37 3 Measurement of Cortisol NANCY A. NICOLSON INTRODUCTION TO THE HYPOTHALAMIC-PITUITARY- ADRENOCORTICAL AXIS The hypothalamic-pituitary-adrenocortical (HPA) axis and its end product, cortisol, are thought to be important mediators of the relationship between stressful life experi- ences and health outcomes. The HPA response is a component of the organism’s adaptive system for maintaining function under changing environmental circum- stances. Over the long term, however, chronic overactivation following repeated stressors can give rise to wear and tear or allostatic load (McEwen, 2003). Both mal- adaptive responses to stress and distur- bances in the functioning of the HPA axis have been implicated in a wide variety of syndromes and illnesses, including cardio- vascular illness, insulin resistance syndrome and diabetes, cognitive decline during aging, fatigue and pain syndromes, and psychiatric disorders such as depression and posttrau- matic stress disorder (PTSD), among others (Charmandari, Tsigos, & Chrousos, 2005). As the name indicates, the main compo- nents of the HPA axis are the hypothalamus, the pituitary gland, and the adrenal cortex (see Figure 3.1). The hypothalamus releases corticotropin-releasing hormone (CRH, also known as CRF) into the portal blood vessels connecting the hypothalamus to the anterior pituitary. CRH, which works synergisti- cally with arginine vasopressin (AVP) released from the hypothalamus, then trig- gers the pituitary to secrete adrenocorticotropic hormone (ACTH) into the bloodstream. After reaching the adrenal cortex, ACTH stimulates the release of glucocorticoids (GCs)—in humans, cortisol. This entire pro- cess takes place within a matter of minutes. The HPA axis is regulated by a complex neg- ative feedback system, with circulating gluco- corticoids inhibiting activity at the level of the hippocampus, the hypothalamus, and the pituitary. In general, hippocampal structures exert inhibitory influences on the axis at the level of the hypothalamus, whereas the amygdala plays an activating role (Herman & Cullinan, 1997). Mineralocorticoid (MR) and glucocorticoid (GR) receptors in the brain are thought to play different but com- plementary roles in regulating normal circa- dian activity, preparing the organism to respond to external stimuli, and facilitating recovery of disturbed homeostasis after acutely stressful situations (de Kloet, 1991). CHAPTER 03 - Luecken - 45370.qxd 7/6/2007 8:28 PM Page 37