Salivary Cortisol Response to ACTH Stimulation Is a Reliable Alternative to Serum Cortisol in Evaluating Hypoadrenalism

Abstract

Context: The serum total cortisol response to the ACTH stimulation test is widely used to assess adrenocortical function but is affected by changes in cortisol-binding globulin (CBG) concentration. Salivary cortisol reflects free cortisol concentrations and may offer a reliable alternative. Objectives: (1) To establish the salivary cortisol response to ACTH stimulation in healthy volunteers and patients with altered CBG concentrations; (2) to evaluate the performance of a lower reference limit (LRL) determined in healthy volunteers in patients with suspected hypoadrenalism (SH-patients). Design: A 250 μg ACTH stimulation test was undertaken in 139 healthy volunteers, 24 women taking an estradiol-containing oral contraceptive pill (OCP-females), 10 patients with low serum protein concentration (LP-patients), and 30 SH-patients. Salivary cortisol was measured by liquid chromatography-tandem mass spectrometry. Mean and LRL of the 30-minute salivary cortisol response (mean - 1.96 standard deviation) were derived from log-transformed concentrations. The LRL was applied as a diagnostic cut-off in SH-patients, with comparison to the serum response. Results: Mean CBG concentrations (range) were 58 (42-81) mg/L, 64 (43-95) mg/L, 41 (28-60) mg/L, and 116 (84-159) mg/L in males, females, LP-patients, and OCP-females, respectively. The mean 30-minute salivary cortisol concentration was 19.3 (2.5th-97.5th percentile 10.3-36.2) nmol/L in healthy volunteers. Corresponding values were not different in OCP-females [19.7 (9.5-41.2) nmol/L; P =. 59] or LP-patients [19.0 (7.7-46.9) nmol/L; P =. 97]. Overall diagnostic agreement between salivary and serum responses in SH-patients was 79%. Conclusion: Salivary cortisol response to ACTH stimulation offers a reliable alternative to serum and may be especially useful in conditions of altered CBG concentration.