The Stress Response and the HPA Axis

Stress is almost universally recognised as bad for health and almost universally poorly defined. Patients describe it as a feeling, researchers measure it as a hormone level, and popular health writing often treats it as a condition of exhausted glands. For practitioners, a clear understanding of the physiology of the stress response makes it possible to take stress seriously as a clinical mediator without falling into the diagnostic confusion that surrounds it.

2 systems working together

The body responds to perceived challenge through 2 linked systems.

The sympathetic nervous system acts within seconds. It releases adrenaline and noradrenaline, raising heart rate and blood pressure, redirecting blood to muscles, releasing glucose and heightening alertness. This is the familiar fight or flight response.

The hypothalamic pituitary adrenal axis, or HPA axis, acts over minutes to hours. The hypothalamus releases corticotropin releasing hormone, which stimulates the pituitary to secrete adrenocorticotropic hormone, ACTH, which in turn stimulates the adrenal cortex to release cortisol. Cortisol then feeds back to the hypothalamus and pituitary to switch the response off.

Cortisol’s effects are wide ranging. It raises blood glucose by promoting glucose production and opposing insulin, redistributes energy, modulates immune and inflammatory responses, affects mood and memory, and influences sleep and appetite. These effects are essential in the short term. They become harmful when they persist.

The daily rhythm of cortisol

Cortisol is not constant. In healthy people it follows a pronounced daily pattern: it rises sharply in the first 30 to 45 minutes after waking, a phenomenon called the cortisol awakening response, then declines through the day to its lowest point around midnight. This rhythm is driven by the body’s central clock and reinforced by light exposure, sleep timing and meal timing.

The rhythm matters clinically. Shift work, irregular sleep, evening light exposure and chronic stress can flatten or shift it. A flattened daily cortisol pattern has been associated in research with poorer health outcomes, although the use of cortisol profiles for individual diagnosis outside specific endocrine conditions remains unvalidated.

From adaptation to wear and tear

The concept of allostasis describes how the body maintains stability through change, adjusting its physiology to meet demands. When demands are frequent, prolonged or not followed by recovery, the cumulative cost, called allostatic load, contributes to disease. Several patterns are recognised: repeated activation without adaptation, failure to switch off the response after a stressor ends, and in some cases a blunted response that fails to mount adequately.

The consequences of chronic stress activation are well documented across systems.

Stress also acts indirectly, through behaviour: poor sleep, comfort eating, alcohol, smoking and reduced activity often accompany it, and each is a mediator in its own right.

The adrenal fatigue question

A popular theory holds that chronic stress exhausts the adrenal glands, leading to inadequate cortisol production and a syndrome of fatigue, low mood, cravings and poor stress tolerance called adrenal fatigue. The theory is appealing, because it gives a biological name to a real experience. It is not, however, supported by evidence.

A systematic review of studies examining adrenal fatigue found no consistent evidence that the condition exists as a distinct entity, and no validated test to diagnose it. Endocrine societies do not recognise it as a diagnosis. The adrenal glands do not appear to become exhausted by psychological stress in the way the theory proposes; changes in cortisol patterns in chronically stressed people are more plausibly explained by changes in the regulation of the HPA axis by the brain.

This matters for 3 reasons. First, labelling patients with adrenal fatigue may lead to treatment with unregulated adrenal extracts or hydrocortisone, which can suppress the body’s own adrenal function and cause harm. Second, the label can distract from the actual mediators, such as sleep, workload, mood and relationships. Third, it can delay diagnosis of real conditions that cause similar symptoms.

The alternative is not to dismiss the patient’s experience. It is to describe it accurately: chronic stress and disrupted HPA axis regulation, with identifiable causes and effective responses.

Real adrenal disorders

Genuine adrenal disorders are uncommon but important, and they require medical diagnosis.

• Primary adrenal insufficiency, often autoimmune in origin, causes fatigue, weight loss, low blood pressure, salt craving and skin darkening, and can progress to a life threatening crisis.
• Secondary adrenal insufficiency, most often caused by stopping long term glucocorticoid treatment abruptly, including high dose inhaled or topical steroids in some cases.
• Cushing syndrome, caused by excess cortisol, produces central weight gain, thin skin, easy bruising, muscle weakness and raised glucose and blood pressure.

Validated tests exist for these conditions, including morning cortisol, stimulation tests and late night salivary cortisol, interpreted by clinicians trained to use them.

Assessing stress in practice

For most patients, stress is best assessed through history rather than hormone testing.

• What are the current sources of pressure: work, caring, finances, relationships, health?
• How long has this been going on? Where is it on the timeline?
• How does it affect sleep, appetite, alcohol, activity and mood?
• What helps, and what has the patient tried?
• What support do they have?
• Is there evidence of anxiety or depression that needs specific assessment?

Validated questionnaires, such as the Perceived Stress Scale, can help quantify stress and track change. Screening for depression and anxiety using established tools is appropriate where symptoms suggest them.

What helps

The evidence for stress management interventions is strongest for approaches that change behaviour and the way people respond to pressure.

• Sleep is both damaged by stress and a buffer against it. Regular sleep timing and adequate duration are foundational.
• Physical activity reduces stress and anxiety symptoms and improves sleep.
• Mindfulness based programmes have moderate evidence for reducing anxiety, depression and pain in systematic reviews.
• Cognitive behavioural approaches are effective for anxiety, insomnia and stress related problems.
• Social connection is strongly associated with health and resilience.
• Structural change, such as renegotiating workload or accessing caring support, often has more impact than any technique.
• Breathing techniques and relaxation practices can reduce acute arousal and are simple to teach.

Supplements marketed for stress, such as ashwagandha, have limited and mixed evidence, and some have safety concerns. They should not substitute for addressing the sources of stress.

An illustrative case

A 45 year old teacher arrives convinced she has adrenal fatigue after a salivary cortisol test ordered online. She is exhausted, sleeps poorly, craves sugar in the afternoon and has gained weight. Her timeline shows 2 years of caring for a parent with dementia while working full time.

The practitioner acknowledges the reality of her exhaustion and explains why adrenal fatigue is not a recognised diagnosis, without implying that her symptoms are imagined. Her doctor checks for anaemia, thyroid disease and depression, and arranges appropriate adrenal testing only because she reports salt craving and dizziness; the results are normal. The plan addresses her actual mediators: respite care for her parent, a protected sleep routine, a daily walk, regular meals with protein to reduce afternoon cravings, and a referral to a counsellor. Over 3 months her sleep and energy improve. The label changed from adrenal fatigue to caregiver stress, and the plan changed with it.

Stress as a clinical variable

Stress is not a vague lifestyle issue or a hormone deficiency. It is a physiological state with measurable consequences, arising from identifiable circumstances, and it responds to specific interventions. Treating it with that seriousness, and describing it accurately, is one of the most useful things a practitioner can do for patients with chronic illness.