Master cortisol, aldosterone, and catecholamines. Diagnose Cushing’s syndrome and Addison’s disease for ASCP BOC.
ASCPprep.com | Clinical Chemistry
Chapter 12 — The Adrenal Cortex
ASCP Board Exam · Lab-Focused Study Guide
Section 1 — Priority Map & Quick Foundation
| Topic | Priority | Why It’s Tested |
|---|---|---|
| HPA axis & cortisol feedback (CRH→ACTH→cortisol) | HIGH | Foundation for every Cushing/Addison question; diurnal rhythm & feedback are heavily tested. |
| RAAS & aldosterone regulation | HIGH | Renin–angiotensin logic underlies hypertension/hypokalemia vignettes and the ARR. |
| Cushing syndrome — diagnosis & localization | HIGH | Dexamethasone suppression, midnight salivary cortisol, UFC, IPSS are classic items. |
| Adrenal insufficiency / Addison (cosyntropin test) | HIGH | Primary vs secondary distinction by ACTH + electrolytes is a guaranteed question. |
| Primary aldosteronism / Conn (ARR) | HIGH | High aldosterone + low renin + the >25–30 ratio is a signature pattern. |
| CAH — 21-hydroxylase deficiency | HIGH | 17-OHP elevation + salt-wasting; ~95% of CAH; contrast with 11β & 17α. |
| Steroidogenesis enzymes (StAR, CYP11A, CYP17, CYP21, CYP11B1/B2) | HIGH | Zone-by-zone enzyme map explains every CAH and the cortisol/aldosterone split. |
| Pheochromocytoma (plasma free metanephrines) | MEDIUM | Medullary but always paired with cortex; best screen + clonidine test tested. |
| HSD11B2 / MR protection & apparent mineralocorticoid excess | MEDIUM | Explains why cortisol doesn’t flood the MR; licorice & AME vignettes. |
| Adrenal androgens (DHEA, DHEA-S) | MEDIUM | DHEA-S marks adrenal source; very high values flag carcinoma. |
| Transport (CBG) & urinary metabolites | MEDIUM | Total vs free cortisol pitfalls; 17-OHCS/17-KS, Porter-Silber, Zimmermann. |
| Liddle / Bartter / Gitelman channelopathies | LOW | Low-yield; distinguished by renin/aldosterone & drug response. |
| Anatomy & embryology | LOW | Few facts (vein drainage, zones, neural-crest medulla) appear occasionally. |
Key Point — Focus vs Skim
Focus hard on the four hormone-axis patterns (cortisol feedback, RAAS, the dexamethasone/cosyntropin logic, and the ARR) plus the 21-hydroxylase pathway — these generate most questions. Skim exact gene loci, amino-acid counts, and kDa sizes: recognize the names, don’t memorize the numbers.
Focus hard on the four hormone-axis patterns (cortisol feedback, RAAS, the dexamethasone/cosyntropin logic, and the ARR) plus the 21-hydroxylase pathway — these generate most questions. Skim exact gene loci, amino-acid counts, and kDa sizes: recognize the names, don’t memorize the numbers.
Quick Foundation (start here if it’s all new)
- The adrenal cortex makes steroid hormones from cholesterol; the inner medulla (neural-crest) makes catecholamines.
- Three cortical zones, outside→in: Glomerulosa → aldosterone, Fasciculata → cortisol, Reticularis → androgens.
- Aldosterone tells the kidney to keep salt/water and dump K⁺ and H⁺ → raises blood pressure.
- Cortisol raises blood glucose, fights inflammation, and is released under stress on a daily (diurnal) clock.
- Two control circuits: RAAS (renin→angiotensin) drives aldosterone; the HPA axis (CRH→ACTH) drives cortisol.
- Disease is too much (Cushing, Conn, pheo) or too little (Addison) — and either primary (gland) or secondary (pituitary).
- Work-up uses stimulation tests for suspected deficiency and suppression tests for suspected excess.
Analogy Picture a thermostat-controlled furnace. The HPA axis is the thermostat: CRH/ACTH turn the furnace (cortisol) up; once warm, cortisol feeds back and shuts the thermostat off. In Cushing the furnace is stuck ON; in Addison the furnace won’t light even when the thermostat (ACTH) screams for heat.
Why this matters clinically: nearly every adrenal diagnosis is solved by two questions — is the hormone high or low, and is the problem in the gland or in the pituitary signal above it.
| Concept | Plain-English Explanation |
|---|---|
| Mineralocorticoid | “Salt steroid” — keeps sodium/water, raises BP (aldosterone). |
| Glucocorticoid | “Sugar steroid” — raises glucose, calms inflammation (cortisol). |
| Primary disease | The adrenal gland itself is broken. |
| Secondary disease | The pituitary/hypothalamus signal is broken; gland is fine. |
| Stimulation test | Push the gland (cosyntropin/CRH/metyrapone) to confirm deficiency. |
| Suppression test | Try to switch it off (dexamethasone) to confirm excess. |
Section 2 — Core Content Tables
Cortisol (Glucocorticoid)
| Feature | Details |
|---|---|
| Definition | Principal glucocorticoid; the body’s main stress steroid. |
| Tissue source | Zona fasciculata (largest zone, ~75% of cortex). |
| Regulation | HPA axis: CRH → ACTH → cortisol; cortisol feeds back (chiefly on the hypothalamus). |
| Mechanism of rise | ACTH (via cAMP/PKA) drives StAR + steroidogenic enzymes → more synthesis. Rises with stress, surgery, hypoglycemia. Diurnal: peak ~2 h before waking, nadir near midnight (after falling asleep). |
| Actions | ↑ gluconeogenesis & blood glucose, insulin resistance, protein/fat catabolism, central fat redistribution, anti-inflammatory (induces IκB, blocks NFκB), maintains vascular tone. |
| Transport | 80–90% bound to CBG (transcortin), ~7% albumin, 2–3% free. Half-life 60–80 min. |
| Assay | Immunoassay or LC-MS/MS (serum/urine/saliva); 24-h urine free cortisol by tandem MS is most sensitive for Cushing. |
| Key interferences | Estrogen/pregnancy ↑ CBG → high TOTAL but normal FREE cortisol; immunoassay cross-reactivity with metabolites. |
Cortisol is the analyte behind both Cushing (excess) and Addison (deficiency); always interpret it together with ACTH and the time of day.
Pre-analytical — Cortisol Draw 07:00–10:00 to honor the diurnal rhythm; note collection time on the tube. Midnight salivary cortisol captures the normal nadir (lost in Cushing). Stress, acute illness, and obesity raise values. Estrogens/OCPs raise total cortisol via CBG. Saliva is stable at room temperature for days.
Aldosterone (Mineralocorticoid)
| Feature | Details |
|---|---|
| Definition | Principal mineralocorticoid; the body’s salt-retaining steroid. |
| Tissue source | Zona glomerulosa (lacks CYP17 → cannot make cortisol/androgens). |
| Regulation | RAAS (angiotensin II) + high K⁺; ACTH is only a minor stimulus — mostly pituitary-independent. |
| Mechanism of rise | Angiotensin II → CYP11B2 (aldosterone synthase). Rises with hypovolemia, low renal perfusion, hyponatremia, upright posture, hyperkalemia. |
| Actions | At DCT/collecting duct: ↑ ENaC + Na⁺/K⁺-ATPase → Na⁺/H₂O retention, K⁺ and H⁺ excretion → ↑ BP, hypokalemia, alkalosis. |
| Transport | Mostly weakly albumin-bound (CBG sites occupied by cortisol). Half-life 20–30 min (<15 min by some estimates). |
| Assay | Immunoassay / LC-MS/MS; paired with plasma renin activity as the ARR. |
| Key interferences | Posture, sodium intake, time of day, K⁺, and many antihypertensives shift aldosterone & renin — control them before an ARR. |
Aldosterone is read against renin: the aldosterone-to-renin ratio (>25–30) screens for primary aldosteronism.
Pre-analytical — Aldosterone/Renin Standardize posture and sodium intake; ideally correct hypokalemia first. Many drugs interfere — spironolactone, ACE inhibitors/ARBs, β-blockers, diuretics, NSAIDs alter renin and aldosterone. Estrogen raises angiotensinogen → ↑ PRA. Renin samples are temperature-sensitive (cryoactivation of prorenin).
ACTH & the HPA Axis
| Feature | Details |
|---|---|
| Definition | Anterior-pituitary peptide that drives adrenal cortisol synthesis. |
| Origin | Cleaved from POMC by PC1/3 in corticotrophs; ACTH = amino acids 1–39 (active domain = N-terminal 24, used as cosyntropin). |
| Mechanism | Binds melanocortin-2 receptor → cAMP/PKA → StAR + CYP enzymes → cortisol. Also a minor aldosterone & androgen stimulus. |
| Clinical use | High ACTH + low cortisol = primary (Addison); low ACTH + low cortisol = secondary. ACTH excess → hyperpigmentation (MSH-like activity within ACTH). |
| Assay | Two-site immunometric (IRMA/chemiluminescent) assay. |
| Interferences | Pulsatile + diurnal secretion; very labile peptide. |
Pre-analytical — ACTH Collect in a chilled EDTA tube, keep on ice, centrifuge cold and freeze promptly — ACTH is rapidly degraded by plasma proteases. Draw at a defined time (08:00 baseline) because of diurnal rhythm.
Adrenal Androgens (DHEA & DHEA-S)
| Feature | Details |
|---|---|
| Source | Zona reticularis (site of DHEA → DHEA-S sulfation via SULT2A1). |
| Mechanism | CYP17 (17,20-lyase) makes DHEA/androstenedione; peripherally converted to testosterone. |
| Clinical use | DHEA-S = marker of adrenal androgen source; circulates ~100× DHEA. Very high DHEA-S (>1000 µg/dL) suggests adrenal carcinoma. Drive adrenarche, axillary/pubic hair. |
| Transport | DHEA/DHEA-S mostly albumin-bound; testosterone/DHT on SHBG. |
| Assay | Immunoassay / LC-MS/MS; urinary 17-ketosteroids reflect androgen metabolites. |
Pre-analytical — DHEA-S DHEA-S has a long half-life and no marked diurnal swing, so timing is forgiving — an advantage over DHEA for assessing adrenal androgen output.
Steroidogenic Enzymes (zone map)
| Enzyme | Step / Zone | Exam hook |
|---|---|---|
| StAR | Cholesterol into mitochondria | Rate-limiting transport; defect = congenital lipoid adrenal hyperplasia. |
| CYP11A (P450scc) | Cholesterol → pregnenolone | Rate-limiting enzymatic step; 20,22-desmolase. |
| 3β-HSD | Δ5 → Δ4 steroids | Deficiency = salt-wasting + ambiguous genitalia in males. |
| CYP17 | 17-hydroxylase / 17,20-lyase (F & R) | Absent in glomerulosa; deficiency → no sex steroids, HTN. |
| CYP21 (21-hydroxylase) | 17-OHP → 11-deoxycortisol | ~95% of CAH; ↑17-OHP, salt-wasting. |
| CYP11B1 (11β-hydroxylase) | 11-deoxycortisol → cortisol | Deficiency → DOC excess → hypertension; blocked by metyrapone. |
| CYP11B2 (aldosterone synthase) | DOC → aldosterone | Driven by angiotensin II, not ACTH. |
| HSD11B2 | Cortisol → cortisone | Protects the MR from cortisol; lost in AME/licorice. |
Key Point Only the glomerulosa makes aldosterone (it alone has CYP11B2 driven by angiotensin II) and it cannot make cortisol/androgens because it lacks CYP17. Everything ACTH-driven (CYP11A, CYP17, CYP21, CYP11B1) lives in the fasciculata/reticularis.
Catecholamines / Metanephrines (medulla — pheochromocytoma)
| Feature | Details |
|---|---|
| Source | Adrenal medulla chromaffin cells (neural crest). PNMT converts NE → epinephrine, and PNMT needs cortisol from the cortex. |
| Best screen | Plasma free metanephrines (most sensitive) or 24-h urine fractionated metanephrines; VMA has poor sensitivity/specificity. |
| Confirmatory | Clonidine suppression: NE fails to fall in pheochromocytoma. Chromogranin A elevated in ~80%. |
| End product | Urinary VMA (degradation product of epinephrine/norepinephrine). |
Pre-analytical — Metanephrines Draw plasma free metanephrines supine after rest to cut false positives; avoid interfering foods/drugs. 24-h urine needs acid preservative and complete collection (report per creatinine).
Section 3 — Visual Memory Hooks
Mnemonic — Zones & products “GFR → Salt, Sugar, Sex”: Glomerulosa = Salt (aldosterone), Fasciculata = Sugar (cortisol), Reticularis = Sex (androgens). “The deeper you go, the sweeter it gets” (Salt → Sugar → Sex).
Mnemonic — Pathway across the page (Fig. 66.6) Moving down a column adds hydroxyls (more potent corticoid); moving right across goes toward sex steroids. Aldosterone is bottom-left (glomerulosa), androgens are far right.
Mnemonic — CAH blood pressure split “21 drops the pressure, 11 & 17 raise it.” 21-hydroxylase = salt-wasting/hypotension; 11β and 17α accumulate mineralocorticoids (DOC) → hypertension.
Mnemonic — Conn vs everything else HTN + low K⁺ + low renin: if aldosterone is HIGH → Conn; if aldosterone is LOW → a cortisol/ENaC mimic (licorice/AME, Liddle).
Pattern Triggers — “If you see X → think Y → because Z”
| If you see… | Think… | Because… |
|---|---|---|
| HTN + hypokalemia + high aldosterone + low renin | Primary aldosteronism (Conn) | Autonomous aldosterone suppresses renin → high ARR. |
| HTN + hypokalemia + low aldosterone + low renin | AME / licorice / Liddle | Cortisol or ENaC drives the MR effect without aldosterone. |
| Low cortisol + high ACTH + hyperpigmentation + ↑K⁺/↓Na⁺ | Primary adrenal insufficiency (Addison) | Gland failure; ACTH/MSH high; aldosterone lost. |
| Low cortisol + low ACTH, normal electrolytes | Secondary insufficiency | Pituitary signal low; aldosterone (RAAS) preserved. |
| Cortisol not suppressed by dexamethasone | Cushing syndrome | Autonomous cortisol ignores feedback. |
| Virilized newborn + ↑17-OHP + salt-wasting | 21-hydroxylase CAH | Block shunts precursors to androgens; aldosterone lost. |
| Episodic HTN, palpitations, sweating + ↑plasma metanephrines | Pheochromocytoma | Tumor secretes catecholamines, metabolized to metanephrines. |
| DHEA-S >1000 µg/dL | Adrenal carcinoma | Massive adrenal androgen output. |
Commonly Confused — side by side
| Pair | One | The other |
|---|---|---|
| Cushing syndrome vs disease | Syndrome = any cause of cortisol excess | Disease = pituitary ACTH adenoma specifically |
| 21- vs 11β-hydroxylase | 21: salt-wasting, hypotension | 11β: DOC excess, hypertension |
| Primary vs secondary adrenal insufficiency | Primary: ↑ACTH, salt-wasting, pigmented | Secondary: ↓ACTH, electrolytes OK |
| Conn vs AME/licorice | Conn: aldosterone HIGH | AME: aldosterone LOW (cortisol on MR) |
| Liddle vs Conn (treatment) | Liddle: responds to triamterene/amiloride, not spironolactone | Conn: responds to spironolactone |
| 17-OHCS vs 17-KS | 17-OHCS: cortisol-related (Porter-Silber) | 17-KS: androgens (Zimmermann) |
| Dexamethasone vs cosyntropin | Dex: suppression (suspected excess) | Cosyntropin: stimulation (suspected deficiency) |
Diagnostic Window / Timing
| Marker / Test | Timing / Onset | Peak | Best Clinical Use |
|---|---|---|---|
| Serum cortisol (diurnal) | Lowest near midnight | ~2 h before waking (early AM) | Draw 07:00–10:00; midnight value screens Cushing. |
| Rapid cosyntropin test | Baseline, then ACTH | Cortisol at 30 & 60 min | Adrenal reserve; normal peak ≥18–20 µg/dL. |
| CRH stimulation | IV ovine CRH | ACTH ~30 min, cortisol ~60 min | Separate secondary vs tertiary; Cushing disease responds. |
| Overnight dexamethasone | 1 mg at 22:00–24:00 | Cortisol at 08:00 next day | Screen Cushing; normal suppresses ≤1.8–2 µg/dL. |
| Metyrapone | 30 mg/kg at midnight | 11-deoxycortisol at 08:00 | Pituitary ACTH reserve; normal 11-deoxycortisol >7 µg/dL. |
Section 4 — Diagnostic Flowcharts
1) Low cortisol — is it primary or secondary?
| 08:00 cortisol LOW (<3 µg/dL highly suggestive of insufficiency) | |
| Measure baseline ACTH | → high vs low |
| ACTH HIGH + ↑K⁺ / ↓Na⁺ + hyperpigmentation | → cosyntropin: cortisol fails to reach ≥18–20 |
| Primary adrenal insufficiency (Addison) | Check 21-hydroxylase antibodies (autoimmune, ~70%) |
| ACTH LOW, electrolytes normal | → metyrapone / CRH to localize |
| Secondary/tertiary insufficiency | Image pituitary (MRI); review prior steroid use |
⚠ Common mistake Calling it “secondary” while ignoring a high ACTH. High ACTH + salt-wasting + pigmentation is PRIMARY — the gland, not the pituitary.
2) Hypertension + hypokalemia — which mineralocorticoid state?
| Hypertension + unprovoked hypokalemia | |
| Measure aldosterone & renin (ARR) | → classify |
| Aldosterone HIGH, renin LOW, ARR >25–30 | → confirm with saline/captopril suppression |
| Primary aldosteronism (Conn) | Adrenal vein sampling to lateralize adenoma vs hyperplasia |
| Aldosterone LOW, renin LOW | → ask about licorice / drug response |
| AME / licorice (responds to nothing but stopping cortisol-on-MR) or Liddle (triamterene, not spironolactone) | Cortisol or ENaC drives the MR |
⚠ Common mistake Reflexively diagnosing Conn from “HTN + low K⁺.” If aldosterone is LOW, it is NOT Conn — read the aldosterone level before committing.
3) Virilized / salt-issue newborn — which CAH enzyme?
| Ambiguous genitalia ± electrolyte disturbance in a neonate | |
| Measure 17-OHP | → markedly elevated? |
| 17-OHP HIGH + salt-wasting (↓Na⁺,↑K⁺, hypotension) | → |
| 21-hydroxylase deficiency (~95%) | Monitor with 17-OHP / urinary pregnanetriol |
| Virilization + hypertension | → ↑11-deoxycortisol & DOC |
| 11β-hydroxylase deficiency | 17-OHCS elevated (unlike 21-def) |
⚠ Common mistake Treating all virilizing CAH as the same. Blood pressure splits them: 21 → low; 11β → high.
4) Confirmed Cushing — localize the source
| Cushing confirmed (no dex suppression, ↑midnight salivary cortisol, ↑UFC) | |
| Measure ACTH | → dependent vs independent |
| ACTH LOW (suppressed) | → image adrenals |
| ACTH-independent: adrenal adenoma/carcinoma | Very high DHEA-S → suspect carcinoma |
| ACTH HIGH/normal | → high-dose dex + CRH + IPSS |
| IPSS:peripheral >2.0 → pituitary (Cushing disease); <1.4 → ectopic ACTH | Gold standard for pituitary vs ectopic |
⚠ Common mistake Trusting imaging over the petrosal gradient. A peripheral ACTH alone cannot separate pituitary from ectopic — IPSS does.
5) Method selection — which test for which question?
| What is the clinical question? | |
| Suspect deficiency (Addison) | → stimulation: cosyntropin (± metyrapone/CRH) |
| Suspect excess (Cushing) | → suppression: low-dose dexamethasone, midnight salivary cortisol, 24-h UFC |
| Suspect primary aldosteronism | → ARR screen, then saline/captopril suppression |
| Suspect pheochromocytoma | Plasma free metanephrines (sensitive); clonidine suppression to confirm |
⚠ Common mistake Using a suppression test to work up deficiency (or vice-versa). Excess → suppress; deficiency → stimulate.
Section 5 — 25 High-Yield Facts
| # | Fact |
|---|---|
| 1 | Cortex zones outside→in: glomerulosa (aldosterone), fasciculata (cortisol), reticularis (androgens). |
| 2 | The medulla is neural-crest derived and makes catecholamines; the cortex is mesodermal and makes steroids. |
| 3 | Cholesterol is the C27 precursor of all steroid hormones. |
| 4 | StAR transports cholesterol into mitochondria — the rate-limiting step of steroidogenesis. |
| 5 | CYP11A (P450scc, 20,22-desmolase) converts cholesterol → pregnenolone. |
| 6 | The glomerulosa lacks CYP17, so it cannot make cortisol or androgens. |
| 7 | CYP11B2 (aldosterone synthase) is controlled by angiotensin II, not ACTH. |
| 8 | Aldosterone ↑ ENaC → Na⁺/H₂O retention and K⁺/H⁺ excretion (HTN, hypokalemia, alkalosis). |
| 9 | Renin is released by juxtaglomerular cells when renal perfusion or DCT sodium falls. |
| 10 | ACE (mainly in the lung) converts angiotensin I → angiotensin II. |
| 11 | HSD11B2 converts cortisol → cortisone to protect the mineralocorticoid receptor. |
| 12 | 80–90% of cortisol is bound to CBG (transcortin); only 2–3% is free. |
| 13 | Cortisol half-life (60–80 min) > aldosterone half-life (20–30 min). |
| 14 | Cortisol peaks ~2 h before waking and is lowest near midnight (diurnal rhythm). |
| 15 | ACTH is cleaved from POMC by PC1/3; the active domain is the N-terminal 24 aa (cosyntropin). |
| 16 | ACTH excess causes hyperpigmentation via MSH-like activity of the ACTH molecule. |
| 17 | DHEA-S marks the adrenal androgen source and circulates ~100× DHEA. |
| 18 | A normal rapid cosyntropin response is a peak cortisol ≥18–20 µg/dL. |
| 19 | Dexamethasone is used in suppression tests because it does not cross-react with cortisol immunoassays. |
| 20 | Primary aldosteronism screen = aldosterone-to-renin ratio >25–30. |
| 21 | 21-hydroxylase deficiency (~95% of CAH) elevates 17-OHP and causes salt-wasting. |
| 22 | 11β-hydroxylase deficiency causes hypertension via 11-deoxycorticosterone (DOC) accumulation. |
| 23 | Metyrapone blocks CYP11B1; a normal axis raises 11-deoxycortisol >7 µg/dL. |
| 24 | Plasma free metanephrines are the most sensitive screen for pheochromocytoma. |
| 25 | IPSS:peripheral ACTH ratio >2.0 (post-CRH) localizes Cushing to the pituitary. |
Exam Tip — the single most testable pattern Solve every adrenal vignette with the two-axis grid: (1) Is the hormone HIGH or LOW? (2) Is ACTH/renin HIGH or LOW? High cortisol + low ACTH = adrenal tumor; high cortisol + high ACTH = pituitary/ectopic; low cortisol + high ACTH = Addison; low cortisol + low ACTH = secondary.
Quick Interpretation Table
| Lab Finding | Clinical Interpretation |
|---|---|
| High cortisol + LOW ACTH | ACTH-independent (adrenal) Cushing — adenoma/carcinoma. |
| High cortisol + HIGH/normal ACTH | ACTH-dependent — Cushing disease or ectopic ACTH (use IPSS). |
| Low cortisol + HIGH ACTH + ↑K⁺/↓Na⁺ | Primary adrenal insufficiency (Addison). |
| Low cortisol + LOW ACTH, normal electrolytes | Secondary adrenal insufficiency. |
| High aldosterone + LOW renin (ARR >25–30) | Primary aldosteronism (Conn). |
| HTN + low K⁺ + LOW aldosterone + LOW renin | AME / licorice / Liddle (cortisol or ENaC on the MR). |
| ↑17-OHP in a virilized neonate | 21-hydroxylase-deficient CAH. |
| ↑Plasma free metanephrines | Pheochromocytoma. |
Section 8 — Rapid Revision Sheet
📖 Read this 2 hours before your exam Numbers, associations, opposites, and the pairs students mix up. No prose — just triggers.
Numbers / Cutoffs
- Cosyntropin normal peak: cortisol ≥18–20 µg/dL
- Metyrapone: 11-deoxycortisol >7 µg/dL
- ARR (primary aldosteronism): >25–30
- Low-dose dex: suppress to ≤1.8–2 µg/dL
- 8 AM cortisol <3 µg/dL → insufficiency
- IPSS:peripheral ACTH >2.0 → pituitary
- DHEA-S >1000 µg/dL → carcinoma
- Cortisol t½ 60–80 min; aldosterone 20–30 min
Always-together associations
- Aldosterone ↔ angiotensin II / CYP11B2
- Cortisol ↔ ACTH / CYP11B1
- DHEA-S ↔ adrenal androgen source
- 21-OH deficiency ↔ ↑17-OHP
- HSD11B2 ↔ protects the MR
- ACTH excess ↔ hyperpigmentation
- Pheochromocytoma ↔ plasma free metanephrines
Opposites (up vs down)
- Conn: ↑aldosterone, ↓renin, ↓K⁺, ↑BP
- Addison: ↓cortisol, ↑ACTH, ↑K⁺, ↓Na⁺
- Cushing: ↑cortisol, ↑glucose, ↑BP
- 21-OH CAH: salt-WASTING / hypotension
- 11β & 17α CAH: HYPERtension
- Secondary AI: electrolytes preserved
Confusing pairs
- Cushing syndrome (any cause) vs disease (pituitary)
- Conn (↑aldo) vs AME/licorice (↓aldo)
- Liddle (triamterene) vs Conn (spironolactone)
- 17-OHCS/Porter-Silber (cortisol) vs 17-KS/Zimmermann (androgens)
- Dexamethasone = suppress; cosyntropin = stimulate
- Total vs free cortisol (CBG shifts)
Method matching
- Porter-Silber → 17-OHCS
- Zimmermann → 17-ketosteroids
- Pregnanetriol → 17-OHP metabolite (21-def)
- 24-h UFC by LC-MS/MS → most sensitive Cushing test
- ACTH → chilled EDTA, on ice
- VMA → poor sensitivity (don’t pick it)
Drug / interference flags
- Phenytoin/carbamazepine/rifampin → false non-suppression (P450 induction)
- Estrogen/OCP → ↑CBG & ↑PRA (high total cortisol)
- Licorice (glycyrrhetinic acid) → inhibits HSD11B2
- Spironolactone/ACEi/diuretics → distort ARR
Section 9 — Final Memory Map
ADRENAL CORTEX
Zona glomerulosa — Aldosterone (mineralocorticoid)
Regulator: RAAS / angiotensin II + K⁺ (CYP11B2); ACTH minor
Action: ↑Na⁺/H₂O, ↓K⁺/H⁺ → ↑BP
Excess = Conn (↑aldo, ↓renin, ARR >25–30) | Deficit = salt-wasting
Mimics: AME/licorice, Liddle (low aldo, low renin)
Zona fasciculata — Cortisol (glucocorticoid)
Regulator: HPA axis CRH→ACTH (CYP11B1); diurnal, peak early AM
Transport: CBG 80–90%; t½ 60–80 min
Excess = Cushing (no dex suppression, ↑UFC, ↑midnight salivary cortisol)
Deficit = Addison (primary: ↑ACTH, pigment, ↑K⁺/↓Na⁺) vs secondary (↓ACTH)
Tests: cosyntropin (peak ≥18–20), metyrapone (11-deoxycortisol >7), CRH, IPSS >2.0
Zona reticularis — Androgens (DHEA, DHEA-S)
CYP17 (17,20-lyase); DHEA-S marks adrenal source (~100× DHEA)
DHEA-S >1000 µg/dL → carcinoma; urinary 17-KS (Zimmermann)
Steroidogenesis backbone
Cholesterol →(StAR, rate-limiting)→ mito →(CYP11A)→ pregnenolone
21-OH deficiency (~95% CAH): ↑17-OHP, salt-wasting
11β & 17α deficiency: hypertension (DOC)
HSD11B2 protects MR (cortisol→cortisone)
Medulla (paired topic) — Catecholamines
Neural crest; PNMT (needs cortisol) NE→Epi
Pheochromocytoma: plasma free metanephrines (best), clonidine suppression, VMA end-product