125 Rationale and protocol of the WHAT! Trial 6 BACKGROUND Sex hormones have long been known to play a prominent role in the pathophysiology of migraine. Menstruation is an important factor increasing the susceptibility for an upcoming attack, with the highest risk in the period of two days before the menstrual period until the first three days of bleeding.1 Before the onset of menarche, the prevalence of migraine is equal between prepubertal boys and girls, but subsequently the balance shifts towards an increased prevalence of migraine in women, with a peak prevalence between 30 and 40 years of age.2 Hormonal fluctuations during menopausal transition are also associated with increased susceptibility for migraine.3 Furthermore, the majority of women with migraine without aura report improvement of their migraine attacks during pregnancy and breastfeeding.4, 5 Migraine with aura can also improve during pregnancy, but more often remains the same or worsens.6, 7 Despite the well-documented relationship between sex hormones and migraine in women, the underlying mechanisms through which hormonal factors influence migraine susceptibility remain poorly understood. It is hypothesized that perimenstrual migraine might be due to the sudden drop in estradiol prior to menses.8-10 However, a similar decrease in circulating estradiol occurs at ovulation, but this decline does not seem to be consistently related to the provocation of migraine attacks. This may be due to the preventive properties of increasing progesterone levels during ovulation, or its derivate allopregnanolone.11, 12 With this estrogen withdrawal theory in mind, some small studies suggest that combined oral contraceptives might have beneficial effects in migraine.13-15 A small double-blind placebo-controlled crossover study found a 22% reduction in migraine frequency after daily administration of estradiol (1.5 mg).16 However, a 40% increase in migraine frequency was observed five days after cessation of the intervention. It is therefore suggested that a migraine attack can be delayed by preventing the estrogen withdrawal prior to menstruation. Combined oral contraceptives (COC) are the most prescribed type of combined hormonal contraception (CHC). They are primarily composed of an estrogen (typically ethinylestradiol) and progestin to prevent pregnancy in women of childbearing age. The composition of COC includes a wide range of hormones, doses, and regimes. The 21/7 regimen, in which 21 days of pill administration is followed by a seven-day hormone-free interval (HFI), is the most common. As the drop in estrogen levels prior to menstruation is suggested to provoke migraine attacks, studies have been investigating the effect of a shorter or absent HFI and of estrogen supplementation during the HFI on the occurrence of menstrual migraine.10, 17 Shortening the HFI might also lead to a reduction in migraine intensity and frequency.14, 18 However, worsening
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