2025 Highlights in sex and gender differences in migraine

Sex is a critical biological factor known to influence many aspects of migraine, including pathophysiological mechanisms, epidemiology, attack characteristics, treatment response and occurrence of comorbid conditions. Although biological, hormonal and psychosocial factors likely contribute to these differences, the precise mechanisms remain poorly understood. Therefore, recognizing the impact of sex and gender on migraine is essential for advancing precision medicine. Sex refers to biological differences, while gender reflects social roles and identity. Clinical research typically classifies participants by sex, often treating gender as binary. Thus, inclusive approaches, including survey category beyond the traditional binary are needed to further characterize the sex-based biology from gender-related influences. Researchers should carefully design measures that align with their study goals and clearly specify which aspects of gender/sex they aim to assess.

In this editorial, we highlight emerging clinical and preclinical studies published in 2025 that reveal novel mechanistic insights into sex and gender differences in migraine and their implication for treatment, with five key takeaways: (1) calcitonin gene-related peptide (CGRP) remains a central migraine target, but potential sex differences in therapeutic response, both preventive and acute, require adequately powered, sex-stratified clinical studies; (2) preclinical research continues to reveal sex-specific mechanisms, including differential CGRP sensitivity, immune modulation by onabotulinumtoxinA and female-biased pathways, such as NLR family pyrin domain containing 3 (NLRP3) and transient receptor potential melastatin 3 (TRPM3); (3) sex-differences in clinical features, such as photophobia, have been revealed in preclinical models, underscoring the need for sex-informed behavioral research; (4) hormonal factors, including menstrual cycle phase, reproductive stage and hormonal therapies, critically impact migraine attacks and treatment response, underscoring the relevance of incorporating these variables in study design and analysis; and (5) advancing our understanding of sex- and gender-related factors in migraine will require rigorous understanding of the impact of sex hormones in migraine and other primary headaches, as well as closer integration between preclinical and clinical research to improve precision approaches in headache management. The novel concepts and findings revealed in 2025, on sex and gender differences in migraine summarized in this paragraph will be further detailed in this Editorial.

The efficacy of anti-CGRP therapies confirms a major role for this peptide in migraine pathophysiology. Preventive treatments targeting the CGRP pathway have shown efficacy in both men and women with episodic and chronic migraine (1). Recent work have also evaluated the efficacy of acute CGRP-targeted therapies. Post-hoc analysis of ubrogepant and atogepant suggested that, despite small male sample sizes, treatment effects appear similar across sexes (2). However, whether a sex difference exists in outcome for both preventive and acute treatment with small molecule CGRP receptor antagonists remains to be determined, particularly as preclinical studies continue to reveal sex-specific nuances in CGRP signaling. For example, supradural CGRP administration preferentially induces migraine-like pain in female rodents, while a preclinical study demonstrated that, although CGRP produces a female-selective response acutely, increased frequency of migraine attacks (i.e. migraine chronification) enhances CGRP sensitivity in both sexes (3). These findings may partly explain the previously reported limited efficacy of small molecule CGRP receptor antagonists in men with episodic, but not chronic, migraine (1). Nonetheless, adequately powered placebo-controlled and real-world studies are needed to confirm these observations. It is therefore essential that all headache researchers report data by sex and by gender when available, as well as investigate potential sex differences in efficacy, tolerability and adverse event profiles.

Sex-specific mechanisms may also influence the effects of other migraine treatments. While onabotulinumtoxinA appears equally effective for preventing chronic migraine in men and women, a recent preclinical study showed that it shifts dural macrophages toward an anti-inflammatory profile after cortical spreading depression in female mice, suggesting a potential female-specific immune-modulatory mechanism (4).

These findings highlight that sex differences can modulate responses to migraine therapies and should be considered when exploring new treatment targets. At the molecular level, NLRP3 inflammasome activation in the hippocampus drives migraine-like pain selectively in female rodents. NLRP3 inhibition may therefore offer a female-specific approach to block episodic migraine. However, chronic inhibition of NLRP3 can paradoxically induce allodynia potentially limiting clinical benefit, while still providing valuable mechanistic insight into migraine (5). Likewise, activation of TRPM3, widely expressed within the trigeminal system, produces a migraine-related phenotype with greater effects in female afferent and dural vasculature, highlighting TRPM3 antagonists as promising therapeutic targets (6). A phase 2 clinical trial with a TRPM3 antagonist for acute migraine has recently been completed, but it remains to be revealed whether this molecule will be effective and whether the effectiveness, if any, will be selective to women.

Clinical characteristics of migraine also differ between sexes. Photophobia is more commonly reported in women, although it occurs in both sexes. A preclinical model of cortical spreading depression-induced photophobia show that female rats exhibit greater photophobic behaviors than males (7), providing a reliable model and approach to further study sex-specific mechanisms associated with photophobia in migraine. Such behavioral approaches to investigate sex differences in migraine pathophysiology are highly warranted.

An additional key issue in assessing sex differences is accounting for factors such as menstrual cycle phase, life stage (e.g. premenopausal or postmenopausal status at the time of study participation) and the use of hormonal therapies, including oral contraceptives. The following study demonstrates the importance of taking these factors into consideration. While there is no doubt about the efficacy of anti-CGRP monoclonal antibodies, limited impact of this treatment was demonstrated on the reduction of perimenstrual headache days and perimenstrual migraine days in women with menstrually-related migraine (8).

Precision medicine in migraine requires further understanding on how hormones influence disease across lifespan, including the added complexity introduced by dynamic hormonal fluctuations during the reproductive years. Furthermore, women comprise approximately 80% of participants in migraine clinical studies, making male-focused investigation challenging yet necessary. Long-term studies assessing both the efficacy and safety of hormonal treatments commonly used in gynecological practice, along with research in transgender population, could further clarify how sex-specific factors influence migraine pathophysiology.

The future development of successful anti-migraine therapies relies on rigorous, sex-inclusive preclinical research, as well as sex- and gender-stratified clinical trials. Integrating multi-omics data from patients and animal models and increased cohort sizes, combined with AI-based approaches, has the potential to uncover subtle sex-specific patterns in migraine risk, progression and treatment response. An understanding of the biology that underlies sex and gender differences in migraine is steadily advancing the field toward more precise and effective treatment strategies. We encourage preclinical researchers to adopt clinically informed approaches to bridge basic science to clinical applications and ultimately ensure that both women and men benefit from targeted, evidence-based migraine therapies. Recommendations for incorporating sex- and gender-related variables into migraine research are presented in Figure 1.

Figure 1.

Recommendations for addressing sex- and gender-related variables in migraine research. The key biological and sociocultural features that influence the pathophysiology of migraine are illustrated and strategies are outlined that aim to improve the rigor, reproducibility and mechanistic understanding of sex and gender differences in future clinical and preclinical studies in migraine. Researchers can achieve this by considering the impact of sex and gender in study design, ensuring adequate statistical power and control for confounders, systematically collecting data on sex, gender, menstrual cycle, reproductive history and hormone use, and properly reporting the results

In conclusion, incorporating sex differences into migraine research is crucial for improving our understanding and treatment of the disorder. A sex- and gender-focused approach helps close key knowledge gaps and promotes equitable access to effective migraine management for all patients.