145 Migraine attack incidence in relation to ovulation 7 INTRODUCTION Migraine is most burdensome for women, aged 15 to 50 years, with its prevalence being three times higher in women than in men.1, 2 Prepubertally, migraine prevalence is equal in boys and girls, while after menarche, migraine incidence in girls increases.2 Although menstruation and other hormonal milestones are well-known to impact the incidence of migraine, the precise mechanisms by which sex hormones influence migraine susceptibility remain incompletely understood.3-6 It is suggested that a drop in estrogen levels may increase attack susceptibility.7-9 This hypothesis is supported by previous clinical studies, which show that the odds ratio (OR) for migraine occurrence approximately doubles around menstruation.10-12 Migraine attacks that occur between days -2 to +3 of the menstruation are classified as perimenstrual attacks.12-14 These perimenstrual attacks last longer, have a higher recurrence risk with more frequent triptan use, and increased severity of symptoms compared to non-perimenstrual attacks.5, 12, 13 These attacks have migraine without aura characteristics as attacks with aura do not seem to be affected by menstruation.4, 12 In a normal menstrual cycle, there are two key phases of estrogen decline: one after ovulation and another at the onset of menstruation. However, during ovulation the estrogen decline is less steep and without a decline in progesterone.5 Research on ovulation-related migraine attack occurrence remains limited with one study investigating the incidence of migraine in relation to urinary metabolites of estradiol in 120 menstrual cycles of 38 women with migraine.5 Migraine occurred more frequently during the phase of estrogen decline during menstruation, however, no association was found between ovulatory estrogen decline and incidence of attacks. A second study in 81 women with migraine also suggested no association between ovulation and migraine incidence.10 Thus, only two studies have been conducted, both with small sample sizes, and one lacked clear ovulation timing. To accurately pinpoint ovulation, it is crucial to either include only women with regular menstrual cycles (e.g. validated by an e-diary) or women who are closely monitored through measurements of the luteinizing hormone (LH) surge. The length of a menstrual cycle is defined as the number of days between the onset of menses in one cycle and the onset of menses in the next cycle. Menstrual cycles shorter than 21 days or longer than 35 days are considered abnormal.14 The luteal phase of the cycle is relatively constant in all women, lasting approximately 14 days. The variability in cycle length is typically due to differences in the follicular phase, which can range from 10 to 16 days and precedes the ovulation day.14
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