Evaluation of Desmopressin Stimulation Test Specificity in Healthy Volunteers

OBJECTIVE: The desmopressin stimulation test (DesST) is used to identify Cushing disease (CD); reportedly, most healthy people and patients with nonneoplastic hypercortisolism lack a significant response. We aimed to evaluate and improve DesST specificity (Sp). DESIGN: Prospective evaluation of four DesST protocols in healthy volunteers. METHODS: 20 healthy volunteers underwent four DesST protocols in a randomized order. Protocols involved fluid restriction with desmopressin 10 mcg (10NPO; "standard"), 4 mcg (4NPO) and 10 mcg preceded by dexamethasone 1 mg (10+DexNPO); and desmopressin 10 mcg without fluid restriction (10H2O). We evaluated Sp for each protocol, using established response criteria. RESULTS: Previous criteria of relative increases of 35% and/or 20% for ACTH and cortisol, respectively, had low Sp: 50% (95%CI 28-72%; 10NPO) to 85% (95%CI 69-100%; 10+DexNPO). Using absolute ACTH increase >8.1 pmol/L (37 pg/mL) improved Sp to 100% across all protocols. Compared to 10NPO, median ACTH and cortisol were lower throughout during 10+DexNPO, and also at +15 minutes during 4NPO (ACTH: 4.4 vs 4.9 pmol/L [19.9 vs 22.1 pg/mL], p=0.06; cortisol: 248 vs 284 nmol/L [9.0 vs 10.3 mcg/dL], p=0.01). 10H2O and 10NPO results were similar. Adverse events were mild; hyponatremia occurred after 5/80 tests. CONCLUSIONS: After desmopressin, healthy volunteers have small absolute increases in ACTH and cortisol that equate to large relative changes from baseline. Optimized response criteria should likely incorporate absolute values. Fluid restriction did not impact Sp, but using a lower desmopressin dose or dexamethasone pre-treatment are promising ways to improve diagnostic accuracy, if sensitivity is maintained in CD. SIGNIFICANCE STATEMENT: Half of healthy volunteers had a response consistent with Cushing disease (CD) during a commonly used 10 mcg desmopressin stimulation test, interpreted using relative ACTH and/or cortisol increases. This puts the test's reliability for excluding Cushing disease (CD) in question, particularly in settings of mild hypercortisolism. These situations include differentiating CD from nonneoplastic hypercortisolism, identifying cyclic ectopic ACTH-producing tumors during nadir phases, and establishing early CD recurrence. Optimized response criteria likely require absolute ACTH and/or cortisol cut-offs. Using a reduced 4 mcg dose of desmopressin and pre-treatment with 1 mg dexamethasone improved test specificity, offering promising ways to improve test performance if sensitivity is maintained in CD.