Evaluation of desmopressin stimulation test specificity in healthy volunteers.

objectiveThe desmopressin stimulation test (DesST) is used to identify Cushing disease (CD). Reportedly, most healthy people and patients with non-neoplastic hypercortisolism lack a significant response. We aimed to evaluate and improve DesST specificity (Sp).

designProspective evaluation of four DesST protocols in healthy volunteers.

methodsTwenty healthy volunteers underwent four DesST protocols in a randomized order. Protocols involved fluid restriction with desmopressin 10 µg (10NPO; 'standard'), 4 µg (4NPO), and 10 µg preceded by dexamethasone 1 mg (10+DexNPO); and desmopressin 10 µg without fluid restriction (10H2O). We evaluated Sp for each protocol, using established response criteria.

resultsPrevious 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 with 10NPO, median ACTH and cortisol were lower throughout during 10+DexNPO and also at +15 min 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 µg/dL), P = 0.01). 10H2O and 10NPO results were similar. Adverse events were mild; hyponatremia occurred after 5/80 tests.

conclusionAfter 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 and 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 µg desmopressin stimulation test, interpreted using relative ACTH and/or cortisol increases. This puts the test's reliability for excluding CD in question, particularly in settings of mild hypercortisolism. These situations include differentiating CD from non-neoplastic 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 cutoffs. Using a reduced 4 µg dose of desmopressin or pre-treatment with 1 mg dexamethasone improved test specificity, offering promising ways to improve test performance if sensitivity is maintained in CD. CLINICAL TRIAL REGISTRATION NUMBER: NCT06635629.