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Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling.

Habermann-Horstmeier, Lotte, Horstmeier, Lukas M · Journal of translational medicine · 2026 · DOI

Quick Summary

This study examined how immune and gut symptoms are organized differently in women and men with ME/CFS, and whether menopause affects these patterns. Researchers analyzed data from 748 people with ME/CFS and observed that women tend to have two somewhat separate symptom clusters (immune-related and gut-related), while men showed these symptoms more integrated together. Among women, flu-like symptoms were reported more frequently before menopause than after, while gut symptoms remained stable across menopause. These are early findings from a single cross-sectional analysis and require confirmation in future studies.

Why It Matters

Sex differences in ME/CFS symptom presentation and progression remain poorly understood despite evidence that women and men experience the condition differently. This study provides an exploratory framework suggesting that hormonal factors may selectively modulate immune symptoms while gut dysfunction may represent a more persistent process, potentially informing sex-specific phenotyping and treatment stratification. Understanding these differences may help clinicians recognize disease patterns more accurately and guide future mechanistic research.

Observed Findings

In women with ME/CFS, immune symptoms (flu-like illness, infection susceptibility) and gastrointestinal symptoms showed two distinct but moderately correlated symptom clusters, with exploratory factor analysis supporting a two-factor solution.
In men with ME/CFS, immune and gastrointestinal symptoms were observed to cluster together as a single integrated symptom domain, with structural equation modeling showing excellent one-factor fit (CFI = 0.981).
Among women participants, premenopausal status was associated with more frequent reports of flu-like symptoms compared to postmenopausal status, while gastrointestinal symptoms remained relatively stable across menopause.
Across both sexes, susceptibility to infections emerged as the strongest predictor in regression analyses within the immune-gastrointestinal symptom architecture.
Sex-stratified symptom organization was replicated in a stratified training dataset, suggesting model robustness within this cross-sectional sample.

Inferred Conclusions

The authors interpret these findings as suggesting sex-dependent latent structures underlying immune and gastrointestinal symptoms, with women showing partially separable domains and men showing more integrated organization.
The authors propose that immune symptom expression may be hormonally modulated (evidenced by menopausal differences), while gastrointestinal dysfunction may represent a more persistent biological process independent of reproductive status.
The authors conclude that these results support a conceptual framework of sex-dependent neuroimmune-autonomic mechanisms in ME/CFS, potentially involving dynamic hormonal modulation of immune function and stable gut-related pathology.
The authors recommend sex- and hormone-sensitive approaches to phenotyping, mechanistic research, and therapeutic stratification in future ME/CFS investigations.

Remaining Questions

Do the observed differences in symptom clustering between women and men reflect distinct biological mechanisms, or do they represent different temporal trajectories of the same underlying pathology?
What is the causal direction of the menopausal effect on immune symptoms—does menopause directly suppress immune-related symptom expression, or are other age-related physiological changes responsible?
Do these sex-specific symptom architectures predict differential responses to treatments or prognostic trajectories, and should they inform stratification in future clinical trials?
How do these symptom patterns change longitudinally, and do premenopausal women who experience menopause show sustained changes in immune-related symptom burden?

What This Study Does Not Prove

This cross-sectional design does not establish causation and cannot determine whether menopausal status causes the observed changes in immune symptoms or merely correlates with them. The study does not prove that immune and gut symptoms are truly separate biological processes, only that they show different statistical relationships in women versus men. The findings do not confirm any underlying mechanism and require replication in prospective cohorts before informing clinical practice.

Topics

Endocrine Disruption Gut Microbiome Autonomic Nervous System Immune System

Metadata

DOI: 10.1186/s12967-026-08699-6
PMID: 42522006
Evidence level: Single-study or moderate support from human research
Last updated: 29 July 2026

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Primary citation

Habermann-Horstmeier, Lotte & Horstmeier, Lukas M (2026). Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08699-6

BibTeX

@article{mecfsatlas-habermann-horstmeier-2026-sex-menopause,
  author  = {Habermann-Horstmeier, Lotte and Horstmeier, Lukas M},
  title   = {Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling.},
  journal = {Journal of translational medicine},
  year    = {2026},
  doi     = {10.1186/s12967-026-08699-6},
  note    = {PubMed: 42522006},
  url     = {https://www.mecfsatlas.com/evidence/habermann-horstmeier-2026-sex-menopause},
}

Atlas snapshot reference

ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-07-30. https://www.mecfsatlas.com/evidence/habermann-horstmeier-2026-sex-menopause

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Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling.

Quick Summary

Why It Matters

Observed Findings

Inferred Conclusions

Remaining Questions

What This Study Does Not Prove

Topics

Tags

Metadata

Explore further

Cite this study

Evidence Atlas

Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling.

Quick Summary

Why It Matters

Observed Findings

Inferred Conclusions

Remaining Questions

What This Study Does Not Prove

Topics

Tags

Metadata

Explore further

Cite this study