cortisol – American ME and CFS Society

A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study

Abstract:

This pilot study harnessed the power of network medicine to unravel the complex pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). By utilizing a network analysis on whole genome sequencing (WGS) data from the Severely Ill Patient Study (SIPS), we identified ME/CFS-associated proteins and delineated the corresponding network-level module, termed the SIPS disease module, together with its relevant pathways. This module demonstrated significant overlap with genes implicated in fatigue, cognitive disorders, and neurodegenerative diseases.

Our pathway analysis revealed potential associations between ME/CFS and conditions such as COVID-19, Epstein-Barr virus (EBV) infection, neurodegenerative diseases, and pathways involved in cortisol synthesis and secretion, supporting the hypothesis that ME/CFS is a neuroimmune disorder. Additionally, our findings underscore a potential link between ME/CFS and estrogen signaling pathways, which may elucidate the higher prevalence of ME/CFS in females.

These findings provide insights into the pathogenesis of ME/CFS from a network medicine perspective and highlight potential therapeutic targets. Further research is needed to validate these findings and explore their implications for improving diagnosis and treatment.

Source: Li-Yuan Hung, Chan-Shuo Wu, Chia-Jung Chang, Peng Li, Kimberly Hicks, Becky Taurog, Joshua J Dibble, Braxton Morrison, Chimere L Smith, Ronald W Davis, Wenzhong Xiao. A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study.
medRxiv 2024.09.26.24314417; doi: https://doi.org/10.1101/2024.09.26.24314417 https://www.medrxiv.org/content/10.1101/2024.09.26.24314417v1 (Full text available as PDF file)

Lower hair cortisol concentration in adolescent and young adult patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Q-Fever Fatigue Syndrome compared to controls

Abstract:

Background: In patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), momentary cortisol concentrations in blood, urine, and saliva are lower compared to healthy controls. Long-term cortisol concentration can be assessed through hair, but it is unclear whether these concentrations are also lower. Additionally, it is unknown if lower cortisol extends to other patients suffering from persistent fatigue and how hair cortisol concentration (HCC) relates to fatigue levels. Therefore, this study examines HCC in fatigued patients with ME/CFS, Q fever Fatigue Syndrome (QFS), Post-COVID-19 condition (PCC), and Juvenile Idiopathic Arthritis (JIA).

Methods: Adolescent and young adult patients with ME/CFS (n=12), QFS (n=20), PCC (n=8), JIA (n=19), and controls (n=57) were included. Patients participated in a randomized cross-over trial (RCT) targeting fatigue through lifestyle and dietary self-management strategies. HCC was measured pre-post RCT in patients and once in controls, quantified using a LC-MS/MS-based method. Fatigue severity was measured with the Checklist Individual Strength-8. HCC was compared between groups with ANOVAs. Relations between HCC, fatigue severity, and other variables were investigated using linear regression analyses.

Results: The ME/CFS (p=.009) and QFS (p=.047) groups had lower HCC compared to controls. Overall, HCC was negatively associated with the presence of symptoms related to chronic fatigue syndromes (e.g., sleeping issues, often feeling tired, trouble thinking clearly; β=-0.018, p=.035), except in the QFS group (β=.063, p<.001). Baseline HCC did not predict fatigue improvement during the RCT (p=.449), and HCC increased during the trial (M_dif=.076, p=.021) regardless of clinically relevant fatigue improvement (p=.658).

Conclusion: Lower cortisol concentration can also be observed in the long-term. Lower HCC is not limited to ME/CFS, as it was also observed in QFS. The role of cortisol may differ between these diagnoses and appears to be unrelated to fatigue levels.

Source: Vroegindeweij A, Eijkelkamp N, van den Berg SAA, van de Putte EM, Wulffraat NM, Swart JF, Nijhof SL. Lower hair cortisol concentration in adolescent and young adult patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Q-Fever Fatigue Syndrome compared to controls. Psychoneuroendocrinology. 2024 Jun 28;168:107117. doi: 10.1016/j.psyneuen.2024.107117. Epub ahead of print. PMID: 38986244. https://pubmed.ncbi.nlm.nih.gov/38986244/

Quantitative Proteomics of COVID-19 Recovered Patients Identifies Long-Term Changes in Sperm Proteins Leading to Cellular Stress in Spermatozoa

Abstract:

Following an initial recovery, COVID-19 survivors struggle with a spectrum of persistent medical complications, including fatigue, breathlessness, weight loss, hair loss, and attention deficits. Additionally, there is growing evidence of adverse effects of COVID-19 on the male reproductive system. This investigation seeks to understand the long-term ramifications on male fertility by examining hormonal profiles, semen parameters, and sperm proteome of recovered COVID-19 patients compared to controls.

The serum hormone profiles between the two groups showed minimal variations except for prolactin, cortisol, and testosterone levels. Testosterone levels were slightly lower, while prolactin and cortisol were elevated in COVID-19 cases compared to controls.

Though semen parameters exhibited no significant disparities between the COVID-19 and control groups, quantitative proteomics analysis revealed changes in sperm proteins. It identified 190 differentially expressed proteins, of which 161 were upregulated and 29 downregulated in COVID-19 cases.

Western blotting analysis validated the differential expression of serpin B4 and calpain 2. Bioinformatics analysis signifies cellular stress in the spermatozoa of COVID-19 recovered patients and thus, SOD and MDA levels in semen were measured. MDA levels were found to be significantly elevated, indicating lipid peroxidation in COVID-19 samples.

While the effects of COVID-19 on semen parameters may exhibit a potential for reversal within a short duration, the alterations it inflicts on sperm proteome are persisting consequences on male fertility. This study paves the path for further research and emphasizes the significance of comprehending the complex molecular processes underlying the long-term consequences of COVID-19 on male reproductive health.

Source: Chopra P, Tomar AK, Thapliyal A, Ranjan P, Datta SK, Yadav S. Quantitative Proteomics of COVID-19 Recovered Patients Identifies Long-Term Changes in Sperm Proteins Leading to Cellular Stress in Spermatozoa. Reprod Sci. 2024 Apr 24. doi: 10.1007/s43032-024-01560-5. Epub ahead of print. PMID: 38658489. https://pubmed.ncbi.nlm.nih.gov/38658489/

Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis

Abstract:

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Source: Yi-Dan Zhang, Li-Na Wang. Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis. Front. Endocrinol., 09 April 2024, Sec. Neuroendocrine Science, Volume 15 – 2024 | https://doi.org/10.3389/fendo.2024.1373748 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1373748/full

Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study

Abstract:

Background: Long-COVID is defined by persistent symptoms following COVID-19 infection. Approximately 71% of individuals with long-COVID experience ongoing fatigue, post-exertional malaise, and cognitive impairments, which share pathological similarities with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This similarity has prompted studies to explore the characteristics of long-COVID to gain a better understanding of ME/CFS. To gain insights, we investigated the clinical and laboratory characteristics of individuals with fatigue-dominant long-COVID.

Methods: We enrolled 100 subjects (36 males, 64 females) with long-COVID who had a higher score than 60 in modified Korean version of the Chalder Fatigue Scale (mKCFQ11) and higher than 5 in fatigue-focused Visual Analogue Scale (VAS). To investigate fatigue symptoms, the mKCFQ11, the Multidimensional Fatigue Inventory (MFI-20), and VAS for fatigue and brain-fog, along with the Short Form Survey (SF-12) were employed. We also measured three cytokines and cortisol levels for immunological and endocrinological indicators. As a cross-sectional observational study, the data were collected at a single point in time.

Results: The mean scores on the measurements showed severe fatigue, and these scores were significantly correlated, with no differences based on sex, the post-COVID period, or age. Among the laboratory tests, plasma cortisol levels had a significant negative correlation with fatigue scores and a positive correlation with living quality. The negative correlation between cortisol levels and mKCFQ11 scores appeared to be more specific to mental fatigue than physical, which conflicted with other measurements.

Conclusion: Our findings provide the first insights into the characteristics of fatigue in individuals with long-COVID, particularly in terms of fatigue severity and cortisol levels. These results serve as valuable reference data for clinicians dealing with fatigue symptoms in long-COVID patients and for researchers exploring post-viral fatigue symptoms, including ME/CFS, in the future.

Source: Lee JS, Choi Y, Joung JY, Son CG. Clinical and Laboratory Characteristics of Fatigue-dominant Long-COVID subjects: A Cross-Sectional Study. Am J Med. 2024 Feb 6:S0002-9343(24)00057-3. doi: 10.1016/j.amjmed.2024.01.025. Epub ahead of print. PMID: 38331137. https://pubmed.ncbi.nlm.nih.gov/38331137/

Clinical characteristics of female long COVID patients with menstrual symptoms: a retrospective study from a Japanese outpatient clinic

Abstract:

Purpose: To elucidate the impact of long COVID on menstruation and mental health, medical records of patients with long COVID were evaluated.

Methods: Symptoms of long COVID, QOL, mental health, and related endocrine data were compared between two groups with and without menstrual disturbances.

Results: Of 349 female patients who visited our clinic between February 2021 and March 2023, 223 patients with long COVID (aged 18-50 years) were included. Forty-four (19.7%) of the patients had menstrual symptoms associated with long COVID. The patients with menstrual symptoms were older than those without menstrual symptoms (42.5 vs. 38 years). The percentage of patients with menstrual symptoms was higher during the Omicron phase (24%) than during the Preceding (13%) and Delta (12%) phases. Cycle irregularity was the most frequent (in 63.6% of the patients), followed by severe pain (25%), heavy bleeding (20.5%), perimenopausal symptoms (18.2%), and premenstrual syndrome (15.9%). Fatigue and depression were the most frequent complications. Scores for fatigue and for QOL were significantly worse in long COVID patients with menstrual symptoms. Results of endocrine examinations showed significantly increased cortisol levels in patients with menstrual complaints.

Conclusion: Long COVID has an impact on menstrual conditions and on QOL related to menstrual conditions.

Source: Sakurada Y, Matsuda Y, Motohashi K, Hasegawa T, Otsuka Y, Nakano Y, Tokumasu K, Yamamoto K, Sunada N, Honda H, Hagiya H, Ueda K, Otsuka F. Clinical characteristics of female long COVID patients with menstrual symptoms: a retrospective study from a Japanese outpatient clinic. J Psychosom Obstet Gynaecol. 2024 Dec;45(1):2305899. doi: 10.1080/0167482X.2024.2305899. Epub 2024 Jan 25. PMID: 38270210. https://www.tandfonline.com/doi/full/10.1080/0167482X.2024.2305899 (Full text)

Sex and disease severity-based analysis of steroid hormones in ME/CFS

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by decreased daily activity and persistent fatigue after physical and/or cognitive exertion. Although ME/CFS affects both sexes, there is a higher preponderance of cases in women. However, endocrinological studies focused on evaluating this sex-related disparity are limited.

In this scenario, the aim of this study was to measure 9 circulating steroid hormones (SHs) divided into mineralocorticoids (aldosterone), glucocorticoids (cortisol, corticosterone, 11-deoxycortisol, cortisone), androgens (androstenedione, testosterone), and progestins (progesterone, 17α-hydroxyprogesterone) in plasma samples from mild/moderate (ME/CFSmm; females, n=20; males, n=8), severely affected patients (ME/CFSsa; females, n=24; males, n=6), and healthy controls (HC, females, n=12; males, n=17) using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS).

After correction for multiple testing, we observed that circulating levels of 11-deoxycortisol, 17α-hydroxyprogesterone in females, and progesterone in males were significantly different between HC, ME/CFSmm and ME/CFSsa. Comparing two independent groups, we found that female ME/CFSsa had higher levels of 11-deoxycortisol (vs. HC and ME/CFSmm) and 17α-hydroxyprogesterone (vs. HC).

In addition, female ME/CFSmm showed a significant increase in progesterone levels relative to HC. In contrast, we observed that male ME/CFSmm had lower circulating levels of cortisol and corticosterone, while progesterone levels were elevated compared to HC. In addition to these univariate analyses, our correlational and multivariate approaches identified differential associations between our study groups. Also, using two-component partial least squares discriminant analysis (PLS-DA), we were able to discriminate ME/CFS from HC with an accuracy of 0.712 and 0.846 for females and males, respectively.

In conclusion, our findings not only suggest the potential value of including SHs in future studies aimed at improving stratification in ME/CFS, but also provide new perspectives to explore the clinical relevance of these SH-related differences within specific patient subgroups.

Source: Cornelia Pipper, Linda Bliem, Luis León et al. Sex and disease severity-based analysis of steroid hormones in ME/CFS, 13 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3428946/v1] https://www.researchsquare.com/article/rs-3428946/v1 (Full text)

Treatment and outcomes of 95 post-Covid patients with an antidepressant and neurobiological explanations

Abstract:

After Covid-19 infection, 12.5% develop a post-Covid-syndrome. Symptoms affect numerous organ systems, but after one year they are mainly neurological and neuropsychiatric in nature. There is evidence that treatment with selective serotonin reuptake inhibitors (SSRIs) during Covid-19 infection decreases the likelihood of a post-Covid condition, but there is no known research on treating post-Covid syndrome itself with SSRIs.

This study used an exploratory questionnaire and found that 63,4% of 95 post-Covid syndrome patients reported a reasonably good to strong response to an SSRI. Outcomes were measured with three different measures that correlated strongly with each other. Brainfog and sensory overload decreased the most. Patients experienced improved well-being. The response to SSRIs in post-Covid conditions was explained by seven possible neurobiological mechanisms as reported in the recent literature. The promising results of this study should be followed by a randomized controlled trial.

Source: Rus CC, de Vries B, Vries IE, Nutma I, Kooij JJS. Treatment and outcomes of 95 post-Covid patients with an antidepressant and neurobiological explanations. Research Square; 2023. DOI: 10.21203/rs.3.rs-3153645/v1. https://assets.researchsquare.com/files/rs-3153645/v1/ffdd7433-9013-41d5-9f16-154074f3a204.pdf (Full text)

Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia

Abstract:

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them.

Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM.

FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin.

However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS.

In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes.

Source: Otero E, Gálvez I, Ortega E, Hinchado MD. Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia. Biomedicines. 2023; 11(5):1488. https://doi.org/10.3390/biomedicines11051488 https://www.mdpi.com/2227-9059/11/5/1488 (Full text)

The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Purpose: Leptin is a member of the cytokine family; its receptor (LEPR-b) is the longest form receptor expressed in cells of the immune system; wherein LEPR-b deficiency causes a decrease in CD4+ cells. LEPR-b is located in hypothalamic and brain stem nuclei, and it primarily regulates energy status. As well, leptin indirectly regulates widespread pain and exercise tolerance by decreasing circulating cortisol.

Hyperinsulinemia increases leptin production in adipocytes on a diurnal rhythm; however, the precise relationship between insulin, leptin and pro-inflammatory markers remains uncertain. In clinical settings, high-sensitivity C-reactive protein (hsCRP) has been widely used, as an inflammatory predictor for leptin-related cardiometabolic outcomes and chronic inflammatory symptoms.

Leptin-related metabolic and inflammation dysregulations have been clinically reported in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but not fully elucidated. We examined the association of plasma insulin, leptin, and hsCRP levels with ME/CFS self-reported symptom severity.

Methods: Prospective analyses were conducted on ME/CFS patients who met Fukuda/CDC criteria at Birmingham hospital, Alabama, U.S.A. The independent variables were hyperinsulinemia (>174 Î¼IU/mL), hyperleptinemia/hypoleptinemia (>18.3/<3.3 ng/mL), residual inflammation risk (hsCRP â‰¥2 and â‰ 26.2 mg/L) and within-individual-variability (WIV) for each biomarker.

WIV was defined for each individual as standard deviation/sample residuals adjusting for time and calculated from once-daily random plasma samples over 10–12 weeks.

The primary outcomes were:

(1) ME/CFS symptom score trends [generalized pain, persistent fatigue, sleep disturbance, impairment of concentration and memory (brain fog), and post-exertional malaise (PEM)] calculated from the MFI-20 questionnaire with anchors from 0 to 100 and recorded once daily over a matching 12–14 weeks, and

(2) dichotomized symptom severity, with severe symptoms defined as scores > 60/100. After adjusting for age and time, we reported: (1) standard errors (SEM) and p-values for symptom trends using multivariable mixed-effect linear regression models, and (2) odds ratios for severe symptoms using multivariable alternating logistic regression models.

Results: We included 29 ME/CFS patients. All were females and >18 years old. Hyperinsulinemia, hyperleptinemia/hypoleptinemia, and residual inflammation risk were 7%, 80%/7%, and 74%, respectively.

The medians of insulin-WIV, leptin-WIV and hsCRP-WIV were [(0.24; IQR 0.15–0.38), (0.25; IQR 0.15–0.40), (0.33; IQR 0.18–0.51)] respectively. On average, hyperleptinemic patients had the highest leptin-WIV and 50% of them had residual inflammation risk.

Severe (fatigue, pain, brain fog, sleep disturbance, and PEM) were reported in 50%, 29%, 41%, 30%, and 57% of patients, respectively. In the adjusted analysis, worse fatigue scores (7.49; SEM, 2.23; p = 0.002) were associated with higher insulin-WIV.

Hyperleptinemia (OR 1.54; 95% CI 1.13–2.09) compared to hypoleptinemia, and residual inflammation risk (OR 1.65; 95% CI 1.21–2.25) were associated with higher odds of severe fatigue. Worse pain scores (7.17; SEM, 2.30; p = 0.005) were associated with higher leptin-WIV, and (8.45; SEM, 2.25; p = 0.0009) higher hsCRP-WIV, and residual inflammation risk (OR 1.75; 95% CI 1.34–2.29) was associated with higher odds of severe pain.

Severe brain fog scores (9.20; SEM, 2.44; p = 0.0008) were associated with higher insulin-WIV, higher leptin-WIV (4.73; SEM, 2.12; p = 0.03). Residual inflammation risk (OR 1.40; 95% CI 1.16–1.77) was associated with higher odds of severe brain fog.

Hyperleptinemia (OR 0.60; 95% CI 0.43–1.19) was associated with lower odds of severe PEM compared to hypoleptinemia, and better sleep quality was associated (6.07; SEM, 1.70; p = 0.001) with higher insulin-WIV, and (3.37; SEM, 1.47; p = 0.03) higher leptin-WIV.

Conclusions: In patients with ME/CFS, symptoms severity was associated with hyperleptinemia, inflammation and within-individual-variability of these biomarkers. Leptin and hsCRP may be clinically useful in predicting symptom severity.

Larger clinical trials are needed to further examine the prediction and causality of these biomarkers in the development of ME/CFS diagnosis. The efficacy and safety of anti-inflammatory therapies may be evaluated in sub-clusters of ME/CFS with metabolic responses and inflammation dysregulations to improve patient-reported symptoms.

Source: Rahaf Al Assil and Jarred W Younger. “The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” in Karandrea S, Agarwal N, Organizing Committee of Cardiometabolic Health Congress. Report from the Scientific Poster Session at the 16th Annual Cardiometabolic Health Congress in National Harbor, USA, 14–17 October 2021. Proceedings. 2022; 80(1):6. https://doi.org/10.3390/proceedings2022080006 (Full text)