Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome

 Abstract:

Chronic fatigue syndrome (CFS) is a controversial entity whose cause is unknown. In this study we have explored the possibility that progesterone metabolites may be involved. Plasma levels of the progesterone precursor pregnenolone, progesterone itself, and five ring A-reduced metabolites of progesterone were measured in 20 women with CFS and in 13 age-matched controls.

To minimize the contribution of the ovary, women were either post-menopausal or in the follicular phase of the menstrual cycle (day 4-8), and progesterone levels were all well within the expected range (< or = 3.5 nmol/l). Mean values for progesterone and all of its metabolites were higher in CFS patients, the most marked being a 2.3-fold elevation in isopregnanolone (3beta,5alpha-tetrahydroprogesterone; p < or = 0.001). Progesterone levels were correlated with those of its metabolites, but even after controlling for progesterone by ANCOVA, isopregnanolone levels were still elevated (p < or = 0.001). These elevated levels of isopregnanolone could not be attributed to medications (antidepressants and anxiolytics).

When the CFS patients were divided into two groups according to their Hamilton depression scale ratings, mean (+/-SD) isopregnanolone levels were higher (274+/-160 vs 197+/-119 pmol/l) in the less depressed group (ratings 2-14) than in the more depressed group (ratings 17-28), although this difference did not reach significance. Progesterone levels were negatively correlated with Hamilton depression rating scores (r=-0.56; p<0.01). These results suggest that increases in ring A-reduced progesterone metabolites, particularly isopregnanolone, are associated with CFS, and that the pathophysiology of CFS is unlikely to be due to depression.

 

Source: Murphy BE, Abbott FV, Allison CM, Watts C, Ghadirian AM. Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome. Psychoneuroendocrinology. 2004 Feb;29(2):245-68. http://www.ncbi.nlm.nih.gov/pubmed/14604604

 

Association between serotonin transporter gene polymorphism and chronic fatigue syndrome

Abstract:

Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome(CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT, in 78 CFS patients using PCR amplification of the blood genomic DNA.

A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls both by the genotype-wise and the allele-wise analyses (both p<0.05, by chi(2) test and Fisher’s exact test). Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS.

 

Source: Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochekm Biophys Res Commun. 2003 Nov 14;311(2):264-6. http://www.ncbi.nlm.nih.gov/pubmed/14592408

 

An investigation into the psychometric properties of the Hospital Anxiety and Depression Scale in individuals with chronic fatigue syndrome

Abstract:

The study sought to determine the psychometric properties of the Hospital Anxiety and Depression Scale (HADS) in individuals with chronic fatigue syndrome (CFS) assessed using a web-based data collection tool. Exploratory and confirmatory factor analyses were conducted on the HADS to determine its psychometric properties in 117 individuals with CFS. Seven models were tested to determine model fit to the data.

Internal reliability estimations of the anxiety and depression sub-scales were found to be acceptable, however, a three-factor model was found to provide a significantly better fit to the data when compared to the bi-dimensional two-factor structure previously assumed to underpin the HADS’ construct validity.

The clinical utility of the HADS in the assessment of anxiety and depression in CFS appears to be fundamentally compromised by the presence of a three-dimensional underlying factor structure. Future revision of the HADS is recommended if the instrument is to be used reliably to screen CFS patients.

 

Source: McCue P, Martin C, Buchanan T, Rodgers J, Scholey A. An investigation into the psychometric properties of the Hospital Anxiety and Depression Scale in individuals with chronic fatigue syndrome. Psychol Health Med. 2003 Nov;8(4):425-39. doi: 10.1080/1354850310001604568. http://www.ncbi.nlm.nih.gov/pubmed/21974733

 

Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study

Abstract:

BACKGROUND: The role of stress in the onset of chronic fatigue syndrome is unclear. Our objectives in this study were first, to determine the relation between the onset of chronic fatigue syndrome and stressful life events and difficulties. Secondly, we examined the role of a particular type of problem, dilemmas, in the onset of chronic fatigue syndrome.

METHOD: We used a case-control design with 64 consecutive referrals from an Infectious Diseases/ Liaison Psychiatry Fatigue clinic and 64 age- and sex-matched controls from a general practice population control group in Leeds. We had two main outcome measures; the odds ratios of the risk of developing chronic fatigue syndrome after experiencing a severe life event, severe difficulties or both in the year and 3 months preceding onset; and the proportion of subjects in each group who experienced a dilemma prior to onset.

RESULTS: Patients with chronic fatigue syndrome were more likely to experience severe events and difficulties in the 3 months (OR = 9, 95% CI 3.2 to 25.1) and year (OR = 4.3, 95% CI 1.8 to 10.2) prior to onset of their illness than population controls. In the 3 months prior to onset 19 of the 64 patients (30%) experienced a dilemma compared to none of the controls.

CONCLUSIONS: Chronic fatigue syndrome is associated with stressful events and difficulties prior to onset. Those events and difficulties characterized as being dilemmas seem to be particularly important.

 

Source: Hatcher S, House A. Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study. Psychol Med. 2003 Oct;33(7):1185-92. http://www.ncbi.nlm.nih.gov/pubmed/14580073

 

Muscle metabolism with blood flow restriction in chronic fatigue syndrome

Abstract:

The purpose of this study was to determine whether chronic fatigue syndrome (CFS) is associated with reduced blood flow and muscle oxidative metabolism. Patients with CFS according to Centers for Disease Control criteria (n = 19) were compared with normal sedentary subjects (n = 11).

Muscle blood flow was measured in the femoral artery with Doppler ultrasound after exercise. Muscle metabolism was measured in the medial gastrocnemius muscle with (31)P-magnetic resonance spectroscopy. Muscle oxygen saturation and blood volume were measured using near-infrared spectroscopy. CFS and controls were not different in hyperemic blood flow or phosphocreatine recovery rate. Cuff pressures of 50, 60, 70, 80, and 90 mmHg were used to partially restrict blood flow during recovery. All pressures reduced blood flow and oxidative metabolism, with 90 mmHg reducing blood flow by 46% and oxidative metabolism by 30.7% in CFS patients.

Hyperemic blood flow during partial cuff occlusion was significantly reduced in CFS patients (P < 0.01), and recovery of oxygen saturation was slower (P < 0.05). No differences were seen in the amount of reduction in metabolism with partially reduced blood flow.

In conclusion, CFS patients showed evidence of reduced hyperemic flow and reduced oxygen delivery but no evidence that this impaired muscle metabolism. Thus CFS patients might have altered control of blood flow, but this is unlikely to influence muscle metabolism. Furthermore, abnormalities in muscle metabolism do not appear to be responsible for the CFS symptoms.

 

Source: McCully KK, Smith S, Rajaei S, Leigh JS Jr, Natelson BH. Muscle metabolism with blood flow restriction in chronic fatigue syndrome. J Appl Physiol (1985). 2004 Mar;96(3):871-8. Epub 2003 Oct 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680353/ (Full article)

 

Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population

Abstract:

BACKGROUND: Scant research has adequately addressed the impact of chronic fatigue syndrome on patients’ daily activities and quality of life. Enumerating specific problems related to quality of life in chronic fatigue syndrome patients can help us to better understand and manage this illness. This study addresses issues of functional status in persons with chronic fatigue syndrome and other fatiguing illnesses in a population based sample, which can be generalized to all persons with chronic fatigue.

METHODS: We conducted a random telephone survey in Wichita, Kansas to identify persons with chronic fatigue syndrome and other fatiguing illnesses. Respondents reporting severe fatigue of at least 1 month’s duration and randomly selected non-fatigued respondents were asked to participate in a detailed telephone interview. Participants were asked about symptoms, medical and psychiatric illnesses, and about physical, social, and recreational functioning. Those meeting the 1994 chronic fatigue syndrome case definition, as determined on the basis of their telephone responses, were invited for clinical evaluation to confirm a diagnosis of chronic fatigue syndrome. For this analysis, we evaluated unemployment due to fatigue, number of hours per week spent on work, chores, and other activities (currently and prior to the onset of fatigue), and energy level.

RESULTS: There was no difference between persons with chronic fatigue syndrome and persons with a chronic fatigue syndrome-like illness that could be explained by a medical or psychiatric condition for any of the outcomes we measured except for unemployment due to fatigue (15% vs. 40%, P <.01). Persons with chronic fatigue syndrome and other fatiguing illnesses had substantially less energy and spent less time on hobbies, schooling, or volunteer work than did non-fatigued controls (P <.01).

CONCLUSIONS: Persons with chronic fatigue syndrome are as impaired as persons whose fatigue could be explained by a medical or psychiatric condition, and they have less energy than non-fatigued controls.

Comment in: Chronic fatigue and chronic fatigue syndrome in the general population. [Health Qual Life Outcomes. 2003]

 

Source: Solomon L, Nisenbaum R, Reyes M, Papanicolaou DA, Reeves WC. Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population. Health Qual Life Outcomes. 2003 Oct 3;1:48. http://www.ncbi.nlm.nih.gov/pubmed/14577835

 

Patient activism and the struggle for diagnosis: Gulf War illnesses and other medically unexplained physical symptoms in the US

Abstract:

We examine Gulf War illnesses–which include the fatigue, joint pain, dermatitis, headaches, memory loss, blurred vision, diarrhea, and other symptoms reported by Gulf War veterans–in relation to other medically unexplained physical symptoms such as multiple chemical sensitivity,chronic fatigue syndrome, and fibromyalgia. Our intent is to examine the diagnosis negotiations involved in these mysterious diseases, by showing the different forms of legitimacy involved in such interactions.

Factors involved in diagnostic legitimacy are: diagnostic legitimacy in the medical community, lay acceptance of the diagnosis, uncertainty in looking for causes, and social mobilization. We conclude by noting that research may not be able to find any cause for these diseases/conditions; hence, it may be necessary to embrace medical uncertainty, and also to accept patient experience in order to facilitate diagnosis, treatment, and recovery process.

Such a change can alter patients’ expectations and taken-for-granted assumptions about medicine, and perhaps in turn reduce the frequency with which dissatisfied individuals form illness groups that mobilize to challenge what they see as an unresponsive medical system.

 

Source: Zavestoski S, Brown P, McCormick S, Mayer B, D’Ottavi M, Lucove JC. Patient activism and the struggle for diagnosis: Gulf War illnesses and other medically unexplained physical symptoms in the US. Soc Sci Med. 2004 Jan;58(1):161-75. http://www.ncbi.nlm.nih.gov/pubmed/14572929

 

Enterovirus related metabolic myopathy: a postviral fatigue syndrome

Abstract:

OBJECTIVE: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients.

METHODS: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points.

RESULTS: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus.

CONCLUSIONS: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.

Comment in: Enteroviruses in chronic fatigue syndrome: “now you see them, now you don’t”. [J Neurol Neurosurg Psychiatry. 2003]

 

Source: Lane RJ, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1382-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1757378/ (Full article)

 

Enteroviruses in chronic fatigue syndrome: “now you see them, now you don’t”

Comment on: Enterovirus related metabolic myopathy: a postviral fatigue syndrome. [J Neurol Neurosurg Psychiatry. 2003]

 

In the paper by Lane et al(see pp 1382– 1386)1 an association was found between abnormal exercise lactate response and enterovirus sequences in the muscle of some patients with chronic fatigue syndrome (CFS). The paper rekindles the old saga of enteroviruses, muscle inflammation, and fatigue.

You can read the rest of this comment here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1757390/pdf/v074p01361.pdf

 

Source: Dalakas MC. Enteroviruses in chronic fatigue syndrome: “now you see them, now you don’t”. J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1361-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1757390/  (Full article)

 

Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports

Abstract:

Chronic fatigue syndrome (CFS) is characterized by persistent mental and physical fatigue for at least 6 months. Its pathophysiology is unknown and there is no proven effective treatment. We describe three cases who fulfill the criteria of CFS, in whom a defect of neuromuscular transmission and dysautonomia are present and who respond to acetylcholine-esterase inhibition.

Case 1: 18-year-old female with a 3-year history of CFS. Response of compound-muscle-action potential, recorded using surface recording electrode, over left abductor pollicis brevis muscle, to repetitive nerve stimulation (RNS) at a rate of 10 Hz showed a 42% incremental response. Composite autonomic scoring system (CASS) showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2). Serological tests for Epstein-Barr virus (EBV) revealed positive antiviral capsid antigens (anti-VCA) immunoglobulins G (IgG). Oral pyridostigmine therapy (30 mg) resulted in marked improvement in symptoms.

Case 2: 28-year-old female with 10-year history of CFS. RNS, using identical protocol, showed a 60% incremental response over the same muscle. CASS showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2) and this patient was also positive for EBV. This patient responded dramatically to 10-mg pyridostigmine.

Case 3: 29-year-old female with a history of CFS for longer than 15 years. Repetitive stimulation, using identical paradigm to left abductor pollicis brevis muscle, showed a 42% incremental response. CASS showed mildly cholinergic impairment (cardiovagal score: 2; sudomotor score: 1). EBV antibody titers were positive. Patient responded to 30-mg pyridostigmine with an improvement in her fatigue.

These three cases generate the hypothesis that the fatigue in some patients with clinical CFS might be due to a combination of mild neuromuscular transmission defect combined with cholinergic dysautonomia. Support for this thesis derives from the improvement with cholinesterase inhibition.

 

Source: Kawamura Y, Kihara M, Nishimoto K, Taki M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology. 2003 May;9(3):189-194. http://www.ncbi.nlm.nih.gov/pubmed/14567934