The Estrogen-CGRP Axis in Migraine: Neuroimmune Mechanisms, Sex Differences, and Therapeutic Implications

Migraine is a prevalent neurovascular disorder with a pronounced female predominance that cannot be fully explained by general pathophysiological mechanisms alone. Emerging evidence implicates interactions between estrogen and calcitonin gene-related peptide (CGRP) signalling as one potential contributor to sex-related differences in migraine susceptibility. This review synthesizes current mechanistic evidence on how estrogen modulates CGRP signalling, trigeminovascular sensitivity, and neuroimmune activation across the female lifespan, and examines the implications of this axis for pharmacological targeting. Evidence supports a state-dependent association between estrogen status and trigeminovascular excitability, with experimental studies indicating hormonal modulation of CGRP-related signalling, vascular reactivity, and neuroimmune pathways. Clinical and preclinical observations are consistent with increased migraine susceptibility during periods of estrogen withdrawal or instability; however, a direct causal sequence linking estrogen withdrawal to increased CGRP signalling and downstream neuroimmune activation in humans has not been established. Although current clinical data do not demonstrate consistent sex differences in the efficacy of CGRP-targeted therapies, hormonal state and reproductive life stage remain potential modifiers of treatment response that require prospective investigation. The estrogen-CGRP framework provides an integrative perspective on endocrine, neuroimmune, and pharmacological regulation in migraine. Integration of this framework into research design and clinical decision-making may improve the development of sex-informed, mechanism-based therapeutic strategies.