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[Physiology](https://durgical.com/en/physiology/) · [Endocrine](https://durgical.com/en/physiology/#s-endocrine)

# The HPA axis and its circadian rhythm

- Regulation
- Exam priority: high

The brain sends CRH, the pituitary ACTH and the adrenal cortisol. Cortisol is high on waking, low at midnight and rises with stress.

Updated 2026-11-01

Also called: HPA axis, CRH–ACTH–cortisol axis

**See it in 3D:** [Hypothalamus](https://durgical.com/en/anatomy/hypothalamus/) · [Pituitary gland](https://durgical.com/en/anatomy/pituitary-gland/) · [Right adrenal gland](https://durgical.com/en/anatomy/suprarenal-gland-abdomen/)

## Key points

- Cortisol peaks on waking (≈6–8 a.m.) and bottoms out near midnight; loss of the nadir is an early sign of Cushing syndrome.
- ACTH and MSH come from the same POMC: high ACTH (primary insufficiency) → hyperpigmentation.
- Primary insufficiency: cortisol AND aldosterone are missing (hyperkalemia, hyponatremia). Secondary: only cortisol (aldosterone follows renin).
- Long-term outside glucocorticoids suppress CRH and ACTH and atrophy the adrenal: abrupt withdrawal causes insufficiency.
- Stress (surgery, sepsis, hypoglycemia) pushes ACTH and cortisol above the feedback set point.

## What it is

CRH from the paraventricular nucleus, boosted by ADH, drives corticotrophs to release ACTH, which is cut from POMC. ACTH makes the zona fasciculata secrete cortisol, and cortisol brakes both levels. The axis has two drivers: the circadian rhythm of the suprachiasmatic nucleus and stress, which can override the brake.

### Hormone axes and feedback

Hypothalamic–pituitary–adrenal axis **Lesion** None (normal)

Tap a box to see the hormone, or choose a lesion to see the lab pattern.

- Stimulates (+)
- Inhibits / negative feedback (−)
- Level ↑
- Level ↓

Illustrative schematic drawn by Durgical: simplified axes and classic lab patterns; not for clinical decisions.

## Guide values (they depend on time of day and method)

| Parameter | Value | Note |
| --- | --- | --- |
| Serum cortisol at 8 a.m. | ≈5–25 µg/dL (≈140–690 nmol/L) | |
| Midnight cortisol | low, usually
- *+* **CRH (paraventricular nucleus)**: Main stimulus of ACTH secretion.
- *+* **ADH**: Boosts the effect of CRH on corticotrophs.
- *+* **Suprachiasmatic nucleus (light–dark)**: Sets the daily rhythm, with larger pulses late at night.
- *+* **Physical and emotional stress, cytokines (IL-1, IL-6)**: Activate CRH and raise cortisol even when it is already high.
- *−* **Cortisol (long loop)**: Brakes CRH and POMC transcription.
- *−* **Synthetic glucocorticoids**: Suppress the axis like cortisol; with long use they atrophy the cortex.

## Where the lesion is

| Disorder | ACTH | Cortisol | Key feature |
| --- | --- | --- | --- |
| [Primary adrenal insufficiency (Addison)](https://durgical.com/en/conditions/adrenal-insufficiency/) | ↑ | ↓ | Hyperpigmentation, hyperkalemia |
| [Secondary or tertiary insufficiency](https://durgical.com/en/conditions/adrenal-insufficiency/) | ↓ | ↓ | No hyperpigmentation; normal potassium |
| [Cushing disease (pituitary adenoma)](https://durgical.com/en/conditions/cushing-syndrome/) | ↑ | ↑ | Suppresses with high-dose dexamethasone |
| [Cortisol-secreting adrenal tumor](https://durgical.com/en/conditions/cushing-syndrome/) | ↓ | ↑ | Atrophic opposite adrenal |
| [Ectopic ACTH (e.g., small cell lung carcinoma)](https://durgical.com/en/conditions/cushing-syndrome/) | ↑↑ | ↑↑ | Does not suppress; marked hypokalemia |

## Clinical notes

- Adrenal crisis: hypotension that does not respond to fluids, hypoglycemia, hyponatremia; it happens when a person with low reserve meets stress.
- Cushing syndrome from medical glucocorticoids is the commonest cause of hypercortisolism, with low ACTH.
- Late-night salivary cortisol detects the loss of circadian rhythm typical of hypercortisolism.

## Memory aid

"Addison tans, secondary doesn't": only high ACTH colors the skin.

## Test yourself

Think of the answer, then tap the question to see it.

## Why does primary adrenal insufficiency cause hyperkalemia while secondary does not?

In primary disease the whole cortex, glomerulosa included, is destroyed and aldosterone is lost. In secondary disease ACTH is missing, but aldosterone stays under renin–angiotensin and potassium control.

## Why does primary insufficiency darken the skin and mucosa?

Without cortisol there is no brake and the pituitary overproduces POMC; it yields ACTH and α-MSH, which stimulates melanocytes (MC1R receptor).

## Why can stopping a glucocorticoid used for months abruptly cause a crisis?

The drug suppressed CRH and ACTH and the zona fasciculata atrophied. Once it is withdrawn, the axis takes months to recover and cannot respond to stress.

## What does a high midnight cortisol mean in suspected hypercortisolism?

The normal circadian nadir is lost, one of the earliest changes of Cushing syndrome of any cause.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/physiology/the-hpa-axis-and-its-circadian-rhythm/)

## See it in 3D

The structures of Durgical's 3D anatomy where it happens.

- [Hypothalamus](https://durgical.com/en/anatomy/hypothalamus/)
- [Pituitary gland](https://durgical.com/en/anatomy/pituitary-gland/)
- [Right adrenal gland](https://durgical.com/en/anatomy/suprarenal-gland-abdomen/)

## Related topics

- [Actions of cortisol](https://durgical.com/en/physiology/actions-of-cortisol/)
- [Measuring hormones: stimulation and suppression tests](https://durgical.com/en/physiology/measuring-hormones-stimulation-and-suppression-tests/)
- [The endocrine stress response](https://durgical.com/en/physiology/the-endocrine-stress-response/)
- [The adrenal cortex: zones, hormones and androgens](https://durgical.com/en/physiology/the-adrenal-cortex-zones-hormones-and-androgens/)
- [Aldosterone: actions and control](https://durgical.com/en/physiology/aldosterone-actions-and-control/)

## Related conditions

- [Cushing syndrome](https://durgical.com/en/conditions/cushing-syndrome/)
- [Adrenal insufficiency](https://durgical.com/en/conditions/adrenal-insufficiency/)
- [Hyperkalaemia](https://durgical.com/en/conditions/hyperkalaemia/)

## In Biochemistry

- [Cortisol](https://durgical.com/en/biochemistry/molecules/cortisol/)

[← All of physiology](https://durgical.com/en/physiology/)

Educational physiology content; not a diagnostic or treatment guide and no substitute for a health professional's advice. Values are approximate references. No doses are given.

Sources: [17.6 The Adrenal Glands](https://openstax.org/books/anatomy-and-physiology-2e/pages/17-6-the-adrenal-glands) (OpenStax (Rice University), 2022); [Adrenal Insufficiency](https://www.ncbi.nlm.nih.gov/books/NBK441832/) (StatPearls (NCBI Bookshelf), 2024); [Hypercortisolism (Cushing Syndrome)](https://www.ncbi.nlm.nih.gov/books/NBK551526/) (StatPearls (NCBI Bookshelf), 2024); Hall JE. Guyton and Hall Textbook of Medical Physiology, 13th ed. (ch. 78). Reference book used to check facts; its text and figures are not reproduced (Elsevier, 2016).

## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake

Representative model, for educational purposes only.

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/physiology/the-hpa-axis-and-its-circadian-rhythm/