Lecture 1: Introduction to Hormones

The mode of intercellular signaling is defined by how the molecule is delivered, not by the molecule itself. Glucagon enters the bloodstream and acts on distant hepatocytes → endocrine. Islet-cell somatostatin diffuses through interstitial fluid to neighboring alpha and beta cells without relying on systemic circulation → paracrine. The same molecule (e.g., somatostatin) can be endocrine when released by the hypothalamus, paracrine in the islet, and neurocrine in brain synapses — the context determines the term.

When a cell expresses receptors for a ligand it is itself secreting, the signaling is autocrine. Activated T cells and many tumor cells (glioblastomas with PDGF loops, some breast cancers with IGF-1 loops) rely on autocrine signaling for proliferation. Paracrine = to neighbors via interstitial fluid; endocrine = to distant cells via blood; juxtacrine = membrane-to-membrane contact; neurocrine = across a synapse. The defining feature of autocrine is co-expression of ligand and receptor on the same cell.

A neuroendocrine cell is a neuron that releases its product into the bloodstream rather than across a synaptic cleft. Hypothalamic parvocellular neurons releasing CRH, TRH, GnRH, GHRH, and dopamine into the hypophyseal portal system are the archetypal example; magnocellular neurons releasing ADH and oxytocin from the posterior pituitary into systemic circulation are likewise neuroendocrine. The distinguishing features are a neuronal source plus vascular (rather than synaptic) delivery.

The clues — synthesized as a preprohormone, cleaved in the Golgi, stored in granules, and acting in seconds — all point to a peptide hormone. Peptides are water-soluble and cannot cross the plasma membrane, so they signal indirectly via cell-surface receptors and second messengers (cAMP, IP3/DAG, RTK, JAK-STAT). A and B describe steroid/thyroid mechanisms; D is a steroidogenic enzyme; E is incorrect (peptide hormones such as glucagon are readily measured in fasting serum).

A classic USMLE trap. Thyroid hormones are structurally amines (two iodinated tyrosines coupled together), but iodination renders them highly lipophilic. They cross the plasma membrane, bind nuclear receptors (TRα, TRβ), and regulate transcription — behaving like steroids. Onset is hours to days. Don’t equate amine structure with amine mechanism: catecholamines are also amines but do act via GPCRs, the opposite of thyroid hormone.

Insulin is synthesized as proinsulin, which is cleaved 1:1 in secretory granules into mature insulin plus C-peptide. Endogenous hypersecretion (insulinoma) raises insulin, C-peptide, and proinsulin together. Commercial insulin contains no C-peptide and suppresses endogenous β-cells, so exogenous injection produces high insulin with suppressed C-peptide (option A). The peptide-hormone synthesis pathway (preprohormone → prohormone → hormone + byproduct, stored together in vesicles) is the reason C-peptide exists as a distinct endogenous marker.

Endogenously, insulin is stored in β-cell granules as an equimolar mixture with C-peptide (both arise from cleavage of a single proinsulin molecule). Commercial recombinant insulin contains only insulin, so exogenous injection raises serum insulin without raising C-peptide; the high exogenous insulin also feeds back on β-cells, further suppressing endogenous secretion. C-peptide is therefore the key discriminator between endogenous (insulinoma, sulfonylurea) and exogenous hyperinsulinemia.

Catecholamines are synthesized Tyr → L-DOPA → dopamine → norepinephrine → epinephrine. The rate-limiting step is the first: tyrosine → L-DOPA by tyrosine hydroxylase (requires BH4 and O₂; feedback-inhibited by end products; activated by PKA/CaMKII phosphorylation during sympathetic drive). Metyrosine competitively blocks tyrosine hydroxylase, depleting catecholamine stores by 50–80% and preventing intraoperative hypertensive crisis when α-blockade alone is insufficient.

PNMT converts norepinephrine to epinephrine and is induced by very high local cortisol. Only the adrenal medulla is bathed in cortisol via the centripetal intra-adrenal portal blood supply from the overlying cortex, which is why the medulla uniquely makes epinephrine. In Addison disease, low cortisol → no PNMT induction → failed epinephrine synthesis. Norepinephrine is still produced normally by sympathetic post-ganglionic neurons elsewhere, which never need PNMT. This is also why paragangliomas (extra-adrenal chromaffin tumors) release NE rather than epinephrine.

The canonical order is Tyr → L-DOPA → dopamine → norepinephrine → epinephrine. Enzymes/cofactors: tyrosine hydroxylase (rate-limiting; BH4), DOPA decarboxylase (B6/PLP), dopamine β-hydroxylase (vit C, Cu; occurs inside the secretory vesicle), and PNMT (SAM; cortisol-dependent, adrenal medulla only). Phe → Tyr occurs in the liver via phenylalanine hydroxylase but is not part of the catecholamine pathway proper. Mnemonic: ‘Tyrants Don’t Dare Nag Emperors.’

Every steroid hormone begins from cholesterol. The first committed (and rate-limiting) enzymatic step is side-chain cleavage by desmolase (CYP11A1 / P450scc) on the inner mitochondrial membrane, yielding pregnenolone (a C21 steroid). All downstream enzymes (3β-HSD, 17α-hydroxylase, 17,20-lyase, 21-hydroxylase, 11β-hydroxylase, aromatase) act on pregnenolone and its derivatives in a tissue-specific pattern to generate mineralocorticoids, glucocorticoids, androgens, and estrogens.

StAR shuttles cholesterol from the outer to the inner mitochondrial membrane, where desmolase resides. Because desmolase is compartmentally isolated, cholesterol delivery by StAR is the true rate-limiting step of all steroidogenesis — which is why trophic hormones (ACTH, LH, angiotensin II) acutely boost steroid output largely by activating StAR. Loss-of-function mutations cause congenital lipoid adrenal hyperplasia: cholesterol accumulates as cytoplasmic lipid droplets but cannot reach desmolase, so essentially no steroid hormone is made. Patients present with neonatal salt-wasting crisis and 46,XY infants appear phenotypically female because androgens cannot be synthesized.

Peptide hormones are stored in secretory granules because they are water-soluble and cannot cross phospholipid membranes. Steroids are lipophilic, so they diffuse through the membrane of any would-be storage vesicle — keeping a reserve inside the cell is physicochemically impossible. Steroidogenic cells therefore hold cholesterol (often esterified in lipid droplets) as the substrate and activate the synthesis cascade on demand when trophic hormones arrive. This is also why abrupt withdrawal of exogenous glucocorticoids is dangerous: there are no pre-formed cortisol reserves to buffer an acute stress.

Because steroids are lipophilic and poorly soluble in plasma, ~90% of circulating cortisol is bound to corticosteroid-binding globulin (CBG / transcortin) and a small fraction to albumin. Only the remaining free cortisol can diffuse across cell membranes and activate intracellular glucocorticoid receptors. Carrier binding (1) enables systemic circulation of hydrophobic hormone, (2) creates a reserve pool, and (3) prolongs half-life by shielding the hormone from hepatic metabolism and renal clearance. A–C and E are all incorrect (steroids are not stored, use nuclear receptors, have slow onset, and are cholesterol-derived).

Estrogen stimulates hepatic synthesis of thyroxine-binding globulin (TBG). With more carrier, a larger bound pool is needed to keep free T4 at the set-point. Transiently, free T4 dips → TSH briefly rises → thyroid produces more T4 → new equilibrium: total T4 is high while free T4 and TSH are normal. The patient is clinically euthyroid. The same pattern is seen with oral contraceptive use. In nephrotic syndrome the opposite occurs (TBG lost in urine, total T4 falls, free T4 remains normal). Only the free fraction is physiologically active.

Losing TBG reduces plasma T4 binding capacity. Briefly, free T4 rises → TSH is suppressed → thyroid output decreases → free T4 returns to normal. The new equilibrium has less carrier, so total T4 is low while free T4 and TSH are normal — the patient is euthyroid. This is the mirror image of pregnancy/estrogen-induced high-TBG states. Only free hormone is active; total-hormone assays can be misleading when carrier-protein levels change.

Exogenous androgens suppress hepatic SHBG synthesis. With less SHBG, the free testosterone fraction rises disproportionately and is available to aromatase (in adipose, liver, and skin) → conversion to estradiol → stimulation of breast ductal tissue → gynecomastia. Total testosterone may look ‘low-normal’ because the measurement includes the shrunken bound pool. The same principle underlies obesity-associated gynecomastia (more adipose aromatase) — and it illustrates why SHBG changes can have clinical effects even with ‘normal’ total hormone levels. Carrier proteins determine what fraction is biologically available.

GHRH signals via a Gs-coupled GPCR → activates adenylyl cyclase → ↑cAMP → PKA → GH release. A constitutively active Gsα mutation (McCune-Albright; ~40% of sporadic GH adenomas) locks Gs in the ‘on’ state → continuous cAMP elevation → unregulated GH secretion. Before epiphyseal closure this produces gigantism; after closure, acromegaly. The question tests both receptor location (cell-surface GPCR) and mechanism (Gs→cAMP).

Gq activates phospholipase C, which cleaves PIP2 into IP3 + DAG. IP3 opens IP3 receptors on the ER, releasing Ca²⁺ into the cytosol; DAG and Ca²⁺ activate PKC. Blocking Gq abolishes PLC activation → no IP3 → no ER Ca²⁺ release → α1-mediated vasoconstriction fails. Options A and C describe Gs signaling. PDE inhibition pertains to cyclic-nucleotide degradation; E describes nuclear-receptor (steroid/thyroid) signaling. Classic Gq-coupled hormones: oxytocin, TRH, GnRH, angiotensin II, histamine H1, V1 ADH.

GH, prolactin, erythropoietin, and most interleukins/interferons use cytokine receptors, which lack intrinsic kinase activity but recruit and activate JAK2. Activated JAKs phosphorylate STAT transcription factors, which dimerize, enter the nucleus, and drive gene expression. This is why JAK inhibitors (ruxolitinib, tofacitinib) affect many hormone/cytokine pathways. In contrast, insulin uses a true RTK — a frequent USMLE distinguisher.

Phosphodiesterase degrades cAMP (→ AMP) and cGMP (→ GMP). Inhibiting PDE lets cyclic nucleotides accumulate, amplifying whatever Gs or guanylyl-cyclase signal is active. Clinical examples: sildenafil (PDE5 → ↑cGMP → smooth-muscle vasodilation), milrinone (PDE3 → ↑cAMP → cardiac inotropy), theophylline/caffeine (nonselective PDE → ↑cAMP → bronchodilation). Receptor mechanism (cell-surface GPCR → second messenger) determines where these drugs act downstream.

Octreotide is a long-acting somatostatin analog that binds SSTR2/SSTR5 on pituitary somatotrophs. SSTRs are Gi-coupled: Gαi inhibits adenylyl cyclase → ↓cAMP → ↓PKA → decreased GH secretion (and tumor growth suppression). Other indications: carcinoid syndrome, VIPoma, glucagonoma, variceal bleeding. Cabergoline (D2 agonist, also Gi) is an alternative commonly used for prolactinomas. This tests both receptor location (cell-surface GPCR) and mechanism (Gi → ↓cAMP).

Cellular sensitivity to a hormone can be altered in three main ways: (1) change in receptor number, (2) change in receptor affinity (EC50 shift), and (3) change in downstream signaling capacity. In insulin resistance, receptor number falls and post-receptor tyrosine-kinase signaling is impaired, which collapses the Vmax of glucose uptake rather than shifting the EC50 — so even saturating insulin can no longer drive normal uptake. This is precisely the insulin-resistance dose-response pattern illustrated in the lecture.

A permissive effect means one hormone has little or no action on its own but is required for another hormone to exert its full effect. Physiologic cortisol permits catecholamine-mediated vasoconstriction, partly by up-regulating α1-receptor expression. Without cortisol, norepinephrine’s pressor effect is blunted — contributing to the hypotension of Addisonian crisis. Synergism means combined effect exceeds the sum; antagonism is the opposite. This is a classic example of how circulating factors beyond the hormone itself modify cellular sensitivity and response.

EC50 is determined largely by receptor affinity for the ligand. β2-adrenergic receptors have higher affinity for epinephrine than β1 do, so the same epinephrine concentration produces a half-maximal signal at a lower drug concentration — the dose-response curve shifts left. This is a pure receptor-isoform (affinity) effect. Changing receptor number typically shifts Vmax; changes in second messenger identity, G-protein availability, or hormone clearance involve different mechanisms. As the lecture emphasized, sensitivity depends on receptor isoform, affinity, number, post-translational modification, and downstream machinery.