Built from Endocrine Lecture 01 (LOs 1–7). Close notes. Fill from memory. Reveal only after a genuine attempt.

LO 1

ON EXAM — 5 signaling modes: endocrine (blood, systemic), paracrine (local diffusion), autocrine (self), JUXTACRINE (cell-cell contact via membrane proteins or gap junctions), nervous (synapse); plus neuroendocrine hybrid. Key discriminators: distance, speed, specificity, half-life. Exocrine (external surfaces) is NOT an intercellular hormone mode. Know classic examples and traps (paracrine vs autocrine; IGF-1 autocrine in cancer; GAP junctions in myocardium; Notch-Delta in development)

Five modes of intercellular communication — fill in each row (LO 1)

Mode	Route signal takes	Distance / speed	Classic example(s)
Endocrine
Paracrine
Autocrine
Juxtacrine (contact-dependent)
Nervous (synaptic)

TRAP 1: Autocrine = cell signals ITSELF (classic in cancer — tumor makes its own growth factor loop, e.g., IGF-1 or IL-2). Paracrine = cell signals NEIGHBOR. TRAP 2: Juxtacrine is contact-dependent — Notch-Delta during development, B-T cell interactions, gap junctions in cardiac muscle (electrical coupling) — often overlooked.

Neuroendocrine overlap — 3 classic examples (LO 1)

Hypothalamic parvocellular neurons → portal blood → anterior pituitary (CRH, TRH, GnRH, GHRH)

Preganglionic sympathetic neurons (ACh) → adrenal medulla chromaffin cells → epinephrine into systemic blood

Hypothalamic magnocellular neurons (SON/PVN) → axons terminate in posterior pituitary → ADH & oxytocin

Discriminators — endocrine vs nervous vs paracrine (LO 1)

Feature	Endocrine	Nervous	Paracrine
Specificity determined by
Typical response speed
Duration of signal
Amplification

Endocrine vs EXOCRINE (LO 1)

Exocrine — where is the product delivered (and is it a form of intercellular hormonal signaling)?

Give 2 classic exocrine secretions

Pancreas is BOTH — list the endocrine vs exocrine products

Special modes — identify each (LO 1)

Chemical released by neuron that travels via BLOOD to distant target ("hormone made by nerve") — name the mode

Cells coupled by connexons allowing ions/small molecules to pass directly — name the mode

Signaling molecule leaves the body to act on a different individual (rare in humans, common in lower species)

Prostaglandins and histamine — primarily which mode? Why?

LO 2

ON EXAM — classify by 3 properties: STRUCTURE (peptide/protein vs steroid vs amine — tyrosine-derived catecholamine or thyroid), SOLUBILITY (water-soluble vs lipid-soluble → predicts receptor location), STORABILITY (stored in vesicles vs made on-demand vs uniquely stored on thyroglobulin). Thyroid hormone is THE EXCEPTION: amine structurally but lipid-soluble and signals through nuclear receptor

Hormone classes by structure, solubility, storability (LO 2)

Property	Peptide / protein	Steroid	Amine — catecholamine	Amine — thyroid (EXCEPTION)
Structure
Solubility
Storability (where / how long)
Receptor location
Action speed
Examples (≥ 3)

Why thyroid hormone is the exception (LO 2)

Thyroid is classified as an amine because…

Thyroid is lipid-soluble because… (what modification?)

Receptor location & family

Thyroid storage is UNIQUE — describe it

Storability drives release kinetics (LO 2)

Class	Stimulus → release pathway	Time to blood peak
Peptide (stored)
Steroid (on-demand)
Catecholamine (stored)
Thyroid (stored extracellularly)

LO 3

ON EXAM — Tyr → DOPA (TH, RATE-LIMITING, needs BH₄, cytosol); DOPA → DA (AADC / DOPA decarboxylase, PLP); DA pumped into vesicle by VMAT2; DA → NE (DBH, inside vesicle, needs Cu²⁺ + ascorbate); NE exits vesicle, methylated in cytosol; NE → Epi (PNMT, cortisol-induced, ONLY in adrenal medulla). Degradation: COMT + MAO → metanephrines, VMA, HVA

Full catecholamine pathway — fill in every box (LO 3)

Substrate	Enzyme	Cofactor(s)	Location (cytosol / vesicle / cell type)	Product	Clinical hook
Phenylalanine				Tyrosine
Tyrosine				L-DOPA
L-DOPA				Dopamine
Dopamine				Norepinephrine
Norepinephrine				Epinephrine

Rate-limiting step: tyrosine hydroxylase (LO 3)

Which step is rate-limiting for the WHOLE pathway?

Essential cofactor (besides O₂)

How is TH acutely activated (covalent modification)?

How is TH chronically upregulated (adrenal vs neuronal)?

Product that feedback-inhibits TH

Drug that inhibits TH and its clinical use

Vesicle biology — the VMAT2 step (LO 3)

Which enzyme works INSIDE the vesicle (not in cytosol)?

How does dopamine get INTO the vesicle?

What drug class targets VMAT2 (and its clinical use)?

For adrenal medulla epinephrine: where is PNMT located (cytosol or vesicle)?

Why does NE need to leave the vesicle to be methylated, and then re-enter?

Why PNMT is UNIQUE to adrenal medulla (LO 3)

Anatomic arrangement that exposes medullary cells to very high cortisol

Effect of cortisol on PNMT expression

Why sympathetic post-ganglionic neurons make NE but NOT Epi

What happens to PNMT expression in bilateral adrenalectomy or hypopituitarism?

Degradation & urinary metabolites (LO 3)

Substrate	Enzyme(s)	Urinary metabolite measured	Clinical use
Dopamine
Norepinephrine
Epinephrine

HIGH-YIELD: Plasma free metanephrines are the best screening test for pheochromocytoma (higher sensitivity than 24-hr urinary metanephrines). VMA (final common degradation product of NE/Epi) and HVA (dopamine metabolite) are classically used for neuroblastoma screening in children.

Enzyme / cofactor deficiencies — clinical syndromes (LO 3)

Phenylalanine hydroxylase deficiency (or BH₄ deficiency) → which disease?

Tyrosine hydroxylase deficiency → clinical syndrome

AADC deficiency → clinical picture

DBH deficiency → labs + clinical features

L-DOPA given WITHOUT carbidopa → side effects and why carbidopa fixes them

Entacapone (COMT inhibitor) — mechanism + why used with L-DOPA

LO 4

ON EXAM — INITIAL STEP of steroidogenesis is the rate-limiting one. TWO sub-steps: (1) STAR SHUTTLES cholesterol from outer to INNER mitochondrial membrane (this is the acute regulated step — induced by ACTH via cAMP/PKA), (2) CYP11A1 (P450scc / "cholesterol side-chain cleavage enzyme" / DESMOLASE) on the inner mitochondrial membrane cleaves cholesterol → PREGNENOLONE. Cofactors: O₂, NADPH via adrenodoxin/adrenodoxin reductase. StAR mutations → congenital lipoid adrenal hyperplasia. CYP11A1 deficiency → failure of ALL adrenal + gonadal steroidogenesis

Sources of cholesterol for steroidogenic cells (LO 4)

Source	Mechanism / transporter	Relative contribution
Circulating LDL
Circulating HDL
De novo synthesis
Intracellular lipid droplets (stored as cholesteryl esters)

KEY: In humans, adrenal cortex relies mainly on LDL-derived cholesterol (via LDLR). Stored cholesteryl esters in lipid droplets are mobilized by cholesteryl ester hydrolase (CEH, a.k.a. HSL), which is activated by PKA under ACTH stimulation.

The TWO sub-steps of the initial step (LO 4)

Sub-step	Enzyme / protein	What moves / what reaction	Subcellular site	Regulation
1. Shuttle
2. Cleavage

StAR protein (LO 4)

Full name of StAR

What does StAR physically MOVE?

Where does it move cholesterol FROM and TO?

How quickly is StAR induced by ACTH (minutes vs hours)?

Signaling cascade from ACTH → StAR transcription

StAR mutation → what inherited disease and phenotype?

CYP11A1 (P450scc / desmolase) (LO 4)

Substrate → product for CYP11A1

Cofactors required

Electron-donor system that reduces CYP11A1

Why is this the biochemical rate-limiting enzyme (even though StAR is the regulated step)?

CYP11A1 complete loss → expected phenotype for 46,XX and 46,XY

Why pregnenolone matters (LO 4)

Pregnenolone is the common precursor for which 5 classes of steroids?

Acute ACTH stimulation raises steroid output in minutes — which step is responsible?

Chronic ACTH raises steroid output more slowly — via what mechanism?

LH in ovary/testis does the analogous job — via which receptor & second messenger?

Clinical correlates of the initial step (LO 4)

Congenital lipoid adrenal hyperplasia — what accumulates in the adrenal, and what's the presentation?

Drug that blocks the initial step (anti-steroidogenic) — use in Cushing

Ketoconazole blocks multiple CYP enzymes including CYP11A1 — endocrine side effects

Why does chronic hyperlipidemia NOT cause hypersteroidogenesis? (What is the rate-limiting bottleneck?)

LO 5, 6, 7

ON EXAM — Carrier proteins (SHBG, CBG, TBG, albumin) buffer free hormone, extend half-life, but only FREE hormone is active; pregnancy/OCPs raise TBG → total T₄ ↑, free T₄ normal. Receptors classified by subcellular location: surface (GPCR, RTK, JAK-STAT, ligand-gated ion channel, guanylyl cyclase) for water-soluble; nuclear (Type 1 steroid HSP/cytoplasm/homodimer vs Type 2 TR/VDR/RAR already on DNA with RXR partner) for lipid-soluble. Sensitivity set by receptor number (up/downregulation), affinity (K_d), spare receptors, desensitization (phosphorylation, internalization), coupling efficiency

Carrier proteins and the free-hormone hypothesis (LO 5)

Carrier	Binds	Effect on half-life	Clinical pearl
SHBG
CBG (transcortin)
TBG
Albumin

Which fraction is biologically active (bound or free)?

Pregnancy ↑ TBG → what happens to total T₄, free T₄, TSH?

When binding-protein status is uncertain, which lab to order?

Receptor classification by subcellular location (LO 6)

Feature	Cell-surface receptor	Nuclear receptor
Ligand solubility
Signal mechanism
Action speed
Example ligands
Exception that breaks the rule

Membrane receptor families — name the signal mechanism (LO 6)

GPCR — Gs / Gi / Gq (list one classic hormone each)

RTK — mechanism + 2 classic hormones

JAK-STAT — mechanism + 2 classic hormones

Guanylyl cyclase — hormone + second messenger

Ligand-gated ion channel — classic example

Nuclear receptor Type 1 vs Type 2 (LO 6)

Feature	Type 1 (steroid)	Type 2 (TR, VDR, RAR, PPAR…)
Resting location
Dimer partner
Bound to HSP90 at rest?
Members

Cellular sensitivity + response (LO 7)

How does receptor NUMBER change (up / downregulation) — 1 example of each

Affinity (K_d) — low K_d vs high K_d: which means higher affinity?

"Spare receptors" — what does it mean and how does it affect EC₅₀ vs K_d?

Desensitization mechanisms (name 3)

Tachyphylaxis — define + one clinical example

Post-receptor signaling efficiency — what else can change cellular response independent of receptor number?

LO 1–7 · USMLE Step 1 Style

9 questions — weighted toward expanded LOs (signaling, catecholamines, steroid initial step).

Q1. A pancreatic islet δ-cell releases somatostatin, which binds receptors on nearby α- and β-cells within the same islet, inhibiting their secretion. Somatostatin released in this fashion is NOT found in appreciable concentrations in the systemic circulation. Which form of intercellular communication is this?

A. Endocrine
B. Paracrine
C. Autocrine
D. Juxtacrine
E. Neuroendocrine

B — Paracrine.
Local diffusion to adjacent cells of the same tissue, without entering systemic blood, defines paracrine. Contrast with: endocrine (blood, systemic); autocrine (same cell); juxtacrine (membrane-membrane contact); neuroendocrine (neuron releases hormone into blood). The islet has all of these: somatostatin→α/β (paracrine), insulin→distant muscle (endocrine), IGF-1→self on tumor cells (autocrine).

Q2. A newly identified signaling molecule binds a transmembrane ligand on an adjacent cell without any secretion into extracellular fluid. Binding triggers intracellular signaling in BOTH cells simultaneously. This is an example of which mode of intercellular communication?

A. Endocrine
B. Paracrine
C. Autocrine
D. Juxtacrine (contact-dependent)
E. Exocrine

D — Juxtacrine.
Juxtacrine = contact-dependent signaling via membrane-anchored ligands (e.g., Notch — Delta/Jagged), or via gap junctions (connexons). Examples: Notch–Delta in developmental fate decisions; immunological synapse (MHC–TCR); cardiac myocyte gap junctions (electrical coupling). No secreted intermediate — distinguishes it from paracrine.

Q3. A 19-year-old with Parkinson-like early-childhood dystonia has markedly low CSF dopamine, undetectable homovanillic acid, and normal phenylalanine. Brain MRI is normal. A trial of L-DOPA + carbidopa dramatically improves symptoms. Which enzyme is MOST likely deficient?

A. Phenylalanine hydroxylase (PAH)
B. Tyrosine hydroxylase (TH)
C. Aromatic L-amino acid decarboxylase (AADC)
D. Dopamine β-hydroxylase (DBH)
E. Phenylethanolamine N-methyltransferase (PNMT)

B — Tyrosine hydroxylase (TH) deficiency.
TH (Tyr → L-DOPA) is the rate-limiting catecholamine enzyme. Deficiency → low dopamine, low NE, low Epi, and low CSF HVA (dopamine metabolite). Phenylalanine is normal (PAH intact). L-DOPA BYPASSES the TH step, and carbidopa prevents peripheral AADC conversion so more L-DOPA reaches the brain. AADC deficiency would fail to improve with L-DOPA (A is not the answer because Phe is normal; PAH deficiency = PKU with high Phe).

Q4. A 28-year-old man presents with chronic orthostatic hypotension, ptosis, and anhydrosis of the upper body. Plasma norepinephrine is very low; dopamine is HIGH; DOPA is normal. The patient dramatically improves on droxidopa (a synthetic NE precursor). Which enzyme is deficient?

A. Tyrosine hydroxylase
B. AADC
C. Dopamine β-hydroxylase (DBH)
D. PNMT
E. COMT

C — Dopamine β-hydroxylase (DBH) deficiency.
DBH converts DA → NE inside the vesicle; loss → HIGH dopamine (spills over into synapses) with LOW NE and Epi. Classic: severe orthostatic hypotension, ptosis, anhidrosis, sexual dysfunction. Treatment = droxidopa (L-threo-DOPS), which bypasses DBH because AADC can decarboxylate it directly to NE in the peripheral nervous system.

Q5. After a patient is placed on long-term high-dose prednisone, PNMT expression in the adrenal medulla DECREASES, and epinephrine/NE ratio falls. Which BEST explains the normal relationship between cortisol and PNMT?

A. PNMT is a Gs-coupled receptor that is internalized by cortisol
B. PNMT is normally INDUCED by very high local cortisol reaching the medulla via the adrenal cortico-medullary portal system; exogenous steroids suppress pituitary ACTH, lowering endogenous cortisol in this portal → PNMT decreases
C. PNMT is a cortisol-binding protein that titrates free cortisol
D. PNMT uses cortisol as a cofactor
E. PNMT and cortisol are unrelated

B — Cortical cortisol INDUCES medullary PNMT via a local portal system.
The adrenal has a cortico-medullary portal venous system that bathes chromaffin cells in very high local cortisol → cortisol induces PNMT transcription → NE is methylated to Epi (the medulla's unique ability). Exogenous glucocorticoids suppress pituitary ACTH → endogenous cortical cortisol falls → the medulla's local cortisol exposure falls → PNMT decreases. This is also why sympathetic ganglia (no cortisol exposure) produce NE, not Epi.

Q6. A neonate presents with ambiguous genitalia, salt-wasting crisis, and bilaterally enlarged adrenal glands on imaging. ALL steroid hormones (cortisol, aldosterone, androgens, 17-OH progesterone) are UNDETECTABLE. Cholesteryl esters accumulate massively in the adrenal cortex. Which enzyme or protein is MOST likely defective?

A. 21-hydroxylase (CYP21A2)
B. 11β-hydroxylase (CYP11B1)
C. 17α-hydroxylase (CYP17A1)
D. Steroidogenic Acute Regulatory protein (StAR)
E. Aldosterone synthase (CYP11B2)

D — StAR mutation (congenital lipoid adrenal hyperplasia).
If cholesterol can't be shuttled from the outer to inner mitochondrial membrane, CYP11A1 has no substrate → pregnenolone cannot form → NO steroids of any class are made. Cholesterol accumulates in lipid droplets (massive adrenal enlargement). Phenotype: salt-wasting adrenal crisis and 46,XY neonates under-virilize (looking female) because testosterone requires pregnenolone too. This confirms StAR is the regulated, rate-limiting step of steroidogenesis.

Q7. An investigator studies the initial step of steroid biosynthesis. In vitro, adrenal mitochondria are provided with excess cholesterol, adrenodoxin, adrenodoxin reductase, NADPH, and O₂. Which enzyme DIRECTLY converts cholesterol to pregnenolone, and where in the mitochondrion does it act?

A. CYP21A2 (21-hydroxylase) — smooth ER
B. CYP17A1 (17α-hydroxylase) — smooth ER
C. CYP11A1 (P450scc / desmolase) — inner mitochondrial membrane
D. 3β-hydroxysteroid dehydrogenase (3β-HSD) — smooth ER
E. HMG-CoA reductase — ER

C — CYP11A1 on the inner mitochondrial membrane.
CYP11A1 (= P450scc = “cholesterol side-chain cleavage enzyme” = “desmolase”) sits on the INNER mitochondrial membrane and cleaves the cholesterol side chain to yield pregnenolone. Cofactors required: NADPH, O₂, and the adrenodoxin / adrenodoxin reductase electron shuttle. Access to substrate depends on StAR, which delivers cholesterol across the outer membrane into the inner membrane.

Q8. A 35-year-old woman on oral contraceptives has an elevated total T₄ but normal TSH and free T₄, and is clinically euthyroid. The MOST LIKELY mechanism is:

A. Autonomous thyroid adenoma
B. Estrogen-driven increase in TBG synthesis raises total T₄ while free T₄ remains normal
C. Elevated thyroid-stimulating antibody
D. Subclinical hyperthyroidism
E. Hypoalbuminemia

B — Estrogen raises TBG → total T₄ ↑ but FREE T₄ unchanged.
Carrier proteins buffer total hormone levels but only FREE hormone is active (free-hormone hypothesis). Estrogen (pregnancy, OCPs) increases hepatic TBG → more bound T₄ → total T₄ rises, but the pituitary senses normal free T₄ → TSH normal → patient is euthyroid. Always order free T₄ when carrier-protein status is changing.

Q9. A researcher compares two tissues: in tissue A, the biologic response reaches maximum when only 10% of receptors are occupied; in tissue B, the response plateaus only when >95% of receptors are occupied. Which BEST describes tissue A?

A. Tissue A has a HIGHER K_d than tissue B
B. Tissue A has spare receptors → EC₅₀ < K_d
C. Tissue A has no receptors
D. Tissue A is undergoing tachyphylaxis
E. Tissue A is signaling through a competitive antagonist

B — Tissue A has spare receptors (EC₅₀ < K_d).
Spare receptors means full biological response requires only partial receptor occupancy — EC₅₀ (concentration giving half-maximal EFFECT) < K_d (concentration giving half-maximal BINDING). Amplification in downstream signaling (e.g., second-messenger cascades, enzyme amplification) drives full response at low occupancy. Classic examples: insulin on adipocytes; β-adrenergic receptors in heart. Tissues with no spare receptors (like skeletal muscle nicotinic) show EC₅₀ = K_d.

Intro to Hormones — Active Recall