🧠 The Adrenal Axis - Adrenal insufficiency, Cushing's syndrome and Adrenal crisis.

 The hypothalamic-pituitary-adrenal (HPA) axis is your body’s central stress-response system. It’s not just about cortisol, it’s about how the brain, pituitary, and adrenal glands coordinate to keep you alive under pressure. Whether you’re managing infection, trauma, or emotional strain, the HPA axis is quietly adjusting your metabolism, blood pressure, and immune response.

 

🔗 HPA Axis: The Stress Circuit

The HPA axis is a classic three-step hormonal cascade:

1. Hypothalamus releases CRH (corticotropin-releasing hormone)
2. Anterior pituitary releases ACTH (adrenocorticotropic hormone)
3. Adrenal cortex (zona fasciculata) releases cortisol

Cortisol then feeds back to suppress CRH and ACTH — a negative feedback loop that keeps the system in balance.

🧠 Reasoning tip: Always ask: Is the signal being sent? Is the gland responding? Is feedback working?

🧠 The Adrenal Glands:

Before we talk about cortisol, we need to meet the glands that make it.

You have two adrenal glands, perched like little caps on top of your kidneys. Each gland has two distinct parts:

• The adrenal cortex (outer layer)
• The adrenal medulla (inner core)

They’re embryologically and functionally separate and they produce very different hormones.

🧪 Cortex: Three Zones, Three Hormones

The adrenal cortex is divided into three concentric zones, each with a different role:

1. Zona glomerulosa (outermost)

• Produces aldosterone
• Regulated by the renin-angiotensin system, not ACTH
• Controls sodium retention and potassium excretion → affects blood pressure

2. Zona fasciculata (middle layer)

• Produces cortisol
• Regulated by ACTH from the pituitary
• Supports stress response, glucose metabolism, and vascular tone

3. Zona reticularis (innermost cortex)

• Produces androgens (e.g. DHEA)
• Minor role in adults, more relevant in puberty and certain pathologies

💡 ACTH stimulates both cortisol and androgens — but not aldosterone

💧 Aldosterone 

It’s tempting to think ACTH controls everything the adrenal cortex does, but aldosterone plays by different rules.

Aldosterone is made in the zona glomerulosa, the outermost layer of the adrenal cortex. Unlike cortisol and androgens, it’s not primarily regulated by ACTH. Instead, it responds to:

• Low blood pressure or volume → sensed by the kidneys
• High potassium levels → directly stimulates secretion
• Renin–angiotensin system → angiotensin II acts on the adrenal cortex

🧠 Reasoning tip:
If a patient has low cortisol but normal potassium and blood pressure, the zona glomerulosa may still be working. That’s why secondary adrenal insufficiency (low ACTH) doesn’t cause hyperkalaemia, aldosterone is preserved.

💡 Aldosterone’s job is to retain sodium, excrete potassium, and keep blood pressure up. It’s a volume regulator, not a stress hormone.

⚡ Medulla: The Sympathetic Core

The adrenal medulla is part of the sympathetic nervous system. It produces:

• Adrenaline (epinephrine)
• Noradrenaline (norepinephrine)

These catecholamines are released in response to direct neural stimulation, not ACTH. They act fast - increasing heart rate, dilating pupils, mobilising glucose - and complement the slower cortisol response.

🧠 Cortisol Production: From Signal to Secretion

Let’s trace the path:

1. Stress or circadian cues stimulate the hypothalamus → releases CRH

2. CRH acts on the anterior pituitary → releases ACTH

3. ACTH travels via the bloodstream to the zona fasciculata of the adrenal cortex

4. Cortisol is synthesised from cholesterol, via a series of enzymatic steps

5. Cortisol enters circulation and exerts effects on multiple tissues

6. Cortisol feeds back to suppress CRH and ACTH → negative feedback loop

💡 Cortisol is lipophilic — it travels bound to cortisol-binding globulin (CBG) and acts via intracellular receptors.

⏰ Cortisol and the Clock — Circadian Rhythms Matter

Cortisol isn’t just a stress hormone, it’s a daily rhythm hormone. Even in the absence of acute stress, your body releases cortisol in a circadian pattern:

• Highest in the early morning (around 6–8 AM)
• Lowest in the late evening and overnight

This rhythm is driven by the suprachiasmatic nucleus in the hypothalamus, which responds to light and sleep–wake cycles. It helps you wake up, mobilise energy, and prepare for the day.

🧠 Reasoning tip:
Always interpret cortisol levels in context. A “low” cortisol at 8 AM is concerning. A “low” cortisol at midnight is normal. That’s why we test morning cortisol when assessing adrenal function.

💡 Cortisol is both a stress responder and a circadian signal — it’s part of your body’s internal clock, not just its emergency alarm.

⚡ Cortisol in Action: What It Does

Cortisol is a glucocorticoid, but its effects span multiple systems. It’s designed to help you survive stress, but chronic excess or deficiency can cause serious dysfunction.

🧬 Metabolic Effects

• Increases gluconeogenesis in the liver
• Mobilises amino acids from muscle
• Promotes lipolysis in adipose tissue
• Antagonises insulin → raises blood glucose

💡 Cortisol ensures fuel availability during stress, even if it means breaking down muscle.

🩺 Cardiovascular Effects

• Upregulates α1 adrenergic receptors → enhances vasoconstriction
• Maintains vascular tone → supports blood pressure
• Permissive effect on catecholamines (adrenaline, noradrenaline)

💡 Without cortisol, vasopressors don’t work properly, that’s why adrenal crisis causes shock.

🧠 CNS and Immune Effects

• Modulates mood, alertness, and memory
• Suppresses inflammation and immune activation
• Inhibits cytokine release and leukocyte migration

💡 Cortisol is anti-inflammatory, but chronic excess can impair healing and immunity

📉 Adrenal Insufficiency:  

Cortisol is your body’s stress-response hormone. When levels drop too low, the effects ripple across multiple systems. Adrenal insufficiency means the body can’t produce enough cortisol , the hormone that helps you survive stress, maintain blood pressure, and regulate glucose. But the cause matters. Is the adrenal gland failing? Or is the signal from the brain missing?

There are three main types:

• Primary: the adrenal gland itself is damaged (e.g. Addison’s disease)
• Secondary: the pituitary isn’t producing ACTH
• Tertiary: the hypothalamus isn’t producing CRH — often due to long-term steroid use

(exactly as we explained with the thyroid axis, remember?)

🧠 Reasoning Through the Axis

Start by asking:

• Is the signal being sent (CRH → ACTH)?
• Is the gland responding (cortisol)?
• Is feedback working?

In primary adrenal insufficiency, the gland is damaged, often by autoimmune attack. The brain keeps sending ACTH, but the gland can’t respond. Cortisol is low, ACTH is high, and feedback fails.

In secondary or tertiary insufficiency, the gland is intact but under-stimulated. ACTH is low, cortisol is low, and the gland gradually atrophies from disuse.

🩺 Clinical Presentation: What Cortisol Deficiency Looks Like

Cortisol affects multiple systems, so deficiency causes widespread symptoms:

• Fatigue and weakness set in — the body can’t mobilise energy from fat or muscle
• Weight loss occurs — appetite drops, and catabolism accelerates
• Hypotension develops — cortisol normally enhances adrenergic tone; without it, blood pressure falls
• Hyponatraemia emerges — cortisol suppresses ADH; deficiency leads to water retention and sodium dilution
• Hypoglycaemia is common — especially in children or fasting adults, because gluconeogenesis falters
• Hyperkalaemia appears in primary adrenal failure — aldosterone is also low, so potassium builds up
• Skin pigmentation is a hallmark of primary failure — ACTH rises to compensate, and its precursor (POMC) also produces MSH, stimulating melanocytes

💡If the patient is pigmented, hypotensive, and hyperkalaemic, the adrenal gland itself is failing. If they’re hypotensive but not pigmented or hyperkalaemic, the problem may be central.

💡 Pigmentation is the pituitary’s cry for help — ACTH is high, but the adrenals aren’t listening. It can look like a sun tan but also be patchy and more focused in areas of friction- nipples, axillae, gums, tongue.

🧪 Investigations: What to Order and Why

Diagnosing adrenal insufficiency means testing both the output and the feedback loop.

• Morning cortisol: low levels suggest insufficiency — but timing matters
• ACTH: high in primary failure (Addison’s), low in secondary or tertiary
• Synacthen test: synthetic ACTH should stimulate cortisol; failure confirms adrenal dysfunction
• Electrolytes: sodium drops in all forms; potassium rises only in primary (due to aldosterone loss)
• Glucose: often low, especially in children or during fasting

🧠 Always interpret cortisol in context — time of day, stress level, and recent steroid use all matter.

🩺 Addison’s Disease — Primary Adrenal Failure

Addison’s disease is a classic example of primary endocrine failure. The adrenal glands themselves are damaged (most often by autoimmune destruction ) and can no longer produce cortisol or aldosterone.

Here’s how to reason through it:

• The hypothalamus and pituitary are still working. They’re sending CRH and ACTH, trying to stimulate the adrenals.
• But the adrenals can’t respond. Cortisol stays low, and aldosterone drops too.
• The pituitary ramps up ACTH in response, and because ACTH shares a precursor with MSH, the patient develops skin pigmentation.

Clinically, the patient is exhausted, hypotensive, and often nauseated. Their sodium is low (due to water retention and aldosterone loss), their potassium is high (because aldosterone normally promotes excretion), and their glucose is low (because cortisol supports gluconeogenesis).

💡 The body is shouting for help, but the adrenals are silent. That’s Addison’s.

If the patient becomes acutely unwell - vomiting, collapsing, unable to maintain blood pressure - they’re in adrenal crisis. It’s not subtle. It’s a failure of the stress-response system itself. You treat first (hydrocortisone, fluids), and confirm later.

⚠️ Adrenal Crisis: When the System Collapses

Adrenal crisis is a medical emergency. It happens when a patient with adrenal insufficiency faces a stressor (infection, surgery, trauma ) and can’t mount a cortisol response.

🧠 Why It Happens

Cortisol is essential for surviving stress. It maintains blood pressure, supports glucose production, and modulates inflammation. Without it, the body spirals into shock.

In crisis, the patient may have:

• Vomiting and abdominal pain
• Severe hypotension or collapse
• Confusion or coma
• Hypoglycaemia
• History of adrenal disease or steroid use

💡 Steroid withdrawal is a common cause — the HPA axis takes time to recover after suppression.

🩺 Management:  

• IV hydrocortisone: replaces cortisol and supports blood pressure
• IV fluids: normal saline for volume, dextrose for glucose
• Correct electrolytes: especially sodium and potassium
• Monitor glucose and vitals closely

🧠 Don’t wait for labs — if adrenal crisis is suspected, act immediately

📈 Cushing’s Syndrome: 

Cushing’s syndrome is the opposite problem — too much cortisol, from either endogenous overproduction or exogenous steroids.

🧠 Reasoning Through the Source

Cushing’s syndrome means too much cortisol. But the source matters: 

• Is the cortisol coming from the adrenal gland, the pituitary, or outside the axis?
• Is ACTH high or low?
• Is feedback working?

Pituitary adenoma → high ACTH, high cortisol (Cushing’s disease)

Adrenal adenoma → high cortisol, low ACTH

Ectopic ACTH producing tumour (e.g. small cell lung cancer) → very high ACTH, very high cortisol

Steroid use → high cortisol, suppressed axis

🩺 Clinical Features: What Cortisol Excess Looks Like

Cortisol acts on metabolism, skin, bone, mood, and reproductive hormones. Its effects are slow and cumulative — which is why patients often present late, with a constellation of signs that only make sense when viewed together.

• Central obesity: cortisol redistributes fat to the trunk, face, and neck
• Moon face and buffalo hump: classic fat pads from altered lipid metabolism
• Thin skin and easy bruising: cortisol inhibits collagen synthesis and protein repair
• Purple striae: dermal tearing from skin thinning and abdominal fat expansion and  impaired dermal integrity
• Hypertension: cortisol upregulates adrenergic receptors and enhances vasoconstriction
• Hyperglycaemia: cortisol antagonises insulin and promotes gluconeogenesis
• Osteoporosis: cortisol inhibits osteoblasts and increases bone resorption
• Mood changes: insomnia, irritability, emotional lability — cortisol affects the limbic system
• Menstrual irregularities: cortisol suppresses GnRH and downstream gonadotropins

💗 Cushing’s Syndrome vs Cushing’s Disease

This distinction trips up many students — not because the definitions are hard, but because the reasoning behind them is rarely explained.

Cushing’s syndrome is the name we give to the clinical state of cortisol excess. It doesn’t care where the cortisol is coming from — just that there’s too much of it. That excess might be due to:

• A pituitary adenoma producing ACTH
• An adrenal tumour producing cortisol directly
• Ectopic ACTH from a non-pituitary source (like small cell lung cancer)
• Or simply taking too many steroids

Cushing’s disease is specific: it refers only to the case where a pituitary adenoma is producing excess ACTH, which then drives the adrenals to overproduce cortisol.

So the reasoning goes like this:
If a patient has signs of cortisol excess — central obesity, striae, hypertension, hyperglycaemia — you’re dealing with Cushing’s syndrome.
If you then find that the excess is being driven by a pituitary tumour, you’ve narrowed it to Cushing’s disease.

💡 The key is not memorising definitions, but asking: Where is the signal coming from? Is the feedback loop broken centrally or peripherally?

 🧪 Investigations: What to Order and How to Interpret

You don’t just measure cortisol — you test the feedback loop.

1. 24-hour urinary cortisol

• Measures total free cortisol over time
• Elevated in true Cushing’s syndrome

2. Dexamethasone suppression test

• Dexamethasone mimics cortisol → should suppress ACTH and cortisol
• If cortisol stays high, feedback is broken → suggests autonomous production

3. ACTH level

• High ACTH → pituitary or ectopic source
• Low ACTH → adrenal source or exogenous steroids

4. Imaging

• Pituitary MRI if ACTH is high
• Adrenal CT if ACTH is low
• Chest CT if ectopic ACTH suspected

🧠 You’re not just measuring hormones — you’re testing the system’s ability to regulate itself.

🧠 Wrapping Up: Why the HPA Axis Matters

The adrenal axis is your body’s emergency response system — but it’s also a quiet regulator of daily physiology. It teaches students to reason through feedback loops, distinguish central from peripheral failure, and recognise when stress physiology becomes pathology. Whether you’re managing shock, fatigue, or steroid tapering, understanding the HPA axis helps you think like a clinician.

📚 Want to learn more?

• 🧠 All endocrine system posts →
• 🧬 The HPA axis →
• 🦋 The thyroid axis →
• 💊 The adrenal axis →
• 📏 The Growth Axis – Part 1: Physiology and disorders of height and growth →
• 🎭 The Growth Axis – Part 2: Famous faces of endocrinology →