What it is:Three disorders of the same small gland, running in opposite directions. Cushing syndromeis too much cortisol. Hyperaldosteronismis too much aldosterone. Adrenal insufficiency (Addison disease)is too little cortisol, often too little aldosterone too. Same organ, same hormones, opposite management logic.
The core problem:Every adrenal hormone problem traces back to the hypothalamic-pituitary-adrenal (HPA) axis and three enzyme-defined zones of the adrenal cortex. Once you know which zone and which enzyme step is broken, the drugs write themselves: block synthesis, block the receptor, or replace what's missing.
What you do about it:Excess states get steroidogenesis inhibitors, receptor blockers, or surgery. Deficiency states get hormone replacement dosed to mimic the body's own rhythm. The one true emergency here is adrenal crisis, which gets IV hydrocortisone immediately, before labs come back.
Your professor's framing: think of the adrenal cortex as a three-lane factory. Zona Glomerulosamakes mineralocorticoid (think "salt"), zona Fasciculatamakes glucocorticoid (think "sugar"), zona Reticularismakes androgens (think "sex"). GFR = salt, sugar, sex, outside in. Every disease in this chapter is one of those lanes running too fast or too slow, and every drug either speeds it up, slows it down, or replaces its output.
The adrenal glands sit on top of each kidney. The medulla(10% of the gland) makes catecholamines and isn't part of this chapter. The cortex(90%) is where all three diseases here originate, and it's built from three concentric zones, each making a different hormone family from the same starting material: cholesterol.
15% of cortex. Makes aldosteronevia aldosterone synthase (CYP11B2). Driven mainly by angiotensin II and serum K⁺, not ACTH.
60% of cortex, cholesterol-rich. Makes cortisolvia 17α-hydroxylase (CYP17) and 11β-hydroxylase (CYP11B1). Driven by ACTH.
25% of cortex. Makes adrenal androgens(DHEA, androstenedione) via CYP17. Regulator less well defined.
Hypothalamus releases CRH→ anterior pituitary corticotropes release ACTH→ zona fasciculata makes cortisol. Cortisol then feeds back to shut down its own trigger at both the hypothalamus and pituitary. This loop has a built-in circadian rhythm: cortisol synthesis is roughly 12-25 mg/day at baseline (up to 300 mg/day under severe stress), plasma levels trough near midnight and peak around 6-8 AM. That's why replacement dosing is front-loaded to the morning and diagnostic cortisol levels are drawn at 8 AM, not at random.
Cortisol acts through three time-scaled mechanisms once it crosses the (lipophilic) cell membrane and binds the glucocorticoid receptor: non-genomic effectswithin minutes (membrane signaling, rapid anti-inflammatory action), transrepressionover hours (blocks NF-κB and AP-1, the master switches for inflammatory gene transcription), and transactivationover days (GR dimer binds glucocorticoid response elements and turns on anti-inflammatory genes). This is why steroids "kick in" on different timelines depending on what you're treating, and why abrupt withdrawal after chronic dosing is dangerous: the negative feedback loop has been suppressed for so long the pituitary and adrenal need time to wake back up.
| Tissue | Effect of excess cortisol | Clinical result |
|---|---|---|
| Liver | ↑ Gluconeogenesis, ↓ peripheral glucose uptake | Hyperglycemia, "steroid diabetes" |
| Muscle | Protein catabolism, ↓ synthesis | Proximal myopathy, thin limbs |
| Adipose | Lipolysis in extremities, lipogenesis centrally | Central obesity, moon face, buffalo hump |
| Skin | ↓ Collagen synthesis | Thin skin, easy bruising, poor wound healing |
| Bone | Inhibits osteoblasts, stimulates osteoclasts, ↓ Ca²⁺ absorption | Osteoporosis, fracture risk |
| Immune system | ↓ Lymphocytes, ↓ eosinophils/basophils, ↑ mature neutrophils | Infection susceptibility, masked fever |
Every physical finding in Cushing syndrome is just this table happening on purpose, at high dose, for months.
Results from supraphysiologic glucocorticoid exposure, either exogenous (by far the most common cause overall, from steroid prescriptions) or endogenous overproduction. Endogenous disease is classified by whether ACTH is driving it.
| Category | % of endogenous cases | Mechanism |
|---|---|---|
| ACTH-dependent | ~80% | Pituitary adenoma overproducing ACTH (Cushing disease, 85% of this group) causing bilateral adrenal hyperplasia; or ectopic ACTH from a nonendocrine tumor (pancreas, thyroid, small-cell lung cancer) |
| ACTH-independent | ~20% | Adrenal adenoma or carcinoma secreting cortisol autonomously, low ACTH from feedback suppression |
Cushing disease is not the same as Cushing syndrome.Cushing syndrome is the umbrella term for any cause of hypercortisolism. Cushing disease specifically means a pituitary adenoma making excess ACTH. All Cushing disease is Cushing syndrome; not all Cushing syndrome is Cushing disease.
| Finding | Frequency |
|---|---|
| Central obesity, facial rounding (moon face) | 90% |
| Hypertension | 75-85% |
| Peripheral fat accumulation | 50% |
| Hirsutism (women) | 80% |
| Amenorrhea (women) | up to 75% |
| Psychiatric changes | up to 55% |
| Osteoporosis / bone pain | ~50-60%; ~20% progress to compression fracture |
Also expect proximal myopathy (can't rise from a chair without using the arms), abdominal striae (purple, from thin atrophic skin), easy bruising, facial plethora, glucose intolerance, and recurrent fungal skin infections. Buffalo hump(dorsocervical fat) is nonspecific; increased supraclavicular fat padsare more specific for Cushing syndrome.
Cushing syndrome carries real mortality, mostly from hypertension, diabetes, cardiovascular disease, and electrolyte abnormalities. Untreated, average survival is only about 4-5 years from diagnosis. This is not a cosmetic diagnosis.
Step 1, is cortisol actually elevated?Before anything else, take a careful history to rule out exogenous steroid exposure, including topical and inhaled products, since that's the most common cause of the Cushingoid picture and needs no further workup beyond stopping the drug. Confirm hypercortisolism with one or more of:
Step 2, what's the source?This is the harder question and needs plasma ACTH, adrenal/chest/abdominal CT, pituitary MRI, and in ambiguous cases the metyrapone stimulation test, CRH stimulation test, inferior petrosal sinus sampling, or adrenal vein catheterization. Low or undetectable ACTH points to an autonomous adrenal source (image the adrenals); normal-to-high ACTH points to a pituitary or ectopic source (image the pituitary, consider petrosal sinus sampling to localize further).
Goals:remove the source of hypercortisolism, limit morbidity/mortality, and return the patient to normal function while minimizing the pituitary or adrenal deficiencies that treatment itself can cause.
| Etiology | Procedure | Cure rate |
|---|---|---|
| Pituitary tumor (Cushing disease) | Transsphenoidal resection | ~98% |
| Adrenal tumor | Laparoscopic adrenalectomy | ~95% for adenomas; needs 6-12 months of postoperative steroid replacement |
| Ectopic ACTH-producing lung tumor | Thoracotomy / resection | 10-30% |
Pituitary radiotherapy is an option when surgery can't fully resect (tumor invading the dura or cavernous sinus): improves ~50% of patients within 3-5 years but raises the risk of hypopituitarism.
Drugs are second-line: used when the tumor can't be localized, the patient isn't a surgical candidate, disease persists or relapses after surgery, or as a bridge before surgery to control severe hypercortisolism. There is no preferred order between the drug classes below, because head-to-head trials don't exist in a disease this rare (well under 1 in 1,000 people).
Ketoconazoleinhibits 11β- and 17α-hydroxylase (and other CYP450 enzymes), lowering cortisol over several weeks. Also antiandrogenic, useful in women with hirsutism but causes gynecomastia and hypogonadism in men. Watch for reversible transaminase elevation (hepatotoxicity risk is why baseline LFTs plus weekly ALT monitoring is required), GI upset, and dermatologic reactions. Requires acidic gastric pH to absorb, so avoid PPIs and H2RAs, and it's a strong CYP3A4 inhibitor, so watch for interactions with macrolides, dihydropyridine CCBs, and simvastatin/atorvastatin.
Metyraponeinhibits 11β-hydroxylase, the final step of cortisol synthesis. Blocking that step shunts precursors toward androgen production (acne, hirsutism) and toward mineralocorticoid-active intermediates (11-deoxycorticosterone), causing hypokalemia and hypertension. The sudden drop in cortisol also triggers a compensatory ACTH surge. Because it blocks the last step rather than an early one, you must co-administer glucocorticoid replacement. It's the preferred agent in pregnancy (compassionate use).
Etomidatealso inhibits 11β-hydroxylase but is IV-only, reserved for acute severe hypercortisolemia or perioperative control. Bolus 0.03 mg/kg then continuous infusion 0.1-0.3 mg/kg/h with frequent cortisol monitoring to avoid overshooting into adrenal insufficiency. Osilodrostatis a newer oral 11β-hydroxylase inhibitor for Cushing disease when surgery isn't an option or hasn't cured it; correct hypokalemia/hypomagnesemia before starting and get a baseline ECG plus a 1-week follow-up ECG to watch for QTc prolongation.
Mitotaneis cytotoxic to the adrenal cortex, causing actual atrophy of the zona fasciculata and reticularis (the zona glomerulosa is relatively spared acutely but can be damaged with long-term use). Because it destroys tissue rather than just inhibiting an enzyme, effects build over weeks to months, and about a third of patients have sustained cortisol suppression that persists even after stopping the drug. Lifelong glucocorticoid replacement is often required, and roughly half of patients treated more than 6 months develop permanent hypoadrenalism. Consider hospitalization at initiation given significant neurologic and GI toxicity (nausea, diarrhea, lethargy, somnolence). It's primarily used in adrenal carcinoma, since the drug is taken up by both malignant and healthy adrenal tissue.
Pasireotideis a somatostatin analog that suppresses pituitary ACTH secretion at its source, the only ACTH-modulating drug with consistent evidence in Cushing disease (cyproheptadine, bromocriptine, and cabergoline are proposed but inconsistent). Approved when pituitary surgery isn't an option or hasn't cured the disease. Watch for hyperglycemia (its most clinically limiting effect), GI upset, cholelithiasis, and QT prolongation.
Mifepristoneis a glucocorticoid (and progesterone) receptor antagonist. It doesn't lower cortisol at all, it blocks cortisol's effect at the tissue level, so ACTH and cortisol levels actually rise on this drug (never use it to trend response). Approved specifically for Cushing syndrome patients with type 2 diabetes or glucose intolerance who aren't surgical candidates or failed surgery. Because it blocks the receptor systemically, adverse effects mimic hypoadrenalism: nausea, hypokalemia, and (from unopposed RAAS activation) hypertension and edema.
Excess aldosterone secretion, split by where the stimulus originates.
Muscle weakness, fatigue, paresthesias, headache, polydipsia, and nocturnal polyuria. Exam findings: hypertension (often resistant), and in severe cases tetany or paralysis from the electrolyte derangement. Labs show suppressed renin, elevated aldosterone, hypokalemia, hypomagnesemia, hypernatremia (>142 mEq/L), and elevated bicarbonate (>31 mEq/L) from the alkalosis that accompanies potassium wasting.
BP >150/100 mmHg on three separate days, treatment-resistant hypertension, diuretic-induced hypokalemia, hypertension with an adrenal incidentaloma, hypertension with sleep apnea, hypertension with early-onset family history (HTN or stroke <40 years old), or hypertension with a first-degree relative who has PA. This is a much bigger slice of "routine hypertension" than most people assume.
Screen with the plasma aldosterone concentration-to-renin activity ratio (ARR). A ratio >30 ng/dL per ng/(mL·h) combined with a plasma aldosterone concentration >15 ng/dL is suggestive of PA. A positive screen still needs confirmation, since false positives are common: oral sodium-loading test, saline infusion test, fludrocortisone suppression test, or captopril challenge test. A positive confirmatory test means aldosterone secretion is happening autonomously despite maneuvers that should suppress it, which is diagnostic.
An aldosterone-producing adenoma is surgically resected (laparoscopic), curing up to 72% of patients. Bilateral adrenal hyperplasia is treated medicallywith an aldosterone receptor antagonist, since there's no single tumor to remove.
| Agent | Notes |
|---|---|
| Spironolactone | Nonselective aldosterone antagonist. Most effective, but poor receptor selectivity causes GI upset, impotence, gynecomastia, and menstrual irregularities alongside the expected hyperkalemia risk. |
| Eplerenone | Selective aldosterone antagonist, much lower affinity for androgen/progesterone receptors, so far fewer sex-steroid side effects. Trade-off is it's a weaker antagonist milligram for milligram. |
| Amiloride | Potassium-sparing diuretic, not a true aldosterone antagonist. Less effective than spironolactone; patients often need an additional agent to control BP. |
Secondary hyperaldosteronismis treated by fixing the underlying trigger; spironolactone can bridge the gap until the cause is identified and corrected. Second-line add-ons for PA without dedicated outcome data include CCBs, ACE inhibitors, and diuretics like chlorthalidone.
Deficiency of adrenal hormones, and where the axis breaks changes what's missing.
| Primary (Addison disease) | Secondary | |
|---|---|---|
| Where it breaks | The adrenal cortex itself is destroyed | Pituitary (no ACTH) or hypothalamus (no CRH); or HPA suppression from exogenous steroid withdrawal, the most common cause overall |
| Main cause | Autoimmune destruction, 80-90% of cases in developed countries (antibodies against 21-hydroxylase); TB dominant in developing countries. Drug-induced: ketoconazole, or enzyme inducers that accelerate cortisol clearance (rifampin, phenytoin, carbamazepine, phenobarbital) | Abrupt discontinuation of chronic exogenous glucocorticoids (can occur up to a year after tapering off); also mirtazapine and progestins |
| Hormones lost | Cortisol, aldosterone, andandrogens | Cortisol only, aldosterone spared since RAAS still drives the zona glomerulosa independently of ACTH |
| ACTH level | High (400-2000 pg/mL) - no negative feedback, and no cortisol to suppress it | Low-normal (5-50 pg/mL) - the pituitary itself isn't making it |
| Typical age / sex | 20s-40s, women affected 2-3x more than men | Later in life, 50s-60s |
Hyperpigmentation is a primary-disease-only finding.Skin, gums, and inner cheeks darken because the sky-high ACTH is cleaved from the same precursor (POMC) as melanocyte-stimulating hormone, so ACTH itself stimulates melanin production. Secondary AI never has this, because ACTH is low, not high. Later in primary disease, that same process can paradoxically cause vitiligo from melanocyte destruction.
Symptoms build gradually and are notoriously vague, which is why this diagnosis gets missed for months: weakness, fatigue, weight loss, nausea, vomiting, abdominal pain, headache, depression, and postural dizziness. Salt cravingis specific to primary disease (loss of aldosterone drives real sodium wasting). Signs include postural hypotension, decreased body hair (loss of adrenal androgens, more noticeable in women), amenorrhea, and cold intolerance. As it progresses toward acute crisis: fever, vomiting, hypotension, and shock.
Always think of adrenal insufficiency when a patient is hypotensive, hyponatremic, and "just not doing well" without an obvious explanation. It's a classic mimic of other diagnoses because nothing about the presentation screams "endocrine."
Goals:control symptoms and hemodynamics, prevent adrenal crisis, and replace hormones in a way that mimics the body's own diurnal pattern as closely as possible, without over-replacing into iatrogenic Cushing syndrome.
Hydrocortisoneis the agent of choice because, like endogenous cortisol, it has both glucocorticoid andmineralocorticoid activity. Cortisone acetate is an equivalent alternative. Both are dosed 2-3 times daily to approximate the natural rhythm.
| Regimen | Typical dosing |
|---|---|
| Hydrocortisone | 15-25 mg/day total; ~2/3 of the dose in the morning, ~1/3 in the early afternoon (6-8 hours later). A common split: 20 mg AM, 10 mg early afternoon. |
| Cortisone acetate | 20-35 mg/day, equivalent dosing pattern |
| Prednisolone | 3-5 mg once daily - the pick when multidose adherence is a real concern |
The morning-heavy split isn't arbitrary, it's chasing the same curve the HPA axis makes on its own, peaking 6-8 AM and troughing near midnight. Never dose near bedtime: it disrupts sleep and works against the natural rhythm you're trying to imitate.
Fludrocortisone 0.05-0.2 mg once daily, needed in primary adrenal insufficiency to replace lost aldosterone and maintain volume status. Not needed in secondary disease, since the RAAS-driven zona glomerulosa is untouched. Patients on adequate fludrocortisone don't need to restrict dietary salt. Note that high-dose glucocorticoids have mineralocorticoid activity of their own, so sometimes dedicated mineralocorticoid replacement isn't necessary even in primary disease if the glucocorticoid dose is generous enough.
| Situation | Adjustment |
|---|---|
| Strenuous exercise | Extra 5-10 mg hydrocortisone (or equivalent) beforehand |
| Febrile illness, minor injury | Double the daily dose until recovery |
| Major trauma, surgery, critical illness | Up to 10x the usual daily dose may be needed; IV therapy if vomiting |
Women with persistent low mood, low energy, or low libido despite adequate cortisol/aldosterone replacement can be considered for adjunct DHEA 25-50 mg dailyafter checking a baseline level.
Monitoring maintenance therapyis mostly clinical: reassess every 6-8 weeks with body weight, postural blood pressures, subjective energy, and signs of over-replacement (development of Cushingoid features means the dose is too high). Reduction in excess skin pigmentation is a useful marker of adequate primary-disease treatment.
A true endocrine emergency: acute, severe cortisol deficiency causing volume depletion and hypotension that can progress to shock. The most common trigger is abrupt withdrawal of chronic glucocorticoid therapyor a failure to increase the dose during physical stress (infection, surgery, trauma) in someone with known or unrecognized adrenal insufficiency.
If adrenal crisis is suspected, give hydrocortisone immediately. Do not delay treatment to wait for a cosyntropin stimulation test result. Hemodynamic improvement within 1-2 hours of parenteral glucocorticoid is itself almost diagnostic.
Mineralocorticoid replacement is not required in the acute setting as long as the total daily hydrocortisone dose exceeds 50 mg, since that dose alone provides enough mineralocorticoid receptor activation. Add fludrocortisone 0.1 mg daily only once the hydrocortisone dose has been tapered down and hyperkalemia reappears.
All patients with known adrenal insufficiency should carry a medical alert card or wear a bracelet/necklace, and have access to an injectable hydrocortisone kit for emergencies or acute illness at home.
This shows up constantly outside this chapter too, anywhere a patient is on chronic systemic steroids for another condition. Stopping abruptly after prolonged use risks precipitating the exact adrenal crisis described above, because exogenous steroid has been suppressing the HPA axis the whole time, and the adrenal glands haven't had to make their own cortisol.
| Duration of therapy | AI risk | Approach |
|---|---|---|
| ≤3 weeks | Low | Can generally stop without a taper (unless the underlying disease needs a taper for its own reasons); testing for AI not routinely needed |
| >3 weeks | High, assume HPA suppression is present | Gradual taper required before full discontinuation |
How to taper:generally continue the same formulation the patient is already on, unless they're on a long-acting agent (dexamethasone), in which case switch to a short-acting one (hydrocortisone) to make the taper more controllable. Reduce the total daily dose by roughly 10-20% every 1-4 weeks; a full taper can take up to 6 months depending on cumulative exposure. The taper is individualized to the patient's comorbidities, dose, and duration of use.
Fever, myalgia, arthralgia, malaise, nausea/vomiting, hypotension, and flare of the underlying disease the steroid was treating. These mimic both adrenal crisis and disease relapse, which is exactly why the taper has to be gradual and monitored rather than guessed at.
| Cushing Syndrome - Pharmacotherapy | |||
|---|---|---|---|
| Drug | Initial | Usual range | Max |
| Metyrapone | 0.5-1 g/day divided q4-6h | 1-2 g/day divided q4-6h | 6 g/day |
| Ketoconazole | 200 mg once or twice daily | 200-1200 mg/day divided BID | 1600 mg/day divided QID |
| Mitotane | 0.5-1 g/day, ↑ by 0.5-1 g/day q1-4wk | 1-4 g/day with food | 12 g/day |
| Mifepristone | 300 mg daily, ↑ by 300 mg/day q2-4wk | 600-1200 mg/day | 1200 mg/day or 20 mg/kg/day |
| Cabergoline | 0.5 mg once weekly | 0.5-7 mg once weekly | 7 mg/week |
| Pasireotide | 0.6-0.9 mg SC twice daily | 0.3-0.9 mg BID | 1.8 mg/day |
| Etomidate (acute, IV only) | 0.03 mg/kg bolus | 0.1-0.3 mg/kg/h infusion | Titrate to cortisol level |
| Hyperaldosteronism | |||
| Spironolactone | 25 mg once daily | 25-400 mg/day, titrate q4-8wk | 400 mg/day |
| Eplerenone | 50 mg once daily | Titrate q4-8wk to 50 mg BID; up to 200-300 mg/day | ~300 mg/day |
| Amiloride | 5 mg twice daily | 20 mg/day divided BID | 30 mg/day |
| Adrenal Insufficiency - Maintenance | |||
| Hydrocortisone | 15-25 mg/day; ~2/3 AM, ~1/3 early afternoon | ||
| Cortisone acetate | 20-35 mg/day, same split | ||
| Prednisolone | 3-5 mg once daily | ||
| Fludrocortisone (primary AI only) | 0.05-0.2 mg once daily | ||
| DHEA (select women, adjunct) | 25-50 mg daily | ||
| Adrenal Crisis - Acute IV Therapy | |||
| Hydrocortisone IV | 100 mg rapid bolus, then 200 mg/24h (or 50 mg q6h) x24h, then 100 mg/24h x1 day, then oral taper | ||
| Fludrocortisone (only if needed after taper) | 0.1 mg daily | ||
| Dextrose 25% (for hypoglycemia) | 2-4 mL/kg, max single dose 25 g | ||
| Agent | Anti-inflammatory potency | Equivalent dose (mg) | Half-life (min) | Sodium-retaining potency |
|---|---|---|---|---|
| Cortisone | 0.8 | 25 | 30 | 2 |
| Hydrocortisone | 1 | 20 | 90 | 2 |
| Prednisone | 3.5 | 5 | 60 | 1 |
| Prednisolone | 4 | 5 | 200 | 1 |
| Triamcinolone | 5 | 4 | 300 | 0 |
| Methylprednisolone | 5 | 4 | 180 | 0 |
| Betamethasone | 25 | 0.6 | 100-300 | 0 |
| Dexamethasone | 30 | 0.75 | 100-300 | 0 |
Sodium-retaining potency drops to zero as anti-inflammatory potency climbs. That's why dexamethasone and betamethasone are useless as mineralocorticoid replacement (never use them for Addison disease), while hydrocortisone and cortisone are the only two agents with meaningful dual activity, which is exactly why they're the maintenance and crisis drugs of choice.
| Parameter | When | Watching for |
|---|---|---|
| 24-hr UFC / serum cortisol | Throughout Cushing pharmacotherapy (all agents except mifepristone) | Adequate suppression without overshooting into adrenal insufficiency |
| LFTs / ALT | Baseline, then weekly on ketoconazole | Hepatotoxicity |
| ECG / QTc | Baseline and 1 week after starting osilodrostat or pasireotide | QT prolongation |
| Potassium, magnesium | Before and during osilodrostat; regularly on any aldosterone antagonist or amiloride | Hypokalemia (from steroidogenesis inhibitors shunting toward mineralocorticoid precursors) or hyperkalemia (from aldosterone antagonists) |
| Blood pressure, weight, energy level | Every 6-8 weeks on AI maintenance therapy | Under- or over-replacement |
| Skin pigmentation | Each visit, primary AI | Improvement = adequate glucocorticoid replacement |
| Signs of Cushingoid change | Each visit, AI maintenance | Over-replacement |
| Electrolytes (Na⁺, K⁺) | Regularly in primary AI and in hyperaldosteronism treatment | Volume status and mineralocorticoid balance |
| Bone density | Periodically with chronic glucocorticoid exposure (Cushing or exogenous steroid use) | Steroid-induced osteoporosis |