179 Estradiol and other sex-hormone dynamics in menstrual migraine 8 could indirectly increase estradiol by increasing FSH secretion from the pituitary. However, FSH plasma levels were comparable between groups. Similarly, increased LH receptor sensitivity might explain the higher estradiol peak, as LH stimulates theca cell androgen production, which is converted to estradiol in granulosa cells. Yet, testosterone levels were also comparable between groups. Alternatively, our results suggest involvement of the final step in estrogen biosynthesis. Cytochrome P450 aromatase (CYP19) catalyzes the conversion of C19 androgens into aromatic C18 estrogens (eFigure 1).26 Altered aromatase activity or sensitivity might explain the higher peak and late-luteal decline in estradiol plasma levels observed in women with menstrual migraine, despite similar gonadotropin or other HPO axis hormone levels. The CYP19A1 gene encodes the CYP19 enzyme, whose activity is influenced by various factors, including cytokines, underscoring a complex regulatory network. Polymorphisms in CYP19A1 and related genes (COMT, CYP1A1) were investigated, but no association with migraine was found.27 Large GWAS studies are needed to confirm if (menstrual) migraine in women has a distinct genetic basis from men and to identify contributing genes. The International Headache Genetics Consortium is pursuing this. Estradiol plays a complex role in pain modulation. Women exhibit higher pain sensitivity, with fluctuations in estradiol increasing sensitivity.28-30 Estradiol may suppress pain by binding to nuclear estrogen receptors (ERα and ERβ) in the trigeminal ganglia, regulating inflammatory genes and reducing cell excitability, while it may also modulate pain by upregulating nociceptive ion channels such as anoctamin (ANO1) and transient receptor potential vanilloid 1 (TRPV1).31 Drops in estrogen may increase calcitonin gene-related peptide (CGRP) levels, a neuropeptide involved in pain transmission and migraine headache.32 Plasma CGRP levels are generally higher in women than in men.33 Secondly, estrogen may also enhance neurogenic vasodilation through gene regulation.34 Ovariectomized rats treated with 17β-estradiol showed enhanced neurogenic vasodilation, an effect absent with other hormonal treatments or placebo.35 In addition, neuropeptides Y and galanin, which modulate CGRP mechanisms in trigeminal neurons, may influence head pain fluctuations during the estrus cycle in mice.36 However, differences in hormonal cycles between rodents (4-5 days) and humans may complicate translation of findings from rodent models.37, 38 Thirdly, female FHM1 mutant mice showed greater susceptibility to cortical spreading depolarizations (CSD) - the underlying mechanism for aura that can trigger the trigeminovascular system - compared to males. This sex difference was abrogated by ovariectomy and partially restored by estrogen replacement.39 Fourthly, estradiol also modulates activity of specific hypothalamic neurons via nuclear estrogen receptor activation and rapid membrane receptor signaling mechanisms.29, 38, 40 This influences nitric oxide (NO) production, serotonergic signaling, and endogenous opioid tone,
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