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The metabolic pathway showing the steps involved in the synthesis of cortisol from cholesterol. Cholesterol is converted to pregnenolone by desmolase, which is then converted to progesterone by 3-B-hydroxysteroid. Progesterone is converted to 17-a-hydroxyprogesterone (17-OH progesterone) by 17-hydroxylase. The 17-OH progesterone is then converted to 11-deoxycortisol by the enzyme 21-hydroxylase. Finally, 11-deoxycortisol is converted into cortisol by 11-hydroxylase. DHEA: dehydroepiandrosterone.
Source publication
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood traum...
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Citations
... [3,5] Several mechanisms leading to dysregulation have been implicated and supported by observational patient studies, [6][7][8][9] including an interplay between inflammatory pathways, [9] overactivated glial cells, [10] altered serotonin transmission, [11,12] and neuroendocrine dysfunction. [13,14] Without a definitive underlying mechanism, there are currently no medications specifically indicated for ME/CFS approved by the United States Food and Drug Administration (U.S. FDA) that address the disease directly. Instead, treatment plans include pharmacologic interventions that attempt to alleviate symptoms like depression, orthostatic intolerance, and pain, or to address perpetuating factors. ...
This study was a phase 4, double-blind, randomized, placebo-controlled trial of solriamfetol in adults with ME/CFS. Eligible participants were randomly assigned to receive 75mg (titrated to 150mg as needed) solriamfetol or placebo. Solriamfetol demonstrated good safety and efficacy in improving fatigue and executive functioning in patients with ME/CFS. As a dual norepinephrine-dopamine reuptake inhibitor and wakefulness-promotion, solriamfetol has the potential to improve fatigue symptoms of ME/CFS.
... Glucocorticoids, also called stress hormones, released from the activated HPA axis, play a vital role in the neuroendocrine system and are required for stress adaptation (5,6). The major structures within the HPA axis involve the hypothalamus, pituitary, and adrenal glands. ...
... First, the hypothalamus releases corticotropin releasing hormone (CRH) that in turn stimulates the pituitary to produce proopiomelanocortin (POMC). POMC, then, converts into adrenocorticotropic hormone (ACTH) that is secreted into the systemic circulation and acts at the adrenal gland to stimulate the synthesis and secretion of glucocorticoids, including cortisol and cortisone (6). A proper increase of the levels of glucocorticoids is important for stress response, however, dysregulation or prolonged HPA axis activation is energetically costly and is associated with numerous physiological and psychological disease states such as chronic fatigue syndrome including CRF (7,8). ...
... We further examined the mRNA expression of CRH and POMC (the precursor of ACTH). They are two other key hormones related to the activation of the HPA axis and are released by the hypothalamus and pituitary, respectively (6). As shown in Figure 4, compared to the control group, CDDP significantly increased POMC mRNA expression in the pituitary, although only slightly increased CRH Expression of MCP-1 and CCR2 in the plasma or brainstem tissue As shown in Figure 5, administration of CDDP alone significantly increased the MCP-1 content in the plasma at week 4 and 12, (p < 0.05). ...
Introduction
Cancer-related fatigue (CRF) is a common symptom induced by chemotherapy. The main objective of the present study was to investigate whether quercetin regulates the hypothalamic-pituitary-adrenal (HPA) axis and chemoattractant protein-1 (MCP-1) signaling, two factors contributing to CRF in mice exposed to cisplatin.
Methods
Male BALB/c mice were randomly assigned to the following five groups for 15 weeks: Control, CDDP, CDDP+TAK779 (an antagonist of MCP-1 receptor, human CC chemokine receptor R2 (CCR2)), CDDP+OQ (a diet containing 1% quercetin) and CDDP+IQ (quercetin given by ip, 10 mg/kg, 3 times/week).
Results
The results first showed that OQ and IQ significantly increased grip strength and locomotor activity, decreased plasma cortisol/corticosterone levels, and decreased the corticotropin releasing hormone (CRH) mRNA level in the brain tissues in mice exposed to CDDP. OQ and IQ also decreased CDDP-induced plasma levels of MCP-1 as well as the mRNA expression of MCP-1 and CCR2 in the brain stem. TAK779 significantly increased grip strength and tended to decrease the cortisol/corticosterone levels in CDDP-exposed mice, indicating the association between the HPA axis and MCP-1 signaling.
Conclusion
Taken together, the study suggests that quercetin could attenuate CDDP-induced CRF through the mechanisms associated with downregulation of the HPA axis and MCP-1 signaling in mice.
... Furthermore, eligible participants for the study will likely be younger than 40 years of age and generalizability of the results will be limited to some extent. However, our target sample represents a young and healthy population from which we would expect minor risk of morbidity being associated with dysregulations of biological stress systems including, for example, major depression [37], chronic fatigue [65], hypertension [66], or the metabolic syndrome [67]. Future studies should investigate whether the findings derived from this study generalize to more diverse populations, including individuals from other groups of age (e.g., above 40 years), or to individuals with existing health conditions related to stress system dysregulation. ...
Background
Changes in response patterns of biological stress systems, including responses of the sympathetic nervous system (SNS) and the hypothalamus–pituitary–adrenal (HPA) axis to repeated stress, can promote the development and progression of chronic diseases via changes in downstream inflammatory processes. The aim of this project is thus to investigate, whether habituation of biological stress system activity including responses of the inflammatory system can be modified. Aiming to test for possible paths of action, a randomized controlled study with two intervention programs designed to manipulate cognitive coping strategies will be carried out. By increasing either ruminative or self-compassionate thoughts among healthy young adults, the intervention programs are expected to affect the regulation of occurring emotions as expressed by the responsiveness of biological systems during repeated stress exposure.
Methods
In this study, a total of 120 healthy adults will complete the Trier Social Stress Test (TSST) on two consecutive days. Immediately after the first stress induction, participants will be randomly assigned to two experimental conditions designed to manipulate cognitive coping strategies (rumination vs. self-compassion) or a control condition. Measures of HPA axis (salivary cortisol) and autonomic activity (salivary alpha amylase, heart rate, heart rate variability) as well as inflammatory markers (plasma interleukin(IL)-6, expression rates of pro- and anti-inflammatory cytokine genes) will be repeatedly assessed throughout the experimental sessions. Response and habituation indices of these measures will be calculated and compared between the experimental conditions and the control condition.
Discussion
The results should provide insight into whether modifying response patterns of biological stress systems could reverse a significant biological mechanism in the development of stress-related diseases.
Trial registration
German Clinical Trials Register (DKRS), DRKS00034790. Registered on August 12, 2024, https://www.drks.de/DRKS00034790.
... Cortisol is produced and regulated by a major hormonal control center, the hypothalamicepituitaryeadrenal (HPA) axis, regulated by the sympathetic nervous system (Guilliams and Edwards, 2010). Adrenocorticotropic hormone then stimulates the adrenal cortex, the last region of the HPA, triggering the release of cortisol (in humans) and corticosterone (in humans, rats, and mice) (Tomas et al., 2013). Cortisol interacts with the cytoplasmic glucocorticoid receptor. ...
As a powerful natural antioxidant, ginseng effectively modulates apoptosis by reducing the excessive inflammatory response in acute or chronic inflammation. When this homeostasis is disturbed, it can damage the immune system and lead to several fatal diseases. Ginseng has excellent anti stress effects, as compared to appropriate controls. Prolonged cortisol secretion results in immunosuppression. Cortisol is produced and regulated by a major hormonal control center, the hypothalamicepituitaryeadrenal (HPA) axis, regulated by the sympathetic nervous system. Adrenocorticotropic hormone then stimulates the adrenal cortex, the last region of the HPA, triggering the release of cortisol (in humans) and corticosterone (in humans, rats, and mice). Cortisol interacts with the cytoplasmic glucocorticoid receptor. This hormone-receptor complex moves to the nucleus and regulates the expression of several genes. Ginseng has the potential to improve anxiety. Chronic stress can trigger such diseases because of abnormal immune responses and hormonal disorders. However, regular ingestion of ginseng has both preventive and therapeutic effects on several human diseases, including heart disease, stroke, diabetes mmellitus (DM), rheumatoid arthritis (RA), osteoporosis, erectile dysfunction (ED), and allergic asthma. When a person faces a stressful environment, ginseng can improve their response by regulating the function of the HPA axis. Ginseng also has applications beyond everyday use in healthy people. It provides a potential treatment agent for patients with HPA axis disorders associated with hypersecretion of cortisol, including depression, asthma, hypertension, and posttraumatic stress disorder. Ginseng is an effective antioxidant, and also improves vasomotor function and prevents blood clots. These effects positively improve cardiovascular health. Ginseng alleviates such stress and could thus help to prevent CVD. By regulating brain cell necrosis and the production of pro inflammatory factors; it contributes to the prevention of deadly brain inflammation. Ginseng has been used for the treatment or prevention of diseases for thousands of years in eastern countries, and over the last three decades, it has gained popularity in the Americas, Canada, and Europe. Ginseng occupies a prominent position on the list of best-selling natural products in the world (FM, 2009). It is included in the pharmacopoeias of China, Japan, Germany, France, Austria, and the United Kingdom. Asian ginseng (Panax ginseng Meyer) and American ginseng (Panax quinquefolius L.) are the two most recognized ginseng botanicals in the world. These ginsenosides, which are extracted from the ginseng roots, leaves, stems, and fruit, have multiple pharmacological effects. They are subdivided into about 100 different categories. Ginsenosides have effective treatment for organ damage and cell death, as well as for immunological and metabolic diseases. In addition, these pharmacologically active constituents have been shown to support neurogenesis, synaptogenesis, neuronal growth, and neurotransmission, thus helping to protect the central nervous system from unexpected events; ginseng is also reported to be excellent for improving memory.
... Recognizing this association is crucial, as prompt identification of this comorbidity may lead to improved outcomes. One hypothesis suggests that the chronic inflammation associated with UC may impact the hypothalamic-pituitary-adrenal (HPA) axis, which plays a critical role in regulating stress and appetite (8,9). This dysregulation could potentially lead to the development of eating disorders in UC patients. ...
Background
Evidence for anorexia and bulimia in relation to the risk of ulcerative colitis (UC) is limited and inconsistent. The objective of this research was to utilize bi-directional, two-sample Mendelian randomization (MR) analysis to predict the causal association between anorexia nervosa and bulimia nervosa with UC.
Methods
The genome-wide association studies (GWAS) provided data for anorexia and bulimia from the UK Biobank, utilizing single-nucleotide polymorphisms (SNP) as instrumental variables. Additionally, genetic associations with UC were collected from various sources including the FinnGen Biobank, the UK Biobank and the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The main analytical approach utilized in this study was the inverse-variance-weighted (IVW) method. To evaluate horizontal pleiotropy, the researchers conducted MR-Egger regression and MR-PRESSO global test analyses. Additionally, heterogeneity was assessed using the Cochran’s Q test.
Results
This study found a negative association between genetically predicted bulimia (OR = 0.943, 95% CI: 0.893–0.996; p = 0.034) and the risk of UC in the IIBDGC dataset, indicating that individuals with bulimia have approximately a 5.7% lower risk of developing UC. No association was observed in the other two datasets. Conversely, genetically predicted anorexia was not found to be causally associated with UC. In bi-directional Mendelian randomization, UC from the IIBDGC dataset was negatively associated with the risk of anorexia (OR = 0.877, 95% CI: 0.797–0.965; p = 0.007), suggesting that UC patients have approximately a 12.3% lower risk of developing anorexia, but not causally associated with bulimia.
Conclusion
Genetically predicted bulimia may have a negative association with the onset of UC, while genetically predicted anorexia does not show a causal relationship with the development of UC. Conversely, genetically predicted UC may have a negative association with the development of anorexia.
... Its post-treatment rise, in tandem with the observed reduction in fatigue symptoms, raises an intriguing hypothesis. This pattern could suggest a potential recalibration of the HPA axis, which is frequently dysregulated in chronic fatigue conditions (Tomas et al., 2013). However, the correlation between cortisol levels and fatigue scores was not statistically significant, necessitating cautious interpretation of these initial results. ...
Background
Persistent post-infectious symptoms, predominantly fatigue, characterize Long COVID. This study investigated the efficacy of Myelophil (MYP), which contains metabolites extracted from Astragalus membranaceus and Salvia miltiorrhiza using 30% ethanol, in alleviating fatigue among subjects with Long COVID.
Methods
In this prospective observational study, we enrolled subjects with significant fatigue related to Long COVID, using criteria of scores of 60 or higher on the modified Korean Chalder Fatigue scale (mKCFQ11), or five or higher on the Visual Analog Scale (VAS) for brain fog. Utilizing a single-arm design, participants were orally administered MYP (2,000 mg daily) for 4 weeks. Changes in fatigue severity were assessed using mKCFQ11, Multidimensional Fatigue Inventory (MFI-20), and VAS for fatigue and brain fog. In addition, changes in quality of life using the short form 12 (SF-12) were also assessed along with plasma cortisol levels.
Results
A total of 50 participants (18 males, 32 females) were enrolled; 49 were included in the intention-to-treat analysis with scores of 66.9 ± 11.7 on mKCFQ11 and 6.3 ± 1.5 on the brain fog VAS. After 4 weeks of MYP administration, there were statistically significant improvements in fatigue levels: mKCFQ11 was measured at 34.8 ± 17.1 and brain fog VAS at 3.0 ± 1.9. Additionally, MFI-20 decreased from 64.8 ± 9.8 to 49.3 ± 10.8, fatigue VAS dropped from 7.4 ± 1.0 to 3.4 ± 1.7, SF-12 scores rose from 53.3 ± 14.9 to 78.6 ± 14.3, and plasma cortisol levels also elevated from 138.8 ± 50.1 to 176.9 ± 62.0 /mL. No safety concerns emerged during the trial.
Conclusion
Current findings underline MYP’s potential in managing Long COVID-induced fatigue. However, comprehensive studies remain imperative.
Clinical Trial Registration
https://cris.nih.go.kr, identifier KCT0008948.
... Since stress has been described as a potential trigger for ME/ CFS (422) and cause of symptom flare-ups (423, 424), it is likely that the HPA axis-the neurobiological stress system-may be implicated in ME/CFS (53, 425,426), as well as abnormalities in growth hormone (GH) secretion and dysfunctional adrenergic metabolism (255). Immune and inflammatory responses in the blood are mediated by the HPA axis to prevent any autoimmune alterations (63). ...
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.
... Their symptoms can have an adverse impact on daily functioning, school or work participation, and mental well-being (1-6), cumulating developmental challenges for young adulthood and beyond. The aetiology and pathophysiology of ME/CFS is largely unknown even though several theories have been developed (5,(7)(8)(9)(10)(11)(12)(13). Some immunological studies suggest that ME/CFS symptoms could be related to changes in the hypothalamic-pituitary-adrenal (HPA) axis, which controls the release of the stress hormone cortisol (5,11,12,14,15). ...
... The aetiology and pathophysiology of ME/CFS is largely unknown even though several theories have been developed (5,(7)(8)(9)(10)(11)(12)(13). Some immunological studies suggest that ME/CFS symptoms could be related to changes in the hypothalamic-pituitary-adrenal (HPA) axis, which controls the release of the stress hormone cortisol (5,11,12,14,15). ...
... Hypofunction of the HPA-axis has frequently been observed in patients with ME/CFS through low cortisol concentrations in blood, urine, and particularly the salivary cortisol awakening response (CAR) when compared to controls (11,14,(16)(17)(18). Research has linked more pronounced hypofunction to increased symptom severity (11,17,19), identified moderating factors that lower cortisol concentration (i.e., female sex, early-life stressors, low activity levels, sleep disturbances, depression) (17), and studied the use of hydrocortisone as pharmacological treatment of ME/CFS (20). ...
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 (Mdif=.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.
... Therefore, some researchers have proposed that the changes in the HPA axis in CFS patients may be an incidental phenomenon that occurs later in the disease course rather than having special etiological significance (34). However, considering that HPA axis dysfunction may play an etiological and pathological role in CFS, it is still necessary to investigate the association of the HPA axis with typical symptoms of CFS (35). ...
... Although it is still not clear whether HPA axis dysfunction is the cause or an incidental phenomenon of CFS, the HPA axis is clearly a potentially important target for studying treatment strategies (35). Table 1 lists the 7 RCTs of TCM treatment methods that reported changes in HPA axis indicators (60)(61)(62)(63)(64)(65)(66). ...
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.
... The exact etiology of CFS remains unclear. However, diverse theories have been proposed, including sequelae of infectious diseases, dysregulation of the immune-inflammatory system, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction [3,6]. ...
Background
Previous serological studies have indicated an association between viruses and atypical pathogens and Chronic Fatigue Syndrome (CFS). This study aims to investigate the correlation between infections from common pathogens, including typical bacteria, and the subsequent risk of developing CFS. The analysis is based on data from Taiwan’s National Health Insurance Research Database.
Methods
From 2000 to 2017, we included a total of 395,811 cases aged 20 years or older newly diagnosed with infection. The cases were matched 1:1 with controls using a propensity score and were followed up until diagnoses of CFS were made.
Results
The Cox proportional hazards regression analysis was used to estimate the relationship between infection and the subsequent risk of CFS. The incidence density rates among non-infection and infection population were 3.67 and 5.40 per 1000 person‐years, respectively (adjusted hazard ratio [HR] = 1.5, with a 95% confidence interval [CI] 1.47–1.54). Patients infected with Varicella-zoster virus, Mycobacterium tuberculosis, Escherichia coli, Candida, Salmonella, Staphylococcus aureus and influenza virus had a significantly higher risk of CFS than those without these pathogens (p < 0.05). Patients taking doxycycline, azithromycin, moxifloxacin, levofloxacin, or ciprofloxacin had a significantly lower risk of CFS than patients in the corresponding control group (p < 0.05).
Conclusion
Our population-based retrospective cohort study found that infection with common pathogens, including bacteria, viruses, is associated with an increased risk of developing CFS.
