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21.5: Hypothalamic-Pituitary Axis
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21.5: Hypothalamic-Pituitary Axis

The response to stress—be it physical or psychological, acute or chronic—involves activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. The HPA axis is part of the neuroendocrine system because it involves both neuronal and hormonal communication. Its function is to regulate homeostatic systems—metabolic, cardiovascular, and immune—providing the necessary means to respond to a stressor.

What Happens During Stress

In response to stress, the neurons in the hypothalamus release corticotropin-releasing hormone, or CRH, into the bloodstream. CRH takes a short journey to the pituitary gland where it stimulates the release of adrenocorticotropic hormone, or ACTH. The site of action for ACTH are the adrenal glands which lay just on the surface of the kidneys. When stimulated, the adrenal glands release two types of stress messages.

Neural stimulation initiates the first message—the release of epinephrine and norepinephrine from the adrenal medulla. This activates the sympathetic nervous system resulting in elevated heart rate, blood flow, and respiration—processes designed to activate states of alertness and arousal. These two chemicals are also referred to as adrenaline and noradrenaline, respectively.

ACTH initiates the second message—the release of glucocorticoids by the adrenal cortex. In humans, cortisol is the primary hormone involved in the stress response. While the first messages stimulate systems, the second messages fortify some systems and inhibit other non-vital systems. Cortisol mobilizes glucose fuel reserves and promotes gluconeogenesis via the catabolism of fatty acids and proteins. It also temporarily inhibits the immune and inflammatory responses. Then, when blood cortisol levels reach a certain threshold, it triggers a negative feedback loop which inhibits both the hypothalamus and pituitary activity. This deactivates the HPA axis and brings the stress response to a stop.

Chronic activation of the HPA axis, either through chronic stress or chronic acute stress, can lead to a depletion of cortisol. Since cortisol has multiple functions during stress and non-stress periods this can lead to chronic pain, depression, infertility, and may play a role in substance abuse and addiction.


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