Salivary Cortisone to Estimate Cortisol Exposure and Sampling Frequency Required Based on Serum Cortisol Measurements

J Clin Endocrinol Metab. 2019 Mar 1;104(3):765-772. doi: 10.1210/jc.2018-01172.


Context: Population studies frequently measure cortisol as a marker of stress, and excess cortisol is associated with increased mortality. Cortisol has a circadian rhythm, and frequent blood sampling is impractical to assess cortisol exposure. We investigated measuring salivary cortisone and examined the sampling frequency required to determine cortisol exposure.

Methods: Serum and saliva with cortisol and cortisone were measured by liquid chromatography-tandem mass spectrometry in independent cohorts. The relationship between serum cortisol and salivary cortisone was analyzed in cohort 1 using a linear mixed effects model. The resulting fixed effects component was applied to cohort 2. Saliva cannot easily be collected when a patient is sleeping, so we determined the minimum sampling required to estimate cortisol exposure [estimated area under the curve (eAUC)] using 24-hour cortisol profiles (AUC24) and calculated the relative error (RE) for eAUC.

Results: More than 90% of variability in salivary cortisone could be accounted for by change in serum cortisol. A single serum cortisol measurement was a poor estimate of AUC24, especially in the morning or last thing at night (RE >68%); however, three equally spaced samples gave a median RE of 0% (interquartile range, -15.6% to 15.1%). In patients with adrenal incidentalomas, eAUC based on three serum cortisol samples showed a difference between those with autonomous cortisol secretion and those without (P = 0.03).

Interpretation: Accepting that most people sleep 7 to 8 hours, ∼8-hourly salivary cortisone measurements provide a noninvasive method of estimating 24-hour cortisol exposure for population studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Gland Neoplasms / blood*
  • Adult
  • Aged
  • Area Under Curve
  • Circadian Rhythm / physiology*
  • Cortisone / analysis*
  • Female
  • Healthy Volunteers
  • Humans
  • Hydrocortisone / blood*
  • Hydrocortisone / physiology
  • Male
  • Middle Aged
  • Retrospective Studies
  • Saliva / chemistry*
  • Time Factors
  • Young Adult


  • Cortisone
  • Hydrocortisone

Supplementary concepts

  • Adrenal incidentaloma

Associated data

  • EudraCT/2013-000260-28