Sex Hormones and CGRP

  • Eloísa Rubio-BeltránEmail author
  • Alejandro Labastida-Ramírez
Part of the Headache book series (HEAD)


Migraine is three times more prevalent in women than in men. The mechanisms behind the sex disparity in migraine are not completely understood, but it is thought to be mediated through changes in ovarian steroid hormones. Migraine pathophysiology is considered to involve an activation of the trigeminovascular system and the subsequent release of calcitonin gene-related peptide (CGRP); therefore, an interaction between ovarian steroid hormones, the trigeminovascular system, and CGRP has been suggested. Although studies are scarce, it has been shown that indeed there is a cross talk and that further studies could lead to the development of sex-specific treatments.

This chapter provides a summary of the studies that have evaluated the sex differences in CGRP, in both preclinical and clinical models of migraine and their possible implications for migraine pathophysiology and treatment.


Migraine Trigeminovascular system CGRP Estrogen Ovarian steroid hormones Sex 


  1. 1.
    Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2013;53(8):1278–99.PubMedCrossRefGoogle Scholar
  2. 2.
    Kurth T, Winter AC, Eliassen AH, Dushkes R, Mukamal KJ, Rimm EB, et al. Migraine and risk of cardiovascular disease in women: prospective cohort study. BMJ. 2016;353:i2610.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology. 1972;22(4):355.PubMedCrossRefGoogle Scholar
  4. 4.
    Pavlović JM, Allshouse AA, Santoro NF, Crawford SL, Thurston RC, Neal-Perry GS, et al. Sex hormones in women with and without migraine. Evidence of migraine-specific hormone profiles. Neurology. 2016;87(1):49–56.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A. Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology. 2006;67(12):2154–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Somerville BW. The influence of progesterone and estradiol upon migraine. Headache: The Journal of Head and Face Pain. 1972;12(3):93–102.CrossRefGoogle Scholar
  7. 7.
    Pringsheim T, Gooren L. Migraine prevalence in male to female transsexuals on hormone therapy. Neurology. 2004;63(3):593–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Martin VT, Pavlovic J, Fanning KM, Buse DC, Reed ML, Lipton RB. Perimenopause and menopause are associated with high frequency headache in women with migraine: results of the American Migraine Prevalence and Prevention study. Headache: The Journal of Head and Face Pain. 2016;56(2):292–305.CrossRefGoogle Scholar
  9. 9.
    Kvisvik EV, Stovner LJ, Helde G, Bovim G, Linde M. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain. 2011;12(4):443–51.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Glintborg D, Hass Rubin K, Nybo M, Abrahamsen B, Andersen M. Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome. Eur J Endocrinol. 2015;172(5):627–38.PubMedCrossRefGoogle Scholar
  11. 11.
    Tietjen GE, Conway A, Utley C, Gunning WT, Herial NA. Migraine is associated with menorrhagia and endometriosis. Headache: The Journal of Head and Face Pain. 2006;46(3):422–8.CrossRefGoogle Scholar
  12. 12.
    Spierings ELH, Padamsee A. Menstrual-cycle and menstruation disorders in episodic vs chronic migraine: an exploratory study. Pain Med. 2015;16(7):1426–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Shuster LT, Faubion SS, Sood R, Casey PM. Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches. Curr Neurol Neurosci Rep. 2011;11(2):131–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Smitherman TA, Kolivas ED. Resolution of menstrually related migraine following aggressive treatment for breast cancer. Headache: The Journal of Head and Face Pain. 2010;50(3):485–8.CrossRefGoogle Scholar
  15. 15.
    Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553–622.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache. 2017;57(Suppl 2):47–55.PubMedCrossRefGoogle Scholar
  17. 17.
    Mayberg M, Langer RS, Zervas NT, Moskowitz MA. Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science. 1981;213(4504):228–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Goadsby PJ, Hoskin KL. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat. 1997;190(3):367–75.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Goadsby PJ, Lipton RB, Ferrari MD. Migraine — current understanding and treatment. N Engl J Med. 2002;346(4):257–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298(5871):240–4.CrossRefGoogle Scholar
  22. 22.
    Amara SG, Arriza JL, Leff SE, Swanson LW, Evans RM, Rosenfeld MG. Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science. 1985;229(4718):1094–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 2015;1600:93–109.PubMedCrossRefGoogle Scholar
  24. 24.
    Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain. 2013;14(11):1289–303.PubMedCrossRefGoogle Scholar
  25. 25.
    Mulderry PK, Ghatei MA, Spokes RA, Jones PM, Pierson AM, Hamid QA, et al. Differential expression of alpha-CGRP and beta-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience. 1988;25(1):195–205.PubMedCrossRefGoogle Scholar
  26. 26.
    Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33(1):48–56.PubMedCrossRefGoogle Scholar
  28. 28.
    Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54–61.PubMedCrossRefGoogle Scholar
  29. 29.
    Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377(22):2113–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol. 2018;75:187.PubMedCrossRefGoogle Scholar
  32. 32.
    Yuan H, Lauritsen CG, Kaiser EA, Silberstein SD. CGRP monoclonal antibodies for migraine: rationale and progress. BioDrugs. 2017;31(6):487–501.PubMedCrossRefGoogle Scholar
  33. 33.
    Gupta S, McCarson KE, Welch KM, Berman NE. Mechanisms of pain modulation by sex hormones in migraine. Headache. 2011;51(6):905–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Bolay H, Berman NE, Akcali D. Sex-related differences in animal models of migraine headache. Headache. 2011;51(6):891–904.CrossRefGoogle Scholar
  35. 35.
    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(5):674–92.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Vermeer LMM, Gregory E, Winter MK, McCarson KE, Berman NEJ. Exposure to bisphenol a exacerbates migraine-like behaviors in a multibehavior model of rat migraine. Toxicol Sci. 2014;137(2):416–27.PubMedCrossRefGoogle Scholar
  37. 37.
    Giuffrè R, Palma E, Liccardo G, Sciarra F, Pastore F, Concolino G. Sex steroid hormones in the pathogenesis of chronic subdural haematoma. Neurochirurgia. 1992;35(04):103–7.PubMedGoogle Scholar
  38. 38.
    Gonzales RJ, Ansar S, Duckles SP, Krause DN. Androgenic/estrogenic balance in the male rat cerebral circulation: metabolic enzymes and sex steroid receptors. J Cereb Blood Flow Metab. 2007;27(11):1841–52.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Kemper MF, Zhao Y, Duckles SP, Krause DN. Endogenous ovarian hormones affect mitochondrial efficiency in cerebral endothelium via distinct regulation of PGC-1 isoforms. J Cereb Blood Flow Metab. 2013;33(1):122–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Zuloaga KL, O’Connor DT, Handa RJ, Gonzales RJ. Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries. Steroids. 2012;77(8):835–44.PubMedCrossRefGoogle Scholar
  41. 41.
    Puri V, Cui L, Liverman CS, Roby KF, Klein RM, Welch KMA, et al. Ovarian steroids regulate neuropeptides in the trigeminal ganglion. Neuropeptides. 2005;39(4):409–17.PubMedCrossRefGoogle Scholar
  42. 42.
    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. 2012;19(4):151–7.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Bereiter DA, Cioffi JL, Bereiter DF. Oestrogen receptor-immunoreactive neurons in the trigeminal sensory system of male and cycling female rats. Arch Oral Biol. 2005;50(11):971–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Liverman C, Brown J, Sandhir R, McCarson K, Berman N. Role of the oestrogen receptors GPR30 and ERα in peripheral sensitization: relevance to trigeminal pain disorders in women. Cephalalgia. 2009;29(7):729–41.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Fenzi F, Rizzzuto N. Estrogen receptors localization in the spinal trigeminal nucleus: an immunohistochemical study in humans. Eur J Pain. 2011;15(10):1002–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Alimy-Allrath T, Ricken A, Bechmann I. Expression of estrogen receptors α and β in the trigeminal mesencephalic nucleus of adult women and men. Ann Anat. 2014;196(6):416–22.PubMedCrossRefGoogle Scholar
  47. 47.
    Glinskii OV, Abraha TW, Turk JR, Rubin LJ, Huxley VH, Glinsky VV. Microvascular network remodeling in dura mater of ovariectomized pigs: role for angiopoietin-1 in estrogen-dependent control of vascular stability. Am J Physiol Heart Circ Physiol. 2007;293(2):H1131–H7.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Murata T, Dietrich HH, Xiang C, Dacey RG. G Protein–coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats. Stroke. 2013;44(3):779–85.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Meffre D, Delespierre B, Gouézou M, Leclerc P, Vinson GP, Schumacher M, et al. The membrane‐associated progesterone‐binding protein 25‐Dx is expressed in brain regions involved in water homeostasis and is up‐regulated after traumatic brain injury. J Neurochem. 2005;93(5):1314–26.PubMedCrossRefGoogle Scholar
  50. 50.
    Khalid H, Shibata S, Kishikawa M, Yasunaga A, Iseki M, Hiura T. Immunohistochemical analysis of progesterone receptor and Ki-67 labeling index in astrocytic tumors. Cancer. 1997;80(11):2133.PubMedCrossRefGoogle Scholar
  51. 51.
    Manteniotis S, Lehmann R, Flegel C, Vogel F, Hofreuter A, Schreiner BSP, et al. Comprehensive RNA-seq expression analysis of sensory ganglia with a focus on ion channels and GPCRs in trigeminal ganglia. PLoS One. 2013;8(11):e79523.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Haywood SA, Simonian SX, van der Beek EM, Bicknell RJ, Herbison AE. Fluctuating estrogen and progesterone receptor expression in brainstem norepinephrine neurons through the rat estrous cycle*. Endocrinology. 1999;140(7):3255–63.PubMedCrossRefGoogle Scholar
  53. 53.
    Lin IC, Slemp AE, Hwang C, Karmacharya J, Gordon AD, Kirschner RE. Immunolocalization of androgen receptor in the developing craniofacial skeleton. J Craniofac Surg. 2004;15(6):922–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Lee KS, Zhang Y, Asgar J, Auh QS, Chung M-K, Ro JY. Androgen receptor transcriptionally regulates μ-opioid receptor expression in rat trigeminal ganglia. Neuroscience. 2016;331:52–61.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Simerly R, Swanson L, Chang C, Muramatsu M. Distribution of androgen and estrogen receptor mRNA‐containing cells in the rat brain: an in situ hybridization study. J Comp Neurol. 1990;294(1):76–95.PubMedCrossRefGoogle Scholar
  56. 56.
    Labastida-Ramirez A, Rubio-Beltran E, Villalon CM, MaassenVanDenBrink A. Gender aspects of CGRP in migraine. Cephalalgia. 2017.; 333102417739584.Google Scholar
  57. 57.
    Moussaoui S, Duval P, Lenoir V, Garret C, Kerdelhue B. CGRP in the trigeminal nucleus, spinal cord and hypothalamus: effect of gonadal steroids. Neuropeptides. 1996;30(6):546–50.CrossRefGoogle Scholar
  58. 58.
    Wang D, Zhao J, Wang J, Li J, Yu S, Guo X. Deficiency of female sex hormones augments PGE2 and CGRP levels within midbrain periaqueductal gray. J Neurol Sci. 2014;346(1):107–11.PubMedCrossRefGoogle Scholar
  59. 59.
    Pardutz A, Multon S, Malgrange B, Parducz A, Vecsei L, Schoenen J. Effect of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen. Eur J Neurosci. 2002;15(11):1803–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Gon G, Giaid A, Steel JH, O’Halloran DJ, Noorden SV, Ghatei MA, et al. Localization of immunoreactivity for calcitonin gene- related peptide in the rat anterior pituitary during ontogeny and gonadal steroid manipulations and detection of its messenger ribonucleic acid. Endocrinology. 1990;127(6):2618–29.PubMedCrossRefGoogle Scholar
  61. 61.
    Yang Y, Ozawa H, Lu H, Yuri K, Hayashi S, Nihonyanagi K, et al. Immunocytochemical analysis of sex differences in calcitonin gene-related peptide in the rat dorsal root ganglion, with special reference to estrogen and its receptor. Brain Res. 1998;791(1):35–42.PubMedCrossRefGoogle Scholar
  62. 62.
    Gangula PRR, Lanlua P, Wimalawansa S, Supowit S, DiPette D, Yallampalli C. Regulation of calcitonin gene-related peptide expression in dorsal root ganglia of rats by female sex steroid hormones1. Biol Reprod. 2000;62(4):1033–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Mowa CN, Usip S, Collins J, Storey-Workley M, Hargreaves KM, Papka RE. The effects of pregnancy and estrogen on the expression of calcitonin gene-related peptide (CGRP) in the uterine cervix, dorsal root ganglia and spinal cord. Peptides. 2003;24(8):1163–74.PubMedCrossRefGoogle Scholar
  64. 64.
    Sarajari S, Oblinger MM. Estrogen effects on pain sensitivity and neuropeptide expression in rat sensory neurons. Exp Neurol. 2010;224(1):163–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Herbison AE, Spratt DP. Sexually dimorphic expression of calcitonin gene-related peptide (CGRP) mRNA in rat medial preoptic nucleus. Mol Brain Res. 1995;34(1):143–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Yuri K, Kawata M. Estrogen affects calcitonin gene-related peptide- and methionine-enkephalin-immunoreactive neuron in the female rat preoptic area. Neurosci Lett. 1994;169(1):5–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Gupta S, Villalon CM, Mehrotra S, de Vries R, Garrelds IM, Saxena PR, et al. Female sex hormones and rat dural vasodilatation to CGRP, periarterial electrical stimulation and capsaicin. Headache. 2007;47(2):225–35.PubMedCrossRefGoogle Scholar
  68. 68.
    Martin VT, Lee J, Behbehani MM. Sensitization of the trigeminal sensory system during different stages of the rat estrous cycle: implications for menstrual migraine. Headache. 2007;47(4):552–63.PubMedGoogle Scholar
  69. 69.
    Krause DN, Duckles SP, Pelligrino DA. Influence of sex steroid hormones on cerebrovascular function. J Appl Physiol. 2006;101(4):1252–61.PubMedCrossRefGoogle Scholar
  70. 70.
    Jana B, Palus K, Meller K, Calka J. Porcine dorsal root ganglia ovarian neurons are affected by long lasting testosterone treatment. Physiol Res. 2016;65(6):1019–30.PubMedGoogle Scholar
  71. 71.
    Valdemarsson S, Edvinsson L, Hedner P, Ekman R. Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Invest. 1990;50(4):385–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Ma QL, Zhou HY, Sun M. Relationship between sex hormone levels and blood calcitonin gene-related peptide/endothelin-1 in postmenopausal women with coronary heart disease. Hunan Yi Ke Da Xue Xue Bao. 2001;26(2):146–8.PubMedGoogle Scholar
  73. 73.
    Stevenson JC, Macdonald DW, Warren RC, Booker MW, Whitehead MI. Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed). 1986;293(6558):1329–30.CrossRefGoogle Scholar
  74. 74.
    Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816.CrossRefGoogle Scholar
  75. 75.
    Van der Schueren BJ, Rogiers A, Vanmolkot FH, Van Hecken A, Depre M, Kane SA, et al. Calcitonin gene-related peptide8-37 antagonizes capsaicin-induced vasodilation in the skin: evaluation of a human in vivo pharmacodynamic model. J Pharmacol Exp Ther. 2008;325(1):248–55.PubMedCrossRefGoogle Scholar
  76. 76.
    Sinclair SR, Kane SA, Van der Schueren BJ, Xiao A, Willson KJ, Boyle J, et al. Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974). Br J Clin Pharmacol. 2010;69(1):15–22.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Vermeersch S, Benschop RJ, Van Hecken A, Monteith D, Wroblewski VJ, Grayzel D, et al. Translational pharmacodynamics of calcitonin gene-related peptide monoclonal antibody LY2951742 in a capsaicin-induced dermal blood flow model. J Pharmacol Exp Ther. 2015;354(3):350–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Ibrahimi K, Vermeersch S, Frederiks P, Geldhof V, Draulans C, Buntinx L, et al. The influence of migraine and female hormones on capsaicin-induced dermal blood flow. Cephalalgia. 2017;37(12):1164–72.PubMedCrossRefGoogle Scholar
  79. 79.
    Ibrahimi K, Vermeersch S, Danser A, Villalón C, Meiracker A, Hoon JD, et al. Development of an experimental model to study trigeminal nerve-mediated vasodilation on the human forehead. Cephalalgia. 2014;34(7):514–22.PubMedCrossRefGoogle Scholar
  80. 80.
    Ibrahimi K, van Oosterhout WPJ, van Dorp W, Danser AHJ, Garrelds IM, Kushner SA, et al. Reduced trigeminovascular cyclicity in patients with menstrually related migraine. Neurology. 2015;84(2):125–31.CrossRefGoogle Scholar
  81. 81.
    Gazerani P, Kaeseler Andersen O, Arendt-Nielsen L. A human experimental capsaicin model for trigeminal sensitization. Gender-specific differences. Pain. 2005;118(1):155–63.PubMedCrossRefGoogle Scholar
  82. 82.
    Yamagata K, Sugimura M, Yoshida M, Sekine S, Kawano A, Oyamaguchi A, et al. Estrogens exacerbate nociceptive pain via up-regulation of TRPV1 and ANO1 in trigeminal primary neurons of female rats. Endocrinology. 2016;157(11):4309–17.PubMedCrossRefGoogle Scholar
  83. 83.
    Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139(7):1987–93.PubMedCrossRefGoogle Scholar
  84. 84.
    Maleki N, Linnman C, Brawn J, Burstein R, Becerra L, Borsook D. Her versus his migraine: multiple sex differences in brain function and structure. Brain. 2012;135(8):2546–59.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70(16):1304–12.PubMedCrossRefGoogle Scholar
  86. 86.
    Olesen J, Diener H-C, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene–related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104–10.PubMedCrossRefGoogle Scholar
  87. 87.
    Ho TW, Ho A, Ge Y, Assaid C, Gottwald R, MacGregor EA, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine. Cephalalgia. 2015;36(2):148–61.PubMedCrossRefGoogle Scholar
  88. 88.
    Negro A, Lionetto L, Simmaco M, Martelletti P. CGRP receptor antagonists: an expanding drug class for acute migraine? Expert Opin Investig Drugs. 2012;21(6):807–18.PubMedCrossRefGoogle Scholar
  89. 89.
    Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology. 2014;83(11):958–66.PubMedCrossRefGoogle Scholar
  90. 90.
    MaassenVanDenBrink A, Meijer J, Villalón CM, Ferrari MD. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37(9):779–88.PubMedCrossRefGoogle Scholar
  91. 91.
    Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, et al. Blocking CGRP in migraine patients - a review of pros and cons. J Headache Pain. 2017;18(1):96.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Bigal ME, Walter S, Bronson M, Alibhoy A, Escandon R. Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP. Cephalalgia. 2014;34(12):968–76.PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Eloísa Rubio-Beltrán
    • 1
    Email author
  • Alejandro Labastida-Ramírez
    • 1
  1. 1.Division of Vascular Medicine and Pharmacology, Department of Internal MedicineErasmus Medical CenterRotterdamThe Netherlands

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