19 General introduction 1 also observed during the perimenopausal period, which may explain the increased incidence of attacks during this time (Figure 3).18 A study suggested that women with migraine exhibit a faster decline in urinary conjugated oestrogens (E1c) after the luteal peak compared to women without migraine.27 Another study found a lower serum estradiol on days 19-21 of the menstrual cycle (luteal phase) in women with menstrual migraine, but no differences at the day of menstruation onset.28 Both studies found no differences in progesterone concentrations. Since results were inconsistent and migraine attacks were not defined, further research is needed to determine whether women with migraine truly have different hormonal levels compared to controls, or if similar hormonal fluctuations make (genetically) predisposed women susceptible for attacks at certain time points. Sex hormone receptors are present in various migraine-related brain areas, including several of the trigeminovascular system (Figure 4).29, 30 Oestrogens classically bind to nuclear receptors, mediating gene expression, but membrane-associated forms of oestrogen receptors, such as the G-protein coupled oestrogen receptor (GPER), have also been identified.31 Therefore, oestrogen can have both immediate and delayed effects. After a rapid drop in estradiol levels different effects of estradiol may occur. The effects mediated through membrane receptors quickly dissipate, while those mediated through nuclear receptors may persist, possibly predisposing for migraine attacks.32 A similar decrease in circulating estradiol occurs at ovulation, but ovulation has not been clearly linked to an increased incidence of migraine attacks. One explanation might be that estradiol levels do not remain elevated for a sufficiently long enough time before declining in the early luteal phase.33 If the period of elevation is too short, the subsequent drop might not have as significant an impact as the longer period of elevation observed in the late luteal phase. Alternatively, rising levels of progesterone, or its metabolite allopregnanolone, may counteract the effects of drop of estradiol, as these hormones have an inhibitory effect on neuronal excitability, unlike estrogens.34 However, accurately pinpointing the exact timing of ovulation without measuring the preceding luteinizing hormone (LH) surge poses challenges, thus limiting the availability of conclusive evidence. Although it is assumed that sex hormones also influence CGRP levels in the trigeminovascular system, the limited studies are inconsistent. Sex hormone receptors, such as oestrogen receptors, show co-expression with CGRP receptors in the trigeminovascular system (Figure 4).29 Plasma CGRP levels are higher in women than in men, and the use of the combined contraceptive pill is associated with
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