The role of the HPA-axis in understanding psychopathology: cause, consequence, mediator, or moderator?

Abstract

Human life is not without stressful challenges. These challenges may be even needed to fully exploit one’s potential, and not only include negative experiences in case of the loss of a loved significant other but also be positively colored, such as moving to a new job and trying to meet high-set expectations. We have been endowed with biobehavioral mechanisms to deal with such challenges. One of these mechanisms is the hypothalamus–pituitary–adrenal (HPA)-axis which is a central component of the body’s neuroendocrine response to stress. The hypothalamus secretes corticotropin-releasing hormone (CRH), which in turn stimulates the release of adrenocorticotropic hormone (ACTH) in the anterior pituitary. ACTH in turn stimulates the adrenal cortex to secrete cortisol. Cortisol is known as the major end product of the HPA-axis in humans [1]. Yet, activity of the HPA-axis does not end with the production of cortisol. The HPA-axis is controlled by negative feedback regulation that tends to normalize secretion of cortisol [1]. Elevated cortisol levels reduce ACTH levels as a consequence of negative feedback regulation, followed by a reduction in cortisol levels; in case of reduced cortisol levels, there is less negative feedback regulation at the pituitary, followed by an elevation in ACTH levels [2]. In normal nonstressful situations, cortisol secretion follows a circadian rhythm characterized by high levels in the morning followed by a decrease throughout the rest of the day. Generally, cortisol levels rise in about half an hour after awakening, which is known as the cortisol awakening response (CAR). The CAR is probably related to the