178 Chapter 8 DISCUSSION Women with migraine have higher peak estradiol plasma levels during the luteal phase, followed by a steeper decline preceding menstruation when compared to healthy controls. No differences were observed in other sex hormones between the groups, or in estradiol levels during other phases of the menstrual cycle. Our findings align with a study that reported a steeper decline in urinary estrogen (E1c) among women with migraine versus controls.12 However, this study classified participants based on self-reported migraine history and assessed perimenstrual headaches rather than migraine attacks, which may have led to false positives due to the poor sensitivity of this approach.1 In contrast to our study, they found comparable peak levels between migraineurs and controls, which may stem from methodological differences, as urinary estrogen measurements are influenced by hydration and kidney function, leading to variablilty.12 An older and rather small study suggested higher peak estradiol plasma levels in women with menstrual migraine.20 In contrast, two other studies reported lower estradiol plasma levels in women with migraine during the luteal phase.21, 22 However, these latter two studies included participants with irregular menstrual cycles and determined sampling based on the first day of menstruation, a method prone to more variability and with reduced reliability in women with irregular cycles. The variability is typically due to differences in the follicular phase, which can range from 10 to 16 days and precedes the LH surge.23 The luteal phase of the cycle is relatively constant in all women, lasting approximately 14 days. By anchoring our measurements to the LH surge, we were able to assess hormone levels in a standardized manner, reducing inter-individual variability. Given the known link between BMI and estrogen metabolism,24 we included BMI as a covariate. Our focus was on comparing estrogen levels in women with and without menstrual migraine, and the differences observed were not explained by BMI. Taken together, our study is the first large-scale investigation with a stringent methodology for reliably defining migraine days, accurately aligning patients and controls with their menstrual cycles, and measuring blood samples on multiple days of the cycle. It clearly demonstrates that a higher peak in estradiol during the luteal phase, followed by a subsequent steeper decline, is associated with menstrual migraine. There are several potential explanations for these findings. A higher estradiol peak might suggest increases in estradiol synthesis, perturbed metabolism, or reduced receptor sensitivity. Given that all other hypothalamic-pituitary-ovarian (HPO) axis hormone levels were comparable, altered hypothalamic-pituitary feedback appears less likely (eFigure 1).25 For instance, a decrease in inhibin A levels or sensitivity
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