Per-LO coverage of in-house lecture material with mechanism-focused active recall: synthesis flow charts, MOA pathways, hormone properties, definitions, and if-then cause/effect chains. Lecture 01 · Endocrine Block · Intro to Hormones — LOs 1–7
Per-Lecture: In-house lecture & LOs 1–7
In-House Anki:Bioch::ENDO::01-Intro-Hormones
Study Guide: Biochem · Unit 1 (Introduction to Hormone Action)
Name the three chemical classes of hormones used in lecture, with an example of each and a note on hydrophilic vs hydrophobic.
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Answer
1. Amino-acid derivatives (small molecules built from single AAs) — generally HYDROPHILIC: catecholamines (E, NE, DA), melatonin; the EXCEPTION is thyroid hormone which is hydrophobic.
3. Lipid derivatives — HYDROPHOBIC: • Steroids (built from cholesterol): cortisol, aldosterone, sex steroids, vitamin D. • Eicosanoids (built from arachidonic acid): prostaglandins, thromboxanes, leukotrienes, prostacyclins.
LO 2 · Solubility / Signaling Lecture Notes · In House Anki
How does solubility predict storage, circulation, receptor location, AND the signaling mode (direct vs indirect)?
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Answer
HYDROPHILIC (peptides, catecholamines) → STORED in vesicles → travel FREE in plasma → short ½-life (min) → cannot cross membrane → MEMBRANE receptors → INDIRECT signaling (transduction via 2nd messengers / ion channels / enzymes) with amplification.
HYDROPHOBIC (steroids, thyroid hormone, vitamin D) → NOT stored in most cells → travel BOUND to carriers → long ½-life (hr–days) → CROSS plasma membrane → INTRACELLULAR receptors (cytoplasm/organelle/nucleus, often transcription factors) → DIRECT signaling with slower gene-expression effects.
LO 2 · Glycoproteins Lecture Notes · In House Anki
What are the four glycoprotein hormones and what is the structural feature they share?
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Answer
TSH, LH, FSH, hCG
Shared α-subunit (identical across all four). Unique β-subunit confers specificity.
Clinical: hCG β-subunit similarity to TSH-β → molar pregnancy / choriocarcinoma can cause hyperthyroidism via TSH receptor cross-reactivity.
LO 3 · Catecholamines Lecture Notes · In House Anki
Write out the catecholamine synthesis pathway from precursor to epinephrine, naming each enzyme.
Rate-limiting actually = StAR protein (transports cholesterol from outer → inner mito membrane). Without StAR, desmolase has no substrate.
Stimulated by: ACTH (adrenal), LH (gonads) via cAMP/PKA.
LO 4 · Steroid Classes (C21/C19/C18) Lecture Notes · In House Anki
How are steroids classified by carbon count, and which classes are C21, C19, and C18?
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Answer
C21 steroids — progestins (progesterone) + corticoids (cortisol, aldosterone). Retain the cholesterol side chain largely intact.
C19 steroids — androgens (DHEA, androstenedione, testosterone). Side chain removed.
C18 steroids — estrogens (estradiol, estrone). Androgens further modified — aromatization of the A-ring by aromatase removes one more carbon → C18.
Vitamin D (secosteroid; calcitriol) is derived from cholesterol via UV photolysis → has a broken B-ring. Made in skin → liver → kidney.
LO 5 · Carriers Lecture Notes · In House Anki
Match each carrier protein to its hormone: CBG, TBG, SHBG, DBP, albumin.
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Answer
CBG (transcortin) → cortisol (also binds progesterone) TBG → T3 & T4 SHBG → testosterone, estradiol, DHT DBP → vitamin D / 25-OH-D Albumin → non-specific, low affinity, high capacity (all steroids, thyroid hormone)
LO 5 · Free Hormone Lecture Notes · In House Anki
State the free hormone hypothesis and give one clinical example of why it matters.
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Answer
Only the FREE (unbound) fraction is biologically active and available to receptors. Carrier-bound hormone = inactive reservoir.
Pregnancy: estrogen ↑↑ hepatic TBG → ↑total T4 — but free T4 unchanged → patient EUTHYROID despite high total T4.
Measure FREE T4, not total, to assess thyroid function in pregnancy or with OCPs.
LO 5 · Half-Life Lecture Notes · In House Anki
Why do lipid-soluble hormones (cortisol, T4) have long half-lives while water-soluble hormones (insulin, ACTH) have short ones?
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Answer
Carrier-bound hormones are protected from renal filtration and enzymatic degradation → slow release of free form → long ½-life (T4 ≈ 7 days; cortisol ≈ 60–90 min).
Water-soluble peptides circulate FREE → rapidly filtered/degraded by proteases → short ½-life (insulin ≈ 5 min; ACTH ≈ 10 min).
LO 6 · Receptor Types Lecture Notes · In House Anki
Classify hormone receptors by location + signaling, and match hormone class to receptor type.
LO 7 · Down-regulation Lecture Notes · In House Anki
Define receptor down-regulation and give a major clinical example.
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Answer
Prolonged high hormone levels → cell reduces receptor number (internalization/degradation) + reduces post-receptor signaling → decreased sensitivity to that hormone.
LO 7 · Permissiveness Lecture Notes · In House Anki
Define hormone permissiveness and give a high-yield example.
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Answer
Permissiveness: one hormone is REQUIRED for another hormone's full effect, even though hormone A has no direct effect itself.
Classic example:Cortisol permits catecholamine vascular effects → addisonian crisis presents with hypotension refractory to pressors because catecholamines can't vasoconstrict without permissive cortisol.
Also: T3 permits β-adrenergic sensitivity → tachycardia in hyperthyroidism.
LO 7 · Synthesis vs. Storage Lecture Notes · In House Anki
Contrast hormones released by synthesis-on-demand vs. stored-and-released. Give one example of each.
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Answer
Stored & released on demand (FAST, seconds): peptides (insulin, glucagon, GH, ACTH) stored in vesicles; catecholamines in chromaffin granules; thyroid hormone in colloid.
Synthesis-on-demand (SLOW, min–hr): steroid hormones — not stored; substrate + enzyme expression up-regulated when needed (e.g., ACTH → StAR induction → cortisol within minutes, peak hours).
LO 2 · Eicosanoids Lecture Notes · In House Anki
What are the eicosanoids, what single precursor molecule are they all built from, and name the four subclasses.
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Answer
Eicosanoids = lipid-derivative autacoids (act locally as hormones / paracrine / autocrine signals). All derived from arachidonic acid (20-carbon PUFA released from membrane phospholipids by phospholipase A2).
Four subclasses: • Prostaglandins (PGE₂, PGF₂α, PGD₂) — via COX • Thromboxanes (TXA₂) — via COX (platelets) • Prostacyclin (PGI₂) — via COX (endothelium) • Leukotrienes (LTB₄, LTC₄/D₄/E₄) — via lipoxygenase
LO 6 · Direct vs Indirect Lecture Notes · In House Anki
Define "direct" and "indirect" hormone signaling as used in the lecture. Which hormone classes use each, and how does the lag time differ?
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Answer
Indirect signaling — hydrophilic hormone binds a MEMBRANE receptor and transduces a signal across the bilayer (via 2nd messenger, ion channel, or enzyme). Amplification + fast onset (seconds–minutes). Used by peptides + catecholamines.
Direct signaling — hydrophobic hormone CROSSES the membrane and directly binds an INTRACELLULAR receptor (often a transcription factor in cytoplasm or organelle). No transduction step needed. Slower onset (hours) because it must change gene transcription. Used by steroids + thyroid hormone.
Caveat: some hydrophobic hormones also have rapid membrane-bound receptor effects — it's receptor-dependent.
LO 1 · Target Cells & Specificity Lecture Notes · In House Anki
Hormones reach nearly every cell in the body via the bloodstream — so what determines which cells respond?
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Answer
Receptors create specificity. A "target cell" is simply a cell that expresses the receptor for a given hormone. Cells without the receptor are effectively deaf to the hormone's signal, even though the hormone physically reaches them.
Consequences: • A tissue's sensitivity profile depends entirely on which receptors it expresses. • Pharmacologic blockers (e.g., spironolactone at the mineralocorticoid receptor) work by occupying the target receptor. • Receptor cross-reactivity (hCG at TSH-R in molar pregnancy; cortisol at MR when 11β-HSD2 is overwhelmed) explains unexpected clinical phenotypes.
LO 2 · Regulated vs Constitutive Lecture Notes · In House Anki
Define "regulated" vs "constitutive" hormone secretion. Which hormone classes use each pathway?
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Answer
REGULATED secretion: hormone is pre-synthesized, packaged into secretory granules/vesicles, and released by Ca²⁺-triggered exocytosis ONLY upon stimulus. Fast (seconds). • Peptides (insulin, ACTH, GH, PTH) — in secretory granules • Catecholamines — in chromaffin granules • Thyroid hormone — stored bound to thyroglobulin in colloid (unique: intra-lumenal store)
CONSTITUTIVE secretion: hormone is synthesized de novo on demand, cannot be stored, diffuses out immediately as it is made. Slow (min–hr). • Steroids — cholesterol → hormone via StAR + enzymes • Eicosanoids — arachidonic acid → PGs/LTs, locally
Rule of thumb: Lipid-soluble = can't be stored in vesicles → constitutive.
Anki #25 · LO 3 · Catecholamine Control In House Anki
Catecholamine production by neuroendocrine cells in the adrenal medulla is controlled by _____ ganglionic _____ fibers.
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Answer
Preganglionic sympathetic fibers. Adrenal chromaffin cells are modified postganglionic neurons — they receive direct preganglionic cholinergic input (ACh via nicotinic receptors) and dump Epi/NE straight into the bloodstream, bypassing the usual two-neuron chain.
Anki #37 · LO 1 · Juxtacrine In House Anki
_____ signaling involves direct cell-to-cell contact via growth factors and cytokines.
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Answer
Juxtacrine signaling. Requires membrane-bound ligand on one cell binding a receptor on an adjacent cell. Examples: Notch–Delta in development; membrane-bound TNF-α; EGF family members tethered to donor cell surface.
Anki #39 · LO 2 · Glycoprotein Subunits In House Anki
Glycoprotein hormones (FSH, LH, TSH, hCG) share a common _____ subunit and differ in _____ subunit.
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Answer
Shared alpha (α) subunit; unique beta (β) subunit confers specificity. Clinical: hCG-β is what pregnancy tests detect; hCG cross-reacts with TSH-R in molar pregnancy (high hCG → thyrotoxicosis).
Anki #40 · LO 6 · Receptor Location In House Anki
Steroid hormones act via _____ receptors; peptide hormones act via _____ receptors.
Anki #59 · LO 4 · Vitamin D Activation In House Anki
Vitamin D is activated in two _____ reactions: _____ (liver) and _____ (kidney).
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Answer
Two hydroxylation reactions: 25-hydroxylation in liver → 25-OH-D (calcidiol; storage form) then 1α-hydroxylation in kidney PCT → 1,25-(OH)₂-D (calcitriol; active form). Kidney step is rate-limiting — ↑ by PTH, ↓ Pi, ↓ Ca²⁺; ↓ by FGF23.
Anki #104 · LO 5 · TBG & Estrogen In House Anki
Estrogen increases TBG → _____ T4 but _____ free T4.
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Answer
Estrogen (pregnancy, OCPs) stimulates hepatic TBG synthesis. ↑ Total T4 (more carrier-bound) but normal free T4 (biologically active fraction unchanged). Patient is EUTHYROID. Always measure FREE T4 — not total — to judge thyroid status.
FIB 01 · LO 1 Lecture Notes · Study Guide
A hormone that acts on the SECRETING cell itself is called _____________ signaling, while one acting on an IMMEDIATE NEIGHBOR is called _____________.
Hint: "auto" = self; "para" = alongside.
FIB 02 · LO 2 Lecture Notes · Study Guide
Peptide hormones are synthesized as inactive _____________, cleaved in the RER/Golgi, and stored in secretory vesicles. Steroid hormones are NOT stored and must be _____________ on demand from cholesterol.
FIB 03 · LO 2 Lecture Notes · Study Guide
The four glycoprotein hormones — TSH, LH, FSH, hCG — share an identical _____________ subunit, with specificity conferred by the unique _____________ subunit.
Hint: hCG-β cross-reactivity with TSH causes hyperthyroidism in molar pregnancy.
FIB 04 · LO 3 Lecture Notes · Study Guide
The rate-limiting enzyme of catecholamine synthesis is _____________. The enzyme that converts norepinephrine → epinephrine is _____________, which is induced by cortisol.
Hint: PNMT is found only in the adrenal medulla because cortisol from the cortex induces it.
FIB 05 · LO 4 Lecture Notes · Study Guide
All steroid hormones are derived from _____________. The initial (rate-limiting) step is cleavage of the side chain by _____________, facilitated by the _____________ protein which shuttles substrate into mitochondria.
FIB 06 · LO 5 Lecture Notes · Study Guide
According to the free hormone hypothesis, only the _____________ fraction of a hormone is biologically active. In pregnancy, estrogen increases liver TBG production → total T4 rises but _____________ T4 is unchanged.
FIB 07 · LO 5 Lecture Notes · Study Guide
Match the carrier: cortisol travels on _____________; testosterone/estradiol on _____________; thyroid hormone on _____________.
FIB 08 · LO 6 Lecture Notes · Study Guide
Water-soluble hormones use _____________ receptors and act through second messengers, producing FAST effects. Lipid-soluble hormones use _____________ receptors and alter gene transcription, producing SLOW but long-lasting effects.
FIB 09 · LO 6 Lecture Notes · Study Guide
Insulin binds a _____________-type receptor (tyrosine kinase). GH and prolactin use _____________-STAT signaling. PTH, ADH (V2), and glucagon use Gs → _____________.
FIB 10 · LO 7 Lecture Notes · Study Guide
Prolonged exposure to HIGH hormone levels causes receptor _____________, which is the basis of insulin resistance in T2DM. Prolonged LOW levels cause receptor _____________, seen in denervation hypersensitivity.
FIB 11 · LO 2 Lecture Notes · Study Guide
Eicosanoids (prostaglandins, thromboxanes, leukotrienes, prostacyclins) are all derived from the 20-carbon fatty acid _____________, which is released from membrane phospholipids by _____________. NSAIDs block the COX arm of this pathway.
Hint: corticosteroids inhibit this enzyme — explaining their broader anti-inflammatory effect vs. NSAIDs.
FIB 12 · LO 7 Lecture Notes · Study Guide
On a hormone dose-response curve, the hormone concentration producing half the maximal response is called the _____________. In insulin resistance, this value is _____________ (higher/lower), corresponding to a _____________ shift of the curve.
FIB 13 · LO 2 Lecture Notes · Study Guide
Match each hormone class to its storage form: Peptide hormones are stored in _____________; catecholamines are stored in _____________; thyroid hormone is stored as iodinated _____________ in follicular colloid; and steroid hormones are _____________ (stored/not stored).
Hint: Steroids are made on demand — substrate (cholesterol) is stored, not the hormone itself.
FIB 14 · LO 4 Lecture Notes · Study Guide
The three adrenal cortex zones make DIFFERENT steroid products based on which enzymes they express. Zona _____________ → aldosterone (lacks 17α-hydroxylase); zona _____________ → cortisol; zona _____________ → DHEA / androgens. In 21-hydroxylase deficiency (the most common CAH), substrate builds up upstream and is shunted into the _____________ pathway, causing virilization.
Hint: Mnemonic "GFR" (outer → inner) = Glomerulosa / Fasciculata / Reticularis. Blocking an enzyme shunts substrate to alternate arms.
Instructions: Drag and drop the items into the correct order, then click "Check Order." Use "Show Answer" if you get stuck.
Nuclear receptor — hours to days (must alter gene transcription + make new protein)
Drill 6 · LO 6 — Gs-GPCR Cascade: Hormone Binding → Cellular Response Lecture Notes · Study Guide
Tests Reference tab → "Membrane Receptor Signaling Quick Map" (Gs row). Order the six intracellular events after a Gs-coupled hormone (e.g., glucagon, PTH, ACTH, β-adrenergic) binds its receptor.
⠿Adenylyl cyclase converts ATP → cAMP (second messenger amplification)
PKA phosphorylation → response — glucose mobilization (glucagon), steroid synthesis (ACTH), Ca reabsorption (PTH), etc.
Drill 7 · LO 4 — Cortisol Biosynthesis: Cholesterol → Cortisol Lecture Notes · Study Guide
Tests Reference tab → "Steroid Biosynthesis Roadmap" (zona fasciculata pathway). Order the six enzymatic steps from cholesterol precursor to finished cortisol.
⠿17α-hydroxylase (CYP17) → 17-OH-Pregnenolone
⠿StAR protein shuttles cholesterol into inner mitochondrial membrane (ACTH-regulated)
Late T2DM — β-cell exhaustion + severe insulin resistance
Score: 0/4 correct
Set 8 · LO 2/5 — Hormone → Half-Life Range (Reference Tab)
Tests the "Hormone Class Master Table" + free-hormone / carrier concepts. Half-life tracks solubility and carrier status: hydrophilic = short, steroid = hours, thyroid = days.
Hormone
Epinephrine (catecholamine)
Insulin (peptide)
Cortisol (steroid)
T4 / Thyroxine
T3 / Triiodothyronine
Approximate Half-Life
~7 days (longest — hydrophobic, highly bound to TBG)
~1–2 minutes (shortest — hydrophilic, no carrier)
~1.5 days (hydrophobic, less TBG affinity than T4)
~60–90 minutes (hydrophobic, bound to CBG/albumin)
~5–10 minutes (hydrophilic peptide)
Score: 0/5 correct
Set 9 · LO 3 — Drug / Inhibitor → Target Catecholamine Enzyme (Reference Tab)
Tests the "Catecholamine Biosynthesis Enzyme Map" from a pharmacology angle. Each drug or condition blocks a specific enzyme in the Tyr → L-DOPA → DA → NE → Epi pathway.
Dopamine β-hydroxylase — ↓ NE + Epi; ↑ dopamine (makes cocaine more toxic)
Tyrosine hydroxylase — blocks RATE-LIMITING step; ↓ all catecholamines
PNMT (fails to be induced without local cortisol) — ↓ Epi from adrenal medulla
DOPA decarboxylase (AADC) — peripheral block only (does not cross BBB)
Score: 0/4 correct
Set 10 · LO 5 — Clinical Scenario → Carrier Change + Lab Pattern (Reference Tab)
Tests the "Carrier Protein Quick Reference" + free hormone hypothesis. Each scenario changes a specific carrier; only FREE hormone tracks clinical status.
↓ SHBG (insulin suppresses) → ↓ TOTAL testosterone with normal FREE → eugonadal
↑ TBG + ↑ CBG (estrogen-driven) → ↑ TOTAL T4 and ↑ TOTAL cortisol; FREE hormones normal → euthyroid + eucortisolic
↓ albumin (urinary loss or ↓ synthesis) → ↓ TOTAL hormones; FREE fractions unchanged
Score: 0/4 correct
If-Then Cascade Drills: Each drill starts with an initial perturbation (a trigger — drug, enzyme defect, clinical state). Click "Predict →" at each step to test your downstream reasoning: molecular change → hormone/carrier/enzyme consequence → measured labs → clinical finding. Use these as mini "flowchart in your head" rehearsals before you open the reference table to verify.
Cascade 1 · LO 5 — Carrier Change → Lab Pattern: Pregnancy & TBG/CBG Lecture Notes · Study Guide
Estrogen induces hepatic TBG and CBG gene transcription → more carrier protein synthesized and secreted by the liver. SHBG is also induced, but TBG and CBG are the main clinical story here.
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Step 2 Hormone kinetics
↑ TBG binds more T4/T3 → initially ↓ free T4 → TSH rises briefly → thyroid compensates by producing more T4 → TOTAL T4 rises, free T4 normalizes. ↑ CBG does the same for cortisol: total cortisol rises, free cortisol stays normal.
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Step 3 Labs
TOTAL T4 ↑ · FREE T4 NORMAL · TSH NORMAL TOTAL cortisol ↑ · FREE cortisol NORMAL · 24-hr urine FREE cortisol NORMAL SHBG ↑ → TOTAL testosterone ↑ (free usually normal)
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Step 4 Clinical
Patient is clinically EUTHYROID and EUCORTISOLIC. Do NOT start levothyroxine or work up Cushing based on elevated totals. The teaching point: always order FREE T4 and either 24-hr urine free cortisol or late-night salivary cortisol in pregnancy/OCP users — totals will mislead you.
Cascade 2 · LO 5 — Carrier Change → Lab Pattern: Hyperinsulinemia & SHBG Lecture Notes · Study Guide
Chronic high insulin suppresses hepatic SHBG gene transcription → liver secretes LESS SHBG into the blood. (The same insulin signal also suppresses IGFBP-1.)
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Step 2 Hormone kinetics
↓ SHBG means less testosterone and estradiol can be carrier-bound → more of each is free transiently, but over time gonadal feedback adjusts production so that FREE hormone re-equilibrates. Net: TOTAL testosterone falls, FREE testosterone stays near-normal.
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Step 3 Labs
SHBG ↓ · TOTAL testosterone ↓ · FREE testosterone NORMAL (or slightly elevated) · LH/FSH normal. Similar pattern for free estradiol.
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Step 4 Clinical
The obese man with low TOTAL testosterone is most often eugonadal — he does NOT need testosterone replacement based on low total alone. Always confirm with FREE (or bioavailable) testosterone. PCOS presents the mirror image in women: hyperinsulinemia → ↓ SHBG → ↑ FREE testosterone → clinical hyperandrogenism (hirsutism, acne, anovulation).
Cascade 3 · LO 4 — Enzyme Affected → Downstream Effect: 21-OH Deficiency (Classic CAH) Lecture Notes · Study Guide
TriggerClassic salt-wasting 21-hydroxylase (CYP21) deficiency — ~95% of CAH cases.
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Step 1 Enzyme block
21-hydroxylase (CYP21) normally acts on BOTH the cortisol arm (17-OH-progesterone → 11-deoxycortisol) and the aldosterone arm (progesterone → 11-DOC). With enzyme loss, BOTH arms are interrupted.
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Step 2 Substrate shunt
Upstream 17-OH-progesterone accumulates and is shunted through the intact 17,20-lyase pathway → ↑ DHEA + androstenedione (→ testosterone peripherally). Progesterone also accumulates but is not as potently androgenic.
↑ 17-OH-progesterone (the classic newborn screening marker; the analyte is specifically above the 21-OH block). ↑ ACTH · ↓ cortisol · ↓ aldosterone · ↑ renin Electrolytes: ↓ Na⁺, ↑ K⁺, metabolic acidosis (hyponatremia + hyperkalemia + acidosis → salt-wasting crisis). ↑ DHEA-S, ↑ androstenedione, ↑ testosterone (especially relevant in XX infants).
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Step 5 Clinical
Neonate presents in the first 1–2 weeks with salt-wasting crisis: poor feeding, vomiting, dehydration, lethargy, hypotension, hyperkalemia, metabolic acidosis. XX infants have ambiguous genitalia from in-utero virilization (clitoromegaly, fused labia). XY infants have normal male genitalia but present with adrenal crisis — easy to miss until the electrolyte panel comes back. Treatment: replace cortisol (hydrocortisone) + fludrocortisone (mineralocorticoid) + salt.
Cascade 4 · LO 3 — Enzyme Affected → Downstream Effect: Carbidopa + L-DOPA in Parkinson's Lecture Notes
Trigger
Parkinson's patient started on oral L-DOPA combined with carbidopa. Why the combination?
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Step 1 Enzyme block
Carbidopa inhibits DOPA decarboxylase (AADC) — the enzyme that converts L-DOPA → dopamine. Critically, carbidopa does NOT cross the blood-brain barrier, so it inhibits AADC in the periphery but NOT in the CNS.
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Step 2 Drug kinetics
Without carbidopa, ~95% of oral L-DOPA is converted to dopamine peripherally (gut, liver, vascular tissue) and never reaches the CNS. With carbidopa, peripheral AADC is blocked → much more L-DOPA survives to cross the BBB → central AADC (in surviving nigrostriatal neurons) converts it to dopamine where it's needed.
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Step 3 CNS outcome
More central dopamine → improved nigrostriatal dopaminergic tone → reduction in bradykinesia, rigidity, tremor. Effective L-DOPA dose is lowered (because more reaches the brain), and the ratio of L-DOPA to peripheral dopamine shifts favorably.
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Step 4 Side-effect profile
Peripheral dopamine formation is the main source of the bad side effects: nausea and vomiting (area postrema — outside the BBB!), orthostatic hypotension, and arrhythmias. By blocking peripheral AADC, carbidopa dramatically reduces these side effects. This is a pure application of the "block the enzyme upstream where you DON'T want the product" principle from the catecholamine enzyme map.
Cascade 5 · LO 5 — Carrier Change → Lab Pattern: Hypoalbuminemia Lecture Notes · Study Guide
Trigger
Patient with nephrotic syndrome (urinary albumin loss) or advanced cirrhosis (↓ hepatic albumin synthesis). Serum albumin 1.8 g/dL (normal 3.5–5.0).
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Step 1 Molecular
↓ Albumin — the "low-affinity, high-capacity" bulk carrier — affects MANY hormones simultaneously (cortisol that spills over from CBG, steroids, thyroid hormones, many drugs).
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Step 2 Hormone kinetics
Total hormone concentrations fall proportionally (less carrier to occupy). Free fraction initially ↑ transiently → sensed by feedback → hormone production ADJUSTS DOWN so that free hormone returns to normal. Crucially, CBG/TBG/SHBG are not the primary bulk carriers for most hormones, so their function is preserved.
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Step 3 Labs
TOTAL cortisol ↓ · FREE cortisol normal · ACTH normal TOTAL T4 ↓ · FREE T4 normal · TSH normal TOTAL calcium may be ↓ (roughly 0.8 mg/dL per 1 g/dL drop in albumin) · IONIZED calcium NORMAL
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Step 4 Clinical
Patient is clinically normal for these axes — no replacement indicated. The teaching: always correct total calcium for albumin (or just order ionized). In nephrotic syndrome, don't chase low total T4 with levothyroxine if TSH + free T4 are normal. Same for cortisol.
Cascade 6 · LO 2/6 — Glycoprotein α/β Subunits → Cross-Reactivity: Molar Pregnancy Hyperthyroidism Lecture Notes · Study Guide
Trigger
19-year-old woman with hydatidiform mole (or metastatic choriocarcinoma) — serum β-hCG > 1,000,000 mIU/mL (normal pregnancy peaks ~100,000).
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Step 1 Molecular
Glycoprotein hormones TSH, LH, FSH, and hCG share an identical α-subunit. The β-subunits confer receptor specificity — but hCG-β has partial amino-acid homology to TSH-β and can weakly bind/activate the TSH receptor on thyroid follicular cells.
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Step 2 Receptor activation
At pathologic hCG levels (molar pregnancy, choriocarcinoma), the weak cross-reactivity becomes clinically meaningful → TSH receptor (a Gs-coupled GPCR) activated → ↑ cAMP in follicular cells → ↑ T4/T3 synthesis and release.
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Step 3 Labs
↑ Free T4 · ↓ TSH (suppressed by thyroid hormone's negative feedback on pituitary) · ↑↑ β-hCG (sign of the trigger) · negative TSI/TRAb (distinguishes from Graves').
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Step 4 Clinical
Transient hyperthyroidism — heat intolerance, tremor, tachycardia, weight loss — alongside signs of the trophoblastic disease (vaginal bleeding, grape-like vesicles, exaggerated nausea, rapid uterine enlargement). Treating the mole (D&C) resolves the hyperthyroidism because the trigger disappears. Similar cross-reactivity drives gestational transient thyrotoxicosis in normal pregnancy (milder).
Cascade 7 · LO 3 — Enzyme Affected → Downstream Effect: Metyrosine Pre-Op Pheochromocytoma Lecture Notes · Study Guide
Trigger
Patient with a functional pheochromocytoma being prepared for surgery. Metyrosine (α-methyl-para-tyrosine) is started 1–3 weeks preoperatively.
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Step 1 Enzyme block
Metyrosine is a competitive inhibitor of tyrosine hydroxylase (TH) — the rate-limiting step of catecholamine biosynthesis (tyrosine → L-DOPA). No other enzyme can compensate.
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Step 2 Pathway effect
Block at TH → ALL downstream catecholamines are depleted: ↓ L-DOPA, ↓ dopamine, ↓ norepinephrine, ↓ epinephrine. The tumor (and the rest of the body) gradually exhausts its stored catecholamine pool.
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Step 3 Labs / physiology
↓ Urinary metanephrines + VMA (catecholamine metabolites). Blood pressure falls; heart rate may rebound ↑ transiently (baroreflex), but is typically blunted too. Always combined with α-blockade (e.g., phenoxybenzamine) THEN β-blockade — never β-blockade alone (unopposed α → crisis).
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Step 4 Clinical
During tumor handling, intraoperative catecholamine release is much smaller → safer hemodynamics, reduced risk of hypertensive crisis, arrhythmia, and stroke. Side effects of metyrosine mirror the block: sedation, depression, Parkinsonism (↓ CNS dopamine), galactorrhea (↓ dopamine → disinhibited prolactin).
Cascade 8 · LO 3/7 — Enzyme Affected + Loss of Permissiveness: Primary Adrenal Insufficiency (Addison) Lecture Notes · Study Guide
Trigger
Patient with autoimmune primary adrenal insufficiency (Addison's disease) — adrenal cortex destroyed; cortex-derived cortisol falls to near zero. Adrenal medulla is anatomically present.
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Step 1 PNMT induction fails
PNMT (phenylethanolamine-N-methyltransferase) in the adrenal medulla requires high local cortisol delivered by the intra-adrenal portal venous system. Without cortisol, PNMT gene expression is NOT induced → ↓ NE→Epi conversion → ↓ medullary epinephrine output.
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Step 2 Loss of permissiveness
Cortisol is permissive for catecholamine vasoconstriction — it up-regulates α₁-adrenergic receptors on vascular smooth muscle. Without cortisol, α₁ receptor expression falls → catecholamines can't effectively constrict vessels even if they are present.
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Step 3 Hemodynamics
Double hit: less circulating Epi (PNMT failure) + blunted vascular response to whatever catecholamines exist (loss of permissiveness) → refractory hypotension. Mineralocorticoid failure compounds this by causing volume depletion (↓ Na⁺ reabsorption, ↑ K⁺ retention).
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Step 4 Labs + Clinical
Labs: ↓ cortisol, ↑ ACTH (loss of feedback) → hyperpigmentation (ACTH shares precursor POMC with α-MSH); ↓ aldosterone, ↑ renin, ↓ Na⁺, ↑ K⁺; ↓ urinary metanephrines over time. Clinical: fatigue, weight loss, salt craving, abdominal pain, hyperpigmentation of palmar creases + buccal mucosa, postural dizziness. Crisis trigger: any stressor (illness, surgery, trauma) → refractory shock despite IV fluids + pressors until IV hydrocortisone is given.
Cascade 9 · LO 7 — Receptor Sensitivity → Dose-Response Curve: Hyperinsulinemia → T2DM Evolution Lecture Notes · Study Guide
Trigger
Obese patient with chronic hyperinsulinemia (fasting insulin persistently elevated over months to years).
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Step 1 Receptor
Prolonged HIGH ligand exposure → insulin receptors are internalized (endocytosed), and those remaining are desensitized (ser/thr phosphorylation of IRS). Result: ↓ receptor NUMBER + ↓ receptor AFFINITY.
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Step 2 Dose-response curve
Curve shifts RIGHTWARD (↑ EC50 — more insulin needed for half-max response) AND Vmax decreases (plateau lowered — maximum response is blunted). This combination is the classic "insulin resistance" curve.
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Step 3 Compensation
Pancreatic β-cells sense hyperglycemia and secrete MORE insulin to overcome resistance → serum insulin rises further → receptors down-regulate further (positive-feedback to pathology). Euglycemia is maintained briefly through hyperinsulinemia.
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Step 4 β-cell exhaustion
Over years, chronic hypersecretion + glucotoxicity + lipotoxicity exhaust β-cells (amyloid deposition, apoptosis). Insulin secretion falls → euglycemia can no longer be maintained → overt T2DM (fasting glucose > 126 mg/dL, A1c > 6.5%).
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Step 5 Clinical evolution
Progression: metabolic syndrome (central obesity + dyslipidemia + HTN + hyperinsulinemia, acanthosis nigricans) → impaired fasting glucose / prediabetes → early T2DM (high insulin, high glucose) → late T2DM (low insulin, very high glucose — insulin-requiring). Reversibility is greatest early; β-cell mass loss is increasingly irreversible. Key targets: weight loss, exercise (restore receptor sensitivity), metformin (↑ receptor sensitivity peripherally).
Cascade 10 · LO 2/4 — Enzyme Affected → Downstream Effect: NSAIDs Block COX → Eicosanoid Loss Lecture Notes · Study Guide
Trigger
Patient started on a non-selective NSAID (ibuprofen, naproxen) for chronic pain.
↓
Step 1 Enzyme block
Arachidonic acid is released from membrane phospholipids by phospholipase A2, then metabolized by either COX → prostaglandins / thromboxanes / prostacyclin OR 5-LOX → leukotrienes. NSAIDs inhibit COX-1 and COX-2, leaving the LOX arm intact.
↓
Step 2 Loss of prostanoids
↓ PGE2 (inflammation, pain, fever, protective GI mucus, renal vasodilation) ↓ PGI2 / prostacyclin (vasodilation, anti-platelet) ↓ TXA2 (platelet aggregation, vasoconstriction) — especially after COX-1 inhibition in platelets LOX arm is NOT blocked → leukotrienes can rise (substrate shunt) → can precipitate aspirin-sensitive asthma.
↓
Step 3 Therapeutic effects
Anti-inflammatory (↓ PGE2 in tissue) · Analgesic (↓ peripheral sensitization of nociceptors) · Antipyretic (↓ PGE2 at hypothalamic set-point) · Anti-platelet (↓ TXA2; aspirin is irreversible and potent on platelet COX-1).
↓
Step 4 Side effects
GI: ↓ PGE2 → ↓ mucus + ↓ bicarbonate → peptic ulceration, bleeding. Renal: ↓ PGE2/PGI2 → loss of afferent arteriolar vasodilation → ↓ GFR, especially in hypovolemia → AKI. Cardiovascular: ↓ PGI2 + ↑ Na/H₂O retention → ↑ BP; COX-2-selective agents shift the PGI2 / TXA2 balance toward pro-thrombotic (↑ MI, stroke risk). Asthma: shunted leukotrienes can trigger bronchospasm in sensitive patients.
Test Trap Mode: Each statement is either TRUE or FALSE as written. Many are designed to catch common exam errors. Click T or F — then read the explanation carefully.
Trap 01 · LO 1 Lecture Notes
"A paracrine signal is characterized by a hormone being secreted into the bloodstream and acting on nearby cells."
Trap 02 · LO 2 Lecture Notes
"Steroid hormones, unlike peptide hormones, are stored in secretory vesicles and released on demand."
Trap 03 · LO 3 Lecture Notes
"The rate-limiting enzyme in catecholamine biosynthesis is dopamine β-hydroxylase."
Trap 04 · LO 3 Lecture Notes · Study Guide
"PNMT converts norepinephrine to epinephrine and is found throughout the sympathetic nervous system."
Trap 05 · LO 4 Lecture Notes
"Cortisol, aldosterone, estrogen, and thyroid hormone all derive from cholesterol and share the same first enzymatic step."
Trap 06 · LO 5 Lecture Notes · Study Guide
"A pregnant woman with elevated total T4 but normal free T4 is hyperthyroid and should be treated with methimazole."
Trap 07 · LO 6 Lecture Notes
"Nuclear receptors (like the glucocorticoid receptor) produce rapid effects within seconds because they act directly on ion channels."
Trap 08 · LO 7 Lecture Notes · Study Guide
"In insulin resistance, pancreatic β-cells respond by up-regulating insulin receptors on hepatocytes to compensate."
Trap 09 · LO 2 Lecture Notes
"Prostaglandins, thromboxanes, and leukotrienes are peptide hormones derived from precursor amino acids in the liver."
FALSE. Eicosanoids (prostaglandins, thromboxanes, leukotrienes, prostacyclins) are LIPID derivatives built from arachidonic acid, which is released from membrane phospholipids by phospholipase A2. They act locally (paracrine/autocrine), not as classical systemic hormones, and are NOT peptide hormones.
Trap 10 · LO 5 Lecture Notes · Study Guide
"The protein-bound fraction of a circulating hormone is the biologically active fraction, because it is protected from degradation."
FALSE. Per the free hormone hypothesis, only the free (unbound) fraction is biologically active — it is what binds receptors and senses feedback. Carrier-bound hormone is INACTIVE but serves as a reservoir that extends half-life and protects from renal/hepatic clearance. Changes in carrier levels (pregnancy → ↑TBG, ↑CBG) shift TOTAL hormone but NOT free hormone → patient remains clinically euthyroid / eucortisolic.
Trap 11 · LO 6 Lecture Notes · Study Guide
"The thyroid hormone receptor (TR) sits in the cytoplasm and only enters the nucleus AFTER binding T3, like the glucocorticoid receptor."
FALSE — classic board trap. TR (and RAR, VDR) are already bound to DNA (HRE) in the absence of hormone, actively REPRESSING transcription. When T3 arrives it DE-REPRESSES and activates transcription. Glucocorticoid receptor (GR) IS cytoplasmic until cortisol binds → then translocates. Know the distinction: steroid receptors (GR/MR/AR/PR/ER) = cytoplasmic→nuclear; thyroid/retinoid receptors (TR/RAR/VDR) = DNA-bound repressors.
Trap 12 · LO 7 Lecture Notes · Study Guide
"Permissiveness means one hormone amplifies the effect of another; in the absence of the permissive hormone, the primary hormone has zero effect."
TRUE. Permissiveness = one hormone is REQUIRED for another to exert its full effect. Classic example: cortisol is permissive for catecholamine vasoconstriction — without cortisol, α₁ receptors fail to up-regulate and catecholamines cannot maintain vascular tone → addisonian shock. Another example: thyroid hormone is permissive for normal growth via upregulation of GH receptors.
Trap 13 · LO 3 Lecture Notes
"Post-ganglionic sympathetic neurons and the adrenal medulla both release epinephrine as their primary catecholamine, because both express PNMT."
FALSE. Post-ganglionic sympathetic neurons release NOREPINEPHRINE (they lack PNMT). Only the adrenal medulla expresses PNMT, because PNMT is induced by local cortisol delivered via the intra-adrenal portal venous system from the adrenal cortex. This is why adrenal medulla output is ~80% epinephrine while sympathetic nerves release NE at target organs.
Trap 14 · LO 1 Lecture Notes
"Neural signaling acts over seconds to minutes, while endocrine signaling is essentially instantaneous because hormones reach target organs in milliseconds."
FALSE — reversed. Neural signaling is FAST (milliseconds, via synapse); endocrine signaling is SLOW (seconds → hours, because hormones must travel through the bloodstream to reach distant targets and then trigger intracellular cascades). This trade-off is exactly why the body has both systems: nervous for rapid discrete responses, endocrine for sustained coordinated responses.
Trap 15 · LO 4 Lecture Notes · Study Guide
"The zona reticularis is the dominant source of cortisol in the adrenal cortex, while the zona fasciculata produces DHEA and other androgen precursors."
FALSE — reversed. The zones go outer → inner as G-F-R: zona Glomerulosa → ALDOSTERONE (regulated by Ang II / K⁺); zona Fasciculata → CORTISOL (regulated by ACTH); zona Reticularis → DHEA / androgens. A useful mnemonic is "Salt, Sugar, Sex" for glomerulosa/fasciculata/reticularis products. Reticularis lacks 21-hydroxylase and aldosterone synthase, so it CAN'T make cortisol or aldosterone.
Trap 16 · LO 4 Lecture Notes · Study Guide
"In classic 21-hydroxylase deficiency (the most common CAH), substrate backs up and is shunted through the intact 17α-hydroxylase pathway — leading to ↑ DHEA/androgens, virilization, and ↓ cortisol AND ↓ aldosterone."
TRUE. 21-hydroxylase (CYP21) deficiency accounts for ~95% of CAH. Blocking the 21-OH step prevents conversion to both 11-deoxycorticosterone (aldo arm) AND 11-deoxycortisol (cortisol arm) → ↓ aldo (salt-wasting, hyperkalemia, hypotension) + ↓ cortisol (loss of negative feedback → ↑ACTH). Upstream substrate (progesterone / 17-OH-progesterone — the classic screening marker) shunts through the intact 17,20-lyase pathway to DHEA → VIRILIZATION. This is the "block upstream → substrate shunt downstream" principle used throughout steroid biochemistry.
Reference Tab MCQs: Ten Step 1-style questions that directly test the content of the Reference tables. Select the best answer — the explanation appears automatically.
Question 1 of 10 · LO 2 — Hormone Class Properties Lecture Notes · Study Guide
A medical student reviews the Hormone Classes Master Comparison and asks: "Which class behaves like a steroid (carrier-bound, nuclear receptor, long half-life) despite being structurally an amine?"
ACatecholamines
BThyroid hormone (T3/T4)
CEicosanoids
DPeptide hormones
EVitamin D
B — Thyroid hormone. Per the reference table, thyroid hormone is an amine (derived from tyrosine + iodine on thyroglobulin) but behaves like a steroid: hydrophobic, carrier-bound (TBG), long half-life (T4 ~7 days), nuclear receptor. Catecholamines (A) are hydrophilic amines with GPCR signaling. Eicosanoids (C) are lipid-derived but act locally via GPCRs. Vitamin D (E) is a secosteroid (also nuclear receptor) — correct in signaling but structurally a steroid, not an amine.
Question 2 of 10 · LO 3 — Catecholamine Pharmacology Lecture Notes
Per the Catecholamine Biosynthesis Enzyme Map, carbidopa is added to L-DOPA for Parkinson's treatment because carbidopa:
AInhibits tyrosine hydroxylase in the periphery
BInhibits peripheral DOPA decarboxylase and does not cross the BBB
CInhibits central PNMT so NE is not converted to Epi
B. The enzyme map shows DOPA decarboxylase (AADC) is the second step (L-DOPA → Dopamine). Carbidopa blocks this enzyme only in the periphery because it does not cross the BBB → more administered L-DOPA reaches the CNS, where central DOPA decarboxylase converts it to active dopamine. Bonus: less peripheral dopamine → fewer side effects (nausea, hypotension). α-methyltyrosine (metyrosine) is the drug that blocks TH (A) — used in pheo pre-op. PNMT (C) is only in adrenal medulla.
Question 3 of 10 · LO 6 — Receptor Signaling Pathways Lecture Notes · Study Guide
Per the Membrane Receptor Signaling Quick Map, which of the following hormone pairs both use the Gq → IP3/DAG/Ca²⁺ pathway?
AGlucagon and PTH
BInsulin and IGF-1
CGnRH and TRH
DSomatostatin and α₂-adrenergic
EGH and prolactin
C. Gq-coupled hormones per the table: GnRH, TRH, ADH-V1, angiotensin II, oxytocin, α₁-adrenergic, gastrin (mnemonic: "GOAT HAG"). Glucagon + PTH (A) use Gs → cAMP. Insulin + IGF-1 (B) use RTK. Somatostatin + α₂ (D) use Gi → ↓cAMP. GH + prolactin (E) use JAK-STAT.
Question 4 of 10 · LO 5 — Carrier Proteins Lecture Notes · Study Guide
Per the Carrier Proteins reference table, a 24-year-old woman on combined oral contraceptives has a total serum cortisol of 32 μg/dL (upper normal 22). She feels well and has no Cushing features. The BEST explanation is:
AEstrogen directly activates the adrenal fasciculata
BEstrogen ↑ hepatic CBG → ↑ total cortisol; free cortisol is normal (free-hormone hypothesis)
CEstrogen displaces cortisol from albumin, raising free cortisol
DEstrogen blocks hepatic 11β-HSD → ↑ active cortisol
EOCPs contain cortisone which cross-reacts with the cortisol assay
B. Per the Carrier Proteins table, CBG (transcortin) binds cortisol (and progesterone). Estrogen (pregnancy, OCPs) induces hepatic CBG synthesis → more carrier → ↑ TOTAL cortisol. Only the free fraction is biologically active → patient is eucortisolic. Always order 24-hr urine FREE cortisol or late-night salivary cortisol (free) — not total — to evaluate suspected Cushing in OCP users.
Question 5 of 10 · LO 7 — Dose-Response Curve Lecture Notes · Study Guide
Per the Hormone Response Curves reference table, an insulin dose-response curve in a patient with severe T2DM shows a RIGHTWARD shift with a LOWERED maximum response. Which single statement best explains this combination?
C. A pure rightward shift = ↓ affinity (↑ EC50, same Vmax). A pure lowered Vmax = ↓ receptor number (same EC50). When BOTH occur together — as in chronic insulin resistance / T2DM — the curve shifts RIGHT (more insulin needed for any response) AND the maximum response is BLUNTED (down-regulation of insulin receptors after sustained hyperinsulinemia).
Question 6 of 10 · LO 2 — Glycoprotein Hormone Subunits Lecture Notes
A patient with a molar pregnancy presents with hyperthyroidism despite a TSH <0.01 mIU/L. Per the Hormone Classes reference, which subunit of the glycoprotein hormones is likely responsible for the cross-reactivity with TSH receptor?
ACommon α-subunit
Bβ-subunit of hCG cross-reacting with TSH-β
CUnique γ-subunit found only in molar trophoblasts
DPost-translational glycosylation on FSH receptor epitope
EA splice variant of LH specific to placental cells
B. Per the reference table, TSH, LH, FSH, and hCG all share the common α-subunit but differ in β-subunit. The hCG β-subunit has amino acid homology to TSH-β, allowing hCG to weakly activate TSH receptors on thyroid follicular cells. This cross-reactivity is especially potent in molar pregnancy (↑↑↑ hCG) and choriocarcinoma.
Question 7 of 10 · LO 3 — Catecholamine Synthesis Rate-Limiting Step Lecture Notes
Per the Catecholamine Biosynthesis Enzyme Map, which enzyme catalyzes the rate-limiting step of catecholamine synthesis, and which cofactor is required?
ATyrosine hydroxylase with tetrahydrobiopterin (BH4)
BDOPA decarboxylase with pyridoxal phosphate (B6)
CDopamine β-hydroxylase with vitamin C
DPNMT with S-adenosylmethionine (SAM)
ETyrosine hydroxylase with vitamin B12
A. Per the enzyme map, tyrosine hydroxylase (TH) catalyzes tyrosine → L-DOPA and is the rate-limiting step. It requires tetrahydrobiopterin (BH4), which is regenerated by dihydrofolate reductase. This is the principal control point for catecholamine synthesis.
Question 8 of 10 · LO 4 — Steroid Biosynthesis Initial Step Lecture Notes
Per the hormone biosynthesis pathways, which enzyme catalyzes the initial (rate-limiting) step of steroid hormone biosynthesis, converting cholesterol to pregnenolone?
C. P450 side-chain cleavage enzyme (desmolase / CYP11A1) catalyzes cholesterol → pregnenolone in the inner mitochondrial membrane. This is the first committed and rate-limiting step of steroid biosynthesis, regulated by ACTH via StAR protein (steroidogenic acute regulatory protein).
Question 9 of 10 · LO 5 — Carrier Proteins and Pregnancy Lecture Notes · Study Guide
A pregnant woman has an elevated total T4 (12.0 ng/dL, normal 5–12) but normal free T4 (1.2 ng/dL, normal 0.8–1.8) and normal TSH. Per the Carrier Proteins reference, the BEST explanation is:
AShe has gestational thyroiditis with transient hyperthyroidism
BEstrogen ↑ hepatic TBG synthesis → ↑ total T4; free hormone is normal (free-hormone hypothesis)
EPregnancy increases iodine excretion, concentrating T4 in serum
B. Per the Carrier Proteins table, TBG (thyroxine-binding globulin) carries ~70% of circulating T4. Estrogen (pregnancy, OCPs) induces hepatic TBG synthesis → more carrier → ↑ total T4, but only free T4 (and TSH-regulated hormone secretion) adjusts to maintain euthyroid state. The patient is clinically euthyroid.
Question 10 of 10 · LO 6 — Receptor Tyrosine Kinase Signaling Lecture Notes
Per the Membrane Receptor Signaling Quick Map, insulin acts through which class of receptor and which intracellular pathway, distinguishing it from Gq-coupled hormones?
AGPCR coupled to Gq → IP3/DAG/Ca²⁺
BGPCR coupled to Gi → ↓cAMP
CReceptor tyrosine kinase (RTK) with PI3K/Akt and RAS/MAPK pathways
DSerine/threonine kinase coupled to Smad signaling
ENicotinic receptor directly gating Ca²⁺ channels
C. Per the reference table, insulin is a peptide hormone that acts via receptor tyrosine kinase (RTK). Upon ligand binding, the insulin receptor undergoes autophosphorylation and recruits IRS proteins, activating PI3K/Akt (glucose uptake, glycogen synthesis) and RAS/MAPK (mitogenic effects). This is structurally and mechanistically distinct from GPCR-coupled second messengers.
Hormone Class Master Table Lecture Notes · Study Guide
Class
Solubility
Carrier?
Receptor Location
Examples
Half-Life
Amino-acid derivatives (catecholamines)
Hydrophilic
No (free in plasma)
Cell SURFACE (GPCR)
Epi, NE, dopamine
Minutes
Amino-acid derivatives (thyroid)
Hydrophobic (exception\!)
Yes (TBG, TTR, albumin)
NUCLEAR (TR)
T3, T4
T3 ~1.5d · T4 ~7d
Peptide / protein
Hydrophilic
No
Cell SURFACE (GPCR, RTK, JAK-STAT)
Insulin, GH, ACTH, TSH, PTH, ADH
Minutes
Steroid
Hydrophobic
Yes (CBG, SHBG, albumin, DBP)
NUCLEAR / cytoplasmic
Cortisol, aldosterone, sex steroids, vit D
Hours
Eicosanoids
Hydrophobic
No (act locally)
Cell SURFACE (GPCR, mostly)
Prostaglandins, leukotrienes, thromboxanes
Seconds (paracrine/autocrine)
Mnemonic: "Hydrophilic = Helpless to cross membrane → Hits surface receptors." Thyroid hormone is the classic exception — amine structure but steroid-like behavior.
Membrane Receptor Signaling Quick Map Lecture Notes · Study Guide
BH4; inhibited by α-methyltyrosine (metyrosine, used pre-op pheo)
2
DOPA decarboxylase (AADC)
L-DOPA → Dopamine
No
Pyridoxal phosphate (B6); inhibited peripherally by carbidopa
3
Dopamine β-hydroxylase (DBH)
Dopamine → Norepinephrine
No
Vitamin C; inside synaptic vesicles
4
PNMT
Norepinephrine → Epinephrine
No
SAM as methyl donor; INDUCED by local cortisol — only in adrenal medulla
Why only adrenal medulla makes Epi: PNMT requires high local cortisol concentrations from adrenal cortex (delivered via the intra-adrenal portal venous system). Postganglionic sympathetic neurons release NE because they lack PNMT.
Steroid Biosynthesis Roadmap Lecture Notes · Study Guide
Local; phospholipase A2 inhibited by cortisol; COX inhibited by NSAIDs
—
Key concept: If you block an enzyme, substrate BUILDS UP upstream and gets shunted to alternate pathways. This is the basis of CAH presentations (e.g., 21-OH deficiency → ↑ androgens, ↓ cortisol & aldo).
Carrier Protein Quick Reference Lecture Notes · Study Guide
Carrier Protein
Hormones Carried
Affinity / Capacity
Clinical Pearl
TBG (Thyroxine-Binding Globulin)
T4 (~70%), T3
HIGH affinity, LOW capacity
Estrogen (pregnancy, OCPs) ↑ TBG → ↑ TOTAL T4 but FREE T4 normal → euthyroid. Always order FREE T4 + TSH.
CBG (Transcortin)
Cortisol, progesterone
HIGH affinity, LOW capacity
Estrogen ↑ CBG → ↑ total cortisol but free cortisol normal. Use 24-hr URINE FREE cortisol or late-night SALIVARY (free) for Cushing workup.
SHBG (Sex Hormone Binding Globulin)
Testosterone, estradiol, DHT
HIGH affinity, LOW capacity
Estrogen, hyperthyroid → ↑ SHBG; obesity, T2DM, hyperinsulinism → ↓ SHBG (hence low total but normal-free testosterone in obese men).
DBP (Vitamin D Binding Protein)
Vitamin D and metabolites
HIGH affinity
Total 25-OH vitamin D measurement is standard; free fraction may matter in CKD or critical illness.
Albumin
Many hormones (low affinity, high capacity)
LOW affinity, HIGH capacity
Acts as a "buffer" reservoir; hypoalbuminemia (cirrhosis, nephrotic syndrome) lowers TOTAL hormone concentrations without changing free fraction.
Free-hormone hypothesis: Only the unbound (free) fraction of hormone is biologically active and senses feedback. Carrier-bound hormone is a circulating reservoir that protects from degradation and renal excretion.