Tag: women

Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group

Abstract:

Background: Muscle-related symptoms are among the most disabling manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), yet their position within the broader symptom architecture of the disease remains unclear. We hypothesized that muscle symptoms may represent a candidate integrative symptom within a broader shared symptom-dysregulation structure and their symptom associations differ according to sex and menopausal status.

Methods: Cross-sectional data from 736 individuals with physician-diagnosed ME/CFS enrolled in the APAV-ME/CFS registry were analysed. Muscle problems served as the primary outcome variable. Associations with 14 symptom domains were examined using multivariable logistic regression. Pearson and tetrachoric correlations, exploratory factor analysis, and structural equation modeling (SEM) were used to identify latent symptom structures. Exploratory analyses were stratified by sex, menopausal status, and disease duration.

Results: In the full multivariable model (non-robust estimates), breathing problems (OR 2.49 [95% Conf. Interval: 1.42-4.38], p = 0.001), flu-like symptoms (OR 1.97 [1.14-3.42], p = 0.015), and temperature-regulation disorders (OR 1.97 [1.10-3.51], p = 0.021) independently predicted muscle problems. A reduced physiological model (not-robust estimates) additionally identified cardiovascular symptoms (OR 1.87 [1.09-3.24], p = 0.024) as a significant predictor. Tetrachoric correlations demonstrated substantial latent associations between muscle problems and breathing difficulties (ρ = 0.52), cardiovascular symptoms (ρ = 0.49), temperature-regulation disorders (ρ = 0.49), visual disturbances (ρ = 0.39), and flu-like symptoms (ρ = 0.39). Factor analysis and SEM supported a single latent physiological dysregulation factor with good model fit (RMSEA = 0.046, CFI = 0.971, TLI = 0.952, SRMR = 0.026).

The sex-stratified analyses revealed differences in the pattern of statistically significant symptom associations across the subgroups. However, the overall test of the symptom-by-sex interaction terms did not provide evidence for a statistically established difference in the symptom associations by sex. Thus, the subgroup-specific patterns should primarily be interpreted as descriptive and exploratory. At the individual symptom level, the association between breathing-related symptoms and muscle problems showed a statistically significant interaction with sex, suggesting that this association may differ between women and men. However, this finding should be interpreted cautiously given the non-significant overall interaction test and the wide confidence interval of the interaction estimate.

In women, all five physiological symptoms independently predicted muscle problems, whereas in men only breathing problems and temperature-regulation disorders remained significant. Women classified as premenopausal and postmenopausal based on an age-defined proxy showed different patterns of symptom associations with muscle problems in subgroup-specific analyses. Women in the premenopausal age-proxy group showed significant associations with cardiovascular symptoms, visual disturbances, and temperature-regulation disorders, whereas women classified as postmenopausal showed significant associations with breathing difficulties and flu-like symptoms. However, the overall menopausal-by-symptom interaction was not statistically significant (Wald χ2 (5)=5.96, p = 0.310).

The specified latent physiological factor showed statistical comparability across the cross-sectional disease-duration groups. Gastrointestinal complaints loaded substantially on the latent factor despite lacking an independent association with muscle problems in multivariable regression. Urogenital symptoms also showed a smaller but significant association with the latent factor and substantial item-specific variance.

Conclusions: Muscle symptoms may represent a candidate integrative symptom within a latent physiological symptom-dysregulation factor encompassing respiratory, cardiovascular, thermoregulatory, visual, and flu-like symptoms in this ME/CFS sample. Secondary analyses suggested that gastrointestinal complaints were also part of the broader physiological symptom pattern, although they were not independently associated with muscle problems. The specified latent physiological factor showed no overall statistical evidence of measurement differences across the cross-sectional disease-duration groups. However, subgroup-specific symptom patterns differed descriptively by sex and age-defined menopausal-status proxy group.

Women classified as premenopausal were characterized primarily by cardiovascular, visual, and thermoregulatory symptom associations, whereas women classified as postmenopausal and men showed greater prominence of breathing-related symptoms. Flu-like symptoms were independently associated with muscle problems in the postmenopausal subgroup but not in the premenopausal subgroup. Because the corresponding interaction term was not statistically significant, this subgroup contrast should be interpreted as an exploratory difference in association rather than as evidence of a menopause-specific effect. More broadly, the findings are compatible with the hypothesis that the latent symptom-dysregulation factor may reflect a chronic PEM-associated multisystem response.

Whether this symptom-dysregulation factor corresponds to interacting autonomic, vascular, immunological, and metabolic processes remains to be determined by longitudinal and biomarker-based studies. ME/CFS phenotyping may improve patient stratification and facilitate the development of mechanism-based therapeutic approaches.

Source: Habermann-Horstmeier L, Horstmeier LM. Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group. J Transl Med. 2026 Sep 28;24(1):1216. doi: 10.1186/s12967-026-09018-9. PMID: 42806383. https://link.springer.com/article/10.1186/s12967-026-09018-9 (Full text)

Long-Term Follow-Up of Women with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A 16-Year Longitudinal Study

Abstract

Background and Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by persistent or relapsing fatigue lasting at least six months, not alleviated by rest and not previously present. It is accompanied by post-exertional symptom exacerbation and non-restorative sleep. Fatigue is often disabling and reduces daily activity by more than 50%. This study aimed to evaluate the long-term frequency of somatic and psychiatric disorders in women previously diagnosed with ME/CFS and to describe the long-term clinical course, laboratory findings, and fatigue-related changes during a 16-year follow-up period.

Materials and Methods: Sixteen years ago, 40 women diagnosed with ME/CFS according to then-current CDC criteria were enrolled at the Clinic for Infectious Diseases and the Center for Laboratory Medicine, University Clinical Center of Vojvodina. All participants provided informed consent. After 16 years, 20 women agreed to follow-up evaluation. At both time points, participants underwent structured questionnaires, clinical examination, psychological assessment, and comprehensive laboratory testing, including hematological, biochemical, endocrinological, and virological analyses. Fatigue severity was assessed using the FibroFatigue Scale (FFS) and the Multidimensional Assessment of Fatigue (MAF) scale.

Results: During follow-up, 15% of participants were diagnosed with rheumatoid arthritis, 10% with cervical or breast cancer, 5% experienced premature myocardial infarction, 5% developed bronchial asthma, and 20% were diagnosed with clinical depression. Progression of ME/CFS was observed in 15%, while 5% reported infertility. Additionally, 15% developed arterial hypertension. Only 15% of participants did not report symptom worsening or new diagnoses.

Conclusions: Over the 16-year follow-up, 85% of women with ME/CFS developed significant somatic or psychiatric conditions. These findings suggest that women diagnosed with ME/CFS may experience substantial long-term somatic and psychiatric disease burden, supporting the need for continued clinical monitoring and individualized follow-up.

Source: Tomić S, Pastornački A, Drljača M, Glogovac J, Bošković V, Brkić S. Long-Term Follow-Up of Women with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A 16-Year Longitudinal Study. Medicina (Kaunas). 2026 Jun 8;62(6):1114. doi: 10.3390/medicina62061114. PMID: 42356126; PMCID: PMC13303535. https://pmc.ncbi.nlm.nih.gov/articles/PMC13303535/ (Full text)

Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research

Abstract:

Hormonal dysregulation is increasingly reported in ME/CFS and Long COVID, yet the broader role of neuroendocrine disruption in these conditions remains underexplored. While changes in steroid, peptide, and neuropeptide hormones have been identified, these findings are often considered in isolation and without attention to their timing or integration within broader physiological systems. The hypothalamic-pituitary axes regulate endocrine, immune, autonomic, nervous, and metabolic functions, systems commonly affected in both conditions, yet their circadian and menstrual dynamics are rarely investigated.

In this review, we examine the evidence for neuroendocrine dysfunction in ME/CFS and Long COVID, focusing on hormone output, functional assays, receptor expression, and the coordination of endocrine biorhythms. Sex hormone signalling emerges as a key area of vulnerability, particularly given the female predominance in both conditions and the complexity of reproductive hormone regulation.

We argue that accurate hormone measurement and time-structured sampling, including circadian and menstrual rhythms, are essential for detecting meaningful biological differences. By embedding chronobiology-aware, dense-sampling strategies and integrating multi-omic analyses into multi-system study designs, we outline a framework for investigating dynamic endocrine mechanisms underlying symptom variability and multisystem dysfunction, which may ultimately support the development of more targeted, personalised interventions.

Source: Thomas N, Huang K, Schneider-Futschik EK, Pollack B, Tal MC, Fineberg D, Wang X, Gurvich C, Pretorius R, Bergquist J, Armstrong CW. Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research. Front Neuroendocrinol. 2026 Jun 19:101268. doi: 10.1016/j.yfrne.2026.101268. Epub ahead of print. PMID: 42320559. https://www.sciencedirect.com/science/article/abs/pii/S0091302226000385 (Full text)

Long COVID disability burden in US adults

Abstract:

Background: Five years since the scientific and patient communities first identified the syndrome now known as Long COVID, affected individuals lack treatments, and the US lacks population-based data on its disability burden and correlation with National Institutes of Health (NIH) funding. Moreover, akin to other debilitating conditions it often co-occurs with, e.g., Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia, Long COVID disproportionately impacts females whose concerns are often marginalized.

Methods: We quantify Long COVID years lived with disability (YLDs= prevalence x disability weight) in US adults and its actual/YLD-commensurate average annual NIH FY2022-2024 funding versus 68 comparator conditions, by sex predominance. We derive Long COVID prevalence from Census Bureau surveys (9/2022-8/2023) and apply disability weights from the Global Burden of Disease Study.

Results: Long COVID YLDs approximate those of Alzheimer’s and Asthma. Long COVID received 14% of its disability commensurate funding: $106 million vs. $739.8 million. ME/CFS is the most under-funded condition, receiving <1% of its YLD proportionate funding. Among conditions analyzed, 24 are female-predominant (we estimate Long COVID funding two ways), 12 male-predominant, and 33 show no sex predominance. Among the 12 below-median funded/above-median YLD conditions, 7/12 are female-predominant, none are male-predominant. Median funding/per YLD is 5.2 times higher for male- vs. female-predominant conditions (7.0 vs 1.3 million per YLD, p = 0.007). Overall, YLDs explain 6.5% of funding variance in a linear regression model using YLD as the sole predictor (Adjusted R-squared: 0.065).

Conclusions: With chronic conditions like Long COVID rising, disability burden merits greater consideration in funding decisions, as does biological sex.

Source: Bonuck K, Gao Q, Congdon S, Kim RS. Long COVID disability burden in US adults. Commun Med (Lond). 2026 Mar 31;6(1):177. doi: 10.1038/s43856-026-01516-7. PMID: 41917225. https://www.nature.com/articles/s43856-026-01516-7 (Full text)

Extracellular Vesicle Protein and MiRNA Signatures as Biomarkers for Post-Infectious ME/CFS Patients

Abstract:

Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with unresolved pathophysiology and limited diagnostic options. Extracellular vesicles (EVs) carry disease-specific protein and miRNA signatures and may enable improved disease profiling. We aimed to identify novel protein and miRNA markers as potential biomarkers in plasma EVs from female ME/CFS patients, including post-COVID-19 ME/CFS and post-infectious ME/CFS of other origins, compared with healthy controls.

EVs were isolated from plasma by size-exclusion chromatography and characterized for number, size, morphology, and surface marker expression. Flow cytometry showed that small EVs strongly expressed tetraspanins, with only minor differences between ME/CFS patients and healthy donors. Proteomic profiling of EVs from ME/CFS patients identified altered cargo proteins, including hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit compared with healthy controls (n ≤ 10/cohort). Small RNA sequencing followed by qPCR revealed significant downregulation of hsa-let-7b-5p in EVs from post-COVID-19 ME/CFS patients (n = 12) versus healthy controls (n = 15). Reduced hsa-let-7b-5p expression correlated with impaired physical functioning and increased fatigue, pain, and immune activation.

These findings indicate that EV cargo differences, particularly hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit, as well as hsa-let-7b-5p, represent promising candidates for ME/CFS diagnosis and patient stratification.

Source: Seifert M, Schäfers J, Douglas FF, Schwarzburg C, Boristowski D, Birke A, Klein O, Sotzny F, Rubarth K, Windzio L, Beez CM, Peters CK, Wittke K, Scheibenbogen C, Greco A. Extracellular Vesicle Protein and MiRNA Signatures as Biomarkers for Post-Infectious ME/CFS Patients. Int J Mol Sci. 2026 Feb 28;27(5):2314. doi: 10.3390/ijms27052314. PMID: 41828537. https://www.mdpi.com/1422-0067/27/5/2314 (Full text)

ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid are characterized by post-exertional malaise (PEM). Similarities in disease presentation suggest important commonalities in bioenergetic impairment, but this hypothesis has not been demonstrated. The metabolic underpinnings of each disease can be elucidated by two cardiopulmonary exercise tests (CPET) administered 24 hours apart. This retrospective study examined physiological responses on two-day CPET in people with ME/CFS (63 females and 21 males), Long Covid (52 females and 27 males), and matched non-disabled control participants (51 females and 20 males).

Data were analyzed within sexes using repeated measures analysis of variance. All participants met maximal effort criteria. There were significant reductions in oxygen consumption (O₂) and workload at the ventilatory anaerobic threshold (VAT) in both patient groups compared to non-disabled controls, with larger effect sizes at VAT than at peak exertion. Performance decrements were observed in both sexes.

Females exhibited more pronounced abnormalities and significant group by test effects. No significant differences were observed between patient groups. Severe disability based on impaired O₂ was prevalent in both patient groups. Hemodynamic and ventilatory measures were within normal ranges. ME/CFS and Long Covid both involve a functionally significant bioenergetic failure complicated by inadequate post-exertional recovery, which is similar between the conditions and unexplained by hemodynamic and ventilatory changes.

Findings support the utility of two-day CPET as an objective measure of PEM and functional impairment. Future studies may integrate mechanistic biomarkers with two-day CPET as trial endpoints and to establish likely responses to treatments for PEM.

Source: Todd Davenport, Staci Stevens, Jared Stevens et al. ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing, 22 January 2026, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-8606329/v1] https://www.researchsquare.com/article/rs-8606329/v1 (Full text available as PDF file)

Contested and neglected: Social and medical marginalization in severe Chronic Fatigue Syndrome

Highlights:

  • Severe ME/CFS patients face deep social, medical, and structural exclusion.
  • Delegitimation of illness leads to isolation, distress, and denied support.
  • Gendered stigma shapes how women’s pain is dismissed in health care.
  • Twitter (now X) offers access to the voices of an otherwise unreachable patient group.
  • This study urges reforms in care, disability access, and illness recognition.

Abstract:

This study addresses the persistent invisibility of people with severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in research by centering their voices and examining how social and institutional forces shape their lives. As a medically contested illness, ME/CFS—especially in its severe form—renders patients both physically incapacitated and socially invisible.
Drawing on qualitative content analysis of 342 tweets under the hashtag #severeME, we identify how contested legitimacy, gendered stigma, and systemic marginalization structure the daily realities of 161 individuals with severe ME/CFS or their caregivers. Our findings highlight profound functional debilitation, emotional isolation, and exclusion from care and disability systems. We argue for the urgent need to legitimize contested illnesses, reform models of care, and extend disability protections to restore dignity and support to this neglected population.
Source: Bita Nezamdoust, Erin Ruel. Contested and neglected: Social and medical marginalization in severe Chronic Fatigue Syndrome. Social Science & Medicine, Volume 388, 2026, 118766. ISSN 0277-9536. https://www.sciencedirect.com/science/article/pii/S0277953625010974 (Full text)

Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS

Abstract:

Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study reveals that female LC patients (LCF) with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and depleted regulatory T cells-suggesting persistent immune activation. Elevated CD71+ erythroid cells and disrupted erythropoiesis contribute to fatigue and tissue damage in LCF.

Cytokine profiling indicates a stronger pro-inflammatory response in LCF compared to males (LCM), along with markers of gut barrier dysfunction. Hormonal analysis shows reduced testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, potentially explaining cognitive symptoms. We also identify biomarkers that distinguish LCF from LCM and correlate with sex-specific clinical symptoms.

Overall, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with females exhibiting more severe inflammation. These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.

Source: Shahbaz S, Osman M, Syed H, Mason A, Rosychuk RJ, Cohen Tervaert JW, Elahi S. Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS. Cell Rep Med. 2025 Nov 7:102449. doi: 10.1016/j.xcrm.2025.102449. Epub ahead of print. PMID: 41205594. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00522-1 (Full text)

Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome

Abstract:

Background: Hypermobility Spectrum Disorders (HSD) and hypermobile Ehlers-Danlos syndrome (h-EDS) are multisystemic connective tissue disorders involving joint hypermobility and numerous other manifestations. Autonomic dysfunction, chronic pain, and chronic fatigue are known comorbidities of HSD and h-EDS that can affect patient quality of life (QoL), but there are limited data on the severity of autonomic symptoms, prevalence of comorbid conditions and QoL in patients with HSD/h-EDS.

Methods: We utilized the Composite Autonomic Symptom Scale (COMPASS-31) to assess autonomic symptom severity, Short-Form 36 (SF-36) to assess QoL, and the Beck Depression Inventory Second Edition (BDI-II) in a cohort of women with physician-diagnosed HSD or h-EDS, who completed these questionnaires anonymously.

Results: 84 women (mean age of 37.1 ± 8.4 years) completed the study. 58.3 % reported having physician-diagnosed postural orthostatic tachycardia syndrome (POTS), 32.1 % had mast cell activation syndrome (MCAS), 54.8 % had migraine, 26.2 % had myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 98.8 % reported experiencing chronic pain. Importantly, 25 % of patients reported having all three diagnoses: HSD/h-EDS, POTS and MCAS. Mean COMPASS-31 score was 54.45 (range 18.79-80.93), indicating severe autonomic dysfunction, which was significantly higher than in patients with multiple sclerosis, diabetic neuropathy, scleroderma, and psoriatic arthritis as shown in prior studies. Mean SF-36 score was 32.38 (SD = 22.91) indicating poor QoL, which was worse than in patients with POTS, multiple sclerosis, rheumatoid arthritis, and lupus as determined by prior studies.

Conclusions: This study demonstrates that women with HSD/h-EDS experience severe autonomic dysfunction, chronic pain, chronic comorbid conditions and reduced QoL. More than half of participants in this cohort had POTS and migraine, with one in four having a clinical triad of HSD/h-EDS, POTS and MCAS.

Source: Collins Hutchinson ML, Liang E, Fuster E, Blitshteyn S. Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome. Auton Neurosci. 2025 Oct 14;262:103356. doi: 10.1016/j.autneu.2025.103356. Epub ahead of print. PMID: 41118678. https://pubmed.ncbi.nlm.nih.gov/41118678/

Exploratory study on autoantibodies to arginine-rich human peptides mimicking Epstein-Barr virus in women with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrom

Abstract:

Introduction: Epstein-Barr virus (EBV) infection is a well-established trigger and risk factor for both myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID syndrome (PCS). In previous studies, we identified elevated IgG responses to arginine-rich (poly-R) sequences within the EBV nuclear antigens EBNA4 and EBNA6 in post-infectious ME/CFS (piME/CFS). Building on these findings, this exploratory study examines IgG reactivity to poly-R-containing EBV-derived peptides and homologous human peptides in women with PCS and ME/CFS.

Methods: IgG reactivity to poly-R containing peptides derived from EBNA4 and EBNA6, and homologous human 15-mer peptides and the corresponding full-length proteins, was assessed using a cytometric bead array (CBA) and a multiplex dot-blot assay. Serum samples were analyzed from 45 female PCS patients diagnosed according to WHO criteria, including 26 who also met the Canadian Consensus criteria for ME/CFS (pcME/CFS), 36 female patients with non-COVID post-infectious ME/CFS (piME/CFS), and 34 female healthy controls (HC).

Results: Autoantibodies targeting poly-R peptide sequences of the neuronal antigen SRRM3, the ion channel SLC24A3, TGF-β signaling regulator TSPLY2, and the angiogenesis-related protein TSPYL5, as well as full-length α-adrenergic receptor (ADRA) proteins, were more frequently detected in patient groups. Several of these autoantibodies showed positive correlations with core symptoms, including autonomic dysfunction, fatigue, cognitive impairment, and pain.

Conclusion: This exploratory study identify autoantibodies directed against EBV mimicking arginine-rich sequences in human proteins, suggesting a potential role for molecular mimicry in the pathogenesis of PCS and ME/CFS.

Source: Hoheisel Friederike , Fleischer Kathrin Maria , Rubarth Kerstin , Sepúlveda Nuno , Bauer Sandra , Konietschke Frank , Kedor Peters Claudia , Stein Annika Elisa , Wittke Kirsten , Seifert Martina , Bellmann-Strobl Judith , Mautner Josef , Behrends Uta , Scheibenbogen Carmen , Sotzny Franziska. Exploratory study on autoantibodies to arginine-rich human peptides mimicking Epstein-Barr virus in women with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Volume 16 – 2025. DOI=10.3389/fimmu.2025.1650948 ISSN=1664-3224 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1650948/full (Full text)