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The Low-Dose Dexamethasone Suppression Test: A Reevaluation in Patients with Cushing’s Syndrome

The 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 44106

Address all correspondence and requests for reprints to: James W. Findling, M.D., St. Luke’s Physician’s Office Building, Endocrinology, Suite 245, 2801 W. Kinnickinnic River Parkway, Milwaukee, Wisconsin 53215-3660. E-mail: james.findling{at}aurora.org.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Low-dose dexamethasone suppression testing has been recommended for biochemical screening when Cushing’s syndrome is suspected. The criterion for normal suppression of cortisol after dexamethasone is controversial. To assess diagnostic utility (sensitivity), we report the results of low-dose dexamethasone suppression testing in 103 patients with spontaneous Cushing’s syndrome. There were 80 patients with Cushing’s disease (78%), 13 with the ectopic ACTH syndrome (13%), and 10 with cortisol-producing adrenocortical adenomas (10%). Fourteen (18%) of 80 patients with Cushing’s disease suppressed serum cortisol to less than 5 µg/dl (<135 nmol/liter) after the overnight 1-mg test, whereas six patients (8%) actually showed suppression of serum cortisol to less than 2 µg/dl (<54 nmol/liter). In addition, the 2-d, low-dose dexamethasone 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.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
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 patients with the Cushing’s phenotype may be very difficult. There are remarkable similarities between the metabolic syndrome and Cushing’s syndrome. Excessive and sustained cortisol secretion has long been associated with the entire clinical spectrum of the metabolic syndrome including obesity, insulin resistance, dyslipidemia, hypertension, and diabetes (1, 2). Clinical improvement (e.g. blood pressure reduction, 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 emphasize the importance of discovering and treating even mild Cushing’s syndrome (2, 3, 4).

Biochemical confirmation of Cushing’s syndrome has relied upon the measurement of urinary free cortisol over a 24-h period and low-dose dexamethasone suppression testing (1). Low-dose dexamethasone suppression testing, especially 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 dexamethasone suppression testing, it has previously been thought that false-negative results were relatively rare (1).

There are three major concerns about applying published results 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 suppression testing has been based on compilations of studies using different cut points, different protocols, and different methods of cortisol measurement (6). Finally, recommendations 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 practice. 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 effectiveness of tests in clinical practice using a variety of approaches and reference laboratories has not been extensively evaluated.

We studied 203 consecutive patients with Cushing’s syndrome referred to a single endocrinologist over a 15-yr period. To assess the effectiveness of low-dose dexamethasone suppression testing as a screening test, we now report the results from 103 of these 203 patients 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 Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Study design and population

We evaluated a case series of 203 consecutive patients with Cushing’s syndrome referred to a single clinician (J.W.F.) from 1984–1998, of whom 103 had 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 referring 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 testing

Most biochemical test results were provided by the referring physician(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 1 mg of dexamethasone was given at 2300 h with serum cortisol measured the following morning or 0.5 mg of dexamethasone was given every 6 h for 48 h, with measurement of urine free cortisol and/or 17-hydroxycorticosteroids (17OH-corticosteroids). One patient underwent the overnight 1-mg dexamethasone suppression test three times, and all three results were included in the analyses to avoid bias.

Statistical analysis

Continuous variables were compared using the nonparametric Mann-Whitney U test. Frequencies were analyzed by the Pearson ² test. Statistical analyses were performed using SPSS 11.0 (SPSS, Chicago, IL). A P < 0.05 is reported as statistically significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patient characteristics

The clinical characteristics of the 103 patients who underwent dexamethasone testing did not differ from the 100 patients who did not in terms of etiology of Cushing’s syndrome, duration of disease, prevalence of hypokalemia, and basal values of urinary free cortisol and ACTH. The 103 patients who underwent dexamethasone testing were slightly older; the median age was 44 yr (range, 10–78 yr) in the tested group vs. 40 yr (range, 11–79 yr) in the group that was not tested (P = 0.035). We report detailed results of the 103 patients with dexamethasone testing, of which 71 were women (69%). There were 80 cases of Cushing’s disease (78%), 13 cases of the ectopic ACTH syndrome (13%), and 10 cases of adrenal tumors (10%). Median baseline data were urinary free cortisol of 211 µg/24 h [range, 47–10,460 µg/24 h (median, 570 nmol/24 h; range, 127–28,240 nmol/24 h)] and plasma ACTH of 57 pg/ml [range, 1–649 pg/ml (median, 13 pmol/liter; range, 4–144 pmol/liter)]. Among the patients with a pituitary etiology (Cushing’s disease), the median plasma ACTH was 58 pg/ml [range, 6–210 pg/ml (median, 13 pmol/liter; range, 1.3–47 pmol/liter)].

Test characteristics of low-dose dexamethasone suppression testing

Figure 1 shows that, in patients with Cushing’s disease, six had serum cortisol of 2 µg/dl or less (<54 nmol/liter), and eight had serum cortisol of 2–5 µg/dl (54–135 nmol/liter), yielding false-negative rates of 7.5% and 17.5%, respectively. Patients with Cushing’s disease whose postdexamethasone cortisol levels were 2 µg/dl or less (<54 nmol/liter) had baseline urine-free cortisols of 51–275 µg/24 h (138–742 nmol/24 h). Among the patients with adrenal tumors, the postdexamethasone cortisol levels ranged from 9.0–30.0 µg/dl (240–800 nmol/liter). One patient underwent low-dose dexamethasone testing three times, with morning serum cortisol values of 3, 6, and 12 µg/dl (81, 162, and 324 nmol/liter). Because two of three of these results were true positives (>5 µg/dl), we included all three in the analysis to be conservative.

View larger version (7K): [in this window] [in a new window]   FIG. 1. Distribution of plasma cortisol levels after 1 mg dexamethasone given at 2300 h in patients with Cushing’s disease (n = 82 data points). To convert to nmol/liter, multiply morning cortisol by 27.6. Therefore, the scale of plasma cortisol is <55 to >276 nmol/liter.

Serum cortisol after the 1-mg test correlated with the 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), but it did not correlate with urinary 17OH-corticosteroids after the 2-d test (r = 0.038, P = 0.91). Because there were some extremely elevated levels of urinary free cortisol among patients with ectopic ACTH syndrome and adrenal tumors, we assessed the relationship between cortisol and other tests in the patients with Cushing’s disease (Fig. 2). In this subgroup of patients with Cushing’s disease, serum cortisol after the 1-mg test correlated with the baseline urinary free cortisol (r = 0.535, P < 0.001), urinary-free cortisol (r = 0.730, P = 0.001), and urinary 17OH-corticosteroids (r = 0.800, P = 0.005) after the 2-d test. However, there was no significant correlation with plasma ACTH (r = 0.058, P = 0.612).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Correlation between serum cortisol after overnight dexamethasone suppression and baseline urinary free cortisol in patients with Cushing’s disease (r = 0.52, P < 0.001, n = 82 data points). To convert urine free cortisol to nmol/liter, multiply by 2.76. Therefore, the scale of urine free cortisol is 28–27,600 nmol/d. To convert morning cortisol (serum) to nmol/liter, multiply by 27.6. Therefore, the scale of morning cortisol is 0–1656 nmol/liter.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

A recent survey of laboratories in the United Kingdom indicated that the majority of pathologists recommended the overnight low-dose dexamethasone suppression test as a screening procedure for patients with suspected Cushing’s syndrome (16, 17). Among 127 laboratories, 91 used a dose of 1 mg, three used a dose of 1.5 mg, and 33 used a dose of 2 mg. Reported cutoff values for the suppression of serum cortisol in other studies using contemporary immunoassay techniques range from 3.6–7.2 µg/dl (70–100 nmol/liter). These pathologists suggested that dexamethasone-induced suppression of plasma cortisol to less than 1.8 µg/dl (<50 nmol/liter) effectively 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 diagnosis, complications, and treatment of Cushing’s syndrome (18). As our study demonstrates, some patients with mild Cushing’s disease demonstrated marked sensitivity to dexamethasone 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 achieved 100% sensitivity. Moreover, as the cutoff value is lowered to increase the sensitivity, the false-positive rate for the low-dose dexamethasone suppression test will inevitably increase significantly, thereby decreasing the overall diagnostic utility of this test.

Gorges et al. (9) studied 247 patients with suspected Cushing’s syndrome, of whom 103 patients had the disorder. They found that the 1.5-mg overnight dexamethasone suppression test had a sensitivity of 98% and 94% using cutoffs of 2.6 µg/dl (70 nmol/liter) and 5.2 µg/dl (140 nmol/liter), respectively. The lowest plasma cortisol achieved after the low-dose test in a patient with proven Cushing’s syndrome was 1.2 µg/dl (32 nmol/liter). Some investigators have demonstrated that the measurement of serum cortisol (rather than urinary steroids) after the 2-d, low-dose dexamethasone suppression testing provides improved sensitivity and specificity. Newell-Price et al. (19) reported that a serum cortisol of less than 1.8 µg/dl (50 nmol/liter) after the administration of 0.5 mg dexamethasone every 6 h for 48 h resulted in a sensitivity of 98%. They also found that only three of 150 patients with histologically proven Cushing’s disease suppressed to less than 1.8 µg/dl (50 nmol/liter) (19). Invitti et al. (20) reported another large series using criteria for suppression of serum cortisol to less than 5 µg/dl (135 nmol/liter) after the overnight 1-mg dexamethasone suppression test as well as suppression of urine free cortisol and 17OH-corticosteroids less than 20 µg/24 h (55 nmol/d) and 3.5 mg/24 h (7 µmol/d), respectively, after 0.5 mg of dexamethasone every 6 h for 2 d. They found the sensitivity to be 95% for the overnight test and 93% for the 2-d test. Their total series consisted of 426 patients, in whom 104 had 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 the classic 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 conditions (21). The classic 2-d, low-dose dexamethasone suppression test yielded a sensitivity of only 79%, a specificity of 74%, and a diagnostic accuracy of 71% using urinary steroid measurements. Our study showed that 14 (17%) of 80 patients with Cushing’s disease suppressed serum cortisol to less than 5 µg/dl (<135 nmol/liter) after the overnight 1-mg test. In addition, six patients actually showed suppression of serum cortisol to less than 2 µg/dl (<54 nmol/liter) with the overnight test. The 2-d, low-dose dexamethasone suppression 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 58 patients 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 hypercortisolism were more likely to suppress their plasma cortisol to low levels after the overnight 1-mg dexamethasone suppression test. All eight patients with Cushing’s disease whose cortisol level decreased to 2–5 µg/dl (54–135 nmol/liter) had surgically proven ACTH-secreting microadenoma.

Of the six patients with Cushing’s disease who had cortisol values of less than 2 µg/dl (<54 nmol/liter) after the overnight test, three patients did not have either ACTH-secreting pituitary microadenomas or evidence of secondary adrenal insufficiency after hemihypophysectomy. Although the hypercortisolism remitted in the other three patients after surgery, 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 suppression test in the diagnosis of Cushing’s disease is somewhere between 93–96% when a strict criteria of less than 2 µg/dl (<54 nmol/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 suppression 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 performed in a clinical research center using a single methodology and batch assays. Similarly, it is not likely that dexamethasone 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 obtained by practicing physicians.

A limitation of this study is a possibility of selection bias, especially because disease prevalence is important in generalizing clinical prediction rules. Ideally, evaluation of dexamethasone suppression testing should be performed on a population-based rather than a referral-based sample. Spontaneous Cushing’s syndrome is an unusual disorder. Consequently, all large series of patients reflect referral patterns. Bias may result from the referral of difficult cases for specialized 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 testing for the diagnosis of Cushing’s syndrome has been overestimated. 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 confounds 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, 25, 26).

We conclude that some patients with spontaneous Cushing’s syndrome, particularly those with mild hypercortisolism, 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 Cushing’s syndrome, and a much lower value for serum cortisol (i.e. <1.8 µg/dl; <50 nmol/liter) should be used to achieve adequate sensitivity.

	Acknowledgments

 
The authors thank Drs. Joseph Shaker, Steven Magill, and Beth Lalande for their invaluable contributions to this study.

	Footnotes

 
Abbreviation: 17OH-corticosteroid, 17-Hydroxycorticosteroids.

Received February 10, 2003.

Accepted November 24, 2003.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Findling, J. W. Articles by Aron, D. C. Search for Related Content PubMed PubMed Citation Articles by Findling, J. W. Articles by Aron, D. C.