Low-dose Dexamethasone Administration Research Articles

Comparison of high-versus low-dose corticosteroid administration on post-tonsillectomy outcomes.

Intraoperative steroids have been shown to decrease post-tonsillectomy morbidity; however, optimal dosing of corticosteroids is unknown. This study evaluates the effects of high-versus low-dose dexemethasone administration (0.5mg/kg vs. 0.1mg/kg) on post-tonsillectomy outcomes. Nonrandomized controlled study. Academic Medical Center. Pediatric patients undergoing tonsillectomy at the University of Michigan between 2017 and 2018 were identified. Uncomplicated patients between 1 and 18 years who received dexamethasone during their operation were included. Patients were categorized by high- or low-dose dexamethasone administration and outcomes assessed included revisits within 30 days for pain, vomiting/dehydration, and post-operative bleeding. The number of postoperative phone calls was also assessed. A total of 1641 patients were included in the study. No significant differences in steroid group outcomes were observed regarding vomiting (1.65% vs 1.7%, p=0.618), bleeding (1.09% vs 1.3%, p=0.579), pain (1.64% vs 0.62%, p=0.141), other morbidities (3.83% vs 3.57%, p=0.493) or post-operative phone calls (10.6% vs 9.9%, p=0.81). Post-tonsillectomy bleeding was higher for infectious etiology versus sleep disordered breathing (p=0.005); however, no rate differences for vomiting or pain were noted. Controlling for indication, no differences in hospital return rates were seen between steroid groups. No statistically significant differences in post-tonsillectomy outcome measures were observed based on administration of either high- or low-dose dexamethasone. With no observed outcome differences related to steroid dosing, we transitioned to routine use of low-dose dexamethasone for tonsillectomy and adenoidectomy.

OR24-06 USP8 Genetic Variants May Contribute to the Development of Bilateral Adrenal Hyperplasia and ACTH-Independent Cushing Syndrome

Background: Bilateral adrenocortical hyperplasias (BAHs), including primary pigmented nodular adrenocortical disease (PPNAD), isolated micronodular adrenocortical disease (iMAD) and primary macronodular adrenocortical hyperplasia (PMAH), are rare causes of ACTH-independent Cushing syndrome (CS). PPNAD and iMAD usually present in children or adolescents as multiple small (<1cm), cortisol-producing adrenocortical nodules. On the other hand, PMAH is most frequently identified in older patients with multiple large adrenal nodules. Most patients with PPNAD have PRKAR1A mutations whereas patients with PMAH may harbor variants in other genes (ARMC5, MC2R, GNAS, APC, MEN1). Even though several genes have been associated with ACTH-independent CS, there are still cases that the genetic cause has not been elucidated. Clinical cases: Herein, we present two unrelated patients with ACTH-independent CS that harbor USP8 gene variants. USP8 is mainly known for being mutated in Cushing disease but as a deubiquitinase it may be involved into the Wnt/β-Catenin signaling pathway.The first patient was diagnosed with BAH on prenatal ultrasound (26 gestational week) and subsequently required bilateral adrenalectomy for CS as she had virilization, hirsutism, hypertension and cardiac hypertrophy 9 weeks old. Adrenalectomy revealed that she had iMAD. She also presented with hemihypertrophy of the right leg, labia and mild newborn hypoglycemia, however she was negative for Beckwith-Wiedemann mutation. Gene analysis of PRKAR1A did not reveal any mutations. After whole exome sequencing (WES), we found a novel heterozygous USP8 variant (c.1387_1393delinsT, p.Ala463_Ile465delinsPhe) at germline level and loss of heterozygosity (LOH) at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in both of her adrenals compared to a control tissue.The second case is a 59-year old female with osteoporosis who failed to suppress cortisol levels after low dose dexamethasone administration. MRI revealed an adenoma on the right adrenal (2.6cm). She underwent right adrenalectomy and was found to have PMAH. We performed WES in germline level and we detected a novel heterozygous missense USP8 variant (c.287A>G, p.Lys96Arg) that is present also at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in her adrenal tumor compared to the control tissue. No LOH was identified. Conclusion: This is the first report of the association of USP8 in ACTH-independent CS and the preliminary findings support UPS8 involvement in the development of adrenocortical disease. We are currently performing further in vitro studies to evaluate the effect of these two USP8 variants into the canonical Wnt pathway which is commonly involved in adrenocortical disorders.

GLCCI1 rs37973

Glucocorticoids are the primary anti-inflammatory therapy for asthma, but their effects are characterized by some interindividual variability that might have a genetic basis.We aimed to determine the relationship between pulmonary function change and the variant of the glucocorticoid-induced transcript 1 (GLCCI1) gene in patients with asthma receiving long-term ICS treatment, the association of GLCCI1 genotypes and the level of GLCCI1 expression and cytokines production.A total of 418 patients with asthma, including 25 individuals from 11 families with a history of asthma, were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1 on changes in lung function in response to inhaled glucocorticoids were assessed. The expression levels of GLCCI1 mRNA and cytokines were also measured.The SNP rs37973 in GLCCI1 was independently associated with changes in forced expiratory volume at one second (FEV1) and FEV1%pred. Individuals homozygous for the wild-type allele who had a percent FEV1 change greater than 5% were more common than individuals homozygous for the rare allele. When patients were stratified according to genotype, GLCCI1 expression was enhanced upon administration of low-dose dexamethasone among patients with the rs37973 A allele; however, GG homozygotes required high-dose dexamethasone to achieve enhanced GLCCI1 expression. Furthermore, the levels of some cytokines were significantly reduced after glucocorticoid treatment in individuals with the AA and AG genotypes.The genetic variant rs37973 in GLCCI1 is associated with poorer clinical therapeutic response to inhaled glucocorticoids in a Chinese asthma population.

ATM splicing variants as biomarkers for low dose dexamethasone treatment of A-T

BackgroundAtaxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. Treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome. Nevertheless, the molecular mechanism underlying the glucocorticoid action in AT patients is not yet understood. Recently, we have demonstrated that Dexamethasone treatment may partly restore ATM activity in AT lymphoblastoid cells by a new ATM transcript, namely ATMdexa1.ResultsIn the present study, the new ATMdexa1 transcript was also identified in vivo, specifically in the PMBCs of AT patients treated with intra-erythrocyte Dexamethasone (EryDex). In these patients it was also possible to isolate new “ATMdexa1 variants” originating from canonical and non-canonical splicing, each containing the coding sequence for the ATM kinase domain. The expression of the ATMdexa1 transcript family was directly related to treatment and higher expression levels of the transcript in patients’ blood correlated with a positive response to Dexamethasone therapy. Neither untreated AT patients nor untreated healthy volunteers possessed detectable levels of the transcripts. ATMdexa1 transcript expression was found to be elevated 8 days after the drug infusion, while it decreased 21 days after treatment.ConclusionsFor the first time, the expression of ATM splicing variants, similar to those previously observed in vitro, has been found in the PBMCs of patients treated with EryDex. These findings show a correlation between the expression of ATMdexa1 transcripts and the clinical response to low dose dexamethasone administration.

Unforeseen role for glucocorticoids in combinatorial anti-obesity pharmacology.

Unforeseen role for glucocorticoids in combinatorial anti-obesity pharmacology.

Stronger pharmacological cortisol suppression and anticipatory cortisol stress response in transient global amnesia.

Transient global amnesia (TGA) is a disorder characterized by a sudden attack of severe anterograde memory disturbance that is frequently preceded by emotional or physical stress and resolves within 24 h. By using MRI following the acute episode in TGA patients, small lesions in the hippocampus have been observed. Hence, it has been hypothesized that the disorder is caused by a stress-related transient inhibition of memory formation in the hippocampus. To study the factors that may link stress and TGA, we measured the cortisol day-profile, the dexamethasone feedback inhibition and the effect of experimental exposure to stress on cortisol levels (using the socially evaluated cold pressor test and a control procedure) in 20 patients with a recent history of TGA and in 20 healthy controls. We used self-report scales of depression, anxiety and stress, and a detailed neuropsychological assessment to characterize our collective. We did not observe differences in mean cortisol levels in the cortisol day-profile between the two groups. After administration of low-dose dexamethasone, TGA patients showed significantly stronger cortisol suppression in the daytime profile compared to the control group (p = 0.027). The mean salivary cortisol level was significantly higher in the TGA group prior to and after the experimental stress exposure (p = 0.008 and 0.010 respectively), as well as prior to and after the control condition (p = 0.022 and 0.024, respectively). The TGA group had higher scores of depressive symptomatology (p = 0.021) and anxiety (p = 0.007), but the groups did not differ in the neuropsychological assessment. Our findings of a stronger pharmacological suppression and higher cortisol levels in anticipation of experimental stress in participants with a previous TGA indicate a hypersensitivity of the HPA axis. This suggests that an individual stress sensitivity might play a role in the pathophysiology of TGA.

Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

BMP-2 Adverse Reactions Treated With Human Dose Equivalent Dexamethasone in a Rodent Model of Soft-Tissue Inflammation

Basic science rodent model of bone morphogenetic protein-2 (BMP-2) soft-tissue inflammation. This study investigated the anti-inflammatory effect of human dose equivalent (HDE) dexamethasone (DM) for treatment of BMP-2-related soft-tissue inflammation in a rodent model and suggests an appropriate dose for utilization in the clinical practice of spine surgeons. BMP-2 is frequently used in spinal surgery to augment fusion. Yet, side effects of soft-tissue inflammation have been observed. DM decreases proinflammatory cytokine production and cellular immune response. However, the anti-inflammatory effects of HDE DM in a rodent model of BMP-2-associated soft-tissue inflammation have not been reported. Five, 10, and 15 mg of HDE DM were administered 3 times perioperatively to rodent cohorts receiving BMP-2 paraspinal implants and compared against BMP-2 only positive controls and phosphate buffer negative controls (n = 6 subjects per group). Histopathology, magnetic resonance imaging, and gross dissection were used as measures of cellular, edematous, and exudative inflammatory response. Serial killings were made on day 2 and day 7 postoperatively. Magnetic resonance imaging volume rendering demonstrated inflammatory edema decreased by 49% from 605.4 mm to 304.03 mm in subjects treated with 5, 10, or 15 mg of HDE DM (P < 0.05). Histopathological analysis demonstrated inflammatory cross-sectional area decreased 28.8% from 1.84 mm to 1.31 mm in subjects treated with 5, 10 or 15 mg of HDE DM (P < 0.05). Immune cellular infiltration depth decreased 38.5% from 0.26 mm to 0.16 in subjects treated with 15 mg of HDE DM (P < 0.05). Gross anatomical inflammatory exudates were prevented in 100% of subjects treated with 10 or 15 mg of HDE DM (P < 0.05). Low-dose DM administration is effective in controlling the cellular inflammation and edema resulting from BMP-2. Ten or 15 mg of DM might be considered by spine surgeons for controlling the inflammation and edema seen in spine surgery with BMP-2.

The Role of Unilateral Adrenalectomy in Corticotropin‐Independent Bilateral Adrenocortical Hyperplasias

The objective of the present study was twofold: to demonstrate our experience with unilateral adrenalectomy in the treatment of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS) caused by bilateral adrenocortical hyperplasias, and to evaluate the long-term results as evidenced by the main laboratory and clinical findings. From February 2000 to August 2009, unilateral adrenalectomy was performed on 27 patients with ACTH-independent CS and bilateral adrenocortical hyperplasias, including 14 patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and 13 patients with primary pigmented nodular adrenocortical disease (PPNAD). Signs and symptoms of CS, endocrine examinations, and radiographic imaging were evaluated preoperatively and postoperatively. At a median follow-up of 69 months (range: 23-120 months) for AIMAH and 47 months (range: 16-113 months) for PPNAD, 25 patients were cured by unilateral adrenalectomy. Serum cortisol level, daily urinary free cortisol (UFC), and plasma ACTH regained the normal range in both AIMAH and PPNAD patients at monthly follow-up visits; the circadian serum cortisol rhythm returned to normal, and a normal responsiveness to overnight low-dose dexamethasone administration (LDDST) became obvious. Both systolic and diastolic blood pressure (BP) levels were significantly reduced: 85 % of patients recovered normal BP levels, and the remaining patients need antihypertensive drugs, but at a reduced dose. No surgery-related morbidity occurred, and there was no sign of further enlargement of the residual adrenal gland after successful unilateral adrenalectomy. One patient with PPNAD and another patient with AIMAH with similar weights and sizes of the bilateral adrenals needed contralateral adrenalectomy. Unilateral adrenalectomy may be the suitable treatment for selected patients with AIMAH and PPNAD. It can achieve long-term remission of CS and improve glycemic control and BP values.

Routine screening for Cushing's syndrome is not required in patients presenting with hirsutism

Prevalence of Cushing's syndrome (CS) in patients presenting with hirsutism is not well known. Screening of CS in patients with hirsutism. Referral hospital. This study was carried out on 105 patients who were admitted to the Endocrinology Department with the complaint of hirsutism. All the patients were evaluated with low-dose dexamethasone suppression test (LDDST) for CS. Response to LDDST in patients presenting with hirsutism. All the patients had suppressed cortisol levels following low-dose dexamethasone administration excluding CS. The etiology of hirsutism was polycystic ovary syndrome in 79%, idiopathic hirsutism in 13%, idiopathic hyperandrogenemia in 6%, and nonclassical congenital hyperplasia in 2% of the patients. Routine screening for CS in patients with a referral diagnosis of hirsutism is not required. For the time being, diagnostic tests for CS in hirsute patients should be limited to patients who have accompanying clinical stigmata of hypercortisolism.

Thromboelastometry in veal calves to detect hemostatic variations caused by low doses of dexamethasone treatment

BackgroundThe illegal administration of hormones, steroids, β-agonists and other anabolic agents to productive livestock in the European Union continues, despite the long-term ban on their use and despite the measures provided under the directives to monitor certain substances and residues thereof in the interest of protecting consumer health and animal wellbeing. Often administered in low doses in the form of a drug cocktail, these compounds escape detection by common analytical techniques. The aim of this study was to determine whether low-dose dexamethasone administration (0.4 mg orally per day, for 20 days) in white-meat calves produced variations in blood coagulation, as measured by thromboelastometry. A second aim was to determine whether such variations could be valid in detecting illicit low-dose dexamethasone treatment.ResultsThe study population was 42 Friesian calves kept under controlled conditions until 6 months of age. The calves were subdivided into 2 groups: a control group (group A, n = 28) and a group treated with dexamethasone (group B, n = 14) for 20 days beginning at 5 months of age. When compared against the age-matched control group, the dexamethasone-treated calves showed a significant increase in alpha angle, maximum clot firmness and a significant decrease in clot formation time on all thromboelastometric profiles (P < 0.05). The clotting time was significantly decreased on the in-TEM® profile but increased on the ex-TEM® and fib-TEM® profiles (P <0.05). The Receiver Operating Characteristic curves, plotted for the Maximum Clot Elasticity (MCE), had a cut-off value ≥488.23 mm for in-TEM® MCE [Se 85.7%, (95% CI 57.2-98.2); Sp 100% 96.43% (95% CI 81.7-99.9] and a cut-off value ≥63.94 mm for fib-TEM® MCE [Se 92.8 (95% CI 66.1-99.8); Sp 89.3% (95% CI 71.8-97.7)]. In order to increase the sensitivity of the test two parameters (in-TEM® and fib-TEM® MCE) were used as two parallel tests; subsequently, the sensitivity rose to a point value of 99% (95% CI 85.4-99.9).ConclusionsThromboelastometry identified a state of hypercoagulability in the dexamethasone-treated subjects. Furthemore, the results of this preliminary study suggest that TEM may be useful in the detection of illicit low-dose dexamethasone treatment.

Enhanced cortisol suppression following administration of low-dose dexamethasone in first-episode psychosis patients

Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis and hyper-activity of this system have been described in patients with psychosis. Conversely, some psychiatric disorders such as post-traumatic stress disorder (PTSD) are characterised by HPA hypo-activity, which could be related to prior exposure to trauma. This study examined the cortisol response to the administration of low-dose dexamethasone in first-episode psychosis (FEP) patients and its relationship to childhood trauma. The low-dose (0.25 mg) Dexamethasone Suppression Test (DST) was performed in 21 neuroleptic-naïve or minimally treated FEP patients and 20 healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. FEP patients reported significantly higher rates of childhood trauma compared to controls (p = 0.001) and exhibited lower basal (a.m.) cortisol (p = 0.04) and an increased rate of cortisol hyper-suppression following dexamethasone administration compared to controls (33% (7/21) vs 5% (1/20), respectively; p = 0.04). There were no significant group differences in mean cortisol decline or percent cortisol suppression following the 0.25 mg DST. This study shows for the first time that a subset of patients experiencing their first episode of psychosis display enhanced cortisol suppression. These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored.

Low-dose dexamethasone administration for 3 weeks favorably affects plasma HDL concentration and composition but does not affect very low-density lipoprotein kinetics

Subclinical hypercortisolemia often occurs in subjects with features of the metabolic syndrome, and it has been suggested that it may be, at least in part, responsible for the development of these metabolic abnormalities. However, the metabolic effects of glucocorticoid administration to mimic subclinical glucocorticoid excess have not been evaluated. We used stable isotope-labeled tracer methods in conjunction with magnetic resonance techniques to measure the effect of glucocorticoid excess within the physiological range (~0.7 mg dexamethasone/day for 3 weeks) on glucose and free fatty acid (FFA) rates of appearance (Ra) into plasma, intrahepatic triglyceride (TG) content, very low-density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 (apoB-100) kinetics and plasma lipoprotein subclass concentrations, and particle sizes in nine overweight and obese individuals. Dexamethasone treatment led to a very small but significant increase in body weight (from 87.4±7.1 to 88.6±7.2 kg; P=0.003) and increased HDL-cholesterol (from 45.9±2.8 to 55.1±4.6 mg/dl; P=0.037) and HDL particle (from 33.7±2.2 to 41.4±4.2 nmol/l; P=0.023) concentrations in plasma but had no effect on intrahepatic TG content, glucose and FFA Ra in plasma, hepatic VLDL-TG and VLDL-apoB-100 secretion rates and mean residence times in the circulation, plasma TG and LDL-cholesterol concentrations, and plasma lipoprotein particle sizes. Subclinical hypercortisolemia does not have significant adverse metabolic consequences.

Prevention of postoperative nausea and vomiting in children following adenotonsillectomy, using tropisetron with or without low-dose dexamethasone

Postoperative nausea and vomiting (PONV) after adenotonsillectomy in children is, in spite of the prophylactic administration of tropisetron, still a frequent event. The aim of this study was to evaluate the benefit of the additional systemic administration of low-dose dexamethasone (0.15 mg x kg(-1)) for the prevention of PONV. With hospital ethics committee approval, we investigated children undergoing adenotonsillectomy receiving tropisetron (0.1 mg x kg(-1); maximum dose, 2 mg) or tropisetron (0.1 mg x kg(-1); maximum dose, 2 mg) plus dexamethasone (0.15 mg x kg(-1); maximum dose, 6 mg) intraoperatively. The incidence of vomiting episodes and the need for postoperative analgesics were recorded. Patient data were analyzed using the t-test and the chi(2) test (significance level of P = 0.05). Data values are means +/- SD. Ninety children (39 girls and 51 boys), aged 5.6 +/- 2.8 years and weighing 21.9 +/- 8.8 kg, were enrolled in the study. The overall incidence of vomiting was 38.9% within the first 24 h (67 vomiting events) and 44.4% within 48 h postoperatively (87 vomiting events). The incidence of vomiting in the tropisetron-only group was 53.3% (24/45) at 24 h and 60% (27/45) at 48 h (24 h: P < 0.001 and 48 h: P = 0.04) and 24.4% (11/45) at 24 h and 28.9% (13/45) at 48 h in the tropisetron-dexamethasone group. The need for postoperative nalbuphine was double in patients treated with tropisetron-dexamethasone (0.61 mg +/- 0.36 mg x kg(-1) x 48 h(-1)) compared to that in patients receiving only tropisetron (0.31 mg +/- 0.28 mg x kg(-1) x 48 h(-1); P < 0.0001). A low-dose bolus of dexamethasone (0.15 mg x kg(-1)) in combination with tropisetron, compared to tropisetron alone, considerably reduced the incidence of vomiting in children following pediatric adenotonsillectomy.

The dexamethasone‐suppressed corticotropin‐releasing hormone stimulation test and the desmopressin test to distinguish Cushing's syndrome from pseudo‐Cushing's states

Summary Objective Cushing's syndrome (CS), when fully expressed, is easily diagnosed. Mild cases, however, may require careful distinction from pseudo-Cushing's states as may occur in depression, alcoholism, polycystic ovary disease and visceral obesity. The aim of the present study is a reappraisal of the diagnostic accuracy of the two tests most commonly used to differentiate CS from pseudo-Cushing's: corticotropin-releasing hormone (CRH) stimulation after low dose dexamethasone administration and desmopressin stimulation. Design The study population comprised 32 patients with CS and 23 with pseudo-Cushing's evaluated retrospectively. Methods Urinary free cortisol (UFC), serum cortisol at midnight and after low dose dexamethasone (1 mg overnight and 2 mg over two days) were measured. Further, patients were tested with dexamethasone + CRH and desmopressin and the diagnostic performances of the two tests were compared in the entire series as well as in patients with mild hypercortisolism only (i.e. UFC < 690 nmol/24 h). Results As expected, measurement of UFC, assessment of cortisol rhythmicity and inhibition after 1 mg/2 mg dexamethasone failed to clearly classify patients with pseudo-Cushing's. Administration of CRH following 2-mg dexamethasone achieved 100% sensitivity but 62·5% specificity. Conversely, desmopressin testing correctly classified all but two patients with pseudo-Cushing's (90% specificity) with 81·5% sensitivity. Diagnostic accuracy was comparable in the subgroup with mild hypercortisolism (21 CS, all 23 pseudo-Cushing's patients). Desmopressin offered an incremental diagnostic effectiveness of 35·8/million inhabitants compared with dexamethasone + CRH as a second-line test. Conclusions Neither of the two tests guarantees absolute diagnostic accuracy. The specificity of dexamethasone + CRH is less brilliant than previously reported and appears to be inferior to desmopressin stimulation. The greatest diagnostic effectiveness results from the low-dose dexamethasone test combined with the desmopressin test. Skilful use of dynamic testing and balanced clinical judgement are necessary to distinguish between Cushing's syndrome and pseudo-Cushing's.

The dexamethasone‐suppressed corticotropin‐releasing hormone stimulation test and the desmopressin test to distinguish Cushing's syndrome from pseudo‐Cushing's states

Cushing's syndrome (CS), when fully expressed, is easily diagnosed. Mild cases, however, may require careful distinction from pseudo-Cushing's states as may occur in depression, alcoholism, polycystic ovary disease and visceral obesity. The aim of the present study is a reappraisal of the diagnostic accuracy of the two tests most commonly used to differentiate CS from pseudo-Cushing's: corticotropin-releasing hormone (CRH) stimulation after low dose dexamethasone administration and desmopressin stimulation. The study population comprised 32 patients with CS and 23 with pseudo-Cushing's evaluated retrospectively. Urinary free cortisol (UFC), serum cortisol at midnight and after low dose dexamethasone (1 mg overnight and 2 mg over two days) were measured. Further, patients were tested with dexamethasone + CRH and desmopressin and the diagnostic performances of the two tests were compared in the entire series as well as in patients with mild hypercortisolism only (i.e. UFC < 690 nmol/24 h). As expected, measurement of UFC, assessment of cortisol rhythmicity and inhibition after 1 mg/2 mg dexamethasone failed to clearly classify patients with pseudo-Cushing's. Administration of CRH following 2-mg dexamethasone achieved 100% sensitivity but 62.5% specificity. Conversely, desmopressin testing correctly classified all but two patients with pseudo-Cushing's (90% specificity) with 81.5% sensitivity. Diagnostic accuracy was comparable in the subgroup with mild hypercortisolism (21 CS, all 23 pseudo-Cushing's patients). Desmopressin offered an incremental diagnostic effectiveness of 35.8/million inhabitants compared with dexamethasone + CRH as a second-line test. Neither of the two tests guarantees absolute diagnostic accuracy. The specificity of dexamethasone + CRH is less brilliant than previously reported and appears to be inferior to desmopressin stimulation. The greatest diagnostic effectiveness results from the low-dose dexamethasone test combined with the desmopressin test. Skilful use of dynamic testing and balanced clinical judgement are necessary to distinguish between Cushing's syndrome and pseudo-Cushing's.

Myostatin Gene Deletion Prevents Glucocorticoid-Induced Muscle Atrophy

Glucocorticoids mediate muscle atrophy in many catabolic states. Myostatin expression, a negative regulator of muscle growth, is increased by glucocorticoids and myostatin overexpression is associated with lower muscle mass. This suggests that myostatin is required for the catabolic effects of glucocorticoids. We therefore investigated whether myostatin gene disruption could prevent muscle atrophy caused by glucocorticoids. Male myostatin knockout (KO) and wild-type mice were subjected to dexamethasone treatment (1 mg/kg.d for 10 d or 5 mg/kg.d for 4 d). In wild-type mice, daily administration of low-dose dexamethasone for 10 d resulted in muscle atrophy (tibialis anterior: -15%; gastrocnemius: -13%; P < 0.01) due to 15% decrease in the muscle fiber cross-sectional area (1621 +/- 31 vs. 1918 +/- 64 microm(2), P < 0.01). In KO mice, there was no reduction of muscle mass nor fiber cross-sectional area after dexamethasone treatment. Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity. In contrast, the mRNA of these enzymes and the proteasomal activity were not significantly affected by dexamethasone in KO mice. Muscle IGF-I mRNA was paradoxically decreased in KO mice (-35%, P < 0.05); this was associated with a potentially compensatory increase of IGF-II expression in both saline and dexamethasone-treated KO mice (2-fold, P < 0.01). In conclusion, our results show that myostatin deletion prevents muscle atrophy in glucocorticoid-treated mice, by blunting the glucocorticoid-induced enhanced proteolysis, and suggest an important role of myostatin in muscle atrophy caused by glucocorticoids.

Changes in Insulin Secretion and Glucose Metabolism Induced by Dexamethasone in Lean and Obese Females

In healthy lean individuals, changes in insulin sensitivity occurring as a consequence of a 2-day dexamethasone administration are compensated for by changes in insulin secretion, allowing glucose homeostasis to be maintained. This study evaluated the changes in glucose metabolism and insulin secretion induced by short-term dexamethasone administration in obese women. Eleven obese women with normal glucose tolerance were studied on two occasions, without and after 2 days of low-dose dexamethasone administration. A two-step hyperglycemic clamp (7.5 and 10 mM glucose) with 6,6 (2)H(2) glucose was used to assess insulin secretion and whole body glucose metabolism. Results were compared with those obtained in a group of eight lean women. Without dexamethasone, obese women had higher plasma insulin concentrations in the fasting state, during the first phase of insulin secretion, and at the two hyperglycemic plateaus. However, they had normal whole body glucose metabolism compared with lean women, indicating adequate compensation. After dexamethasone, obese women had a 66% to 92% increase in plasma insulin concentrations but a 15.4% decrease in whole body glucose disposal. This contrasted with lean women, who had a 91% to 113% increase in plasma insulin concentrations, with no change in whole body glucose disposal. Dexamethasone administration led to a significant reduction in whole body glucose disposal at fixed glycemia in obese but not lean women. This indicates that obese women are unable to increase their insulin secretion appropriately.

Case Report: Pancreatic neuroendocrine tumor with ectopic ACTH-production upon second recurrence

A 54-year-old woman suffered from diarrhoea, heartburn and unspecific abdominal pain. A tumor in caput pancreatis with metastases in lymphatic nodules was diagnosed and completely resected. The histological diagnosis was carcinoid. Fourteen months after surgery abdominal CT and somatostatin-receptor scintigraphy suggested relapse of the tumor. At this time the patient reported no symptoms. Laboratory values were all in the normal range. A second in toto resection was performed. Histological investigation confirmed relapse of the pancreas carcinoid without metastases. Eight months later the patient suffered from adynamia, mental disorder, muscle weakness, weight loss, plethora and developed diabetes mellitus. Further laboratory investigation showed hypokalemia, increased serum cortisol, 24h-urinary cortisol and ACTH. Subsequent endocrinological testing revealed no suppression of 8.00 a.m. serum cortisol after administration of low-dose dexamethasone as well as lack of suppression of 8.00 a.m. serum cortisol after high-dose dexamethasone. ACTH remained high and did not rise further after injection of CRH. Therefore an ectopic ACTH production was supposed. The search for a focus of ectopic ACTH production disclosed an intensive enhancement of the tracer ventro-medial of the left kidney in octreotid scintigraphy. In abdominal MRI a tumor of 3×4x5cm size lateral of the superior mesenteric artery was seen. A rest-pancreatectomy with splenectomy and left-side adrenalectomy was performed. The pathological diagnosis was a second relapse of the pancreatic neuroendocrine carcinoma without metastases. In contrast to the primary tumor and the first relapse, immunostaining of tissue for ACTH was strongly positive. This is to our knowledge the first case describing a pancreatic neuroendocrine tumor which started to produce ACTH de novo at the time of the second relapse after two complete tumor resections. The case underscores the importance of keeping in mind a possible hormone shift of neuroendocrine tumors even after complete tumor resection and in the absence of metastases.

Cortisol levels are positively correlated with hippocampal N-acetylaspartate

Background This study examined the relationship of hypothalamic–pituitary–adrenal measures and hippocampal N-acetylaspartate (NAA) in posttraumatic stress disorder (PTSD) patients and control subjects. Methods Eleven patients with combat-related PTSD and 11 control subjects were evaluated with magnetic resonance spectroscopy as well as by morning salivary cortisol samples before and after administration of low-dose dexamethasone (.5 mg). Results Left hippocampal NAA was strongly associated with both pre-dexamethasone cortisol levels ( n = 22, r = .53, p = .013) and post-dexamethasone cortisol levels ( n = 22, r = .63, p = .002). After accounting for clinical symptom severity and hippocampal volume, cortisol levels accounted for 21.9% of the variance ( F = 5.6, p = .004) in left hippocampal NAA and 12.6% of the variance ( F = 3.2, p = .035) in right hippocampal NAA. Conclusions This study shows a positive relationship between cortisol levels and hippocampal NAA in subjects without hypercortisolemia. Within the range of values seen in our subjects, cortisol may have a trophic effect on the hippocampus.