Understanding migraine throughout a woman's life and the role of calcitonin gene-related peptide: A narrative review.

Migraine is a common, chronic, and highly disabling neurological disorder that affects women at a significantly higher rate than men. The prevalence of migraine is 3- to 4-fold higher in women than in men, 1 , 2 with a cumulative lifetime incidence of 43% for women and 18% for men. 3 Differences in migraine prevalence between men and women vary according to age ( Figure 1 ). The prevalence of migraine is similar between boys and girls (approximately 5%) up until puberty, at which time prevalence rises at a much greater rate in girls than in boys. 4 , 5 The onset of menstruation marks a common increase in the onset of migraine. 2 , 3 In 15- to 39-year olds, worldwide prevalence of migraine increased by nearly 40% compared to 1990, with female rates consistently exceeding male rates across all age categories. 6 The discrepancy between men and women is most evident between 30 and 40 years of age, after which prevalence declines, most dramatically in women. Between 1990 and 2021 there was 48% increase in the prevalence of migraine among women of childbearing age. 7 After 50 years of age, migraine prevalence slowly returns to similar rates for men and women, due largely to the onset of menopause. 4 , 5 , 8 The higher prevalence of migraine in women may be attributed to changes in sex hormones. Fluctuations in sex hormones preceding menstruation may lower the threshold needed to trigger a migraine attack. 9 – 11 One-year prevalence of migraine with or without aura. Note. Reprinted from: Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. 4 Worldwide, migraine is among the most disabling medical disorders and is associated with considerable personal and social burden due to pain, disability, and impaired quality of life. 12 , 13 Migraine significantly impairs functional ability at work, school, and home, as well as in social situations. 14 – 16 In women of reproductive age (15–49 years), migraine is the leading cause of disability worldwide. 17 Women experience more frequent headaches, more intense headache pain, a higher risk of experiencing chronic migraine (⩾15 headache days per month), and greater headache-related disability than men. 9 , 18 , 19 The impact of migraine has been shown to extend to many important aspects of life including marital and family relationships, parenting, career stability, as well as overall health. 15 , 18 , 20 Individuals with migraine are at increased risk for comorbid conditions, such as anxiety, depression, asthma, epilepsy, and stroke. 21 Furthermore, there is a considerable stigma and misunderstanding associated with migraine, with a widespread conviction that migraine is “just a headache.” 22 , 23 Women with migraine also have more medical comorbidities and more mental health conditions than men, such as anxiety and depression 24 and in the American Migraine Prevalence and Prevention (AMPP) Study, women reported greater use of emergency departments and urgent care centers for headache than men. 9 The growing body of evidence that highlights the interplay between migraine and the female reproductive system suggests a significant association between migraine and endometriosis, a common disease in adolescents and young women characterized by the existence of endometrial tissue outside the uterus. Individuals with endometriosis have been reported to be more than twice as likely to experience migraine than those without endometriosis. 25 Among individuals with endometriosis, age of menarche was inversely associated with the prevalence of having migraine. 25 Given the differences in migraine prevalence, migraine attack frequency and intensity between men and women, this review aimed to explore migraine throughout the reproductive stages of a woman’s life: puberty and menstruation, pregnancy, and perimenopause through postmenopause. As sex hormones act as a driving force for many of these disparities, the focus on the role of estrogen, and the importance of its interplay with calcitonin gene-related peptide (CGRP)-related therapeutic targets. A comprehensive literature search was conducted using the PubMed database to identify relevant articles on migraine and hormonal influences across the female lifespan. The search included publications from January 1990 to February 2024 and was limited to English-language articles. The search was initiated in December 2023 and completed in February 2024. Medical Subject Headings terms used in the search included: “Migraine Disorders AND Calcitonin Gene-Related Peptide,” “Migraine Disorders AND Puberty,” “Migraine Disorders AND Menstruation,” “Migraine Disorders AND Perimenopause,” “Migraine Disorders AND Pregnancy,” “Migraine Disorders AND Menopause,” “Migraine Disorders AND Estrogens,” Titles and abstracts were screened to determine relevance based on their focus on hormonal modulation of migraine pathophysiology or treatment outcomes. Additional sources were identified through citation chaining (snowballing), which included relevant references cited within primary articles and reviews. Articles identified through this secondary process were included even if they fell outside the initial 1990 start date. Migraine is a neurovascular disease characterized by unilateral, pulsating headache lasting 4 to 72 h, which can be exacerbated by physical activity and is typically accompanied by various combinations of photophobia, phonophobia, nausea, and vomiting. 26 A single migraine attack is a multiphasic event that may last up to 7 days in some individuals and is generally comprised of four overlapping phases: prodrome, aura, headache, and postdrome ( Figure 2 ). Prodrome occurs in an estimated 80% of individuals, 2 to 48 h before the headache phase and consists of a wide range of premonitory symptoms including (but not limited to), fatigue, impaired concentration, mood changes, water retention, food cravings, phonophobia, and photophobia. Approximately one-third of people with migraine experience migraine with aura, categorized by transient, focal neurological symptoms, which can occur for up to an hour before the onset of headache. 26 The headache phase with associated symptoms can last up to 3 days and, finally, the postdrome can last up to 2 days. The likelihood of a migraine attack may be increased by the presence of migraine triggers. These can be internal factors such as fluctuations in sex hormones, or external factors such as stress, poor sleep quality, weather changes, and certain foods and alcohol. The most commonly reported triggers include menstruation, stress, and changes in barometric pressure. 27 Consistent with increased prevalence, women report more migraine triggers than men, even when menstruation is disregarded. 27 The multiphasic nature of a single migraine attack. Note. Reprinted from: Ferrari MD, et al. Migraine. Nat Rev Dis Primers . 2022;8(2). 116 Advances in the treatment of migraine include agents that target CGRP and its receptor. CGRP is a 37-amino acid peptide produced by the alternative processing of the mRNA for calcitonin. 28 CGRP is predominantly released from sensory nerves and is a potent vasodilator, with predicted roles in pain and cardiovascular regulation. 29 Although CGRP does not regulate systemic blood pressure, it does influence blood pressure in peripheral arterial vessels by inducing vasodilation 30 and may play a protective role in certain pathological states. 31 CGRP is also a mediator of numerous immune regulatory responses (especially those relevant to inflammation). 32 Previous research established that CGRP is released from trigeminal ganglion cells 33 with substantial perivascular innervation in the trigeminal system. The role of the trigeminal system in migraine has been reviewed elsewhere. 34 As research into the pathophysiology of cranial pain syndromes, migraine, and the perivascular nerve control of brain circulation advanced, CGRP emerged as a candidate for a prominent mediator of migraine. CGRP plasma levels are elevated during and outside of migraine attacks in individuals with migraine. 35 – 38 Intravenous infusion of CGRP produces migraine-like attacks in the majority of individuals with a history of migraine. 38 Furthermore, CGRP is selectively released from the trigeminal system during migraine attacks, and blocking CGRP signaling through various mechanisms (e.g. inhibiting release, blocking the CGRP receptor, binding to the CGRP ligand) has been shown to effectively treat migraine attacks and/or reduce attack frequency. 39 CGRP-dependent mechanisms may also be important in the transition of episodic migraine (<15 headache days per month) to chronic migraine (⩾15 headache days per month). In mouse models of chronic migraine, supradural CGRP elicited migraine-like behaviors in male and female mice and was accompanied by an increase of CGRP expression in trigeminal ganglion cells and sensitization to CGRP-induced nociception. 40 As such, while naïve female mice have a higher number of CGRP-positive trigeminal ganglion cells than male mice, CGRP-targeting therapies may become more important for men as migraine frequency increases. There are few clinical studies that have specifically examined the sex-specific response to agents that target CGRP and its receptor for the acute treatment or prevention of migraine. A subpopulation analysis of data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, and of atogepant found that these treatments were equally effective in men and women for migraine prevention, but that these agents may be less effective in men for the treatment of migraine. 41 CGRP signaling is known to be influenced by sex hormones and differences between men and women have been described. 19 Plasma CGRP levels are higher in women than in men, and even higher in women using estrogen-containing hormonal contraceptives. 42 CGRP levels may be regulated by estrogen, with estrogen receptors co-expressed on cells that either produce or respond to CGRP. 43 – 45 As fluctuations in the sex hormone estrogen can influence the susceptibility to migraine in women (as well as in men), a more thorough understanding of CGRP and its interplay with female sex hormones, such as estrogen, may help lead to improvements in the treatment and management of migraine. In considering the role of sex hormones in migraine throughout a woman’s life, it is important to note the inherent limitations of the terms “woman/female” and “man/male.” It is rare that migraine studies distinguish between sex assigned at birth and gender identity. This can make it challenging to discern what factors, such as hormonal, psychological/stressors, etc., may be driving differences in those individuals with migraine reported as male and female. Further consideration should be given to transgender individuals, who may or may not be receiving gender-affirming hormone therapy, including estrogen. Although not the focus of this review, it is interesting to note that testosterone levels are lower in men with migraine compared to men without migraine. 46 A case study of two transmasculine patients who used gender-affirming hormone therapy with testosterone found the frequency and/or intensity of headache symptoms improved. 47 Although testosterone has an antinociceptive effect, limited evidence of its specific role in migraine means that it is not a consideration in migraine management. 46

The menopausal transition is the period of approximately 2 to 8 years, when menses become irregular, to the year after the end of menses, commonly termed perimenopause. The prevalence of migraine may increase as women progress through the menopausal transition. During perimenopause, 8% to 13% of women report the new onset of migraine. 102 In the AMPP study of 3,664 women with migraine (mean age 46 years), the risk of high-frequency headache (>10 headache days per month) was significantly greater in the perimenopause and early postmenopause stages compared with premenopause. 103 During perimenopause, estrogen levels decline and fluctuate, which may be one trigger for migraine attacks during perimenopause. 102 This decline and fluctuation in estrogen levels may reduce the threshold for a migraine attack by allowing an increase in CGRP signaling, thereby facilitating trigeminal transmission. 43 Notably, vasomotor symptoms such as hot flushes, night sweats, and palpitations are more common among women with migraine. 104 Elevated levels of CGRP/CGRP signaling during menopause linked to declining and fluctuating levels of estrogen may also modulate vasomotor symptoms during menopause. Ovariectomized mice displayed a greater exaggerated, flush-like temperature increase after physical exercise compared with normal mice. This reaction was completely blocked by a CGRP antagonist. 105 In ovariectomized mice lacking αCGRP, the flush-like temperature increases were strongly attenuated, suggesting that CGRP may be an important mediator of hot flushes. 105 In postmenopausal women, the serum concentration of CGRP was found to increase by over 70% during hot flushes compared with between hot flushes. 106 Circulating CGRP levels also vary according to menopausal status. Circulating CGRP levels are higher in the postmenopausal women compared with premenopausal women and, among women who experienced hot flushes, postmenopausal women had higher CGRP levels than the premenopausal women. 107 Consistently, postmenopausal women who experience hot flushes have higher 24-h urinary secretion of CGRP than premenopausal women and postmenopausal women who do not experience hot flushes. 108 Furthermore, administration of exogenous human CGRP leads to local reddening for as long as 1 to 6 h after administration. 29 , 109 As perimenopause may be a period of increased migraine prevalence and vasomotor symptoms, and because decreasing and fluctuating levels of estrogen may act as a migraine trigger, HRT may be an option for certain individuals. Although HRT can play a valuable role in reducing the symptoms of migraine, it may still be associated with serious complications, and may even exacerbate migraine symptoms in some individuals. 46 As such, careful consideration is needed before including HRT in migraine treatment plans. Indeed, high doses of oral estrogen have been associated with triggering new migraine with aura or worsening existing migraine with aura. 110 This is consistent with the observation that estrogen addition and withdrawal may each trigger a headache and that hormonal fluctuations are also important in migraine, rather than the level of hormones. There are limited data on the changes and role of CGRP as related to HRT and migraine; however, following 3 months of HRT, CGRP plasma concentrations increase to levels similar to those in healthy fertile women. 111 , 112 After natural menopause, migraine symptoms improve in the majority of women, but may worsen in women with surgically or pharmacologically induced menopause. 113 , 114 During postmenopause, estrogen levels remain at a stable low level and do not exhibit the erratic fluctuations observed in perimenopause. A decrease in plasma CGRP is also observed in postmenopausal women compared with fertile women. 112 This decrease in plasma CGRP may partly account for the general decrease in migraine prevalence and severity observed post menopause.

The extent and precise influence of estrogen in migraine is not fully understood; however, there is clear evidence that fluctuations in circulating estrogen play an important role in migraine pathogenesis. An overview of the changes in plasma estrogen and migraine incidence over the course of a woman’s reproductive life is summarized in Figure 3 . In migraine without aura, migraine attacks are most likely to occur and to be severe, approximately 2 days before menstruation, 48 when plasma estrogen levels sharply decline. 49 Consistently, attacks of migraine without aura tend to diminish during pregnancy, coinciding with stable elevated plasma estrogen levels, and typically return postpartum when estrogen levels rapidly decrease. 50 , 51 Stabilizing estrogen levels via treatment with oral contraceptives or hormone replacement therapy (HRT) can be preventive, 52 whereas sudden cessation of hormonal contraceptive use is associated with an increase in attacks that are both severe and long-lasting. 53 However, other types of migraine attacks may be affected differently by estrogen. Compared with individuals with migraine without aura, a lower percentage of women with migraine with aura showed improvement or remission of migraine during pregnancy, and the use of oral contraceptives is more likely to worsen migraine attacks in individuals with migraine with aura. 54 Furthermore, women with migraine with aura who use combined hormonal contraceptives (ethinylestradiol dose between 20 and 40 μg) have an approximate twofold increased risk of ischemic stroke. 55 There is some evidence to suggest that low dose formulations (⩽20 μg ethinylestradiol) do not hold the same risk of ischemic stroke in women with migraine with aura. 56 As such, the relationship between estrogen and CGRP may be different in migraine with aura, but the underlying reasons for this are not fully understood. Susceptibility to migraine attack, CGRP signaling and hormone balance in the estrogen withdrawal hypothesis throughout a woman’s life. Note. CGRP = calcitonin gene-related peptide. This pathophysiological mechanism, that is, the sharp decline in estrogen observed before menstruation that increases the risk of a migraine attack, is called the “estrogen withdrawal hypothesis.” This hypothesis was first proposed in 1972 by Brian W. Sommerville, 57 and subsequent studies have confirmed that migraine attacks are associated with a decline in estrogen in the late luteal (pre-menstrual) phase of the menstrual cycle. 49 , 58 The Study of Women’s Health Across the Nation found that the rate of estrogen decline in the late luteal phase is 30% faster among women with migraine compared to those without. 59 However, the rate of estrogen decline does not distinguish cycles with and without a migraine headache, suggesting neuroendocrine vulnerability in women with migraine. 59 The authors propose a “2-hit” hypothesis of perimenstrual migraine initiation in which a more rapid decline of estrogen is an endogenous trait of women with migraine making them more vulnerable to migraine attacks when exposed to common triggers, such as stress, disrupted sleep, foods, and wine. 59 Krause et al. have proposed a menstrual migraine model to help explain the estrogen withdrawal hypothesis based on hormonal balance in the trigeminal ganglion. High and stable levels of estrogen (ovulation and luteal phases of menstrual cycle, pregnancy, exogenous estrogen) are proposed to suppress CGRP signaling and thus the trigeminal system, reducing the likelihood of migraine. 43 When estrogen levels fluctuate and decline (menstruation, postpartum, contraceptive pill cessation, menopause), there is a shift toward a pro-migraine state as the decrease in estrogen allows for an increase in CGRP signaling, facilitating trigeminal transmission ( Figure 3 ). 43 It should be noted that other hormones may also play a role in migraine, including oxytocin, progesterone, and prolactin. Although not the focus of this review, it is interesting to note that estrogen regulates both the release of oxytocin and expression of the oxytocin receptor. Furthermore, during the menstrual cycle, there are parallel fluctuations in estrogen and oxytocin ( Figure 3 ). In rats, oxytocin receptor expression was demonstrated in CGRP-containing trigeminal ganglion neurons, whose releases were inhibited by oxytocin. 60 The ability of intranasal oxytocin to reduce the frequency of headaches was investigated in a placebo-controlled study in individuals with chronic and high-frequency migraine; however, the study did not meet its primary endpoint. 61 The ovarian hormone progesterone also displays some parallel fluctuations with estrogen, most notably a decrease just before menstruation; however, unlike estrogen withdrawal, progesterone withdrawal does not appear to trigger migraine attacks and administration of progesterone does not confer any protection against them. 57 There is some evidence that progesterone may have a modest effect on reducing migraine attacks and their severity, but this evidence is largely based on observational data with small numbers. 62 Interestingly, progesterone appears to have the opposing effect on CGRP expression in rat placentas, with progesterone stimulating CGRP receptor expression and estrogen inhibiting expression. 63 The pituitary-derived hormone prolactin may also contribute to sex-dependent differences observed with migraine. Prolactin is present in men and women, but circulates at higher levels in women. High prolactin levels are an adjunctive worsening factor in migraine 64 and dysregulation of prolactin receptors may contribute to increased risk of migraine attack from subthreshold stimuli and progression to chronic migraine in women. 65 Administration of prolactin causes migraine-like behavior in female but not in male rodents, which is not prevented by ovariectomy. 66 Notably, crosstalk between CGRP and prolactin systems has been observed, with prolactin promoting CGRP release in female but not in male rodents, resulting in female-specific migraine-like behavioral. 66 Sexual diversity in pain pathways is increasingly recognized, with specific relevance to migraine, female sex hormones, and CGRP. MRI studies have revealed sex-related differences in structure and function of various brain regions implicated in migraine. 67 In mouse pain models, a clear sexual diversity wherein CGRP promotes pain in female but not male mice has been demonstrated. 68 In human dorsal root ganglia, sensory fibers that transmit nociceptive (damaging or potentially damaging stimuli) information to the central nervous system are sexually diverse. 69 In females, these sensory fibers have higher levels of the CGRP protein, compared with males. 69 Sex differences in the pathophysiology of migraine may be highly influenced by the interaction of sex hormones with CGRP. Early studies in humans demonstrated that plasma CGRP levels were higher in women than in men, and even higher in women using estrogen-containing hormonal contraceptives. 42 Notably, estrogen receptors co-localize with CGRP receptors at several sites involved in migraine pathophysiology. 43 In the trigeminal ganglion of male and female rats, estrogen receptors were found in neurons that also expressed CGRP or the CGRP receptor. Compared with males, females expressed more estrogen receptors in these neurons. 70 A separate study that examined the trigeminal ganglia of rats reported that the absence of estrogen can lead to an increase in CGRP. Ovariectomized rats have a 600% increase in CGRP in the trigeminal ganglion, which reduces to a 150% increase after the administration of estrogen. 71 Treatment of ovariectomized rats with estradiol, which is commonly used in HRT in postmenopausal women, increases plasma CGRP levels. 72 , 73 Application of CGRP directly to the brain (dura) of rats or mice causes behavioral responses consistent with headache, which was only observed in female rodents. 74 These animal study observations suggest agreement with the dual role of estrogen in both CGRP synthesis and release. 43 The hormonal diversity demonstrated in animal studies may shed light on the basic mechanisms, underpinning the hormonal discrepancies related to migraine in the female body and brain.

Migraine can be considered a predominantly female disorder, with prevalence almost four times that observed in men. This divergence in migraine prevalence between men and women begins with the onset of puberty and is largely driven by changes in sex hormones. Unstable and declining levels of estrogen can predispose women to the onset of migraine attacks, whereas high and stable levels of estrogen can, under certain conditions, exert a protective effect. During a woman’s reproductive years, the risk of a migraine attack may be highest during the perimenstrual period and lowest during ovulation. During pregnancy, there is a substantial reduction in migraine intensity and frequency, particularly during the third trimester. As women enter perimenopause, the prevalence of migraine tends to increase relative to both pre- and postmenopause. After natural menopause, migraine prevalence in women decreases. The changing nature of migraine throughout a woman’s life, as well as the differences between men and women in both the prevalence and presentation of migraine, highlight the need for better understanding and acknowledgement by both women with migraine and women’s healthcare providers. Patient and healthcare provider awareness is vital in eliminating any potential gender-driven stigma about the experience of pain, which can negatively impact health outcomes for both women and men. 115 Although not a focus of this review, sexual disparity in migraine and the influence of sex hormones reinforces the need to rethink a binary sex model in the treatment and management of migraine. A more informed, personalized approach can only improve outcomes, including those for transgender individuals, for whom there are limited data. In this review, we highlighted the growing body of evidence that the interplay between estrogen and CGRP plays an important role in the frequency and severity of migraine throughout a woman’s life. During periods when estrogen levels are relatively high and stable, such as the luteal phases of menstrual cycle, pregnancy, or due to HRT/hormone-based contraception, estrogen may suppress CGRP signaling and thereby lower the likelihood of a migraine attack. During periods when estrogen levels fluctuate and decline, including menstruation, postpartum, contraceptive pill cessation, and menopause, suppression of CGRP signaling is reduced, facilitating trigeminal transmission and moving an individual toward a pro-migraine state, in which they may be more susceptible to migraine triggers. Dysregulation of CGRP may also contribute to the pathogenesis of various conditions at important life milestones including endometriosis in adolescents and young women, preeclampsia during pregnancy, and vasomotor symptoms during perimenopause. The precise mechanisms stemming from changes in hormones to the triggering of a migraine attack are complex and not fully understood. We have focused on the role of estrogen and CGRP to better understand the disproportionate influence of migraine in women, and how the physiological responses observed are influenced by a myriad of factors, including the type of migraine and the stage of life. The role of other hormones such as oxytocin, sexual diversity in pain pathways, and genetic factors may also be important in CGRP signaling associated with migraine and are yet to be fully elucidated. Given the disparity in migraine prevalence among men and women, research is needed to define potentially sexually diverse outcomes to migraine treatment, considering variations in hormonal status. This may be particularly relevant for CGRP-targeting therapies. At the time of writing, most published studies are limited in terms of equal representation of men and women. Most clinical trials for migraine are not only heavily female-weighted, owing to the disparity in migraine prevalence, but also the stigma around migraine in men. This is complicated further as preclinical studies tend to use male animals, thereby preventing a fuller understanding and highlighting the need for more research in hormones and the sexual diversity of migraine. In summary, the relationship between estrogen and CGRP is crucial in understanding migraine pathophysiology, observed sexual diversity, and elevated female prevalence of migraine. Fluctuations in estrogen levels and the associated modulation of CGRP signaling are key factors in determining the likelihood of a migraine attack throughout a woman’s life. In addition to the limitations of current research discussed previously, further research is needed to address the role and interplay of estrogen and CGRP, including the use of CGRP-targeted migraine treatments, in women undergoing in vitro fertilization, intrauterine insemination, and oocyte cryopreservation. As these procedures have become more commonplace, there is a need to better understand how migraine can be managed and the potential impact of CGRP pathway inhibitors, especially as hormone supplementation is used at various stages throughout these procedures. Finally, as the use of CGRP pathway inhibitors in the treatment of migraine is relatively recent, further research is needed to better understand potential differences in male–female response to CGRP pathway inhibitors and the potential impact of long-term treatment. As CGRP is a potent vasodilator and is considered to play a protective role in certain pathological states, including preeclampsia during pregnancy, careful monitoring is required going forward.