Adrenal Disorders

Two small glands, each weighing about four grams, sit like caps on top of your kidneys — and yet they produce hormones you cannot live without. The adrenal glands make cortisol (your stress and metabolic hormone), aldosterone (your salt-and-blood-pressure hormone), and catecholamines like adrenaline. When these glands make too much or too little, the whole body feels it: blood pressure swings, blood sugar drifts, electrolytes shift, and in the extreme, a patient can collapse and die within hours. This is why adrenal disorders reward the clinician who understands the underlying physiology — the signs and symptoms are almost always predictable from "which hormone is high or low."

In this topic we build that physiology first, then walk through the four disorders you must know cold: Cushing syndrome (too much cortisol), Addison disease (too little cortisol and aldosterone), primary hyperaldosteronism (too much aldosterone), and pheochromocytoma (too many catecholamines). Master the hormones and the diseases explain themselves.

Learning Objectives

• Describe the anatomy of the adrenal cortex and medulla and the hormones each zone produces.
• Explain the regulation and physiological actions of cortisol and aldosterone.
• Recognise the clinical features, causes, and diagnostic workup of Cushing syndrome.
• Recognise the features, causes (Addison disease vs secondary), and emergency management of adrenal insufficiency, including adrenal crisis.
• Understand the presentation, diagnosis, and safe management sequence of pheochromocytoma.
• Distinguish primary from secondary causes across all these disorders using ACTH, renin, and dynamic testing.

Quick Answer

The adrenal cortex has three zones producing three classes of steroid: the zona glomerulosa makes aldosterone (a mineralocorticoid, regulated by renin–angiotensin and potassium), the zona fasciculata makes cortisol (a glucocorticoid, regulated by pituitary ACTH), and the zona reticularis makes androgens — remember "GFR = salt, sugar, sex." The medulla makes catecholamines. Cushing syndrome is cortisol excess (most often from prescribed steroids, or from an ACTH-secreting pituitary adenoma called Cushing disease). Addison disease is primary adrenal failure — loss of both cortisol and aldosterone — classically autoimmune, presenting with fatigue, weight loss, low blood pressure, and hyperpigmentation. Pheochromocytoma is a catecholamine-secreting tumour causing episodic hypertension, headache, sweating, and palpitations. Diagnosis rests on measuring the hormone and localising the problem (adrenal vs pituitary vs ectopic) using ACTH levels and dynamic suppression or stimulation tests.

Where It Came From

For most of medical history the adrenal glands were an anatomical curiosity with no known function — Bartolomeo Eustachi drew them in 1563, but no one knew what they did. The turning point came from a physician at Guy's Hospital in London. In 1855, Thomas Addison published On the Constitutional and Local Effects of Disease of the Suprarenal Capsules, describing patients with a wasting illness marked by weakness, "feebleness of the heart's action," gastric upset, and a strange bronze discoloration of the skin. At autopsy their adrenal glands were destroyed — usually by tuberculosis. Addison had proven, for the first time, that these glands were essential to life. The disease that bears his name was the founding observation of endocrinology's understanding of the adrenal.

A year later the French physiologist Charles-Édouard Brown-Séquard confirmed the point experimentally: removing the adrenal glands from animals killed them. The motivating need was stark — before hormone replacement existed, Addison disease was uniformly fatal. The pieces fell into place over the next century: adrenaline was isolated around 1900 (the first hormone ever purified), cortisol ("compound F") was characterised in the 1930s–40s, and Edward Kendall, Philip Hench, and Tadeusz Reichstein shared the 1950 Nobel Prize for isolating the adrenal cortical hormones — work that also gave medicine cortisone as an anti-inflammatory drug. Harvey Cushing described the pituitary-driven cortisol excess syndrome in 1912 and 1932. Jerome Conn described primary aldosteronism in 1955. Each discovery answered a lethal clinical problem: how to keep an Addisonian alive, and how to recognise the mirror-image diseases of hormone excess.

Adrenal Anatomy and the Two Key Hormones

The adrenal gland is really two organs in one. The outer cortex (about 90% of the gland) is steroid-producing tissue arranged in three concentric zones; the inner medulla is modified nervous tissue that makes catecholamines.

The cortex — "GFR: salt, sugar, sex, and deeper you go the sweeter it gets":

• Zona Glomerulosa (outer): aldosterone (mineralocorticoid) — controls salt.
• Zona Fasciculata (middle): cortisol (glucocorticoid) — controls sugar and stress.
• Zona Reticularis (inner): adrenal androgens (DHEA) — the sex steroids.

Cortisol

Cortisol is secreted by the fasciculata under control of the hypothalamic–pituitary–adrenal (HPA) axis: the hypothalamus releases CRH, which drives the pituitary to release ACTH, which stimulates cortisol production. Cortisol then feeds back negatively to shut off CRH and ACTH — the loop that every diagnostic test in this field exploits. Secretion follows a diurnal rhythm, peaking in the early morning and reaching its nadir around midnight.

Cortisol's actions are broad and catabolic — it prepares the body to survive stress and fasting:

• Metabolic: raises blood glucose (stimulates gluconeogenesis, antagonises insulin), promotes protein breakdown in muscle and lipolysis (with fat redistribution centrally).
• Cardiovascular: permits catecholamines to work (permissive effect), maintaining vascular tone and blood pressure.
• Immune/anti-inflammatory: suppresses inflammation and immune activity — the basis of therapeutic steroids.
• Other: at high levels cortisol also binds mineralocorticoid receptors, causing sodium retention and potassium loss.

Aldosterone

Aldosterone is the master regulator of sodium and potassium balance. Its two main triggers are the renin–angiotensin–aldosterone system (RAAS) — activated by low renal perfusion or low sodium — and high serum potassium. Aldosterone acts on the distal nephron to reabsorb sodium (and water follows) and excrete potassium and hydrogen ions. The net effect is to raise blood volume and blood pressure and to lower serum potassium. Note that ACTH plays little role here; aldosterone survives even when ACTH is absent, which is why secondary adrenal insufficiency (pituitary failure) spares aldosterone.

Cushing Syndrome — Cortisol Excess

Cushing syndrome is the clinical state of chronic cortisol excess from any cause. Cushing disease is the specific subset caused by an ACTH-secreting pituitary adenoma. Keep the two words distinct — examiners love this.

Causes (divide by ACTH):

• Exogenous (most common overall): prescribed glucocorticoids. Always the first thing to ask about.
• ACTH-dependent: pituitary adenoma (Cushing disease, ~70% of endogenous cases) or ectopic ACTH (e.g., small-cell lung carcinoma).
• ACTH-independent: adrenal adenoma or carcinoma making cortisol autonomously (ACTH is suppressed low).

Clinical features flow directly from cortisol's actions: central obesity with thin limbs, a rounded "moon face," a dorsocervical fat pad ("buffalo hump"), purple abdominal striae, easy bruising and thin skin, proximal muscle weakness (from protein breakdown), hyperglycaemia or frank diabetes, hypertension, osteoporosis, and immunosuppression. Excess androgens may cause hirsutism and acne in women. Psychiatric changes (depression, psychosis) are common.

Diagnostic approach — two steps:

1. Confirm excess cortisol using any of: 24-hour urinary free cortisol, late-night salivary cortisol (loss of diurnal nadir), or the overnight 1 mg dexamethasone suppression test (a normal HPA axis suppresses morning cortisol; Cushing does not).
2. Find the source by measuring ACTH. If ACTH is suppressed → adrenal tumour (image the adrenals). If ACTH is normal/high → the high-dose dexamethasone test and pituitary MRI distinguish pituitary (usually suppresses) from ectopic (usually does not); inferior petrosal sinus sampling can confirm a pituitary source.

Treatment targets the cause: surgical resection (transsphenoidal for pituitary adenoma, adrenalectomy for adrenal tumour), tapering exogenous steroids, and drugs such as ketoconazole or metyrapone to block cortisol synthesis when surgery is delayed.

Adrenal Insufficiency — Addison Disease

Adrenal insufficiency is failure to produce enough cortisol (and, in primary disease, aldosterone too). The distinction between primary and secondary is clinically decisive.

• Primary (Addison disease): the adrenal glands themselves fail. Both cortisol and aldosterone are lost, and ACTH rises (no negative feedback). In developed countries the commonest cause is autoimmune adrenalitis; worldwide, tuberculosis remains important (Addison's original cases). Other causes: adrenal haemorrhage (Waterhouse–Friderichsen syndrome in meningococcaemia), metastases, and adrenoleukodystrophy.
• Secondary: the pituitary fails to make ACTH (tumour, or — most commonly — suppression from chronic exogenous steroids that are then stopped abruptly). Cortisol is low but aldosterone is preserved (RAAS is intact), and there is no hyperpigmentation.

Clinical features: insidious fatigue, weakness, weight loss, anorexia, nausea, abdominal pain, salt craving, and postural hypotension. The hallmark of primary disease is hyperpigmentation — of skin creases, buccal mucosa, and scars — because the ACTH precursor (POMC) is co-processed into melanocyte-stimulating hormone, so high ACTH darkens the skin. Laboratory clues in primary disease: hyponatraemia, hyperkalaemia (from aldosterone loss), and sometimes hypoglycaemia.

Diagnosis: low morning cortisol with a high ACTH suggests primary insufficiency. Confirm with the short Synacthen (ACTH stimulation) test — give synthetic ACTH and measure cortisol; a failure to rise confirms adrenal failure.

Adrenal crisis is the emergency you must never miss. Precipitated by infection, surgery, trauma, or missed steroid doses, it presents with profound hypotension/shock, vomiting, abdominal pain, confusion, and hypoglycaemia. Treatment is immediate and does not wait for confirmatory tests: IV hydrocortisone (100 mg) and aggressive IV normal saline, plus treatment of the precipitant. Do not delay steroids to complete a diagnostic workup — a delay can be fatal.

Case Vignette

A 34-year-old woman reports six months of fatigue, a 7 kg weight loss, dizziness on standing, and craving salty snacks. You notice her palm creases and gums look unusually dark. Blood pressure is 96/60 lying, 78/50 standing. Sodium 128, potassium 5.6. You suspect Addison disease: the combination of hyperpigmentation, postural hypotension, low sodium and high potassium points to primary adrenal failure with loss of both cortisol and aldosterone. You check morning cortisol and ACTH and arrange a short Synacthen test — and counsel her about lifelong replacement and "sick-day rules."

Pheochromocytoma — Catecholamine Excess

A pheochromocytoma is a tumour of the adrenal medulla that secretes catecholamines (adrenaline and noradrenaline). The classic teaching mnemonic is the "rule of 10s" (traditionally: ~10% bilateral, ~10% extra-adrenal, ~10% malignant, ~10% familial — modern data revise these upward, but the phrase still helps recall). Extra-adrenal tumours along the sympathetic chain are called paragangliomas.

Clinical features are episodic and dramatic, driven by catecholamine surges. The classic triad is episodic Headache, sweating (diaphoresis), and palpitations/tachycardia — with paroxysmal or sustained hypertension as the central sign. Attacks may include pallor, anxiety, tremor, and a sense of impending doom. Pheochromocytoma is a curable cause of secondary hypertension and should be considered in young patients with resistant hypertension or hypertensive spells. It associates with syndromes: MEN 2A/2B, von Hippel–Lindau, and neurofibromatosis type 1.

Diagnosis: measure plasma free metanephrines or 24-hour urinary metanephrines (breakdown products of catecholamines — more reliable than measuring catecholamines directly). Once biochemically confirmed, localise with CT or MRI of the abdomen, and MIBG scintigraphy if needed.

Management — the sequence is critical and a favourite exam point: the patient must be alpha-blocked first (e.g., phenoxybenzamine) for 1–2 weeks before surgery, and only then beta-blocked if needed for tachycardia. Giving a beta-blocker first is dangerous: it removes beta-mediated vasodilation and leaves unopposed alpha vasoconstriction, which can precipitate a hypertensive crisis. Definitive treatment is surgical removal (adrenalectomy) after adequate blockade.

Real-World Applications

• Recognising iatrogenic Cushing and secondary insufficiency: the single most common adrenal problem in practice is caused by doctors — long courses of prednisolone. This produces cushingoid features while on the drug and adrenal suppression when it is stopped. Patients on steroids for more than a few weeks must taper slowly and receive stress-dose steroids during illness or surgery.
• Sick-day rules save lives: every patient with adrenal insufficiency should carry a steroid emergency card, double their oral hydrocortisone during fever or infection, and have an emergency IM hydrocortisone kit. Educating patients here directly prevents fatal adrenal crises.
• Screening for a curable killer: measuring metanephrines before removing any adrenal "incidentaloma," and before giving contrast or anaesthesia, prevents lethal catecholamine surges from an unsuspected pheochromocytoma.
• Emergency medicine: unexplained shock that responds poorly to fluids and pressors — especially with hyponatraemia, hyperkalaemia, and hypoglycaemia — should prompt empirical hydrocortisone for possible adrenal crisis.

Common Mistakes

• Confusing Cushing syndrome with Cushing disease. Why wrong: they are not synonyms. Correction: Cushing syndrome = cortisol excess from any cause; Cushing disease = specifically a pituitary ACTH-secreting adenoma. Always name the source.
• Expecting hyperkalaemia and hyperpigmentation in secondary adrenal insufficiency. Why wrong: secondary disease is pituitary ACTH deficiency — aldosterone (RAAS-driven) is preserved, so potassium is usually normal, and ACTH is low, so there is no pigmentation. Correction: hyperkalaemia and hyperpigmentation are features of primary (Addison) disease only.
• Beta-blocking a pheochromocytoma before alpha-blocking it. Why wrong: unopposed alpha-adrenergic vasoconstriction can trigger a hypertensive crisis. Correction: always alpha first, beta second.
• Delaying steroids in suspected adrenal crisis to finish tests. Why wrong: crisis can kill within hours; a single dose does not invalidate a later workup. Correction: treat first with IV hydrocortisone and saline, investigate after.

Comparison and Connections

Feature	Cushing syndrome	Addison disease (primary)	Pheochromocytoma
Hormone problem	Cortisol excess	Cortisol + aldosterone deficiency	Catecholamine excess
Zone/tissue	Cortex (fasciculata)	Whole cortex destroyed	Medulla
Blood pressure	High	Low (postural drop)	High (episodic)
Sodium / Potassium	Na high-ish, K low	Na low, K high	Usually normal
Skin	Striae, bruising, thin skin	Hyperpigmentation	Pallor in attacks
Key test	Dexamethasone suppression	Short Synacthen (stimulation)	Plasma/urine metanephrines
ACTH	High (pituitary) or low (adrenal)	High	Normal

The unifying theme: suppression tests diagnose excess (a healthy axis shuts off; a diseased one does not), while stimulation tests diagnose deficiency (a healthy gland responds; a failed one cannot). This logic recurs throughout endocrinology.

Practice Questions

Recall

Q: Which adrenal zone produces aldosterone, and what two stimuli mainly regulate it? A: The zona glomerulosa (outermost cortex). It is regulated chiefly by the renin–angiotensin system (in response to low renal perfusion/sodium) and by high serum potassium.

Understanding

Q: Why does primary adrenal insufficiency cause hyperpigmentation but secondary insufficiency does not? A: In primary disease the adrenal is destroyed, cortisol is low, and negative feedback is lost, so the pituitary makes very high ACTH. ACTH is cleaved from POMC, which also yields melanocyte-stimulating hormone, so excess ACTH stimulates skin pigmentation. In secondary disease the pituitary itself is failing, so ACTH is low — no pigmentation.

Application

Q: A patient with a confirmed pheochromocytoma is scheduled for adrenalectomy. What must be done before surgery and why? A: Adequate alpha-blockade (e.g., phenoxybenzamine) for one to two weeks to control blood pressure and expand the contracted blood volume, adding a beta-blocker only afterwards for tachycardia. This prevents an intraoperative hypertensive crisis and post-removal hypotension. Beta-blockade alone first risks unopposed alpha vasoconstriction.

Analysis

Q: A patient has clinical Cushing features. The overnight dexamethasone test fails to suppress cortisol, and ACTH is low. Where is the lesion, and what is your next step? A: A low ACTH means the excess cortisol is being made autonomously by the adrenal (ACTH-independent), suppressing pituitary ACTH by feedback. The lesion is an adrenal tumour (adenoma or carcinoma). Next step: image the adrenal glands with CT and plan adrenalectomy.

FAQ

Is Addison disease the same as adrenal insufficiency? Addison disease specifically means primary adrenal insufficiency (the gland itself fails, losing both cortisol and aldosterone). "Adrenal insufficiency" is the broader umbrella that also includes secondary (pituitary ACTH deficiency) and tertiary (hypothalamic/steroid-withdrawal) causes.

Can stress really trigger an adrenal crisis? Yes — in someone who already has adrenal insufficiency. A normal adrenal ramps up cortisol during infection, surgery, or trauma; a failing one cannot, so physiological stress can tip the patient into life-threatening crisis. This is why "sick-day" dose increases exist.

Why is exogenous steroid use the most common cause of both Cushing and adrenal insufficiency? Taking steroids gives you cortisol excess (cushingoid features) while suppressing your own HPA axis. If you then stop suddenly, your suppressed adrenals cannot restart quickly enough, and you become insufficient. The same drug causes both faces of the coin depending on timing.

Do all pheochromocytomas cause constant high blood pressure? No. Classically the hypertension is paroxysmal — coming in spells with headache, sweating, and palpitations — though a substantial proportion have sustained hypertension. Normal blood pressure between attacks does not rule it out.

How do suppression and stimulation tests differ, and when do I use each? Use a suppression test (like dexamethasone) when you suspect too much hormone — a healthy axis will suppress, a diseased one won't. Use a stimulation test (like short Synacthen) when you suspect too little — a healthy gland responds, a failed one can't.

Quick Revision

• Cortex zones (GFR): Glomerulosa → aldosterone (salt); Fasciculata → cortisol (sugar/stress); Reticularis → androgens (sex). Medulla → catecholamines.
• Cortisol: raises glucose, is catabolic, permissive for catecholamines, anti-inflammatory; controlled by ACTH; diurnal (high AM).
• Aldosterone: retains Na/water, excretes K/H; driven by RAAS and high K; independent of ACTH.
• Cushing = cortisol excess. Confirm with dexamethasone suppression; localise with ACTH. Cushing disease = pituitary adenoma.
• Addison = primary adrenal failure (autoimmune #1, TB historically); low Na, high K, hyperpigmentation, high ACTH. Confirm with short Synacthen.
• Adrenal crisis: shock + IV hydrocortisone + saline immediately; do not wait for tests.
• Pheochromocytoma: episodic headache/sweating/palpitations + hypertension; test metanephrines; alpha-block before beta-block before surgery.
• Rule: suppression tests find excess; stimulation tests find deficiency.

Related Topics

Prerequisites

• Endocrinology overview
• Adrenal gland anatomy — see Anatomy
• Steroid and hormone signalling — see Physiology

Related Topics

• Renin–angiotensin–aldosterone system and blood pressure — see Cardiology
• Autoimmune disease mechanisms — see Immunology
• Glucocorticoids as drugs — see Pharmacology

Next Topics

• Thyroid Disorders (../Thyroid_Disorders/index.md if present)
• Diabetes Mellitus and glucose regulation
• MEN syndromes and endocrine tumours — see Medical Genetics