HPA Axis · Adrenal Health · Functional Investigation
The science behind why 'just relax' is not clinical advice. Long-running stress changes blood sugar, immune, thyroid, gut and sleep physiology. Some of those links are well established, some are mostly mechanism, and this page says which is which. Understanding what's actually happening is the first step toward doing something useful about it.
This is part of The Gap — a series of clinical essays on what medicine misses and what functional investigation offers instead.
I want to start with a word that has almost lost its meaning.
Stress.
It's used to describe being late for a meeting, losing a loved one, working a sixty-hour week, living in a war zone, and worrying about a parking fine. It's the explanation offered for fatigue, insomnia, anxiety, weight gain, hair loss, digestive problems, hormonal disruption, and recurrent infections. It's what doctors say when they can't find another explanation.
The word has been used so broadly that it has become almost clinically useless. Which is a problem, because the underlying biology it describes is one of the most important and most consistently underinvestigated areas in functional medicine.
What we colloquially call stress is, at the physiological level, a cascade of hormonal and neurochemical events involving the hypothalamus, the pituitary gland, the adrenal glands, the immune system, the gut, and ultimately every cell in the body. It is not a feeling. It is a biochemical state — one that, when sustained, produces measurable, testable, and clinically significant changes in physiology.
The advice to "just relax" is not wrong because relaxation doesn't help. It's wrong because it treats a biochemical problem as though it were primarily a psychological one — and in doing so, it misses what's actually happening and what can actually be done about it.
The hypothalamic-pituitary-adrenal axis is the primary neuroendocrine system through which the body responds to perceived threat. A stressor is perceived. The hypothalamus releases CRH. CRH signals the pituitary to release ACTH. ACTH stimulates the adrenal cortex to produce cortisol. Cortisol then feeds back to both the hypothalamus and the pituitary, suppressing further CRH and ACTH release. This negative feedback loop is the mechanism by which the stress response is meant to be self-limiting.
This is an elegant and effective system — for the kind of stressors it evolved to handle. A predator. A fight. A flood. Acute, time-limited, physically demanding threats followed by resolution.
It is considerably less elegant when applied to the kind of stressors that characterise contemporary life. Financial pressure that lasts years. Relationship conflict that is never resolved. Work demands that have no off switch. Chronic low-grade inflammation from gut dysbiosis, toxic load, or poor sleep. These are not acute threats. They are sustained activations of a system that was not designed for sustained activation.
When the HPA axis is stimulated for months, it doesn't always go the same way. A meta-analysis of human studies found cortisol is raised early in a stressor and tends to fall as time passes; some long-running stressors produce a high, flat daily curve, and people with PTSD tend to run lower (Miller 2007). Tissues can also become less responsive to cortisol's signal, which is called glucocorticoid resistance (Cohen 2012). So "chronic stress" can mean high cortisol, low cortisol or a flattened rhythm, which is one reason to measure rather than assume.
Blood sugar. Cortisol raises blood glucose; that is one of its main jobs. When cortisol stays high for a long time, as in Cushing's syndrome or long-term steroid treatment, blood glucose and insulin resistance rise with it. Evidence: strong for sustained high cortisol. Whether everyday chronic stress does the same depends on whether cortisol is actually raised, which varies from person to person, so the link from stress to abdominal weight gain and type 2 diabetes is plausible and partly supported, not settled. Evidence: mixed.
Immune disruption. Short bursts of cortisol damp inflammation. Under long-running stress, immune cells can become less responsive to that signal. In a study that exposed volunteers to a cold virus, people who had recently had a long-term threatening life event showed this resistance, were more likely to develop a cold, and produced more inflammatory signalling once infected (Cohen 2012). Raised CRP and IL-6 are often reported in chronically stressed groups, though not in every person. Evidence: moderate.
Sleep. Cortisol normally falls through the day, reaches its lowest point around midnight and starts rising again in the early hours, ahead of waking. Stress disrupts sleep, and early waking is common under stress and in depression. The popular explanation, that a cortisol spike at 3 or 4 am wakes you, is plausible but hasn't been shown, and no home test measures cortisol at that hour. Evidence: mechanism only for the 3 am explanation.
Thyroid. High glucocorticoid levels can lower TSH and shift T4 conversion away from active T3 and towards reverse T3. The pattern is clearest in severe illness and with high-dose steroid treatment. Reverse T3 is inactive; the common claim that it blocks T3 by competing for its receptor isn't supported. How much ordinary chronic stress shifts thyroid conversion is not well established, so a stressed person with normal TSH and T4 shouldn't be told their thyroid is "functionally underperforming" on that basis alone. Evidence: strong at high doses and in severe illness; untested for everyday stress.
Sex hormone disruption. Under long-running stress, cortisol output and DHEA output can change in different directions, and the ratio between them is sometimes used as a marker. The popular explanation, that the body ‘steals’ shared building blocks to make cortisol, doesn’t fit how these hormones are made: cortisol is made mainly in one zone of the adrenal gland (the zona fasciculata) and DHEA in another (the zona reticularis). Both respond to ACTH, but DHEA has other regulators too (Endotext, Adrenal Androgens, 2019). It is a pattern to measure, not a mechanism to assume. Chronic stress is associated with reduced libido and menstrual changes, though the routes are several and not settled.
Gut barrier. Acute psychological stress can make the gut more permeable in people. In one study, a public-speaking task raised small-intestinal permeability in volunteers whose cortisol rose; the effect was reproduced by giving CRH (the brain's upstream stress hormone) and blocked by a mast-cell stabiliser, which points at CRH and mast cells rather than cortisol acting directly (Vanuytsel 2014). Evidence: moderate for a short-term effect. Whether chronic stress keeps the gut barrier more open over months, and how much that matters for symptoms, is less clear in humans. The idea that a leaky gut then feeds back to raise stress is a reasonable hypothesis, not an established loop. Evidence: mechanism only.
Brain structure. The hippocampus has many cortisol receptors. In Cushing's disease, where cortisol is very high for months, hippocampal volume is reduced and partly recovers once cortisol is brought down (Starkman 1999). Animal studies show sustained stress hormones shrink hippocampal nerve connections. Evidence: strong for very high cortisol. In people with ordinary chronic stress the evidence is associations, not proof that stress shrinks the hippocampus. Evidence: mixed.
I should address this directly because it is a source of genuine confusion.
The term "adrenal fatigue" is not an accepted medical diagnosis. Conventional endocrinologists correctly point out that true adrenal insufficiency (Addison's disease) is a distinct and serious condition, and that the evidence for adrenal glands "wearing out" under psychological stress is not robust. They are right about this. The adrenal glands do not typically fail.
A systematic review of 58 studies found no substantiation for adrenal fatigue as a condition (Cadegiani 2016). What is real is that some people are profoundly fatigued, feel worse after exercise rather than better, are lowest in the morning, and have flat daily cortisol curves or low waking cortisol on testing. That is a measured pattern worth investigating. It is not proof that the adrenals are "exhausted", and a single day's curve can be thrown by a bad night or by samples taken at the wrong times (Stalder 2016).
A single morning cortisol blood test shows cortisol at one point in time. It tells you nothing about the diurnal pattern, the cortisol awakening response, the metabolised cortisol output across the day, or the relationship between cortisol and DHEA.
The DUTCH Plus combines dried urine samples collected across the day with saliva samples taken after waking. It measures the cortisol awakening response (from the saliva, and only valid if each sample is timed exactly from waking (Stalder 2016); studies in burnout and fatigue have found it both blunted and normal), the daily cortisol curve across four or five urine samples, metabolised cortisol (an estimate of total cortisol output), DHEA and DHEA-S and their ratio to cortisol, and oestrogen and progesterone metabolites.
A single blood test can't show a daily pattern. That is one reason people can be told their cortisol is normal while the pattern across the day is not. It is also why a pattern from one collection day should be read with the day it came from.
Inflammation switches on an enzyme that diverts tryptophan, the building block of serotonin, towards a different pathway (kynurenine). In people given immune-stimulating drugs for cancer, blood tryptophan fell, and the size of the fall tracked the depressive symptoms that developed (Capuron 2002). Evidence: moderate in that setting. Whether ordinary chronic stress lowers brain serotonin this way hasn't been shown. Evidence: mechanism only. None of this is a reason to avoid or stop an antidepressant; that is a decision for you and your GP. It is a reason to look for inflammation and its causes as well.
Motivation and reward can be affected too. In humans, inflammation reduces the brain's response to anticipated reward and is linked to lower dopamine release, and this tracks reduced motivation (Felger 2017). Animal studies show chronic stress changes dopamine signalling. Evidence: moderate for inflammation, mostly animal for stress. This may be part of why long-running stress flattens motivation. Loss of interest or pleasure is also a core symptom of depression, which needs assessing by your GP, not ruling out.
The organic acids test (OAT) reports urinary breakdown products: VMA and HVA from adrenaline, noradrenaline and dopamine, quinolinic and kynurenic acid from the kynurenine pathway, and 5-HIAA from serotonin. These mostly reflect the whole body, diet and gut bacteria, not levels in the brain. They can point at inflammation or a nutrient issue; they are not a reading of your brain's neurotransmitter status. Evidence for reading them as brain status: none.
Managing a stress-related pattern means addressing the load, the actual sources of HPA activation, and treating what testing finds. The order matters.
First, investigate. Find out what the HPA axis is actually doing, which needs a daily pattern rather than a single cortisol reading. The DUTCH Plus shows the cortisol pattern; the GI-MAP adds the gut; blood chemistry adds nutritional and inflammatory context; the OAT can add nutrient and inflammation clues.
Second, reduce the load where possible. Poor sleep, blood sugar swings, gut problems and ongoing illness are all stressors on the body, and fixing them reduces the load even when the life stressors remain.
Third, support specifically, and in proportion to the evidence. Ashwagandha: a meta-analysis of 9 small trials (558 people) found lower perceived stress, lower anxiety scores and slightly lower blood cortisol than placebo (Arumugam 2024); the trials were short, and liver injury has been reported, so read the cautions on the ashwagandha page first. Evidence: moderate, short-term. Rhodiola and eleuthero have fewer and weaker trials. No adaptogen has been shown to reliably change the cortisol awakening response. Magnesium: three small trials in older adults found people fell asleep about 17 minutes faster, with low-quality evidence (Mah 2021). Evidence: weak. Vitamin B5 and vitamin C are used in making adrenal hormones, but there is no trial evidence that supplementing either changes cortisol in people who aren't deficient. Evidence: mechanism only. Enough dietary protein matters for general repair and for the amino acids neurotransmitters are made from.
Fourth, be patient. Stress-related patterns build over months or years, and they rarely resolve in weeks.
You cannot meditate your way out of an untreated gut infection or a blood sugar problem. You cannot willpower your way out of a biochemical state.
What you can do is investigate it properly, understand what's actually happening, and address it systematically — with the specificity that the individual biochemistry requires. That is the difference between managing stress and resolving it.
DUTCH Plus · Organic Acids Test · GI-MAP · TDG Five-Test Programme
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