Adrenocorticosteroid Pharmacology · Module 4 of 4

Mineralocorticoid Pharmacology, Adrenal Insufficiency, Congenital Adrenal Hyperplasia, and Cushing Syndrome

MR receptor signaling, fludrocortisone, MR antagonists, replacement therapy, and Cushing pharmacotherapy

11β-HSD2 is the gating mechanism that prevents cortisol from activating the mineralocorticoid receptor under normal conditions — cortisol has equal or greater affinity for the MR than aldosterone, but 11β-HSD2 in aldosterone-sensitive distal nephron cells rapidly converts cortisol to inactive cortisone; when 11β-HSD2 is inhibited (licorice/glycyrrhizic acid) or saturated (high-dose glucocorticoid therapy), cortisol activates renal MR and produces apparent mineralocorticoid excess: hypertension, hypokalemia, and suppressed renin/aldosterone; this explains glucocorticoid-induced hypertension beyond simple MC receptor cross-reactivity.
MR antagonists differ in selectivity, which determines their side effect profiles and indications — spironolactone: potent but off-target androgen/progesterone receptor antagonism → gynecomastia/sexual dysfunction in men, menstrual irregularities; indications include HFrEF (RALES), primary aldosteronism, cirrhotic ascites, resistant hypertension, and acne/hirsutism; eplerenone: steroidal, selective (no sex hormone receptor cross-reactivity), 60× less potent than spironolactone, no gynecomastia; HFrEF (EMPHASIS-HF) and post-MI LV dysfunction (EPHESUS); finerenone: non-steroidal, balanced heart/kidney distribution, approved specifically for cardiorenal protection in diabetic kidney disease + elevated albuminuria (FIDELIO-DKD, FIGARO-DKD).
Primary vs. secondary adrenal insufficiency differ in one critical pharmacological consequence — primary (Addison disease): destroys all three cortical zones → both glucocorticoid and mineralocorticoid deficiency; elevated ACTH (cortisol deficiency removes feedback) co-secretes MSH → hyperpigmentation; hyperkalemia and hyponatremia; requires both hydrocortisone and fludrocortisone; secondary (pituitary ACTH deficiency or glucocorticoid suppression): zona glomerulosa intact (RAAS-driven) → mineralocorticoid preserved → no mineralocorticoid replacement needed; no hyperpigmentation; no hyperkalemia.
Mifepristone monitoring is counterintuitive — it blocks glucocorticoid receptor negative feedback at the pituitary, so cortisol and ACTH rise substantially during therapy; urinary free cortisol and late-night salivary cortisol are unreliable efficacy monitors; use clinical status and glycemic parameters instead; hypokalemia is common (cortisol activates MR when GR is blocked); progesterone receptor antagonism causes endometrial thickening and vaginal bleeding; indicator of adrenal crisis during mifepristone therapy: hemodynamic instability (cortisol cannot exert effect even if it rises).
Mitotane requires therapeutic drug monitoring and induces its own glucocorticoid replacement requirements — target plasma 14–20 mg/L; below 14 = reduced antitumor efficacy; above 20 = cerebellar ataxia, confusion, peripheral neuropathy; half-life 18–159 days from adipose accumulation; adrenal insufficiency persists long after discontinuation; mitotane induces CYP3A4 and increases corticosteroid-binding globulin, reducing free cortisol → all patients require glucocorticoid replacement at 2–3× normal physiological doses during therapy.

Abbreviations: MR = mineralocorticoid receptor · 11β-HSD2 = 11-beta-hydroxysteroid dehydrogenase type 2 · ENaC = epithelial sodium channel · RAAS = renin-angiotensin-aldosterone system · HFrEF = heart failure with reduced ejection fraction · CKD = chronic kidney disease · ACTH = adrenocorticotropic hormone · MSH = melanocyte-stimulating hormone · CAH = congenital adrenal hyperplasia · 17-OHP = 17-hydroxyprogesterone · CYP11B1 = 11-beta-hydroxylase · UFC = urinary free cortisol · GR = glucocorticoid receptor · CBG = corticosteroid-binding globulin

Mineralocorticoid Receptor Pharmacology and Antagonists

Aldosterone and 11β-HSD2 Gating

Renal MR + the Cortisol Problem

Aldosterone binds distal nephron MR → transcription of ENaC subunits and Na⁺/K⁺-ATPase → Na⁺ reabsorption + K⁺ secretion → BP ↑, hypokalemia at pharmacological concentrations
Aldosterone regulated by RAAS (angiotensin II via AT1) and serum K⁺ directly — NOT by ACTH
Cortisol has equal or greater MR affinity than aldosterone — 11β-HSD2 converts cortisol to inactive cortisone in aldosterone-sensitive cells, protecting MR selectivity
11β-HSD2 inhibition (licorice/glycyrrhizic acid) or saturation (high-dose glucocorticoids) → cortisol activates MR → apparent mineralocorticoid excess: hypertension, hypokalemia, suppressed renin/aldosterone
Non-epithelial MR activation (heart, vasculature, podocytes): fibrosis, endothelial dysfunction, proteinuria — independent of sodium-retaining renal effect; explains cardiorenal benefit of MR antagonists

Mineralocorticoid Receptor Antagonists

Spironolactone vs. Eplerenone vs. Finerenone

Spironolactone (steroidal): potent; off-target AR and PR antagonism → gynecomastia/sexual effects in men, menstrual irregularities; active metabolite canrenone (t½ 14–20 h); indications: HFrEF (RALES ↓ mortality), primary aldosteronism, cirrhotic ascites, resistant hypertension, acne/hirsutism
Eplerenone (steroidal, selective): no androgen/progesterone receptor cross-reactivity → no gynecomastia; 60× less potent than spironolactone; indications: HFrEF (EMPHASIS-HF), post-MI LV dysfunction (EPHESUS); twice daily
Finerenone (non-steroidal): balanced heart/kidney distribution; short t½ (2–3 h) may reduce hyperkalemia; indication: diabetic CKD + elevated albuminuria on max RAAS blockade (FIDELIO-DKD, FIGARO-DKD) — first MR antagonist for cardiorenal protection in DKD
All MR antagonists: monitor serum K⁺; hyperkalemia is major dose-limiting AE, especially eGFR <60 or concurrent RAAS blockade

Adrenal Insufficiency Replacement and CAH Suppression

Feature	Primary Adrenal Insufficiency (Addison)	Secondary Adrenal Insufficiency
Cause	Adrenal destruction (autoimmune most common); all three zones affected	ACTH deficiency from pituitary disease or glucocorticoid suppression
ACTH	Elevated (cortisol deficiency removes feedback) → MSH co-secretion → hyperpigmentation	Low or inappropriately normal; no hyperpigmentation
Mineralocorticoid	Deficient (zona glomerulosa destroyed) → hyperkalemia, hyponatremia, postural hypotension	Preserved (zona glomerulosa responds to RAAS) → no hyperkalemia
Replacement	Hydrocortisone 15–25 mg/day divided (10 mg AM + 5 mg mid-morning + 5 mg early afternoon) + fludrocortisone 50–200 mcg/day	Hydrocortisone 15–25 mg/day divided only; NO mineralocorticoid replacement needed
CAH (21-hydroxylase)	Children: hydrocortisone 10–15 mg/m²/day in 3 divided doses (short t½ protects growth hormone surge); Adults: prednisolone 2–4 mg/day or dexamethasone 0.25–0.5 mg at bedtime for nocturnal ACTH suppression; monitor 17-OHP (target 300–1000 nmol/L, not normalization), androstenedione, plasma renin activity, and growth velocity

Cushing Syndrome Pharmacotherapy by Mechanism

Steroidogenesis Inhibitors — Adrenal Level

Block Cortisol Production

Metyrapone: CYP11B1 inhibitor; fastest onset (hours); precursor accumulation (deoxycorticosterone → Na retention/hypertension; androgen shunting → acne/hirsutism); oral; use: rapid pre-op control, ectopic ACTH
Osilodrostat: potent selective CYP11B1 inhibitor; UFC normalization ~50–70% in phase 3; modest CYP11B2 inhibition at high doses; approved 2020 for Cushing disease post-surgery failure; twice daily oral
Ketoconazole: inhibits CYP17A1, CYP11A1, CYP11B1; hepatotoxicity (monthly LFTs); potent CYP3A4 inhibitor; not FDA-approved but widely used off-label
Etomidate: ONLY parenteral steroidogenesis inhibitor; sub-anesthetic IV infusion (0.03–0.1 mg/kg/h); ICU use for acute severe hypercortisolism (ectopic ACTH) unable to take orals; rapid and titratable

Receptor/Pituitary-Level Agents

Block GR or Reduce ACTH

Mifepristone: competitive GR and PR antagonist; approved for Cushing syndrome hyperglycemia (not surgical candidates); cortisol and ACTH RISE during therapy → UFC/late-night salivary cortisol unreliable; monitor clinically and glycemically; hypokalemia (cortisol activates MR when GR blocked); PR antagonism → endometrial thickening/vaginal bleeding
Pasireotide: SSA preferentially binding SSTR1/2/3/5 (SSTR5 at high density on corticotroph adenomas); suppresses ACTH secretion directly; UFC normalization ~25–30%; major limitation: hyperglycemia in ~70% (suppresses insulin + incretin secretion from pancreatic islets); SC twice-daily or IM monthly LAR
Mitotane: adrenocorticolytic (DDT derivative); cytotoxic to adrenocortical mitochondria + inhibits steroidogenic enzymes; primary agent for adrenocortical carcinoma; t½ 18–159 days (adipose accumulation); therapeutic drug monitoring (target 14–20 mg/L); induces CYP3A4 + ↑ CBG → all patients need 2–3× normal GC replacement; above 20 mg/L: cerebellar ataxia, confusion

Chapter Complete — Adrenocorticosteroid Pharmacology (CORT) · Key Rules

The 11β-HSD2 gating rule: cortisol has equal or greater affinity for the mineralocorticoid receptor than aldosterone — the renal enzyme 11β-HSD2 inactivates cortisol to cortisone before it can activate the receptor. Licorice and high-dose glucocorticoids disable this gate, causing cortisol-mediated mineralocorticoid excess with hypertension, hypokalemia, and suppressed renin/aldosterone. The same mechanism explains why hydrocortisone (and prednisolone) contribute more to sodium retention than methylprednisolone or dexamethasone (which have negligible intrinsic MC activity and are less efficient at saturating 11β-HSD2).

Mifepristone monitoring is inverted: the drug blocks GR feedback to the pituitary, so cortisol and ACTH levels rise — UFC and late-night salivary cortisol cannot be used to monitor efficacy. Endpoints are clinical improvement and glycemic control. Adrenal crisis during mifepristone therapy presents with hemodynamic instability rather than elevated cortisol because the receptor is blocked even when cortisol is high; etomidate is available as parenteral backup to quickly reduce cortisol production in crisis. For Cushing disease: pituitary surgery first; pasireotide for failures (but 70% hyperglycemia); osilodrostat or metyrapone for persistent disease; mifepristone when hyperglycemia dominates; mitotane for adrenocortical carcinoma with mandatory TDM.

CAH monitoring requires knowing what not to target: normalizing 17-OHP often requires glucocorticoid excess; the goal is 300–1000 nmol/L 17-OHP, not normalization. Growth velocity is the override signal — if a child's growth velocity is below the 25th percentile, reduce the glucocorticoid dose even if androgen markers are suboptimally controlled, because GC-induced growth suppression is irreversible once epiphyses fuse. Children receive hydrocortisone (short t½ protects nocturnal GH surge); adults can switch to prednisolone or low-dose dexamethasone at bedtime for sustained nocturnal ACTH suppression.

CORT chapter pharmacological core: steroid synthesis zones are enzymatically segregated (zona glomerulosa has CYP11B2/no CYP17A1; zona fasciculata has CYP17A1+CYP11B1/no CYP11B2) and independently regulated (cortisol by ACTH; aldosterone by RAAS+K⁺). GR signaling has two mechanistically separable nuclear modes (transactivation drives adverse metabolic effects; transrepression drives anti-inflammatory benefit). Biologic duration always exceeds plasma half-life because gene expression changes outlast plasma levels. Fludrocortisone is the only oral mineralocorticoid replacement; all MR antagonists risk hyperkalemia, especially with concurrent RAAS blockade or CKD.

Suggested References

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Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter 40: Estrogens, Progestins, and the Female Reproductive Tract	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed. — Chapter 44: Estrogens and Progestins	McGraw-Hill; 2023
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Bakris GL et al.	Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes (FIDELIO-DKD)	N Engl J Med. 2020;383(23):2219–2229
Bornstein SR et al.	Diagnosis and Treatment of Primary Adrenal Insufficiency: Endocrine Society Guideline	J Clin Endocrinol Metab. 2016;101(2):364–389
Speiser PW et al.	Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: Endocrine Society Guideline	J Clin Endocrinol Metab. 2010;95(9):4133–4160
Feelders RA et al.	Advances in the medical treatment of Cushing syndrome	Lancet Diabetes Endocrinol. 2019;7(4):300–312
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Fleseriu M et al.	Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in Cushing syndrome	J Clin Endocrinol Metab. 2012;97(6):2039–2049
Colao A et al.	A 12-month phase 3 study of pasireotide in Cushing disease	N Engl J Med. 2012;366(10):914–924
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