Introduction
Migraine is generally considered a woman’s complaint owing to its preponderance among women and the greater healthcare resource use by women for migraine headache. Epidemiological data subdivide the prevalence of migraine by age group. In prepubertal children, the 1-year prevalence is roughly the same for boys and girls (overall range, 2–5%; 2.4% and 2.5% in girls and boys, respectively, aged 7–9 years; 5.4% and 3.9% in girls and boys, respectively, aged 10–12 years) [
1]. Starting at puberty with its accompanying hormonal changes, the prevalence increases in both sexes, and it is higher in girls than boys from 13 to 15 years (6.4% and 4.0%, respectively). This sex-related difference in prevalence remains throughout life. Between 10 and 20% of women report experiencing their first migraine attack at the start of menarche [
2]. Migraine incidence peaks first at around age 35 years (25–30% of women and 8% of men) [
3] and then again at around age 50, after which it declines with advancing age [
4]. The elderly suffer less frequently from migraine but more often from secondary headache than young people. The decline in migraine frequency is proportional to advancing age, starting at the sixth/seventh decade, and further decreases after age 75. Nevertheless, new onset migraine after age 65 is noted to occur in 0.5% of the population [
5].
The American Migraine Prevalence and Prevention (AMPP) study reported a cumulative incidence of lifetime migraine in 43% of women and 18% of men [
6], a slightly lower rate than more recent data reveal, according to which the risk of migraine is 3.25 times higher for women than for men [
4,
7]. The estimated prevalence of migraine in the Italian population is 32.9% in women and 13.0% in men [
4]. A recent national survey of pharmacies in Italy revealed a prevalence of 43% of “definite migraine” (defined by the ID Migraine questionnaire) [
7] in a female-to-male ratio of 4.9: 1 [
8]. These survey findings show that migraine is much more common in the general population than the data from public healthcare databases would indicate; the reason is that many migraine sufferers choose to self-medicate rather than consult a headache specialist for diagnosis and treatment.
Clinical characteristics of migraine in men and women
The sex-related differences of migraine hold epidemiological and clinical relevance. Most studies agree that there are no sex-related differences in attack frequency: 1 to 4 monthly headache days (MHD) on average for both sexes (48.8% in women and 45.3% in men) [
4,
9,
10]. Bolay reported that high frequency migraine (> 10 MHD) is more common among men than women (16.7% and 14.9%, respectively; prevalence rate [PR] 0.90; 95% confidence interval [CI] 0.83–0.97). Attack frequency differs between age groups: migraine without aura (MO) is higher among 18–29-year-olds than among 40–49-year-olds (
p < 0.0001) and after age 50 (
p = 0.0013). Similarly, migraine with aura (MA) is more frequent in women aged 18 to 29 years than in those aged 30 to 39 years (
p = 0.0308). This difference in attack frequency between age groups is significant for women but not for men migraineurs [
10]. Attack duration of MO and MA is also age-related: shorter in 18–29-year-olds and longer in women aged 30 and over (
p = 0.0407 for MO and
p = 0.0043 for MA).
Most studies report longer attack duration in women than in men (28.4 h in men and 36.7 h in women;
p = 0.01) and a higher recurrence rate. Study findings diverge on whether attack intensity differs between the sexes [
4,
10‐
13]. Because the perception of pain intensity is subjective, whereas attack duration is an objective measure, some researchers report that, at equal pain scores for men and women, the longer duration of attacks and recovery time may be the reasons why women grade their pain intensity higher than men. Added to this is the commonplace belief that, because of gender roles, men are less likely to rate their perception of pain intensity as high [
14].
In general, the characteristic symptoms accompanying migraine (e.g., nausea, vomiting, phonophobia, photophobia, cutaneous allodynia) are more frequent among women than men [
4,
10‐
13]. Studies have found that, except for vomiting, among patients with MO, nausea, phonophobia, and photophobia are significantly more frequent in women (
p < 0.001 for all symptoms), whereas among patients with MA, sex-related differences were found for nausea (65.6% in women and 48.6% in men;
p = 0.049) and phonophobia (70.2% in women and 51.4% in men;
p = 0.033) but not for vomiting and photophobia [
9].
MA is less frequent than MO in both men and women. A UK study [
15] reported a MA 1-year prevalence of 5.8% (2.6% in men and 7.7% in women). MA is more prevalent among women (range, 2.6–10.8% in women and 1.2–3.7% in men) [
16]. The frequency of symptoms accompanying aura differs between the sexes: visual aura (1.8% in men and 4.2% in women); sensorimotor aura (0.3% in men and 1.7% in women); and visual and sensorimotor aura combined (0.4% in men and 1.9% in women) [
15].
The Global Burden of Disease study (2015) classified migraine as the fourth leading cause of years living with disability (YLD) for women and the eighth cause among men [
17], indicating that disability due to migraine is another sex-related factor. Women are 1.34 times more likely (95% CI 1.21–1.48) than men (12.4% for women and 9.3% for men) to report grade IV disability due to migraine in the past 3 months on the Migraine Disability Assessment (MIDAS) questionnaire. Women are also more likely to report inability to carry out household chores (odds ratio [OR] 1.5, 95% CI 1.44–1.56), to take part in social or family activities (OR 1.11, 95% CI 1.06–1.17), and to reduce by at least 50% work or school activity for at least 1 day due to migraine [
10]. Studies consistently report greater migraine-related disability in women: 34% of women and 25% of men stated that they lost work or school time more than rarely. Further, over 45% of patients who reported having never or only rarely missed work or school days due to migraine stated that they needed 2 h of bed rest on average [
12]. Whereas women reported that they were unable to resume their daily activities for 3 to 6 days after an attack, men stated that they resumed activities on the second day after an attack [
10].
The impact of migraine-related disability is especially critical for the toll it takes on the quality of life of migraine sufferers besides the social costs it incurs. A US study published in 1999 [
18] reported that women generated about 80% of medical costs directly correlated with migraine treatment and that the indirect costs correlated with lost productivity were 50% higher for women than for men. These data are underestimated since they do not take into account unemployment and underemployment rates due to migraine. The estimated annual mean pro capita cost of migraine is €1222 (95% CI 1055–1389) in Europe, 93% of which are indirect costs. No data on sex-related differences in costs are available [
19].
Overall, these sex-related differences in the clinical and epidemiological aspects of migraine translate into differences in migraine treatment between men and women. An Italian survey of patients who purchase headache pain relievers at a pharmacy revealed that men consult a doctor less often than women for treatment (65.7% and 72.4%, respectively;
p = 0.003; OR 0.71, 95% CI 0.57–0.89), whereas women are more likely to talk with their primary provider (40.5% and 35.9%, respectively;
p = 0.082; OR 1.211 95% CI 0.976–1.503) or contact a headache center (21.7% and 17.4%;
p = 0.004, OR 1.31 95% CI 1–07-1.72) [
20]. Unlike men, women are more likely to visit the emergency department because of intense migraine pain. These data are consistent with the data for the percentage difference between the sexes in medications use for acute migraine attack or prophylaxis. Compared with men, women use more prescription medications (PR 1.33, 95% CI 1.23–1.43) and are more likely to use triptans (OR 1.41, 95% CI 1.12–1.78) or drug combinations (OR 1.49, 95% CI 1.04–2.14) but less likely not to take acute medications (PR 0.65, 95% CI 0.52–0.80) [
10,
11,
13]. In contrast, no significant difference between the sexes was found for the use of nonsteroidal anti-inflammatory drugs or ergot derivatives (55.6% vs. 51.6% and 8.7% vs. 9.3%, respectively) [
20]. Women are more likely than men to use preventive treatment (OR 1.37, 95% CI 1.27–1.48). While guidelines for the acute and preventive management of migraine make no distinction between the sexes (except for menstrual migraine treated with hormone therapy), sex differences in the pharmacokinetics of triptans are well documented: peak plasma concentration (Cmax) and area under the curve (AUC) of plasma concentration are higher in women [
21]. The clinical relevance of these sex-related differences in triptans pharmacokinetics is controversial since studies have found no correlation between these data and patient response. A study comparing four different triptans found no significant difference in treatment response or recurrence rates at 24 and 48 h between men and women [
22].
Data disagree on the likelihood that female sex is a risk factor for transition from episodic to chronic migraine. Some studies have reported that the transition in women is more likely (OR 2.9 95% CI 1.2–6.9) [
11], while others have found a nearly similar transition rate within 1 year (5.4% in men and 4.4% in women) [
23].
Compared with men with migraine, women migraineurs have more comorbidities (average, 11 and 5 comorbidities in women and men, respectively) and more mental comorbidities (e.g., anxiety and depression), whereas men have more somatic disorders (e.g., obesity). The data for these differences are discrepant, however. Restless legs syndrome is associated with migraine and is more common among women than men in the general population; however, some studies have reported a greater risk for developing the syndrome in men migraineurs [
24].
Migraine is a recognized risk factor for the development of cardiovascular disease. Because most studies have involved female subjects, the data for males are scarce. The risk of ischemic stroke is twofold higher for women with MA. The data for defining the risk of hemorrhagic stroke in men are insufficient. The incidence of myocardial infarction seems to be higher among migraineurs than nonmigraineurs (OR 1.33, 95% CI 1.08–1.64), but small male sample size precludes reliable analysis of sex-related differences. MA is associated with a higher risk of venous thrombosis in patients under age 55 years (adjusted hazard ratio [aHR] 3.322, 95% CI 1.509–7.312), specifically among women (aHR 2.81, 95% CI 1.41–5.58 for women and aHR 1.81, 95% CI 0.72–4.55 for men) [
11,
25].
Numerous factors underlie the sex-related differences in migraine characteristics: hormonal, genetic, epigenetic, and environmental aspects contribute in different ways to brain structure, function, and plasticity.
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