Hypothalamic-pituitary-adrenal Axis

The hypothalamic-pituitary-adrenal axis (HPA axis) is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland, and the adrenal glands (small, conical organs on top of the kidneys). The interactions among these organs constitute the hypothalamic-pituitary-adrenal axis, a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. A wide variety of species, from the most ancient organisms to humans, share components of the HPA axis. It is the common mechanism for interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome.

The hypothalamic-pituitary-adrenal axis is a feedback. The main hormones that activate the HPA axis are corticotropin-releasing hormone (CRH), arginine vasopressin (AVP) and adrenocorticotropin hormone (ACTH). The loop is completed by the negative feedback of cortisol on the hypothalamus and pituitary. The simultaneous release of cortisol into the circulation has a number of effects, including elevation of blood glucose for increased metabolic demand. Cortisol also negatively affects the immune system and prevents the release of immunotransmitters. Interference from other brain regions (eg hippocampus and amygdala) can also modify the HPA axis, as can neuropeptides and neurotransmitters.

The key elements of the HPA axis are the paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons that synthesize and secrete vasopressin and corticotropin-releasing hormone (CRH). These two peptides regulate the anterior lobe of the pituitary gland. corticotropin-releasing hormone and vasopressin are released from neurosecretory nerve terminals at the median eminence. They are transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk. There, CRH and vasopressin act synergistically to stimulate the secretion of stored ACTH from corticotrope cells. ACTH is transported by the blood to the adrenal cortex of the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids such as cortisol from cholesterol. Cortisol is a major stress hormone and has effects on many tissues in the body, including on the brain.

Release of CRH from the hypothalamus is influenced by stress, by blood levels of cortisol and by the sleep/wake cycle. In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30–45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. An abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome (MacHale, 1998), insomnia (Backhaus, 2004) and burnout (Pruessner, 1999).