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

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.

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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.

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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

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