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Review
. 2024 Apr 24;25(1):63.
doi: 10.1186/s10194-024-01771-w.

Female-selective mechanisms promoting migraine

Shagun Singh #  1 , Caroline M Kopruszinski #  2 , Moe Watanabe  2 , David W Dodick  3   4 , Edita Navratilova  2   3 , Frank Porreca  5   6
Affiliations
Review

Female-selective mechanisms promoting migraine

Shagun Singh et al. J Headache Pain. .

Abstract

Sexual dimorphism has been revealed for many neurological disorders including chronic pain. Prelicinal studies and post-mortem analyses from male and female human donors reveal sexual dimorphism of nociceptors at transcript, protein and functional levels suggesting different mechanisms that may promote pain in men and women. Migraine is a common female-prevalent neurological disorder that is characterized by painful and debilitating headache. Prolactin is a neurohormone that circulates at higher levels in females and that has been implicated clinically in migraine. Prolactin sensitizes sensory neurons from female mice, non-human primates and humans revealing a female-selective pain mechanism that is conserved evolutionarily and likely translationally relevant. Prolactin produces female-selective migraine-like pain behaviors in rodents and enhances the release of calcitonin gene-related peptide (CGRP), a neurotransmitter that is causal in promoting migraine in many patients. CGRP, like prolactin, produces female-selective migraine-like pain behaviors. Consistent with these observations, publicly available clinical data indicate that small molecule CGRP-receptor antagonists are preferentially effective in treatment of acute migraine therapy in women. Collectively, these observations support the conclusion of qualitative sex differences promoting migraine pain providing the opportunity to tailor therapies based on patient sex for improved outcomes. Additionally, patient sex should be considered in design of clinical trials for migraine as well as for pain and reassessment of past trials may be warranted.

Keywords: Calcitonin gene related peptide; Gepants; Migraine; Nociceptor; Pain; Prolactin; Sexual dimorphism.

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Conflict of interest statement

Shagun Singh, Caroline M. Kopruszinski, Moe Watanabe and Edita Navratilova declare that they have no personal, financial, or relational conflicts of interest with this work. Frank Porreca has served as a consultant or received research funding from Amgen, Acadia, Blackthorn, Teva, Abbvie, Eli Lilly, Hoba, Allergan, Ipsen, and Proximagen and is a founder of Catalina Pharma and Axon Therapeutics. David W. Dodick reports the following conflicts within the past 12 36 months: Consulting: Amgen, Atria, CapiThera Ltd., Cerecin, Ceruvia Lifesciences LLC, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, GlaxoSmithKline, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, Pfizer. Honoraria: American Academy of Neurology, Headache Cooperative of the Pacific, Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company (Clinical Education Alliance LLC), Teva (speaking), Amgen (speaking), Eli Lilly (speaking), Lundbeck (speaking), Pfizer (speaking), Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, Medica Communications LLC, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Non-profit board membership: American Brain Foundation, American Migraine Foundation, ONE Neurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Arizona Brain Injury Alliance, Domestic Violence HOPE Foundation/Panfila. Research support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Henry Jackson Foundation, Patient Centered Outcomes Research Institute (PCORI). Stock options/shareholder/patents/board of directors: Aural analytics (options), Axon Therapeutics (shares/board), ExSano (options), Palion (options), Man and Science, Healint (options), Theranica (options), Second Opinion/Mobile Health (options), Epien (options), Nocira (options), Matterhorn (shares), Ontologics (shares), King-Devick Technologies (options/board), EigenLyfe (shares), AYYA Biosciences (options), Cephalgia Group (shares/board), Atria Health (options/employee). Patent 17189376.1-1466:vTitle: Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (Non-royalty bearing). Patent application submitted: Synaquell® (Precon Health).

Figures

Fig. 1
Fig. 1
Cross-talk between prolactin and CGRP to produce migraine-like pain selective to females. A Increased CGRP release can be observed following prolactin sensitization of nociceptors selectively in females. B Application of prolactin to the mouse dura mater produces headache-like pain behaviors in female, but not male, mice. Prolactin-induced migraine-like pain behavior in females is blocked by a CGRP receptor antagonist [46]. C Application of CGRP to the mouse dura mater produces female-selective headache-like pain behavior which is blocked by a prolactin receptor antagonist [46]. PRL may be an upstream mechanism for CGRP-related migraine-like pain selectively in females
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