The Low-Dose Dexamethasone Suppression Test:A Reevaluation in Patients with Cushing’s SyndromeJAMES W.FINDLING,HERSHEL RAFF,ANDDAVID C.ARONThe Endocrine-Diabetes Center (J.W.F.,H.R.),St.Luke’s Medical Center and Medical College of Wisconsin,Milwaukee,Wisconsin 53215;and Division of Clinical and Molecular Endocrinology,Department of Medicine (D.C.A.),Louis Stokes Department of Veterans Affairs Medical Center and Case Western Reserve University School of Medicine,Cleveland,Ohio 44106Low-dose dexamethasone suppression testing has been rec-ommended for biochemical screening when Cushing’s syn-drome is suspected.The criterion for normal suppression of cortisol after dexamethasone is controversial.To assess diag-nostic utility (sensitivity),we report the results of low-dose dexamethasone suppression testing in 103patients with spon-taneous Cushing’s syndrome.There were 80patients with Cushing’s disease (78%),13with the ectopic ACTH syndrome (13%),and 10with cortisol-producing adrenocortical adeno-mas (10%).Fourteen (18%)of 80patients with Cushing’s dis-ease suppressed serum cortisol to less than 5g/dl (<135nmol/liter)after the overnight 1-mg test,whereas six patients (8%)actually showed suppression of serum cortisol to less than 2g/dl (<54nmol/liter).In addition,the 2-d,low-dose dexameth-asone suppression test yielded false-negative results in 38%of patients when urine cortisol was used and 28%when urinary 17-hydroxycorticosteroids were used.Serum cortisol after the 1-mg test correlated with baseline urinary free cortisol (r ؍0.705,P <0.001),plasma ACTH level (r ؍0.322,P ؍0.001),and urinary free cortisol after the 2-d test (r ؍0.709,P ؍0.001).This study provides evidence that low-dose dexamethasone may suppress either plasma cortisol or urinary steroids to levels previously thought to exclude Cushing’s syndrome and that these tests should not be used as the sole criterion to exclude the diagnosis of endogenous hypercortisolism.(J Clin Endocrinol Metab 89:1222–1226,2004)THE DIAGNOSIS OF spontaneous Cushing’s syndrome is a very challenging problem in clinical endocrinology (1).The differentiation of patients with true pathological endogenous hypercortisolism from the large number of pa-tients with the Cushing’s phenotype may be very difficult.There are remarkable similarities between the metabolic syn-drome and Cushing’s syndrome.Excessive and sustained cortisol secretion has long been associated with the entire clinical spectrum of the metabolic syndrome including obe-sity,insulin resistance,dyslipidemia,hypertension,and di-abetes (1,2).Clinical improvement (e.g.blood pressure re-duction,weight reduction,and improvement in glycemic control)has been observed after adrenal surgery in some patients with incidentally discovered adrenocortical tumors and subclinical hypercortisolism.These observations em-phasize the importance of discovering and treating even mild Cushing’s syndrome (2–4).Biochemical confirmation of Cushing’s syndrome has re-lied upon the measurement of urinary free cortisol over a 24-h period and low-dose dexamethasone suppression test-ing (1).Low-dose dexamethasone suppression testing,espe-cially the 1-mg overnight test,has been the mainstay of biochemical screening and is recommended in most standard texts.Although it has been appreciated for many years that false-positive results are not uncommon with low-dose dexa-methasone suppression testing,it has previously been thought that false-negative results were relatively rare (1).There are three major concerns about applying publishedresults in clinical practice.First,the methodology of cortisol assays has changed over time,with newer assays having higher specificity (1,5).Second,the number of patients with Cushing’s syndrome in most series is relatively small.Consequently,the recommendations regarding low-dose dexamethasone sup-pression testing has been based on compilations of studies using different cut points,different protocols,and different methods of cortisol measurement (6).Finally,recommenda-tions have not sufficiently taken into account the distinction between efficacy and effectiveness (7).As applied to diagnostic testing,efficacy refers to the degree to which the test has been shown scientifically under ideal conditions to accomplish the desired outcome.In contrast,effectiveness refers to the degree to which the test achieves this outcome in actual clinical prac-tice.Most published studies have been performed in research venues using the same intramural assays and methodologies,and thus,are efficacy studies.On the other hand,the effective-ness of tests in clinical practice using a variety of approaches and reference laboratories has not been extensively evaluated.We studied 203consecutive patients with Cushing’s syn-drome referred to a single endocrinologist over a 15-yr pe-riod.To assess the effectiveness of low-dose dexamethasone suppression testing as a screening test,we now report the results from 103of these 203patients who had completed such testing.This study,performed in clinical practice,shows that some patients with Cushing’s syndrome suppress either plasma cortisol or urinary steroids to levels previously thought to exclude the diagnosis.Patients and MethodsStudy design and populationWe evaluated a case series of 203consecutive patients with Cushing’s syndrome referred to a single clinician (J.W.F.)from 1984–1998,of whomAbbreviation:17OH-corticosteroid,17-Hydroxycorticosteroids.JCEM is published monthly by The Endocrine Society (),the foremost professional society serving the en-docrine community.0021-972X/04/$15.00/0The Journal of Clinical Endocrinology &Metabolism 89(3):1222–1226Printed in U.S.A.Copyright ©2004by The Endocrine Societydoi:10.1210/jc.2003-0302071222103had completed low-dose dexamethasone suppression testing and were used for analysis of effectiveness.The diagnosis of spontaneous Cushing ’s syndrome was established in almost all patients by the re-ferring endocrinologist.The diagnosis of endogenous hypercortisolism was based on clinical findings and elevations of urinary free cortisol.Many other patients were referred with possible Cushing ’s syndrome,and the diagnosis was excluded.However,because these results were not available for analysis,our study is limited to the issue of test sensitivity.Biochemical testingMost biochemical test results were provided by the referring physi-cian(s).Measurement of both plasma cortisol and urine free cortisol used a variety of methods.Low-dose dexamethasone suppression testing was performed by the referring physician or by the consultant as follows.Either 1mg of dexamethasone was given at 2300h with serum cortisol measured the following morning or 0.5mg of dexamethasone was given every 6h for 48h,with measurement of urine free cortisol and/or 17-hydroxycorticosteroids (17OH-corticosteroids).One patient under-went the overnight 1-mg dexamethasone suppression test three times,and all three results were included in the analyses to avoid bias.Statistical analysisContinuous variables were compared using the nonparametric Mann-Whitney U test.Frequencies were analyzed by the Pearson 2test.Statistical analyses were performed using SPSS 11.0(SPSS,Chicago,IL).A P Ͻ0.05is reported as statistically significant.ResultsPatient characteristicsThe clinical characteristics of the 103patients who under-went dexamethasone testing did not differ from the 100patients who did not in terms of etiology of Cushing ’s syn-drome,duration of disease,prevalence of hypokalemia,andbasal values of urinary free cortisol and ACTH.The 103patients who underwent dexamethasone testing were slightly older;the median age was 44yr (range,10–78yr)in the tested group vs.40yr (range,11–79yr)in the group that was not tested (P ϭ0.035).We report detailed results of the 103patients with dexamethasone testing,of which 71were women (69%).There were 80cases of Cushing ’s disease (78%),13cases of the ectopic ACTH syndrome (13%),and 10cases of adrenal tumors (10%).Median baseline data were urinary free cortisol of 211g/24h [range,47–10,460g/24h (median,570nmol/24h;range,127–28,240nmol/24h)]and plasma ACTH of 57pg/ml [range,1–649pg/ml (me-dian,13pmol/liter;range,4–144pmol/liter)].Among the patients with a pituitary etiology (Cushing ’s disease),the median plasma ACTH was 58pg/ml [range,6–210pg/ml (median,13pmol/liter;range,1.3–47pmol/liter)].Test characteristics of low-dose dexamethasone suppression testingFigure 1shows that,in patients with Cushing ’s disease,six had serum cortisol of 2g/dl or less (Ͻ54nmol/liter),and eight had serum cortisol of 2–5g/dl (54–135nmol/liter),yielding false-negative rates of 7.5%and 17.5%,respectively.Patients with Cushing ’s disease whose postdexamethasone cortisol levels were 2g/dl or less (Ͻ54nmol/liter)had baseline urine-free cortisols of 51–275g/24h (138–742nmol/24h).Among the patients with adrenal tumors,the postdexamethasone cortisol levels ranged from 9.0–30.0g/dl (240–800nmol/liter).One patient underwent low-dose dexamethasone testing three times,with morningse-F IG .1.Distribution of plasma cortisol levels after 1mg dexamethasone given at 2300h in patients with Cushing ’s disease (n ϭ82data points).To convert to nmol/liter,multiply morning cortisol by 27.6.Therefore,the scale of plasma cortisol is Ͻ55to Ͼ276nmol/liter.Findling et al.•Dexamethasone Testing in Cushing ’s Syndrome J Clin Endocrinol Metab,March 2004,89(3):1222–12261223rum cortisol values of3,6,and12g/dl(81,162,and324 nmol/liter).Because two of three of these results were true positives(Ͼ5g/dl),we included all three in the analysis to be conservative.Characteristics of patients with Cushing’s disease whose postdexamethasone cortisol was2g/dl or less(Ͻ54nmol/ liter)are shown in Table1.Of these six patients with Cush-ing’s disease,two patients had proven ACTH-secreting pituitary microadenomas.The remaining four patients did not have histologically proven ACTH-secreting tumors.Of these,three patients actually had intermittent elevations of urinary cortisol,and the dexamethasone suppression testing may have been performed when the patient was eucorti-solemic.Nonetheless,of the four patients without histolog-ically proven corticotroph adenomas,one patient had tran-sient secondary adrenal insufficiency followed by clinical and biochemical remission after hemihypophysectomy.Two of the patients developed eucortisolemia after partial hy-pophysectomy but did not develop secondary adrenal in-sufficiency,and one patient had permanent hypoadrenalism after hypophysectomy.It is possible that the hypercorti-solism in these other three patients was not due to pathologic Cushing’s syndrome.Furthermore,the eight patients with postdexamethasone cortisol levels of2–5g/dl(54–135 nmol/liter)had surgically confirmed ACTH-secreting pitu-itary adenomas.We next examined the results of2-d,low-dose dexameth-asone suppression tests.This test was performed in a total of 59patients;the urinary-free cortisol responses were assessed in54patients,and the17OH-corticosteroid responses were assessed in30patients.The postdexamethasone values for urinary free cortisol ranged from undetectable to3286g/24 h(8850nmol/d);the17OH-corticosteroid values ranged from undetectable to102mg/24h(282mol/d).Nine pa-tients had urinary free cortisol that suppressed to less than 10g/24h(Ͻ27nmol/24h;16.7%false negative).Two patients had urinary17OH-corticosteroid levels that sup-pressed to less than2.5mg/d(Ͻ6.9mol/d;6.7%false negative),and five patients had levels that suppressed to3 mg/24h or less(Յ8mol/d;16.7%false negative). Serum cortisol after the1-mg test correlated with the base-line urinary free cortisol(rϭ0.705,PϽ0.001),plasma ACTH level(rϭ0.322,Pϭ0.001),and urinary-free cortisol after the 2-d test(rϭ0.709,Pϭ0.001),but it did not correlate with urinary17OH-corticosteroids after the2-d test(rϭ0.038,Pϭ0.91).Because there were some extremely elevated levels of urinary free cortisol among patients with ectopic ACTH syn-drome and adrenal tumors,we assessed the relationship between cortisol and other tests in the patients with Cush-ing’s disease(Fig.2).In this subgroup of patients with Cush-ing’s disease,serum cortisol after the1-mg test correlated with the baseline urinary free cortisol(rϭ0.535,PϽ0.001), urinary-free cortisol(rϭ0.730,Pϭ0.001),and urinary 17OH-corticosteroids(rϭ0.800,Pϭ0.005)after the2-d test. However,there was no significant correlation with plasma ACTH(rϭ0.058,Pϭ0.612).DiscussionThis study provides evidence that neither the overnight 1-mg dexamethasone suppression test nor the2-d,low-dose dexamethasone suppression test should be used as the sole criterion to exclude the diagnosis of Cushing’s syndrome. Previous studies have shown the sensitivity of low-dose dexamethasone suppression testing,particularly the over-night1-mg dexamethasone test,to range from83–100%(5,6, 8–15).These studies have differed in the type of cortisol assays used,the doses of dexamethasone employed,and the criteria for a positive test.A recent survey of laboratories in the United Kingdom in-dicated that the majority of pathologists recommended the overnight low-dose dexamethasone suppression test as a screening procedure for patients with suspected Cushing’s syn-drome(16,17).Among127laboratories,91used a dose of1mg, three used a dose of1.5mg,and33used a dose of2mg. Reported cutoff values for the suppression of serum cortisol in other studies using contemporary immunoassay techniques range from3.6–7.2g/dl(70–100nmol/liter).These patholo-gists suggested that dexamethasone-induced suppression of plasma cortisol to less than1.8g/dl(Ͻ50nmol/liter)effec-tively excluded Cushing’s syndrome.The application of this stringent cutoff to safely exclude Cushing’s syndrome was also endorsed recently at an international workshop on the diag-nosis,complications,and treatment of Cushing’s syndrome (18).As our study demonstrates,some patients with mild Cush-ing’s disease demonstrated marked sensitivity to dexametha-sone suppression;therefore,a much lower cutoff value than has been previously used in clinical practice should be used to achieve adequate sensitivity.However,our data from clinical practice patterns in the United States provide evidence that there is no cutoff value that achieved100%sensitivity.More-over,as the cutoff value is lowered to increase the sensitivity,TABLE1.Characteristics of patients with Cushing’s disease and postdexamethasone cortisol levels2g/dl or lessCase no.Age(yr)Baseline UFC[g/d(nmol/d)]Other findings Pathology 138202(558)Abnormal dexamethasone-CRH test ACTH pituitary tumor278128(353)Abnormal dexamethasone-CRH test ACTH pituitary tumor33697(268)Intermittent Cushing’s Hemihypophysectomy resulted insecondary adrenal insufficiencyand clinical remission 440275(759)Abnormal dexamethasone-CRH test Hypophysectomy;no tumor541274(756)Intermittent Cushing’s Hemihypophysectomy resulted inbiochemical remission 62751(141)Intermittent Cushing’s Hemihypophysectomy resulted inbiochemical remissionUFC,Urinary free cortisol.1224J Clin Endocrinol Metab,March2004,89(3):1222–1226Findling et al.•Dexamethasone Testing in Cushing’s Syndromethe false-positive rate for the low-dose dexamethasone sup-pression test will inevitably increase significantly,thereby de-creasing the overall diagnostic utility of this test.Gorges et al.(9)studied 247patients with suspected Cush-ing ’s syndrome,of whom 103patients had the disorder.They found that the 1.5-mg overnight dexamethasone suppression test had a sensitivity of 98%and 94%using cutoffs of 2.6g/dl (70nmol/liter)and 5.2g/dl (140nmol/liter),re-spectively.The lowest plasma cortisol achieved after the low-dose test in a patient with proven Cushing ’s syndrome was 1.2g/dl (32nmol/liter).Some investigators have dem-onstrated that the measurement of serum cortisol (rather than urinary steroids)after the 2-d,low-dose dexamethasone suppression testing provides improved sensitivity and spec-ificity.Newell-Price et al.(19)reported that a serum cortisol of less than 1.8g/dl (50nmol/liter)after the administration of 0.5mg dexamethasone every 6h for 48h resulted in a sensitivity of 98%.They also found that only three of 150patients with histologically proven Cushing ’s disease sup-pressed to less than 1.8g/dl (50nmol/liter)(19).Invitti et al.(20)reported another large series using criteria for sup-pression of serum cortisol to less than 5g/dl (135nmol/liter)after the overnight 1-mg dexamethasone suppression test as well as suppression of urine free cortisol and 17OH-corticosteroids less than 20g/24h (55nmol/d)and 3.5mg/24h (7mol/d),respectively,after 0.5mg of dexameth-asone every 6h for 2d.They found the sensitivity to be 95%for the overnight test and 93%for the 2-d test.Their total series consisted of 426patients,in whom 104had adrenal-dependent Cushing ’s syndrome.Because the sensitivity of dexamethasone suppression testing in patients with adrenal tumors is higher than in other causes of Cushing ’s syndrome,the high prevalence of adrenal-dependent hypercortisolism in their series biased the results in such a way as to put the dexamethasone test in an even more favorable light.The National Institutes of Health group evaluated theclassic 2-d,low-dose dexamethasone suppression test in a large series of patients with mild Cushing ’s syndrome and compared them to patients with pseudo-Cushing ’s condi-tions (21).The classic 2-d,low-dose dexamethasone suppres-sion test yielded a sensitivity of only 79%,a specificity of 74%,and a diagnostic accuracy of 71%using urinary steroid mea-surements.Our study showed that 14(17%)of 80patients with Cushing ’s disease suppressed serum cortisol to less than 5g/dl (Ͻ135nmol/liter)after the overnight 1-mg test.In addition,six patients actually showed suppression of se-rum cortisol to less than 2g/dl (Ͻ54nmol/liter)with the overnight test.The 2-d,low-dose dexamethasone suppres-sion test yielded false-negative results in 38%of our patients when urine free cortisol was used and 28%of our patients when urinary 17OH-corticosteroids were used.The results of our study are also similar to those reported by Streeten et al.(22),who showed that,in 58patients with proven Cushing ’s disease,23%had suppression of urine free cortisol to very low levels after the low-dose dexamethasone suppression test.There was remarkable and significant correlation of basal urine free cortisol and the plasma cortisol after the low-dose dexamethasone suppression test in our patients with Cushing ’s disease.In other words,patients with mild degrees of hyper-cortisolism were more likely to suppress their plasma cortisol to low levels after the overnight 1-mg dexamethasone suppres-sion test.All eight patients with Cushing ’s disease whose cor-tisol level decreased to 2–5g/dl (54–135nmol/liter)had sur-gically proven ACTH-secreting microadenoma.Of the six patients with Cushing ’s disease who had cortisol values of less than 2g/dl (Ͻ54nmol/liter)after the over-night test,three patients did not have either ACTH-secreting pituitary microadenomas or evidence of secondary adrenal insufficiency after hemihypophysectomy.Although the hy-percortisolism remitted in the other three patients after sur-gery,it is possible that the cortisol excess in these patients may not have been due to pathological Cushing ’s syndrome.The intermittent nature of hypercortisolism in two of these patients would also confound the postoperative biochemical evaluation.Consequently,this observational data suggests that the sensitivity of the overnight 1-mg dexamethasone suppres-sion test in the diagnosis of Cushing ’s disease is somewhere between 93–96%when a strict criteria of less than 2g/dl (Ͻ54nmol/liter)is used as normal cortisol suppression.We studied the sensitivity of low-dose dexamethasone suppression testing for the diagnosis of Cushing ’s syndrome.Our analysis relied upon the results of dexamethasone sup-pression testing supplied by referring clinicians.This means that a variety of clinical laboratories and methods were used to measure plasma and urinary steroids.This approach is not likely to provide the precision found in efficacy studies per-formed in a clinical research center using a single method-ology and batch assays.Similarly,it is not likely that dexa-methasone suppression testing in a real-world setting can match that achieved in the research setting.Therefore,our data are more representative of the results likely to be ob-tained by practicing physicians.A limitation of this study is a possibility of selection bias,especially because disease prevalence is important in gen-eralizing clinical prediction rules.Ideally,evaluation of dexa-methasone suppression testing should be performed onaF IG .2.Correlation between serum cortisol after overnight dexa-methasone suppression and baseline urinary free cortisol in patients with Cushing ’s disease (r ϭ0.52,P Ͻ0.001,n ϭ82data points).To convert urine free cortisol to nmol/liter,multiply by 2.76.Therefore,the scale of urine free cortisol is 28–27,600nmol/d.To convert morn-ing cortisol (serum)to nmol/liter,multiply by 27.6.Therefore,the scale of morning cortisol is 0–1656nmol/liter.Findling et al.•Dexamethasone Testing in Cushing ’s Syndrome J Clin Endocrinol Metab,March 2004,89(3):1222–12261225population-based rather than a referral-based sample.Spon-taneous Cushing’s syndrome is an unusual disorder.Con-sequently,all large series of patients reflect referral patterns. Bias may result from the referral of difficult cases for spe-cialized expertise,such as inferior petrosal sinus sampling. Such difficult cases may be those with atypical laboratory results.Nonetheless,our observations strongly suggest that the sensitivity for low-dose dexamethasone suppression test-ing for the diagnosis of Cushing’s syndrome has been over-estimated.The problem of intermittent hypercortisolism in some patients with Cushing’s syndrome provides further diagnostic uncertainty in the evaluation of this enigmatic disorder(23).We certainly acknowledge that some of these false-negative,low-dose dexamethasone suppression results may be due to this intermittency.The interval time between the low-dose dexamethasone test and urine cortisol may also account for some of this discordance.The phenomenon of intermittent or periodic hypercortisolism potentially con-founds any diagnostic study for Cushing’s syndrome.We currently use repeated measurements of late-night salivary cortisol to confirm the presence or absence of intermittent hypercortisolism(24–26).We conclude that some patients with spontaneous Cush-ing’s syndrome,particularly those with mild hypercorti-solism,may suppress plasma or urinary steroids after low-dose dexamethasone to levels previously thought to exclude the diagnosis.Therefore,low-dose dexamethasone tests should not be used alone to exclude the diagnosis of Cush-ing’s syndrome,and a much lower value for serum cortisol (i.e.Ͻ1.8g/dl;Ͻ50nmol/liter)should be used to achieve adequate sensitivity.AcknowledgmentsThe authors thank Drs.Joseph Shaker,Steven Magill,and Beth La-lande for their invaluable contributions to this study.Received February10,2003.Accepted November24,2003.Address all correspondence and requests for reprints to:James W. 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