The HPA axis: how your brain controls cortisol

The hypothalamic-pituitary-adrenal axis, or HPA axis, is the control system for cortisol. It links a part of your brain, a gland at the base of your brain and the two adrenal glands above your kidneys. Together they decide how much cortisol your body makes, and when.

Most readers land here after seeing a phrase like “adrenal axis dysfunction” or “HPA axis suppression”. This page explains the normal system first, then what those phrases usually refer to.

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How the chain works

There are three steps. A 2018 review lays them out (Front Behav Neurosci, 2018), and MedlinePlus describes the same chain.

1. Hypothalamus. This part of the brain makes corticotropin-releasing hormone, called CRH. It tells the pituitary gland how much ACTH to make.
2. Pituitary gland. CRH makes the pituitary release ACTH (adrenocorticotropic hormone) into the blood.
3. Adrenal glands. ACTH reaches the outer layer of the adrenal glands, the cortex, and tells it how much cortisol to make (MedlinePlus).

The loop closes by negative feedback. As MedlinePlus puts it, the rising cortisol in the blood signals the hypothalamus to stop making the hormone that tells the pituitary to make ACTH. The review adds that glucocorticoids act on the pituitary, the hypothalamus and other brain regions to control the axis in short and long feedback loops.

Think of a thermostat. MedlinePlus says that if cortisol drops too low, ACTH rises to trigger the adrenal glands to make more, and if cortisol is high, ACTH falls so the adrenal glands make less.

What turns the axis up and down

Two things change how much cortisol the chain asks for.

The body clock. A master clock in the hypothalamus drives a daily rise and fall in CRH and ACTH, and so in cortisol (Endocrine Reviews, 2017). ACTH and cortisol are highest in the early morning and lowest around midnight. The daily curve is built from short pulses that come every 60 to 90 minutes. See when cortisol is highest.

Stress. Physical and psychological stressors reach the hypothalamus and activate the axis, as the 2018 review describes. The HPA axis is the slower part of the stress response. The fast part comes from the sympathetic nerves and adrenaline, covered in cortisol vs adrenaline.

ACTH is short-lived. A 2023 laboratory review gives its half-life in the body as about 6 to 7 minutes (Diagnostics, 2023). That is one reason blood samples for ACTH need careful handling. See the ACTH blood test.

What “suppression” means

HPA axis suppression usually refers to the feedback loop being turned down from outside. NIDDK describes how this happens with long-term corticosteroid medicine. Prescription doses can push blood cortisol above what the body makes on its own. Over time the hypothalamus makes less CRH, so there is less ACTH, and the adrenal glands stop making their own cortisol.

NIDDK says that after the medicine is stopped, the adrenal glands may be slow to restart and might not work normally for many months. This is why doctors lower the dose gradually over weeks or months and watch for symptoms. NIDDK calls the result tertiary adrenal insufficiency, and says suddenly stopping corticosteroids after taking them for a long time is the most common cause of adrenal insufficiency overall.

So, if you take a steroid medicine, do not stop it or change the dose because of anything you read here. Ask your prescriber. Only they can plan a safe taper.

Similar logic applies after treatment for Cushing’s syndrome. NIDDK says that when a tumor that made too much ACTH or cortisol is removed, the supply of excess hormone suddenly disappears and the adrenal glands may be slow to restart.

Conditions that involve the axis

NIDDK describes three levels of adrenal insufficiency, depending on where the chain is affected:

• Primary (Addison’s disease): the adrenal glands themselves are damaged.
• Secondary: the pituitary doesn’t make enough ACTH.
• Tertiary: the hypothalamus makes less CRH, as above.

At the other end, Cushing’s syndrome is too much cortisol over a long period. NIDDK says it can come from long-term glucocorticoid medicine or from tumors, either in the pituitary, where they make too much ACTH, or in the adrenal gland, where they make too much cortisol. MedlinePlus also lists tumors outside the pituitary that make ACTH.

This is why ACTH is often measured with cortisol. The pair helps a clinician work out which gland is involved, according to MedlinePlus. The pattern is for a clinician to read, not something to decode alone. For the full set of tests, see the cortisol test guide.

What “HPA axis dysfunction” does and doesn’t mean

Online, “HPA axis dysfunction” or “adrenal axis dysfunction” is often used for tiredness, poor sleep or stress, sometimes alongside a saliva test panel. That isn’t a medical diagnosis.

• A 2024 paper in the Journal of the Endocrine Society says “adrenal fatigue” has never been scientifically proven to exist, and that the multi-sample saliva cortisol profiles sold to diagnose it have never been validated as tools to assess HPA axis function (J Endocr Soc, 2024). See adrenal fatigue.
• The same paper names the validated tests of the axis: cortisol, ACTH and the cosyntropin (ACTH) stimulation test, and says results are usually normal in people given the “fatigue” label.

If you have symptoms that worry you, tell a clinician. NIDDK lists long-lasting fatigue, muscle weakness, loss of appetite, weight loss and abdominal pain as the most common symptoms of adrenal insufficiency, and MedlinePlus lists weight gain, thin arms and legs, a round face, easy bruising and wide purple streaks on the skin for too much cortisol. Each of these has other causes.

How the axis is tested

Clinicians don’t test “the axis” in one step. They use cortisol, ACTH and dynamic tests that push or suppress the chain:

• ACTH stimulation test. An injection of man-made ACTH, with blood drawn before and after. NIDDK says the normal response is a rise in cortisol.
• Dexamethasone suppression test. A low dose of dexamethasone at night and a blood draw the next morning. NIDDK says that normally cortisol in the blood drops after dexamethasone, and that levels that don’t drop suggest Cushing’s syndrome.
• Late-night saliva and 24-hour urine tests. Used when too much cortisol is suspected.

All of these belong with a clinician. A single blood cortisol can’t diagnose or rule out Cushing’s syndrome or adrenal insufficiency.

Questions people ask

Is the HPA axis the same as the adrenal axis?

People use “adrenal axis”, “pituitary-adrenal axis” and “hypothalamic pituitary adrenal axis” loosely for the same system. HPA axis is the standard short form.

Can the HPA axis recover?

NIDDK says that after long-term steroid medicine is stopped under a doctor’s plan, the adrenal glands may be slow to resume work, and that recovery can take many months. The speed varies from person to person, and your prescriber should watch you for symptoms during that time.

Does stress “break” the HPA axis?

Stress activates the axis, which is what it is built to do. A 2017 review describes cortisol staying high at its usual low point, which flattens the daily rhythm, as a hallmark of what researchers call “allostatic load”, the wear and tear of coping with chronic stress. That is a model from research, not a diagnosis. It gives no way to tell from one result whether you are affected.

Keep reading

• ACTH blood test

  The pituitary hormone that tells the adrenal glands to make cortisol.

• ACTH vs cortisol

  How the two tests are used together.

• What is cortisol?

  The hormone, its jobs and why levels change.

• Low cortisol

  Causes, symptoms, emergency signs and testing.