What does the HPA axis control?
The HPA axis is the control system for glucocorticoid production. Glucocorticoids are the hormones of the adrenal cortex that include cortisol, the main one, and their production is under the control of this axis. The cortex does not decide by itself how much cortisol to make: it is the last station of a chain of command that starts in the hypothalamus and runs through the anterior pituitary.
Mineralocorticoid production is different. It is mainly controlled by the RAAS. The cortex makes more than one hormone family (structure and hormone families), and these two families are regulated by separate signals. Because the signals are separate, the amount of one can change without the other.
Three features together set the cortisol level: a stress-driven feedforward limb, a circadian rhythm and negative feedback.
How does a stress reach the cortex?
Cortisol is needed most when the body is stressed, so the chain starts there. In response to any endogenous or exogenous stress, the hypothalamus releases CRH. CRH acts on the anterior pituitary.
ACTH is not made as a finished hormone. CRH activates pituitary pro-hormone convertase 1 (PC1), and PC1 cleaves POMC into several peptide products. These products include ACTH. ACTH is a 39-amino-acid peptide, and it drives the adrenal cortex.
Why is cortisol not constant through the day?
But the chain does not wait for stress. The hypothalamus does not release CRH only in response to stress: CRH production has a circadian rhythm, which is set by the suprachiasmatic nucleus of the hypothalamus. So the axis runs all the time at a baseline that a clock sets, and stress adds to it.
CRH release peaks before waking and is lowest during the evening. Cortisol follows the same pattern a short time later, because cortisol sits downstream of CRH and ACTH, so a rhythm at the top is passed down the chain with a delay.
What stops the chain from running away?
A chain that only pushes would drive cortisol ever higher. The glucocorticoids restrain their own production by negative feedback. Circulating cortisol acts on the hypothalamus and the anterior pituitary, and it suppresses the release of CRH and ACTH. Because the hormone at the end of the chain reports back to both upstream stations, the chain is a loop and not a one-way line.
The brake works in both directions. A rise in cortisol limits further ACTH secretion, and a fall in cortisol releases that brake. The result is a self-regulating loop that keeps cortisol within its working range.
The loop works whether the glucocorticoid in the blood is the body’s own or is given as treatment. A glucocorticoid supplied from outside the body suppresses ACTH in the same way.
What does the loop make possible?
Because the brake responds in a predictable way, it can be used as a question. The loop makes the axis testable: whether ACTH can be suppressed reveals where in the axis an abnormality lies.
Once ACTH reaches the adrenal cortex, what does it set in motion inside the cell to turn cholesterol into cortisol?