Aldosterone, the principal endogenous mineralocorticoid, acts through the MR (mineralocorticoid receptor) to regulate sodium and potassium homeostasis in the renal collecting duct. However, MR is expressed not only in epithelial tissues but also in the heart, vasculature, brain, and adipose tissue, and its activation in these non-epithelial sites drives adverse remodeling processes that are independent of its renal sodium-retaining effects. This dual biology explains why MR antagonists have proven beneficial in heart failure and kidney disease beyond their diuretic and antihypertensive effects.
The MR (mineralocorticoid receptor) belongs to the nuclear receptor superfamily and shares approximately 57% amino acid identity with the GR (glucocorticoid receptor) in its ligand-binding domain, a homology with important pharmacological consequences. In the distal nephron and collecting duct, aldosterone binds MR and triggers the classical genomic signaling sequence: MR-ligand complex translocates to the nucleus, binds mineralocorticoid response elements in target gene promoters, and drives transcription of ENaC (epithelial sodium channel) subunits (alpha, beta, and gamma) and the Na/K-ATPase (sodium-potassium adenosine triphosphatase). The resulting increase in apical ENaC expression and basolateral Na/K-ATPase activity creates an electrochemical gradient that drives sodium reabsorption from tubular lumen into the interstitium, with potassium secreted into the lumen as the counterion. This sodium reabsorption is accompanied by water retention, expanding extracellular fluid volume and raising blood pressure, while the potassium secretion produces hypokalemia at pharmacological aldosterone concentrations.1 Non-genomic aldosterone effects, operating within seconds to minutes through membrane-associated MR signaling, include activation of MAPK (mitogen-activated protein kinase) and PKC (protein kinase C) pathways that modulate ion channel trafficking and contribute to the rapid renal sodium-retaining response before transcriptional changes occur.
A critical pharmacological principle governing MR pharmacology is that cortisol, the principal glucocorticoid, binds MR with affinity equal to or greater than that of aldosterone. Under physiological conditions, this potentially promiscuous activation of MR by cortisol is prevented by the enzyme 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2), which is co-expressed with MR in aldosterone-sensitive distal nephron cells and rapidly converts cortisol to the inactive metabolite cortisone before it can activate MR. This enzyme creates a protected compartment in which aldosterone, which is not a substrate for 11beta-HSD2, can selectively activate MR despite circulating cortisol concentrations that are 100- to 1000-fold higher than aldosterone. When 11beta-HSD2 is overwhelmed or inhibited, cortisol inappropriately activates MR, producing the syndrome of apparent mineralocorticoid excess. Pharmacologically, this mechanism explains the sodium-retaining adverse effects of glucocorticoids at high doses discussed in Module 3: high pharmacological glucocorticoid concentrations saturate 11beta-HSD2, allowing cortisol overflow to activate renal MR and produce sodium retention and hypertension.2
MR expression in non-epithelial tissues, particularly the heart, vascular smooth muscle, endothelium, and kidney mesangial cells, mediates adverse remodeling effects that are independent of the sodium-retaining renal action. In the heart, aldosterone-MR activation promotes cardiac fibrosis through upregulation of collagen synthesis, inflammation via macrophage MR activation, and oxidative stress through NADPH (nicotinamide adenine dinucleotide phosphate)-oxidase induction. In the vasculature, MR activation impairs endothelial function by reducing nitric oxide (NO) bioavailability and promoting inflammation, accelerating vascular stiffness and arteriosclerosis. In the kidney beyond the collecting duct, MR activation in podocytes and mesangial cells promotes glomerular inflammation and proteinuria, contributing to progression of DKD (diabetic kidney disease) and other proteinuric nephropathies independently of blood pressure effects. The recognition that non-epithelial MR activation drives end-organ damage in the heart and kidney has provided the pharmacological rationale for MR antagonists as cardiorenal protective agents in conditions where aldosterone and cortisol chronically over-activate MR in these tissues.3
Apparent mineralocorticoid excess (AME) is a syndrome of hypertension, hypokalemia, and suppressed plasma renin and aldosterone caused by inability of 11beta-HSD2 to protect renal MR from cortisol activation. Genetic AME results from inactivating mutations in the HSD11B2 gene encoding 11beta-HSD2. Acquired AME occurs with licorice and carbenoxolone ingestion: glycyrrhizic acid in licorice competitively inhibits 11beta-HSD2, allowing cortisol to activate MR. High-dose glucocorticoid therapy produces a partial acquired AME when cortisol (or its synthetic analogs) overwhelms 11beta-HSD2 capacity. Treatment of genetic AME uses MR antagonists; recognition of the acquired forms requires medication and dietary history.
Aldosterone secretion from the zona glomerulosa is regulated primarily by the RAAS (renin-angiotensin-aldosterone system) and by serum potassium, not by ACTH (adrenocorticotropic hormone), as discussed in Module 1. Renin, released from juxtaglomerular cells in response to reduced renal perfusion pressure, converts angiotensinogen to angiotensin I, which is cleaved by ACE (angiotensin-converting enzyme) to angiotensin II. Angiotensin II binds AT1 (angiotensin type 1) receptors on zona glomerulosa cells, activating calcium-dependent signaling that drives CYP11B2 (aldosterone synthase) expression and aldosterone output. Elevated serum potassium directly depolarizes zona glomerulosa cells through a calcium-dependent mechanism, independently increasing CYP11B2 activity. This potassium sensitivity makes aldosterone a direct regulator of potassium homeostasis, with the resulting kaliuretic effect serving as a classical negative feedback loop: aldosterone secretion is driven by hyperkalemia and suppressed as potassium falls toward normal.1
Drugs acting at the MR (mineralocorticoid receptor) span a pharmacological range from potent agonists (fludrocortisone) to competitive antagonists (spironolactone, eplerenone) to selective non-steroidal antagonists (finerenone). Their clinical applications reflect distinct MR biology in different tissues: fludrocortisone replaces deficient aldosterone in adrenal insufficiency, while MR antagonists exploit the cardiorenal protective effects of blocking non-epithelial MR in heart failure and kidney disease.
Fludrocortisone acetate is a synthetic fluorinated mineralocorticoid with approximately 125-fold greater mineralocorticoid potency than hydrocortisone and approximately 10-fold greater glucocorticoid potency than hydrocortisone, though it is used clinically at doses where its glucocorticoid activity is negligible. It is the only oral mineralocorticoid replacement agent in clinical use and is essential for the management of primary adrenal insufficiency (AI), in which aldosterone deficiency causes sodium wasting, hypovolemia, hyperkalemia, and hypotension. The standard replacement dose is 50 to 200 micrograms per day orally, adjusted to achieve a plasma renin activity in the mid-normal range, normal serum sodium and potassium, absence of postural hypotension, and absence of edema or hypertension that would suggest over-replacement. Fludrocortisone is also used at doses of 100 to 300 micrograms per day for orthostatic hypotension in autonomic failure, POTS (postural orthostatic tachycardia syndrome), and the salt-wasting forms of CAH (congenital adrenal hyperplasia). Its principal adverse effects at replacement doses are sodium retention, hypertension, edema, and hypokalemia, all predictable from its mineralocorticoid mechanism, and are managed by dose reduction and sodium-potassium monitoring.4
Spironolactone is a steroidal MR antagonist with a complex pharmacology that reflects its structural similarity to steroid hormones. As a competitive MR antagonist, it blocks both aldosterone and cortisol from binding MR, reducing ENaC expression and Na/K-ATPase activity and producing natriuresis with potassium retention (potassium-sparing diuresis). Its major off-target effects arise from cross-reactivity with other steroid hormone receptors: spironolactone antagonizes the androgen receptor (AR), producing gynecomastia, decreased libido, and erectile dysfunction in men and menstrual irregularities in women at doses greater than 50 to 100 mg per day; it also has weak progestogenic activity at the progesterone receptor. Spironolactone's active metabolite canrenone contributes substantially to its pharmacological effect, with a combined half-life for the parent and active metabolites of approximately 14 to 20 hours. Clinical indications include heart failure (reduced ejection fraction, NYHA (New York Heart Association) class II–IV, with mortality benefit demonstrated in the RALES (Randomized Aldactone Evaluation Study) trial), primary hyperaldosteronism (medical management pending surgery, or long-term for patients who are not surgical candidates), resistant hypertension (as a fourth-line agent), hepatic cirrhosis with ascites (where aldosterone-mediated sodium retention is a major driver of ascites formation), and acne/hirsutism in women (exploiting its anti-androgenic activity).3
Eplerenone is a selective steroidal MR antagonist that was developed specifically to reduce the off-target receptor interactions of spironolactone. Unlike spironolactone, eplerenone has negligible affinity for the androgen receptor, progesterone receptor, and glucocorticoid receptor, producing the same MR blockade without gynecomastia, sexual side effects, or menstrual irregularities. The selectivity comes at a cost in potency: eplerenone is approximately 60-fold less potent than spironolactone at MR, requiring doses of 25 to 50 mg twice daily compared with spironolactone 25 to 50 mg once daily for equivalent MR blockade, with correspondingly higher cost. The EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial established eplerenone mortality benefit in post-myocardial infarction patients with left ventricular dysfunction and heart failure or diabetes, and the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial demonstrated mortality and hospitalization benefit in chronic heart failure with reduced ejection fraction (HFrEF). Eplerenone is preferred over spironolactone in men and in patients where anti-androgenic effects are undesirable.5
Finerenone is a non-steroidal MR antagonist with a distinctly different binding mode from spironolactone and eplerenone. Its non-steroidal scaffold allows a distinct interaction with the MR ligand-binding pocket that produces MR antagonism with high selectivity (no AR [androgen receptor], PR [progesterone receptor], or GR [glucocorticoid receptor] cross-reactivity), balanced tissue distribution between the kidney and the heart (unlike spironolactone and eplerenone, which preferentially distribute to the kidney), and a shorter half-life of approximately 2 to 3 hours that may reduce the risk of hyperkalemia compared with longer-acting steroidal MR antagonists. The FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Outcomes in Diabetic Kidney Disease) trial demonstrated that finerenone reduced the composite cardiorenal endpoint in patients with type 2 diabetes and DKD (diabetic kidney disease) with elevated albuminuria despite maximum tolerated RAAS (renin-angiotensin-aldosterone system) blockade, and the FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trial extended these findings to patients with earlier-stage DKD.
Finerenone is the first MR antagonist approved specifically for the cardiorenal indication in DKD, establishing MR antagonism alongside SGLT-2 (sodium-glucose cotransporter-2) inhibitors as a cornerstone of cardiorenal protection in this population.6 The principal monitoring requirement for all MR antagonists is serum potassium: hyperkalemia is the major dose-limiting adverse effect, particularly in patients with eGFR (estimated glomerular filtration rate) below 60 mL per minute per 1.73 m2 or those on concurrent RAAS blockade.
Spironolactone: Steroidal. Potent MR antagonist. Off-target AR antagonism (gynecomastia, sexual effects). Active metabolite canrenone. Indications: HFrEF (RALES), primary hyperaldosteronism, ascites, resistant hypertension, acne/hirsutism (women). Once daily dosing.
Eplerenone: Steroidal. Selective MR antagonist (no AR/PR/GR cross-reactivity). 60-fold less potent than spironolactone at MR. No gynecomastia or sexual effects. Indications: HFrEF (EMPHASIS-HF), post-MI LV dysfunction (EPHESUS). Twice daily dosing. Higher cost.
Finerenone: Non-steroidal. High MR selectivity. Balanced heart/kidney distribution. Shorter half-life (2–3 h). No gynecomastia. Indication: DKD with type 2 diabetes + elevated albuminuria on maximum RAAS blockade (FIDELIO-DKD, FIGARO-DKD). Monitor potassium closely especially with low eGFR.
Adrenal insufficiency requires lifelong hormone replacement that mimics the physiological diurnal cortisol pattern as closely as possible while ensuring adequate stress-response reserve. The pharmacological distinction between primary and secondary AI (adrenal insufficiency) has direct implications for replacement strategy: only primary AI requires mineralocorticoid replacement, because the zona glomerulosa remains responsive to the RAAS (renin-angiotensin-aldosterone system) in secondary AI where the pituitary rather than the adrenal gland is the site of failure.
Primary AI (adrenal insufficiency), the most common cause of which in high-income countries is autoimmune adrenalitis (Addison disease), is characterized by destruction of all three cortical zones, producing combined glucocorticoid and mineralocorticoid deficiency alongside loss of adrenal androgen production. Secondary AI results from pituitary ACTH (adrenocorticotropic hormone) deficiency (from pituitary tumor, surgery, radiation, or infiltrative disease) or tertiary AI from hypothalamic CRH (corticotropin-releasing hormone) deficiency, both of which produce glucocorticoid deficiency alone because the zona glomerulosa retains its RAAS-driven aldosterone production. The biochemical hallmarks that distinguish primary from secondary AI are the plasma ACTH level (elevated in primary AI because loss of cortisol negative feedback drives ACTH hypersecretion; low or inappropriately normal in secondary AI) and the presence or absence of features of mineralocorticoid deficiency: hyperkalemia, hyponatremia, and postural hypotension occur in primary AI but not in secondary AI.7
Diagnostic testing for AI uses dynamic stimulation tests that assess adrenocortical reserve rather than basal cortisol alone, which may be normal in mild or partial insufficiency. The LDSST (low-dose short Synacthen test), using 1 microgram of synthetic ACTH (cosyntropin, tetracosactide) administered intravenously, is the most widely used diagnostic test in current practice. A peak serum cortisol below 500 nmol per liter (approximately 18 micrograms per deciliter) at 30 minutes post-injection indicates adrenal insufficiency and has high sensitivity for both primary and secondary AI when used with appropriate population-specific cutoffs. In patients with suspected secondary or tertiary AI of recent onset (pituitary surgery within the preceding 4 to 8 weeks), the LDSST may give false-negative results because the adrenal gland has not yet atrophied and still responds acutely to exogenous ACTH; the ITT (insulin tolerance test), which measures the cortisol response to insulin-induced hypoglycemia and thereby tests the entire HPA (hypothalamic-pituitary-adrenal) axis including the hypothalamic and pituitary components, is preferred in this context and is the gold standard for assessing growth hormone reserve concurrently.7
Hydrocortisone is the preferred glucocorticoid for replacement in both primary and secondary AI because its pharmacokinetic profile most closely approximates endogenous cortisol: identical molecule, relatively short half-life of approximately 1.5 hours, and absence of the prolonged HPA suppression associated with more potent synthetic glucocorticoids. The target replacement dose is 15 to 25 mg per day in adults, given in divided doses that mimic the physiological diurnal cortisol rhythm: the largest dose (typically 10 mg) is taken on waking to match the early morning cortisol peak, a smaller second dose (5 mg) is taken at early afternoon, and a third dose (5 mg, if used) is taken in the late afternoon but not at bedtime to avoid suppressing the early morning cortisol surge. Modified-release hydrocortisone formulations designed to deliver an extended, peak-and-trough release profile more closely approximating the physiological curve are available in some countries and reduce the need for multiple daily doses.8 Prednisolone 3 to 5 mg once daily in the morning and dexamethasone 0.25 to 0.5 mg once daily are alternatives for patients with compliance difficulties, but their longer half-lives make precise diurnal rhythm replication impossible and increase the risk of overnight HPA suppression.
Mineralocorticoid replacement with fludrocortisone 50 to 200 micrograms per day orally is mandatory in primary AI but not required in secondary or tertiary AI. Dose adequacy is monitored by measuring plasma renin activity (target: mid-normal range for the assay used), serum sodium and potassium (both should be normal), and lying-to-standing blood pressure (postural drop greater than 20 mmHg systolic or 10 mmHg diastolic suggests under-replacement). Under-replacement produces sodium wasting, volume depletion, hyperkalemia, and persistent postural symptoms despite adequate glucocorticoid replacement; over-replacement produces sodium retention, hypertension, edema, and hypokalemia. Fludrocortisone requirements may increase in hot weather or with vigorous physical activity due to sodium losses in sweat, requiring temporary dose increases. DHEA (dehydroepiandrosterone) replacement at 25 to 50 mg per day orally is sometimes considered in women with primary AI and low DHEA-sulfate levels who have persistent fatigue, impaired well-being, and reduced libido despite adequate glucocorticoid and mineralocorticoid replacement, though the evidence base for DHEA replacement is limited compared with glucocorticoid and mineralocorticoid therapy.4
Adrenal crisis is a life-threatening emergency characterized by acute hemodynamic collapse in the context of AI, precipitated most commonly by intercurrent illness (infection), surgical stress, vomiting or diarrhea preventing oral steroid absorption, or omission of steroid doses. Clinical presentation includes severe hypotension and tachycardia refractory to IV (intravenous) fluids and vasopressors, hyponatremia (from ADH [antidiuretic hormone] excess and sodium wasting in primary AI), hyperkalemia (primary AI only), hypoglycemia (from cortisol-dependent gluconeogenesis impairment), fever, and altered consciousness. Emergency management requires immediate IV hydrocortisone 100 mg as a bolus, followed by hydrocortisone 200 mg per day by continuous IV infusion or 50 mg IV every 6 hours, along with aggressive IV normal saline resuscitation to replace the sodium and volume deficit. A random cortisol and ACTH sample should be drawn before the hydrocortisone bolus when logistically possible, but treatment must never be delayed to await laboratory results. Response to hydrocortisone is typically rapid: hemodynamic improvement within 30 to 60 minutes supports the diagnosis.7 Sick-day rules for all AI patients must be reinforced at every clinical contact: double or triple the daily hydrocortisone dose for any febrile illness, and use IM (intramuscular) or IV hydrocortisone 100 mg if unable to take oral medication.
Primary AI: replace glucocorticoid (hydrocortisone 15–25 mg/day divided) AND mineralocorticoid (fludrocortisone 50–200 micrograms/day). Elevated ACTH causes hyperpigmentation (MSH co-secretion). Crisis risk is higher because both glucocorticoid and mineralocorticoid deficiency contribute to hemodynamic instability. Secondary AI: replace glucocorticoid only. No mineralocorticoid required (zona glomerulosa intact). No hyperpigmentation (ACTH low). Crisis is less severe and more directly related to glucocorticoid deficiency than primary AI. Both: sick-day rules, medical alert identification, and emergency hydrocortisone kit with written instructions are mandatory for all patients.
CAH (congenital adrenal hyperplasia) due to 21-hydroxylase deficiency is the most common adrenal enzyme disorder and represents a pharmacological challenge of balancing adequate ACTH (adrenocorticotropic hormone) suppression to limit androgen excess against the adverse effects of the doses required to achieve that suppression. The therapeutic goal is not normalization of cortisol but suppression of the excess androgenic precursors that accumulate proximal to the enzymatic block, using the smallest glucocorticoid dose sufficient to prevent virilization and maintain normal growth and metabolic parameters.
CYP21A2 (cytochrome P450 21A2) encodes 21-hydroxylase, the enzyme that converts 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol in the glucocorticoid pathway and progesterone to deoxycorticosterone in the mineralocorticoid pathway. In classic 21-hydroxylase deficiency, impaired cortisol and aldosterone synthesis reduces negative feedback on the HPA (hypothalamic-pituitary-adrenal) axis, driving compensatory ACTH (adrenocorticotropic hormone) hypersecretion and bilateral adrenocortical hyperplasia. The excess ACTH drives the accumulation of precursors proximal to the enzymatic block, particularly 17-OHP and progesterone, which are shunted into the intact adrenal androgen synthesis pathway through CYP17A1 (cytochrome P450 17A1) to produce excess DHEA (dehydroepiandrosterone) and androstenedione. The salt-wasting form (approximately 75% of classic cases) has less than 1% of normal CYP21A2 activity, producing combined cortisol and aldosterone deficiency with risk of neonatal adrenal crisis from salt wasting; the simple virilizing form (approximately 25%) has sufficient residual CYP21A2 to maintain aldosterone production but not cortisol, producing virilization without salt wasting. Non-classic CAH represents partial CYP21A2 deficiency with elevated 17-OHP and mildly elevated androgens presenting in childhood or adulthood as premature pubarche, acne, hirsutism, or menstrual irregularities without adrenal crisis risk.9
The pharmacological goal of glucocorticoid therapy in CAH is to provide sufficient exogenous glucocorticoid to suppress ACTH output from the pituitary, reducing the androgenic precursor overproduction without causing glucocorticoid excess that would impair linear growth in children or produce Cushingoid adverse effects in adults. In children, hydrocortisone is the agent of choice at doses of 10 to 15 mg per square meter per day in two or three divided doses, because its short half-life reduces the suppressive effect on the nocturnal growth hormone surge and on linear bone growth compared with longer-acting synthetic glucocorticoids. Hydrocortisone must be given in divided doses, typically three times daily in children, to maintain sufficient adrenal androgen suppression throughout the 24-hour period; a once-daily dose would leave a prolonged period of inadequate suppression between doses when ACTH rises and androgen precursors accumulate. The pharmacological challenge is that the dose required to suppress androgen precursors to normal is often at or above doses that cause measurable growth impairment, making monitoring of both androgen control and linear growth velocity essential throughout childhood.9
In adults with CAH, prednisolone 2 to 4 mg per day in one or two divided doses is an alternative to hydrocortisone that provides more sustained ACTH suppression over 24 hours, exploiting its longer half-life to reduce the nocturnal ACTH rebound that drives early morning androgen precursor accumulation. Dexamethasone 0.25 to 0.5 mg at bedtime has been used in adults specifically to suppress the nocturnal ACTH surge that drives the early morning 17-OHP rise, but its potency and long half-life carry higher risk of glucocorticoid excess and are associated with metabolic adverse effects including weight gain, insulin resistance, and bone loss with prolonged use; it should be reserved for patients inadequately controlled on hydrocortisone or prednisolone rather than used as first-line therapy. Monitoring adequacy of glucocorticoid therapy in CAH relies on serum 17-OHP (target: morning fasting level in the range of 300 to 1000 nmol per liter in most guidelines, accepting mild elevation rather than normalization to avoid glucocorticoid excess), androstenedione (target: within or slightly above the normal range for age and sex), plasma renin activity (in salt-wasting CAH with fludrocortisone, target mid-normal range), and clinical markers including growth velocity and pubertal progression in children.9
Fludrocortisone replacement in salt-wasting CAH follows the same principles as in primary AI (adrenal insufficiency): doses of 50 to 200 micrograms per day with dose monitoring guided by plasma renin activity, serum electrolytes, and blood pressure. Salt supplementation in neonates with salt-wasting CAH is necessary in the first year of life because breast milk and formula do not contain sufficient sodium to offset renal salt losses in the context of severe mineralocorticoid deficiency, even with fludrocortisone replacement; sodium chloride supplementation 1 to 3 mEq per kg per day is typically added until dietary sodium intake from table foods is established. Adequacy of mineralocorticoid replacement must be verified throughout childhood and adolescence, as fludrocortisone requirements often decrease with age as the adrenal gland responds to improving glucocorticoid suppression of the mineralocorticoid deficiency pathway. Over-treatment with glucocorticoids in CAH suppresses the RAAS (renin-angiotensin-aldosterone system) as well as the HPA (hypothalamic-pituitary-adrenal) axis, making plasma renin activity an unreliable guide to mineralocorticoid adequacy in over-suppressed patients; accurate assessment of mineralocorticoid status in CAH requires careful interpretation of renin in the context of glucocorticoid dose and timing.4
17-OHP (morning fasting): Target 300–1000 nmol/L; normalization often requires glucocorticoid excess and is not the goal. Very high (>3000 nmol/L) indicates under-treatment; suppressed (<1 nmol/L) indicates over-treatment.
Androstenedione: Target within or slightly above age- and sex-specific normal range. Persistently elevated despite adequate 17-OHP suppression suggests adrenal rest tumor or non-compliance.
Plasma renin activity (salt-wasting form): Target mid-normal range on fludrocortisone. Elevated renin suggests under-replacement; suppressed renin may indicate over-replacement of either fludrocortisone or glucocorticoid.
Growth velocity (children): Must be monitored at every visit. Consistently below the 25th percentile for height-age warrants dose reduction even if androgen markers are not optimally controlled, because glucocorticoid-induced growth impairment is irreversible once epiphyses fuse.
Cushing syndrome pharmacotherapy targets the excess cortisol production or action that drives the clinical syndrome, using mechanistically distinct drug classes that act at different nodes of the HPA (hypothalamic-pituitary-adrenal) axis or adrenal steroidogenesis pathway. Agent selection depends on the etiology of hypercortisolism: pituitary adenoma (Cushing disease, approximately 70% of endogenous Cushing syndrome), adrenal adenoma or carcinoma (approximately 20%), and ectopic ACTH (adrenocorticotropic hormone) secretion (approximately 10%).
Metyrapone inhibits CYP11B1 (cytochrome P450 11B1), the enzyme responsible for the final step of cortisol synthesis: the conversion of 11-deoxycortisol to cortisol. By blocking this step, metyrapone rapidly and dose-dependently reduces cortisol production within hours of administration, making it one of the fastest-acting agents for controlling severe hypercortisolism. The resulting accumulation of 11-deoxycortisol and its precursors provides a metabolic marker of drug effect (elevated 11-deoxycortisol confirms CYP11B1 inhibition) and also drives adrenal androgen excess (because ACTH-stimulated precursors are shunted to the androgen pathway), producing acne, hirsutism, and menstrual irregularities in women. The precursor accumulation also includes deoxycorticosterone, which has mineralocorticoid activity and can cause sodium retention, hypertension, and hypokalemia at high metyrapone doses. Metyrapone is available orally and is used in the short-term management of severe Cushing syndrome before surgery, for perioperative control, and as long-term medical therapy in patients not suitable for surgery.10 UFC (urinary free cortisol) and LNSC (late-night salivary cortisol) are the primary biochemical monitoring tools during steroidogenesis inhibitor therapy, with dose adjustments targeting normalization or reduction to within twice the upper limit of normal.
Osilodrostat is a potent and selective CYP11B1 inhibitor approved by the FDA in 2020 for the treatment of Cushing disease in adults who are not candidates for pituitary surgery or in whom pituitary surgery has not been curative. It inhibits CYP11B1 with higher potency and selectivity than metyrapone, while also having modest inhibitory activity against CYP11B2 (aldosterone synthase) at higher doses, which may partially offset the mineralocorticoid precursor accumulation seen with metyrapone. Two phase 3 osilodrostat registration trials demonstrated normalization of UFC in approximately 50 to 70% of patients at 24 and 48 weeks respectively, with sustained efficacy over longer treatment periods. Adverse effects parallel those of metyrapone: adrenal insufficiency (dose-dependent, managed by dose reduction), androgen excess (acne, hirsutism), and potential hypertension from mineralocorticoid precursors. The advantage of osilodrostat over metyrapone is its twice-daily oral dosing, superior potency at lower doses, and the accumulating evidence from registration trials supporting its efficacy and safety profile.10
Ketoconazole, an imidazole antifungal agent, inhibits multiple adrenal steroidogenic enzymes including CYP17A1 (cytochrome P450 17A1, also called 17-alpha-hydroxylase/17,20-lyase), CYP11A1 (cholesterol side-chain cleavage), and CYP11B1, producing broader suppression of steroidogenesis than the selective CYP11B1 inhibitors. It also inhibits testicular and ovarian steroidogenesis, reducing sex hormone production and potentially causing hypogonadism. Ketoconazole has a significant hepatotoxicity risk, with rare but serious cases of acute liver failure, and is not approved by the FDA for Cushing syndrome in the United States though it is used off-label and is approved in Europe. Its use requires baseline liver function tests and monitoring every 4 weeks during therapy; it should be avoided in patients with pre-existing liver disease. Ketoconazole is also a potent CYP3A4 (cytochrome P450 3A4) inhibitor, producing multiple drug interactions including dangerous increases in the plasma concentrations of drugs metabolized by CYP3A4. Despite its limitations, ketoconazole remains commonly used for Cushing syndrome in countries where osilodrostat or metyrapone are unavailable.11
Etomidate is an imidazole anesthetic agent that inhibits CYP11B1 at sub-anesthetic IV (intravenous) infusion doses of 0.03 to 0.1 mg per kilogram per hour, providing rapid and titratable cortisol suppression in severely ill patients with severe Cushing syndrome who cannot take oral medication. It is the only parenterally available agent for acute hypercortisolism control and is used in ICU settings for patients with florid ectopic ACTH syndrome or severe Cushing disease awaiting surgery. Its ultra-short onset and offset allow precise cortisol titration with continuous UFC monitoring. At the sub-anesthetic doses used for hypercortisolism, sedation is mild and generally tolerated in the ICU context, though patients require monitoring for respiratory depression and blood pressure effects. Adrenal insufficiency is the expected complication of successful treatment and must be anticipated and managed with hydrocortisone supplementation when UFC falls below normal.11
Mifepristone is a competitive antagonist at the GR (glucocorticoid receptor) and at the progesterone receptor, and was approved by the FDA in 2012 for the treatment of hyperglycemia associated with endogenous Cushing syndrome in adults with type 2 diabetes or impaired glucose tolerance who are not candidates for surgery or in whom surgery has not been curative. Its mechanism is distinct from all steroidogenesis inhibitors: rather than reducing cortisol production, mifepristone blocks GR at the receptor level, preventing cortisol from exerting its biological effects on target tissues. This means that plasma cortisol and ACTH levels rise substantially during mifepristone treatment (because the cortisol negative feedback on the pituitary and hypothalamus also operates through GR, and blocking GR removes this feedback), making UFC and LNSC unreliable biomarkers of treatment response; clinical and glycemic parameters are the primary efficacy endpoints during mifepristone therapy. The progesterone receptor antagonism produces a functional anti-progestogen effect, causing endometrial thickening and vaginal bleeding in premenopausal women and potentially masking adrenal insufficiency by maintaining mineralocorticoid effects while blocking glucocorticoid effects; hypokalemia from mineralocorticoid escape (cortisol activating MR when GR is blocked) is a common adverse effect.12
Pasireotide is a somatostatin receptor analog that binds preferentially to somatostatin receptor subtypes 1, 2, 3, and 5, including subtype 5 (SSTR5), which is expressed at high density on corticotroph adenoma cells in Cushing disease. By activating SSTR5, pasireotide inhibits ACTH secretion from corticotroph adenoma cells, reducing both ACTH-driven adrenal cortisol production and the excessive ACTH that maintains the hyperplastic adrenal cortex in Cushing disease. The phase 3 pasireotide registration trial demonstrated UFC normalization in approximately 25 to 30% of patients with Cushing disease at 12 months. The major limitation of pasireotide is its pronounced hyperglycemic effect: because somatostatin receptor activation in pancreatic islets suppresses both insulin and incretin secretion, pasireotide produces hyperglycemia or worsening diabetes in approximately 70% of patients, often severe enough to require antidiabetic therapy initiation. Pasireotide is administered subcutaneously twice daily (short-acting formulation) or intramuscularly monthly (long-acting release formulation); the long-acting release form is preferred for established responders to improve adherence.13
Mitotane is an adrenocorticolytic agent used primarily for adrenocortical carcinoma, a rare but aggressive malignancy that frequently produces Cushing syndrome from autonomous cortisol production. Mitotane is a derivative of the insecticide DDT (dichlorodiphenyltrichloroethane) and produces selective cytotoxic damage to adrenocortical cells through a mechanism involving CYP11A1 inhibition and mitochondrial disruption in adrenocortical mitochondria, leading to progressive adrenocortical destruction. It also inhibits multiple steroidogenic enzymes, providing dual antitumor and cortisol-lowering effects. Mitotane is highly lipophilic with a very long half-life (18 to 159 days) due to extensive accumulation in adipose tissue, requiring months to reach steady-state plasma concentrations and producing prolonged adrenal insufficiency that persists long after drug discontinuation. All patients on mitotane require glucocorticoid replacement, typically at doses two to three times the normal replacement dose because mitotane also increases CBG (corticosteroid-binding globulin) expression, reducing free cortisol and accelerating glucocorticoid metabolism via CYP3A4 induction. Therapeutic drug monitoring of plasma mitotane concentrations (target 14 to 20 mg per liter) guides dose optimization, as concentrations below 14 mg per liter are associated with reduced antitumor efficacy and concentrations above 20 mg per liter produce severe neurological toxicity including cerebellar ataxia, confusion, and peripheral neuropathy.14
Cushing disease (pituitary ACTH excess): first-line is pituitary surgery; medical therapy for surgical failures or candidates. Pasireotide targets pituitary directly (reduces ACTH). Steroidogenesis inhibitors (metyrapone, osilodrostat, ketoconazole) reduce adrenal output. Mifepristone blocks GR peripherally, useful when hyperglycemia is the dominant concern. Adrenal adenoma: surgery is curative; medical therapy is pre-operative bridging only. Ectopic ACTH: control primary tumor if possible; metyrapone or ketoconazole for rapid cortisol reduction; etomidate for acute severe hypercortisolism. Adrenocortical carcinoma: mitotane is the primary pharmacological agent, often combined with steroidogenesis inhibitors for cortisol control while awaiting adrenocorticolytic effect.
Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889–1916.
doi:10.1210/jc.2015-4061Quinkler M, Stewart PM. Hypertension and the cortisol-cortisone shuttle. J Clin Endocrinol Metab. 2003;88(6):2384–2392.
doi:10.1210/jc.2003-030138Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709–717.
doi:10.1056/NEJM199909023411001Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881–1893.
doi:10.1016/S0140-6736(03)13492-7Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21.
doi:10.1056/NEJMoa1009492Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219–2229.
doi:10.1056/NEJMoa2025845Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364–389.
doi:10.1210/jc.2015-1710Crowley RK, Argese N, Tomlinson JW, Stewart PM. Central hypoadrenalism. J Clin Endocrinol Metab. 2014;99(11):4027–4036.
doi:10.1210/jc.2014-2476Speiser PW, Azziz R, Baskin LS, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(9):4133–4160.
doi:10.1210/jc.2009-2631Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A. Advances in the medical treatment of Cushing syndrome. Lancet Diabetes Endocrinol. 2019;7(4):300–312.
doi:10.1016/S2213-8587(18)30155-4Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807–2831.
doi:10.1210/jc.2015-1818Fleseriu M, Biller BMK, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing syndrome. J Clin Endocrinol Metab. 2012;97(6):2039–2049.
doi:10.1210/jc.2011-3350Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing disease. N Engl J Med. 2012;366(10):914–924.
doi:10.1056/NEJMoa1105743Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356(23):2372–2380.
doi:10.1056/NEJMoa063360