Salivary cortisol as a biomarker in stress research Dirk H. Hellhammer a, * , Stefan Wu ¨st a,b , Brigitte M. Kudielka a,c a Psychology, Department of Clinical and Physiological Psychology, University of Trier, Johanniterufer 15, 54290 Trier, Germany b Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, J5, 68159 Mannheim, Germany c Jacobs Center on Lifelong Learning and Institutional Development, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany Received 15 July 2008; received in revised form 30 October 2008; accepted 31 October 2008 1. Introduction Today, salivary cortisol is routinely used as a biomarker of psychological stress and related mental or physical diseases. Most studies consider salivary cortisol levels a reliable mea- sure of hypothalamus—pituitary—adrenal axis (HPAA) adapta- tion to stress. However, the stress response of the HPAA is rather complex and modulated by numerous factors. Cortisol levels in saliva are partly dissociated from levels of para- ventricular corticotrophin releasing factor (CRF), arginine vasopressin (AVP), adrenocorticotropic hormone (ACTH), and cortisol in blood or urine. Under several circumstances a partial but significant dissociation between salivary cortisol levels and other HPAA related endocrine signals can be observed. This paper describes such dissociations and puta- tive mechanisms. We aim to illustrate the physiological significance of salivary cortisol as a biomarker of HPAA responsivity by addressing several sources of variance con- tributing to such dissociations. 2. Dissociations with CRF/AVP The process between the initiation of an HPAA response in the central nervous system and salivary cortisol variations as an outcome measure is modulated by numerous psychological and biological events. Psychological events initiate an HPAA response by predominantly activating CRF/AVP neurons in the paraventricular nucleus (PVN) of the hypothalamus (see Chrousos and Kino, 2007 for a review). The degree of activa- tion will vary, depending on the psychological components of the situation, such as unpredictability, uncontrollability, novelty, anticipation, ego-involvement, habituation, etc. Psychoneuroendocrinology (2009) 34, 163—171 KEYWORDS Stress response; Cortisol; CRF; AVP; ACTH Summary Salivary cortisol is frequently used as a biomarker of psychological stress. However, psychobiological mechanisms, which trigger the hypothalamus—pituitary—adrenal axis (HPAA) can only indirectly be assessed by salivary cortisol measures. The different instances that control HPAA reactivity (hippocampus, hypothalamus, pituitary, adrenals) and their respective modulators, receptors, or binding proteins, may all affect salivary cortisol measures. Thus, a linear relationship with measures of plasma ACTH and cortisol in blood or urine does not necessarily exist. This is particularly true under response conditions. The present paper addresses several psychological and biological variables, which may account for such dissociations, and aims to help researchers to rate the validity and psychobiological significance of salivary cortisol as an HPAA biomarker of stress in their experiments. # 2008 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +49 651 2012928; fax: +49 651 2012934. E-mail address: albertz@uni-trier.de (D.H. Hellhammer). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/psyneuen 0306-4530/$ — see front matter # 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2008.10.026