Hypothalamic-pituitary-adrenal axis

The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components of the neuroendocrine system: the hypothalamus, the pituitary gland, and the adrenal glands. The HPA axis controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure.

Feedback loop
The negative feedback loop of the HPA axis can be described by these three components:


 * 1) The paraventricular nucleus of the hypothalamus contains neuroendocrine neurons that synthesize and secrete vasopressin and corticotropin-releasing hormone (CRH).
 * 2) These two peptides regulate the secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland. ACTH in turn acts on the adrenal cortex, which produces glucocorticoid hormones (mainly cortisol in humans as well as mineralocorticoids like aldosterone) in response to stimulation by ACTH.
 * 3) Glucocorticoids in turn act back on the hypothalamus and pituitary to suppress CRH and ACTH production in a negative feedback cycle.

In the brain, cortisol acts on two types of receptor – mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neurons. Vasopressin can be thought of as "water conservation hormone" and is also known as "antidiuretic hormone." It is released when the body is dehydrated and has potent water-conserving effects on the kidney. It is also a potent vasoconstrictor.

Role in the body
Release of CRH from the hypothalamus is influenced by stress, physical activity, illness, by blood levels of cortisol and by the sleep/wake cycle (circadian rhythm). 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. This corresponds to the rest-activity cycle of the organism. An abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome.

The HPA axis has a central role in regulating many homeostatic systems in the body, including the metabolic system, cardiovascular system, immune system, reproductive system and central nervous system. The HPA axis integrates physical and psychosocial influences in order to allow an organism to adapt effectively to its environment, use resources, and optimize survival.

Anatomical connections between brain areas such as the amygdala, hippocampus, prefrontal cortex and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the amygdala's central nucleus, which then projects out to several parts of the brain involved in responses to fear. At the hypothalamus, fear-signaling impulses activate both the sympathetic nervous system and the modulating systems of the HPA axis.

Glucocorticoids have many important functions, including modulation of stress reactions, but in excess they can be damaging. Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids. Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress.

Immune system
There is bi-directional communication and feedback between the HPA axis and immune system. A number of cytokines, such as IL-1, IL-6, IL-10 and TNF-alpha can activate the HPA axis, although IL-1 is the most potent. The HPA axis in turn modulates the immune response: high levels of cortisol suppress immune and inflammatory reactions and trigger immune cells such as monocytes and neutrophils to release anti-inflammatory cytokines (e.g. IL-4, IL-10, and IL-13). This helps to protect the organism from a lethal overactivation of the immune system, and minimizes tissue damage from inflammation.

Role in human disease
Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.

The relationship between chronic stress and its concomitant activation of the HPA axis, and dysfunction of the immune system is unclear; studies have found both immunosuppression and hyperactivation of the immune response.

Notable studies

 * 1996, Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome
 * 2000, Chronic Fatigue Syndrome: A Dysfunction of the Hypothalamic-Pituitary-Adrenal Axis (Abstract)
 * 1996, Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome
 * 2018, High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology (Abstract)