Advancing understanding of migraine pathophysiology and therapy by consideration of patient sex

For reasons that are not well understood, the majority of those who are impacted by recurrent and chronic pain are women. The disproportionate representation of women in most pain syndromes has been formally recognized for many years. In 1986, the International Association for the Study of Pain (IASP) declared the “Global Year Against Pain in Women” and, more recently, this organization declared 2024 to be the “Global Year of Sex and Gender Disparities in Pain” (1). Such position statements from professional societies have spurred interest among basic scientists and clinicians in understanding the relationship of sex and pain. Disparities in prevalence have raised questions about possible sexual dimorphism in mechanisms promoting pain in men and women. Genome wide association studies (GWAS) have identified genetic markers that have increased our understanding of sex disparities in specific pain conditions in men and women (2). Mechanistic differences in how pain is produced are likely to contribute to differences in prevalence. However, with the exception of hormonal replacement therapies in women, sex is not currently a major consideration in how pain in general or migraine in particular is managed. Unraveling mechanistic differences promoting pain could allow the discovery of sex-specific therapies providing a fundamental application of “precision medicine”.

As in most other pain conditions, women are over-represented in migraine, with female prevalence estimated at approximately 3:1 worldwide (3). As a result, our understanding of the treatment of this disorder is largely based on clinical trials that have been conducted almost exclusively in women, providing data that are not analyzed or reported on the basis of sex. Recent examination of data from clinical trials of migraine therapies have begun to prompt us to reconsider the possibility of a differential response to treatment based on patient sex (4). Consideration of sexual dimorphism in migraine reveals many examples of gaps in our knowledge. While migraine is the most disabling condition in people under the age of 50 years worldwide, compared to men, women with migraine report greater disability, including limitations in work, social activities and daily functioning. The disproportionate disability has been shown in clinic-based, cross-sectional and population-based studies (5–9). Women have also been reported to experience more severe headache associated with nausea, vomiting, unilateral head pain, pulsing or throbbing pain, photophobia, phonophobia, blurred vision and visual aura (10).

The underlying mechanisms that explain these differences in disability and pain severity among women with migraine have not been clearly elucidated. Similarly, explanations of why women experience greater stress responses that may act as triggers to increase migraine frequency remain uncertain. Gaps in our knowledge reflect the current state of our understanding and highlight opportunities to address questions of sexual dimorphism, allowing us to improve the lives of men and women who suffer from migraine, from other headache disorders as well as other pain conditions. Advancing our knowledge will require complementary insights from studies in patients and from preclinical mechanistic investigations of clinically relevant headache models.

Like other neurological disorders, our understanding of underlying migraine pathophysiology is limited. The consideration of potential contributions of sexually dimorphic mechanisms in promoting migraine therefore provides an opportunity to increase our understanding of pathophysiology and to improve therapeutic outcomes for both men and women. Clinically astute observations of increased calcitonin gene-related peptide (CGRP) levels in the jugular outflow of patients experiencing migraine (11) led to investment by the pharmaceutical industry in the discovery and development of CGRP-targeting therapies. The successful proof of concept report of efficacy of BIBN4096 (i.e. olcegepant, an experimental drug that is not clinically available) (12) confirmed a likely causal role of CGRP in promoting migraine and stimulated efforts to identify more bioavailable molecules that could be evaluated and commercialized.

Therapies targeting CGRP or its receptor are now approved and widely used for acute and preventive treatment of migraine. Several large real-world studies with CGRP or CGRP-receptor monoclonal antibodies have shown short-term effectiveness with 50% responder rates ranging from 56 to 77% (13). These therapies represent a remarkable success story that highlights the interwoven contributions of clinical and preclinical investigations and expertise in drug discovery and development. Nevertheless, despite the impact that the biologics and small molecules targeting CGRP have had on the lives of many patients, only one in five experience an acute treatment response (14), only a fraction of eligible patients have access, only about half of patients respond to biologics for prevention and less than half of those who are treated successfully initially remain on these biologics long-term (14,15). The acute and preventive treatment of migraine remains a very large unmet medical need.

Estrogen and/or its withdrawal has long been considered to be a key factor in the female prevalence of migraine, including a causal link between decreasing luteal levels and menstrual migraine attacks, and fluctuating levels around perimenopause (16). However, despite decades of investigation, the precise manner by which estrogen or CGRP may promote migraine remain unclear. Nearly 20 years ago, a remarkable preclinical study showed that incubation of rodent trigeminal ganglion cells with estrogen upregulated the expression of prolactin, another female predominant hormone, as well as an isoform of the prolactin receptor (17). Prolactin was demonstrated to sensitize rat or mouse trigeminal ganglion neurons to enhance the evoked release of CGRP. Critically, these effects occurred preferentially in neurons from female animals providing surprising and unexpected evidence that trigeminal nociceptors were sexually dimorphic. The significance of this early study is now increasingly apparent with more recent data demonstrating that human nociceptors are also sexually dimorphic with differentiation possible at the transcript (18), protein and functional levels (19). Expression of CGRP transcript is higher (18) in female, than male, human post-mortem dorsal root ganglion cells (19). Prolactin selectively increases the excitability (i.e. sensitizes) of female post-mortem human dorsal root ganglion cells. By contrast, orexin B sensitized male human post-mortem dorsal root ganglion cells revealing a double functional dissociation of mechanisms that lower activation thresholds selectively increasing the likelihood of nociceptor activation and pain episodes in either women or men. While confirmation in human post-mortem trigeminal ganglion cells has not been possible to date as a result of the limited sample availability, it seems reasonable to speculate that sensitization of the trigeminal neurons may show similar sexual dimorphism. Prolactin circulates at higher levels in women than in men and is under dual control of estrogen and stress (20,21). Sensitization of rodent female trigeminal ganglion cells by prolactin has been shown to increase release of CGRP and, consistent with female selective actions, dural application of CGRP has been demonstrated to produce pain behaviors at much lower doses in female rodents (22). Migraine-like pain behaviors can be produced in female mice by dural application prolactin and can be blocked by antagonists of either prolactin receptors or CGRP receptors (23). Similarly, the migraine-like pain behaviors observed in female mice following dural CGRP are antagonized by either prolactin receptor or CGRP receptor antagonists, revealing mechanistic cross-talk between these mediators (23).

Reports of female selective actions of CGRP in promoting headache behaviors have been met with some skepticism. The apparent disconnect between preclinical and clinical observations has prompted a re-examination of the data supporting the relative efficacy of CGRP targeting therapies in in men and women. Importantly, almost all data supporting the efficacy of CGRP targeting therapies in migraine are based on observations made in patient cohorts comprised primarily of women. Additionally, a major limitation of outcomes of clinical trials was the failure to report data analyzed on the basis of sex. Collectively, this has resulted in broad and generalized conclusions about the efficacy of CGRP targeting therapies and migraine pathophysiology in patients of both sexes, but with minimal evidence supporting the efficacy in men.

Perhaps the most important outcome of preclinical studies is to raise awareness of the gaps in our knowledge including whether the efficacy of CGRP targeting therapies for acute or preventive migraine therapy were indeed similar across sexes. An analysis of pivotal phase 3 data reported by the pharmaceutical industry to the US Food and Drug Administration for approval of small molecule CGRP receptor antagonists for acute migraine demonstrated evidence of efficacy in women but evidence for efficacy of these drugs in men was lacking (24). A recent post-hoc analysis of ubrogepant in acute migraine concluded, however, that “although analysis power for males is limited due to small sample sizes, evidence supports similar treatment effects in males and females with migraine” (25). Prospective and rigorous real-world evidence and placebo-controlled trials adequately powered to detect between sex differences will be required before consensus is reached.

The consideration of possible sexual dimorphism in migraine has also stimulated the important pathophysiological distinction between individual attacks and the disease itself. By contrast to the possible female selectivity of gepant molecules for the acute treatment of discrete attacks, analysis of CGRP targeting therapies revealed that antibodies and gepant molecules used for prevention show apparently similar effects in both men and women (24). Clinical studies on efficacy of therapies for acute or preventive treatment of migraine rely on different patient populations, particularly with regard to the frequency of attacks. Migraine attacks are associated with amplification of nociception including both peripheral and central sensitization that may result from decreased thresholds for nociceptor activation, increased synaptic plasticity and loss of net descending inhibition (26). Each migraine attack may produce a priming effect so that normally subthreshold stimuli are now amplified to effectively elicit another attack. These concepts suggest the possibility of pathophysiological adaptations as frequency of migraine increases that may be relevant to the actions of CGRP.

In this regard, preclinical investigations have recently demonstrated that dural application of ineffective subthreshold doses of CGRP in naïve female or male rodents can produce robust headache-like behaviors in both sexes following repeated prior exposure to migraine promoting substances such as nitroglycerine (27). Female animals may be more sensitive compared to males at baseline but, following repeated migraine-like episodes, both sexes become increasingly sensitized to the actions of dural CGRP. Such preclinical observations may help to understand the apparently similar clinical effects of CGRP prevention therapies in men and women (24). Pathophysiological adaptations could have significant clinical implications so that men experiencing more frequent migraine might respond more favorably to CGRP prevention therapies. Additionally, these possibilities may also be relevant to the puzzling efficacy of gepant molecules in the acute treatment of breakthrough attacks in patients on stable CGRP preventive monoclonal antibodies. While this practice is widely employed and anecdotal data is available, there are no controlled data evaluating the efficacy and safety of gepant molecules for the acute treatment of individual attacks in both men and women on CGRP targeting antibody prevention therapies.

Mechanistic discussions of migraine inevitably focus on the headache, but future studies may additionally focus on the potential contributions of sexually dimorphic mechanisms on other clinically important features of the migraine syndrome such as cognition, fatigue, vertigo/dizziness and return to function. The emphasis on headache predictably leads to consideration of neuronal mechanisms, but the possibility of sexually dimorphic mechanisms in vasomotor response of meningeal blood vessels or lymphatic system remains to be further explored (28–30). The role and involvement of the cerebral vasculature in migraine has been passionately debated and, while for several decades the contribution of the blood vessel has been minimized, recent pharmacological, genetic and imaging studies have once again raised the potential for the role of the vessel and neurovascular unit in migraine pathophysiology (2,31–33). Even in these studies, while the majority of experimental subjects are female, the differentiation in outcomes between females and males is not reported. Indeed, sexually dimorphic estrogen receptor expression between male and female rats in neuronal and cerebral blood vessels has been shown, suggesting that estrogen could have a modulatory role on both trigeminal neuronal activity and vasomotor tone (34), although see also Ahnstedt et al. (35). In addition, differences in CGRP receptor expression and function, mediated in part by estrogen which upregulates CGRP expression, may also contribute both to the observed sex differences in migraine prevalence and severity, as well as response to CGRP targeted therapies (28).

As noted above, the development of CGRP targeting therapies is a remarkable success story but unmet medical needs in migraine remain and the field must continue to progress. The sexual dimorphism in nociception biology, and the difference between females and males in the prevalence, clinical features, disability and disease progression of migraine, should raise the question as to whether there is also a sexually dimorphic response to treatment. It is critical that future studies are sufficiently powered to allow conclusions relevant to both men and women and that subgroup analysis by sex is presented to allow potential mechanistic interpretations. Building on the success of bedside-to-bench and back-to-bedside translation exemplified by CGRP targeted therapies provides exciting opportunities for future progress that may lead to the discovery and development of sex-specific therapeutics for the treatment of headache disorders and other pain conditions that can improve the lives of men and women.

Clinical implications