180 Chapter 8 all involved in migraine pathophysiology.32, 41, 42 The decline in estradiol may lower serotonergic tone and dopamine activity.38 Estradiol also interacts with estrogen receptors on kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the hypothalamus, regulating pulsatile GnRH secretion. Through negative feedback, estradiol suppresses GnRH pulses during the luteal phase to control gonadotropin levels.43, 44,45 Fifthly, the late-luteal decline in estradiol affecting GnRH signaling might also affect other hypothalamic systems involved in energy balance, arousal, and pain modulation, contributing to migraine prodromes and PMS symptoms like yawning, cravings, and fatigue.46, 47, 48 Furthermore, since estradiol is known to stimulate oxytocin mRNA expression and production in the hypothalamus, a subsequent decline in oxytocin might also play a role.29 Our study’s strengths include the use of a well-defined cohort of healthy controls and women with menstrual migraine defined by a validated e-headache diary.14-16 Aligning measurements with the LH surge ensured consistency across individuals on subsequent days. A potential limitation is the slightly higher average age in women with migraine. However, sensitivity analyses in which age was equalized between groups showed consistent results, suggesting age did not influence our findings. Moreover, our focus on a premenopausal cohort helped minimize age-related hormonal variability, and statistical corrections for age showed minimal impact.49, 50 Nevertheless, these findings may not be generalizable to women with irregular menstrual cycles or those in the perimenopausal transition. Our study was also not powered to compare cycles with and without attacks but all women met MM diagnosis, however, future studies might be useful to explore whether estrogen plasma levels differ between cycles with and without perimenstrual attacks. Article highlights • Women with menstrual migraine have a higher luteal estradiol peak and a more pronounced decline 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. • Clinical research should prioritize interventions to stabilize estradiol levels during the perimenstrual period, potentially offering new treatment options.
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