Molecular Mechanisms of Hormones Implicated in Migraine and the Translational Implication for Transgender Patients

Overview

Journal Front Pain Res (Lausanne)

Date 2023 Oct 5

PMID 37795389

Authors

Cameron I Martinez

Erika Liktor-Busa

Tally M Largent-Milnes

Affiliations

Soon will be listed here.

Abstract

Migraine is a primary headache disorder recognized by the World Health Organization as one of the most poorly understood and debilitating neurological conditions impacting global disability. Chronic pain disorders are more frequently diagnosed among cisgender women than men, suggesting that female sex hormones could be responsible for mediating chronic pain, including migraine and/or that androgens can be protective. This review discusses the major gonadal hormones, estrogens, progesterone, and testosterone in the context of molecular mechanisms by which they play a role in migraine pathophysiology. In addition, the literature to date describing roles of minor sex hormones including prolactin, luteinizing hormone, follicular stimulating hormone, and gonadotropin releasing hormone in migraine are presented. Because transgender and gender non-conforming (trans*) individuals are an underserved patient population in which gender-affirming sex hormone replacement therapy (HRT) is often medically necessary to align biological sex with gender identity, results from cisgender patient populations are discussed in the context of these major and minor sex hormones on migraine incidence and management in trans* patients.

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References

Katsarava Z, Buse D, Manack A, Lipton R . Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep. 2011; 16(1):86-92. PMC: 3258393. DOI: 10.1007/s11916-011-0233-z. View

Brennan K, Romero Reyes M, Lopez Valdes H, Arnold A, Charles A . Reduced threshold for cortical spreading depression in female mice. Ann Neurol. 2007; 61(6):603-6. DOI: 10.1002/ana.21138. View

Shields L, Seifert T, Shelton B, Plato B . Testosterone levels in men with chronic migraine. Neurol Int. 2019; 11(2):8079. PMC: 6589638. DOI: 10.4081/ni.2019.8079. View

Gordon A, Krieger N, Okechukwu C, Haneuse S, Samnaliev M, Charlton B . Decrements in health-related quality of life associated with gender nonconformity among U.S. adolescents and young adults. Qual Life Res. 2017; 26(8):2129-2138. PMC: 5511094. DOI: 10.1007/s11136-017-1545-1. View

Braidman I, Rose D . Effects of sex hormones on three glucocorticoid-inducible enzymes concerned with amino acid metabolism in rat liver. Endocrinology. 1971; 89(5):1250-5. DOI: 10.1210/endo-89-5-1250. View

Allena M, De Icco R, Sances G, Ahmad L, Putorti A, Pucci E . Gender Differences in the Clinical Presentation of Cluster Headache: A Role for Sexual Hormones?. Front Neurol. 2019; 10:1220. PMC: 6882735. DOI: 10.3389/fneur.2019.01220. View

Perusquia M, Stallone J . Do androgens play a beneficial role in the regulation of vascular tone? Nongenomic vascular effects of testosterone metabolites. Am J Physiol Heart Circ Physiol. 2010; 298(5):H1301-7. PMC: 2867446. DOI: 10.1152/ajpheart.00753.2009. View

Favoni V, Giani L, Al-Hassany L, Asioli G, Butera C, de Boer I . CGRP and migraine from a cardiovascular point of view: what do we expect from blocking CGRP?. J Headache Pain. 2019; 20(1):27. PMC: 6734543. DOI: 10.1186/s10194-019-0979-y. View

Fioroni L, d Andrea G, Alecci M, Cananzi A, Facchinetti F . Platelet serotonin pathway in menstrual migraine. Cephalalgia. 1996; 16(6):427-30. DOI: 10.1046/j.1468-2982.1996.1606427.x. View

10.

Eikermann-Haerter K, Baum M, Ferrari M, van den Maagdenberg A, Moskowitz M, Ayata C . Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice. Ann Neurol. 2009; 66(4):564-8. PMC: 2783310. DOI: 10.1002/ana.21779. View

11.

Jimenez Caballero P, Munoz Escudero F . Peripheral endothelial function and arterial stiffness in patients with chronic migraine: a case-control study. J Headache Pain. 2013; 14:8. PMC: 3619990. DOI: 10.1186/1129-2377-14-8. View

12.

Davey R, Grossmann M . Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev. 2016; 37(1):3-15. PMC: 4810760. View

13.

Allais G, Chiarle G, Sinigaglia S, Airola G, Schiapparelli P, Benedetto C . Gender-related differences in migraine. Neurol Sci. 2020; 41(Suppl 2):429-436. PMC: 7704513. DOI: 10.1007/s10072-020-04643-8. View

14.

Samulowitz A, Gremyr I, Eriksson E, Hensing G . "Brave Men" and "Emotional Women": A Theory-Guided Literature Review on Gender Bias in Health Care and Gendered Norms towards Patients with Chronic Pain. Pain Res Manag. 2018; 2018:6358624. PMC: 5845507. DOI: 10.1155/2018/6358624. View

15.

Charles A, Baca S . Cortical spreading depression and migraine. Nat Rev Neurol. 2013; 9(11):637-44. DOI: 10.1038/nrneurol.2013.192. View

16.

Chen Y, Navratilova E, Dodick D, Porreca F . An Emerging Role for Prolactin in Female-Selective Pain. Trends Neurosci. 2020; 43(8):635-648. DOI: 10.1016/j.tins.2020.06.003. View

17.

Fernandez J, Kendjorsky K, Narla A, Villasante-Tezanos A, Tannock L . Assessment of Gender-Affirming Hormone Therapy Requirements. LGBT Health. 2019; 6(3):101-106. PMC: 6477580. DOI: 10.1089/lgbt.2018.0116. View

18.

Martin V, Behbehani M . Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis--part I. Headache. 2006; 46(1):3-23. DOI: 10.1111/j.1526-4610.2006.00309.x. View

19.

Gazerani P . A link between migraine and prolactin: the way forward. Future Sci OA. 2021; 7(9):FSO748. PMC: 8558870. DOI: 10.2144/fsoa-2021-0047. View

20.

Chauvel V, Vamos E, Pardutz A, Vecsei L, Schoenen J, Multon S . Effect of systemic kynurenine on cortical spreading depression and its modulation by sex hormones in rat. Exp Neurol. 2012; 236(2):207-14. DOI: 10.1016/j.expneurol.2012.05.002. View