The lifetime prevalence of migraine is much higher in females than in males.1 During a One Topic, Two Views session at the 19th Congress of the International Headache Society (IHC), Prof. Anne MacGregor (Barts Health NHS Trust, United Kingdom) and Prof. Dale Nyholt (Queensland University of Technology, Australia) discussed whether hormonal fluctuations or genetics are the key factor for this difference in prevalence between females and males.
Are hormonal fluctuations the key factor behind the higher prevalence of migraine in females versus males?
Adolescence and perimenopause are periods of increased migraine prevalence in females.1 Prof. MacGregor described how migraine is affected by fluctuating estrogen levels, with clinical evidence to support estrogen ‘withdrawal’ as a trigger of attacks of menstrual migraine without aura, while high estrogen levels can trigger migraine with aura. One study showed that preceding ovulation, estrogen levels were relative to normal in migraine patients with aura, but were increased in migraine patients without aura.2 These results suggest that estrogen is an important factor in the clinical expression of migraine.
“Just having estrogen around – in males or females – is associated with a higher prevalence of migraine.”
– Prof. Anne MacGregor (Barts Health NHS Trust, United Kingdom)
Prof. MacGregor also highlighted that estrogen is not just an ovarian hormone, but is also active in the pathophysiology of migraine in the brain. She stated that estrogen affects the trigeminovascular system, nitric oxide production, serotonergic actions, and also calcitonin gene-related peptide (CGRP) expression and function.
Prof. MacGregor emphasized that increased levels of estrogen is also associated with migraine prevalence in males. This is supported by a study in non-obese males with migraine who showed increased levels of estrogen and evidence of androgen deficiency compared with healthy volunteers.3 She concluded by highlighting the importance of not only hormonal fluctuations, but also increased levels of estrogen in the prevalence of migraine.
Are genetic differences between males and females the main factor responsible for the higher numbers of migraine in females versus males?
Prof. Nyholt opened his presentation by describing how the heritability of migraine indicates that genetic factors are important. He discussed the results of twin studies in migraine, which found no conclusive evidence for genetic sex-specific effects and no significant sex differences in the magnitude of genetic influences.4
Prof. Nyholt then described the findings of molecular genetic studies, focusing on genome-wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) in migraine cases. Prof. Nyholt described how an analysis of 146 index SNPs with association with migraine found that the effect sizes were similar in male and female subgroups. However, as the SNPs were identified via a fixed-effect meta-analysis, these results were not surprising.5 His own research showed that no female sex hormone genes have been robustly implicated in migraine GWAS. Prof. Nyholt stated that any differences in common genetic risk across females and males is far outweighed by the similarities.
He concluded that the difference in migraine prevalence between the sexes is most likely due to critical hormone-responsive genes, shared by both males and females, being influenced differently in the alternative hormonal environment of the male or female throughout their lifespan.
The session closed with a consensus that both hormones and genetics play a significant role in the difference in migraine prevalence between males and females. The interplay between these factors is complex, with many questions yet to be answered.
Victor TW, et al. Migraine prevalence by age and sex in the United States: a life-span study. Cephalalgia 2010;30:1065–1072.
Nagel-Leiby S, et al. Ovarian steroid levels in migraine with and without aura. Cephalalgia 1990;10:147–152.
Van Oosterhout WPJ, et al. Female sex hormones in men with migraine. Neurology 2018;91:e374–e381.
Mulder EJ, et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res 2003;6:422–431.
Antilla V, et al. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet 2013;45:912–917.