Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing’s syndrome

Abstract

ObjectiveTo evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing’s disease (CD) and ectopic Cushing’s syndrome (ECS).MethodsRetrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing’s syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency. Optimal cut-offs were calculated via receiver operating characteristic (ROC) analysis using CD as reference.Results469 patients were analyzed [78% females; median age 43 years (IQR 19)]. CRH test and overnight 8 mg DST were performed in 420 [CD, n=394 (94%); ECS, n=26 (6%)] and 237 patients [228 CD (96%), 9 ECS (4%)]. Both tests were performed in 205 patients (44%). The post-CRH %-increase at 30 minutes of both ACTH (cut-off ≥31%, sensitivity 83%, specificity 85%, AUC 0.81) and cortisol (cut-off ≥12%, sensitivity 82%, specificity 89%, AUC 0.86) discriminated best between CD and ECS. A test duration of >60 minutes did not improve diagnostic performance of the CRH test. The optimal cortisol cut-off for the %-suppression during the 8 mg DST was ≥55% (sensitivity 80%, specificity 78%, AUC 0.75).ConclusionThe CRH test has equivalent sensitivity but higher specificity than the 8 mg DST and is therefore the test of first choice. The diagnostic outcome of ACTH and cortisol is well comparable, however, sampling beyond 60 minutes post-CRH does not provide diagnostic benefits.

Utility of Simple and Non-Invasive Strategies Alternative to Inferior Petrosal Sinus Sampling and Peripheral CRH Stimulation in Differential Diagnosis of ACTH-Dependent Cushing Syndrome

“…Our findings are consistent with a previous study by Newell-Price et al that reported sensitivity and specificity estimates of 70 % and 100 %, respectively for > 105 % ACTH response, and 85 % and 100 %, respectively for > 14 % cortisol response following human CRH stimulation [28]. Recent studies, including the ones by Detomas et al ( ≥ 31 % ACTH rise, sensitivity, and specificity: 83 % and 85 %, respectively; ≥ 12 % cortisol rise: 82 % and 89 %, respectively) and Ceccato et al ( ≥ 31 % ACTH rise: 91 % and 80 %, respectively; ≥ 20 % cortisol rise: 86 % and 80 %, respectively) have demonstrated similar performance, albeit at different cut-offs [29,30].…”

“…and 80%, respectively; ≥20% cortisol rise: 86% and 80%, respectively) have demonstrated similar performance, albeit at different cut-offs [29,30].…”

“…Furthermore, BIPSS can have false negative and false positive results and the accuracy in clinical practice is far from 100 % [5,9]. For instance, in a recent study, using a post-CRH IPS: P ACTH cut-off ≥ 2.1, Detomas et al, reported 9 false negative results out of 103 CD cases (sensitivity 91 %) and 1 false positive result out of 14 EAS cases (specificity 93 %) [10]. Overall, the sensitivity and specificity of BIPSS varies between 88-100 % and 67-100 %, respectively [5].…”

Pitfalls in the Diagnosis and Management of Hypercortisolism (Cushing Syndrome) in Humans; A Review of the Laboratory Medicine Perspective

“…People with Cushing disease have a more pronounced increase in ACTH and cortisol concentration after CRH administration than those with ectopic ACTH, but it is not recommended to establish a diagnosis of Cushing syndrome [ 1 , 118 ]. Performance is superior to the 8 mg overnight dexamethasone suppression test and is recommended over it when a pituitary adenoma has not been identified on imaging; however, CRH is difficult to obtain [ 26 , 123 ].…”

Bilateral inferior petrosal sinus sampling: Procedural data from a German single-center study

“…Noninvasive methods to differentiate between CD and ECS are dynamic endocrine tests (like the CRH-stimulation test and the high-dose dexamethasone suppression test) and high-resolution, gadolinium-enhanced magnetic resonance imaging (MRI) of the sellar region 4 . While the former is characterized by low diagnostic accuracy, MRI is often not able to identify small pituitary lesions and carries the risk of misjudging non-functioning adenomas as the source of cortisol excess 5 .…”