Suboptimal Rise In Awakening-Induced Cortisol Is An Accurate Marker Of Cortisol Insufficiency In Patients With Normal Renal Function (Egfr > 60ml/Min)

Background: The insulin tolerance test is the gold standard for diagnosis of cortisol insufficiency. However, it is cumbersome, invasive, requires supervised hospital facilities and has unpleasant side-effects. A non-invasive outpatient-based test will be useful. We hypothesized that free cortisol concentrations in multiple spot urine samples can be used to diagnose cortisol insufficiency in patients with normal renal function (eGFR > 60 mL/min).Method: Patients and controls provided urine samples at bedtime (S1), and first (S2) and second (S3) void the next day. Cortisol and creatinine were measured in all three samples, and cortisol: creatinine ratio (S1, S2 and S3) was used for further analysis. The sum of S1+S2+S3 was used to calculate total cortisol secretion (T). Variation (V) in cortisol secretion in response to circadian rhythm was calculated as the modulus of the difference between S1 and S2 and S2 and S3.Results: Samples were collected from 96 controls and 11 patients. S1 was significantly lower vs. S2 and S3 in controls (P < 0.0001) but not in patients. S2, S3, T and V were significantly lower in patients vs. controls (P < 0.0001). ROC curve analysis using insulin tolerance test as gold standard showed that S2, S3, T and V were all equally accurate diagnostic markers for cortisol insufficiency (AUC: 0.87, NPV: 100%). The best balance of sensitivity and specificity was achieved using T (sensitivity: 100%, specificity: 58%).Conclusion: Multiple spot urine samples test is an accurate, relatively inexpensive, non-invasive, convenient outpatient-based screening test for exclusion of cortisol insufficiency.