Three components
HPA axis = Hypothalamus + Pituitary + Adrenal cortex. The stress response and metabolic regulation system:
- Hypothalamus releases CRH
- CRH triggers anterior pituitary to release ACTH
- ACTH stimulates adrenal cortex to release cortisol
- Cortisol feeds back to hypothalamus and pituitary, suppressing CRH/ACTH
CRH from hypothalamus
Corticotropin-releasing hormone is a 41-amino-acid peptide released from paraventricular nucleus neurons. Triggered by physical stress, psychological stress, low blood sugar, inflammatory signals, and circadian inputs. CRH neurons integrate these signals.
ACTH from pituitary
Adrenocorticotropic hormone is released from anterior pituitary corticotrope cells in response to CRH. ACTH circulates to adrenal cortex and triggers cortisol production. ACTH levels reflect HPA axis activation.
Cortisol from adrenal
The adrenal cortex (zona fasciculata) produces cortisol from cholesterol via several enzymatic steps. Cortisol effects:
- Mobilizes glucose (gluconeogenesis, glycogenolysis)
- Mobilizes fat and protein for energy
- Suppresses immune function (anti-inflammatory)
- Affects mood, alertness
- Modulates sleep-wake
- Influences memory and attention
- Affects cardiovascular tone
Acute cortisol release in response to stress is adaptive. Chronic elevation is pathological.
Feedback regulation
Cortisol suppresses CRH and ACTH through feedback. The system maintains tight regulation in healthy state. In chronic stress, feedback can become dysregulated, the HPA axis stays activated despite normal cortisol levels.
Diurnal rhythm
Cortisol follows a strong daily pattern:
- Lowest around midnight (~3 µg/dL)
- Begins rising 2-3 hours before waking
- Peaks shortly after waking (cortisol awakening response, 50-75% rise from baseline within 30 min of waking)
- Declines through the day
- Lowest in evening
The rhythm is essential for normal function. Loss of the rhythm (flattened curve) is one of the cleanest signs of HPA dysregulation.
Chronic dysregulation
Chronic stress produces:
- Initial phase: elevated cortisol overall
- Intermediate phase: high evening cortisol, low morning rise (flattened curve)
- Late phase: blunted overall curve, reduced cortisol response to acute stress
The flattened curve is what produces many burnout symptoms, fatigue (low morning cortisol), sleep difficulty (high evening cortisol), reduced stress response capacity.
"Adrenal fatigue" as a clinical concept is debatable (adrenals aren't fatigued in the cellular sense), but the regulatory dysfunction underlying the term is real.
Lab assessment
HPA axis testing options:
- AM serum cortisol, single point; misses curve
- Salivary cortisol curve, 4 samples (waking, +30 min, midday, evening), shows rhythm
- 24-hour urinary cortisol, total daily output
- DHEA-S, companion marker; cortisol/DHEA ratio reflects axis state
- ACTH, to differentiate primary vs. secondary issues
OPTML hormone panels include cortisol assessment.
The clinical insight: Chronic HPA dysregulation is one of the most common drivers of midlife symptoms, fatigue, sleep problems, anxiety, weight gain. Treatment requires addressing chronic stressors, supporting sleep, and often hormone replacement of what's been depleted (DHEA, sometimes thyroid, sometimes sex hormones).
Bottom line
The HPA axis is the body's stress response system. Chronic activation produces dysregulation with flattened cortisol curves and downstream sex hormone, metabolic, and immune effects. Understanding the axis clarifies what burnout actually is and why treatment requires more than just "managing stress."