Migraine in women; is it all about hormones?

It is well known that migraine is three times more prevalent in women than in men. The occurrence of migraine attacks seems highly related to hormonal changes such as during the menarche, pregnancy, or menopause, and migraine attacks are often triggered by the menstruation. Thus, a prominent role for female sex hormones in the pathophysiology of migraine is likely. Unfortunately, evidence on the exact role of female sex hormones in relation to migraine attacks is limited. There are some reports about hormonal treatment of migraine attacks with, e.g., oral contraceptives and (post)menopausal hormone replacement therapy. Literature on these treatments seems to be inconclusive, potential findings are obscured by differences in study design, but more importantly, also by differences in type of oral contraceptive (e.g., low vs. high dose of estrogen) or hormone replacement therapy (e.g., oral vs dermal delivery, which may have consequences on hormone level fluctuations). Moreover, although recent literature suggests that estradiol levels in patients with menstrually related migraine may be different from those in healthy individuals at some stages of the menstrual cycle [1, 2], there is no concise overview of sex hormonal levels of migraine patients compared to healthy women. Finally, there are reports of mutations in hormone-related genes such as genes encoding for estradiol receptors, but it is not yet clear how these findings should be interpreted. Apart from the role of female sex hormones in the pathophysiology of migraine, it is not known whether the response to the currently available antimigraine treatments is similar in women and in men. Individual studies do mostly not indicate such a difference, however, in view of the limited power of such individual studies (including only very few studies in men), a meta-analysis on this topic is urgently needed. In this grant application, we will also include a study on the potentially different placebo response in migraine between women and men. In this application, we propose to systematically review the literature on female sex hormone levels in women with migraine in comparison to healthy females, taking into account (i) the type of migraine attacks (menstrually related migraine vs. migraine not related to the menstrual cycle); (ii) the time point during the menstrual cycle on which female sex hormone levels were determined; (iii) the effects of oral contraceptives or other hormone-based interventions that may affect the incidence of migraine attacks; and (iv) mutations in hormone-related genes that have been described to be related to the occurrence of migraine. Secondly, we will perform a meta-analysis on the effect of gender on the response to the currently available acute and prophylactic antimigraine treatments. The results of our analyses will provide best available insight into the current state of knowledge concerning hormones and migraine. This topic has not been systematically reviewed as it is methodologically and pathophysiologically complicated. We consider it very likely that the review will indicate where are major gaps in the knowledge of this topic, thus providing an indication for the direction of future research. The results of the meta-analysis will indicate whether gender differences do not only affect the pathophysiology of migraine, but also the response to its pharmacological treatment.