Sex- and Menopause-Related Differences in Immune and Gastrointestinal Symptom Architecture in ME/CFS: Evidence from Factor Analysis and Structural Equation Modeling

Abstract Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterized by neuroimmune, autonomic, and gastrointestinal dysfunction. Previous studies identified coherent symptom domains involving Brain , Autonomic , Gut , and Immune manifestations and demonstrated pronounced sex-specific differences in neurocognitive–sensory and autonomic symptom organization. However, whether immune-related and gastrointestinal symptoms form distinct or integrated latent structures in women and men with ME/CFS remains unclear. In addition, the potential influence of menopausal status on these symptom domains has not been systematically investigated. Methods: Data from 748 adults with medically diagnosed ME/CFS (608 women, 137 men) from the APAV-ME/CFS study were analyzed. Symptoms were coded dichotomously. Sex-stratified analyses included cross-tabulations, Cramér’s V, tetrachoric correlations, logistic and linear regression models, exploratory factor analysis, and structural equation modeling (SEM). Additional subgroup analyses compared pre- and postmenopausal women. Model robustness was evaluated using a stratified training dataset. Results: In women, Immune (flu-like symptoms, susceptibility to infections) and Gut (gastrointestinal complaints, food intolerances) symptoms formed two distinct but related clusters, characterized by moderate within-cluster correlations (tetrachoric ρ = .47–.60) and weaker cross-cluster associations (ρ = .30–.35). Exploratory factor analysis supported a two-factor solution, and SEM demonstrated superior fit for a two-factor model (CFI = .913; RMSEA = .119). In men, all four symptoms loaded onto a single integrated Gut/Immune factor, with consistently high intercorrelations across domains (ρ = .43–.68). SEM confirmed excellent fit for a one-factor model (CFI = .981; RMSEA = .074). Susceptibility to infections emerged as the dominant predictor in regression analyses. Among women, menopausal status selectively affected immune-related symptoms. Premenopausal women reported flu-like symptoms more frequently than postmenopausal women, whereas gastrointestinal symptoms and food intolerances remained stable across groups. These findings suggest differential hormonal sensitivity of immune versus gastrointestinal symptom trajectories. Conclusions: Immune and gastrointestinal symptoms in ME/CFS exhibit sex-specific latent structures. Women demonstrate two partially separable but related symptom domains, whereas men show a more integrated immune–gastrointestinal architecture. Furthermore, menopausal status appears to selectively modulate immune-related symptom expression while leaving gastrointestinal symptom patterns comparatively stable. Together, these findings support the concept of sex-dependent neuroimmune–autonomic mechanisms in ME/CFS and are consistent with a dynamic, hormonally modulated immune component alongside a more persistent gut-related process. The results highlight the importance of sex- and hormone-sensitive approaches to phenotyping, mechanistic research, and therapeutic stratification in ME/CFS.