Hormone-dependent immune regulation shapes asthma heterogeneity across the female lifespan

Asthma exhibits pronounced sex differences across the human lifespan, shifting from a predominance in males during childhood toward an increased prevalence, severity, and heterogeneity in females following puberty. These epidemiological patterns are not paralleled by uniform changes in disease phenotype, with adult females exhibiting a higher prevalence of non-type 2 inflammation. Mechanistically, estrogen has emerged as a key regulator of this heterogeneity through its pleiotropic effects on immune and structural cells. However, the immunological actions of estrogen are highly context-dependent, varying with receptor subtype (ERα versus ERβ), hormone concentration, and prevailing inflammatory milieu. Rather than uniformly amplifying immunity, estrogen's principal nuclear receptors exert opposing effects. ERα predominantly promotes immune activation, whereas ERβ exerts counterbalancing anti-inflammatory and bronchoprotective functions. Estrogen promotes immune amplification rather than polarization by simultaneously disrupting regulatory pathways and enhancing T helper 2 (Th2)-, T helper 17 (Th17)-, and innate immune system-mediated responses. Sex chromosome-linked and epigenetic mechanisms, including X-chromosome inactivation escape, further contribute to immune activation in females, although direct evidence in the asthma-specific context remains limited. Importantly, asthma phenotypes are shaped across the female lifespan by interactions between hormonal signaling and other contributing factors such as obesity and other comorbidities, viral infection, and environmental pollutant exposure, as well as emerging non-type 2 pathways including NLRP3 inflammasome activation and neutrophil extracellular trap formation, leading to context-dependent inflammatory patterns. This review summarizes the role of estrogen receptors and various cell types in mediating asthma heterogeneity, providing a mechanistic basis for sex-specific disease variation and highlighting the need for precision strategies that account for hormonal and life-stage differences.