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A J Cleare

Publications and source records attributed to A J Cleare.

At least 19 recordsLinked to original sources
PubMed2005

Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome.

BACKGROUND: The aim of the present study was to obtain a naturalistic measure of diurnal hypothalamic-pituitary-adrenal (HPA) axis output in CFS patients unaffected by medication or comorbid psychiatric disorder likely to influence the axis. METHOD: Cortisol and cortisone levels were measured in saliva samples collected from 0600 h to 2100 h at 3-h intervals in CFS patients and healthy controls. RESULTS: Mean cortisol and cortisone concentrations were significantly lower in patients than controls across the whole day, as were levels at each individual time point except 2100 h. Cosinor analysis showed a significant diurnal rhythm of cortisol and cortisone that was not phase-shifted in CFS compared to controls. However, there was a lower rhythm-adjusted mean and a lower amplitude in CFS patients. The cortisol/cortisone ratio showed no diurnal rhythm and did not differ between CFS subjects and controls. LIMITATIONS: The sample size was relatively small, and drawn from specialist referral patients who had been ill for some time; generalisation of these results to other populations is therefore unwarranted. CONCLUSION: The main findings of this study are to provide further evidence for reduced basal HPA axis function in at least some patients with CFS and to show for the first time that salivary cortisone is also reduced in CFS and has a diurnal rhythm similar to that of cortisol. We have also demonstrated that the cortisol/cortisone ratio remains unchanged in CFS, suggesting that increased conversion of cortisol to cortisone cannot account for the observed lowering of salivary cortisol.

Adult↗
PubMed2005

Association of chronic fatigue syndrome with human leucocyte antigen class II alleles.

BACKGROUND: A genetic component to the development of chronic fatigue syndrome (CFS) has been proposed, and a possible association between human leucocyte antigen (HLA) class II antigens and chronic fatigue immune dysfunction has been shown in some, but not all, studies. AIMS: To investigate the role of HLA class II antigens in CFS. METHODS: Forty nine patients with CFS were genotyped for the HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the frequency of these alleles was compared with a control group comprising 102 normal individuals from the UK. All patients and controls were from the same region of England and, apart from two patients, were white. RESULTS: Analysis by 2 x 2 contingency tables revealed an increased frequency of HLA-DQA1*01 alleles in patients with CFS (51.0% v 35%; odds ratio (OR), 1.93; p = 0.008). HLA-DQB1*06 was also increased in the patients with CFS (30.2% v 20.0%; OR, 1.73, p = 0.052). Only the association between HLA-DQA1*01 and CFS was significant in logistic regression models containing HLA-DQA1*01 and HLA-DRQB1*06, and this was independent of HLA-DRB1 alleles. There was a decreased expression of HLA-DRB1*11 in CFS, although this association disappeared after correction for multiple comparisons. CONCLUSIONS: CFS may be associated with HLA-DQA1*01, although a role for other genes in linkage disequilibrium cannot be ruled out.

Adult↗
PubMed2004

Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome.

BACKGROUND: An association between chronic fatigue syndrome (CFS) and abnormalities of the hypothalamo-pituitary-adrenal axis has been described, and other adrenal steroid abnormalities have been suggested. Dehydroepiandrostenedione (DHEA) and its sulphate (DHEA-S), apart from being a precursor of sex steroids, have other functions associated with memory, depression and sleep. It has been suggested that CFS may be associated with a state of relative DHEA(-S) deficiency. Therefore we investigated basal levels of DHEA(-S), the cortisol/DHEA molar ratio and the responsiveness of DHEA to stimulation by corticotrophin-releasing hormone (CRH). Recent studies have also suggested that low dose hydrocortisone may be effective at reducing fatigue in CFS. We therefore also assessed these parameters prior to and following treatment with low dose oral hydrocortisone. METHODS: Basal levels of serum DHEA, DHEAS and cortisol were measured in 16 patients with CFS without depression and in 16 controls matched for age, gender, weight, body mass index and menstrual history. CRH tests (1 g/kg i.v.) were carried out on all subjects and DHEA measured at 0, +30 and +90 min. In the patient group, CRH tests were repeated on two further occasions following treatment with hydrocortisone (5 or 10 mg, p.o.) or placebo for 1 month each in a double-blind cross over study protocol. RESULTS: Basal levels of DHEA were higher in the patient, compared to the control, group (14.1+/-2.2 vs. 9.0+/-0.90 ng/ml, P=0.04), while levels of DHEAS in patients (288.7+/-35.4 microg/dl) were not different from controls (293.7+/-53.8, P=NS). Higher DHEA levels were correlated with higher disability scores. Basal cortisol levels were higher in patients, and consequently the cortisol/DHEA molar ratio did not differ between patients and controls. Levels of DHEA (8.9+/-0.97 ng/ml, P=0.015) and DHEAS (233.4+/-41.6 microg/dl, P=0.03) were lower in patients following treatment with hydrocortisone. There was a rise in DHEA responsiveness to CRH in the patients after treatment but this did not attain significance (AUCc: 2.5+/-1.7 ng/ml h pre-treatment vs. 6.4+/-1.2 ng/ml h post-hydrocortisone, P=0.053). However, those patients who responded fully to hydrocortisone in terms of reduced fatigue scores did show a significantly increased DHEA responsiveness to CRH (AUCc: -1.4+/-2.5 ng/ml h at baseline, 5.0+/-1.2 ng/ml h after active treatment, P=0.029). CONCLUSIONS: DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.

Adult↗
PubMed2003

Predictors of fatigue following the onset of infectious mononucleosis.

BACKGROUND: Infectious mononucleosis (IM) is a risk factor for chronic fatigue. Reduced activity is the most consistent factor found to be associated with poor outcome following the onset of infectious mononucleosis. However, little is known about the biological mechanisms involved in the pathogenesis of chronic fatigue following IM and no study, so far, has examined the relation between certain illness beliefs and poor outcome. This study explored immunological, endocrine, behavioural and cognitive responses to the acute illness and assessed which components of these groups of risk factors predicted a chronic course. METHOD: Using a prospective cohort design, 71 primary care patients with IM were enrolled onto the study and interviewed. Their recovery was explored by postal questionnaire up to 1 year later. RESULTS: In the univariate analysis, increased baseline levels of immune activation were associated with fatigue at baseline and 3 months. Cortisol levels were not associated with fatigue at any point. Using multivariate models of clinical and psychosocial baseline factors, severity of symptoms and illness perceptions were found to predict fatigue 3 months later. At 6 months, fatigue was best predicted by female gender and illness perceptions, and at 12 months by female gender and a symptoms-disability factor. CONCLUSIONS: In the multivariate analysis no factors were found to predict poor outcome at all time-points. Instead the pattern of predictors changed over time, partly but not completely consistent with our a priori predictions. Larger studies are needed to explore further the predictive nature of biopsychosocial factors in the pathogenesis of chronic fatigue related to IM. The psycho-behavioural predictors found in this study are amenable to intervention. Such interventions should be tested in randomized controlled trials.

Adult↗
PubMed2002

Antinuclear autoantibodies (ANA) in Gulf War-related illness and chronic fatigue syndrome (CFS) patients.

It is established that veterans of the 1991 Gulf War have an increased frequency of experiencing multiple symptoms. The underlying mechanism of these ailments is unclear, although they do not correspond to any clearly defined syndrome. The most common symptoms overlap with those of chronic fatigue syndrome (CFS). CFS was recently associated with a novel subtype of antinuclear autoantibody (ANA) that reacts with nuclear envelope (NE) antigens. NE autoantibodies are not known to be linked with any distinct clinical condition, but have been observed in patients with unusual mixed chronic autoimmune disorders and connective tissue diseases. In this study we examined whether NE ANAs are a feature of patients with CFS and symptomatic Gulf War veterans (sGWV). We studied the prevalence of ANA in 130 sGWV, 90 well Gulf War veterans (wGWV), 128 symptomatic Bosnia and Era veterans (sBEV), 100 CFS patients, and 111 healthy control subjects matching for age and sex. We found no significant difference in the prevalence of ANAs between any of the groups. None of the patients/or veterans we studied had ANA of the NE type. Our results show that multisymptom illness due to CFS or related to Gulf War service is not associated with antinuclear autoimmunity.

Adult↗
PubMed2001

Basal activity of the hypothalamic-pituitary-adrenal axis in patients with depersonalization disorder.

Depersonalisation disorder may occur during severe anxiety or following a traumatic event, suggesting a possible role of stress hormones. This study investigated basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with depersonalisation disorder. Salivary cortisol levels were measured at four time points over 12 h in patients with depersonalisation disorder (N=13), major depressive disorder (MDD, N=14) and healthy controls (N=13). Beck Depression Inventory scores were significantly higher in depersonalised subjects than controls, while MDD subjects demonstrated higher scores than both groups. Basal cortisol levels of depersonalised subjects were significantly lower than those of MDD subjects but not healthy controls. These results point to reduced basal activity of the HPA axis in depersonalisation disorder. This pilot study supports the distinction between depersonalisation disorder and major depressive disorder which should be examined in a larger sample.

Adult↗
PubMed2001

The neuroendocrinology of chronic fatigue syndrome and fibromyalgia.

BACKGROUND: Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and 5-HT function, make some form of hypothesis (3) most likely. We review the methodology and results of studies of the HPA and other neuroendocrine axes in CFS. METHOD: Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy. A search was also performed on the King's College CFS database, which includes over 3000 relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991). RESULTS: One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function, and enhanced 5-HT function on neuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS. CONCLUSIONS: The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether these changes are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studies of populations at risk for CFS will help to resolve these issues.

Adrenocorticotropic Hormone↗
PubMed2001

Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion.

OBJECTIVE: Previous studies have suggested that chronic fatigue syndrome (CFS) is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS. DESIGN: (i) A comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo-controlled crossover study of the effects of hydrocortisone on leptin levels in CFS. PATIENTS: Thirty-two medication free patients with CFS but not comorbid depression or anxiety. Thirty-two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls. MEASUREMENTS: We measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo-controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo. RESULTS: At baseline, there was no significant difference in plasma leptin between patients [mean 13.8, median 7.4, interquartile range (IQR) 18.0 ng/ml] and controls (mean 10.2, median 5.5, IQR 11.3 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment-responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone-induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS. CONCLUSIONS: We conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.

Adult↗
PubMed2001

Urinary free cortisol in chronic fatigue syndrome.

OBJECTIVE: The authors measured 24-hour urinary free cortisol in a group of well-characterized patients with chronic fatigue syndrome. METHOD: They obtained 24-hour urine collections from 121 consecutive clinic patients with chronic fatigue syndrome and 64 comparison subjects without the syndrome. RESULTS: Urinary free cortisol was significantly lower in the subjects with chronic fatigue syndrome regardless of the presence or absence of current or past comorbid psychiatric illness. Lower levels of urinary free cortisol were not related to medication use, sleep disturbance, or disability levels. CONCLUSIONS: There is mild hypocortisolism in chronic fatigue syndrome. Whether a primary feature or secondary to other factors, hypocortisolism may be one factor contributing to the symptoms of chronic fatigue syndrome.

Adult↗
PubMed2001

Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy.

These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation with hydrocortisone therapy would improve the core symptoms. We measured ACTH and cortisol responses to human CRH, the insulin stress test, and D-fenfluramine in 37 medication-free patients with CDC-defined chronic fatigue syndrome but no comorbid psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n = 37) had a pituitary challenge test (human CRH) and a hypothalamic challenge test [either the insulin stress test (n = 16) or D-fenfluramine (n = 21)]. Baseline cortisol concentrations were significantly raised in the chronic fatigue syndrome group for the human CRH test only. Baseline ACTH concentrations did not differ between groups for any test. ACTH responses to human CRH, the insulin stress test, and D- fenfluramine were similar for patient and control groups. Cortisol responses to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH and D-fenfluramine to be lower in the chronic fatigue syndrome group. These differences were significant when ACTH responses were controlled. Urinary free cortisol levels were lower in the chronic fatigue syndrome group compared with the healthy group. These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal CRH secretion in chronic fatigue syndrome. These data further suggest that the hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output. Thirty-two patients were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled cross-over design, with 28 days on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ. However, a differential effect was seen in those patients who responded to active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.

Adrenocorticotropic Hormone↗
PubMed2000

Ipsapirone challenge in aggressive men shows an inverse correlation between 5-HT1A receptor function and aggression.

Previous studies have suggested that 5-HT(1A) receptor function is linked to aggression. We studied 12 healthy men selected to have high trait levels of aggression. They filled in various self-rating measures of aggression, and underwent a double blind, crossover challenge with ipsapirone (20 mg orally) and a placebo. On both occasions, we measured the endocrine (ACTH, cortisol, growth hormone and prolactin), hypothermic and bodily symptom responses every 30 min for 180 min. We found that subjects with blunted neuroendocrine responses to the ipsapirone challenge had significantly higher self-ratings of aggression on a number of measures. The same relationship held using the bodily symptom response to ipsapirone: blunted responses were associated with higher ratings of aggression. We conclude that impaired 5-HT(1A) receptor function is associated with increased aggressiveness.

Adult↗
PubMed2000

Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome.

GH deficiency states and chronic fatigue syndrome (CFS) share several characteristics, and preliminary studies have revealed aspects of GH dysfunction in CFS. This study assessed indexes of GH function in 37 medication-free CFS patients without comorbid psychiatric illness and 37 matched healthy controls. We also assessed GH function before and after treatment with low dose hydrocortisone, which has been shown recently to reduce fatigue in CFS. We measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH excretion. We also performed 2 dynamic tests of GH function: a 100-microg GHRH test and an insulin stress test using 0.15 U/kg BW insulin. There were no differences between patients and controls in basal levels of IGF/IGFBP or in urinary GH excretion. GH responses to both the GHRH test and the insulin stress test were no different in patients and controls. CFS patients did have a marginally reduced suppression of IGFBP-1 during the insulin stress test. Hydrocortisone treatment had no significant effect on any of these parameters. There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone treatment appears to have little impact on GH function.

Adult↗
PubMed1999

Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.

BACKGROUND: Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment. METHODS: In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat. FINDINGS: None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher's exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo. INTERPRETATION: In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

Adult↗
PubMed1999

Peripheral hormonal responses to D-fenfluramine as a probe of central serotonergic function in humans.

We tested the hypothesis that D-fenfluramine (DFEN)-elicited cortisol (CORT) release in humans may be mediated by a direct effect on the adrenal gland by pretreating subjects with dexamethasone (DEX), to prevent release of ACTH from the pituitary, followed by a DFEN challenge test. Eight healthy subjects (four males; four female) (mean age = 38.1 +/- 8.4 years (SD)] were studied > 1 week apart (same phase of menstrual cycle) and testing order was randomised. On the with-DEX day (DEX+), subjects took 2 mg DEX orally at 10 p.m.; 30 mg DFEN was then given orally at 9 a.m. and samples were taken at 0-5 h for PRL and CORT. Peak hormone responses (delta values) were calculated by subtracting baseline values from the maximum levels post-DFEN administration. Peak and baseline hormonal values were compared between the two test conditions; DFEN-induced CORT and PRL responses were compared across all time points, with and without DEX. There was no significant difference in delta PRL between the two test conditions (DEX- and DEX+), but delta CORT values were significantly reduced after DEX: mean delta CORT DEX- = 68.4 +/- 26.3 nmol/l; DEX+ = 0.0 nmol/l (all blunted) (df 7,1; P = 0.03). The completely blunted peripheral cortisol response indicates that DFEN cortisol responses are of central origin only.

Adrenocorticotropic Hormone↗