Where are the men? A systematic review of sex bias in human provocation models of migraine.

ObjectiveHuman provocation models are widely used to investigate migraine mechanisms and validate therapeutic targets. Despite well-known sex differences in migraine, concerns persist regarding sex representation and reporting in experimental research. This systematic review evaluated sex distribution, sex-specific analyses, and the consideration of female-specific biological factors in randomized, placebo-controlled migraine provocation studies.MethodsPubMed and Embase were systematically searched for randomized, placebo-controlled provocation studies in adults with migraine, following PRISMA 2020 guidelines. Data were extracted on participant sex distribution, sex-stratified outcome reporting, and consideration of female-specific variables, including menstrual cycle, hormonal contraception, and pregnancy status.ResultsFifty-eight studies published between 1972 and 2025 were included. Women represented 82% of participants, while men accounted for 18%. No study performed sex-stratified analyses of provoked headache or migraine outcomes. Sex was rarely discussed as a biological variable or limitation. Female-specific factors were largely overlooked, with menstrual cycle phase unreported in over 90% of studies and inconsistent reporting of hormonal contraception and pregnancy status.ConclusionsMigraine provocation studies show marked sex imbalance and a systematic lack of sex-disaggregated analyses. Although these models have demonstrated substantial translational relevance, particularly in supporting the development of anti-CGRP therapies, the absence of sex-disaggregated analyses and limited consideration of biological sex constrain the assessment of translational applicability across sexes.