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      Sex and Gender Considerations in Episodic Migraine

      review-article
      1 , , 2
      Current Pain and Headache Reports
      Springer US
      Gender, Sex, Episodic migraine, Gender minority, Sex hormones, CGRP

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          Abstract

          Purpose of Review

          We seek to update readers on recent advances in our understanding of sex and gender in episodic migraine with a two part series. In part 1, we examine migraine epidemiology in the context of sex and gender, differences in symptomatology, and the influence of sex hormones on migraine pathophysiology (including CGRP). In part 2, we focus on practical clinical considerations for sex and gender in episodic migraine by addressing menstrual migraine and the controversial topic of hormone-containing therapies. We make note of data applicable to gender minority populations, when available, and summarize knowledge on gender affirming hormone therapy and migraine management in transgender individuals. Finally, we briefly address health disparities, socioeconomic considerations, and research bias.

          Recent Findings

          Migraine is known to be more prevalent, frequent, and disabling in women. There are also differences in migraine co-morbidities and symptomatology. For instance, women are likely to experience more migraine associated symptoms such as nausea, photophobia, and phonophobia. Migraine pathophysiology is influenced by sex hormones, e.g., estrogen withdrawal as a known trigger for migraine. Other hormones such as progesterone and testosterone are less well studied. Relationships between CGRP (the target of new acute and preventive migraine treatments) and sex hormones have been established with both animal and human model studies. The natural course of migraine throughout the lifetime suggests a contribution from hormonal changes, from puberty to pregnancy to menopause/post-menopause. Treatment of menstrual migraine and the use of hormone-containing therapies remains controversial. Re-evaluation of the data reveals that stroke risk is an estrogen dose- and aura frequency-dependent phenomenon. There are limited data on episodic migraine in gender minorities. Gender affirming hormone therapy may be associated with a change in migraine and unique risks (including ischemic stroke with high dose estrogen).

          Summary

          There are key differences in migraine epidemiology and symptomatology, thought to be driven at least in part by sex hormones which influence migraine pathophysiology and the natural course of migraine throughout the lifetime. More effective and specific treatments for menstrual migraine are needed. A careful examination of the data on estrogen and stroke risk suggests a nuanced approach to the issue of estrogen-containing contraception and hormone replacement therapy is warranted. Our understanding of sex and gender is evolving, with limited but growing research on the relationship between gender affirming therapy and migraine, and treatment considerations for transgender people with migraine.

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          Most cited references83

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          Pathophysiology of Migraine: A Disorder of Sensory Processing.

          Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.
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            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.

            The strikingly higher prevalence of migraine in females compared with males is one of the hallmarks of migraine. A large global body of evidence exists on the sex differences in the prevalence of migraine with female to male ratios ranging from 2:1 to 3:1 and peaking in midlife. Some data are available on sex differences in associated symptoms, headache-related disability and impairment, and healthcare resource utilization in migraine. Few data are available on corresponding sex differences in probable migraine (PM) and other severe headache (ie, nonmigraine-spectrum severe headache). Gaining a clear understanding of sex differences in a range of severe headache disorders may help differentiate the range of headache types. Herein, we compare sexes on prevalence and a range of clinical variables for migraine, PM, and other severe headache in a large sample from the US population. This study analyzed data from the 2004 American Migraine Prevalence and Prevention Study. Total and demographic-stratified sex-specific, prevalence estimates of headache subtypes (migraine, PM, and other severe headache) are reported. Log-binomial models are used to calculate sex-specific adjusted prevalence ratios and 95% confidence intervals for each across demographic strata. A smoothed sex prevalence ratio (female to male) figure is presented for migraine and PM. One hundred sixty-two thousand seven hundred fifty-six individuals aged 12 and older responded to the 2004 American Migraine Prevalence and Prevention Study survey (64.9% response rate). Twenty-eight thousand two hundred sixty-one (17.4%) reported "severe headache" in the preceding year (23.5% of females and 10.6% of males), 11.8% met International Classification of Headache Disorders-2 criteria for migraine (17.3% of females and 5.7% of males), 4.6% met criteria for PM (5.3% of females and 3.9% of males), and 1.0% were categorized with other severe headache (0.9% of females and 1.0% of males). Sex differences were observed in the prevalence of migraine and PM, but not for other severe headache. Adjusted female to male prevalence ratios ranged from 1.48 to 3.25 across the lifetime for migraine and from 1.22 to 1.53 for PM. Sex differences were also observed in associated symptomology, aura, headache-related disability, healthcare resource utilization, and diagnosis for migraine and PM. Despite higher rates of migraine diagnosis by a healthcare professional, females with migraine were less likely than males to be using preventive pharmacologic treatment for headache. In this large, US population sample, both migraine and PM were more common among females, but a sex difference was not observed in the prevalence of other severe headache. The sex difference in migraine and PM held true across age and for most other sociodemographic variables with the exception of race for PM. Females with migraine and PM had higher rates of most migraine symptoms, aura, greater associated impairment, and higher healthcare resource utilization than males. Corresponding sex differences were not observed among individuals with other severe headache on the majority of these comparisons. Results suggest that PM is part of the migraine spectrum whereas other severe headache types are not. Results also substantiate existing literature on sex differences in primary headaches and extend results to additional headache types and related factors. © 2013 American Headache Society.
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              Migraine: the seventh disabler

              With the agreement of the Editors-in-Chief, this editorial is published simultaneously by Cephalalgia, Headache and The Journal of Headache and Pain. On 15th December 2012, a special edition of Lancet published the principal findings of the Global Burden of Disease Survey 2010 (GBD2010). Few reports are likely to have more profound meaning for people with headache, or carry greater promise for a better future, than the seven papers (and one in particular [1]) that were presented. GBD2010 was not the first such survey to be conducted, nor the first to give some recognition to the burden of migraine. The Global Burden of Disease Survey 2000 (GBD2000), conducted 12 years ago by the World Health Organization (WHO), listed migraine as the 19th cause of disability in the world, responsible for 1.4% of all years of life lost to disability (YLDs) [2]. This finding has been cited repeatedly ever since; it has fuelled attempts to generate political acceptance of headache as a public-health priority [3], and given credibility to calls for greater investment in headache care and research. It pushed headache into WHO’s field of view, and became an essential part of the platform on which the Global Campaign against Headache has since been built [3-5]. In spite of all this, GBD2000 considerably underreported the disability that migraine imposed on people throughout the world, and gave a very poor account of headache disorders collectively. The evidence was not there. For more than half the world’s population, estimates for migraine were based on very little: data of acceptable quality were not in existence for China, India and most other countries in South East Asia, most of Africa, all of the Eastern Mediterranean and all of eastern Europe [6]. Headache disorders other than migraine did not feature in GBD2000 at all; for these disorders, at that time, dependable evidence was lacking everywhere. Filling this evidence gap has been a priority of the Global Campaign in its first years [7]. As a result, GBD2010 has been much better informed and built on much sounder foundations than its predecessor (we return to this point later). GBD2010 was not a simple update of GBD2000, but a complete rerun: an entirely new world survey. Working with many partners, the Global Campaign against Headache being one, it took from the world literature all the epidemiological evidence pertaining to burdensome diseases, assessed it for quality and derived from it, for each of 21 world regions, best age-related estimates of prevalence. Like GBD2000, it measured burden in disability-adjusted life years (DALYs), separated into the two components of YLDs and years of life lost to early mortality (YLLs); for headache, only the former are relevant. New disability weights (DWs) were assigned to each disease: lay descriptions of the various health states that were predictable sequelae of each disease were fed into a web-based worldwide consultation, which conducted an iterative series of comparisons, one health state with another. For migraine and tension-type headache (TTH), descriptions were agreed of average cases and three health states of each: ictal (during attacks), interictal (between attacks), and the health state associated with medication-overuse headache (MOH), which was considered as a potential complication of either. Information from published studies on frequency and duration of migraine or TTH episodes was pooled in order to estimate the average proportions of time (pT) spent in the ictal as opposed to interictal state. MOH was assumed to be continuous (pT=1) when present. YLDs for each of these states were then derived as products of prevalence, pT and DW, and for each disease as the sum of YLDs for each health state. Data were included from 84 studies of migraine in 43 countries in 16 of the 21 world regions, and from 45 studies of TTH in 34 countries in 13 world regions. TTH (estimated global prevalence 20.1%) and migraine (14.7%) ranked respectively as second and third most common diseases in the world (behind dental caries) in both males and females. For migraine, the estimated proportion of time spent in the ictal state was 5.3%, and the DW assigned to migraine episodes was 0.433 (43.3% disability). On the basis of ictal disability alone, migraine was ranked seventh highest among specific causes of disability globally (responsible for 2.9% of all YLDs), and in the top ten causes of disability in 14 of the 21 world regions, showing little evidence of a gradient falling from west to east or of being a disorder preferentially of rich countries. Migraine was, by a wide margin, the leading cause of disability among neurological disorders, accounting for over half of all YLDs attributed to these. For TTH, the estimated proportion of time spent with headache was 2.4%, and the DW assigned to headache episodes was 0.040 (4% disability). TTH accounted for only 0.23% of all YLDs, much less than predicted [6], which undoubtedly was because of the very low DW accorded to the ictal state. Regrettably, GBD2010 is still an incomplete account of the global burden of headache, and it continues to underestimate the disability arising from headache disorders. TTH got in, but MOH, which would probably have added much more substantially to the total YLDs, was excluded late in the survey for reasons not made clear and despite the evidence submitted in support of it. Also at a late-stage, the inclusion of interictal disability was considered inconsistent with measurements made of other chronic episodic conditions, which penalized migraine more than TTH. Even so, this very high-profile survey of the world’s causes of ill health better recognizes headache than anything before, and this is a big step forward. We might be satisfied by this; but rather we should be appalled. GBD measures disease burden as it is – alleviated by whatever treatments are made available. Headache disorders are among the top ten causes of disability because they are common and disabling; that is clear. Headache is one of the most frequent medical complaints: almost everybody has experienced it, at least 10% of adults everywhere are sometimes disabled by it, and up to 3% live with it on more days than not [6]. But for what conceivable reason do headache disorders remain among these ignominious top ten when they are largely treatable? Another recent global survey, conducted collaboratively by WHO and Lifting The Burden, described “worldwide neglect of major causes of public ill-health, and the inadequacies of responses to them in countries throughout the world” [8]. It drew attention to the very large numbers of people disabled by headache who do not receive effective health care. The barriers responsible for this might vary throughout the world, but poor awareness of headache in a context of limited resources generally – and in health care in particular – was constantly among them [8]. The consequences are inevitable: illness that can be relieved is not, and heavy burdens, both individual and societal [9], persist when they can be mitigated. The findings of GBD2010 sadly reflect this. GBD2010 sends out a clarion call, conveying a message of which governments need to take note [3]. Experience suggests this call will need constantly to be re-echoed, but the opportunity to use GBD2010 – for a better future for people with headache – must not be missed. Competing interest The authors served on the Neurologic Disorders Expert Group in Headache for the Global Burden of Disease 2010 Study (funded by the Bill & Melinda Gates Foundation), and are directors and trustees of Lifting The Burden, which conducts the Global Campaign against Headache in official relations with WHO. TJS is honorary Global Campaign Director.
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                Author and article information

                Contributors
                Sarah.Ahmad@ucsf.edu
                Nicole.Rosendale@ucsf.edu
                Journal
                Curr Pain Headache Rep
                Curr Pain Headache Rep
                Current Pain and Headache Reports
                Springer US (New York )
                1531-3433
                1534-3081
                9 June 2022
                9 June 2022
                2022
                : 26
                : 7
                : 505-516
                Affiliations
                [1 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Headache Division, , University of California, ; San Francisco, CA USA
                [2 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Neurohospitalist Division, , University of California, ; San Francisco, CA USA
                Author information
                http://orcid.org/0000-0001-5500-3100
                http://orcid.org/0000-0002-2431-5440
                Article
                1052
                10.1007/s11916-022-01052-8
                9325838
                35679008
                627d8ef5-1fa2-49a3-8f58-d87c9114d1f6
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 28 March 2022
                Categories
                Episodic Migraine (S Nahas, Section Editor)
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2022

                Anesthesiology & Pain management
                gender,sex,episodic migraine,gender minority,sex hormones,cgrp
                Anesthesiology & Pain management
                gender, sex, episodic migraine, gender minority, sex hormones, cgrp

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