Adrenal Insufficiency

When the gland that makes your stress hormone quits, the skin tells on it first. Read the tan, name the level, and never replace the thyroid before the adrenal.

A 33-year-old woman comes to the office because of weeks of weakness and light-headedness on standing. You notice her skin looks deeply tanned even where the sun never reaches: her palm creases and the inside of her cheeks. Seven days ago another clinic started her on levothyroxine for a high TSH, and she has felt worse since. Today her blood pressure is 82/50, heart rate 102, and serum sodium is 133.

Additional studies are ordered. Which result is most likely?

A low serum cortisol

A high serum cortisol

A suppressed (low) TSH

A high serum aldosterone

The Core Mechanism

Set the Lesion, Watch the Hormones Move

One control panel, three states. The adrenal answers to two separate bosses: ACTH from the pituitary drives cortisol, while renin and angiotensin II drive aldosterone. Break the gland or break the pituitary and watch which hormones fall and which one holds. This single picture explains every clue on the page.

ACTH

Normal

Cortisol

Normal

Aldosterone

Normal

Potassium

4.0

Pigment

Normal

Healthy axis. Two command lines feed the adrenal: ACTH from the pituitary drives cortisol, and renin with angiotensin II drives aldosterone. Tap a break above and watch which hormone falls and which one holds.

You are about to write her orders.

AttendingHang on, what are you reaching for?

YouFludrocortisone. Her pituitary is out, so I figured her aldosterone was gone too.

AttendingWho told you ACTH runs aldosterone?

You...it does not?

AttendingNever has. Look at the diagram, two arrows, two different bosses. ACTH only ever bought you cortisol. Aldosterone answers to renin and angiotensin II, and it could not care less what the pituitary is doing.

YouSo her aldosterone is just fine.

AttendingPotassium is normal, she is not wasting salt, and that fludro goes back in the drawer.

If the potassium is high, stop blaming the pituitary and look at the gland.

Why high ACTH paints the skin

The pituitary does not make ACTH out of nothing. It cuts ACTH out of a long parent protein called POMC (pro-opiomelanocortin). The same scissors that release ACTH also release MSH, melanocyte-stimulating hormone.

Adrenal dies → cortisol drops → the brake on the pituitary is gone.
Pituitary floors the accelerator → POMC production soars.
More POMC means more ACTH and more MSH together.
MSH switches on melanocytes → the palms, knuckles, scars, and inside of the cheeks darken.

So a tan in places the sun never reaches is not a skin disease. It is the pituitary screaming for a cortisol that the dead adrenal can no longer send.

Generalized hyperpigmentation of the skin in Addison disease

📷 Addison disease: diffuse hyperpigmentation from high ACTH and MSH · tap to expand

This is what high ACTH looks like on the surface. Secondary adrenal insufficiency, where ACTH is low, never produces this.

From the Attending

Stop staring at the cortisol number for a second. Look at the skin. Dark palms and dark gums mean ACTH is high, and ACTH is only high when the gland it is yelling at has gone silent. That puts the lesion in the adrenal, every time. Pigment is a free ACTH assay you can read across the room.

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The Decoder

Primary vs Secondary in One Screen

Same low cortisol, two completely different patients. The split is whether aldosterone survives. Sort the findings first, then check the table.

🪹

Primary (Addison)

The gland itself is destroyed

tap to flip

Adrenal is the problem

Cortisol low, aldosterone low
ACTH high → hyperpigmentation
Hyperkalemia, hyponatremia, salt craving
Causes: autoimmune (most common), TB, hemorrhage
Needs hydrocortisone and fludrocortisone

🧠

Secondary

The pituitary stops sending ACTH

tap to flip

Pituitary ACTH supply fails

Cortisol low, aldosterone preserved
ACTH low → no hyperpigmentation
Potassium normal (renin-angiotensin still runs aldosterone)
Causes: stopping steroids, pituitary tumor, Sheehan
Needs hydrocortisone only

🌡

Tertiary

The hypothalamus goes quiet

tap to flip

Low CRH at the top

Behaves like secondary: aldosterone preserved, no dark skin
Classic cause: chronic exogenous steroids suppressing CRH
The patient who stops prednisone after months
Recovery of the axis can take many months
Taper steroids, never stop them cold

Stop flipping them: count up from the gland

3Hypothalamustertiary

2Pituitarysecondary

1Adrenal glandprimary

Primary is the Producer: the gland that actually makes the hormone. The brain only barks orders, so "primary is the brain" cannot be right. Worker down is primary, manager down is secondary.

The 10-second trick

The pill is cortisol to your brain.

A daily steroid reads as cortisol at the hypothalamus and the pituitary, so both switch their signals off. The adrenal, never paged, slowly shrinks. That one idea is the whole reason you taper instead of stopping cold.

What does the hypothalamus do? (tap)

What does the pituitary do? (tap)

Stop the steroid suddenly. What happens? (tap)

Does the steroid need to reach the brain? (tap)

Sort the Finding

Each finding belongs to one side. Tap Primary or Secondary, then tap Check. No dragging, it all works on a phone.

Feature	Primary (Addison)	Secondary
ACTH level	High	Low
Hyperpigmentation	Yes	No
Aldosterone	Low	Preserved
Potassium	High	Normal
Salt craving	Common	Absent
Mineralocorticoid replacement	Needed	Not needed

Predict each row out loud, then tap a cell to check it (or reveal the whole table below).

⚠

The one fact that decides everything

Aldosterone is run mostly by the renin-angiotensin system and potassium, not by ACTH. So when the pituitary fails, aldosterone keeps working. That is why secondary disease has normal potassium and no salt wasting, while primary disease loses aldosterone and floods with potassium. No hyperkalemia, no dark skin: look above the adrenal.

So what is actually wrong with the gland?

Same low cortisol on both sides, but the adrenal is in completely different shape. Tap each one.

Primary

What is wrong with the adrenal?

It is destroyed. Autoimmune adrenalitis (most common in the US), TB (most common worldwide), or sudden bilateral hemorrhage. The cortisol cells and the aldosterone cells are physically gone, so ACTH can scream from above and nobody answers.

Tap to reveal

Secondary

What is wrong with the adrenal?

Nothing. The gland is healthy and idle. The pituitary simply stopped sending ACTH (a tumor, surgery, or steroid withdrawal). Hand the gland ACTH and it fires right back up, and aldosterone never even noticed, because renin runs it.

Tap to reveal

Why aldosterone loss makes you crave salt

Salt craving is one of the loudest primary-only signs. Walk the chain and it stops being a random symptom.

What is aldosterone's one job? (tap)

So what happens to sodium? (tap)

Why crave salt specifically? (tap)

Which side of the disease is this? (tap)

Eating salt by the spoonful is a dead adrenal talking.

You admit you keep flipping the two.

YouI keep mixing up primary and secondary.

AttendingTwo fire stations. Primary: the station burned to the ground. The alarm rings, nothing rolls out, because there are no trucks left.

YouAnd secondary?

AttendingSecondary: the trucks are washed, waxed, and bored out of their minds. Nobody pulled the alarm. Hand the pituitary its alarm back, give ACTH, and they roll instantly.

YouSo primary the gland is rubble, secondary the gland is fine and just idle.

Read the potassium and the skin. High potassium with dark skin means the station burned down. That is primary.

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The Killer Detail

Never Replace the Thyroid First

The opening case got worse the week levothyroxine started. That is not a coincidence. It is the single most tested sequencing error in adrenal insufficiency.

Your attending drops the opening chart in front of you on rounds.

AttendingHigh TSH, so the last clinic started levothyroxine. Seven days later she is hypotensive, sodium of 133, palms like a catcher's mitt. What did the thyroid pill do to her cortisol?

YouNothing? Thyroid and adrenal are separate axes.

AttendingWrong, and it is the kind of wrong that fills a code cart. Thyroid hormone turns up the whole body, and that includes how fast the liver chews through cortisol.

YouWait. The liver chews up cortisol?

Attending(gives you a long look) Every minute of every day. Her gland was already limping along making just barely enough. You floored her metabolism, the liver cleared cortisol faster, and the thin reserve she had went up in smoke. You wrote a prescription for a crisis and signed your name to it.

YouSo check and replace the adrenal before I ever touch the thyroid.

Glucocorticoid first, thyroid second. In any patient who might have both deficiencies, replace cortisol before levothyroxine, or you precipitate adrenal crisis.

The mechanism in four beats

Thyroid hormone raises the metabolic rate of nearly every tissue.
That includes hepatic clearance of cortisol: cortisol gets broken down faster.
A healthy adrenal just makes more cortisol to keep up. A failing adrenal cannot.
Available cortisol falls below the line that keeps blood pressure up → adrenal crisis.

This pairing shows up because autoimmune Addison disease travels with autoimmune thyroid disease (autoimmune polyglandular syndrome). The patient legitimately has both, so the order you treat them in is the whole game.

👑 Board rule: hypothyroidism plus hypotension, hyperpigmentation, or hyponatremia means check the adrenal before replacing thyroid. Steroids go in first.🔑Adrenal before Thyroid. A before T, alphabetical, same as the gland that matters most when the pressure is dropping.

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Workup and Treatment

Prove It, Localize It, Replace It

Three decisions: is cortisol low, can the gland respond, and where is the break. Answer each one before you reveal it.

A stable outpatient has fatigue, postural dizziness, and a tan. What is the best first screening test?

Cortisol peaks in the early morning, so a low 8 AM cortisol is the cleanest screen. A random afternoon level is normally low anyway and tells you nothing. Screen at the peak: 8 AM cortisol.

The morning cortisol is low. How do you prove the adrenal cannot respond?

Give synthetic ACTH (cosyntropin) and measure cortisol at 30 and 60 minutes. A healthy adrenal jumps; a failed one stays flat. Dexamethasone suppression and urine free cortisol are for excess cortisol (Cushing), the opposite problem. Confirm deficiency with the cosyntropin stimulation test.

Cortisol stayed flat after cosyntropin. How do you separate primary from secondary?

The plasma ACTH level localizes the break. High ACTH means the adrenal is the problem (primary). Low or inappropriately normal ACTH means the pituitary supply failed (secondary). Imaging comes after you know where to look. High ACTH equals primary, low ACTH equals secondary.

Then Replace What Is Missing

Glucocorticoid: hydrocortisone

Replace cortisol in everyone. Hydrocortisone covers the daily need.

Why hydrocortisone: it mirrors the body own cortisol and lets you mimic the natural higher-in-the-morning rhythm.

Mineralocorticoid: fludrocortisone, primary only

Add fludrocortisone in primary disease to replace the lost aldosterone. Secondary patients keep their own aldosterone, so they do not need it.

Why only primary: secondary disease spares aldosterone, which is why their potassium is normal in the first place.

Name trick

Flu-dro: fluid up, potassium drops.

It is just the aldosterone the dead gland can no longer make. Flu for the fluid it holds onto: it saves sodium, water follows, and the low pressure and low sodium climb back up. Dro for the potassium it drops. That is the exact primary deficit it repairs, the salt wasting and the hyperkalemia at once.

Stress dosing

Triple the glucocorticoid during illness, injury, or surgery. The failing gland cannot mount its own stress response.

Why stress dose: a normal adrenal multiplies cortisol output under stress. Replacement patients must do that by hand.

Adrenal crisis: intravenous hydrocortisone now

For a hypotensive, vomiting, or obtunded patient, give IV hydrocortisone plus aggressive normal saline and dextrose before any confirmatory test. Treat first, prove later.

Why not wait: crisis kills in hours. If you must protect the diagnostic test, dexamethasone treats without clouding a later cosyntropin assay.

From the Attending

In a crisis you do not have time to be elegant. Draw the cortisol and ACTH on the way in if you can, then push hydrocortisone and pour in saline. Nobody ever died from one dose of steroid given to a patient who turned out fine. They die from the dose you held while you waited for a number. Treat the crisis, then confirm it.

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The Emergency

Crisis and the Hemorrhage That Causes It

Acute adrenal failure presents as shock that will not answer to fluids alone. One classic cause destroys both glands in a single afternoon.

Recognize the crisis

Hypotension and shock out of proportion to the illness, poorly responsive to fluids until steroid is given.
Hyponatremia, hyperkalemia, and often hypoglycemia.
Nausea, vomiting, abdominal pain that can mimic an acute abdomen.
Often triggered: an infection, surgery, missed steroid dose, or, as you saw, a new levothyroxine prescription.

Crisis = cortisol demand outruns supply

Demand spikes

Infection or illness, the number one trigger (vomiting also blocks the oral dose)
Surgery, trauma, or major physical stress

Supply drops

Missed or abruptly stopped steroids
Both glands destroyed at once (Waterhouse-Friderichsen)
Faster cortisol clearance: levothyroxine, rifampin, phenytoin

Levothyroxine is the sneaky one boards love. The patient who actually crashes usually just caught a stomach bug and skipped a dose.

You think you have spotted the trigger.

YouSo the levothyroxine tipped her into crisis.

AttendingThis time, sure. That is the one they put on exams. You know what actually fills my pager? A known Addison patient who caught a stomach bug, threw up the morning hydrocortisone, and never doubled the dose.

YouSo infection plus a missed dose.

AttendingEvery time. The exotic trigger is fun. The common one is a virus and a skipped pill.

Any stress raises the cortisol the body demands. A gland that cannot answer goes into crisis, which is why sick-day rules and stress dosing are the whole game.

Waterhouse-Friderichsen syndrome

This is acute primary adrenal insufficiency from bilateral adrenal hemorrhage. Classic story: a child or young adult with Neisseria meningitidis sepsis spirals into disseminated intravascular coagulation, and the adrenal glands hemorrhage and infarct.

Fever, a spreading petechial and purpuric rash, then refractory shock.
Both glands destroyed at once → sudden loss of cortisol and aldosterone.
Treat the sepsis and give stress-dose steroids: the shock will not lift on antibiotics and pressors alone.

Wait, why does DIC cause bleeding?

Disseminated intravascular coagulation sounds like too much clotting, and at first it is. Walk the paradox.

What sets it off? (tap)

So why bleeding, not just clotting? (tap)

Why the adrenals get wrecked (tap)

DIC clots until it cannot, then bleeds. The adrenals take both hits at once.

Bilateral adrenal hemorrhage of Waterhouse-Friderichsen syndrome on gross pathology

📷 Waterhouse-Friderichsen: hemorrhage into both adrenal glands · tap to expand

Both glands bleed out together, so cortisol and aldosterone collapse at the same moment. That is why the shock is so resistant.

Where the tan hides (and where to look)

In chronic primary disease, hunt the hyperpigmentation in the places people forget to check:

Palmar creases and the dorsal knuckles.
Buccal (inside-cheek) mucosa and the gum line.
Old scars, pressure points (knees, elbows), and the areolae.

Hyperpigmented palms and palmar creases in Addison disease

📷 Palms and palmar creases that stay dark in primary adrenal insufficiency · tap to expand

Facial and generalized hyperpigmentation in Addison disease, before and after

📷 Facial and generalized tanning that deepened as Addison developed · tap to expand

Palmar creases and the buccal mucosa are the highest-yield places to read the high-ACTH signature on exam. The diffuse facial tan is the version that walks in the door.

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Prove It

Board Walkthrough

Board-style vignettes, dealt one round at a time, answer choices shuffled, never repeating until the bank is exhausted. Right-click or long-press a choice to cross it out, double-tap to highlight. Tap a wrong answer first to see why it almost works, then read the glowing clues.

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Medically reviewed by Fatima Ali, DO and Kaitlyn Cocuzzo, MD · Last reviewed June 2026

Bone Wizardry is an independent educational resource for visual learning in the medical sciences. It is not affiliated with, endorsed by, or sponsored by any licensing or examination board, contains no real or recalled examination questions, and does not guarantee any educational or examination outcome.

Sources: standard endocrinology and internal medicine references on the hypothalamic-pituitary-adrenal axis, Addison disease, and adrenal crisis.