What is the significance of hormones in the pathophysiology of migraine?
Migraine is a complex neurovascular disease characterized by the dysfunction of the nociceptive trigeminovascular system in its pathophysiology. Its prevalence is 2-3 times higher in women than in men. The cause of this difference has not yet been fully elucidated, but it appears that the fluctuation of ovarian hormone levels and its influence on CGRP plays an important role. The following article summarizes findings on the hormonal influence of migraine and also discusses new prophylactic drugs – anti-CGRP antibodies.
Introduction
Sex differences are evident in the case of migraine. Besides a higher prevalence, women experience more intense and frequent headaches compared to men, have a higher risk of migraine transitioning to chronicity, and a higher risk of cardiovascular events. Differences first appear during puberty when the incidence of the disease begins to increase in women. With menarche, the fluctuation of ovarian hormone levels begins, which influences the occurrence of migraine during different reproductive periods. Hormonal contraception or hormone replacement therapy can also act as factors in the development of migraine.
Ovarian Hormones and CGRP
Scientists are working to explain the differences between genders, and according to available data, ovarian hormones, particularly estrogen, play a key role, with receptors located in various parts of the trigeminovascular system. Fluctuating levels of ovarian hormones likely have a significant impact on the homeostasis of CGRP (calcitonin gene-related peptide), a neuropeptide that is crucial in the development of migraines. CGRP is produced by neurons throughout the trigeminovascular system. During a migraine attack, CGRP is released into the perivascular space, causing neurogenic vasodilation and nociceptive transmission. Various experimental studies have focused on exploring the interaction between ovarian hormones and CGRP.
Animal studies have shown that the activation of the CGRP system in female rats depends on the estrous cycle of the animal. Recent experimental clinical studies used the method of measuring skin vasodilation mediated by the release of CGRP, induced by stimulating a peripheral sensory neuron (on the forearm and forehead in the V1 dermatome) with capsaicin. The studies demonstrated differences between sexes in the release of CGRP in healthy individuals and patients with migraine, as well as its modulation by changing levels of estrogen and progesterone during the menstrual cycle. The CGRP system was most reactive in women around menstruation when estrogen levels are low. Furthermore, the influence of the menstrual cycle on vasodilation induced by the trigeminal nerve was observed in healthy women with regular cycles, postmenopausal women, and patients with menstrual migraine.
New Agents Acting Against CGRP
Based on the fact that CGRP plays a key role in the development of migraine, anti-CGRP monoclonal antibodies (mAbs) have been developed. Currently, three drugs from this group are registered in the Czech Republic for the prophylactic treatment of migraine. Galcanezumab and fremanezumab are humanized mAbs directly against CGRP, and erenumab is a fully human mAb targeting the CGRP receptor. Long-term side effects are not yet fully elucidated, but all these agents have demonstrated their efficacy, good tolerance, and safety in randomized clinical trials.
Insights from Meta-analysis
Specific data were provided by a meta-analysis published in 2019 focusing on the efficacy and safety of erenumab in the treatment of migraine patients. The authors included 5 randomized controlled trials comparing erenumab with placebo, involving a total of 2928 patients. The results of the analysis indicate that erenumab, compared to placebo, significantly increased the occurrence of at least a 50% reduction in the number of days with migraine per month, significantly reduced the average number of migraine days per month, and the number of days patients had to use any acute migraine medication. No increased risk of adverse effects compared to placebo was recorded.
Summary and Conclusion
Current knowledge suggests that the influence of estrogen on CGRP represents a key factor for sex differences in migraine, but the exact mechanism of this interaction remains unclear. New drugs targeting the CGRP peptide or its receptor appear promising in the prophylactic treatment of migraine and so far show good efficacy and safety in clinical studies.
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Sources:
1. Labastida-Ramírez A., Rubio-Beltrán E., Villalón C. M. et al. Gender aspects of CGRP in migraine. Cephalalgia 2019 Mar; 39 (3): 435–444, doi: 10.1177/0333102417739584.
2. Zhu C., Guan J., Xiao H. et al. Erenumab safety and efficacy in migraine: a systematic review and meta-analysis of randomized clinical trials. Medicine (Baltimore) 2019 Dec; 98 (52): e18483, doi: 10.1097/MD.0000000000018483.
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