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Dexamethasone-Suppressed Corticotropin-Releasing Hormone Stimulation Test for Diagnosis of Mild Hypercortisolism

Division of Endocrinology, Diabetes, Metabolism, and Nutrition (D.E., N.N., T.N., W.F.Y., P.C.C.), and Division of Biostatistics (T.P., T.C.), Mayo Clinic College of Medicine, Rochester, Minnesota, 55905

Address all correspondence and requests for reprints to: Dana Erickson, M.D., 200 1st Street SW, Rochester, Minnesota 55905. E-mail: erickson.dana{at}mayo.edu.

	Abstract

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Context: The definitive diagnosis of Cushing’s syndrome (CS) in the setting of mild disease, as well as exclusion of CS in the setting of conditions that might mimic this clinical entity (pseudo-Cushing’s syndrome), continues to present a significant challenge to the clinician.

Objective: The aim of the study was to review characteristics of the combined dexamethasone-suppressed CRH stimulation test in patients evaluated at an academic center for the possibility of mild CS.

Design, Patients, and Methods: We conducted a retrospective review of 66 patients. A total of 51 patients underwent final statistical analysis: 21 (41%) had Cushing’s disease, and 30 were considered to have pseudo-CS based on the clinical scenario, comorbidities, and follow-up. Sensitivity, specificity, and diagnostic accuracy of cortisol and ACTH levels for the diagnosis of Cushing’s disease were calculated at 1 min before, and 15, 30, 45, and 60 min after CRH administration. Diagnostic cutoffs for each parameter were determined by minimizing the absolute difference between sensitivity and specificity. Diagnostic accuracy was characterized by the area under the receiver operating characteristic curve, determined using the trapezoid rule.

Results: The highest diagnostic accuracy was provided by the serum ACTH level at 15 min post-CRH, in which the area under the receiver operating characteristic curve was 99.7%, and a cutoff of more than 27 pg/ml (>5.9 pmol/liter) provided a sensitivity of 95% and specificity of 97% for the diagnosis of CS. A 15-min post-CRH cortisol greater than 2.5 µg/dl (70 nmol/liter) provided a sensitivity and specificity of 90 and 90%, respectively.

Conclusions: Our results differ from previous studies because our data suggest that when using the combined dexamethasone-suppressed CRH stimulation test, a 15-min post-CRH ACTH value greater than 27 pg/ml (5.9 pmol/liter) had the highest diagnostic accuracy for the detection of CS. However, the sensitivity and specificity for this test were not statistically different from the sensitivity and specificity of other tests, such as those measuring post-CRH stimulated ACTH levels or post-CRH cortisol levels at other time points. Therefore, clinicians should be cautious about interpretation of suppression and stimulation tests in the diverse population of patients with hypercortisolism.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
DEFINITIVE DIAGNOSIS OF pituitary dependent Cushing’s syndrome (CS) [Cushing’s disease (CD)] in the setting of mild disease, as well as exclusion of CS in the setting of conditions that might mimic this clinical entity [pseudo-CS (PCS)], continue to present a significant challenge for the clinical endocrinologist. The entity of PCS is thought to be caused by increased CRH stimulation in the setting of chronic conditions, which can result in clinical and biochemical manifestations that mimic CD. These conditions include chronic psychiatric problems (depression, anorexia nervosa, and severe anxiety), alcoholism, severe obesity (1), severe stress (2), and renal failure (3). In these clinical settings, patients are thought to have a decreased ACTH response to exogenous CRH stimulation, while the ability to suppress cortisol after exogenous administration of dexamethasone persists (4). The standard 2-mg, 2-d low-dose dexamethasone suppression test used for diagnosis of CS for many years showed excellent accuracy in some studies (5), while not in others (6). However, these studies are difficult to compare directly because different end points in interpretation (plasma or urinary cortisol suppression) were used. Discrepancies and various reported sensitivities and specificities of this standard test may also be explained by the types of patients studied, difference in the degree of hypercortisolism, differences in study entry criteria (patients mostly with proven CS), and degree of glucocorticoid receptor suppressibility (5, 6, 7). The dexamethasone-suppressed CRH stimulation test was developed with a goal of better diagnostic distinction between CS and PCS. Although the combined dexamethasone-suppressed CRH stimulation test is used in the clinical setting, data from only a few academic and clinical endocrine centers are available, and this test needs further validation (4, 8, 9).

The purpose of our study was to review the results of the combined dexamethasone-suppressed CRH stimulation test in a heterogeneous group of patients evaluated at our academic center for possible mild CS. Although it has been suggested that this test is difficult to execute and cumbersome, all of the included patients successfully completed this study on an outpatient ambulatory basis with close cooperation of the nursing staff in our Endocrine Testing Center.

	Patients and Methods

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A total of 66 patients who underwent evaluation for the presence of possible mild hypercortisolism and completed dexamethasone-suppressed CRH stimulation testing between July 1997 and January 2005 in the Endocrine Testing Center at Mayo Clinic, Rochester, MN, were included in the study. The institutional review board of the Mayo Foundation approved the retrospective study, and signed research authorization was verified for all medical records used. Further approval was received to contact the patients for follow-up questionnaire and, if needed, laboratory analysis. The dexamethasone-CRH test was indicated by one of five endocrinologists with specialty in pituitary-adrenal disorders. Retrospective analysis showed that each of the patients had a history of either mild hypercortisolism (24-h urinary free cortisol excretion less than 3-fold increased above the upper limit of normal) or had clinical features suggestive of CS (e.g. combination of hirsutism, truncal obesity, striae, hypertension, and features of the metabolic syndrome). None had hepatic or renal disease. Patients with clear-cut clinical evidence of CS in association with definitive abnormal baseline biochemical evaluation do not routinely undergo dexamethasone suppression tests at our institution.

CD was confirmed on the basis of positive immunohistochemistry for ACTH in the pituitary tumor removed with transsphenoidal surgery, or when tissue was not available for pathological studies (e.g. tumor lost in suction or no tumor found), by evidence of biochemical and clinical remission after transsphenoidal surgery. A diagnosis of PCS was based on the lack of severe features of CS at initial presentation, or improvement or lack of progression of signs of possible CS during follow-up. A detailed medical history of comorbidities in PCS patients was obtained.

Of 66 patients, 51 underwent final statistical analysis. Three patients were excluded because no definitive proof of CD, as defined previously, was available. Two were excluded because the patients were using medications that potentially could interfere with dexamethasone metabolism. Three patients declined participation in research studies. Seven patients had dexamethasone-suppressed CRH testing performed while on oral estrogen therapy (in the form of contraceptives or postmenopausal hormone replacement) and were excluded. Of the 51 patients, 21 (41%) had CD. Median age was 46 yr, and 37 (73%) were female. A total of 30 (59%) patients were considered to have PCS based on the lack of progression, or reversal of mild possible manifestations of CD and the fact that multiple comorbidities were present (Table 1). These comorbidities (one or more) included: depression diagnosis (nine patients); some depressive symptoms or patients on antidepressants for unclear reasons (4); obstructive sleep apnea (five patients); severe headache (three patients); chronic narcotic pain medication use (three patients); severe anxiety (two patients); and neurological disorder (four patients). Of the PCS patients, 18 had tests performed because of suspicious clinical features of CS, or borderline elevation of urinary or plasma cortisol in outside institutions. The remaining 12 patients with PCS had, in addition to clinical suspicion, elevated baseline 24-h urinary cortisol in our institution. Imaging studies (magnetic resonance imaging or computed tomography) of the sella were performed in all 21 patients with CD, and were positive in 11 patients, equivocal in five, and negative in five. Imaging of the sella was performed in 23 of the 30 patients with PCS, and was negative in 16 patients, equivocal in three patients and positive in four. Of the 51 patients, five (10%) had the dexamethasone-suppressed CRH stimulation testing performed in a setting of clinical evaluation for possible recurrent CD; they had undergone prior pituitary surgery for CS, three patients at outside institutions, and one had surgery for CS 15 yr before evaluation.

Diagnostic tests

Patients underwent baseline measurements of morning and afternoon plasma cortisol and ACTH concentrations, and had one to three baseline 24-h urinary free cortisol and creatinine collections. This was followed by dexamethasone-suppressed ovine CRH (oCRH) stimulation testing, as described previously (8). All tests were performed in the outpatient Endocrine Testing Center. Subjects initiated 0.5 mg dexamethasone orally every 6 h for eight doses (first dose at 1200 h). oCRH (Acthrel; Ferring Pharmaceuticals, Inc., Tarrytown, NY) in a dose of 1 µg/kg, maximum 100 µg, was administered iv 2 h after completion of the last dose of dexamethasone. Twenty-four hour urinary free cortisol and creatinine excretion were obtained the second day of dexamethasone suppression testing. Plasma cortisol and plasma ACTH were measured 1 min before oCRH stimulation, and 15, 30, 45, and 60 min after oCRH stimulation. Patients were observed for 20 min after completion of the procedure.

Assays

All assays were performed by Mayo Medical Laboratories. Plasma cortisol was measured by an automated chemiluminescent immunoenzymatic assay system (Beckman Access; Beckman Coulter, Brea, CA). Intraassay and interassay coefficients of variation (CVs) were 5.5 and 8.2%, respectively. The detection limit of the assay is 0.1 µg/dl and CV at low control of 1.9 µg/dl is 8.2%. Plasma ACTH assays were analyzed by automated immunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA). Intraassay CVs were 14, 2.3, 1.3, and 2.6% at 3.7, 16, 102, and 444 pg/ml, respectively. Interassay precision was 13.7, 5, 5.9, and 3.0% at 4.2, 15, 94, and 441 pg/ml, respectively.

The assay method for urinary free cortisol assays evolved over the duration of the study period. Initially, urinary free cortisol was measured by competitive binding assay, then HPLC assay, and currently by liquid chromatography-tandem mass spectrometry assay (LC-MS/MS), as described previously (10). The LC-MS/MS assay (Applied Biosystems, Foster City, CA) has intraassay CVs of 2.0, 4.6, and 20.8% at 15.1, 2.17, and 0.21 µg/dl, respectively, and interassay CVs of 12.2, 7, 7.7, and 7.4% at 0.2, 2, 5, 9, and 23.8 µg/dl, respectively. The HPLC assay had an interassay CV of 5.7% and intraassay CV less than 5%. The original competitive protein binding assay had interassay and intraassay CVs of 6.1 and 6%, respectively.

Statistical analysis

The diagnosis of CD or PCS was made at the last follow-up. Those patients with no follow-up past the initial visit were designated as having PCS, realizing that some of these patients may have had CD if follow-up was available. Reported sensitivity, specificity, and diagnostic accuracy are based on this definition of the gold standard. Diagnostic accuracy was characterized by the area under the receiver operating characteristic (ROC) curve, determined using the Mann-Whitney U statistic, which is equivalent to the trapezoid rule (11, 12, 13).

Sensitivity, specificity, and diagnostic accuracy of the plasma cortisol and ACTH levels were calculated at 1 min before, and 15, 30, 45, and 60 min after oCRH administration. Cutoffs for plasma cortisol and ACTH level for each time point were determined by minimizing the absolute difference between sensitivity and specificity. Statistical comparisons of sensitivity and specificity between plasma cortisol and ACTH and other tests were performed using McNemar’s test.

Because of the lack of follow-up in some cases of PCS, we also validated the sensitivity and specificity estimates. We did this validation by postulating that a fixed percentage of 1, 5, 10, and 20% of the 14 PCS patients without follow-up beyond the initial visit would have had CD if followed longer. We did this to see what effect it would have on our estimates of diagnostic accuracy, sensitivity, and specificity if some of these 14 PCS patients had CD. For example, using a random number generator (14, 15) based on a uniform distribution, we assigned a diagnosis of CD or PCS to the 14 PCS patients using the fixed percentage. Thus, for the assessment of a 1%, we assigned those of the 14 with a random number generated value less than 0.01 to a diagnosis of CD, and recalculated the sensitivity and specificity as if those subjects had CD in addition to those known to have CD. We made this random assignment 500 times. For each of these random assignments of 1%, we assessed the sensitivity estimates in which the specificity was greater than or equal to 95%. We kept the maximum sensitivity where the specificity was greater than or equal to 95% and the corresponding specificity from each run, and then averaged the sensitivity and specificity values from the 500 runs. We repeated this process using estimates of 5, 10, and 20%.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Post-CRH stimulated ACTH levels as well as post-CRH cortisol levels provided high diagnostic accuracy. The area under the ROC curve was 0.97 for all values of both cortisol and the ACTH. Although not statistically different from other test values, the ACTH value at 15 min post-CRH administration had the highest diagnostic accuracy to distinguish CD from PCS. An ACTH value of more than 27 pg/ml (5.9 pmol/liter) diagnosed CD with 95% sensitivity, 97% specificity with an ROC curve of 99.7% (Table 2).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Despite continuous advances in laboratory and imaging technology, the appropriate diagnosis of mild CD states and verification of PCS continue to represent a difficult challenge (16). The combined low-dose dexamethasone-suppressed CRH stimulation test, developed to help address the diagnostic dilemma of patients with equivocal physical or biochemical findings, has had extremely high specificity, sensitivity, and diagnostic accuracy (8).

In our study of a relatively large heterogeneous group of patients evaluated for the presence of hypercortisolism and possible CD by a combined dexamethasone-suppressed CRH stimulation test, the ACTH levels obtained 15 min after administration of CRH had the highest diagnostic accuracy in establishing the presence of CD. The cutoff of 27 pg/ml (5.9 pmol/liter) at 15 min after CRH stimulation had 95% sensitivity and 97% specificity, and 99.7% diagnostic accuracy (Fig. 1). However, ACTH levels at all reported time points had high diagnostic accuracy, as did post-CRH plasma cortisol values. Sensitivity and specificity values were not statistically significantly different from sensitivity and specificity of the ACTH level 15 min after administration of CRH. Post-CRH plasma cortisol value obtained 15 min after CRH of more than 2.5 µg/dl (>70 nmol/liter) had a sensitivity and specificity of 90 and 90%, respectively, diagnostic accuracy of 97%, while a 30-min plasma cortisol value of more than 8 µg/dl (>223 nmol/liter) had a sensitivity of 95% and a specificity of 93%.

View larger version (17K): [in this window] [in a new window]   FIG. 1. Individual data graphically showing diagnostic results of selected tests with highest diagnostic accuracy. Left, Values of plasma ACTH obtained 15 min after oCRH administration in patients with PCS and CD. Right, Values of serum cortisol obtained 15 min after oCRH administration in patients with PCS and CD.

Our results indicating that an ACTH value obtained 15 min after CRH administration had the highest diagnostic accuracy differ from the study by Yanovski et al. (4, 8), which reports that a post-CRH 15 min cortisol of more than 1.4 µg/dl (>38 nmol/liter) has the highest diagnostic accuracy for distinguishing mild CD from PCS. If we had applied a 15-min cortisol cutoff value of more than 1.4 µg/dl (>38 nmol/liter) to our study group, the sensitivity of the test would be 100% and specificity 76%. Seven patients from our group would have been misclassified as having CD. This cutoff has been previously reported in literature to have 100% specificity and 100% sensitivity, as well as 100% diagnostic accuracy. Variations in the sensitivity of plasma cortisol assays might be one possible explanation for the different results we obtained.

Recently, Martin et al. (9) studied 36 individuals with clinical suspicion of CS. These included eight patients with CD, four with adrenal CS, and 24 with PCS. The authors found no additional diagnostic benefit of the combined dexamethasone-suppressed CRH stimulation test compared with standard low-dose dexamethasone protocol. In addition, the former was less specific [67% for a serum cortisol of >1.4 µg/dl (>38 nmol/liter)]. The patient population in this study was somewhat similar to ours (e.g. clinical, not only biochemical evidence of hypercortisolism, variety of comorbidities), but also included patients with adrenal CS. In addition, these authors used human CRH (100 µg) for stimulation and also a slightly different low-dose dexamethasone protocol.

There was an increase in both the ACTH and cortisol after the CRH stimulation in the CS group of our study population in concordance with the findings of the previous studies.

Examination of the degree of urinary cortisol post 2 d, 2-mg dexamethasone suppression revealed that three patients with CD (15%) had suppressed urinary cortisol below the lower limit of assay detection, while five patients (17%) with PCS did not have suppressed urinary cortisol values. When pre-CRH levels of plasma cortisol were analyzed at a cutoff of more than 1.8 µg/dl (>50 nmol/liter), the sensitivity was 95%, and the specificity was 83%, recognizing a slightly different timing of dexamethasone administration compared with the standard low-dose dexamethasone suppression test.

The differences among our study and previous reports might be attributed to differences in study populations. We could further speculate that various comorbidities in the setting of PCS, especially the relatively frequent finding of obstructive sleep apnea, may lead to elevations of other ACTH secretagogues such as TNF and IL-6, which have influenced tissue sensitivity to glucocorticoids in vitro (17). In addition, subtle differences in the assays used across the different studies likely contribute to differences in outcomes.

The limitations of our study include the retrospective nature of the study and the fact that dexamethasone levels were not measured. We did not perform dexamethasone levels in the clinical practice routinely because dynamic suppression tests were not performed in patients who take medications, which interfere with dexamethasone metabolism or in patients who suffer from malabsorption. Our patients met with the endocrine nursing staff and were followed daily to avoid any misunderstanding of the procedure and noncompliance with dexamethasone administration. Development of sensitive LC-MS/MS plasma synthetic glucocorticoid assays will allow clinicians to measure the levels of dexamethasone routinely in the future.

A lack of follow-up data is another limitation in our study. In an attempt to overcome this problem, especially the concern that some of the patients with PCS diagnosis might have progressed to CD, we performed a validation analysis of the sensitivity and specificity estimates. If 1, 5, 10, or 20% of the 14 PCS patients with no follow-up had CD, the sensitivity of the ACTH level at 15 min would be 94, 92, 89, and 84% respectively, while specificity results would be 97, 96, 96, and 96%, respectively. We elected to exclude women on estrogen therapy because of concerns regarding elevation of total plasma cortisol values (due to cortisol binding globulin elevation) from our final analysis. In the future, validation of plasma-free cortisol assays might provide insight into these clinical circumstances. Therefore, at the present time, we would recommend that estrogen therapy should be withheld for a duration of 4–6 wk before the dexamethasone-suppressed CRH stimulation test.

In conclusion, in our data, the dexamethasone-suppressed CRH stimulation test indicates that a 15-min post-oCRH ACTH value of more than 27 pg/ml (>5.9 pmol/liter) had the highest diagnostic accuracy, and, thus, the best joint sensitivity and specificity for detection of CD. When plasma cortisol values are applied, the 15-min cortisol value of more than 2.5 mg/dl (>70 nmol/liter) had a sensitivity of 90% and specificity of 90%. Due to the relatively small sample size (51 patients) common to studies of mild CD, none of the tests based on the post-CRH stimulated ACTH levels or the post-CRH cortisol levels had sensitivity or specificity values significantly different from one another. Thus, when considering our data and those reported by others, it is clear the dexamethasone-suppressed CRH stimulation test cannot be used as a definitive standard to exclude spontaneous CS. In addition, the expense of this test should be considered. Therefore, clinicians should be cautious when interpreting suppression and stimulation testing results found in the diverse population of patients with suspected hypercortisolism.

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online May 8, 2007

Abbreviations: CD, Cushing’s disease; CS, Cushing’s syndrome; CV, coefficient of variation; LC-MS/MS, liquid chromatography-tandem mass spectrometry assay; oCRH, ovine CRH; PCS, pseudo-CS; ROC, receiver operating characteristic.

Received December 5, 2006.

Accepted April 26, 2007.

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This Article Abstract Full Text (PDF) All Versions of this Article: 92/8/2972    most recent Author Manuscript (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 Erickson, D. Articles by Christianson, T. Search for Related Content PubMed PubMed Citation Articles by Erickson, D. Articles by Christianson, T. Related Collections Adrenal and Hypertension Neuroendocrinology and Pituitary Endocrine Oncology