Do diurnal salivary cortisol curves carry meaningful information about the regulatory biology of the HPA axis in healthy humans?

Salivary cortisol stress biomarkers have been extensively used in epidemiological work to document links be-tween stress and ill health. There has been little effort to ground field friendly cortisol measures in the hypothalamic-pituitary-adrenal (HPA) axis regulatory biology that is likely relevant to delineating mechanistic pathways leading from stress exposure to detrimental health outcomes. Here, we utilized a healthy convenience sample (n = 140) to examine normal linkages between extensively collected salivary cortisol measures and available laboratory probes of HPA axis regulatory biology. Participants provided 9 saliva samples per day over 6 days within a month, while engaging in usual activities, and also participated in 5 regulatory tests (adreno-corticoptripin stimulation, dexamethasone/corticotropin-releasing-hormone stimulation, metyrapone, dexa-methasone suppression, and Trier Social Stress Test). Logistical regression was used to test specific predictions linking cortisol curve components to regulatory variables and to explore widely for non-predicted associations. We found support for 2 of 3 original hypotheses, showing associations (1) between cortisol diurnal decline and feedback sensitivity as measured by dexamethasone suppression, and (2) between morning cortisol levels and adrenal sensitivity. We did not find links between central drive (metyrapone test) and end of day salivary levels. We confirmed an a priori expectation of limited linkage between regulatory biology and diurnal salivary cortisol measures, beyond those predicted. These data support an emerging focus on measures related to diurnal decline in epidemiological stress work. They raise questions about the biological meaning of other curve components, including morning cortisol levels, and perhaps CAR (Cortisol Awakening Response). If morning cortisol dynamics are linked to stress, more work on adrenal sensitivity in stress adaptation and stress-health links may be warranted.