2019). In this study, the investigators propose that the hypothalamus has a central role in generating a migraine attack and participates in complex oscillating neural networks that alter susceptibility thresholds.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Schulte, L. H. & May, A. Of generators, networks and migraine attacks. Curr. Opin. Neurol. 30, 241–245 (2017).

    Article  PubMed  Google Scholar 

  89. Napadow, V., Sclocco, R. & Henderson, L. A. Brainstem neuroimaging of nociception and pain circuitries. Pain Rep. 4, e745 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Marciszewski, K. K. et al. Changes in brainstem pain modulation circuitry function over the migraine cycle. J. Neurosci. 38, 10479–10488 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Karsan, N. & Goadsby, P. J. Imaging the premonitory phase of migraine. Front. Neurol. 11, 140 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Tu, Y. et al. Abnormal thalamocortical network dynamics in migraine. Neurology 92, e2706–e2716 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Peng, K. P. & May, A. Migraine understood as a sensory threshold disease. Pain 160, 1494–1501 (2019).

    Article  PubMed  Google Scholar 

  94. Maleki, N. & Androulakis, X. M. Is there any MRI pattern that discriminates female from male migraine patients? Front. Neurol. 10, 961 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Hu, B. et al. Structural and functional brain changes in perimenopausal women who are susceptible to migraine: a study protocol of multi-modal MRI trial. BMC Med. Imaging 18, 26 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Iyengar, S., Johnson, K. W., Ossipov, M. H. & Aurora, S. K. CGRP and the trigeminal system in migraine. Headache 59, 659–681 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Eftekhari, S. et al. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 1600, 93–109 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Charles, A. & Pozo-Rosich, P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet 394, 1765–1774 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Pavlovic, J. M. et al. Efficacy and safety of erenumab in women with a history of menstrual migraine. J. Headache Pain 21, 95 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ornello, R. et al. Menstrual headache in women with chronic migraine treated with erenumab: an observational case series. Brain Sci. 11, 370 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ho, T. W., Ho, A. P. & Ge, Y. J. Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine. Cephalalgia 36, 148–161 (2016).

    Article  PubMed  Google Scholar 

  102. Warfvinge, K. & Edvinsson, L. Distribution of CGRP and CGRP receptor components in the rat brain. Cephalalgia 39, 342–353 (2019).

    Article  PubMed  Google Scholar 

  103. Hewitt, S. C. & Korach, K. S. Estrogen receptors: new directions in the new Millennium. Endocr. Rev. 39, 664–675 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Levin, E. R. Extranuclear steroid receptors are essential for steroid hormone actions. Annu. Rev. Med. 66, 271–280 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Prossnitz, E. R. & Hathaway, H. J. What have we learned about GPER function in physiology and disease from knockout mice? J. Steroid Biochem. Mol. Biol. 153, 114–126 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bereiter, D. A., Cioffi, J. L. & Bereiter, D. F. Oestrogen receptor-immunoreactive neurons in the trigeminal sensory system of male and cycling female rats. Arch. Oral. Biol. 50, 971–979 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Warfvinge, K. et al. Estrogen receptors alpha, beta and GPER in the CNS and trigeminal system - molecular and functional aspects. J. Headache Pain 21, 131 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rossetti, M. F., Cambiasso, M. J., Holschbach, M. A. & Cabrera, R. Oestrogens and progestagens: synthesis and action in the brain. J. Neuroendocrinol. https://doi.org/10.1111/jne.12402 (2016).

    Article  PubMed  Google Scholar 

  109. Dun, S. L. et al. Expression of estrogen receptor GPR30 in the rat spinal cord and in autonomic and sensory ganglia. J. Neurosci. Res. 87, 1610–1619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fan, X., Kim, H. J., Warner, M. & Gustafsson, J. A. Estrogen receptor beta is essential for sprouting of nociceptive primary afferents and for morphogenesis and maintenance of the dorsal horn interneurons. Proc. Natl Acad. Sci. USA 104, 13696–13701 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Amandusson, A. & Blomqvist, A. Estrogen receptor-alpha expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat. Eur. J. Pain 14, 245–248 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  113. Greco, R. et al. Effect of sex and estrogens on neuronal activation in an animal model of migraine. Headache 53, 288–296 (2013).

    Article  PubMed  Google Scholar 

  114. Vanderhorst, V. G., Gustafsson, J. A. & Ulfhake, B. Estrogen receptor-alpha and -beta immunoreactive neurons in the brainstem and spinal cord of male and female mice: relationships to monoaminergic, cholinergic, and spinal projection systems. J. Comp. Neurol. 488, 152–179 (2005).

    Article  PubMed  Google Scholar 

  115. Llorente, R. et al. G protein-coupled estrogen receptor immunoreactivity fluctuates during the estrous cycle and show sex differences in the amygdala and dorsal hippocampus. Front. Endocrinol. 11, 537 (2020).

    Article  Google Scholar 

  116. Nomura, M., McKenna, E., Korach, K. S., Pfaff, D. W. & Ogawa, S. Estrogen receptor-beta regulates transcript levels for oxytocin and arginine vasopressin in the hypothalamic paraventricular nucleus of male mice. Brain Res. Mol. Brain Res. 109, 84–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Sandweiss, A. J. et al. 17-β-Estradiol induces spreading depression and pain behavior in alert female rats. Oncotarget 8, 114109–114122 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Eikermann-Haerter, K. et al. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J. Clin. Invest. 119, 99–109 (2009).

    CAS  PubMed  Google Scholar 

  119. Al-Hassany, L. et al. Giving researchers a headache - sex and gender differences in migraine. Front. Neurol. 11, 549038 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Martin, V. T. & Behbehani, M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis — part I. Headache 46, 3–23 (2006).

    Article  PubMed  Google Scholar 

  121. Allais, G. et al. Gender-related differences in migraine. Neurol. Sci. 41, 429–436 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Paredes, S., Cantillo, S., Candido, K. D. & Knezevic, N. N. An association of serotonin with pain disorders and its modulation by estrogens. Int. J. Mol. Sci. 20, 5729 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  123. Artero-Morales, M., Gonzalez-Rodriguez, S. & Ferrer-Montiel, A. TRP channels as potential targets for sex-related differences in migraine pain. Front. Mol. Biosci. 5, 73 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  124. Bi, R. Y. et al. Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ. PLoS One 12, e0178589 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  125. Saleeon, W., Jansri, U., Srikiatkhachorn, A. & Bongsebandhu-Phubhakdi, S. The estrous cycle modulates voltage-gated ion channels in trigeminal ganglion neurons. J. Physiol. Sci. 65 (Suppl. 2), S29–S35 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Vermeer, L. M., Gregory, E., Winter, M. K., McCarson, K. E. & Berman, N. E. Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat. Exp. Neurol. 263, 8–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Puri, J., Bellinger, L. L. & Kramer, P. R. Estrogen in cycling rats alters gene expression in the temporomandibular joint, trigeminal ganglia and trigeminal subnucleus caudalis/upper cervical cord junction. J. Cell Physiol. 226, 3169–3180 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Puri, V. et al. Effects of oestrogen on trigeminal ganglia in culture: implications for hormonal effects on migraine. Cephalalgia 26, 33–42 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Puri, V. et al. Ovarian steroids regulate neuropeptides in the trigeminal ganglion. Neuropeptides 39, 409–417 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Mecklenburg, J. et al. Transcriptomic sex differences in sensory neuronal populations of mice. Sci. Rep. 10, 15278 (2020). A mouse study that offers insight into sex dimorphism by demonstrating that a large number of female-specific genes related to nociception are expressed uniquely in trigeminal ganglia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Martin, V. T., Lee, J. & Behbehani, M. M. Sensitization of the trigeminal sensory system during different stages of the rat estrous cycle: implications for menstrual migraine. Headache 47, 552–563 (2007).

    Article  PubMed  Google Scholar 

  132. Xin, Q., Bai, B. & Liu, W. The analgesic effects of oxytocin in the peripheral and central nervous system. Neurochem. Int. 103, 57–64 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Hiroi, R. et al. The androgen metabolite, 5alpha-androstane-3beta,17beta-diol (3beta-diol), activates the oxytocin promoter through an estrogen receptor-beta pathway. Endocrinology 154, 1802–1812 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hrabovszky, E. et al. Estrogen receptor-beta in oxytocin and vasopressin neurons of the rat and human hypothalamus: Immunocytochemical and in situ hybridization studies. J. Comp. Neurol. 473, 315–333 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Narita, K., Murata, T. & Matsuoka, S. The ventromedial hypothalamus oxytocin induces locomotor behavior regulated by estrogen. Physiol. Behav. 164, 107–112 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Condes-Lara, M. et al. Paraventricular hypothalamic influences on spinal nociceptive processing. Brain Res. 1081, 126–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Garcia-Boll, E., Martinez-Lorenzana, G., Condes-Lara, M. & Gonzalez-Hernandez, A. Inhibition of nociceptive dural input to the trigeminocervical complex through oxytocinergic transmission. Exp. Neurol. 323, 113079 (2020).

    Article  CAS  PubMed  Google Scholar 

  138. Loup, F., Tribollet, E., Dubois-Dauphin, M., Pizzolato, G. & Dreifuss, J. J. Localization of oxytocin binding sites in the human brainstem and upper spinal cord: an autoradiographic study. Brain Res. 500, 223–230 (1989).

    Article  CAS  PubMed  Google Scholar 

  139. Freeman, S. M., Inoue, K., Smith, A. L., Goodman, M. M. & Young, L. J. The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). Psychoneuroendocrinology 45, 128–141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Han, Y. & Yu, L. C. Involvement of oxytocin and its receptor in nociceptive modulation in the central nucleus of amygdala of rats. Neurosci. Lett. 454, 101–104 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Moreno-Lopez, Y., Martinez-Lorenzana, G., Condes-Lara, M. & Rojas-Piloni, G. Identification of oxytocin receptor in the dorsal horn and nociceptive dorsal root ganglion neurons. Neuropeptides 47, 117–123 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Kubo, A. et al. Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia. Pain 158, 649–659 (2017).

    Article  CAS  PubMed  Google Scholar 

  143. Pierce, M. L., Mehrotra, S., Mustoe, A. C., French, J. A. & Murray, T. F. A comparison of the ability of Leu(8)- and Pro(8)-oxytocin to regulate intracellular Ca2+ and Ca2+-activated K+ channels at human and marmoset oxytocin receptors. Mol. Pharmacol. 95, 376–385 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Gong, L. et al. Oxytocin-induced membrane hyperpolarization in pain-sensitive dorsal root ganglia neurons mediated by Ca2+/nNOS/NO/KATP pathway. Neuroscience 289, 417–428 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Hobo, S., Hayashida, K. & Eisenach, J. C. Oxytocin inhibits the membrane depolarization-induced increase in intracellular calcium in capsaicin sensitive sensory neurons: a peripheral mechanism of analgesic action. Anesth. Analg. 114, 442–449 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Vecsernyes, M., Jojart, I., Jojart, J., Laczi, F. & Laszlo, F. A. Presence of chromatographically identified oxytocin in human sensory ganglia. Brain Res. 414, 153–154 (1987).

    Article  CAS  PubMed  Google Scholar 

  147. Kai-Kai, M. A., Swann, R. W. & Keen, P. Localization of chromatographically characterized oxytocin and arginine-vasopressin to sensory neurones in the rat. Neurosci. Lett. 55, 83–88 (1985).

    Article  CAS  PubMed  Google Scholar 

  148. Eftekhari, S. et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 169, 683–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Aggarwal, M., Puri, V. & Puri, S. Effects of estrogen on the serotonergic system and calcitonin gene-related peptide in trigeminal ganglia of rats. Ann. Neurosci. 19, 151–157 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Stucky, N. L. et al. Sex differences in behavior and expression of CGRP-related genes in a rodent model of chronic migraine. Headache 51, 674–692 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Edvinsson, J. C. A. et al. C-fibers may modulate adjacent Adelta-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J. Headache Pain 20, 105 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  152. Hidalgo-Lopez, E. et al. Human menstrual cycle variation in subcortical functional brain connectivity: a multimodal analysis approach. Brain Struct. Funct. 225, 591–605 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Petersen, N., Kilpatrick, L. A., Goharzad, A. & Cahill, L. Oral contraceptive pill use and menstrual cycle phase are associated with altered resting state functional connectivity. Neuroimage 90, 24–32 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Allais, G., Chiarle, G., Sinigaglia, S. & Benedetto, C. Menstrual migraine: a review of current and developing pharmacotherapies for women. Expert Opin. Pharmacother. 19, 123–136 (2018).

    Article  CAS  PubMed  Google Scholar 

  155. Ansari, T., Lagman-Bartolome, A. M., Monsour, D. & Lay, C. Management of menstrual migraine. Curr. Neurol. Neurosci. Rep. 20, 45 (2020).

    Article  PubMed  Google Scholar 

  156. Bartolini, M. et al. Frovatriptan versus almotriptan for acute treatment of menstrual migraine: analysis of a double-blind, randomized, cross-over, multicenter, Italian, comparative study. J. Headache Pain 13, 401–406 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Brandes, J. L. et al. Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks. Cephalalgia 29, 1133–1148 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Allais, G. et al. Perimenstrual migraines and their response to preventive therapy with topiramate. Cephalalgia 31, 152–160 (2011).

    Article  PubMed  Google Scholar 

  159. Calhoun, A. H. Understanding menstrual migraine. Headache 58, 626–630 (2018).

    Article  PubMed  Google Scholar 

  160. MacGregor, A. Effects of oral and transdermal estrogen replacement on migraine. Cephalalgia 19, 124–125 (1999).

    Article  CAS  PubMed  Google Scholar 

  161. Gartlehner, G. et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: evidence report and systematic review for the US Preventive services task force. JAMA 318, 2234–2249 (2017).

    Article  PubMed  Google Scholar 

  162. Middeldorp, S. Oral contraceptives and the risk of venous thromboembolism. Gend. Med. 2 (Suppl. A), S3–9 (2005).

    Article  PubMed  Google Scholar 

  163. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 394, 1159–1168 (2019).

    Article  PubMed Central  Google Scholar 

  164. Beaber, E. F. et al. Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age. Cancer Res. 74, 4078–4089 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Smitherman, T. A. & Kolivas, E. D. Resolution of menstrually related migraine following aggressive treatment for breast cancer. Headache 50, 485–488 (2010).

    Article  PubMed  Google Scholar 

  166. May, A. & Schulte, L. H. Chronic migraine: risk factors, mechanisms and treatment. Nat. Rev. Neurol. 12, 455–464 (2016).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Institute of Clinical Sciences Lund, Lund University, Lund, Sweden

    Diana N. Krause, Karin Warfvinge & Lars Edvinsson

  2. Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California at Irvine, Irvine, CA, USA

    Diana N. Krause

  3. Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet, Glostrup, Denmark

    Karin Warfvinge, Kristian Agmund Haanes & Lars Edvinsson

Authors
  1. Diana N. Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karin Warfvinge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristian Agmund Haanes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lars Edvinsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally.

Corresponding author

Correspondence to Lars Edvinsson.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks M. Russell, S. Sacco and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Krause, D.N., Warfvinge, K., Haanes, K.A. et al. Hormonal influences in migraine — interactions of oestrogen, oxytocin and CGRP. Nat Rev Neurol 17, 621–633 (2021). https://doi.org/10.1038/s41582-021-00544-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-021-00544-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing