The HPA Axis —
Why Stress Hormones Run the Show

There is a hierarchy in your hormonal system, and most people — including many practitioners — are working at the wrong level of it.

The client who arrives wanting to address oestrogen dominance. The client who suspects low testosterone. The client who has been told their thyroid is "borderline" and wants to explore natural support. The client who has been prescribed hormone replacement therapy and is wondering whether it is the right intervention. In every one of these conversations, there is a prior question that determines whether the downstream conversation is even the right one to be having:

What is the HPA axis doing?

The hypothalamic-pituitary-adrenal axis is not one of several equally important hormonal systems. It is the command system. It is the system the body uses to determine whether it is safe enough to reproduce, whether it has sufficient resources to maintain metabolic rate, whether the immune system should be investing in long-term defence or immediate threat response. Every other hormonal axis answers to it. And when it is dysregulated — which in a chronically stressed, sleep-deprived, sedentary population it very frequently is — the downstream consequences permeate every other system simultaneously.

What the HPA Axis Actually Does

The hypothalamus — a small region of the brain that sits above the brainstem and acts as the primary interface between the nervous system and the endocrine system — continuously monitors the body's internal and external environment. It receives input from the limbic system (emotional processing), the brainstem (autonomic regulation), the circadian clock (time of day), the immune system (inflammatory signals), and the periphery (blood glucose, temperature, pain signals).

When the hypothalamus detects actual or anticipated threat, it releases corticotropin-releasing hormone (CRH). CRH travels to the pituitary gland and stimulates the release of adrenocorticotropic hormone (ACTH). ACTH travels through the bloodstream to the adrenal cortex and stimulates the production of cortisol.

This is the axis. Hypothalamus → Pituitary → Adrenal → Cortisol. And cortisol then does something remarkable: it feeds back to the hypothalamus and pituitary to suppress further CRH and ACTH production, creating the negative feedback loop that under normal circumstances keeps the system regulated. In sustained stress — where the threat signal is continuous rather than acute — this negative feedback is progressively overridden, and cortisol remains elevated for longer than the biology was designed to sustain.

Cortisol's Job Description

Cortisol is not simply a stress hormone in the pejorative sense. It is one of the most important regulatory molecules in the body, performing essential functions continuously:

• Blood sugar regulation — cortisol raises blood glucose through gluconeogenesis, ensuring the brain and muscles have fuel during stress
• Immune modulation — acute cortisol has anti-inflammatory effects; chronic elevation suppresses immune function
• Circadian rhythm entrainment — the cortisol awakening response (CAR) is the primary biological signal that initiates waking and sets the metabolic tone for the day
• Cardiovascular regulation — cortisol maintains vascular tone and blood pressure
• Cognitive function — moderate cortisol supports memory consolidation; chronic elevation impairs the hippocampus
• Inflammatory resolution — in acute appropriate amounts, cortisol resolves inflammation rather than sustaining it

The problem is not cortisol. The problem is cortisol that is chronically elevated, chronically depleted, or dysregulated in its diurnal pattern — none of which is visible on a standard morning blood cortisol draw, which catches one point on a curve that spans the entire day.

The Cortisol Awakening Response — The Most Important Reading You Are Not Taking

Cortisol follows a precise diurnal pattern in a healthy individual. It begins rising approximately 30 minutes before waking — anticipating the demands of the day — and peaks within 30–45 minutes of waking in what is called the cortisol awakening response (CAR). It then declines progressively throughout the day, reaching its lowest point in the hours around midnight, before beginning to rise again in the early hours of the morning.

The CAR is not merely a wake-up mechanism. It is the body's daily recalibration of immune function, metabolic rate, and cognitive readiness. A robust CAR — a sharp, significant rise in cortisol in the first 45 minutes of waking — is associated with better immune function, better cognitive performance, better mood regulation, and better metabolic health throughout the day. A blunted or absent CAR — one of the most common findings in chronically stressed or exhausted individuals — correlates with immune dysregulation, morning fatigue that does not resolve, cognitive fog, and poor stress tolerance.

A standard blood cortisol draw, typically taken at 9am, captures the tail end of the post-CAR decline. It tells you almost nothing about whether the CAR occurred at all, whether it was appropriately sized, or what cortisol is doing in the afternoon and evening — which is where the most clinically consequential patterns are often found.

The Four Cortisol Patterns — What the DUTCH Plus Reveals

The DUTCH Plus (Dried Urine Test for Comprehensive Hormones) maps cortisol across four or five collection points throughout the day, measuring both free cortisol and cortisol metabolites. This gives a picture of the diurnal curve — not a snapshot but a map — and reveals patterns that a single blood draw cannot.

Each pattern requires a different clinical approach. Pattern one needs cortisol reduction — adaptogenic support, stress physiology management, sleep prioritisation. Pattern three needs output support and recovery — different interventions entirely. Treating pattern three with the same approach as pattern one makes the problem worse. Without the DUTCH map, you are guessing which pattern you are dealing with. With it, you are not.

Pregnenolone Steal — How Stress Depletes Every Other Hormone

This is the mechanism that makes the HPA axis the master system — and makes treating sex hormones or thyroid in isolation fundamentally incomplete.

Pregnenolone is the mother hormone — the precursor from which all steroid hormones are synthesised. From pregnenolone, the body can make cortisol via one pathway, or progesterone, DHEA, testosterone, and oestrogen via others. In a state of chronic stress, the body prioritises the production of cortisol — survival takes precedence over reproduction. The pregnenolone is diverted away from the sex hormone pathways and toward the cortisol pathway.

This is not a theoretical concern. It is the most common hormonal pattern I encounter in clinical practice — and it is the reason why the first question I ask when someone presents with sex hormone dysregulation is not "what are your oestrogen levels" but "what does your cortisol pattern look like?" Because if the answer to the second question is "chronically elevated" or "flat from exhaustion," the answer to the first question is already largely explained.

Total Metabolised Cortisol — The Number Most Practitioners Miss

The DUTCH Plus measures not only free cortisol at each time point but total metabolised cortisol — the sum of all cortisol metabolites in the urine, reflecting total cortisol production over the 24-hour collection period.

This number tells you something that the diurnal curve cannot: whether the adrenal glands are producing a high, normal, or low total volume of cortisol, regardless of when it is being produced. A client can have a relatively normal-looking diurnal curve but a very high total metabolised cortisol — indicating that cortisol production is high throughout, with the variation being relatively smaller than the absolute level. Or they can have a pattern that looks like normal variation but with a total output that is significantly depleted.

Total metabolised cortisol is also the number that indicates how hard the liver is working to clear cortisol from circulation. High total metabolised cortisol in the context of liver markers that suggest congestion — elevated ALT, AST, or phase II detoxification impairment — indicates that the liver's cortisol clearance capacity is compromised, allowing cortisol to accumulate in tissues even when adrenal output is not dramatically elevated.

What the DUTCH Plus Maps That Nothing Else Can

The HPA Axis and Everything Downstream

Every system covered in this series connects back to the HPA axis. The gut — because chronic cortisol reduces secretory IgA, increases intestinal permeability, and alters microbiome composition. The immune system — because sustained cortisol suppresses natural killer cell activity, impairs antibody production, and blunts the innate immune response. The lymphatic system — because sustained sympathetic activation reduces the diaphragmatic pump that drives lymphatic flow. The liver — because cortisol drives gluconeogenesis and increases the metabolic burden on hepatic detoxification pathways.

And the sex hormones and thyroid — which are the subject of Part Two of this series. Because pregnenolone steal depletes the substrate from which oestrogen, progesterone, testosterone, and DHEA are made. And because chronically elevated cortisol directly inhibits the conversion of inactive thyroid hormone T4 to active T3 — the form the body can actually use — through its suppression of the deiodinase enzymes responsible for that conversion.

"The body will always sacrifice reproduction and metabolism to fund survival. This is not a malfunction. It is the design. The HPA axis is prioritising correctly — for the environment it believes you are living in. The clinical question is whether that environment is actually as dangerous as the HPA axis has concluded."