Rate-limiting step: StAR shuttles cholesterol OMM → IMM; acutely induced by ACTH via cAMP/PKA. CKD blocks renal 1α-hydroxylase (vit D) but not the StAR-dependent adrenal cascade.
Cyclopentanoperhydrophenanthrene — 17-carbon sterol nucleus shared by all steroids
Three 6-member rings (A, B, C) + one 5-member ring (D). 17 ring carbons + angular methyls at C-18, C-19 + side chain at C-17
A (upper left), B (lower left), C (lower right), D (upper right — the 5-member ring)
27 carbons total (17 in nucleus + 8 in side chain + 2 methyls at C-18/C-19)
5-member ring containing C-13, C-14, C-15, C-16, C-17; carries the side chain at C-17 and is where androgens/estrogens differ from pregnanes
Starts at A-ring top-left, runs clockwise around outer ring, then inward. C-18 = methyl on C-13 (between C/D rings); C-19 = methyl on C-10 (between A/B). Side chain: C-20 to C-27
Steroid classes by carbon number (LO 1)
Class
Carbons
Loss vs cholesterol
Examples
Signature
Pregnane
21
Lose 6 side-chain carbons (C-22 to C-27); retain 2-carbon side chain at C-17 ending in C-20/C-21
2-carbon side chain off C-17 terminating at C-21; characteristic C-20 ketone in many
Androstane
19
Lose entire side chain (C-20 to C-27); retain only ring structure + angular methyls C-18, C-19
DHEA, androstenedione, testosterone, DHT
No side chain; functional group at C-17 is OH (testosterone) or O (androstenedione, DHEA)
Estrane
18
Lose side chain AND lose C-19 methyl via aromatase during A-ring aromatization
Estradiol (E2), estrone (E1), estriol (E3)
AROMATIC A-ring with 3-OH phenol (not 3-oxo); result of aromatase (CYP19)
Nomenclature conventions (LO 1)
Ketone (C=O) at the numbered carbon. Cortisol has 3-one and 20-one; aldosterone has 3-one, 20-one, and 18-one (aldehyde)
Hydroxyl (-OH) at the numbered carbon. Cortisol: 11β-ol, 17α-ol, 21-ol. Estradiol: 3-ol (phenolic), 17β-ol
Δn or "-ene" = double bond, numbered from lower-numbered carbon. Cortisol is Δ4 (between C-4/C-5). Δ5 steroids (pregnenolone, DHEA) have double bond C5-C6
α = group below plane (dashed line). β = above plane (solid wedge). Angular methyls at C-18, C-19 are β — so β = same side as them
ON EXAM — ALL steroidogenesis shares: LDL cholesterol uptake, StAR shuttle OMM → IMM (ACUTE rate-limiting), CYP11A1 cleaves cholesterol → PREGNENOLONE on IMM (first committed step), adrenodoxin/reductase electron shuttle, 3β-HSD converts Δ5 to Δ4 forms
Δ5 steroids (pregnenolone, 17-OH-pregnenolone, DHEA) have C5-C6 double bond + 3β-OH. 3β-HSD isomerizes to C4-C5 and oxidizes 3β-OH to 3-oxo → Δ4 forms. Required for active hormones
Made in mitochondria by CYP11A1, pregnenolone exits to cytosol, enters smooth ER for further modification (CYP17, 3β-HSD, CYP21), then SHUTTLES BACK to mitochondria for CYP11B1/B2 in the final steps of cortisol and aldosterone synthesis
Steroid intermediates shuttle between mitochondria and SER multiple times. Pregnenolone: mito → SER (17-OH or 3β-HSD) → SER (21-OH) → back to mito for 11β-OH → cortisol. Aldosterone: pathway ends with final 3 reactions all in mitochondria by CYP11B2
LO 3
ON EXAM — 3 cortical zones: Glomerulosa (salt, aldo, CYP11B2 unique), Fasciculata (sugar, cortisol), Reticularis (sex, DHEA). Medulla = neural crest, epi. Glomerulosa: Ang II + K+; fasc/retic: ACTH. Glomerulosa LACKS CYP17 → can't make cortisol or androgens. Aldosterone synthase (CYP11B2) ONLY in glomerulosa
Adrenal anatomy (LO 3)
Layer
Germ layer
Class
Hormone
Regulator
Mnemonic
Glomerulosa
Mesoderm (intermediate)
Mineralocorticoid
Aldosterone (only place)
Ang II + high K+; ACTH minor
"Salt" — outermost controls salt/volume
Fasciculata
Mesoderm (intermediate)
Glucocorticoid
Cortisol (some corticosterone)
ACTH via MC2R → Gs → cAMP
"Sugar" — cortisol raises blood sugar
Reticularis
Mesoderm (intermediate)
Weak androgens
DHEA + androstenedione (plus DHEA-S via SULT2A1)
ACTH; adrenarche ~age 6–8
"Sex" — weak androgens for pubic/axillary hair
Medulla
NEURAL CREST (not mesoderm!)
Catecholamine (amine)
Epinephrine (~80%) + NE (~20%)
Sympathetic ACh on chromaffin cells; cortisol (via portal) induces PNMT
Pheochromocytoma
MNEMONIC: "Salt, Sugar, Sex, Epinephrine". "The deeper you go, the sweeter it gets."
11β-OH + 18-OH + 18-oxidation on DOC → aldosterone. Unique to glomerulosa — only zone that makes aldo
CYP17 (17α-OH)
NO — why glomerulosa can't make cortisol or androgens
YES — allows cortisol synthesis
YES — allows androgen synthesis
17α-hydroxylation: pregnenolone → 17-OH-pregnenolone; required for cortisol AND DHEA paths
CYP17 (17,20-lyase)
NO
LOW activity → funnels to cortisol, not DHEA
HIGH activity → enables DHEA synthesis
17,20-lyase cleaves C17-C20 bond: 17-OH-pregnenolone → DHEA. Activity ratio of CYP17 determines product
Why regulation differs by zone (LO 3)
AT1 receptor on glomerulosa (Gq-coupled → IP3 → ↑Ca2+ → aldo synthesis and release; chronic stim ↑ CYP11B2 transcription)
High extracellular K+ depolarizes glomerulosa → opens voltage-gated Ca2+ channels → Ca2+ influx → activates CYP11B2. MORE DIRECT and rapid than Ang II
MC2R (melanocortin-2 receptor) on fasciculata + reticularis (minimal on glomerulosa). Gs-cAMP-PKA → StAR + steroidogenic enzymes
Glomerulosa has fewer MC2R receptors; dominated by AT1/K+. ACTH has transient/permissive effect but cannot drive sustained aldo excess. Chronic Cushing → HTN via cortisol on MR (not true aldo excess)
Glomerulosa LACKS 17α-hydroxylase (CYP17) → can't make 17-OH-pregnenolone → can't proceed to cortisol or androgen pathways. Explains zone specialization
Fasciculata expresses CYP17 for 17α-hydroxylation but has LOW 17,20-lyase activity → enzyme mostly hydroxylates without cleaving C17-C20 → funnels substrate toward cortisol, not DHEA. Reticularis has high 17,20-lyase → DHEA
SPONGIOCYTES — lipid-rich cells with foamy cytoplasm (lipid droplets = cholesterol reservoir); arranged in long vertical cords ("fascicles")
Small rounded cell nests / clusters ("glomeruli" pattern — hence the name "glomerulosa")
Onset of DHEA/DHEA-S secretion from zona reticularis at ages 6–8 years — drives pubic + axillary hair BEFORE gonadarche (true puberty)
Peaks in mid-20s, declines steadily with age ("adrenopause" — ZR thins, ZF/ZG preserved). Explains age-related decline in adrenal androgens
Pubarche before age 8 (girls) or 9 (boys): early axillary hair, body odor, acne. Usually benign; work up for CAH or androgen tumor if rapidly progressive / virilizing
ZF (primary) and ZR — both under ACTH control → bilateral cortical hyperplasia in Cushing disease or ectopic ACTH. ZG largely ACTH-independent (driven by Ang II + K+)
LO 4
ON EXAM — All 3 paths start Cholesterol → (StAR + CYP11A1) → PREGNENOLONE. Aldo: pregnenolone → progesterone → DOC → corticosterone → aldosterone. Cortisol: pregnenolone → 17-OH-preg → 17-OH-prog → 11-deoxycortisol → cortisol. DHEA: 17-OH-pregnenolone → DHEA → androstenedione → testosterone. 21-OH deficiency is most common CAH
Aldosterone pathway (LO 4)
Step
Substrate
Enzyme
Product
1
Cholesterol
StAR (shuttle) + CYP11A1 (P450scc/desmolase)
Pregnenolone
2
Pregnenolone
3β-HSD
Progesterone
3
Progesterone
21-hydroxylase (CYP21A2)
11-Deoxycorticosterone (DOC)
4
DOC
CYP11B2 performs 11β-OH (in glomerulosa); analogous CYP11B1 role in fasciculata
SULT2A1 (sulfotransferase 2A1, in zona reticularis)
DHEA-S (sulfated)
3
DHEA
3β-HSD
Androstenedione
4
Androstenedione
17β-HSD (17β-hydroxysteroid dehydrogenase)
Testosterone
5
Testosterone / androstenedione
Aromatase (CYP19) in peripheral tissues (ovary granulosa, adipose, skin, bone)
Estradiol / estrone
The "17-OH shunt": In 21-hydroxylase deficiency (most common CAH), cortisol + aldosterone can't be made → 17-OH-progesterone builds up + substrate shunted toward androgens → 46,XX VIRILIZATION + salt-wasting crisis.
Enzymatic checkpoints (LO 4)
Enzyme defect
Blocked
Accumulates / shunted to
BP / salt
46,XX virilization
21-hydroxylase
Aldo AND cortisol paths (progesterone → DOC and 17-OH-prog → 11-deoxycortisol)
17-OH-progesterone accumulates → shunted via 17,20-lyase to DHEA/androstenedione. Diagnostic marker: ↑ 17-OH-progesterone
LOW BP (salt-wasting) + HYPERKALEMIA + hyponatremia (no aldo)
YES — 46,XX infant with virilized genitalia + salt-wasting crisis
11β-hydroxylase
Final cortisol step AND DOC → corticosterone. 11-deoxycortisol and DOC accumulate
DOC has mineralocorticoid activity → HTN. Substrate shunted toward androgens
HIGH BP + hypokalemia + metabolic alkalosis (DOC = weak MR agonist)
YES — "virilized female with HTN" classic stem
17α-hydroxylase
Cortisol AND all sex steroids (no 17α-OH, no 17,20-lyase activity). Aldo path hyperactive
DOC and corticosterone accumulate (both mineralocorticoid activity) → HTN. No sex hormones
HIGH BP + hypokalemia + metabolic alkalosis; aldo paradoxically LOW (RAAS suppressed by HTN)
NO — UNDER-virilized. 46,XX: no puberty/primary amenorrhea. 46,XY: female external, testes present
HTN + hypokalemia + UNDER-virilization (no androgens, no sex steroids). Corticosterone + DOC elevated; aldo paradoxically suppressed. 46,XY female phenotype with undescended testes
CAH mnemonics — lock these in (LO 4)
HYPER-tension = 11 or 17 (both accumulate mineralocorticoid precursor DOC). HYPO-tension / salt-wasting = 21 (no aldosterone made, no DOC buildup)
21 and 11 VIRILIZE (substrate shunts into androgens because the upstream blockade preserves 17,20-lyase access). 17 does NOT virilize — it blocks 17α-hydroxylase UPSTREAM of the androgen branch, so NO sex steroids form (under-virilization; 46,XY presents as phenotypic female)
Incomplete 21-OH deficiency (~20–25% of cases). Enough aldosterone preserved to prevent salt-wasting. Present LATER in childhood with virilization (pubic hair, clitoromegaly, accelerated bone age); ambiguous genitalia at birth in 46,XX without salt-wasting
Mildest 21-OH form — partial enzyme activity. Present in adolescence/adulthood with hirsutism, acne, oligomenorrhea, infertility — OFTEN MISTAKEN FOR PCOS. Differentiate with elevated 17-OH-progesterone on morning labs or ACTH-stimulation test
Rare CAH — blocks Δ5 → Δ4. Low aldo + low cortisol + low potent androgens (testosterone, androstenedione) but HIGH DHEA (still can be made via 17,20-lyase). Salt-wasting + AMBIGUOUS genitalia in BOTH sexes (46,XY under-virilized by weak DHEA only; 46,XX partially virilized by DHEA)
LO 5
ON EXAM — Aldosterone: loose albumin (~60%), t1/2 ~20 min. Cortisol: CBG ~80% + albumin + free; t1/2 ~70-90 min. DHEA-S: albumin-bound, t1/2 8-10 h (LONGEST, most abundant). 11β-HSD2 converts cortisol → cortisone (inactive at MR) in kidney. Pregnancy/OCPs → CBG ↑ → total cortisol ↑ but free normal. Licorice inhibits 11β-HSD2 → apparent mineralocorticoid excess
Circulation (LO 5)
Hormone
Carrier
Free fraction
Half-life
Pearl
Aldosterone
Loose albumin binding (~60%); NO specific mineralocorticoid-binding globulin
~40% free (higher than cortisol due to weak binding)
~20 min (SHORTEST)
Short half-life → single measurements variable. Measured as plasma aldosterone : renin ratio for Conn screening
Cortisol
CBG (transcortin) ~75-80% high-affinity + albumin ~15%
~10% free (biologically active)
~70-90 min
CBG acts as plasma reservoir + extends half-life. Pregnancy/OCPs → CBG ↑ → total ↑ but free normal
DHEA (free)
Weakly bound to albumin
Relatively high free fraction
~30 min (short)
Most circulating DHEA is actually the SULFATED form (DHEA-S), not free DHEA
DHEA-S
Loose albumin — no specific carrier
Moderate free fraction
8-10 hours (LONGEST of any steroid)
MOST ABUNDANT circulating steroid hormone (>100× cortisol). Sulfation by SULT2A1 in zona reticularis dramatically slows clearance. Preferred lab for adrenal androgen output
Aldosterone has SHORTEST half-life (~20 min). DHEA-S has LONGEST (8-10 h+) and is MOST ABUNDANT. Cortisol intermediate (~70-90 min).
Inactivation (LO 5)
Hormone
Main site
Modifications
Urinary form
Aldosterone
Liver
Reduction of Δ4 double bond + 3-oxo → 3-OH; glucuronidation at C-3 or C-18
Tetrahydroaldosterone-3-glucuronide (detectable in 24-h urine)
Tetrahydrocortisol/tetrahydrocortisone glucuronides; free cortisol also in urine (24-h UFC for Cushing screening)
DHEA / DHEA-S
Liver + peripheral tissues
Desulfation (sulfatases in target tissues) regenerates free DHEA → can be converted to androstenedione/testosterone by 3β-HSD and 17β-HSD
17-ketosteroids (androsterone, etiocholanolone)
11β-HSD — cortisol/cortisone switch (LO 5)
Expressed in aldosterone target tissues — kidney collecting duct + distal colon + salivary glands + placenta. Converts cortisol (active at MR) → cortisone (INACTIVE). Prevents cortisol from activating MR
MR has SIMILAR affinity for cortisol and aldosterone. Cortisol plasma ~100-1000× higher than aldo → MR would be saturated by cortisol. 11β-HSD2 in MR target cells converts cortisol → cortisone → MR selectively activated by aldosterone
Expressed in liver + adipose + CNS (glucocorticoid target tissues). Converts cortisone → cortisol (REGENERATES active hormone). Why oral cortisone works (after hepatic activation). Inhibitors studied for metabolic syndrome
AME (Apparent Mineralocorticoid Excess) syndrome — autosomal recessive. Childhood severe HTN + hypokalemia + metabolic alkalosis + low renin + low aldo + normal cortisol. Treat with dexamethasone or spironolactone
Very high cortisol OVERWHELMS kidney 11β-HSD2 → cortisol binds MR → HTN + hypokalemia (especially ectopic ACTH). Mineralocorticoid-like picture without true aldo excess
Carrier protein changes (LO 5)
Estrogen drives hepatic CBG synthesis → CBG ↑ → total cortisol ↑. Free cortisol and ACTH remain normal → eucorticotropic
Liver failure → ↓ CBG synthesis. Nephrotic → urinary CBG loss. Total cortisol ↓. Free cortisol may remain normal
Free cortisol is active fraction; unchanged when CBG varies (free-hormone hypothesis). Short-term, free cortisol defended by HPA axis; total reflects carrier-hormone pool
Free cortisol — 24-h urine free cortisol (UFC), late-night salivary cortisol, or direct plasma free cortisol. Preferred when CBG abnormal (pregnancy, OCPs, liver disease)
LO 6
ON EXAM — ALDO on MR → ENaC, Na-K-ATPase, ROMK, SGK1 → Na+/H2O retention + K+ and H+ secretion (HTN + hypokalemia + metabolic alkalosis). CORTISOL on GR (widely expressed): trans-activation (PEPCK, G6Pase, annexin-1, IκB) + trans-repression (blocks NF-κB, AP-1 → anti-inflammatory). 11β-HSD2 protects MR from cortisol. Spironolactone/eplerenone/finerenone = MR antagonists
PROTEOLYSIS — stimulates ubiquitin-proteasome degradation of myofibrils; reduces AA uptake. Net: muscle wasting + proximal weakness (classic Cushing); AAs released to liver for gluconeogenesis
REGIONAL DIFFERENTIAL — lipolysis in subcutaneous limb fat (thin arms/legs in Cushing); lipogenesis in CENTRAL/TRUNCAL depots (moon facies, buffalo hump). Mechanism: different 11β-HSD1 + insulin sensitivity across depots
IMMUNOSUPPRESSION — lymphocyte apoptosis (↓ lymphocytes); inhibits cytokines (NF-κB block); inhibits PLA2 via annexin-1 (↓ PGs/LTs); demargination of neutrophils (↑ neutrophil count). Risk of opportunistic infection
Osteoporosis — direct inhibition of osteoblasts + stimulation of osteoclasts + ↑ RANKL. Also ↓ intestinal Ca2+ absorption + ↑ urinary Ca2+ → secondary hyperparathyroidism. Hallmark Cushing complication
PERMISSIVE for catecholamines — cortisol up-regulates α1-adrenergic receptors and increases vascular smooth muscle sensitivity to NE/Epi → maintains vascular tone + BP. Why Addisonian crisis includes hypotension refractory to pressors without cortisol
MR specificity — 11β-HSD2 trick (LO 6)
Similar or slightly higher for cortisol than aldosterone. MR is "mineralocorticoid" by physiologic function, not intrinsic affinity
Plasma cortisol ~100-1000× higher than aldosterone
Cortisol would saturate MR in kidney → chronic Na+ retention + K+ loss + HTN → permanent "apparent mineralocorticoid excess"
11β-HSD2 in MR target cells oxidizes cortisol's 11β-OH → 11-ketone → cortisone (low MR affinity). "Pre-receptor metabolism" makes MR functionally specific for aldosterone
MR antagonist (competitive). Used for: Conn, heart failure (RALES), resistant HTN, Cushing, ascites. Side effects: gynecomastia + impotence (AR antagonism), menstrual irregularities (PR activity), hyperkalemia
Selective MR antagonist — minimal AR/PR activity. Fewer sex-hormone side effects. Used in heart failure (EPHESUS post-MI), primary aldo, resistant HTN. Hyperkalemia still a risk
Nonsteroidal MR antagonist. Approved for DIABETIC CKD — reduces CV events + CKD progression. Less hyperkalemia than steroidal MR antagonists
Dexamethasone = pure GR agonist (negligible MR activity) — preferred when you want glucocorticoid without mineralocorticoid side effects (cerebral edema). Hydrocortisone (= cortisol) has some MR activity — physiologic replacement. Potency: dex >> methylprednisolone > prednisone > hydrocortisone
Synthetic MINERALOCORTICOID (high MR activity) + some GR activity. Used in: primary adrenal insufficiency (replaces aldo), orthostatic hypotension. Fludrocortisone > aldosterone in MR potency because it resists 11β-HSD2 inactivation
GR ANTAGONIST (also progesterone receptor antagonist — "RU-486"). Endocrine use: Cushing syndrome with hyperglycemia/diabetes (blocks cortisol action at GR). OB use: medical abortion (via PR antagonism). Does NOT lower cortisol levels — only blocks action, monitor clinically (not by cortisol labs)
Additional clinical pearls & pharmacology (LO 6)
Cortisol has a PERMISSIVE effect on vascular α1-adrenergic receptors — upregulates expression + catecholamine sensitivity. Without cortisol, pressors (NE, phenylephrine) fail to sustain vascular tone. Give IV hydrocortisone 100 mg FIRST — then pressors work. Classic exam and ICU trap
Anastrozole, letrozole (nonsteroidal, reversible); exemestane (steroidal, irreversible). Block aromatase (CYP19) → prevent C19 androgen → C18 estrogen conversion. Used in POSTMENOPAUSAL ER+ breast cancer (postmenopausal women rely on aromatase in adipose/skin for estrogen). Side effects: hot flashes, arthralgia, osteoporosis
Estrogen drives hepatic CBG synthesis → CBG UP → more bound cortisol → total cortisol rises. BUT hypothalamus/pituitary sense FREE cortisol (unchanged) → ACTH unchanged → no true hypercortisolism. Order 24-h urine free cortisol or late-night salivary cortisol to rule out Cushing in pregnancy / OCPs
LO 1–6 · USMLE Step 1 Style
10 questions — answers pre-revealed.
Q1. A C21 molecule with a 4-ring nucleus, a ketone at C-3, a double bond between C-4 and C-5, and hydroxyl groups at C-11 (β), C-17 (α), and C-21 is most likely:
A. Cholesterol
B. Cortisol
C. Testosterone
D. 17β-Estradiol
E. Aldosterone
B — Cortisol. Cortisol is a C21 pregnane with characteristic hydroxyl groups at C-11β, C-17α, C-21, plus 3-oxo-Δ4 A-ring. Cholesterol (A) is C27. Testosterone (C) is C19 with 17β-OH. Estradiol (D) is C18 aromatic. Aldosterone (E) has a distinctive C-18 aldehyde.
Q2. Protein that shuttles cholesterol from OMM to IMM for steroidogenesis?
A. StAR
B. CYP11A1
C. HMG-CoA reductase
D. LDL receptor
E. Adrenodoxin reductase
A — StAR. StAR shuttles cholesterol from OMM to IMM — the acute rate-limiting step, induced within minutes of ACTH via cAMP/PKA/CREB. CYP11A1 then CLEAVES cholesterol to pregnenolone on the IMM, but depends on StAR for substrate access. StAR mutation → congenital lipoid adrenal hyperplasia.
Q3. 52-year-old woman with adrenal adenoma, BP 195/110, K+ 2.8, metabolic alkalosis, elevated aldosterone, SUPPRESSED renin. Zone + signature enzyme?
A. Zona glomerulosa; aldosterone synthase (CYP11B2)
B. Zona fasciculata; CYP11B1
C. Zona reticularis; 17,20-lyase
D. Adrenal medulla; PNMT
E. Zona fasciculata; CYP21A2
A — Zona glomerulosa; aldosterone synthase. Conn syndrome. Aldosterone synthase (CYP11B2) is uniquely expressed in zona glomerulosa — uses DOC and corticosterone as substrates, performs final hydroxylation and C18 oxidation to aldosterone. “Low renin” = PRIMARY (autonomous aldo suppresses RAAS).
A. 11β-hydroxylase; DOC shunt
B. 21-hydroxylase; 17-OH-progesterone → DHEA/androstenedione shunt
C. 17α-hydroxylase; aldosterone shunt
D. 3β-HSD; mineralocorticoid shunt
E. Aldosterone synthase; cortisol shunt
B — 21-hydroxylase deficiency (classic salt-wasting CAH). MOST common CAH. 21-OH converts 17-OH-prog → 11-deoxycortisol AND progesterone → DOC. When blocked: cortisol ↓, aldo ↓ (hyponatremia, hyperkalemia, salt-wasting), 17-OH-progesterone accumulates → shunted via 17,20-lyase to DHEA/androstenedione → VIRILIZATION.
Q5. LONGEST half-life and MOST abundant circulating adrenal steroid?
A. Aldosterone
B. Cortisol
C. Free DHEA
D. DHEA-sulfate (DHEA-S)
E. 17-OH-progesterone
D — DHEA-sulfate. Made in zona reticularis by SULT2A1. Sulfation extends half-life to 8-10+ hours, making DHEA-S the most abundant circulating steroid hormone in humans. Aldosterone: shortest (~20 min). Cortisol: ~70-90 min. Free DHEA: ~30 min.
Q6. Aldosterone transcribes an apical Na+ channel in collecting duct. Gene product?
Q7. MR binds cortisol and aldosterone with similar affinity, but circulating cortisol is ~100-1000× higher than aldosterone. Why doesn't cortisol activate MR in kidney?
A. Cortisol cannot cross the membrane
B. 11β-HSD2 in collecting duct converts cortisol to cortisone (low MR affinity)
C. Cortisol is cleared by liver before reaching kidney
D. MR is only on apical membranes
E. CBG prevents cortisol entry
Q8. 28-year-old HIV/AIDS patient with fatigue, low cortisol, elevated ACTH, hyperpigmentation of palmar creases and buccal mucosa. Mechanism?
A. Aldosterone stimulates melanocytes
B. Low cortisol releases POMC transcription → ACTH + α-MSH rise together; MSH activates melanocortin receptors
C. 17-OH-progesterone stimulates melanocytes
D. Dexamethasone suppresses melanogenesis
E. 11β-HSD2 deficiency causes pigment retention
B — POMC produces both ACTH and α-MSH. Primary adrenal insufficiency (Addison, here HIV-related) → low cortisol → loss of feedback → POMC transcription soars. POMC cleaves to ACTH + β-endorphin + α-MSH. Elevated α-MSH (and ACTH itself) activates MC1R on melanocytes → hyperpigmentation (palmar creases, buccal mucosa, scars). Secondary AI (pituitary) has LOW ACTH → no hyperpigmentation.
Q9. Eplerenone vs spironolactone — which is TRUE of eplerenone?
A. Eplerenone has HIGHER androgen-receptor activity → more gynecomastia
B. Eplerenone is MORE selective for MR, with less PR/AR activity → fewer endocrine side effects
C. Eplerenone blocks only ENaC
D. Eplerenone is a GR antagonist
E. Eplerenone has no effect on K+
B — Eplerenone is more MR-selective. Spironolactone is a promiscuous steroid-receptor antagonist — MR block + anti-androgen + PR effects → gynecomastia, menstrual irregularities, decreased libido. Eplerenone is more MR-selective → fewer sex-hormone side effects but still K+-sparing. Both used in hyperaldo, heart failure, and resistant HTN. Finerenone is newer nonsteroidal MR antagonist for diabetic CKD.
Q10. FIRST committed step of steroid biosynthesis, catalyzed on the inner mitochondrial membrane?
A. Cholesterol transport into mitochondria by StAR
B. Cholesterol → pregnenolone by CYP11A1
C. 17-hydroxylation of pregnenolone by CYP17
D. 21-hydroxylation of 17-OH-progesterone by CYP21A2
E. 11β-hydroxylation of 11-deoxycortisol by CYP11B1
B — CYP11A1 (cholesterol → pregnenolone). CYP11A1 (= P450scc = desmolase) catalyzes cleavage of the cholesterol side chain on the INNER mitochondrial membrane → pregnenolone. This is the first committed step — the first enzymatic reaction irreversibly dedicated to the steroid pathway. StAR (A) is the RATE-LIMITING shuttle (transport, not enzymatic). CYP17, CYP21, CYP11B1 are downstream pathway-specific enzymes.