167 Estradiol and other sex-hormone dynamics in menstrual migraine 8 INTRODUCTION Prepubertal girls have the same migraine prevalence compared to boys, but after menarche the prevalence in women increases to three times more often as compared to men.1, 2 Menstruation increases susceptibility to upcoming migraine (without aura) attacks. Attacks that occur from two days before the menstrual period until the first three days of bleeding are classified as perimenstrual attacks.3, 4 During the peri-menopausal transition, with fluctuations predominantly in estradiol levels, women have an increased susceptibility for attacks.5, 6 In contrast, many women with migraine report improvement of their attacks (without aura) during pregnancy, breastfeeding and after menopause, when hormone levels stabilize.5, 7, 8 It is since long time been hypothesized, based on small studies, that a drop in estradiol prior to menses lowers the threshold for upcoming migraine attacks in women,9-11 but the exact underlying pathophysiological mechanism remains insufficiently understood. A study suggested that women with migraine have a faster decline in urinary conjugated estrogens (E1c) after the luteal peak compared to those without migraine.12 However, this study relied on self-reported migraine diagnoses and linked urine measurements to headaches but not migraine specifically. To provide clearer evidence on the influence of sex-hormonal changes, our study primarily focused on measuring estradiol during the luteal phase of the menstrual cycle, along with other relevant sex hormones, and conducting a pathway analysis to determine whether women with menstrual migraine exhibit distinct hormonal profiles compared to healthy controls. Identifying these biological differences may provide valuable insights into why many women are more susceptible to migraine attacks in response to hormonal fluctuations, potentially paving the way for more targeted and effective treatments. METHODS Participants Dutch participants aged 18 years or older were recruited through our website (www.whatstudy.nl/en), social media, poster recruitment, and outpatient clinic of the Leiden Headache Center. Interested individuals underwent screening to assess eligibility, either via telephone or during their visit at our outpatient clinic. Headache diagnoses were confirmed by a clinician specialized in headache disorders, using the ICHD-3 criteria.13 Participants were required to have regular menstrual cycles lasting between 25 and 32 days with less than 7 days of variance between consecutive
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