Clinical Biochemistry

The HPA Axis, Explained Properly

Stephen Duncan FDN-P BSc Hons MSc  ·  8 min read

Most explanations of the stress response stop at "cortisol is the stress hormone." That's true in roughly the way "the heart pumps blood" is true — accurate, and not enough to be useful.

Here is the version that actually helps you read your own results.

Three organs, one loop

The hypothalamus sits at the base of the brain and monitors everything — blood glucose, inflammatory signals, sleep pressure, light exposure, perceived threat. When it detects demand, it releases CRH, corticotropin-releasing hormone.

The pituitary receives CRH and releases ACTH into the bloodstream.

The adrenal cortex, sitting on top of each kidney, receives ACTH and produces cortisol.

Cortisol then travels back to the hypothalamus and pituitary and tells them to stop. That's negative feedback, and it's the part most explanations leave out — which matters, because most of what goes wrong goes wrong in the feedback rather than the production.

This is a thermostat, not a fuel tank. The question is never simply "how much cortisol." It's whether the loop is regulating properly.

What cortisol is actually for

Cortisol is not a stress hormone that happens to have side effects. It's a metabolic hormone that also responds to stress.

It raises blood glucose. Through gluconeogenesis in the liver, cortisol makes glucose available. This is its primary job and it explains a great deal — including why chronically elevated cortisol drives insulin resistance, and why blood sugar instability drives cortisol.

It runs the daily rhythm. Cortisol should peak shortly after waking and fall through the day to a low at night. That curve is what makes you alert in the morning and lets you sleep at night. It's a circadian hormone at least as much as a stress hormone.

It restrains inflammation. Cortisol is the body's endogenous anti-inflammatory — the reason synthetic glucocorticoids work as drugs. When cortisol signalling is impaired, inflammation goes less well controlled.

It maintains blood pressure and fluid balance, and it suppresses non-urgent functions — digestion, reproduction, immune surveillance, tissue repair — because those can wait until the threat passes. That last point is the one to hold on to. Every symptom of chronic stress is a downstream consequence of the body deprioritising something in order to fund a response that never ends.

The awakening response

Within thirty to forty-five minutes of waking, cortisol should rise sharply — typically fifty to a hundred percent above the waking level. This is the cortisol awakening response, and it's the single most informative part of the curve.

It's what gets you out of bed. It mobilises glucose after an overnight fast, raises blood pressure enough for you to stand up, and shifts the brain into daytime function.

When it's blunted, mornings are genuinely hard. Not psychologically hard — physiologically hard. People describe needing an hour and a coffee before they can hold a conversation, and they're usually apologetic about it, having been told it's a discipline problem.

The awakening response is strongly influenced by light. Getting outside within an hour of waking is one of the few interventions that reliably supports it, and it costs nothing.

Four patterns worth recognising

Cortisol testing across a day, particularly when it also measures total production, resolves into a small number of recognisable pictures.

High free, high total. The system is running hot and producing a lot. Typically wired, anxious, sleeping badly, unable to switch off. Often the earlier stage of a long stress exposure.

Low free, high total. This one catches people out. Free cortisol looks low, so it reads as depletion — but total production is high. The person is making plenty and clearing it rapidly. Treating this as insufficiency, by adding stimulation or replacement, makes it worse.

High free, low total. Production is modest but clearance is slow, so what's made hangs around. Common with impaired liver clearance or thyroid involvement.

Everything low. Genuine suppression of the whole axis. Usually a long exposure — years rather than months — and the picture most often seen in chronic fatigue presentations, where flat curves and absent awakening responses are consistently reported.

You cannot distinguish these with a single morning reading, which is why a single reading so often produces "your cortisol is normal" alongside someone who plainly isn't.

The cortisol–cortisone conversion

Cortisol is active. Cortisone is its inactive form. An enzyme called 11β-HSD2 converts one to the other, and tissues use this to control their own local cortisol exposure independently of what's circulating.

The ratio between them is therefore informative in its own right. A high cortisol-to-cortisone ratio indicates reduced 11β-HSD2 activity, which shows up in insulin-resistant and PCOS pictures.

There's a newer thread here worth knowing about. Certain environmental compounds — some perfluoroalkyl substances, organotins used in pesticides and marine preservatives, and some fungicides — inhibit 11β-HSD2. The effect is potent enough that very low concentrations meaningfully reduce enzyme activity. The consequence would be excess intracellular cortisol without any change in the amount being produced.

This is emerging rather than established, and I'd treat it as a reason to take an exposure history when the pattern is otherwise unexplained rather than as a diagnosis. But it's a good example of why "how much cortisol" is the wrong question.

What drives dysregulation

Rarely one thing. Usually several at once, which is why single-target interventions underperform.

Blood glucose instability is the most common and the most overlooked. Every glucose dip requires cortisol to correct it. Someone eating in a way that produces four or five dips a day is calling on the axis four or five times a day, entirely independently of anything psychological.

Circadian disruption. Light at night, no light in the morning, irregular sleep timing. The axis is anchored by light; without the anchor it drifts.

Inflammatory load from any source — gut, infection, food reactivity, poor recovery from training — drives the axis directly. Inflammation is a demand signal.

Perceived threat, including anticipated and rehearsed threat. The hypothalamus doesn't reliably distinguish a real emergency from a remembered or imagined one.

Overtraining, particularly high intensity added to an already high total load. Training is a stressor. It's a useful one when recovery follows and a harmful one when it doesn't.

Nutrient depletion. Cortisol production consumes vitamin C — the adrenal cortex holds one of the highest tissue concentrations in the body — along with B5 and magnesium.

What to do about it

The interventions are unglamorous and they work in a specific order.

Anchor the rhythm first. Daylight within an hour of waking. Dim light in the evening. Consistent sleep and wake times, including at weekends. This is the foundation and everything else works better on top of it.

Stabilise glucose. Protein at breakfast, avoid long gaps that end in a crash, and stop eating three hours before sleep. If you wake reliably at three or four in the morning, that's usually glucose dropping and cortisol rising to correct it — a fuel problem wearing an insomnia costume.

Reduce total demand before adding anything. Training load, work hours, alcohol, caffeine timing. Adding adaptogens to an unchanged load is treating the smoke.

Then, and only then, target what testing shows. Because the four patterns above need different things, and the wrong one makes people worse.

Where testing fits

A morning serum cortisol answers whether your adrenal glands are diseased. That's a real question, it matters, and if the answer is yes it needs an endocrinologist.

Testing across a day answers a different question: what shape is this system in. Free cortisol at four or more points gives the curve and the awakening response. Metabolised cortisol gives total production, which is what separates the four patterns. Cortisone gives the conversion picture. DHEA-S gives adrenal reserve. Melatonin gives the other end of the circadian axis.

That's a description of how a system is behaving, and it's the right level of question for most people who feel wrong but aren't ill in a way that shows on a standard panel.

It is not a diagnosis of adrenal disease, and shouldn't be presented as one.

Stephen Duncan is a Functional Diagnostic Nutrition Practitioner (FDN-P, BSc Hons, MSc) based in Edinburgh with thirty-seven years in clinical practice.

Educational content, not medical advice. If you have symptoms of adrenal insufficiency — persistent vomiting, dizziness on standing, unexplained weight loss, skin darkening — see a doctor promptly. That is a different and serious condition requiring urgent diagnosis.