24-h Urinary Free Cortisol Research Articles

Once-Daily Evening Dosing of Mometasone Furoate Administered via a Dry Powder Inhaler Does Not Adversely Affect the Hypothalamic-Pituitary-Adrenal Axis

Inhaled corticosteroids can suppress the hypothalamic-pituitary-adrenal (HPA) axis with long-term exposure. This study reports the effects of moderate-dose (400 microg) mometasone furoate administered via dry powder inhaler (MF-DPI) once daily in the evening on the HPA axis in adults with mild to moderate asthma. In this randomized, investigator-blind, placebo-controlled trial, nonsmoking adults aged 18 to 50 years with mild-to-moderate asthma received once-daily MF-DPI 400 microg (2 x 200 microg/inhalation; treatment A), MF-DPI 400 microg (1 x 400 microg/inhalation; treatment B), or placebo (two inhalations, treatment C), delivered at approximately 8:00 pm, for 42 days. Primary end points were area under the serum cortisol concentration-vs-time curve over 24 h (AUC(0-24)), 24-h urinary free cortisol (creatinine corrected) on day 42, maximum serum cortisol concentration (C(max)), time to C(max) (T(max)), and 8 :00 am serum cortisol concentration. This study was initiated April 16, 2001 and completed June 14, 2001. Serum cortisol AUC(0-24), C(max), and 24-h urinary free cortisol levels decreased with all treatments by day 42 with no significant differences between groups. For treatment B, the change in 8:00 am serum cortisol from baseline to day 42 was significantly less than placebo (P = .04), attributed to a large baseline difference between these treatments. A significant difference in T(max) change from baseline by day 42 for treatment B compared with the other treatments (P = .019) was also attributed to significant baseline differences between groups. Actual values at day 42 for T(max) and 8:00 am serum cortisol were not significantly different between treatment groups (P > or = .275). Once-evening moderate dosing (400 microg) MF-DPI does not suppress HPA axis function in adults with mild to moderate asthma.

Screening for Cushing’s Syndrome in Obese Patients

OBJECTIVES:The aim of this study was to examine the frequency of Cushing’s syndrome (CS) in obese patients devoid of specific clinical symptoms of Cushing’s syndrome.METHODS:A total of 150 obese patients (129 female, 21 male; mean age 44.41 ± 13.34 yr; mean BMI 35.76 ± 7.13) were included in the study. As a first screening step, we measured 24-h urinary free cortisol (UFC). An overnight 1-mg dexamethasone suppression test was also performed on all patients. Urinary free cortisol levels above 100 μg/24 h were considered to be abnormal. Suppression of serum cortisol <1.8 μg/dL after administration of 1 mg dexamethasone was the cut-off point for normal suppression. The suppression of the serum cortisol levels failed in all of the patients.RESULTS:Measured laboratory values were as follows: ACTH, median level 28 pg/ml, interquartile range (IQR) 14–59 pg/ml; fasting glucose, 100 (91–113) mg/dL; insulin, 15.7 (7.57–24.45) mU/ml; fT4, 1.17 (1.05–1.4) ng/dL; TSH, 1.70 (0.91–2.90) mIU/L; total cholesterol, 209 (170.5–250) mg/dL; LDL-c, 136 (97.7–163) mg/dL; HDL-c, 44 (37.25–50.75) mg/dL; VLDL-c, 24 (17–36) mg/dL; triglycerides, 120.5 (86–165) mg/dL. The median UFC level of the patients was 30 μg/24 h (IQR 16–103). High levels of UFC (>100 μg/24 h) were recorded in 37 patients (24%). Cushing’s syndrome was diagnosed in 14 of the 150 patients (9.33%). Etiologic reasons for Cushing’s syndrome were pituitary microadenoma (9 patients), adrenocortical adenoma (3 patients), and adrenocortical carcinoma (1 patient).CONCLUSION:A significant proportion (9.33%) of patients with simple obesity were found to have Cushing’s syndrome. These findings argue that obese patients should be routinely screened for Cushing’s syndrome.

Sudden Respiratory Failure in a Patient with Cushing`s Syndrome

A 79 year-old patient with prostate cancer related Cushing's syndrome was referred to ICU for acute respiratory distress occurring two days after introduction of mifepristone. Pneumocystis jirovecii pneumonia was diagnosed. Despite anti pneumocystis therapy and supportive treatment, the patient died of multiple organ failure. The relationship between mifepristone and Cushing's syndrome and potential implications are discussed. Cushing's syndrome is a classical but rare disease resulting from exposure to excessive concentrations of glucocorticoid. When surgery is not feasible medical therapy should be discussed. A 79 year-old man was admitted to intensive care unit for acute respiratory distress. He had been treated for prostate cancer for 12 years, with radiotherapy and hormonotherapy. The last prostate-specific antigen (PSA) level was (0, 24 ng/ml) while pelvis MRI disclosed irregular prostate consistent with radiotherapy after-effects without any sign of recurrence of malignancy. He was referred 3 months before to the general ward because of depression, severe systemic hypertension, hypokalaemia and diabetes mellitus. Endogenous hypercortisolism was diagnosed. Static and dynamic analysis: (plasma cortisol level at 8 am : 1564 nmol/l (normal<200 nmol/l), 24h urinary free cortisol excretion: 20200 nmol/24h (normal <270 nmol/24h), no suppression of plasma cortisol with low dose of dexamethasone, adrenocorticotropic hormone (ACTH) : 145 ng/l.(normal<50 ng/l)) were in favour of an ACTH dependent Cushing's syndrome. Considering normal pituitary MRI, final diagnosis was paraneoplastic Cushing's syndrome. CT scan imaging of the thorax (Fig. 1), abdomen and pelvis disclosed bilateral adrenal hyperplasia but did not show any thoracic or pancreatic tumours which are the most common tumours responsible for ectopic ACTH secretion.

Endothelial Dysfunction Aassociated with Hypercortisolism is Reversible in Cushing's Syndrome

Cushing's syndrome (CS) as represented by chronic glucocorticoid excess is associated with increased rate of cardiovascular morbidity and mortality. Because endothelial dysfunction is an early event of atherosclerosis, we investigated whether endothelial dysfunction is associated with CS and reversible. Twenty-one CS patients due to different causes were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), among whom 12 patients were re-evaluated after surgical and medical treatment; 12 age- and gender-matched subjects served as control. Percent (%) FMD in CS patients (5.8+/-1.9 %) was significantly (p =0.0014) lower than that in control subjects (8.1+/-1.7 %). In CS patients, %FMD showed significant (p < 0.01) negative correlations with morning serum cortisol levels (r =-0.58) and 24-h urinary free cortisol excretion (r =-0.58). After surgical and medical treatment in CS patients, morning cortisol levels significantly (p =0.0025) decreased from 23.4 [15.6-37.3] to 10.2 [7.7-12.9] microg/dL, whereas %FMD significantly (p =0.0024) increased from 5.2+/-1.9 to 7.8+/-2.3 %; changes of %FMD after treatment significantly (p =0.0004) and inversely correlated with those of morning cortisol levels (r =-0.85), but not with those of body mass index, blood pressure, glycemic or lipid profiles. Taken together, the present study clearly revealed that endothelial dysfunction in CS patients is related to hypercortisolemia and reversible after treatment, suggesting the possible role of cortisol excess in the development of endothelial dysfunction, thereby possibly leading to increased cardiovascular complications.

The Relationship Between 24-h Urinary Cortisol and Bone in Healthy Young Women

Cortisol within the normal range has been associated with reduced bone density in the elderly, but little is known about this relationship in healthy young women. The purpose of this study is to assess whether 24-h urinary free cortisol excretion (UFC) is related to bone density in 132 healthy, non-obese, regularly menstruating women, aged 19-35. Participants completed questionnaires (food frequency, demographics, physical activity, dietary restraint, perceived stress, and daily stress) and a 24-h urine collection. UFC was determined by high-throughput liquid chromatography and tandem mass spectrometry. Anthropometrics were completed and a dual energy X-ray absorptiometry scan measured areal bone mineral density (aBMD, g/cm(2)) and bone mineral content (BMC, g) at the lumbar spine (L1-4), hip, and total body (TB) as well as total body lean (LBM) and fat mass. aBMD and BMC were significantly positively associated with height, LBM, physical activity, calcium intake, and duration of previous oral contraceptive use (except L1-4) and negatively with perceived stress. UFC was not correlated with any measured variables except urine volume (r = 0.17, p = 0.046). After adjusting for urine volume, height, LBM, ethnicity, and prior oral contraceptive use, UFC was significantly inversely associated with TB BMC (r = -0.30, p < 0.001) and aBMD (r = -0.27, p = 0.003), L1-4 aBMD (r = -0.19, p = 0.035) and BMC (r = -0.18, p = 0.049), and hip BMC (r = -0.23, p = 0.011). Further adjustment for sport activity, calcium intake and perceived stress did not change these relationships meaningfully except that L1-4 became nonsignificant (p < 0.07). Cortisol within the normal range appears to have a minor negative influence on bone density in healthy young women.

Approach to the Patient with Possible Cushing’s Syndrome

Clinical decision making for patients with suspect hypercortisolism involves a complex diagnostic assessment. Cushing's syndrome remains one of the most challenging endocrine pathologies. Most clinical features overlap with those of common diseases found in the general population, and some patients have an atypical clinical presentation with only isolated symptoms. Recently, several studies have suggested that the prevalence of Cushing's syndrome is higher than previously thought. Therefore, efficient screening tests are needed to identify the few uncovered patients also among unselected high-risk ambulatory patients with disorders potentially related to cortisol excess. The recommended diagnostic tests are 24-h urinary free cortisol, 1-mg overnight dexamethasone suppression test, and late-night salivary cortisol. Once the diagnosis of Cushing's syndrome is established, the next step is the measurement of plasma ACTH. Then, dynamic test and appropriate imaging procedures are the most useful noninvasive investigations for the differential diagnosis. Patients with Cushing's disease are generally responsive to the CRH test and to high-dose glucocorticoid feedback. Bilateral inferior petrosal sinus sampling is considered the gold standard for establishing the origin of ACTH secretion, and it is recommended in patients with ACTH-dependent Cushing's syndrome whose clinical, biochemical, or radiological studies are discordant or equivocal. The present clinical case shows that even if rare, the ectopic ACTH secretion should be considered also in those cases where the pretest probability is low. The management of Cushing's syndrome depends on the exact knowledge of its various causes, paying attention to the many potential diagnostic pitfalls. The choice of test, the modality of specimen collection (blood, urine, and saliva), the quality of measurement (assay methodology and standardization), and close dialogue among endocrinologists, chemical pathologists, and neuroradiologists are key factors for optimal care of patients.

Stress‐related Development of Obesity and Cortisol in Women

Chronic exposure to environmental stress may play a role in the development of obesity, through hyperactivation of the hypothalamic-pituitary-adrenocortical (HPA) axis. This study investigated the dynamics of weight gain and the activity of the HPA axis in women who developed weight gain after a stressful event. This is a case-control retrospective study. Two groups of age-matched premenopausal women were selected. One (n = 14) included women characterized by a rapid weight gain following a stressful event, defined as the "stress-related obesity " (SRO) group, and the other (n = 21) women with nonstress-related development of obesity, defined as the "nonstress-related obesity " (NSRO) group. Twenty-one healthy premenopausal women served as normal-weight controls. Baseline hormonal and metabolic parameters, and 24-h urinary free cortisol (UFC/24 h) excretion rate (as a measure of HPA-axis activity) were measured in all women. Anthropometry, diet, and physical activity were similar in both obese groups. Both obese groups showed similar metabolic and hormonal profiles, but the SRO group had UFC/24 h values (41.1 +/- 14.3 microg) significantly higher (P < 0.001) with respect to the NSRO (26.6 +/- 17.6 microg) or the normal-weight control groups (21.1 +/- 9.8 microg). Moreover, time (years) to achieve maximum Deltaweight gain (kg) and the Deltaweight gain/time ratio were significantly shorter (P < 0.001) and higher (P < 0.001) in the SRO group with respect to the NSRO group, respectively. In the SRO group, there was a tendency to a significant correlation between UFC/24 h and the Deltaweight gain/time ratio. These findings support the concept that SRO has distinct pathophysiological mechanisms, including hyperactivity of the HPA axis.

Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue syndrome?

There is evidence that patients with chronic fatigue syndrome (CFS) have mild hypocortisolism. The clinical significance of this is unclear. We aimed to determine whether hypocortisolism exerted any effect on the response of CFS to cognitive behavioural therapy (CBT). We measured 24-h urinary free cortisol (UFC) in 84 patients with Centers for Disease Control and Prevention (CDC)-defined CFS (of whom 64 were free from psychotropic medication) who then received CBT in a specialist, tertiary out-patient clinic as part of their usual clinical care. We also measured salivary cortisol output from 0800 to 2000 h in a subsample of 56 psychotropic medication-free patients. Overall, 39% of patients responded to CBT after 6 months of treatment. Lower 24-h UFC output was associated with a poorer response to CBT but only in psychotropic medication-free patients. A flattened diurnal profile of salivary cortisol was also associated with a poor response to CBT. Low cortisol is of clinical relevance in CFS, as it is associated with a poorer response to CBT. Hypocortisolism could be one of several maintaining factors that interact in the persistence of CFS.

Long-Term Results of Stereotactic Radiosurgery in Secretory Pituitary Adenomas

To date, no study reported long-term follow-up results of gamma knife stereotactic radiosurgery (SR). The aim of the study was to determine long-term efficacy and adverse effects of SR in secreting pituitary adenomas. We conducted a retrospective study of patients treated by SR in the center of Marseille, France, with a follow-up of at least 60 months. A total of 76 patients were treated by SR for acromegaly (n = 43), Cushing's disease (CD; n = 18), or prolactinoma (n = 15) as a primary (n = 27) or adjunctive postsurgical treatment (n = 49). After withdrawal of antisecretory drugs, patients were considered in remission if they had mean GH levels below 2 ng/ml and normal IGF-I (acromegaly), normal 24-h urinary free cortisol, and cortisol less than 50 nmol/liter after low-dose dexamethasone test (CD) or two consecutive normal samplings of prolactin levels (prolactinoma). After a mean follow-up of 96 months, 44.7% of the patients were in remission. Mean time to remission was 42.6 months. Twelve patients presented late remission at least 48 months after SR. Two patients with CD presented late recurrence 72 and 96 months after SR. Forty percent of patients treated primarily with SR were in remission. Target volume and initial hormone levels were significant predictive factors of remission in univariate analysis. Radiation-induced hypopituitarism was observed in 23% patients; in half of them, hypopituitarism was observed after a mean time of 48 to 96 months. Twenty-four patients were followed for more than 120 months; rates of remission and hypopituitarism were similar to the whole cohort. SR is an effective and safe primary or adjunctive treatment in selected patients with secreting pituitary adenomas.

Relative Growth Hormone Deficiency and Cortisol Excess Are Associated with Increased Cardiovascular Risk Markers in Obese Adolescent Girls

Obesity in adolescents is increasingly prevalent and its impact on cardiovascular risk important to determine. Hormonal predictors of cardiovascular risk markers in obese adolescents are not known. Our objective was to examine whether relative GH deficiency and cortisol excess are determinants of increased cardiovascular risk markers in obese teenage girls. A cross-sectional study was conducted at a clinical research center. Thirty girls (15 obese girls and 15 normal-weight controls) 12-18 years old matched for maturity and race. Inflammatory markers of cardiovascular risk including high-sensitivity C-reactive protein (hsCRP), TNF-alpha receptors 1 and 2, E-selectin, soluble intercellular adhesion molecule-1, and IL-6 were analyzed. Leptin, adiponectin, and 24-h urine free cortisol (UFC) were also measured. A GHRH-arginine stimulation test was performed. The hsCRP levels were higher in obese girls than controls (4.63 +/- 4.81 vs. 0.67 +/- 0.72 mg/liter; P = 0.002 after log conversion), as were other markers of cardiovascular risk. Eight of the 15 obese girls but no normal-weight girl had hsCRP higher than 3 mg/liter (P = 0.002). Body mass index sd score was higher than 4.0 in 87.5% of girls with hsCRP higher than 3 mg/liter and no girls with hsCRP less than 3 mg/liter. Girls with hsCRP higher than 3 mg/liter had higher UFC and lower peak GH compared with those with hsCRP less than 3 mg/liter. Peak GH was an important negative predictor of most markers of increased cardiovascular risk. In addition to peak GH, UFC and adiponectin independently predicted hsCRP. Relative GH deficiency and cortisol excess are significant contributors to increased levels of markers of cardiovascular risk in obese adolescent girls.

Safety, pharmacodynamics and pharmacokinetics of TPI 1020 in smokers with asthma

TPI 1020 is a novel compound with potential for anti-neutrophil effects. TPI 1020 exerts its effects by a dual mechanism of action involving corticosteroid activity and controlled donation of nitric oxide. We assessed the safety, pharmacodynamic and pharmacokinetic activity of ascending doses of TPI 1020 compared to budesonide in asthma. Smokers with mild asthma (n=27) were randomized to receive either 600mcg of TPI 1020 (n=13) or 400mcg of budesonide (n=14) bid for 2weeks followed by 1200 and 800mcg bid, respectively, for an additional week. There was no serious adverse event and all but one adverse event were mild or moderate (severe headache with budesonide). Patients receiving TPI 1020 reported three-fold fewer treatment-emergent AEs (n=13) than those receiving budesonide (n=39). TPI 1020 had similar effects as budesonide on FEV(1), PEF, rescue medication, asthma scoring system, methacholine response, sputum eosinophils and exhaled NO. Sputum neutrophils (%) tended to decrease more with TPI 1020 (32.6% decrease versus 3.7% increase for budesonide); the decrease occurring only in patients with high neutrophils at baseline. A significant difference favoring TPI 1020 was noted for CRP. Budesonide caused a statistically significant decrease in 24h urinary free cortisol over 22days (median of 4.4-2.8mcg/ml, p=0.01) whereas TPI 1020 had no such effect (4.4-5.8mcg/ml), suggesting lower systemic corticosteroid exposure following TPI 1020 treatment. TPI 1020 appears safe in asthmatic smokers and warrants further investigation in respiratory conditions.

A Combined Dexamethasone Desmopressin Test as an Early Marker of Postsurgical Recurrence in Cushing’s Disease

Recurrence of Cushing's disease (CD) after transsphenoidal surgery (TSS) occurs in about 25% of cases. Twenty percent of patients with immediate postsurgical corticotroph deficiency will present late recurrence. The aim of the study was to evaluate a coupled dexamethasone desmopressin test (CDDT) as a predictor of recurrence of CD. We conducted a prospective bicenter study (Marseille and Grenoble, France). We studied 38 patients treated by TSS for CD with a mean follow-up of 60 months. We evaluated 24-h urinary free cortisol, ACTH, and cortisol plasmatic levels and performed low-dose dexamethasone suppression test and CDDT 3 to 6 months after surgery and then yearly. After CDDT, ACTH ratio (ACTHr) was defined as (PeakACTH - BaseACTH)/BaseACTH. Cortisol ratio (Cortisolr) was defined as (PeakCortisol - BaseCortisol)/BaseCortisol. Basal values were observed after low-dose dexamethasone suppression test. Receiver operator characteristics curve defined ACTHr and Cortisolr giving the best sensitivity and specificity associated with recurrence. Ten patients presented recurrence. ACTHr and Cortisolr were superior or equal to 0.5 in all patients with recurrence and in three of 28 patients in remission (100% sensitivity, 89% specificity). The test became positive in eight of 10 patients with recurrence 6-60 months before classical markers of hypercortisolism. Six patients with immediate postsurgical corticotroph deficiency presented recurrence. All of them presented CDDT positivity during the 3 yr after surgery, and recurrence 6 to 60 months after CDDT positivity. CDDT is an early predictor of recurrence of CD and could be of particular interest in the first 3 yr after surgery, by selecting patients at high risk of recurrence despite falsely reassuring classical hormonal markers.

A Subnormal Peak Cortisol Response to Stimulation Testing Does Not Predict a Subnormal Cortisol Production Rate

The decision to commence lifelong glucocorticoid replacement therapy is often based on a cortisol stimulation test. We investigated the relationship between the peak cortisol response to insulin-induced hypoglycemia and daily cortisol production rate (CPR) to ascertain whether provocative tests are accurate in indicating the need to initiate lifelong glucocorticoid replacement. Ten patients (five male; mean age, 44 +/- 13 yr) with pituitary disease and with demonstrably suboptimal peak cortisol response (350-500 nmol/liter) to insulin-induced hypoglycemia, underwent CPR measurement by isotope dilution using gas chromatography-mass spectrometry and 24-h urinary free cortisol (UFC). The median baseline and peak cortisol attained with hypoglycemia were 284 (164-323) and 473.5 (366-494) nmol/liter, respectively. A strong positive correlation was seen between peak stimulated cortisol and CPR (adjusted for body surface area) (r = 0.75; P = 0.02), and in all patients CPR [4.6 (2.9-15.1) mg/d x m(2)] was within the reference range (2.1-12 mg/d x m(2)) or elevated (one patient). A wide range was found for 24-h UFC [116.5 (20.5-265.9) nmol/liter] in this group of patients, and this parameter lacked significant correlation with either serum cortisol concentration or CPR. This is the first study to demonstrate a significant correlation between CPR and peak cortisol values during hypoglycemic challenge. An inadequate cortisol response to hypoglycemia suggests the need for glucocorticoid cover at times of stress, but these data indicate that a suboptimal peak cortisol does not equate to a low CPR and should not be an automatic indication for lifelong glucocorticoid replacement therapy. UFC bears no relation to serum cortisol or CPR and is therefore unhelpful in assessment of such patients.

Outcome of transsphenoidal surgery for Cushing's disease: A high remission rate in ACTH-secreting macroadenomas

Objective Although numerous studies have shown that transsphenoidal surgery is the best initial treatment for Cushing disease offering 59–95% of success, fewer information is available on the long-term outcome in the subgroup of patients harboring ACTH-secreting macroadenomas. The aims of this study were to analyze our 10-year experience with transsphenoidal surgery in Cushing's disease and to examine whether remission rates were different between micro- and macroadenomas. Patients and methods Forty consecutive patients with proven Cushing's disease (28 microadenomas, 12 macroadenomas [diameter: 10–25 mm], 3 patients with no visible adenoma at MRI) underwent transsphenoidal surgery (TSS) assisted by neuronavigation in our center between 1996 and 2007. The diagnosis was made using standard endocrinological criteria including bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation in all patients with discordant or equivocal biochemical and radiological testing. Morning serum cortisol was measured during the first week postoperatively, and a complete endocrine evaluation was made in all patients at 6–8 weeks. Remission at follow-up was defined as a normal postoperative 24-h urinary free cortisol (UFC) or continued need for glucocorticoid hormone replacement after TSS. Results Overall, 32/40 patients (80%) were in remission after one or more TSS. Interestingly, a very good remission rate (92%) was observed in the subset of macroadenomas, similar to that found in the group of microadenomas (84%, NS), while no post-surgical remission was observed in the 3 patients with no visible adenoma at MRI ( p < 0.01). Of the 8 patients not in remission after repeated TSS surgery, 3 underwent radiation therapy and three had bilateral adrenalectomy, allowing remission of their hypercortisolism. There was minor morbidity and no death. Conclusion While our overall results are in accordance with other published series, we show here that ACTH-secreting pituitary macroadenomas are usually not associated with a bad outcome, in contrast with patients with no visible adenoma at preoperative MRI.

Dysfunction of the hypothalamic-pituitary-adrenal axis and functional somatic symptoms: A longitudinal cohort study in the general population

In persons with functional somatic symptoms (FSS), no conventionally defined organic pathology is apparent. It has been suggested that complex interactions of psychological, physiological, and social factors are involved in the etiology of FSS. One of the physiological mechanisms that may contribute to FSS is the function of the hypothalamic-pituitary-adrenal (HPA)-axis. This study investigates the association of HPA-axis function with cross-sectional presence and prospective development of FSS in the general population. This study was performed in a population-based cohort of 741 male and female adults (mean age 53.1, S.D. 10.9). Participants completed the somatization section of the Composite International Diagnostic Interview (CIDI) in which the presence of 43 FSS is surveyed. In addition to the total number of FSS, bodily system FSS clusters with musculoskeletal, gastrointestinal, cardiorespiratory, and general symptoms were constructed. HPA-axis function was assessed by measuring 24-h urinary free cortisol (24-h UFC) excretion. Follow-up measurements were performed approximately 2 years later. All analyses were adjusted for age, gender, body mass index, smoking, alcohol use, depression, exercise frequency, and urinary volume. Regression analysis detected no cross-sectional association between 24-h UFC excretion and the number of FSS (beta=-0.021, t=-0.521, p=0.603). In addition, 24-h UFC excretion was not associated with any of the bodily system FSS clusters (all p>0.050). Furthermore, 24-h UFC excretion did not predict new-onset FSS in the 2-year follow-up period (beta=0.021, t=0.566, p=0.572). We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population. We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population.

Usefulness of adrenal scintigraphy in the follow-up of adrenocortical incidentalomas: a prospective multicenter study

Prognostic factors for progression of benign adrenocortical adenomas (AI) remain poorly known. We assessed the usefulness of (131)I-6-beta-iodomethylnorcholesterol scintigraphy (IMS) to predict the occurrence of adrenal hyperfunction or mass enlargement. Fifty-one consecutive inpatients with unilateral AI and normal 24-h urinary free cortisol (UFC) were enrolled in a multicenter observational prospective study to investigate the relationship between the scintigraphic pattern and the progression of biological abnormalities of the hypothalamo-pituitary-adrenal axis or tumor size. Biochemically defined 'subclinical' Cushing's syndrome (SCS) was found at baseline in 47% of patients. Unilateral uptake (UU) was significantly associated with SCS (P<0.05). During the follow-up (4.3+/-1.6-year): 53% of patients showed unchanged hormonal evaluation, 29% displayed intermittent SCS and 18% showed definitive hormonal progression of SCS but without overt biochemical hypercortisolism. UU was associated with persistence of SCS and hormonal progression (P<0.01). In multivariate analysis, UU and impaired 1 mg dexamethasone suppression were independently associated with hormonal progression. Three patients with UU developed clinical CS despite persistently normal UFC. Tumor size increased in 10% patients and was not associated with any scintigraphic pattern. Evolution of SCS toward overt biochemical CS in patients with AI is a rare event during a 4-year follow-up. UU is predictive for the occurrence of SCS, its persistence and progression within the spectrum of SCS. Further studies aiming to establish the clinical consequences of SCS are needed to recommend IMS as a complementary evaluation in patients with AI and biochemical SCS.

A comparison of the characteristics of disease-free breast cancer survivors with or without cancer-related fatigue syndrome

PurposeTo determine the prevalence of cancer-related fatigue syndrome (CRFS) in a population of disease-free breast cancer survivors and to investigate the relationship between CRFS and clinical variables. Patients and methodsWomen (200) were recruited. All participants were between 3 months and 2 years after completion of primary therapy for breast cancer and were disease free. Subjects completed a diagnostic interview for CRFS and structured psychiatric interview. Participants also completed quality of life, mood and fatigue questionnaires, and provided a blood sample for haematological and biochemical analysis and a 24-h urine specimen for cortisol estimation. Subjects wore a wrist actigraph for 7 days to measure activity and sleep. ResultsSixty women (30% of participants) were found to fulfil the criteria for CRFS. There were statistically significant differences between fatigued and non-fatigued women with respect to fatigue severity (p<0.01), mood (p<0.01) and quality of life scores (p<0.05). There were significant differences in blood variables including raised total white cell count and lower sodium (all p<0.02). There was no difference in the 24h urinary free cortisol levels. Actigraphic data demonstrated significant differences in sleep quality and disturbance, but not in overall levels of daytime activity or circadian rhythm. ConclusionCRFS affects 30% of women after breast cancer treatment and has significant effects on quality of life and mood. There is some evidence that CRFS is related to sleep disturbance or to a persistent inflammatory or immune response.

Reversibles metabolisches Syndrom hormoneller Ursache

A 52-year-old male patient was admitted to the emergency department with dyspnea and hypertensive urgency. During the previous 6 months, the patient had noticed leg edema, weight gain (particularly in the face and abdomen), and impotence. 1.5 years ago, he was diagnosed with hypertension resistant to medication. After an accident at work 1 year ago, osteoporosis was diagnosed with vertebral and rib fractures. Measurement of sleeping midnight salivary cortisol levels together with 24-h urine free cortisol excretion and an overnight low-dose 1-mg dexamethasone suppression test proved overt hypercortisolism. The high-dose 8-mg dexamethasone suppression suggested an adrenal or ectopic source of hypercortisolism. By contrast, elevated adreno-corticotropic hormone (ACTH) levels and a corticotropin-releasing hormone stimulation test gave evidence for a pituitary source of hypercortisolism. However, pituitary magnetic resonance imaging failed to reveal a pituitary adenoma. Moreover, computed tomography scans of thorax and abdomen were negative. In this situation, an inferior petrosal vein sampling was performed and revealed an ACTH gradient (central-systemic) >3 with lateralization to the right side. The patient underwent a selective, partial, transsphenoidal resection and was cured from clinical signs and symptoms caused by hypercortisolism. Subsequent hormonal replacement therapy of postoperative pituitary insufficiency was necessary.

Long‐term basal and dynamic evaluation of hypothalamic–pituitary–adrenal (HPA) axis in acromegalic patients

Long-term effects of trans-naso-sphenoidal surgery (TNS) or long-acting somatostatin analogs (SSA) on the function of hypothalamic-pituitary-adrenal (HPA) axis have been poorly investigated. Aim of this study was to evaluate HPA axis integrity during the follow-up in patients with GH-secreting pituitary adenomas and preserved HPA function post-TNS or prior SSA. This retrospective study investigated 36 acromegalic patients (16M and 20F, age: 47 +/- 13 years), 20 of whom cured by TNS and 16 controlled by SSA therapy (12 previously operated and 4 in primary medical therapy), before and after long-term follow-up (median: 72 months, range: 12-240). No patient previously underwent radiotherapy. HPA function was studied by morning circulating cortisol and ACTH levels, 24-h urinary free cortisol (UFC) and cortisol response to low-dose short Synacthen test (LDSST, 1 microg) with a peak > 500 nmol/l as cut-off for normal function. Serum basal cortisol, ACTH and UFC levels were in the normal range and did not significantly change over time. As far as the cortisol peak after LDSST is concerned, 12 patients (32%, 8 TNS and 4 SSA) developed biochemical hypoadrenalism. None of the patients in primary medical therapy showed cortisol peak < 500 nmol/l. No significant correlations between HPA axis deterioration and follow-up duration, serum GH/IGF-I levels, occurrence of other pituitary deficiencies, presence of secondary empty sella, changes in tumour or residual volume were observed. The HPA axis function must be carefully monitored over the time by dynamic testing in all acromegalic patients, independently from the type of treatment.

The combined low-dose dexamethasone suppression corticotropin-releasing hormone test as a tool to rule out Cushing's syndrome

It remains to be evaluated whether the combined low-dose dexamethasone suppression corticotropin-releasing hormone test (LDDST-CRH test) may add to the diagnostic approach of patients suspected to have Cushing's syndrome (CS). The aim of the present study was to evaluate whether the LDDST-CRH test may have a place in the diagnostic strategy of CS. Prospective evaluation of a consecutive series of patients with suspected CS from 2004 to 2006. All the subjects underwent the same screening protocol including 1 mg dexamethasone suppression test, 24-h urinary free cortisol (UFC), and midnight serum cortisol, followed by the LDDST-CRH test whose results were not used to establish a definitive diagnosis. Plasma dexamethasone concentration was measured 2 h after the last dose of dexamethasone. Patients qualified for CS when at least two screening tests were positive. Sixteen patients had CS while in the remaining 15 subjects CS was excluded. Even if not statistically significant, the sensitivity and the negative predictive value of the cortisol 15 min after CRH were better than the other tests; on the other hand, the test specificity was lower. All of the patients classified as indeterminate were correctly diagnosed by the LDDST-CRH test. Nevertheless, the repeated assessment of the screening tests and the active follow-up gave the same correct results. In all of the patients misclassified by the LDDST-CRH test, the plasma dexamethasone concentrations were in the normal range. Based on our findings, we suggest that the LDDST-CRH test may still find a place as a rule-out procedure in patients who present with indeterminate results after screening and may be unavailable to repeat testing during follow-up.