Built from Endocrine Lecture 03 (LOs 1–5). Use this to check your work after completing the active recall sheet.

LO 1

ON EXAM — GHRH (arcuate, Gs-cAMP on somatotroph) + ghrelin (stomach, GHSR) stimulate; somatostatin (Gi) inhibits; GH uses JAK2-STAT5 (cytokine-family receptor — NOT GPCR); GH → liver → IGF-1 → chondrocytes; IGF-1 carried on IGFBP-3 (>90%); both rise/fall with GH

The GH cascade (LO 1)

Step	Source	Hormone	Receptor + signal	Main effect
1. Hypothalamus (+)	Arcuate nucleus	GHRH	Gs-cAMP on somatotroph	Releases GH (pulsatile)
1. Hypothalamus (−)	Periventricular/arcuate	Somatostatin (SRIF/GHIH)	Gi-↓cAMP on somatotroph	Suppresses GH release
1b. Stomach (+)	Oxyntic cells (stomach fundus)	Ghrelin (hunger hormone)	GHSR (Gq) on somatotroph + arcuate	Stimulates GH + appetite; peaks pre-meals
2. Pituitary	Somatotroph (acidophil, ~50% of anterior pit)	Growth Hormone (GH, somatotropin; 191 aa)	—	Binds GH receptor (JAK2-STAT5) on liver + peripheral tissues
3. Liver	Hepatocytes	IGF-1 (somatomedin C)	IGF-1R (RTK, similar to insulin receptor)	Anabolic growth signal; carried on IGFBP-3
4. Growth plate	Chondrocytes	IGF-1 (endocrine + paracrine)	IGF-1R (RTK)	Chondrogenesis → linear bone growth (pre-fusion) or appositional (post-fusion)

GH receptor mechanics (LO 1)

GH receptor family

CYTOKINE-FAMILY receptor — single-pass transmembrane, no intrinsic kinase (NOT GPCR or RTK)

Ligand binding

DIMERIZATION (two receptors per ligand) → associated JAK2 molecules trans-phosphorylate each other

Key intracellular kinase

JAK2 (Janus kinase 2)

Key transcription factor

STAT5 — phosphorylated → dimer → nucleus → drives IGF-1 transcription

Same mechanism

Prolactin (also JAK2-STAT5). Others in the family: erythropoietin, leptin, IL-2, IFNs

SOCS role

Suppressors of cytokine signaling (SOCS-1, -3) are induced by STAT5 and bind phosphorylated JAK2/GH-R → feedback inhibition. Chronic GH → SOCS up → desensitization

IGF-1 biology (LO 1)

Primary site of synthesis

LIVER (hepatocytes) — >80% of circulating IGF-1; minor local production in chondrocytes, muscle, kidney (paracrine)

IGF-1 receptor

IGF-1R — Receptor Tyrosine Kinase (RTK), similar to insulin receptor (cross-talk at high [IGF-1])

Main binding protein

IGFBP-3 (carries >90%) in a ternary complex with ALS (acid-labile subunit)

IGFBP-3 GH-dependent

IGFBP-3 synthesis is GH-driven. Both IGF-1 and IGFBP-3 rise/fall with GH — measuring both improves axis assessment

IGF-2

Important in FETAL growth + placenta. Imprinting defects → Beckwith-Wiedemann syndrome (overgrowth, macroglossia, Wilms risk). Minor postnatal role

GH vs IGF-1 half-life

GH: ~20 min, pulsatile (unreliable single measurement). IGF-1: ~15 h on IGFBP-3, stable (preferred screen)

KEY: GH has SHORT, pulsatile half-life (~20 min) and varies through the day. IGF-1 is stable (long half-life, carried on IGFBP-3) and reflects integrated GH exposure — preferred screening test for acromegaly/GHD.

LO 2

ON EXAM — GH direct (diabetogenic + lipolytic + anti-insulin): ↑glucose, ↑FFA, ↓muscle/fat glucose uptake. IGF-1 indirect (anabolic/insulin-like): growth, ↑AA uptake, chondrogenesis. "GH keeps glucose HIGH; IGF-1 grows the TISSUES"

Direct (GH) vs indirect (IGF-1) effects (LO 2)

Tissue	Direct GH	Indirect (IGF-1)	Net result
Liver	↑ IGF-1 synthesis; ↑ gluconeogenesis	— (liver is source, not target)	↑ IGF-1 to circulation + ↑ hepatic glucose output
Adipose	LIPOLYSIS (↑ HSL → ↑ FFA); ↓ glucose uptake	Minor (IGF-1 less important here)	↑ FFA, ↓ fat mass (catabolic)
Skeletal muscle	↓ glucose uptake (insulin resistance); ↑ lipolysis	↑ AA uptake, ↑ protein synthesis, muscle hypertrophy	Anabolic for protein, catabolic for glucose/fat
Bone & cartilage	Minimal direct effect	Stimulates CHONDROCYTES → longitudinal growth (pre-fusion) or appositional (post-fusion); osteoblast activity ↑	LINEAR GROWTH in kids; thickened bone/soft tissue in adults

Metabolic signature of GH (LO 2)

GH on serum glucose

Raises glucose (DIABETOGENIC): ↓ peripheral uptake + ↑ hepatic gluconeogenesis + insulin resistance

GH on FFA

Raises FFA (lipolytic) — activates hormone-sensitive lipase in adipose

Counter-regulatory/diabetogenic

Directly opposes insulin: ↓ GLUT4 translocation, activates gluconeogenic enzymes, induces insulin resistance via SOCS + lipotoxicity. Chronic excess → glucose intolerance/diabetes in acromegaly

Hypoglycemia on GH

STRONGLY STIMULATES GH (counter-regulation). Basis of ITT — gold standard for GH DEFICIENCY

4 counter-regulatory hormones

GH + CORTISOL + GLUCAGON + EPINEPHRINE — all oppose insulin; raise glucose during fasting/stress

Insulin resistance mechanism

Chronic GH → ↑ FFAs (lipotoxicity) inhibit muscle insulin signaling; ↑ SOCS → blocks insulin receptor signaling; direct ↓ GLUT4

Growth plate and linear growth (LO 2)

Target cell

Chondrocytes — proliferate and hypertrophy → cartilage matrix → endochondral ossification → linear bone growth

Growth plate closure

Females ~14–16; males ~16–18. Signal to close: ESTROGEN in BOTH sexes (aromatized from testosterone in males). Estrogen-deficient states → tall stature with unfused plates

Pre- vs post-puberty

Pre (open plates) + GH excess → GIGANTISM (linear growth). Post (fused plates) → ACROMEGALY (appositional/width growth in hands, feet, jaw, soft tissues)

AA transporter

IGF-1 stimulates AA uptake via SLC-family transporters + ribosomal biogenesis → protein synthesis in muscle + chondrocytes

LO 3

ON EXAM — GH pulsatile, NIGHT-dominant (largest pulse in N3 SWS, ~1 h after sleep onset); lifetime: neonatal ↑ → childhood moderate → PUBERTY PEAK → adult decline → somatopause (~50%/decade); IGF-1 ↑ → somatostatin ↑; GH short-loop → GHRH ↓

24-hour GH rhythm (LO 3)

Pattern

Pulsatile (mostly night-dominant) — ~4–8 pulses/24 h; largest during sleep

Largest pulse timing

First few hours of night sleep, ~1 h after sleep onset

Sleep stage

Slow-wave sleep (SWS) = N3 (non-REM deep). Sleep deprivation markedly blunts GH

Single random GH

Useless — GH is pulsatile with ~20 min half-life; near zero between pulses even in health

Preferred screening

Serum IGF-1 — stable long half-life, integrates 24-hour GH exposure

Confirmatory acromegaly

OGTT with GH measurement: healthy GH suppresses to <1 ng/mL; acromegaly fails to suppress (may paradoxically rise)

Lifetime GH curve (LO 3)

Life stage	GH / IGF-1 level	Driver / context
Neonate	HIGH GH + IGF-1 at birth	Required for neonatal glucose regulation + early growth
Childhood	Moderate baseline; pulsatile	Steady IGF-1 reflecting ongoing linear growth
Puberty	PEAK GH + IGF-1 of lifetime	Sex steroids (esp. estrogen) amplify GH pulse amplitude → pubertal growth spurt, then plate fusion
Young adult	Steady lower baseline	Important for body composition + metabolism; begins gradual decline from ~age 25–30
Elderly (somatopause)	↓↓ GH + IGF-1 (~50% per decade)	Contributes to age-related ↓ muscle, ↑ fat, ↓ bone. Exogenous GH not recommended (risks)

Feedback architecture (LO 3)

Long-loop

IGF-1 (target hormone) → hypothalamus + pituitary: ↑ somatostatin, direct ↓ somatotroph response to GHRH

Short-loop

GH itself → hypothalamus: ↑ somatostatin, ↓ GHRH

Ultra-short

GHRH inhibits its own release from arcuate neurons (autoregulatory)

IGF-1 two arms

(1) ↑ somatostatin release from hypothalamus → inhibits GH. (2) Directly inhibits somatotroph response to GHRH

LO 4

ON EXAM — STIMULATE: GHRH, ghrelin, SLEEP (SWS), exercise, stress, HYPOGLYCEMIA (ITT), arginine, estrogen (oral), dopamine agonists (paradoxical in acromegaly). INHIBIT: somatostatin, IGF-1, HYPERGLYCEMIA (OGTT), FFA, cortisol, obesity

Physiologic stimulators (LO 4)

Stimulator	Mechanism	Relevance
GHRH	Arcuate → portal blood → Gs-cAMP on somatotroph	Physiologic releasing hormone; sermorelin is an analog
Ghrelin	Stomach oxyntic cells → GHSR (Gq) on somatotroph + arcuate	Pulsatile GH release + appetite; peaks pre-meals; GHRP used in stim testing
Sleep (SWS / N3)	SWS triggers largest endogenous GH pulse	Sleep deprivation blunts GH → metabolic dysfunction; growth failure in kids
Exercise	Acute intense exercise → GH pulse via sympathetic + ghrelin	Physiologic anabolism of training
Hypoglycemia	Low glucose → strong GH stimulus (counter-regulation)	GOLD STANDARD test for GHD = ITT (glucose <40 → measure GH)
Arginine / protein meal	↓ somatostatin + direct stimulation	Arginine + GHRH is a safer alternative to ITT for GHD diagnosis
Estrogen (oral)	Oral estrogen amplifies GH pulse amplitude at puberty and in women	Female > male GH during reproductive years; transdermal estrogen has less effect

Physiologic inhibitors (LO 4)

Inhibitor	Mechanism	Relevance
Somatostatin	Arcuate/periventricular → Gi on somatotroph	Main physiologic brake. Octreotide mimics for acromegaly treatment
IGF-1	Target-organ long-loop feedback (↑ somatostatin + ↓ somatotroph response)	Rises with GH excess → axis shutdown. Pegvisomant breaks this loop → GH paradoxically rises
Hyperglycemia	Via hypothalamic somatostatin	OGTT confirmatory: healthy suppress <1 ng/mL; acromegaly fails
FFA	High FFA suppress GH (partly via somatostatin)	Explains blunted GH in obesity; lipid-heavy meals blunt stim tests
Glucocorticoids (chronic)	Suppress GH axis at multiple levels	Kids on chronic steroids have growth failure; reversible with dose reduction
Obesity	Markedly blunted GH pulses (↑ insulin, ↑ FFA, ↑ leptin resistance)	Can cause false-positive GHD dx; use BMI-adjusted cutoffs

Pharmacology (LO 4)

Drug	Mechanism	Use
Somatropin (rhGH)	Recombinant human GH → GH-R → JAK-STAT → IGF-1 synthesis	Pediatric GHD, Turner, CKD, Prader-Willi, adult GHD
Mecasermin	Recombinant IGF-1 (+ IGFBP-3 as mecasermin-rinfabate)	Laron syndrome (GH-R defect) — GH is useless; give IGF-1 directly. Also severe IGF-1 deficiency
Octreotide / lanreotide	Somatostatin analogs; bind SSTR2/5 → ↓ GH release	First-line medical therapy for acromegaly after surgery. Also carcinoid, VIPoma, variceal bleed
Pegvisomant	PEGylated GH-R ANTAGONIST; blocks dimerization → no JAK-STAT	Acromegaly not controlled by somatostatin analogs. Follow IGF-1 (GH paradoxically ↑)
Cabergoline	D₂ agonist; usually inhibits prolactin, paradoxically suppresses GH in some somatotroph adenomas	Adjunct in mild acromegaly or mixed GH-prolactin adenomas
Sermorelin / tesamorelin	GHRH analogs → Gs-cAMP stim of somatotroph	Sermorelin: GHD dx/therapy. Tesamorelin: HIV lipodystrophy (reduces visceral fat)

PARADOX: In NORMAL people, dopamine agonists suppress prolactin but not GH. In somatotroph adenomas, dopamine agonists can PARADOXICALLY inhibit GH secretion (adjunct in acromegaly).

LO 5

ON EXAM — GIGANTISM: excess GH BEFORE epiphyseal closure → linear growth. ACROMEGALY: excess AFTER closure → APPOSITIONAL (hands, feet, jaw, macroglossia, viscera). Dx: IGF-1 ↑↑; GH fails to suppress on OGTT. Tx: surgery → octreotide → pegvisomant. Pediatric GHD: short stature w/ normal proportions. Laron = GH-R defect (high GH, low IGF-1; treat with mecasermin)

GH EXCESS (LO 5)

Feature	Gigantism	Acromegaly
Timing	BEFORE epiphyseal fusion (pre-/peri-puberty)	AFTER fusion (adult)
Classic findings	Accelerated LINEAR growth → extreme height; lengthened limbs; normal proportions until late	Enlarged hands/feet (ring/shoe changes); coarse facies; PROGNATHISM; frontal bossing; MACROGLOSSIA; tooth spacing; deep voice; organomegaly; thick skin; skin tags; carpal tunnel
Cause	Somatotroph pituitary adenoma; rarely McCune-Albright, Carney, FIPA	Somatotroph pituitary adenoma (>95%); rarely ectopic GHRH (carcinoid, pheo)
CV complications	HTN; cardiomegaly	HTN; concentric hypertrophy → dilated cardiomyopathy; accelerated atherosclerosis — MAIN cause of death
Metabolic	Insulin resistance	Insulin resistance → glucose intolerance → T2DM (up to 30%); dyslipidemia; hyperphosphatemia
Other	Mass effect; headaches; OSA	Bitemporal hemianopsia; headaches; OSA (macroglossia); COLON POLYPS/cancer (screen); arthropathy; carpal tunnel

Diagnosis of GH excess (LO 5)

Best screening

Serum IGF-1 (elevated; reflects chronic GH excess)

Confirmatory

OGTT with GH: healthy suppresses <1 ng/mL at 2 h; acromegaly FAILS to suppress (may paradoxically rise)

Imaging

MRI pituitary after biochemical confirmation — localize somatotroph adenoma

Ectopic GHRH

Rare (<1%): bronchial/pancreatic/thymic carcinoid or pheochromocytoma. Clue: elevated plasma GHRH (normally suppressed when GH is high)

Treatment ladder for acromegaly (LO 5)

First-line

Transsphenoidal pituitary surgery — cures ~80% of microadenomas, ~50% of macroadenomas

Somatostatin analog

Octreotide / lanreotide — SSTR2/5 agonists → ↓ GH release + tumor shrinkage

GH-R antagonist

Pegvisomant — PEGylated mutant GH blocks receptor dimerization → no JAK-STAT → hepatic IGF-1 falls. Monitor IGF-1 (not GH)

Dopamine agonist

Cabergoline — paradoxical GH suppression in a minority (esp. mixed GH-prolactin adenomas or high D₂ expression)

Radiation

Stereotactic (gamma knife) or conventional — reserved for refractory disease. 5–10 years for full effect; risks hypopituitarism

GH DEFICIENCY (LO 5)

Feature	Pediatric GHD	Adult GHD	Laron
Mechanism	Pituitary problem — congenital (PROP1, POU1F1, GHRH-R, GH1) or acquired (craniopharyngioma, trauma)	Pituitary/hypothalamic injury (adenoma, Sheehan, surgery, radiation)	GH RECEPTOR mutation (autosomal recessive) — GH cannot signal
GH level	LOW (poor response to stimulation)	LOW after provocation	HIGH (or normal) — feedback lost
IGF-1 level	LOW	LOW or normal-low (overlapping ref range)	LOW (no GH-R signaling to produce it)
Clinical	Short stature + normal proportions; delayed bone age; chubby cherubic face; central adiposity	Central adiposity; ↓ lean mass; ↓ bone density; ↓ exercise tolerance; ↓ QoL; CV risk	Severe short stature w/ normal proportions; frontal bossing; chubby; infant hypoglycemia; ↓ cancer + ↓ diabetes risk (signaling blunted)
Treatment	Recombinant GH (somatropin)	Recombinant GH — lower doses than pediatric	Recombinant IGF-1 (MECASERMIN) — exogenous GH is useless

Diagnosing GH deficiency (LO 5)

Gold-standard stim test

Insulin tolerance test (ITT) — induce glucose <40 mg/dL → measure peak GH. Healthy adult: >5 ng/mL. GHD: <3–5

Safer alternatives

GHRH + arginine combined stim; glucagon stim. Used in cardiac/seizure risk patients

Random GH

Useless — pulsatile, near zero between pulses. Must use provocative stim

IGF-1 in adult GHD

Can be normal in up to 30–40% of adults with biochemical GHD (age-related ref intervals overlap). Provocative testing required

LO 1–5 · USMLE Step 1 Style

8 questions — answers pre-revealed. Covers all LOs.

Q1. A 48-year-old man with enlarging hands, prognathism, macroglossia, HTN, and glucose intolerance has markedly elevated fasting IGF-1. Best CONFIRMATORY test?

A. Random GH
B. GH after OGTT
C. Insulin tolerance test
D. Arginine-GHRH stim
E. Random cortisol

B — Failure to suppress GH on OGTT.
Acromegaly. Screen with IGF-1. Confirm with OGTT: normally glucose load suppresses GH to <1 ng/mL; in acromegaly the autonomous adenoma fails to suppress (may paradoxically rise). Random GH is uninformative (pulsatile). ITT and arginine-GHRH are for GH DEFICIENCY.

Q2. Primary intracellular signaling of the GH receptor?

A. Gs → cAMP → PKA
B. Gq → IP₃/DAG
C. RTK → Ras/MAPK
D. Cytokine-family receptor → JAK2 → STAT5 → transcription
E. Steroid receptor → HSP90 dissociation

D — JAK2/STAT5.
GH-R is single-pass cytokine-family receptor; ligand-induced dimerization → trans-phosphorylation by associated JAK2 → phosphorylates STAT5 → STAT5 dimer → nucleus → IGF-1 transcription. Prolactin uses the same path. SOCS proteins provide negative feedback.

Q3. A 12-year-old boy with a somatotroph adenoma has accelerated linear growth (95th percentile). Why gigantism rather than acromegaly?

A. Tumor secretes IGF-2 instead of IGF-1
B. Epiphyseal plates not yet fused — IGF-1 drives longitudinal growth
C. GH receptors hyperactive
D. Concurrent precocious puberty
E. Prolactin co-secretion accelerates growth

B — Open epiphyseal plates.
Pre-puberty, plates remain open; IGF-1 stimulates chondrocyte proliferation → linear growth (gigantism). After plates fuse (estrogen-driven), bone grows only APPOSITIONALLY → enlarged hands, feet, jaw, soft tissues (acromegaly).

Q4. GH secretion during sleep?

A. Continuous through all sleep stages
B. Lowest during sleep
C. Largest pulse during REM
D. Largest pulse during slow-wave (N3) sleep, ~1 h after onset
E. Suppressed during sleep, peaks afternoon

D — Largest pulse in slow-wave (N3) sleep.
GH is pulsatile, night-dominant; largest pulse follows sleep onset during deep N3 (slow-wave) sleep. Sleep deprivation blunts GH. This is why a single random GH is uninformative and IGF-1 is preferred for screening.

Q5. 6-year-old: severe short stature, delayed bone age, chubby cherubic appearance. GH HIGH, IGF-1 LOW, no response to exogenous GH. Diagnosis?

A. GHRH receptor mutation
B. Craniopharyngioma
C. GH receptor mutation (Laron)
D. Congenital hypothyroidism
E. Constitutional growth delay

C — Laron syndrome (GH-R mutation).
GH normal/HIGH (feedback lost), IGF-1 LOW (no GH-R signaling). Short stature with normal proportions, chubby, delayed bone age. Exogenous GH useless. Tx: recombinant IGF-1 (mecasermin). Laron patients paradoxically have low rates of cancer and diabetes (blunted GH/IGF-1 signaling).

Q6. 54-year-old with persistent acromegaly 3 months post-op, not controlled on octreotide. Pegvisomant mechanism?

A. Somatostatin agonist
B. D₂ agonist
C. GH receptor ANTAGONIST — blocks dimerization and JAK-STAT
D. GHRH antagonist
E. Recombinant IGF-1

C — GH receptor antagonist.
Pegvisomant is a PEGylated mutated GH analog that binds the receptor but blocks functional dimerization → no JAK2-STAT5 → hepatic IGF-1 falls. Follow IGF-1 (GH paradoxically rises as feedback is lost). Used when surgery + octreotide fail.

Q7. 28-year-old woman post-op/radiation for pituitary macroadenoma, now fatigue + central adiposity. Suspected GH deficiency. Best test?

A. Random GH
B. 24-h urinary GH
C. Insulin tolerance test
D. OGTT GH suppression
E. CT pituitary

C — Insulin tolerance test (ITT).
Gold standard for GHD: induced hypoglycemia (<40 mg/dL) normally triggers GH surge (>5 ng/mL). Failure = GHD. Alternative (safer for cardiac/seizure patients): GHRH + arginine. OGTT is for GH EXCESS. IGF-1 alone can be normal in up to 40% of adult GHD.

Q8. Direct metabolic effects of GH on peripheral tissues?

A. Promotes glucose uptake in muscle + hepatic glycogenesis
B. Inhibits lipolysis + promotes TG storage
C. ↑ lipolysis, ↓ muscle glucose uptake, ↑ hepatic gluconeogenesis → ↑ glucose and FFA
D. Stimulates β-cell insulin secretion
E. Cross-reacts with insulin receptor

C — Lipolytic, anti-insulin, gluconeogenic.
GH's direct effects oppose insulin: ↑ lipolysis in adipose (↑ FFA), ↓ glucose uptake in muscle/fat, ↑ hepatic gluconeogenesis → net hyperglycemia + hyperlipidemia. Chronic excess → glucose intolerance/diabetes in acromegaly. The indirect, growth-promoting effects (via IGF-1) are anabolic, insulin-like. "GH keeps glucose HIGH; IGF-1 grows the TISSUES."

Hypothalamic-Pituitary Relationships II (GH Axis) — Answer Key