Intravenous Dexamethasone Suppression Test Research Articles

Glucocorticoid Sensitivity Among Young Survivors of Childhood Acute Lymphoblastic Leukemia: What Does It Matter?

The aim of the study was to assess glucocorticoid sensitivity in survivors of childhood acute lymphoblastic leukemia using in vivo and in vitro tests. Thirty leukemia survivors of both sexes aged ≥18 years participated in the study and at least two years after therapy withdrawal. In vivo tests comprised: a) a very low dose intravenous dexamethasone suppression test for measurement of serum cortisol before, after, and % suppression, compared with 32 age-matched controls; and b) 0.25 mg overnight oral dexamethasone suppression test for assessment of salivary cortisol before, after, and % suppression. In vitro methods comprised: c) glucocorticoid receptor polymorphisms: BcI1-NR3C1 and A3669G; and d) splicing variant of glucocorticoid receptor GR-α mRNA by real-time quantitative polymerase chain reaction, compared with 32 controls. There was a reduction in salivary cortisol, and 73.3% of leukemia survivors showed high sensitivity according to % suppression after oral dexamethasone (p<0.05). Serum cortisol at baseline, after the test, % suppression after intravenous dexamethasone, and the percentage of high sensitivity were reduced in the leukemia group (%F=36.7; p<0.05). The BcI1-NR3C1 and A3669G polymorphisms were present in 11/30 (36.7%) and 5/30 (16.7%) patients, respectively. GR-α mRNA levels were lower in the leukemia group than in the controls (p<0.05). Survivors of acute lymphoblastic leukemia presented with reduced glucocorticoid sensitivity. Glucocorticoid sensitivity allows individualized treatment to avoid adverse effects and may be involved in cardiovascular disease risk among this particular group of cancer survivors.

Usefulness of the 4-mg intravenous dexamethasone suppression test in differentiating Cushing disease from pseudo-Cushing syndrome - a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Performance of the 4-mg intravenous dexamethasone suppression test in differentiating Cushing disease from pseudo-Cushing syndrome

ContextDiscriminating Cushing disease (CD) from pseudo-Cushing syndrome (PCS) is a challenging task that may be overcome with the 4-mg intravenous (IV) dexamethasone suppression test (DST). ObjectiveAssess the performance of the 4-mg IV DST in the differential diagnosis between CD and PCS in well-characterized patients. DesignRetrospective comparative study of subjects seen in a tertiary care unit (November 2008 to July 2011). MethodsThirty-six patients with PCS and 32 patients with CD underwent 4-mg IV dexamethasone infusions from 11 am to 3 pm. Areas Under ROC Curves (AUCs) were estimated and compared for ACTH and cortisol measured at 4 pm the same day (day 1) and 8 am the next day (day 2). The ROC curve of the marker with the highest AUC was used to determine the threshold with the highest specificity for 100% sensitivity. ResultsThe AUC of ACTH at 8 am on day 2 was estimated at 98.4% (95% CI: [92.1–100]), which is significantly greater than that of ACTH at 4 pm on day 1 (P=0.04) and that of cortisol at 8 am on day 2 (P=0.05). For ACTH at 8 am on day 2, the threshold with the highest specificity for 100% sensitivity was estimated at 14.8ng/L. At this threshold, the sensitivity was estimated at 100% [89–100] and the specificity at 83.3% [67–94]. ConclusionThe 4-mg IV DST is an easy and accurate tool in distinguishing CD from PCS. It deserves thus a better place in establishing the diagnosis of CD.

Persistent glucocorticoid resistance in systemic lupus erythematosus patients during clinical remission

Glucocorticoids (GCs) are key drugs in the treatment of systemic lupus erythematosus (SLE). GC dose reduction during remission is related to disease activity, GC dose used, length of treatment, and individual GC sensitivity. We compared GC receptor α (GRα) isoform and nuclear factor kappaB (NF-κB) messenger RNA quantitation and in vivo GC sensitivity between SLE patients during remission and healthy controls. We performed a cross-sectional study of 19 women aged 22-49 years, including 9 SLE patients in clinical remission taking ≤5 mg prednisone and 10 matched controls. We evaluated GC sensitivity using 2 cortisol suppression tests: a very-low-dose intravenous dexamethasone suppression test (VLD-IV-DST) and a low-dose oral dexamethasone suppression test. GRα and NF-κB mRNA were quantified using real-time polymerase chain reaction. Although basal cortisol and adrenocorticotropic hormone levels were similar between the groups, the percentage of cortisol reduction after the VLD-IV-DST was 56% lower in SLE patients than in controls (P = 0.014). GRα and NF-κB gene expression levels were similar between the groups. The low-dose oral dexamethasone test caused intense cortisol suppression in all individuals, limiting the ability of this test to discriminate individual GC sensitivity. A positive correlation was found between the extent of cortisol suppression in vivo (VLD-IV-DST) and the number of days elapsed since the last flare of lupus activity. Despite clinical remission, SLE patients displayed partial GC resistance recognized by the VLD-IV-DST. The mechanism of this resistance is unrelated to altered GRα and NF-κB mRNA expression.

The 4‐mg intravenous dexamethasone suppression test in the diagnosis of Cushing’s syndrome

Optimal diagnostic criteria for the 4-mg intravenous dexamethasone suppression test (IVDST) in patients with Cushing's syndrome (CS), compared with normal subjects, have not been established. We evaluated the performance of the 4-mg IVDST for differentiating CS from normal subjects and to define the responses in CS of various aetiologies. DESIGN, SUBJECTS, MEASUREMENTS: Thirty-two control subjects [normal and overweight/obese participants with or without type 2 diabetes) were prospectively studied, and data from 66 patients with Cushing's disease (CD), three with ectopic ACTH syndrome (EAS), 14 with adrenal Cushing's (AC)] and 15 with low probability of CS (LPC) from three tertiary hospitals were retrospectively evaluated. Dexamethasone was infused at 1 mg/h for 4 h. Plasma cortisol and ACTH were measured at -60 min (baseline), -5 min, +3 h, +4 h, +5 h and at +23 and +23.5 h on Day 2. Control subjects (including those with type 2 diabetes) exhibited a marked suppression of cortisol which was maintained until Day 2. Two of 15 patients with LPC had Day 2 cortisol results that overlapped with CS. Patients with CD demonstrated partial suppression, with rebound hypercortisolism on Day 2. Patients with AC and EAS did not suppress cortisol levels. Day 2 cortisol level of >130 nmol/l (or >20% of the baseline) diagnosed CS with 100% sensitivity and 96% specificity. While the IVDST allowed complete discrimination between control subjects and CS, 13% of LPC overlapped with CS. Given the small number of EAS, no conclusion can be drawn regarding the utility of this test in the differential diagnosis of CS.

Impact of Prolonged Low-Grade Physical Training on the in vivo Glucocorticoid Sensitivity and on Glucocorticoid Receptor-α mRNA Levels of Obese Adolescents

Background/Aim: Healthy individuals present variable responses of the hypothalamic-pituitary-adrenal (HPA) axis induced by different patterns of physical training. The aim of this study was to evaluate whether prolonged low-grade physical training influences the HPA axis and also glucocorticoid receptor-α (GRα) mRNA levels in mononuclear cells of obese adolescents. Methods: We studied 19 patients with BMI above the 95th percentile (male:female ratio 7:12) aged from 9.5 to 15.5 years. Patients underwent a 12-week physical exercise program. Before and after exercise, in vivo glucocorticoid sensitivity was determined by employing a very-low-dose intravenous dexamethasone suppression test, and in vitro GRα mRNA levels were evaluated by quantitative real-time PCR. Results: After exercise there was a trend to reduce the in vivo glucocorticoid sensitivity (p = 0.071) and a significant increase in GRα mRNA levels (p = 0.025). Conclusion: For this subset of obese adolescents, prolonged low-grade physical training tended to reduce glucocorticoid sensitivity. The discrepancy of cortisol response to dexamethasone and the GRα mRNA measurement suggest a post-receptor phenomenon or should be related to target tissue-specific differences in glucocorticoid sensitivity. Future studies should address the adaptive GRα mRNA during different exercise protocols, and also the correlation of pituitary sensitivity with glucocorticoid target tissue sensitivity.

Quantitation of glucocorticoid receptor alpha and NF-κB pathway mRNA and its correlation with disease activity in rheumatoid arthritis patients

We measured NF-κB, IKK, c-Fos, and GRα mRNA expression and in vivo glucocorticoid sensitivity in patients with rheumatoid arthritis. A very low dose intravenous dexamethasone suppression test and real-time PCR quantitation of mRNA of these genes were performed on blood samples from 21 rheumatoid arthritis patients who were not on glucocorticoids during the previous four months and on blood samples from 20 healthy individuals. Mean rheumatoid arthritis duration was 8.8 years, and mean disease activity, as assessed by Disease Activity Score 28 (DAS28), was 4.45. Basal cortisol and the percentage of cortisol reduction after the very low dose intravenous dexamethasone suppression test, as well as NF-κB, IKK, c-Fos, and GRα mRNA expression, were similar among groups. We did not observe significant correlations between glucocorticoid in vivo sensitivity and DAS28. There was a positive correlation between DAS28 and NF-κB, IKK, and GRα, but not c-Fos. In the multivariate analysis, only NF-κB mRNA remained as an independent variable for predicting DAS28.

Impact of Prolonged Physical Training on the Pituitary Glucocorticoid Sensitivity Determined by Very Low Dose Intravenous Dexamethasone Suppression Test

The activity of the hypothalamic-pituitary-adrenal axis is usually modulated by several stress factors, including exercise. Different responses are induced by physical training according to duration and intensity of exercise. During prolonged training, cortisol remains normal or decreased as a consequence of altered cortisol secretion, metabolism and excretion, and possibly by changes in glucocorticoid sensitivity. The aim of this study was to evaluate the impact of prolonged physical training on the glucocorticoid sensitivity. Eighteen cadets of the Air Force Academy, mean (SD) age: 18.7 (1.0) years, underwent an intensive 6-week preparatory training-period considered adequate by inducing significant changes on body composition measured by bioelectrical impedance. Measurement of individual's pituitary glucocorticoid sensitivity was done by an intravenous very low dose dexamethasone suppression test (20 microg/m (2)) that was performed before and after the training period. Cortisol levels were obtained at basal condition and 120 minutes after the dexamethasone infusion. Basal cortisol showed a significant decrease after prolonged training. The percent cortisol suppression after dexamethasone tended to be lower after the training period. Overall, our data suggest that prolonged physical training is able to reduce glucocorticoid sensitivity, which can have a beneficial impact in chronic stress conditions.

A Very Low Dose Intravenous Dexamethasone Suppression Test as an Index of Glucocorticoid Sensitivity

Background/Aims: The wide variability of responses to corticotherapy suggests a role for individual recognition of steroid sensitivity in order to customize treatment. Oral dexamethasone (DEX) administration may be hindered by the rate of its intestinal absorption and the liver first-passage effect. In this study we suggest that an intravenous very low dose DEX suppression test (VLD IV-DST) can be used as an index for glucocorticoid (GC) sensitivity. Methods: We evaluated 87 normal subjects: 44 prepubertal children, 23 adolescents and 20 adults with a VLD IV-DST using 20 µg/m² of DEX (dose able to recognize GC sensitivity). Cortisol was initially measured at several time-points after DEX prompting us to establish its nadir and subsequent simplification of the test by measuring cortisol at baseline and after 120 min. Results: Baseline cortisol was similar in adolescents and in adults, but lower in children. There was a spectrum of individual responses in all age groups. The percent reduction of cortisol after 120 min was different in these three age groups, with median values of 44.4% in children, 25.9% in adolescents and 61.6% in adults. Conclusion: This simplified VLD IV-DST using 20 µg/m² of DEX is useful to evaluate individual sensitivity to GC in different age groups.

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients

Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women. Ten glucose-normotolerant, fertile, obese women (BMI >40 kg/m2, aged 38.66 +/- 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P = 0.05) and postobese women (P < or = 0.01) as was the decrease in dehydroepiandrosterone (P < or = 0.05 and P < or = 0.01, respectively). CBG decreased from 51.50 +/- 12.76 to 34.33 +/- 7.24 mg/l (P < or = 0.01) following BPD. FCI increased from 11.15 +/- 2.85 to 18.16 +/- 6.82 (P < or = 0.05). Insulin secretion decreased (52.04 +/- 16.71 vs. 30.62 +/- 16.32 nmol/m(-2); P < or = 0.05), and insulin sensitivity increased by 163% (P < or = 0.0001). Serum CBG was related to BMI (r(0) = 0.708; P = 0.0001), body weight (r(0) = 0.643; P = 0.0001), body fat percent (r(0) = 0.462; P = 0.001), C-reactive protein (r(0) = 0.619; P = 0.004), and leptin (r(0) = 0.579; P = 0.007) and negatively to M value (r(0) = -0.603; P = 0.005). After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity.

Dexamethasone Infusion Testing in the Diagnosis of Cushing's Syndrome

Cushing's syndrome and its various aetiologies is a markedly difficult diagnosis to make given its subtle signs, sometime cyclical nature, and the lack of a single definitive diagnostic test. Although a great variety of diagnostic tests have been developed to assist in the diagnosis, even with the best clinical acumen, biochemistry and medical imaging the diagnosis can remain elusive. The long low and high dose oral dexamethasone suppression test is cumbersome, costly and often requiring an extended inpatient stay. The utility of the dexamethasone suppression test would be greatly enhanced if it could be performed as a short outpatient procedure. In this study we sought to confirm and refine the clinical utility of the high dose 4 mg intravenous dexamethasone suppression test as an alternative diagnostic test for Cushing's syndrome. There were a total of 31 subjects: 8 patients with proven pituitary Cushing's disease, 3 with primary adrenal tumors, 10 with pseudo-Cushing's syndrome and 10 healthy controls. All subjects with pseudo-Cushing's syndrome suppress serum cortisol at +5 and at +24 hours. In subjects with pituitary Cushing's disease, 7 out of 8 (88%) had serum cortisol suppressed at +5 hours but rebounded at +24 hours to at least 70% of the original serum level. Primary adrenal tumors showed a pattern of non-suppression throughout. The 4 mg intravenous dexamethasone suppression test is excellent in ruling out pseudo-Cushing's syndrome. This test is much simpler and more convenient than the oral dexamethasone suppression test in confirming clinical suspicion of pituitary Cushing's disease.

The continuous 7-hour intravenous dexamethasone suppression test in the differential diagnosis of ACTH-dependent Cushing's syndrome.

A recent report showing disappointingly low sensitivity and specificity for the oral high dose dexamethasone test in the differential diagnosis of Cushing's syndrome prompted us to re-evaluate the results obtained in our centre using the continuous 7-hour intravenous dexamethasone suppression test for this purpose. 105 patients with ACTH-dependent Cushing's syndrome were included in this study; 78 with Cushing's disease, 8 with ectopic ACTH-secreting tumours and 19 were classified as 'of unknown aetiology'. In 74/78 (94.9%) of patients with Cushing's disease and in 3/8 (37.5%) patients with the ectopic ACTH syndrome, a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values was achieved in the continuous 7-hour intravenous dexamethasone suppression test. Using a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values as the cut-off value, the sensitivity and specificity of the continuous 7-hour intravenous dexamethasone suppression test for the diagnosis of Cushing's disease in patients with ACTH-dependent Cushing's syndrome were 94.9% and 62.5%, respectively. In patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease > 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test, additional localizing investigations such as bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy should be performed when no clearly discernible pituitary adenoma is observed on MRI studies. Patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease < 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test should also undergo bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy to demonstrate the presence of a nonpituitary source of ACTH overproduction.

Establishment of reference values for endocrine tests: I. Cushing's syndrome

Background: For diagnostic tests used in the evaluation of patients with Cushing's syndrome, well defined reference values were lacking in our laboratory. In the present study, we established reference values based upon test results of 50 subjects recruited from the general population.Methods: We studied 50 subjects not suspected of having Cushing's syndrome, equally distributed according to sex and age between 20 and 69 years. In addition to 24 h urinary excretion of free cortisol for two days, a low-dose (1 mg) overnight dexamethasone suppression test, a corticotropin releasing hormone stimulation test (CRH test) and a high-dose (7 mg) intravenous dexamethasone suppression test were performed. Reference values are given as the observed range.Results: There was considerable intra-subject variation in 24 h urinary cortisol excretion which could not be merely attributed to incompleteness of the urine collection. The following reference values were established: 24 h urinary free cortisol excretion: 15–145 nmol/24 h; overnight dexamethasone suppression test: cortisol on day 2 <50–230 nmol/l; CRH test: cortisol increase 15–289%, ACTH increase 36–12.100%; high-dose, intravenous dexamethasone suppression test: cortisol after 7 h <50–97 nmol/l; cortisol after 24 h <50–50 nmol/l. There were no significant effects of age on any of the parameters studied. Apart from higher basal ACTH plasma concentrations in men, no sex differences were observed.Conclusion: We established reference values for tests that can be useful in the evaluation of patients with possible Cushing's syndrome.

Hypercortisolism in septic shock is not suppressible by dexamethasone infusion

To explore the feedback regulation of glucocorticoids on corticotropin secretion in patients with septic and nonseptic circulatory shock. Prospective study. An intensive care unit of a general hospital. Two groups of patients with septic shock (n = 11) or nonseptic shock (n = 7). A control group (n = 20) was also studied. Intravenous dexamethasone (1 mg/hr for 4 hrs) suppression test. Plasma concentrations of corticotropin-releasing factor, beta-lipotropin, and corticosteroid-binding globulin measured by radioimmunoassays, and plasma cortisol measured by radiocompetition assay; the ratio of cortisol to corticosteroid-binding globulin calculated as the free cortisol index. In both groups of patients, the concentrations of plasma cortisol and beta-lipotropin, and the ratio of cortisol to corticosteroid-binding globulin, were higher than normal subjects (p < .001) and were not different between septic and nonseptic shock patients, whereas the plasma corticosteroid-binding globulin concentration was significantly (p < .001) lower in septic shock patients than in normal subjects (444 +/- 154 vs. 696 +/- 56 nmol/L [22.0 +/- 7.6 vs. 34.5 +/- 2.8 mg/L]), but not significantly lower in nonseptic shock patients (607 +/- 157 nmol/L [30.0 +/- 7.8 mg/L]). In contrast to the complete suppressive effect of dexamethasone infusion on cortisol and beta-lipotropin concentrations in normal subjects, dexamethasone did not suppress cortisol or lipotropin in either septic or nonseptic shock patients. During circulatory shock, hypercortisolism is associated with high concentrations of lipotropin, and is not suppressible by intravenous dexamethasone infusion.

Continuous Dexamethasone Infusion for Seven Hours in Patients with the Cushing Syndrome

To determine the usefulness of the continuous intravenous dexamethasone suppression test in the differential diagnosis of patients with the Cushing syndrome. Comparison of the results of this test with those of other tests in the study population and with data from the literature. Referral-based endocrine division in a university hospital. One hundred and twenty-one patients with the Cushing syndrome were evaluated: corticotropin (ACTH)-secreting pituitary tumors, 90 cases; adrenal adenoma, 13; adrenal carcinoma, 9; ectopic ACTH-secreting tumors, 6; corticotropin-releasing-hormone (CRH)-secreting tumors, 2; and autonomous bilateral micronodular adrenal hyperplasia, 1. The continuous intravenous dexamethasone suppression test was done in 101 patients. Dexamethasone (1 mg/h) was administered intravenously for 7 hours. A cortisol decrease of at least 190 nmol/L was defined as a positive response. In identification of patients with ACTH-secreting pituitary adenomas, this test had a sensitivity of 100% (95% CI, 95% to 100%), a specificity of 90% (CI, 70% to 99%), and a diagnostic accuracy of 98% (CI, 93% to 100%). Only two patients had false test results. They both had CRH-secreting tumors. Cortisol secretion was also shown to be sensitive for feedback control in other tests, however. The continuous intravenous dexamethasone suppression test has better diagnostic accuracy than other tests that are currently used in the differential diagnosis of the Cushing syndrome, and this test is very convenient. The only false test results were found in patients with CRH-secreting tumors.

A weight-related intravenous dexamethasone suppression test distinguishes obese controls from patients with Cushing's syndrome.

To establish a rapid test for Cushing's syndrome we measured serum cortisol during and following iv dexamethasone infusion (5 micrograms.kg-1.h-1 for 5 h from 10.00 h) in simple obesity (N = 19) and in Cushing's syndrome (N = 12). We had first established that 5 micrograms.kg-1.h-1 was the lowest dose which consistently lowered serum cortisol in simple obesity. In obesity, serum cortisols ranged from undetectable (less than 30) to 48 nmol/l at 17.00, less than 30 to 37 at 19.00 and less than 30 to 38 at 08.00 h the following day. Serum cortisol at these three times did not show any overlap between simple obesity and Cushing's syndrome. Having established these findings we proceeded to study a group of patients with polycystic ovarian disease. These patients behaved differently. Their values at 17.00 and 19.00 h did not overlap those of Cushing's syndrome. However, at 08.00 h, 5 of the 7 had values within the range seen in Cushing's syndrome with a mean of 290 +/- 99 nmol/l. In conclusion, 17.00 and 19.00 h serum cortisol levels distinguish between Cushing's syndrome and both simple obesity and polycystic ovarian disease. However, in the latter, cortisol suppression is less prolonged than in simple obesity. This finding may be important for our understanding of the pathogenesis of the disease.