In the distal nephron and collecting duct, aldosterone binds the mineralocorticoid receptor and drives transcription of epithelial sodium channel (ENaC) subunits and the sodium-potassium ATPase. The resulting increase in apical ENaC expression drives sodium reabsorption from the tubular lumen into the interstitium, with potassium secreted as the counterion — producing sodium and water retention (raising blood pressure) and potassium loss (hypokalemia at pharmacological aldosterone concentrations). Aldosterone secretion from the zona glomerulosa is regulated by angiotensin II (acting through AT1 receptors) and directly by serum potassium, which depolarizes glomerulosa cells and increases aldosterone synthase (CYP11B2) activity — not by adrenocorticotropic hormone.

Cortisol binds the mineralocorticoid receptor with affinity equal to or greater than aldosterone. Under physiological conditions, the enzyme 11-beta-hydroxysteroid dehydrogenase type 2, co-expressed with the mineralocorticoid receptor in aldosterone-sensitive distal nephron cells, rapidly converts cortisol to inactive cortisone before it can activate the mineralocorticoid receptor. This enzyme creates a protected compartment in which aldosterone — not a substrate for 11-beta-hydroxysteroid dehydrogenase type 2 — can selectively activate the mineralocorticoid receptor despite circulating cortisol concentrations 100- to 1000-fold higher. When this gating fails, cortisol activates renal mineralocorticoid receptors and produces apparent mineralocorticoid excess: hypertension, hypokalemia, and suppressed renin/aldosterone. Acquired apparent mineralocorticoid excess occurs with licorice ingestion (glycyrrhizic acid inhibits 11-beta-hydroxysteroid dehydrogenase type 2) and with high-dose glucocorticoid therapy saturating the enzyme.

In the heart, mineralocorticoid receptor activation promotes cardiac fibrosis through collagen synthesis upregulation and macrophage-driven inflammation. In the vasculature, it impairs endothelial function by reducing nitric oxide bioavailability. In podocytes and mesangial cells, mineralocorticoid receptor activation drives glomerular inflammation and proteinuria, contributing to progression of diabetic kidney disease independently of blood pressure. These non-epithelial effects provide the pharmacological rationale for mineralocorticoid receptor antagonists as cardiorenal protective agents in heart failure and diabetic kidney disease.

Fludrocortisone acetate is a synthetic fluorinated mineralocorticoid with approximately 125-fold greater mineralocorticoid potency than hydrocortisone and the only oral mineralocorticoid replacement agent in clinical use. The standard replacement dose is 50 to 200 micrograms per day, adjusted to achieve mid-normal plasma renin activity, normal serum sodium and potassium, and absence of postural hypotension or over-replacement signs (edema, hypertension). Fludrocortisone is also used at 100 to 300 micrograms per day for orthostatic hypotension in autonomic failure and postural orthostatic tachycardia syndrome. Adverse effects are predictable from its mechanism: sodium retention, hypertension, edema, and hypokalemia.

Primary adrenal insufficiency (most commonly autoimmune adrenalitis — Addison disease) destroys all three cortical zones, producing combined glucocorticoid and mineralocorticoid deficiency. The hallmark is elevated plasma adrenocorticotropic hormone (because cortisol deficiency removes negative feedback, driving adrenocorticotropic hormone hypersecretion), which co-secretes melanocyte-stimulating hormone causing hyperpigmentation. Biochemical features include hyperkalemia and hyponatremia from mineralocorticoid deficiency.

Secondary adrenal insufficiency results from pituitary adrenocorticotropic hormone deficiency; the zona glomerulosa retains renin-angiotensin-aldosterone system-driven aldosterone production, so mineralocorticoid deficiency and hyperkalemia do not occur. Adrenocorticotropic hormone is low or inappropriately normal. No hyperpigmentation. The most common cause in clinical practice is glucocorticoid-induced hypothalamic-pituitary-adrenal axis suppression.

Hydrocortisone is preferred for replacement in both primary and secondary adrenal insufficiency: identical to endogenous cortisol, short plasma half-life of approximately 1.5 hours, no prolonged hypothalamic-pituitary-adrenal suppression. The target dose is 15 to 25 mg per day in divided doses mimicking the physiological diurnal rhythm: largest dose (typically 10 mg) on waking, smaller doses (5 mg each) at mid-morning and early afternoon but not at bedtime. Prednisolone 3 to 5 mg or dexamethasone 0.25 to 0.5 mg once daily are alternatives for compliance issues but cannot replicate the physiological diurnal pattern.

Fludrocortisone 50 to 200 micrograms per day is mandatory in primary adrenal insufficiency. Adequacy is monitored by plasma renin activity (target: mid-normal range), serum electrolytes, and lying-to-standing blood pressure. Under-replacement causes sodium wasting, hyperkalemia, and postural hypotension; over-replacement causes hypertension, edema, and hypokalemia.

Adrenal crisis requires immediate treatment: hydrocortisone 100 mg intravenous bolus, then 200 mg per day by continuous infusion or 50 mg intravenous every 6 hours, plus aggressive normal saline resuscitation. Draw random cortisol and adrenocorticotropic hormone before the dose when logistically possible, but never delay treatment for laboratory results. Hemodynamic improvement within 30 to 60 minutes of hydrocortisone confirms the diagnosis. All patients must receive explicit sick-day rules: double or triple oral hydrocortisone for febrile illness; use intramuscular hydrocortisone 100 mg if unable to take oral medication.

CYP21A2 deficiency impairs conversion of 17-hydroxyprogesterone to 11-deoxycortisol (glucocorticoid pathway) and progesterone to deoxycorticosterone (mineralocorticoid pathway). Cortisol deficiency removes negative feedback, driving adrenocorticotropic hormone hypersecretion and bilateral adrenocortical hyperplasia. The adrenocorticotropic hormone excess drives accumulation of substrates proximal to the block — principally 17-hydroxyprogesterone — which are shunted via CYP17A1 into androgen synthesis, producing dehydroepiandrosterone and androstenedione excess. The salt-wasting form (approximately 75% of classic cases, less than 1% residual CYP21A2 activity) produces combined cortisol and aldosterone deficiency with neonatal adrenal crisis risk. The simple virilizing form (approximately 25%) maintains enough aldosterone production to prevent salt wasting but not enough cortisol to suppress adrenocorticotropic hormone.

In children, hydrocortisone 10 to 15 mg per square meter per day in three divided doses is the agent of choice. The short half-life minimizes suppression of the nocturnal growth hormone surge and linear bone growth compared with longer-acting synthetic glucocorticoids. Divided dosing is essential: a single daily dose would leave prolonged periods of inadequate adrenocorticotropic hormone suppression during which androgens accumulate. The pharmacological challenge is that doses sufficient to normalize androgen precursors often approach doses causing growth impairment — making monitoring of both androgen control and growth velocity essential.

In adults, prednisolone 2 to 4 mg per day in one or two divided doses provides more sustained nocturnal adrenocorticotropic hormone suppression than hydrocortisone. Dexamethasone 0.25 to 0.5 mg at bedtime has been used to suppress the nocturnal adrenocorticotropic hormone surge but carries higher risk of metabolic adverse effects from its potency and long half-life; it should be reserved for patients inadequately controlled on hydrocortisone or prednisolone.

Metyrapone inhibits CYP11B1 (11-beta-hydroxylase), blocking the final conversion of 11-deoxycortisol to cortisol. It rapidly reduces cortisol production within hours and is one of the fastest-acting agents for controlling severe hypercortisolism. Precursor accumulation proximal to the block (11-deoxycortisol and deoxycorticosterone) provides biochemical confirmation of drug effect and drives the adverse effects: deoxycorticosterone has mineralocorticoid activity, causing sodium retention and hypertension; adrenocorticotropic hormone-stimulated precursors shunted to androgen synthesis cause acne, hirsutism, and menstrual irregularities in women. Used orally for short-term control before surgery, perioperative management, and long-term therapy in surgical non-candidates.

Osilodrostat is a potent, selective CYP11B1 inhibitor approved in 2020 for Cushing disease not amenable to surgery or with persistent disease after surgery. It has higher potency and selectivity than metyrapone, with modest CYP11B2 (aldosterone synthase) inhibition at higher doses that may partially offset mineralocorticoid precursor accumulation. Phase 3 trials demonstrated urinary free cortisol normalization in approximately 50 to 70% of patients. Adverse effects parallel metyrapone: adrenal insufficiency (dose-dependent), androgen excess, and potential hypertension from mineralocorticoid precursors. Twice-daily oral dosing.

Ketoconazole inhibits multiple steroidogenic enzymes (CYP17A1, CYP11A1, CYP11B1), producing broad steroidogenesis suppression. Significant hepatotoxicity risk (rare acute liver failure) requires baseline liver function tests and monthly monitoring; not FDA-approved for Cushing syndrome in the United States but widely used off-label and approved in Europe. Potent CYP3A4 inhibitor — multiple drug interactions. Used in countries where osilodrostat or metyrapone are unavailable.

Etomidate is the only parenteral steroidogenesis inhibitor available. At sub-anesthetic intravenous infusion doses (0.03 to 0.1 mg per kilogram per hour), it inhibits CYP11B1 and allows rapid, titratable cortisol suppression in critically ill patients with severe Cushing syndrome unable to take oral medications. Used in intensive care unit settings for acute severe hypercortisolism from ectopic adrenocorticotropic hormone syndrome awaiting surgery.

Mifepristone is a competitive glucocorticoid receptor and progesterone receptor antagonist approved for hyperglycemia associated with endogenous Cushing syndrome in adults with type 2 diabetes or impaired glucose tolerance not candidates for surgery. Because it blocks glucocorticoid receptor negative feedback at the pituitary and hypothalamus, cortisol and adrenocorticotropic hormone levels rise substantially during therapy, making urinary free cortisol and late-night salivary cortisol unreliable monitors — clinical and glycemic parameters are the efficacy endpoints. Hypokalemia is common (cortisol activates mineralocorticoid receptor when glucocorticoid receptor is blocked). Progesterone receptor antagonism causes endometrial thickening and vaginal bleeding in premenopausal women.

Pasireotide is a somatostatin receptor analog preferentially binding somatostatin receptor subtypes 1, 2, 3, and 5 — including subtype 5 expressed at high density on corticotroph adenoma cells. It directly suppresses adrenocorticotropic hormone secretion from the adenoma, reducing cortisol production. Phase 3 trial demonstrated urinary free cortisol normalization in approximately 25 to 30% of patients with Cushing disease. Major limitation: hyperglycemia in approximately 70% of patients (somatostatin receptor activation in pancreatic islets suppresses both insulin and incretin secretion). Available as subcutaneous twice-daily (short-acting) or intramuscular monthly (long-acting release) formulation.

Mitotane is an adrenocorticolytic agent (derivative of the insecticide DDT) used primarily for adrenocortical carcinoma. It produces selective cytotoxic damage to adrenocortical mitochondria and inhibits multiple steroidogenic enzymes, causing progressive adrenocortical destruction with dual antitumor and cortisol-lowering effects. Highly lipophilic; half-life 18 to 159 days from adipose accumulation — months to reach steady-state, and prolonged adrenal insufficiency persists long after discontinuation. All patients require glucocorticoid replacement at two to three times normal replacement doses (mitotane induces CYP3A4, accelerating glucocorticoid metabolism, and increases corticosteroid-binding globulin, reducing free cortisol). Therapeutic drug monitoring (target plasma level 14 to 20 mg per liter): below 14 mg per liter reduces antitumor efficacy; above 20 mg per liter causes severe neurological toxicity (cerebellar ataxia, confusion, peripheral neuropathy).