12.4 — The Adrenal Glands and the Stress Response

Each adrenal gland weighs about 4 grams and sits like a cap on top of a kidney. Remove both and, without replacement, a person dies within days — faster if they become ill, because the hormone they can no longer make is the one that gets a body through illness.

It is also two organs stuck together, from two different germ layers, doing two unrelated jobs (Chapter 4.4). The outer cortex makes steroids on a scale of hours. The inner medulla makes adrenaline on a scale of milliseconds. They share a blood supply and almost nothing else.

The cortex

Three layers, from outside in, producing three classes of steroid — and a memorable order: salt, sugar, sex.

Zona glomerulosa (outer) — aldosterone, the mineralocorticoid. Salt.

Zona fasciculata (middle, thickest) — cortisol, the glucocorticoid. Sugar.

Zona reticularis (inner) — adrenal androgens, mainly DHEA. Sex.

All three are made from cholesterol, through a branching pathway of enzymes. Which enzyme is present in which layer determines what that layer produces.

And that pathway structure explains an entire disease.

Congenital adrenal hyperplasia

A missing enzyme in the pathway — most often 21-hydroxylase — blocks the routes to cortisol and aldosterone.

Three things follow, and they follow inevitably from the plumbing.

Cortisol is low. So there is no negative feedback, so ACTH rises enormously, so the adrenal glands are driven hard and enlarge — the "hyperplasia" of the name.

Aldosterone is low, so salt is lost. A newborn presents in the second week of life with vomiting, dehydration, low sodium, high potassium and shock — a salt-losing crisis, which is fatal if not recognised.

And the precursors pile up behind the block and are diverted down the one remaining open route — androgen production.

So an affected female fetus is exposed to high androgens in the womb and is born with virilised external genitalia, sometimes ambiguous enough that sex assignment is not obvious at birth. Internal reproductive organs are normal, because those depend on the absence of anti-Müllerian hormone rather than on androgens (Chapter 15.3).

One enzyme missing, three consequences, all predictable from a diagram of the pathway.

It is on the newborn screening panel in many countries, and treatment is lifelong steroid replacement, which both replaces what is missing and suppresses the excess androgen drive.

Cortisol

The hormone that gets you through stress, and its actions are best understood as preparing the body to survive a period of demand.

Raises blood glucose — by promoting glucose manufacture in the liver from amino acids and glycerol, and by making tissues less responsive to insulin. It is a counter-regulatory hormone, opposing insulin.

Breaks down protein in muscle and fat in the limbs, supplying the raw materials.

Suppresses inflammation and the immune system — powerfully, and this is why steroids are used as drugs.

Permits the action of adrenaline on blood vessels. Without cortisol, blood vessels do not respond properly to adrenaline, which is why adrenal insufficiency causes low blood pressure that does not respond to the usual treatments. This "permissive" effect is why adrenal crisis is so dangerous.

Suppresses bone formation, wound healing and growth.

Affects mood, sleep and cognition.

And its release follows a strong daily rhythm — highest just before waking, lowest around midnight (Chapter 12.1). Which is why a random cortisol level is uninterpretable and a 9 a.m. one is standard.

The stress response: hypothalamus → CRH → pituitary → ACTH → adrenal cortex → cortisol → negative feedback on both levels above. The whole axis is often abbreviated the HPA axis, and it appears constantly in Volume VI.

Cushing's syndrome — too much cortisol

And the commonest cause by far is treatment with steroids, not disease.

Which is worth saying first, because it means the appearance is familiar to anyone who has known someone on long-term prednisolone.

The features are what cortisol's actions look like when sustained:

Central weight gain with thin limbs — fat is redistributed to the trunk, face and back of the neck while muscle protein is broken down in the limbs. The combination of a round face, a full trunk and thin arms and legs is the recognisable pattern.

Thin skin, easy bruising, and purple stretch marks — from protein breakdown in skin and connective tissue. The stretch marks are wide and purple rather than the pale narrow ones of ordinary weight change, because the skin is thinned enough to show the vessels beneath.

Muscle weakness, particularly proximal — difficulty rising from a chair or climbing stairs.

High blood pressure and high blood glucose.

Osteoporosis, often severe and sometimes presenting as vertebral fractures.

Poor wound healing and frequent infections.

Mood disturbance — commonly depression, sometimes psychosis, and often insomnia.

And in women, excess androgens cause acne, hirsutism and irregular periods.

Causes, once medication is excluded:

Cushing's disease — a pituitary adenoma secreting ACTH. About 70 percent of endogenous cases. Note the distinction: Cushing's disease means the pituitary specifically; Cushing's syndrome means the picture from any cause.

Adrenal adenoma or carcinoma — producing cortisol autonomously.

Ectopic ACTH — from a tumour elsewhere, classically small cell lung cancer (Chapter 12.1). This one develops fast, so the classic body changes may not have had time to appear; instead there is profound weakness, marked hyperpigmentation from the very high ACTH, and severe potassium loss.

Diagnosis uses the suppression principle (Chapter 12.1). Give dexamethasone overnight; a normal axis suppresses cortisol, and Cushing's does not. Then further tests separate pituitary from adrenal from ectopic.

Adrenal insufficiency — too little cortisol

Primary (Addison's disease) — the adrenal glands themselves fail. Autoimmune destruction in about 80 percent of cases in wealthy countries; tuberculosis remains a leading cause worldwide.

Both cortisol and aldosterone are lost.

Secondary — the pituitary is not producing ACTH. Cortisol is lost; aldosterone is preserved, because it is mainly controlled by the renin–angiotensin system rather than by ACTH.

And the commonest cause of secondary insufficiency is abrupt withdrawal of long-term steroid treatment (Chapter 12.1).

The two are distinguished at the bedside by two features.

Pigmentation — present in primary, absent in secondary. High ACTH causes skin darkening (Chapter 12.2), most visible in skin creases, scars, the gum margins and the inside of the cheeks. In secondary insufficiency ACTH is low, so there is no pigmentation.

Electrolytes — primary insufficiency loses aldosterone, so sodium falls and potassium rises. Secondary usually does not.

The chronic presentation is notoriously vague and frequently missed for years: fatigue, weight loss, loss of appetite, nausea, dizziness on standing, muscle and joint aches, and a craving for salt. Depression is a common initial diagnosis.

And the acute presentation is a medical emergency.

Adrenal crisis

Precipitated by any physiological stress in someone whose adrenal reserve is inadequate — infection, surgery, injury, vomiting, or simply missing doses.

Severe weakness, vomiting, abdominal pain, confusion, and profound hypotension that does not respond to fluids — because without cortisol, the blood vessels cannot respond to the body's own adrenaline.

It is fatal if untreated and it is entirely treatable.

The treatment is intravenous hydrocortisone immediately, plus fluids, plus glucose. And the crucial clinical rule: if adrenal crisis is suspected, give steroid before confirming the diagnosis. Blood can be taken first for later analysis, but nothing waits for the result. The risk of a single dose of steroid in someone who did not need it is negligible; the risk of delay in someone who did is death.

Every patient with known adrenal insufficiency should have:

A steroid emergency card and a medical alert bracelet.An emergency injection kit at home, with someone trained to use it.And sick day rules — double the usual dose during any illness with fever, and use the injection if vomiting prevents tablets being absorbed.

This is one of the clearest examples in the whole volume of a condition where the patient's own knowledge is the main determinant of survival, and where inadequate education is a recognised cause of preventable death.

Aldosterone

Controls sodium retention and potassium excretion in the kidney (Chapter 10.2), and it is controlled mainly by the renin–angiotensin system (Chapter 7.6).

Primary hyperaldosteronism (Conn's syndrome) — autonomous overproduction, usually from an adrenal adenoma or from enlargement of both glands.

And it is far commoner than the textbooks used to say. Once thought to cause under 1 percent of hypertension, current estimates put it at 5 to 10 percent, and higher in resistant hypertension.

Which matters enormously, for two reasons. It is potentially curable — an adenoma can be removed, or spironolactone can block it specifically. And it causes more cardiovascular damage than equivalent blood pressure from other causes, because aldosterone itself drives fibrosis in the heart and vessels.

It should be suspected in hypertension that is resistant to three drugs, hypertension with unexplained low potassium, hypertension in a young person, or hypertension with an adrenal nodule found incidentally.

The screening test is the ratio of aldosterone to renin, and it is underused.

The medulla

The inner 10 percent of the gland, and it is not really a gland at all — it is a modified sympathetic ganglion (Chapter 4.4), made of neural crest cells, whose "cells" are modified neurons.

Which is why it responds in under a second, on direct nerve command, while the cortex takes minutes to hours.

It secretes adrenaline (about 80 percent) and noradrenaline (about 20 percent) directly into the blood.

And the division of labour with the sympathetic nerves is worth being precise about. The nerves act locally and instantly and stop instantly. The medulla's hormones circulate and persist for minutes. So a fright produces an immediate response from the nerves, and the shakiness afterwards is the circulating adrenaline.

Adrenaline's actions are the fight-or-flight list of Chapter 11.9, and it is worth noting that you can live perfectly well without an adrenal medulla — the sympathetic nerves cover its functions. You cannot live without the cortex.

Phaeochromocytoma

A tumour of the medulla, secreting catecholamines, usually in episodes.

Rare — perhaps 0.2 to 0.6 percent of hypertension — and dangerous out of proportion to its frequency.

The classic triad is episodic headache, sweating and palpitations, with hypertension that may be sustained or may come in dramatic paroxysms. Attacks can be triggered by exertion, by pressure on the abdomen, or by certain drugs.

The traditional teaching that it follows a "rule of tens" — about 10 percent bilateral, 10 percent outside the adrenal, 10 percent malignant, 10 percent familial — is a useful memory aid and the real figures have shifted, particularly the familial fraction, which is now recognised to be around 30 to 40 percent as more genetic causes have been identified. So genetic testing is offered to essentially everyone diagnosed.

Diagnosis is by measuring metanephrines — the breakdown products, which are produced continuously rather than in bursts, so they do not require catching an attack.

And there is one critical treatment rule. The patient must be given an alpha-blocker before any beta-blocker, and before surgery.

The reason is direct. Adrenaline acts on both alpha receptors (constricting vessels) and beta receptors (dilating some vessels, driving the heart). Block beta first and the alpha effect is left unopposed, so vessels constrict without any counterbalance and blood pressure can rise to a lethal level.

Alpha blockade first, then beta. It is one of the more memorable "never do this" rules in medicine, and it follows entirely from receptor physiology (Chapter 11.9).

The adrenal incidentaloma

An adrenal mass found by chance on a scan done for something else — and this is now common, appearing in 3 to 7 percent of abdominal CT scans in older adults.

Two questions are asked of every one: is it functioning, and is it malignant?

Functioning — tested for cortisol excess, aldosterone excess and catecholamine excess. A substantial minority quietly overproduce cortisol at a subclinical level, which contributes to hypertension, diabetes and osteoporosis and is worth finding.

Malignant — assessed by size and imaging characteristics. Most are benign adenomas.

And the incidentaloma is a good illustration of the general problem of modern imaging: scanning more people finds more things, most of which do not matter, and each requires a decision. The framework of asking two specific questions rather than simply watching is what keeps it manageable.

Steroids as drugs

Because cortisol suppresses inflammation and immunity, synthetic steroids are among the most useful and most double-edged drugs in medicine.

Used in: asthma, COPD, inflammatory bowel disease, rheumatoid arthritis and other autoimmune diseases, allergic reactions, transplant rejection, some cancers, and to mature fetal lungs before preterm delivery (Chapter 8.2).

And the harms of long-term use are the Cushing's list above, plus adrenal suppression.

Three principles govern their use, and they are worth knowing as a patient as much as a prescriber.

Use the lowest effective dose for the shortest necessary time.

Use the local route where possible — inhaled for asthma, topical for skin, injected into a joint — because systemic absorption is far lower.

And taper anything given for more than about three weeks, to allow the suppressed axis to recover.

Patients on long-term steroids need bone protection, blood pressure and glucose monitoring, and a steroid card. And they need to know the sick day rules, because their adrenal glands can no longer respond to illness on their own.

What the next page fixes

The last of the classic endocrine glands sits inside the pancreas and controls the fuel supply to every cell. Chapter 12.5 covers the islets of Langerhans, insulin and glucagon, and the control system whose failure is the commonest endocrine disease in the world.