Tag: hormones

Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry

Abstract:

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterised by unrelenting fatigue, post-exertional malaise, and dysfunction across immune, nervous, metabolism, and endocrine systems. Given the broad role of steroid hormones in regulating these systems, this study investigated differences in the steroid metabolome and network dynamics between ME/CFS patients and matched controls.

Methods: Blood plasma steroid levels were quantified using Ultra-Performance Supercritical Fluid Chromatography- Tandem Mass Spectrometry (UPSFC-MS/MS) in ME/CFS patients (n = 24) and age and gender matched controls (n = 24). Group comparisons of absolute steroid concentrations were performed using Mann-Whitney U tests. Partial Spearman correlation networks were evaluated to examine direct associations between steroids within each group, and centrality metrics were used to evaluate structural differences. Steroid-steroid ratios were analysed to reflect biochemical relationships. Multivariate analysis with Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) was also conducted.

Results: No significant group differences in absolute steroid concentrations were observed following FDR correction. However, network analysis revealed a marked reduction in direct steroid-steroid relationships in ME/CFS, with controls exhibiting 52 significant partial correlations, while the ME/CFS group retained only one (cortisol – corticosterone). Centrality analysis further revealed a shift in network structure, with cortisone emerging as highly central in ME/CFS (degree = 7, betweenness = 16.7), despite being peripheral in controls, and progesterone showing reduced integration in ME/CFS (degree = 3 vs. 12, eigenvector = 0.40 vs. 0.93). Steroid-steroid ratio analysis revealed a higher cortisol-to-pregnanolone ratio and a lower pregnanolone-to-progesterone ratio in ME/CFS, although these findings did not remain significant after FDR correction. OPLS-DA indicated a modest relationship between steroid levels and group classification (R²Y = 22.8%), but negative Q² values suggested poor predictive power.

Conclusions: Despite no significant differences in absolute steroid levels, network analysis revealed profound disruptions in steroid-steroid relationships in ME/CFS compared to controls, suggesting disrupted steroid homeostasis. Collectively the results suggest dysregulation of HPA axis function and progestogen pathways, as demonstrated by altered partial correlations, centrality profiles, and steroid ratios. These findings illustrate the importance of hormone network dynamics in ME/CFS pathophysiology and underscores the need for more research into steroid metabolism.

Source: Thomas, N., Ubhayasekera, S.J.K.A., Armstrong, C.W. et al. Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry. J Transl Med 23, 829 (2025). https://doi.org/10.1186/s12967-025-06841-4 https://link.springer.com/article/10.1186/s12967-025-06841-4 (Full text)

SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis

Abstract:

Background: Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.

Methods: A case-control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors-vildagliptin, saxagliptin, and linagliptin-on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.

Results: ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.

Conclusions: SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.

Note: See Correction: SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis

Source: Rostami-Afshari B, Elremaly W, Franco A, Elbakry M, Akoume MY, Boufaied I, Moezzi A, Leveau C, Rompré P, Godbout C, Mella O, Fluge Ø, Moreau A. SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis. J Transl Med. 2025 Jul 7;23(1):748. doi: 10.1186/s12967-025-06829-0. PMID: 40624584; PMCID: PMC12236014. https://pmc.ncbi.nlm.nih.gov/articles/PMC12236014/ (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available.

Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease’s multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances.

This comprehensive model not only advances our understanding of ME/CFS’s pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease’s complexity and the multifaceted approach required for its study and management.

Source: Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol. 2024 Jun 3;15:1386607. doi: 10.3389/fimmu.2024.1386607. PMID: 38887284; PMCID: PMC11180809. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180809/ (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)

The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure

Abstract:

The etiopathogenesis of fibromyalgia (FM) and chronic fatigue syndrome (CFS) is not yet elucidated. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is reflected in the hormonal disturbances found in FM and CFS. Some study groups have introduced a novel hypothesis that moderate or intermittent intracranial hypertension may be involved in the etiopathogenesis of FM and CFS.

In these conditions, hormonal disturbances may be caused by the mechanical effect of increased cerebrospinal fluid pressure, which hampers blood flow in the pituitary gland. Severe intracranial pressure may compress the pituitary gland, resulting in primary empty sella (ES), potentially leading to pituitary hormone deficiencies.

The aim of this narrative review was to explore whether similar hormonal changes and symptoms exist between primary ES and FM or CFS and to link them to cerebrospinal fluid pressure dysregulation. A thorough search of the PubMed and Web of Science databases and the reference lists of the included studies revealed that several clinical characteristics were more prevalent in primary ES, FM or CFS patients than in controls, including increased cerebrospinal fluid pressure, obesity, female sex, headaches and migraine, fatigue, visual disturbances (visual acuity and eye motility abnormalities), vestibulocochlear disturbances (vertigo and neurosensorial hearing loss), and bodily pain (radicular pain and small-fiber neuropathy).

Furthermore, challenge tests of the pituitary gland showed similar abnormalities in all three conditions: blunted adrenocorticotropic hormone, cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response. The findings of this narrative review provide further support for the hypothesis that moderately or intermittently increased cerebrospinal fluid pressure is involved in the pathogenesis of FM and CFS and should stimulate further research into the etiopathogenesis of these conditions.

Source: Hulens M, Dankaerts W, Rasschaert R, Bruyninckx F, De Mulder P, Bervoets C. The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure. J Pain Res. 2023;16:205-219
https://doi.org/10.2147/JPR.S394321 https://www.dovepress.com/the-link-between-empty-sella-syndrome-fibromyalgia-and-chronic-fatigue-peer-reviewed-fulltext-article-JPR (Full text)

Systemic exertion intolerance disease associated to neuroendocrine dysfunction and cortical atrophy: a case report

Abstract:

Background: Scarce evidence about the organic and functional abnormalities of systemic exertion intolerance disease (SEID) is found in literature and the pathophysiology is still unclear.

Methods: Following the CARE Guidelines, this case report describes a patient with a 5-year history of nonspecific symptoms, lately recognized as SEID.

Results: Low serum thyroid- and adrenocorticotropic stimulating hormone levels, and 24-h urinary cortisol excretion almost twice the upper limit were detected. Computed tomography scan found significant cortical atrophy. Low-dose modafinil improved the clinical outcome, added to nonpharmacologic approach.

Conclusion: To ascertain an accurate SEID diagnosis and treatment are a challenge in daily clinical practice, that must be engaged based in clear methods and good practice recommendations. Thus, family practitioners should be aware of this diagnosis.

Source: López-Amador N. Systemic exertion intolerance disease associated to neuroendocrine dysfunction and cortical atrophy: a case report. Fam Pract. 2022 May 28:cmac060. doi: 10.1093/fampra/cmac060. Epub ahead of print. PMID: 35640045. https://pubmed.ncbi.nlm.nih.gov/35640045/

Oxytocin, the panacea for long-COVID? a review

Abstract:

Objectives: In this hypothesis paper we explore the underlying mechanisms for long-COVID and how the oxytocinergic neurones could be infected by SARS-CoV-2 leading to a reduction in plasma oxytocin (OXT). Furthermore, we aim to review the relevance of OXT and hypothalamic function in recovery from long-COVID symptoms and pathology, through exploring the pro-health effects of the OXT neuropeptide.

Methods: A review of published literature was surveyed using Google Scholar and PubMed.

Results: Numerous experimental data can be shown to correlate with OXT and long-COVID symptoms and conditions, thus providing strong circumstantial evidence to support our hypothesis. It is postulated that the reduction in plasma OXT due to acute and post-viral damage to the hypothalamus and oxytocinergic neurones contributes to the variable multi-system, remitting and relapsing nature of long-COVID. The intranasal route of OXT application was determined to be most appropriate and clinically relevant for the restoration of oxytocinergic function post COVID-19 infection.

Conclusions: We believe it is imperative to further investigate whether OXT alleviates the prolonged suffering of patients with long-COVID. Succinctly, OXT may be the much-needed post-pandemic panacea.

Source: Diep, Phuoc-Tan, Chaudry, Mohammed, Dixon, Adam, Chaudry, Faisal and Kasabri, Violet. “Oxytocin, the panacea for long-COVID? a review” Hormone Molecular Biology and Clinical Investigation, vol. , no. , 2022. https://doi.org/10.1515/hmbci-2021-0034 (Full text)

Hormonal trends in patients suffering from long COVID symptoms

Abstract:

Symptoms of long COVID are complex and long-lasting, and endocrine dysfunction might be involved in the underlying mechanisms. In this study, to clarify the hormonal characteristics of long COVID patients, laboratory data for patients who visited the outpatient clinic for long COVID were evaluated. A retrospective analysis was performed for patients who visited Okayama University Hospital during the period from Feb 2021 to Dec 2021 with focus on the interrelationships between major symptoms and endocrine data.

Information and laboratory data were obtained from medical records for 186 patients. The patients had various symptoms, and the most frequent symptoms were general malaise, dysosmia/dysgeusia, hair loss, headache, dyspnea, and sleeplessness. Patients who were suffering from fatigue and dysosmia/dysgeusia were younger, while hair loss was more frequent in older and female patients.

As for the characteristics of patients suffering from general fatigue, the scores of depression and fatigue were positively correlated with serum levels of cortisol and free thyroxin (FT4), respectively. Also, patients suffering from general fatigue had lower levels of serum growth hormone and higher levels of serum FT4, while patients with dysosmia/dysgeusia had a significantly lower level of serum cortisol. Serum thyrotropin (TSH) levels were higher and the ratios of FT4/TSH were lower in the initially severe cases, suggesting occult hypothyroidism. In addition, the ratios of plasma adrenocorticotropin to serum cortisol were decreased in patients with relatively high titers of serum SARS-CoV-2 antibody. Thus, hormonal changes seem to be, at least in part, involved in the persistent symptoms of long COVID.

Source: Sunada N, Honda H, Nakano Y, Yamamoto K, Tokumasu K, Sakurada Y, Matsuda Y, Hasegawa T, Otsuka Y, Obika M, Hanayama Y, Hagiya H, Ueda K, Kataoka H, Otsuka F. Hormonal trends in patients suffering from long COVID symptoms. Endocr J. 2022 Apr 28. doi: 10.1507/endocrj.EJ22-0093. Epub ahead of print. PMID: 35491089. https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ22-0093/_article (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic systemic disease that manifests via various symptoms such as chronic fatigue, post-exertional malaise, and cognitive impairment described as “brain fog”. These symptoms often prevent patients from keeping up their pre-disease onset lifestyle, as extended periods of physical or mental activity become almost impossible. However, the disease presents heterogeneously with varying severity across patients. Therefore, consensus criteria have been designed to provide a diagnosis based on symptoms. To date, no biomarker-based tests or diagnoses are available, since the molecular changes observed also largely differ from patient to patient.

In this review, we discuss the infectious, genetic, and hormonal components that may be involved in CFS pathogenesis, we scrutinize the role of gut microbiota in disease progression, we highlight the potential of non-coding RNA (ncRNA) for the development of diagnostic tools and briefly mention the possibility of SARS-CoV-2 infection causing CFS.

Source: Deumer US, Varesi A, Floris V, Savioli G, Mantovani E, López-Carrasco P, Rosati GM, Prasad S, Ricevuti G. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview. J Clin Med. 2021 Oct 19;10(20):4786. doi: 10.3390/jcm10204786. PMID: 34682909; PMCID: PMC8538807. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538807/ (Full text)

Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome

Abstract:

Context: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe chronic illness which reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.

Objective: To investigate the occurrence of anti-pituitary (APA) and anti-hypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Design, setting, patients and other participants: This is a case-control study conducted in University Hospital setting (Stanford, Naples). Thirty women with ME/CSF (Group 1) diagnosed according to Fukuda, Canadian, and IOM criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls.

Main outcome measures: APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands and plasma and urinary osmolality. Both APA and AHA titers were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results: Patients in Group 1 showed a high prevalence of AHA (33%) and APA (56%) and a significant lower levels of ACTH/cortisol, and GH peak/IGF1 vs controls (all AHA/APA negative). Patients in Group 1A (13 patients positive at high titers, ≥1:32) showed ACTH/cortisol and GH peak/ IGF1 levels significantly lower and more severe forms of ME/CFS with respect to patients in Group 1B (7 positive at middle/low titers,1:16-1:8) and 1C (10 Ab negative patients).

Conclusions: Both AHA and/or APA at high titers associated with hypothalamic/pituitary dysfunction suggest that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Source: De Bellis A, Bellastella G, Pernice V, Cirillo P, Longo M, Maio A, Scappaticcio L, Maiorino MI, Bellastella A, Esposito K, Montoya JG. Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome. J Clin Endocrinol Metab. 2021 Jul 13:dgab429. doi: 10.1210/clinem/dgab429. Epub ahead of print. PMID: 34254637. https://pubmed.ncbi.nlm.nih.gov/34254637/