## Distinguishing Aldosterone from Cortisol: Mineralocorticoid Activity ### The Key Mechanism: 11β-HSD2 Inactivation **Key Point:** Cortisol and aldosterone have similar affinity for the mineralocorticoid receptor (MR), but cortisol's mineralocorticoid activity is selectively blocked by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in aldosterone-target tissues (kidney, colon). ### How 11β-HSD2 Works 11β-HSD2 catalyzes the conversion of cortisol → cortisone. Cortisone has negligible affinity for MR, effectively inactivating cortisol's mineralocorticoid potential despite its high circulating concentration (cortisol ~400 nmol/L vs aldosterone ~0.1 nmol/L). **Clinical Pearl:** This selective inactivation explains why glucocorticoid excess (Cushing syndrome) causes only modest sodium retention and hypertension despite 1000-fold higher cortisol levels than aldosterone. Aldosterone escapes this inactivation because 11β-HSD2 preferentially acts on 11β-OH glucocorticoids; aldosterone lacks this 11β-OH group and is therefore protected. ### Comparison Table | Feature | Aldosterone | Cortisol | | --- | --- | --- | | **Circulating level** | ~0.1 nmol/L | ~400 nmol/L | | **MR affinity** | Similar | Similar | | **11β-HSD2 substrate** | No (lacks 11β-OH) | Yes → inactivated to cortisone | | **Mineralocorticoid effect** | Potent | Minimal (blocked by 11β-HSD2) | | **Zone of origin** | Zona glomerulosa | Zona fasciculata | **High-Yield:** The structural difference (aldosterone lacks the 11β-hydroxyl group) is the reason it escapes inactivation — this is a key exam discriminator. ### Why This Matters Clinically Licorice toxicity inhibits 11β-HSD2, allowing cortisol to activate MR unopposed → hypertension and hypokalemia mimicking hyperaldosteronism. This proves the enzyme's critical role in selective MR signaling. [cite:KD Tripathi 8e Ch 59]
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