24-h Urinary Cortisol Research Articles

Role of endogenous cortisol on Helicobacter pylori colonization

Background and aims Helicobacter pylori infects the gastric mucosa and can lead to chronic gastritis, gastric ulcer and gastric cancer. Colonization of H. pylori in the gastric mucosa is influenced by a variety of host, bacterial and environmental factors. Host defense mechanisms have been affected by endogenous glucocorticoids. We aimed to investigate the relationship between H. pylori and endogenous glucocorticoid. Materials and methods Forty cases with endoscopically and histologically proven H. pylori and 26 patients who did not have H. pylori on gastric biopsy samples were enrolled in our study. Cortisol was tested from 24-h collected urine samples. Results H. pylori (+) and H. pylori (−) groups consisted of 40 (28 women, 12 men; aged 44.85 ± 12.52 years) and 26 (22 women, 4 men; aged 52.27 ± 15.15 years) patients, respectively. Age and gender were similar in both groups. Body mass index, C-reactive protein and erythrocyte sedimentation rate were not statistically different between the two groups ( p > 0.05). 24-h urine cortisol amount was lower in patients with H. pylori (+) than H. pylori (−) cases. Conclusions Present study demonstrates that patients with gastric H. pylori colonization have significantly lower cortisol levels when compared with H. pylori negative cases. There is a negative correlation between H. pylori colonization and urine cortisol output.

Efficacy and safety of fluticasone propionate/salmeterol 250/50 mcg Diskus administered once daily

The twice daily administration of an inhaled corticosteroid (ICS) and long-acting beta(2)-agonist (LABA) has been shown to be effective in achieving asthma control. The once daily administration of an ICS/LABA may be a treatment option for some patients. To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler (FSC) administered once daily compared with FP once daily, FSC twice daily, or placebo. A 12-week, randomized, double-blind multicenter study conducted in 844 patients > or = 12 years of age who were symptomatic while using a short-acting beta(2)-agonist alone. Blinded treatments included: FSC 250/50 mcg once daily in the evening (FSC 250/50 QD), FP 250 mcg once daily in the evening (FP 250 QD), FSC 100/50 mcg twice daily (FSC 100/50 mcg BID), or placebo. All treatments were delivered via the Diskus device. All treatments demonstrated greater improvements in efficacy measures compared with placebo. Overall, the greatest improvements were observed in the patients receiving FSC, either once or twice daily, compared with the FP 250 QD group. The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24h compared with twice daily dosing. All treatments were well tolerated. No suppression of HPA axis, as assessed by 24-h urinary cortisol excretion, was observed in any of the active treatment groups. In patients symptomatic on a short-acting beta(2)-agonist alone, FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength (FSC 250/50 mcg) administered once daily. However, a once daily regimen was effective and may be a valuable treatment option for some patients. Registered at (http://ctr.gsk.co.uk/welcome.asp) (SAS30022).

Quantitative Ultrasound Technology in Evaluating Bone Status and Osteoporosis in Patients with Cushing's Syndrome

Osteoporosis is a major feature of Cushing's syndrome (CS), and fragility fractures may be the first sign of the disease. The aim of this study was to evaluate the ability of quantitative ultrasound technology (QUS) in diagnosing osteoporosis in patients with CS. Sixty-three consecutive patients (mean age 38.6 +/- 13.0 years), 13 (20.6%) men and 50 (79.4%) women, with confirmed CS underwent both dual-energy X-ray densitometry (DXA) and QUS. Two groups of patients were selected: group A, 23 patients, T-score -2 SD or less (bone mineral density [BMD] femoral neck < or = 695 g/cm(2)), and group B, 40 patients, T-score above -2 SD. Age (42 +/- 12 vs. 37 +/- 13 years) and 24-h free urinary cortisol (499 +/- 345 vs. 469 +/- 319 microg/day) did not differ significantly (P = NS) between groups, while the body mass index did (24.3 +/- 4.1 vs. 28.1 +/- 4.6, P = 0.002). Unlike DXA, QUS values did not differ significantly (P = NS) between groups. Moreover, in the overall population, as well as in a single group, there was no correlation (R < 0.5, P = NS) between QUS and DXA parameters. In conclusion, in our study QUS was not able to differentiate osteoporotic patients from those with normal BMD measured by DXA, and thus QUS technology should not be used to discriminate between osteopenic and nonosteopenic patients with CS.

Increased diagnostic probability of subclinical cushing’s syndrome in a population sample of overweight adult patients with type 2 diabetes mellitus

Endogenous Cushing's Syndrome (CS) is unusual. Patients with subclinical CS (SCS) present altered cortisol dynamics without obvious manifestations. CS occurs in 2-3% of obese poorly controlled diabetics. We studied 103 overweight adult outpatients with type 2 diabetes to examine for cortisol abnormalities and SCS. All collected salivary cortisol at 23:00 h and salivary and serum cortisol after a 1 mg dexamethasone suppression test (DST). Patients whose results were in the upper quintile for each test (253 ng/dL, 47 ng/dL, and 1.8 microg/dL, respectively for the 23:00 h and post-DST saliva and serum cortisol) were re-investigated. Average values from the upper quintile group were 2.5-fold higher than in the remaining patients. After a confirmatory 2 mg x 2 day DST the investigation for CS was ended for 61 patients with all normal tests and 33 with only one (false) positive test. All 8 patients who had two abnormal tests had subsequent normal 24h-urinary cortisol, and 3 of them were likely to have SCS (abnormal cortisol tests and positive imaging). However, a final diagnosis could not to be confirmed by surgery or pathology. Although not confirmatory, the results of this study suggest that the prevalence of SCS is considerably higher in populations at risk than in the general population.

Functional Oncocytic Adrenocortical Carcinoma

We present a case of oncocytic adrenocortical carcinoma in a 25-year-old man who presented with persistent hypertension, hypokalemia, and a large right adrenal mass. Clinical workup revealed increased serum aldosterone level, suppressed serum ACTH level and high 24-h urine cortisol. Histologically the tumor showed several features of malignancy and electron microscopy confirmed oncocytic differentiation. This case is reported as the first case of an aldosterone and cortisol-producing malignancy with an oncocytic phenotype.

Body Mass Index Predicts Aldosterone Production in Normotensive Adults on a High-Salt Diet

The mechanisms underlying obesity-mediated cardiovascular disease are not fully understood. Aldosterone and insulin resistance both are associated with obesity and cardiovascular disease. The objectives of this study were to test the hypotheses that aldosterone production is elevated and associated with insulin resistance in overweight adults on a high-sodium diet. Healthy normotensive adults were categorized as lean body mass index (BMI) less than 25 kg/m(2) (n = 63) or overweight BMI 25 kg/m(2) or greater (n = 57). After 7 d of a high-sodium diet, participants fasted overnight and remained supine throughout hemodynamic and laboratory assessments and angiotensin II (AngII) stimulation. The overweight group, compared with the lean group, had higher 24-h urinary aldosterone (9.0 +/- 0.8 vs. 6.6 +/- 0.5 microg per 24 h; P = 0.003) and higher AngII-stimulated serum aldosterone (11.4 +/- 1.0 vs. 9.0 +/- 0.6 ng/dl; P = 0.04). There were no differences in 24-h urinary cortisol or sodium or supine measurements of plasma renin activity, serum aldosterone, or serum potassium. The homeostasis model assessment of insulin resistance was predicted by urinary aldosterone excretion (r = 0.32, P = 0.03) and serum aldosterone response to AngII stimulation (r = 0.28, P = 0.02) independent of age and BMI. Urinary aldosterone excretion and AngII-stimulated aldosterone are increased in overweight, compared with lean, normotensive adults. The correlation of these measures of aldosterone production with insulin resistance suggests a potential role for aldosterone in the pathophysiology of obesity-mediated insulin resistance.

Long‐term safety of fluticasone furoate nasal spray in adults and adolescents with perennial allergic rhinitis

Fluticasone furoate is a novel-enhanced affinity glucocorticoid and its long-term safety must be assessed. This study was designed to assess the safety and tolerability of 12-month intranasal administration of fluticasone furoate in adult and adolescent patients with perennial allergic rhinitis (PAR). In this randomized, double-blind, placebo-controlled, parallel-group study, 806 patients with PAR were randomized to once daily (od) fluticasone furoate nasal spray 110 microg (n = 605) or vehicle placebo nasal spray (n = 201) for 12 months, following a 7- to 14-day screening period. Safety was assessed by monitoring adverse events (AEs), 24-h urinary cortisol excretion, nasal and ophthalmic examinations, electrocardiograms and clinical laboratory tests. Plasma concentrations of fluticasone furoate were determined from blood samples. Fluticasone furoate was well tolerated. The incidence of most AEs was similar to that observed with placebo, with the exception of epistaxis, which was more frequently reported on active treatment. There were no clinically meaningful differences between fluticasone furoate and placebo in terms of safety assessments, including mean changes in ophthalmic parameters and 24-h urine cortisol excretion. Plasma concentrations of fluticasone furoate were not quantifiable in the majority of patients following intranasal administration. Long-term (12-month) administration of fluticasone furoate 110 microg od revealed an AE profile typical of the intranasal corticosteroid class in both adult and adolescent patients with PAR, with no evidence of clinically relevant systemic corticosteroid exposure.

Comparison of the efficacy and safety of ciclesonide 160 μg once daily vs. budesonide 400 μg once daily in children with asthma

Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg once daily (via Turbohaler) both given in the evening for 12 wk. The primary efficacy end-point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24-h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non-inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: -75, 10 ml, p = 0.0009, one-sided non-inferiority, per-protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two-sided). The effect on the hypothalamic-pituitary-adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one-sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 microg once daily and budesonide 400 microg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24-h urinary cortisol excretion compared with children treated with budesonide after 12 wk.

Randomized comparison of the efficacy and safety of ciclesonide and budesonide in adolescents with severe asthma

The aim of the study was to investigate the efficacy and safety of ciclesonide compared with budesonide in adolescents with severe asthma. In this randomized, double-blind, double-dummy, parallel-group study, patients aged 12-17 years with severe asthma were treated with budesonide 400 microg once daily (QD) in a 2-week run-in period. At randomization, eligible patients were assigned 2:1 to ciclesonide 320 microg QD (ex-actuator) or budesonide 800 microg QD (metered dose), respectively, in the evening. Forced expiratory volume in 1s (FEV(1)) was the primary variable. Patients recorded asthma symptom score and rescue medication use in diaries. Safety assessments included adverse events (AEs) and 24-h urine cortisol. Four hundred and three patients were randomized. Ciclesonide 320 microg QD and budesonide 800 microg QD significantly increased FEV(1) (least-squares mean: 505 and 536 mL, respectively; both p<0.0001 versus baseline) in the intention-to-treat (ITT) population. Lower limits of the 95% confidence intervals (ITT: -138 mL; per-protocol: -122 mL) were above the non-inferiority limit (-150 mL). Median percentage of days without asthma symptoms and without rescue medication use was 84% with ciclesonide and 85% with budesonide. AEs were unremarkable, with no cases of confirmed candidiasis. Median creatinine-adjusted urine cortisol significantly decreased with budesonide treatment (15.9-13.7 nmol cortisol/mmol creatinine; p=0.0086 versus baseline), but not with ciclesonide (p=0.1125). Ciclesonide 320 microg QD showed similar efficacy to budesonide 800 microg QD in adolescents with severe asthma. Ciclesonide was well tolerated and, unlike budesonide, had no effect on urine cortisol levels. EudraCT No.: 2004-001233-41.

Percutaneous laser ablation of unresectable primary and metastatic adrenocortical carcinoma

Purpose To evaluate the feasibility, safety, and clinical benefits of percutaneous laser ablation (PLA) in patients with unresectable primary and metastatic adrenocortical carcinoma (ACC). Patients and methods Four patients with hepatic metastases from ACC and a Cushing's syndrome underwent ultrasound-guided PLA. In one case the procedure was performed also on the primary tumor. Results After three sessions of PLA, the primary tumor of 15 cm was ablated by 75%. After 1–4 (median 1) sessions of PLA, five liver metastases ranging from 2 to 5 cm were completely ablated, while the sixth tumor of 12 cm was ablated by 75%. There were no major complications. Treatment resulted in an improvement of performance status and a reduction of the daily dosage of mitotane in all patients. The three patients with liver metastases presented a marked decrease of 24-h urine cortisol levels, an improved control of hypertension and a mean weight loss of 2.8 kg. After a median follow-up after PLA of 27.0 months (range, 9–48 months), two patients have died of tumor progression, while two other patients remain alive and free of disease. Conclusions Percutaneous laser ablation is a feasible, safe and well tolerated procedure for the palliative treatment of unresectable primary and metastatic ACC. Further study is required to evaluate the impact of PLA on survival.

Gamma knife radiosurgery is a successful adjunctive treatment in Cushing’s disease

Though transsphenoidal surgery remains the first-line treatment of Cushing's disease, recurrence occurs frequently. Conventional radiotherapy and anticortisolic drugs both have adverse effects. Stereotactic radiosurgery needs to be evaluated more precisely. The aim of this study was to determine long-term hormonal effects and tolerance of gamma knife (GK) radiosurgery in Cushing's disease. Forty patients with Cushing's disease treated by GK were prospectively studied over a decade, with a mean follow-up of 54.7 months. Eleven of them were treated with GK as a primary treatment. Radiosurgery was performed at the Department of Functional Neurosurgery of Marseille, France, using the Leksell Gamma Unit B and C models. Median margin dose was 29.5 Gy. Patients were considered in remission if they had normalized 24-h free urinary cortisol and suppression of plasma cortisol after low-dose dexamethasone suppression test. Seventeen patients (42.5%) were in remission after a mean of 22 months (range 12-48 months). The two groups did not differ in terms of initial hormonal levels. Target volume was significantly higher in uncured than in remission group (909.8 vs 443 mm(3), P = 0.038). We found a significant difference between patients who were on or off anticortisolic drugs at the time of GK (20 vs 48% patients in remission respectively, P = 0.02). With 42% of patients in remission after a median follow-up of 54 months, GK stereotactic radiosurgery, especially as an adjunctive treatment to surgery, may represent an alternative to other therapeutic options in view of their adverse effects.

Interleukin-6 production and deregulation of the hypothalamic-pituitary-adrenal axis in patients with major depressive disorders

The present study was designed to determine whether an association exists between HPA activity and cytokine production in major depression (MD). In 9 patients with MD and 11 control subjects of both sexes, all drug-free, activity of the HPA axis was evaluated by circadian rhythm of plasma cortisol, 24-h free urinary cortisol, an overnight 1 mg dexamethasone suppression test, and an oCRF stimulation test. Spontaneous and LPS-stimulated production of IL-1beta, IL-6, and TNFalpha by peripheral blood mononuclear cells were also determined. We found a significantly elevated spontaneous production of IL-6 in patients with MD (3541.2 +/- 726.8 vs 380.4 +/- 77.5 pg/mL in controls, p < 0.05), while LPS-stimulated production was significantly lower in patients than in control subjects (19,867.7 +/- 3649.2 vs 33,142.2 +/- 15,47.2 pg/mL, p < 0.05). The adrenocorticotropic hormone response to oCRF, evaluated as the area under the curve (AUCACTH) was significantly lower in patients than in control subjects (p = 0.02). A positive correlation between AUCACTH and LPS-stimulated IL-6 secretion was observed in patients with MD (r = 0.75, p < 0.05) but not in controls. These findings suggest that the activation of the inflammatory response described in depression might be associated with long-term hyperactivity of the HPA axis.

Clinical Correlates of 24‐H Cortisol and Norepinephrine Excretion Among Subjects Seeking Treatment Following the World Trade Center Attacks on 9/11

Whereas trauma-associated arousal has been linked fairly consistently with elevations in both glucocorticoids and catecholamines, neuroendocrine correlates of hyperarousal in the context of posttraumatic stress disorder (PTSD) have been more variable. Further, neuroendocrine predictors of the development of PTSD following trauma have been related to prior exposure, and data from several laboratories suggests that hyperarousal may develop in a neuroendocrine milieu of relatively diminished basal glucocorticoid secretion. In this article we examined 24-h cortisol and norepinephrine excretion in 42 treatment-seeking survivors of the 9/11 World Trade Center (WTC) attacks, 32 of whom met criteria for PTSD, and 15 of whom met criteria for major depression, at the time of evaluation; 14 of the 15 subjects meeting criteria for major depression also suffered from PTSD. PTSD subjects' 24-h cortisol excretion (46.3 +/- 20.0 microL/dL) was lower than that of the non-PTSD cohort (72.2 +/- 22.4 microL/dL; t = 3.18, df = 37, P = 0.003), and 24-h urinary cortisol was negatively correlated with the experience of the WTC attacks as a Criterion-A event (r = -0.427, P = 0.007), and with self-rated avoidance (r = -0.466, P = 0.003) and total score (r = -0.398, P = 0.012) on the PTSD Symptom Scale (PSS). In contrast, 24-h norepinephrine excretion was not associated with the development of PTSD or with PTSD-related symptoms, but was negatively correlated with days since 9/11 at the time of evaluation (r = -0.393, P = 0.015). The latter finding suggests a relationship of norepinephrine to a dimension of stress-related arousal not captured by the symptom-rating scales chosen for this study to reflect symptoms related to PTSD and other neuropsychiatric disorders, but instead, of one to that of the sudden multidimensional life disruption suffered by the WTC survivors that applied for treatment. These data also confirm, in a naturalistic sample, the previously observed negative association of urinary cortisol excretion with development of PTSD in the aftermath of severe trauma exposure.

Hippocampal volume in aging combat veterans with and without post-traumatic stress disorder: Relation to risk and resilience factors

Objective To examine whether there are post-traumatic stress disorder (PTSD) related differences in hippocampal volume in middle-aged and elderly veterans and to examine the relationship of neuroendocrine activity, memory performance, and measures of risk and resilience for PTSD to hippocampal volume in this cohort. Methods Seventeen veterans with chronic PTSD and 16 veterans without chronic PTSD received an MRI scan followed by neuroendocrine assessment (24-h urinary cortisol excretion and the lysozyme IC 50-DEX, a measure of glucocorticoid receptor (GR) responsiveness), and cognitive testing. Results Veterans with PTSD did not differ from those without PTSD in hippocampal volume, but they did show significantly lower urinary cortisol levels, and poorer memory performance on the Wechsler Logical Memory test and Digit Span test. Smaller left hippocampal volumes were observed in veterans who developed PTSD in response to their first reported traumatic exposure, compared to veterans who had first experienced a traumatic event to which they did not develop PTSD, prior to experiencing a subsequent event that led to PTSD. In contrast, the two neuroendocrine measures were associated with risk factors related to early trauma exposure. Conclusion Although hippocampal volume was not found to differ between subjects with and without PTSD, smaller hippocampal volumes in PTSD may be associated with specific risk and resilience factors. These may be distinct from vulnerability markers associated with increased responsiveness to glucocorticoids and/or other neuroendocrine measures that have been observed in combat-related PTSD.

A4/207 – Ciclesonide 160μg once daily is as effective as budesonide 400μg once daily in improving the quality of life in children with persistent asthma and their caregivers

The efficacy and systemic effects of ciclesonide, a novel glucocorticosteroid, inhaled via pressurized metered-dose inhaler (pMDI) were compared with fluticasone propionate pMDI in 26 patients with asthma, using a randomized, double blind, placebo-controlled, double dummy, 6-period crossover study design. Treatments were placebo, ciclesonide 320 μg (ex-actuator dose) once daily (o.d.), ciclesonide 640 μg o.d., ciclesonide 640 μg twice daily (b.i.d.), fluticasone propionate 440 μg (ex-actuator dose) b.i.d., and fluticasone propionate 880 μg b.i.d. The primary variable was area under the plasma cortisol concentration–time curve over 24 h (plasma cortisol AUC0–24, relative to placebo) derived from samples taken every 2 h, on the 9th day of treatment. Secondary variables were 24-h urinary cortisol excretion and PC20 for adenosine 5′-monophosphate (AMP) (relative to placebo and expressed in doubling concentrations). Ciclesonide did not affect 24-h cortisol secretion. Fluticasone propionate suppressed cortisol secretion as demonstrated by a decrease in plasma cortisol AUC0–24, relative to placebo, by 29% (95% CI 15–41) and 59% (95% CI 51–66) with 440 and 880 μg b.i.d., respectively. PC20 more than doubled with each active treatment, but no statistically significant dose–response effect could be established. It was concluded that moderate to high doses of fluticasone propionate suppressed cortisol secretion, that ciclesonide did not suppress cortisol secretion, and that all active treatments decreased hyperresponsiveness to AMP.

Ciclesonide, a Novel Inhaled Steroid, Does Not Affect Hypothalamic-Pituitary-Adrenal Axis Function in Patients With Moderate-to-Severe Persistent Asthma

Inhaled corticosteroids (ICSs) reduce local airway inflammation, which is an underlying cause of asthma symptoms. However, potential systemic side effects associated with ICS use are a major concern for asthmatic patients. Adult patients (n = 60; > or = 18 years of age) with moderate-to-severe asthma were randomized to receive 4 weeks of treatment with ciclesonide (CIC), 320 microg bid (CIC 640), CIC, 640 microg bid (CIC 1280), fluticasone propionate (FP), 440 microg bid (FP 880), FP 880 microg bid (FP 1760), or placebo (PBO) [all doses expressed as ex-actuator; comparable to ex-valve doses of 800 and 1,600 microg/d for CIC and 1,000 and 2,000 microg/d for FP, respectively]. After 29 days of treatment, CIC 640, CIC 1280, and FP 880 had no significant effect on the mean serum cortisol area under the curve for 0 to 24 h (AUC0-24h). FP 1760 produced a statistically significant suppression in mean serum cortisol AUC0-24h compared to PBO (p = 0.0009; 95% confidence interval [CI] -117.5 [corrected] to -32.1). Results obtained with cosyntropin stimulation revealed no statistically significant differences among the groups. The CIC 640 group demonstrated a significant increase compared to the PBO group in 24-h urinary cortisol levels from baseline at week 4 (p = 0.0224; 95% CI, 0.0023 to 0.0283), while the other treatment groups revealed no change in this parameter. The incidence of treatment-emergent adverse events was similar in all groups, and all adverse events were mild or moderate in severity. Treatment with moderate and high doses of CIC does not result in hypothalamic-pituitary-adrenal-axis suppression as compared with PBO.

A defect in cortisol production in rheumatoid arthritis: why are we still looking?

The question of whether patients with rheumatoid arthritis (RA) might have a defective hypothalamo–pituitary–adrenal (HPA) axis was first raised when RA patients who were treated with glucocorticoids in the 1950s showed dramatic improvement in their symptoms. It was initially hypothesized that this was due to an impaired ability of RA patients to synthesize sufficient amounts of endogenous glucocorticoids, but intensive investigations over the next few decades failed to reveal any significant defects in HPA axis activity in RA patients. In our review of the literature [1] we found no compelling evidence for significant differences in either basal or stress-stimulated HPA axis activity in RA compared with normal healthy individuals. However, we did highlight an inherent defect, which resided in the inability of RA patients to mount an appropriately enhanced glucocorticoid response to increased secretion of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-. ‘In other words’, we concluded, ‘the HPA axis response in RA is defective precisely because it is normal’. Since then, studies by ourselves and others have suggested that this statement may be an oversimplification and that subtle differences in HPA axis activity may exist in subpopulations of RA patients. The purpose of this review is to evaluate progress in assessing the integrity of the HPA axis in RA since this area was previously reviewed [1–3], to determine whether generating information about HPA axis dysfunction in RA is clinically useful, and to discuss whether this area of research remains a fruitful line of enquiry. Persuasive evidence for a major dysfunction in basal circadian HPA axis activity in RA patients remains elusive. In a study of 10 postmenopausal females, plasma adrenocorticotrophic hormone (ACTH) and cortisol were slightly decreased around midnight but were not different from those in healthy controls at other circadian time points [4]. In 17 RA patients of mixed sex with recent disease onset, morning ACTH and cortisol concentrations were similar to those of controls, although the correlation between these hormones was weaker in RA [5]. In contrast, Straub et al. observed significantly higher morning serum cortisol in untreated patients with early RA (34 subjects, largely females) compared with healthy subjects, but no difference in ACTH [6]. However, the ratios of ACTH and cortisol in RA patients in relation to the markedly elevated levels of proinflammatory cytokines IL-6 and TNF- were significantly low compared with healthy controls. Furthermore, the number of swollen joints correlated inversely with the ratio of serum cortisol to IL-6. This suggests that measuring alterations in a single hormonal parameter may be less revealing of the underlying processes of inflammation in RA than measuring a change in the overall milieu of pro- and anti-inflammatory modulators. The low ratios of serum cortisol to IL-6 and TNFin RA cannot be explained by an increased metabolic clearance rate of cortisol [7, 8]. Curiously, in more recent studies by the same group, basal serum cortisol concentrations in RA patients with mild to moderate disease activity were slightly lower [9] and ACTH concentrations were significantly lower [7] compared with healthy controls. Serum cortisol and 24-h urinary cortisol were similar in the two groups [7]. These variations reported in the literature, which may be due to differences in disease duration and/or activity, age and sex of the patient, medication, or sampling time, emphasize the difficulty in pinpointing any specific and reproducible defect in HPA axis activity in RA. In a separate study, diurnal salivary cortisol was elevated in RA patients with recent onset compared with healthy controls, and this effect was positively correlated with disease activity but not with sex or age [10]. However, in these patients the awakening

Neuroendocrine–immune relationships between emotion regulation and health in patients with rheumatoid arthritis

Emotion regulation is hypothesized to be related to health through neuroendocrine-immune changes. This study examined the role of the neuroendocrine variables 24-h urinary cortisol and noradrenaline, and the immune variable serum interleukin 6 as mediators between emotion regulation styles and health (perceived health and disease activity: erythrocyte sedimentation rate (ESR) and Thompson joint score). Sixty patients with rheumatoid arthritis (mean age 59.0+/-11.2 yr; 38 female) participated. Emotion regulation was not associated with immune functioning or disease activity, but it was somewhat related to neuroendocrine functioning: one of the emotion regulation styles, ambiguity, was related to noradrenaline in women (r = 0.39) but not in men. The indicators of neuroendocrine functioning (cortisol and noradrenaline) were correlated (r = 0.40), as were indicators of immune functioning (interleukin 6) and inflammatory activity (ESR; r = 0.53), but analyses did not indicate a role of these physiological variables in mediating between emotion regulation and health: neuroendocrine variables were not related to interleukin 6 or ESR, and none of the physiological parameters was correlated with joint score or perceived health. To examine whether the proposed mediational processes apply to individual patients, a longitudinal within-subjects design is needed. In our cross-sectional study, emotion regulation was somewhat related to neuroendocrine functioning, but our study did not uncover a potential mediational role of cortisol, noradrenaline or interleukin 6 in the relationship between emotion regulation and health in rheumatoid arthritis.

Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5′monophosphate in asthmatic patients

The efficacy and systemic effects of ciclesonide, a novel glucocorticosteroid, inhaled via pressurized metered-dose inhaler (pMDI) were compared with fluticasone propionate pMDI in 26 patients with asthma, using a randomized, double blind, placebo-controlled, double dummy, 6-period crossover study design. Treatments were placebo, ciclesonide 320 μg (ex-actuator dose) once daily (o.d.), ciclesonide 640 μg o.d., ciclesonide 640 μg twice daily (b.i.d.), fluticasone propionate 440 μg (ex-actuator dose) b.i.d., and fluticasone propionate 880 μg b.i.d. The primary variable was area under the plasma cortisol concentration–time curve over 24 h (plasma cortisol AUC 0–24, relative to placebo) derived from samples taken every 2 h, on the 9th day of treatment. Secondary variables were 24-h urinary cortisol excretion and PC 20 for adenosine 5′-monophosphate (AMP) (relative to placebo and expressed in doubling concentrations). Ciclesonide did not affect 24-h cortisol secretion. Fluticasone propionate suppressed cortisol secretion as demonstrated by a decrease in plasma cortisol AUC 0–24, relative to placebo, by 29% (95% CI 15–41) and 59% (95% CI 51–66) with 440 and 880 μg b.i.d., respectively. PC 20 more than doubled with each active treatment, but no statistically significant dose–response effect could be established. It was concluded that moderate to high doses of fluticasone propionate suppressed cortisol secretion, that ciclesonide did not suppress cortisol secretion, and that all active treatments decreased hyperresponsiveness to AMP.

Hypothalamic–Pituitary–Adrenal Axis Activity and Sleep in Posttraumatic Stress Disorder

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis and sleep disturbances have been described separately in post-traumatic stress disorder (PTSD). It is not known if HPA alterations and sleep disturbances are associated in PTSD. This study examined sleep and HPA activity in 20 male medication-free subjects with PTSD and 16 matched healthy controls. Two nights of polysomnography were obtained and 24-h urinary cortisol was collected during day 2. Subjects self-administered a low-dose (0.5 mg) salivary dexamethasone test at home. Compared with controls, PTSD subjects had higher 24-h urinary microg cortisol/g creatinine (mean+/-SD 40+/-17 vs 28+/-12, p=0.03) but not significantly higher 24-h urinary cortisol (mean+/-SD 52+/-15 microg/day vs 43+/-23, p=0.19). PTSD subjects showed a trend towards less cortisol suppression after dexamethasone (73%+/-18 vs 83%+/-10, p=0.06). In the combined sample, delta sleep was significantly and negatively correlated with 24-h urinary cortisol (r=-0.36, p=0.04), and with 24-h urinary cortisol/g creatinine on a trend level (r=-0.34, p=0.06). Our results suggest that increased cortisol is negatively associated with delta sleep. This may contribute to sleep abnormalities in conditions associated with elevated cortisol, possibly including PTSD. Future studies should explore the temporal relationship between HPA activity, sleep disturbances, and psychopathology after a traumatic event.