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The Journal of Clinical Endocrinology & Metabolism 91(7):2582–2586 Copyright 2006 by The Endocrine Society Comparison of the Dexamethasone-Suppressed
Corticotropin-Releasing Hormone Test and Low-Dose
Dexamethasone Suppression Test in the Diagnosis of
Cushing’s Syndrome
N. M. Martin, W. S. Dhillo, A. Banerjee, A. Abdulali, C. N. Jayasena, M. Donaldson, J. F. Todd, andK. Meeran Department of Endocrinology, Imperial College, Faculty of Medicine, Hammersmith Hospital, London W12 0NN,United Kingdom Context: The low-dose dexamethasone suppression test (LDDST) is
the CRH injection, with a value of less than 38 nmol/liter also ex- widely used in confirming a diagnosis of Cushing’s syndrome. CRH administration at the end of an LDDST has been reported to improvethe diagnostic accuracy of this test.
Main Outcome Measure: Diagnosis or exclusion of Cushing’s syn-
drome was the main outcome measure.
Objective: Our objective was to assess whether CRH administration
after a standard LDDST (LDDST-CRH test) improves diagnostic ac-
Results: Twelve subjects were diagnosed with Cushing’s syndrome
(eight Cushing’s disease and four primary adrenal). The sensitivity ofthe LDDST in diagnosing Cushing’s syndrome was 100%, with a Design, Setting, and Participants: Thirty-six individuals with a
specificity of 88%. In contrast, although the sensitivity of the LDDST- clinical suspicion of Cushing’s syndrome each completed a standard CRH test was also 100%, specificity was reduced at 67%. These results LDDST and an LDDST-CRH test at Hammersmith Hospitals NHS give a positive predictive value of 80% for the LDDST and 60% for the Trust, London. The LDDST involved administration of 0.5 mg oral dexamethasone given 6-hourly for 48 h. Serum cortisol was measured6 h after the last dose of dexamethasone, with a value of 50 nmol/liter Conclusion: This small study suggests that the addition of CRH to
or below excluding Cushing’s syndrome. Immediately after this, the the LDDST does not improve the diagnostic accuracy of the standard LDDST-CRH test commenced with administration of a ninth dose of LDDST in Cushing’s syndrome. (J Clin Endocrinol Metab 91:
0.5 mg dexamethasone. Exactly 2 h later, 100 ␮g human-sequence 2582–2586, 2006)
CRH was administered. Serum cortisol was measured 15 min after DIFFERENTIATINGBETWEENCUSHING’Ssyndrome mediately after low-dose dexamethasone administration and pseudo-Cushing’s states in individuals with hy- (dexamethasone-suppressed CRH stimulation test), was su- percortisolism is difficult because of the increasing preva- perior to the standard LDDST in the diagnosis of Cushing’s lence of obesity, hypertension, and type II diabetes mellitus syndrome. Current opinion suggests that in pseudo-Cush- (1– 4). Liddle’s original description of the low-dose dexa- ing’s syndrome, CRH secretion is increased, yet cortisol con- methasone suppression test (LDDST) (5) has been refined in tinues to exert negative feedback on the remainder of the recent years to measure serum cortisol by RIA. Current prac- hypothalamic-pituitary-adrenal axis, hence allowing sup- tice involves the standard LDDST whereby 0.5 mg dexa- pression by exogenous glucocorticoid. In contrast, in indi- methasone is administered orally at strict 6-hourly intervals viduals with Cushing’s syndrome, the hypothalamic- for 48 h, with a cutoff value for suppression of serum cortisol pituitary-adrenal axis is more responsive to exogenous CRH to 50 nmol/liter or below being 98% sensitive for the diag- but less responsive to suppression by dexamethasone. Using nosis of Cushing’s syndrome (6). However, some individuals the dexamethasone-suppressed CRH stimulation test, a se- with Cushing’s syndrome may also adequately suppress rum cortisol of greater than 38 nmol/liter 15 min after CRH their serum cortisol to less than 50 nmol/liter during a stan- administration distinguished Cushing’s syndrome from dard LDDST (7), which may reflect impaired dexamethasone pseudo-Cushing’s states with 100% sensitivity and specific- ity (10). More recently, the same group showed that the Yanovski et al. (10) proposed that CRH administered im- dexamethasone-suppressed CRH stimulation test also cor-rectly distinguished all subjects with mild Cushing’s disease First Published Online May 2, 2006
Abbreviations: CS-excluded, Cushing’s syndrome excluded; LDDST, We evaluated the effects of CRH post-dexamethasone sup- low-dose dexamethasone suppression test; LDDST-CRH test, dexa- pression in the diagnosis of Cushing’s syndrome. By mod- methasone-suppressed CRH test; MRI, magnetic resonance imaging.
ifying previously described protocols (10, 11), our subjects JCEM is published monthly by The Endocrine Society (http://www.
underwent a standard LDDST and after completion of this, endo-society.org), the foremost professional society serving the en-
docrine community.
received CRH (LDDST-CRH test). This enabled us to inves- Martin et al. • LDDST-CRH test in Cushing’s Syndrome J Clin Endocrinol Metab, July 2006, 91(7):2582–2586 tigate subjects by usual diagnostic criteria yet also to study The diagnosis of Cushing’s syndrome was verified by histological any additional diagnostic benefits of CRH administration examination of a pathological specimen after surgery. In those cases where histological confirmation was not possible, diagnosis was con-firmed if clinical and biochemical remission of Cushing’s syndromeoccurred after surgery. In all cases of adrenal-dependent Cushing’s Patients and Methods
syndrome, there was remission of symptoms with biochemical confir- mation of cure on standard LDDST. Six subjects with Cushing’s diseasewere cured after transsphenoidal hypophysectomy. However, two sub- A cohort of 36 individuals who were suspected to have Cushing’s jects with Cushing’s disease, confirmed by inferior petrosal sinus sam- syndrome based on the presence of typical clinical characteristics (1) pling, did not have histology supporting removal of an ACTH-secreting underwent our standard investigative protocol. Each subject completed pituitary adenoma and did not display clinical evidence of cure post- a standard LDDST and an LDDST-CRH test between 2002 and 2004 at operatively. This was confirmed after MRI and repeat standard LDDST Hammersmith Hospitals NHS Trust, London. No individuals had sig- before definitive treatment with bilateral adrenalectomy.
nificant renal or hepatic disease. Subjects were admitted to the Clinical Subjects diagnosed with pseudo-Cushing’s syndrome and those sub- Investigations Unit at Hammersmith Hospital for LDDST-CRH testing jects in which Cushing’s syndrome was excluded (CS-excluded) were and had stopped any estrogen- or glucocorticoid-containing prepara- followed up for progression of Cushingoid features. These subjects were tions for 6 wk before the test. None were taking medications known to followed up for at least 1 yr or until we were confident that Cushing’s induce liver enzymes such as anticonvulsants at the time of the study.
syndrome had been excluded because of lack of progression of clinical After investigation of these 36 individuals, there were 12 confirmed cases symptoms in addition to exclusion on biochemical grounds.
of Cushing’s syndrome (eight Cushing’s disease and four primary ad-renal). Three subjects had a clear underlying cause for pseudo-Cushing’s syndrome (alcohol excess in two, morbid obesity and obstructive sleepapnea in one) that was addressed before repeat biochemical testing.
Plasma cortisol was measured using the Nichols Advantage one-site Sixteen subjects had Cushing’s syndrome excluded on biochemical test- chemiluminescence cortisol assay (Nichols Institute Diagnostics, San ing (CS-excluded). The study protocol was approved by our local re- Clemente, CA). The intraassay coefficient of variation was 4.7%. The search ethics committee, and informed consent was obtained. Studies interassay coefficients of variation were as follows: low values (mean were performed in accordance with the Declaration of Helsinki.
cortisol, 69.6 nmol/liter) 5.5%, medium values (mean cortisol, 452.3nmol/liter) 4.4%, and high values (mean cortisol, 814.2 nmol/liter) 3.8%.
The reported analytical sensitivity of the assay is 22 nmol/liter, and the functional sensitivity is 54 nmol/liter. In our laboratory, the functional A standard LDDST involved 0.5 mg oral dexamethasone given sensitivity (defined as the concentration with a coefficient of variation 6-hourly (0900, 1500, 2100, and 0300 h) for 48 h with a final plasma not to exceed 10%), when estimated from a precision profile using cortisol sample taken 6 h after the last dose of dexamethasone (7). In Nichols reagents, was no more than 15 nmol/liter (see supplemental contrast, the dexamethasone-suppressed CRH stimulation test (10, 11) Table 1, published as supplemental data on The Endocrine Society’s starts at 1200 h, again with eight doses of 0.5 mg oral dexamethasone Journals Online web site at http://www.jcem.endojournals.org). There administered 6-hourly (1200, 1800, 2400, and 0600 h). However, a blood was 1.6% cross-reactivity with 11-deoxycortisol and 5.9% with cortico- sample for serum cortisol is taken 44 h after the start of the test, 2 h after sterone and no significant cross-reactivity with other naturally occurring the last dose of dexamethasone (0800 h) and just before administration of iv CRH. A final blood sample is taken 15 min later. We adapted theYanovski protocol to maintain the final 48-h time point of the standard LDDST so that biochemical diagnosis or exclusion of Cushing’s syn-drome was not compromised in our subjects. In our protocol (LDDST- Sensitivity and specificity for the standard LDDST and LDDST-CRH CRH test), individuals received 0.5 mg dexamethasone orally every 6 h were derived from receiver operating characteristic analysis (12) (Stata (0900, 1500, 2100, and 0300 h) for 48 h. Forty-eight hours after the first version 7.0). The diagnostic accuracy of the standard LDDST and dexamethasone dose (T ϭ 48 h), a blood sample for serum cortisol was LDDST-CRH test was compared using the paired exact test. P Ͻ 0.05 was taken, concluding the standard LDDST. Immediately after this, the considered to be statistically significant.
LDDST-CRH test commenced. A ninth dose of 0.5 mg dexamethasonewas given to maintain cortisol suppression before CRH administration, and after this, subjects were advised to remain nil by mouth to minimizealterations in dexamethasone absorption. Exactly 2 h after the ninth The results for each subject (no. 1–36) after an LDDST and dose, a blood sample was taken (T ϭ 50 h) just before an iv bolus injection LDDST-CRH test are shown in Table 1. After a standard of 100 ␮g human-sequence CRH (human corticorelin-trifluorate; Ferring LDDST, all 12 subjects with Cushing’s syndrome failed to Pharmaceuticals Ltd., Berkshire, UK). A final blood sample was col- suppress their T ϭ 48 h serum cortisol to less than 50 nmol/ lected exactly 15 min after CRH injection (T ϭ 50 h ϩ 15).
Using the LDDST alone, a serum cortisol of 50 nmol/liter or below liter (Fig. 1), giving a sensitivity of 100%. Three individuals excluded Cushing’s syndrome (6). Based on the dexamethasone- with pseudo-Cushing’s syndrome also failed to suppress suppressed CRH stimulation test protocol (10, 11), serum cortisol of less their T ϭ 48 h serum cortisol to below this level, giving the than 38 nmol/liter 15 min after CRH injection (T ϭ 50 h ϩ 15) also LDDST a specificity of 88%. In each of these three cases, excluded Cushing’s syndrome. Therefore, in those patients achieving addressing the cause of the pseudo-Cushing’s state (non- serum cortisol values below both cutoff values, Cushing’s syndrome wasexcluded. Individuals with serum cortisol values exceeding both cutoffs invasive ventilation for obstructive sleep apnea associated were diagnosed with Cushing’s syndrome and underwent additional with morbid obesity for subject 13 and alcohol abstinence for investigations to identify the cause. Subjects with low or suppressed subjects 14 and 15) resulted in adequate suppression of se- ACTH underwent a computed tomography scan of the adrenal glands rum cortisol at T ϭ 48 h on repeat LDDST-CRH testing.
to confirm an adrenal source. All four individuals with adrenal-depen-dent Cushing’s syndrome had low/suppressed ACTH with a solitary After the LDDST-CRH test, the T ϭ 50 h ϩ 15 serum adrenal mass on imaging. All those with ACTH-dependent Cushing’s cortisol was greater than 38 nmol/liter in all 12 Cushing’s syndrome underwent a magnetic resonance imaging (MRI) scan of the subjects, giving a sensitivity for this test of 100% in the pituitary gland and bilateral inferior petrosal sinus sampling to distin- diagnosis of Cushing’s syndrome. Because three pseudo- guish Cushing’s disease from ectopic ACTH production. In those three Cushing’s subjects and five CS-excluded subjects had a T ϭ individuals in which the pituitary MRI did not show a mass lesion,inferior petrosal sinus sampling confirmed and lateralized a pituitary 50 h ϩ 15 serum cortisol that was greater than 38 nmol/liter, the specificity of the LDDST-CRH test was 67% (Fig. 2 and J Clin Endocrinol Metab, July 2006, 91(7):2582–2586 Martin et al. • LDDST-CRH test in Cushing’s Syndrome TABLE 1. Values for serum cortisol after completion of a LDDST
(T ϭ 48 h) and LDDST-CRH test (T ϭ 50 h ϩ 15) in Cushing’s
syndrome (CS), pseudo-Cushing’s states, and in those in which
Cushing’s syndrome was excluded (CS-excluded)
FIG. 1. Serum cortisol on completion of standard LDDST (T ϭ 48 h) in subjects with Cushing’s syndrome, subjects with pseudo-Cushing’s states, and CS-excluded subjects. A serum cortisol value of 50 nmol/ liter or less (dashed line) excluded Cushing’s syndrome.
peat testing 3– 6 months later, and all subsequently demon- strated adequate suppression of serum cortisol after both an LDDST and LDDST-CRH test without any intervention. Fur- thermore, during follow-up of these individuals, there was no progression of Cushingoid features.
The sensitivity, specificity, and positive and negative pre- dictive values for the LDDST and LDDST-CRH test are shown in Table 3. Using a cutoff of 38 nmol/liter as described in the original studies (10, 11), the LDDST-CRH test appeared to be less specific than the LDDST, although this did not reach statistical significance (P ϭ 0.06). However, receiver operating characteristic analysis indicated that using a cutoff of 50 nmol/liter produced the best sensitivity and specificity for the LDDST-CRH test. Nevertheless, when using this cut- off (50 nmol/liter) for the LDDST-CRH test, diagnostic ac- curacy did not differ from that of the standard LDDST Discussion
The absence of a single gold standard test makes the di- agnosis of Cushing’s syndrome problematical. The current Cushing’s syndrome was excluded if patients suppressed serum cortisol to 50 nmol/liter or below after an LDDST or to below 38nmol/liter after an LDDST-CRH test, with no clinical progression offeatures of Cushing’s syndrome. In those subjects with discordantresults, serum cortisol was suppressed to 50 nmol/liter or below oncompletion of an LDDST but elevated above 38 nmol/liter after CRHadministration. These individuals were followed up for progression ofCushingoid features until we were confident that Cushing’s syndromehad been excluded both clinically and on biochemical grounds. UFC,Mean 24-h urinary free cortisol (normal range, 55–270 nmol/24 h).
Table 1) (see supplemental Table 2 for clinical features ofpseudo-Cushing’s and CS-excluded subjects).
Five subjects (no. 32–36), demonstrated discordant results comparing the standard LDDST and LDDST-CRH test. Theirclinical features are shown in Table 2. In these individuals,serum cortisol was suppressed at T ϭ 48 h to less than 50 nmol/liter on completion of the standard LDDST, but at T ϭ IG. 2. Serum cortisol on completion of LDDST-CRH test (T ϭ 50 h ϩ 15) in subjects with Cushing’s syndrome, subjects with pseudo- 50 h ϩ 15 after CRH, serum cortisol was greater than 38 Cushing’s states and CS-excluded subjects. A serum cortisol value of nmol/liter. All subjects within this subgroup underwent re- less than 38 nmol/liter (dashed line) excluded Cushing’s syndrome.
Martin et al. • LDDST-CRH test in Cushing’s Syndrome J Clin Endocrinol Metab, July 2006, 91(7):2582–2586 TABLE 2. Clinical features of subjects with discordant results on LDDST and LDDST-CRH testing
Subject numbers correspond to Table 1. Y indicates a feature is present, and N indicates a feature is absent. Characteristics of those subjects with pseudo-Cushing’s or in CS-excluded subjects are given in supplemental Table 2. BP, Blood pressure; F, female; IGT/DM, impaired glucosetolerance/diabetes mellitus; M, male.
favored diagnostic strategy uses a combination of preoper- the current protocol compared with the original description ative clinical criteria, radiological and endocrine investiga- of the dexamethasone-suppressed CRH stimulation test.
tions, and postoperative histological examination to confirm First, we administered 0.5 mg dexamethasone at 6-hourly the diagnosis. Therefore, because the correct preoperative intervals starting at 0900 h. This contrasts with the original diagnosis may be both costly and time consuming, signifi- protocol, whereby dexamethasone administration com- cant emphasis is placed on endocrine tests that confer high menced at 1200 h. In addition, we used human-sequence diagnostic accuracy. Our findings show that although the CRH at a dose of 100 ␮g compared with the original protocol, standard LDDST and LDDST-CRH test have equally high which used ovine-sequence CRH adjusted according to body sensitivity in the diagnosis of Cushing’s syndrome, the weight. Ovine-sequence CRH has been reported as a more LDDST-CRH test is less specific. Because all subjects with potent stimulus for ACTH and cortisol release compared Cushing’s syndrome failed to suppress serum cortisol using with human-sequence CRH (14). Therefore, in the current the standard LDDST protocol, the addition of CRH to the protocol, using human-sequence CRH, a less effective stim- LDDST did not confer any additional diagnostic benefit.
ulus for ACTH and hence, cortisol secretion, should actually Furthermore, in several cases, the addition of CRH actually increase the specificity of our test. Despite this, the specificity resulted in unnecessary repeat testing in those in which the of 67% using our version of the LDDST-CRH test was less standard LDDST excluded Cushing’s syndrome. Our data than the previously reported 100% specificity (10). Similarly, are not in keeping with an earlier study proposing that that in the original protocol, iv CRH was administered 2 h after the dexamethasone-suppressed CRH stimulation test accu- the eighth dose of dexamethasone, whereas our protocol rately differentiates between pseudo-Cushing’s and Cush- included a ninth dose of dexamethasone 2 h before CRH ing’s syndrome with 100% sensitivity and specificity (10).
injection. Because subjects with pseudo-Cushing’s are re- However, it is important to note that the current study in- ported to remain sensitive to suppression by exogenous glu- volved a smaller number of subjects with Cushing’s syn- cocorticoids, this additional dose of dexamethasone may drome. Nevertheless, another group (13) has also recently have been expected to increase the specificity of the LDDST- suggested that the dexamethasone-suppressed CRH test CRH test using our protocol. The RIA used to measure serum may be less accurate than originally reported in distinguish- cortisol in the current study also differs from that used pre- ing pseudo-Cushing’s states from Cushing’s syndrome.
viously. Nevertheless, despite these differences in the Specific differences between the current study and the LDDST-CRH test protocols, the LDDST-CRH test was not original description of the dexamethasone-suppressed CRH superior to the standard LDDST in the diagnosis of Cush- test by Yanovski et al. (10) should be considered before mak- ing’s syndrome even when using a cutoff of 50 nmol/liter.
ing direct comparisons between both studies. First, in the The dexamethasone-suppressed CRH stimulation test (10, original study, participants with either pseudo-Cushing’s or 11) uses a serum cortisol cutoff of 38 nmol/liter. This is close Cushing’s syndrome had biochemical evidence of mild hy- to the sensitivity limits of many commercially available cor- percortisolism, as evidenced by elevated urinary free cortisol tisol assays. The possibility of high assay variation at low excretion. However, in the current study, subjects were in- cortisol concentrations suggests that the sensitivity of the cluded on clinical evidence alone. Second, in the original assay used is critical to the predictive power of the dexam- study, the majority of pseudo-Cushing’s patients had an ethasone-suppressed CRH stimulation test. The Nichols cor- underlying psychiatric diagnosis rather than morbid obesity tisol assay used in our laboratory has a functional sensitivity with obstructive sleep apnea or alcohol excess as in the cur- of approximately 15 nmol/liter, suggesting sufficient sensi- rent study. Furthermore, there are significant differences in tivity of this assay at cortisol concentrations near the cutoffs TABLE 3. Comparison of the LDDST and LDDST-CRH test in the diagnosis of Cushing’s syndrome
Specificity, sensitivity, and positive and negative predictive values were calculated using cutoff values for serum cortisol of 50 nmol/liter at 48 h (LDDST, column 2), 38 nmol/liter (LDDST-CRH test, column 3) 15 min after CRH administration, 50 nmol/liter 15 min after CRHadministration (LDDST-CRH test, column 4). The 95% confidence interval for each estimate is shown in parentheses.
J Clin Endocrinol Metab, July 2006, 91(7):2582–2586 Martin et al. • LDDST-CRH test in Cushing’s Syndrome of the LDDST and LDDST-CRH tests (50 and 38 nmol/liter, References
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sone-suppressed corticotropin-releasing hormone stimulation test differenti- Acknowledgments
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Dr. Kevin Murphy for helpful discussions.
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between Cushing’s syndrome and pseudoCushing: a reappraisal. Program of
the 87th Annual Meeting of The Endocrine Society, San Francisco, CA, 2005
Received September 28, 2005. Accepted April 24, 2006.
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DST research. Biol Psychiatry 22:373–385 JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.

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