Endocrine Module 04Adrenal Hormone Synthesis & Action

1 · The 4-ring backbone

• Structure:
  • All steroids have 4 fused rings (A, B, C, D) — "cyclopentanoperhydrophenanthrene."end04 lecture
  • Derived from cholesterol, which has 27 carbons.
• Why it matters:
  • The shared backbone means steroid hormones are all lipophilic.
  • Hence they bind carrier proteins (CBG, albumin), cross plasma membranes, and act on intracellular receptors.

2 · Carbon count tells the class

• C21 — progestins and corticoids:
  • Cholesterol (C27) loses 6 carbons in the side-chain cleavage step → pregnenolone (C21).end04 lecture
  • All mineralocorticoids and glucocorticoids retain the C21 scaffold.
• C19 — androgens:
  • 17,20-lyase removes a 2-carbon side chain → androstenedione / DHEA (C19).
• C18 — estrogens:
  • Aromatase removes the C19 methyl group and aromatizes the A-ring → estrone / estradiol (C18).FA 3.11 Adrenal steroids and CAH; Bootcamp 6.10

3 · Double-bond (Δ) nomenclature

• Δ5 pathway:
  • Double bond between C5 and C6 (in the B ring).
  • Pregnenolone, 17-OH-pregnenolone, DHEA are Δ5 compounds.end04 lecture; FA 3.11
• Δ4 pathway:
  • Double bond between C4 and C5 (in the A ring).
  • Progesterone, 17-OH-progesterone, androstenedione are Δ4 compounds.
• 3β-HSD converts Δ5 → Δ4:
  • 3β-hydroxysteroid dehydrogenase moves the double bond from position 5 → 4 and oxidizes the C3 hydroxyl to a ketone.
  • This is the "gate" that converts precursors to the Δ4 pathway.

4 · Reading enzyme names

• Hydroxylases (-hydroxylase):
  • Add an -OH group at a specific carbon (e.g., 21-hydroxylase adds -OH at C21).FA 3.11 Adrenal steroids
• HSDs (hydroxysteroid dehydrogenases):
  • Oxidize/reduce an -OH group at a specific carbon.
  • 3β-HSD (Δ5 → Δ4) and 17β-HSD (androstenedione → testosterone).
• Lyases:
  • Cleave C-C bonds (e.g., 17,20-lyase cleaves between C17 and C20 to make C19 steroids).
• Aromatase:
  • Converts C19 androgens to C18 estrogens by aromatizing the A-ring (removes the C19 methyl).FA 3.11; Bootcamp 6.10

1 · Cholesterol sources

• Primary — LDL-receptor-mediated uptake:
  • Hepatocytes and steroidogenic cells express high levels of LDL-R.
  • ACTH upregulates LDL-R expression with some delay.end04 lecture
• Secondary — stored cholesterol esters:
  • Held in cytoplasmic lipid droplets.
  • Acute mobilization is via HSL.
• Tertiary — de novo synthesis:
  • From acetyl-CoA via HMG-CoA reductase (rate-limiting step for cholesterol synthesis).
  • Less important source for adrenal steroidogenesis.Bootcamp 6.01 Adrenal Gland Physiology

2 · HSL (hormone-sensitive lipase)

• Function:
  • Hydrolyzes cholesterol ester bonds, releasing free cholesterol.end04 lecture
• Activation:
  • PKA-mediated phosphorylation (downstream of cAMP from ACTH or AngII).
• Clinical relevance:
  • Acute steroidogenic response requires HSL + StAR together.

3 · StAR (steroidogenic acute regulatory protein)

• Function:
  • Shuttles cholesterol from the outer to the inner mitochondrial membrane.end04 lecture
  • Without StAR, desmolase sits idle with no substrate — so this transport is the true rate-limiting step.
• Regulation:
  • Transcription upregulated rapidly by cAMP-PKA (in minutes).
  • ACTH (adrenal cortex), LH (gonads), AngII + K⁺ (zona glomerulosa) all drive StAR expression.FA 3.11 Adrenal steroids and CAH
• Classic disease:
  • StAR mutation → congenital lipoid adrenal hyperplasia.
  • Lipid-engorged adrenals, profound deficiency of ALL steroid hormones.AI Generated · see end20 / end06

4 · Desmolase / P450scc / CYP11A1

• Names (all the same enzyme):
  • Cholesterol desmolase.
  • 20,22-desmolase.
  • CYP11A1.
  • P450scc (scc = side-chain cleavage).end04 lecture
• Reaction:
  • Two sequential hydroxylations (C20, C22) followed by C–C bond cleavage.
  • Removes 6 carbons (C27 → C21).
• Location:
  • Inner mitochondrial membrane.
• Cofactors:
  • NADPH, O₂, Fe (P450 heme).
• Pharmacologic inhibitors:
  • Ketoconazole (antifungal; inhibits desmolase + several CYPs).
  • Aminoglutethimide (historical).AI Generated · see end21

5 · cAMP coordinates everything

• Hormonal drivers:
  • ACTH at the adrenal cortex (binds MC2R Gs-coupled GPCR).end04 lecture
  • AngII + K⁺ at zona glomerulosa (binds AT1R Gq; raises intracellular Ca²⁺).
  • LH at gonads.
• Downstream actions:
  • ↑ HSL phosphorylation → more free cholesterol.
  • ↑ StAR transcription → more mitochondrial cholesterol import.
  • ↑ LDLR and P450scc expression (with some delay).end04 lecture

6 · Acute vs. chronic stimulation

• Acute response (minutes):
  • HSL activation + StAR transcription → rapid cortisol release.
• Chronic response (hours–days):
  • Upregulates LDLR for more cholesterol uptake.
  • Upregulates P450scc and downstream enzymes.
  • Causes adrenal cortex hyperplasia (e.g., in Cushing disease).AI Generated · see end19/20

1 · Histologic and functional zonation

• Zona Glomerulosa (15% of cortex):
  • Outermost, just deep to the capsule.
  • Cells in small nests ("glomerular" cluster appearance).end04 lecture; Physeo 6.07 Adrenal Glands
  • Primary stimulus: angiotensin II and K⁺.
• Zona Fasciculata (~75% of cortex, largest):
  • Middle zone, cells in long vertical cords ("fascicles").
  • Cells are lipid-rich ("spongiocytes") with a foamy cytoplasm.
  • Primary stimulus: ACTH.B&B 2.01 Adrenal Glands
• Zona Reticularis (~10% of cortex):
  • Innermost cortical layer, next to the medulla.
  • Cells in a branching reticular network; pigmented (lipofuscin).
  • Primary stimulus: ACTH (same as ZF but different enzyme suite).
• Adrenal medulla:
  • Center of the gland — a modified sympathetic ganglion.
  • Chromaffin cells (postganglionic sympathetic neurons) secrete catecholamines.end04 lecture (brief)

2 · Enzyme fingerprints — which enzymes each zone has

• Has:
  • All early steroidogenic enzymes (desmolase, 3β-HSD, 21-hydroxylase).
  • Aldosterone synthase (CYP11B2) — unique to ZG; catalyzes the final 3 steps to aldosterone.end04 lecture; FA 3.11
• Lacks:
  • 17α-hydroxylase → can't make cortisol or sex steroids.
• Makes:
  • Aldosterone (primary).
  • Traces of other mineralocorticoids (DOC, corticosterone).

• Has:
  • 17α-hydroxylase (activates glucocorticoid pathway).
  • CYP11B1 (11β-hydroxylase, the ZF version of 11β-hydroxylase).end04 lecture
• Has but at low levels:
  • 17,20-lyase — limited androgen output.
• Lacks (vs ZG):
  • Aldosterone synthase → cannot make aldosterone.
• Makes:
  • Cortisol (primary).
  • Corticosterone (minor).
  • Small amounts of adrenal androgens.

• Has:
  • Enhanced 17,20-lyase activity.
  • Sulfotransferase (converts DHEA → DHEA-S).end04 lecture
• Lacks / low:
  • NO 21-hydroxylase (can't make corticoids).
  • LOW 3β-HSD activity (stays in Δ5 pathway).
• Makes:
  • DHEA (primary) and DHEA-S.
  • Androstenedione (minor).
  • Small amounts of testosterone.FA 3.11 Adrenal steroids

3 · Development and lifetime changes in each zone

• Zona Reticularis (adrenarche):
  • Develops and begins secreting DHEA between ages 6–8 (adrenarche).end04 lecture
  • DHEA output peaks in mid-20s.
  • Declines steadily thereafter.
• Aging changes:
  • ZR thins with age → falling DHEA with preserved cortisol/aldosterone.
  • Contributes to age-related decline in adrenal androgen output.

4 · Clinical anchors by zone

• ZG pathology:
  • Primary hyperaldosteronism (Conn syndrome) → aldosterone-secreting adenoma.AI Generated · see end20
• ZF pathology:
  • Cortisol-secreting adenoma → ACTH-independent Cushing syndrome.AI Generated · see end20
  • Chronic ACTH hypersecretion (pituitary Cushing) → ZF hyperplasia.
• ZR pathology:
  • Androgen-secreting adrenal tumors → virilization.AI Generated · see end20
  • Premature adrenarche → early body odor, axillary/pubic hair.
• Medulla pathology:
  • Pheochromocytoma (chromaffin cell tumor) — catecholamine excess, "5 P's."AI Generated · see end20/21

5 · Why zonation matters for CAH

• CAH enzyme deficiencies have different consequences in each zone:
  • 21-hydroxylase deficiency: ZG (aldo) and ZF (cortisol) both impaired; ZR (no 21-hydroxylase anyway) unaffected for its own DHEA output, and substrate shunts into androgens.Bootcamp 6.11 21-hydroxylase Deficiency
  • 11β-hydroxylase deficiency: Cortisol blocked (ZF); DOC builds up (weak mineralocorticoid) + androgens rise.Bootcamp 6.13
  • 17α-hydroxylase deficiency: ZF cortisol and ZR sex steroids blocked; ZG still makes aldosterone / DOC → HTN + sexual infantilism.Bootcamp 6.12

1 · The three critical "forks" in steroidogenesis

• If 17α-hydroxylase is present:
  • Pregnenolone → 17-OH-pregnenolone → continues to cortisol or sex steroids.end04 lecture; FA 3.11
• If absent (ZG):
  • Pregnenolone → progesterone → mineralocorticoid pathway only.

• When active:
  • 17-OH-pregnenolone → DHEA (or 17-OH-progesterone → androstenedione).
• Tissue distribution:
  • High in ZR → mostly DHEA.
  • Low in ZF → little androgen output in normal cortisol synthesis.end04 lecture

• If active:
  • Converts Δ5 compounds (pregnenolone, 17-OH-preg, DHEA) to Δ4 compounds (progesterone, 17-OH-prog, androstenedione).
• Tissue variation:
  • Active in ZG and ZF.
  • Low in ZR → leaves DHEA in the Δ5 form.end04 lecture

2 · CAH deficiencies — how to reason through them

• The rule:
  • Block the enzyme → substrate accumulates upstream → shunts into alternative pathways.FA 3.11 Adrenal steroids and CAH; Pathoma 15.10
  • Cortisol deficiency removes negative feedback → ↑ ACTH → adrenal hyperplasia.

• Blocked steps:
  • Progesterone → DOC (blocks aldosterone).
  • 17-OH-progesterone → 11-deoxycortisol (blocks cortisol).Bootcamp 6.11 21-hydroxylase Deficiency
• Consequences:
  • ↓ cortisol, ↓ aldosterone.
  • Accumulated 17-OH-progesterone shunts into androgen pathway → ↑ androgens.
  • Clinical: salt wasting (hypovolemia, hyponatremia, hyperkalemia), virilization of XX fetuses, ambiguous genitalia.
  • Lab: ↑ 17-OH-progesterone (screening marker, state newborn screen).

• Blocked steps:
  • 11-deoxycortisol → cortisol (blocks cortisol).
  • DOC → corticosterone (blocks aldosterone… BUT).Bootcamp 6.13 11β-hydroxylase Deficiency
• Key twist — DOC accumulates:
  • 11-deoxycorticosterone (DOC) is itself a weak mineralocorticoid.
  • Its accumulation causes hypertension and hypokalemia despite "low" aldosterone.
• Consequences:
  • ↓ cortisol → ↑ ACTH → adrenal hyperplasia.
  • ↑ androgens (substrate shunts).
  • Clinical: virilization + HTN + hypokalemia.

• Blocked steps:
  • Pregnenolone → 17-OH-pregnenolone (blocks cortisol AND sex steroids).Bootcamp 6.12 17α-hydroxylase Deficiency
• Consequences:
  • ↓ cortisol, ↓ sex steroids.
  • Pathway shunts into mineralocorticoids → ↑ aldosterone, ↑ DOC → HTN, hypokalemia.
  • Clinical: 46,XY phenotypic female (no androgens) or 46,XX primary amenorrhea; HTN; hypokalemia.

3 · CAH memory mnemonic

• HYPER / HYPO rule:
  • HYPER-tension = 11 or 17.
  • HYPO-tension = 21.FA 3.11 Adrenal steroids and CAH
• Virilization rule:
  • 21 and 11 virilize (shunt into androgens).
  • 17 does NOT virilize (blocks sex steroids — underdeveloped genitalia).

1 · Carrier proteins — who carries what

• Primary cargo:
  • Cortisol — very high affinity, carries ~90% of cortisol.end04 lecture
  • Aldosterone — low affinity, carries some.
• Regulation (clinically relevant):
  • ↑ by estrogen (pregnancy, OCP, tamoxifen) → ↑ total cortisol but normal free cortisol.AI Generated · see end19/end21
  • ↓ by cirrhosis, nephrotic syndrome, severe sepsis.

• Role:
  • Low-affinity, high-capacity backup carrier for many steroids including aldosterone, DHEA, and DHEA-S.
  • For DHEA-S, albumin binds at HIGH affinity — this is unusual and drives DHEA-S's long half-life.end04 lecture
• Clinical:
  • ↓ albumin (liver failure, nephrotic syndrome, malnutrition) → altered free fractions and pharmacokinetics.

2 · Why DHEA-S lasts so much longer than DHEA

• DHEA:
  • Binds albumin loosely; T½ 15–30 min.
  • Freely filtered by kidneys.
• DHEA-S:
  • Sulfation by sulfotransferase (SULT2A1) in the zona reticularis.
  • The sulfate group drastically increases albumin binding affinity.
  • Bound DHEA-S cannot be filtered → T½ 7–10 hours.end04 lecture
• Why this matters:
  • DHEA-S serves as the circulating reservoir of adrenal androgen precursor.
  • DHEA-S can be reactivated peripherally (by sulfatase) when tissues need DHEA.
  • DHEA-S is the standard lab test for adrenal androgen activity.FA 3.11 Adrenal steroids

3 · Free hormone hypothesis — quick refresher

• Core principle:
  • Only the FREE (unbound) fraction is biologically active.
  • Bound hormone is an inert reservoir in equilibrium (Kd) with free.end01 lecture (previously completed); FA 3.14 Signaling
• Clinical implication:
  • Pregnancy raises CBG → raises TOTAL cortisol but free cortisol stays normal.
  • Don't be fooled by total cortisol in these states.AI Generated · see end19

4 · Hepatic inactivation

• Liver conjugation:
  • Glucuronide or sulfate conjugation at various hydroxyl groups.
  • Conjugated steroids are water-soluble → excreted in urine.end04 lecture
• 11β-HSD:
  • 11β-HSD2 (in aldosterone-target tissues like kidney) converts cortisol → cortisone (inactive at MR).
  • This is how cortisol is kept OFF mineralocorticoid receptors despite 1000× higher concentrations.AI Generated · see end06/end20
  • 11β-HSD1 in liver and adipose does the reverse (cortisone → cortisol) — amplifies cortisol exposure.

• Excretion:
  • DHEA filtered by kidney.
  • DHEA-S largely recirculates due to albumin binding, eventually deconjugated in tissues.end04 lecture

5 · Clinical half-life implications

• Cortisol (~70 min):
  • Short enough to show diurnal variation (peak ~6 AM, nadir ~midnight).
  • Used in midnight salivary cortisol test for Cushing screening.AI Generated · see end19/21
• Aldosterone (~20 min):
  • Too short for casual testing; aldosterone/renin ratio uses morning blood draw.AI Generated · see end20/21
• DHEA-S (7–10 h):
  • Stable single-draw lab — used to evaluate adrenal androgen excess (e.g., hirsutism workup).AI Generated · repro / endocrine

1 · Nuclear receptor mechanism — Type I (steroid) receptors

• Receptor location:
  • MR and GR sit in the cytoplasm, bound to HSP90 and HSP70 chaperones.end04 lecture; FA 3.15 Signaling pathways of steroid hormones

• Steps:
  • Steroid crosses the plasma membrane (lipophilic).
  • Binds receptor → HSPs dissociate.
  • Receptor dimerizes and translocates to nucleus.
  • Dimeric receptor binds palindromic hormone response elements (HRE) on DNA.
  • Transcription is upregulated or repressed (depending on coactivators/corepressors present).

• Genomic effects:
  • Require transcription + translation → take hours.end04 lecture; FA 3.15
• Non-genomic effects:
  • Some steroids have rapid effects (seconds to minutes) via membrane-associated receptors — less well-characterized but increasingly recognized.

2 · Aldosterone effects on the collecting duct

• Apical membrane:
  • ↑ ENaC (epithelial Na channel) — reabsorbs Na⁺ from the tubule.Physeo 6.07 Adrenal Glands; FA 3.11
  • ↑ ROMK (K⁺ channel) — secretes K⁺ into the tubule.
• Basolateral membrane:
  • ↑ Na/K-ATPase — drives the Na⁺ gradient; moves Na⁺ into blood.
• Intercalated cells (a-type):
  • ↑ H⁺-ATPase → secretes H⁺ into tubule.
  • Explains why hyperaldosteronism causes metabolic alkalosis.

• Net electrolyte effect:
  • Na⁺ + water reabsorbed (volume expansion).
  • K⁺ and H⁺ excreted (hypokalemia + metabolic alkalosis with excess aldosterone).AI Generated · see end19/20/21

• Colon, sweat, salivary glands:
  • All conserve Na⁺ and excrete K⁺ under aldosterone's control.
  • Dehydrated patients have low-sodium sweat and saliva as a result.

3 · Cortisol's broad effects

• Liver:
  • ↑ gluconeogenesis, ↑ glycogenesis (when insulin also present).FA 3.12 Cortisol
• Adipose:
  • ↑ lipolysis (releases FFA, glycerol for gluconeogenesis).
  • Redistribution of fat (central obesity in chronic excess).
• Muscle:
  • ↑ protein catabolism → releases AAs for gluconeogenesis.
  • Muscle wasting in chronic excess.
• Net:
  • Hyperglycemic effect — a diabetogenic stress hormone.

• Effects:
  • Suppresses NF-κB and cytokine transcription.
  • Reduces lymphocyte trafficking, eosinophil function.FA 3.12 Cortisol; Pathoma 15.10
  • Demargination of neutrophils (neutrophilia on CBC).
• Clinical uses:
  • Glucocorticoids are cornerstone immunosuppressants for autoimmune disease, transplant, asthma, and many others.AI Generated · see end21

• Cortisol permits catecholamine vasoconstriction:
  • Upregulates α1 adrenergic receptors on vascular smooth muscle.
  • Addisonian crisis = hypotension refractory to pressors until hydrocortisone is given.AI Generated · see end20/21

• Chronic excess:
  • ↓ osteoblast activity, ↑ osteoclast activity → osteoporosis.
  • Thin skin, purple striae, poor wound healing.AI Generated · see end20/21

4 · Cortisol–MR cross-reactivity and 11β-HSD2

• Why this matters:
  • Cortisol binds MR with the same affinity as aldosterone.
  • Cortisol circulates at ~1000× higher concentration than aldosterone.FA 3.11; B&B 2.01

• Expression:
  • 11β-HSD2 is expressed in aldosterone-target tissues (kidney collecting duct).
• Action:
  • Converts cortisol → cortisone (inactive at MR).
  • Protects MR from cortisol activation.Physeo 6.07

• Apparent mineralocorticoid excess syndrome:
  • Genetic 11β-HSD2 deficiency.
  • Glycyrrhizic acid (licorice) inhibits 11β-HSD2.AI Generated · see end20/21
• Clinical picture:
  • HTN with hypokalemia and metabolic alkalosis.
  • LOW renin AND low aldosterone (it's cortisol acting on MR).

5 · Clinical consequences of MR and GR action

• MR antagonists:
  • Spironolactone (nonselective; also binds AR, PR → gynecomastia).
  • Eplerenone (selective MR antagonist; fewer endocrine side effects).AI Generated · see end21
• GR modulators:
  • Dexamethasone, prednisone, hydrocortisone — varying potencies and mineralocorticoid activity.
  • Fludrocortisone — strong mineralocorticoid activity, used in Addison's.
  • Mifepristone — GR antagonist, used in select Cushing cases.AI Generated · see end21