  This article seeks to address the prevailing issue of how to measure specific
process components of psychobiological stress responses. Particularly the
change of cortisol secretion due to stress exposure has been discussed as an
endophenotype of many psychosomatic health outcomes. To assess its process
components, a large variety of non-compartmental parameters (i.e., composite
measures of substance concentrations at different points in time) like the area
under the concentration-time curve (AUC) are utilized. However, a systematic
evaluation and validation of these parameters based on a physiologically
plausible model of cortisol secretion has not been performed so far. Thus, a
population pharmacokinetic (mixed-effects SDE) model was developed and fitted
to densely sampled salivary cortisol data of 10 males from Montreal, Canada,
and sparsely sampled data of 200 mixed-sex participants from Dresden, Germany,
who completed the Trier Social Stress Test (TSST). Besides the two major
process components representing (1) stress-related cortisol secretion
(reactivity) and (2) cortisol elimination (recovery), the model incorporates
two additional, often disregarded components: (3) the secretory delay after
stress onset, and (4) deviations from the projected steady-state concentration.
The fitted model (R2 = 99%) was thereafter used to investigate the correlation
structure of the four individually varying, and readily interpretable model
parameters and eleven popular non-compartmental parameters. Based on these
analyses, we recommend to use the minimum-maximum cortisol difference and the
minimum concentration as proxy measures of reactivity and recovery,
respectively. Finally, statistical power analyses of the reactivity-related sex
effect illustrate the consequences of using impure non-compartmental measures
of the different process components that underlie the cortisol stress response.

Quantitative Methods