LO 1

ON EXAM — GHRH (arcuate, Gs-cAMP on somatotroph) + ghrelin (stomach, GHSR) stimulate; somatostatin (Gi) inhibits; GH uses JAK2-STAT5 (cytokine-family receptor, single pass — NOT a GPCR); GH → liver → IGF-1 (somatomedin C) → chondrocytes of epiphyseal growth plate; IGF-1 carried on IGFBP-3 (>90%); IGFBP-3 synthesis ALSO GH-dependent (so both rise together)

Trace the cascade: hypothalamus → pituitary → liver → target (LO 1)

Step	Source cell / organ	Hormone	Receptor + signal	Main effect
1. Hypothalamus (+)
1. Hypothalamus (−)
1b. Stomach (+)
2. Pituitary
3. Liver
4. Growth plate

GH receptor mechanics (LO 1)

GH receptor family (GPCR / RTK / JAK-STAT / nuclear)?

Ligand binding causes receptor ____ → trans-phosphorylation

Key intracellular kinase activated by GH-R

Key transcription factor phosphorylated by that kinase

Which other hormone uses the SAME JAK-STAT mechanism?

SOCS proteins — role in GH signaling?

IGF-1 biology (LO 1)

Primary site of IGF-1 synthesis (by far)

Receptor IGF-1 binds (and what family?)

Main IGF binding protein in plasma

What makes IGFBP-3 synthesis GH-dependent (clinical implication for labs)?

IGF-1 vs IGF-2 — where does IGF-2 mainly matter?

Half-life of GH vs IGF-1 — which is more stable for measurement?

KEY: GH has a 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 — the preferred screening test for acromegaly.

LO 2

ON EXAM — GH direct (diabetogenic + lipolytic + anti-insulin): ↑blood glucose, ↑FFA, ↓muscle/fat glucose uptake, ↑hepatic gluconeogenesis. IGF-1 indirect (anabolic/insulin-like): growth, ↑AA uptake, ↑protein synthesis, chondrogenesis, linear bone growth. "GH keeps glucose high, IGF-1 grows the tissues"

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

Tissue	Direct GH effect	Indirect (via IGF-1)	Net metabolic result
Liver
Adipose
Skeletal muscle
Bone & cartilage (growth plate)

Metabolic signature of GH (LO 2)

Effect of GH on serum glucose (and mechanism in 1-2 words)

Effect of GH on serum free fatty acids

Why GH is called a "counter-regulatory" / "diabetogenic" hormone

Effect of insulin on GH secretion at the pituitary (hypoglycemia test)

Which 4 hormones together oppose insulin? (GH + ___ + ___ + ___)

Why GH causes insulin RESISTANCE at target tissues

Growth plate and linear growth (LO 2)

Cell type in the epiphyseal plate that IGF-1 stimulates

When do growth plates close (sex-dependent)? What signal closes them?

Pre-puberty vs post-puberty GH excess — why gigantism vs acromegaly?

Which amino acid transporter is upregulated in muscle/chondrocytes by IGF-1?

LO 3

ON EXAM — GH is pulsatile, NIGHT-dominant (largest pulses during slow-wave/N3 sleep, ~1 h after onset); lifetime curve: neonatal ↑ → childhood moderate → PUBERTAL PEAK → adult decline → "somatopause" in elderly (~50% drop per decade); feedback: IGF-1 ↑ → somatostatin ↑; GH short-loop → GHRH ↓

24-hour GH rhythm (LO 3)

Pattern of GH release: pulsatile, continuous, or circadian?

Time of LARGEST GH pulse

Sleep stage that triggers the biggest pulse

Clinical: why is a SINGLE random GH level poor for diagnosis?

Preferred screening test for chronic GH excess

Confirmatory test for acromegaly (uses physiologic GH inhibitor)

Lifetime GH curve (LO 3)

Life stage	GH / IGF-1 level (relative)	Dominant driver / context
Neonate
Childhood (pre-puberty)
Puberty
Young adult
Elderly ("somatopause")

Feedback architecture (LO 3)

Long-loop negative feedback — what from where suppresses GH?

Short-loop negative feedback — what from where to where?

Ultra-short loop — what on what?

How does IGF-1 suppress GH (two arms)?

LO 4

ON EXAM — STIMULATE GH: GHRH, ghrelin, SLEEP (SWS), exercise, stress, HYPOGLYCEMIA (insulin tolerance test gold standard), protein/arginine meals, estrogen (oral), dopamine agonists (paradoxical suppression in acromegaly). INHIBIT: somatostatin, IGF-1, HYPERGLYCEMIA (OGTT suppression test), free fatty acids, cortisol (chronic), obesity, senescence

Physiologic stimulators of GH (LO 4)

Stimulator	Mechanism	Clinical / test relevance
GHRH
Ghrelin
Sleep (SWS / N3)
Exercise
Hypoglycemia
Arginine / protein meal
Estrogen (oral)

Physiologic inhibitors of GH (LO 4)

Inhibitor	Mechanism	Clinical / test relevance
Somatostatin
IGF-1
Hyperglycemia
Free fatty acids
Glucocorticoids (chronic)
Obesity

Pharmacology of the GH axis (LO 4)

Drug	Mechanism	Use
Somatropin (recombinant GH)
Mecasermin
Octreotide / lanreotide
Pegvisomant
Cabergoline / bromocriptine
Sermorelin / tesamorelin

PARADOX: In NORMAL people, dopamine agonists suppress prolactin but have little effect on GH. In somatotroph adenomas, dopamine agonists can PARADOXICALLY inhibit GH secretion (used as adjunct in acromegaly).

LO 5

ON EXAM — GIGANTISM: excess GH BEFORE epiphyseal closure → accelerated linear growth (height). ACROMEGALY: excess AFTER closure → APPOSITIONAL growth (hands, feet, jaw, brow, macroglossia, visceromegaly). Most common cause: somatotroph adenoma. Labs: IGF-1 ↑↑; GH fails to suppress with oral glucose (OGTT). Tx: transsphenoidal surgery → octreotide → pegvisomant. DEFICIENCY in kids: short stature with normal proportions. Laron dwarfism = GH receptor defect (high GH, low IGF-1, treat with mecasermin).

GH EXCESS — gigantism vs acromegaly (LO 5)

Feature	Gigantism	Acromegaly
Timing (before/after growth plate fusion)
Classic physical findings
Most common cause
Cardiovascular complications
Metabolic complications
Other (visual, neurologic, OSA, colon)

Diagnosis of GH excess (LO 5)

Best SCREENING test

CONFIRMATORY test (and expected result in disease)

Imaging after biochemical confirmation

Rare cause of ectopic GHRH (lab clue: elevated GHRH)

Treatment ladder for acromegaly (LO 5)

First-line

Medical — somatostatin analog (name + MOA)

Medical — GH receptor antagonist (name + MOA)

Adjunct — dopamine agonist (and which subset responds?)

Salvage — stereotactic radiation (when used?)

GH DEFICIENCY (LO 5)

Feature	Pediatric GHD	Adult GHD	Laron syndrome
Mechanism
GH level
IGF-1 level
Clinical features
Treatment

Diagnosing GH deficiency (LO 5)

Gold-standard stimulation test

Alternate safer stim test combo

Single random GH level — useful or not, and why?

Why is IGF-1 not always low in adult GHD?

LO 1–5 · USMLE Step 1 Style

8 questions — cover all LOs. Use these after finishing all tabs.

Q1. A 48-year-old man presents with enlarging hands (needing larger rings and gloves), prognathism, coarse facial features, macroglossia, and new-onset hypertension with glucose intolerance. Fasting IGF-1 is markedly elevated. Which of the following is the BEST CONFIRMATORY test?

A. Random GH level
B. GH level after oral glucose tolerance test (OGTT)
C. Insulin tolerance test (induced hypoglycemia)
D. Arginine-GHRH stimulation test
E. Random cortisol level

B — Failure to suppress GH on OGTT.
Acromegaly in an adult. Screen with IGF-1 (stable, long half-life reflects integrated GH exposure). Confirm with oral glucose tolerance test: in healthy individuals, glucose load suppresses GH to <1 ng/mL. In acromegaly, the autonomous somatotroph adenoma fails to suppress (often GH paradoxically rises). Random GH is uninformative because GH is pulsatile; insulin tolerance and arginine-GHRH tests are used to diagnose GH deficiency, not excess.

Q2. Which of the following BEST describes the primary intracellular signaling pathway used by the GH receptor?

A. Gs → adenylyl cyclase → cAMP → PKA
B. Gq → phospholipase C → IP₃ / DAG → Ca²⁺, PKC
C. Receptor tyrosine kinase autophosphorylation → Ras / MAPK
D. Cytokine-family receptor → JAK2 activation → STAT5 phosphorylation → nuclear transcription
E. Lipid-soluble ligand → cytosolic receptor-HSP90 dissociation → gene transcription

D — JAK2 / STAT5 (cytokine-family receptor).
GH receptor is a single-pass, non-kinase cytokine-family receptor. Ligand binding induces receptor dimerization → trans-phosphorylation by associated JAK2 → recruitment and phosphorylation of STAT5 → STAT5 dimer translocates to nucleus → transcription of IGF-1 (hepatocytes) and other target genes. Prolactin uses the same JAK-STAT mechanism. SOCS proteins provide negative feedback.

Q3. A 12-year-old boy with a pituitary somatotroph adenoma has accelerated linear growth (95th percentile for height) but has not yet reached his expected final height. Which BEST explains why he has gigantism rather than acromegaly?

A. The tumor secretes IGF-2 rather than IGF-1
B. His epiphyseal growth plates have not fused, so IGF-1 drives longitudinal bone growth
C. His GH receptors are mutated to be hyperactive
D. He has concurrent precocious puberty
E. Prolactin co-secretion accelerates growth

B — Open epiphyseal growth plates allow longitudinal growth.
Before puberty completes, epiphyseal plates remain open; IGF-1 stimulates chondrocyte proliferation in the growth plate → linear growth (gigantism). After plates fuse (driven by estrogen in both sexes), bone can only grow APPOSITIONALLY, producing enlarged hands, feet, jaw, and soft tissues = acromegaly. Same hormone excess, different result based on skeletal maturity.

Q4. A healthy 22-year-old medical student undergoes a sleep study. Which of the following BEST describes GH secretion during the study?

A. GH is released continuously at a steady baseline through all sleep stages
B. GH declines to its lowest level during sleep
C. The largest GH pulse occurs during REM sleep
D. The largest GH pulse occurs during slow-wave (N3) sleep, roughly 1 hour after sleep onset
E. GH is suppressed during sleep and peaks during afternoon wakefulness

D — Largest pulse in slow-wave (N3) sleep.
GH is pulsatile with night-dominant release; the largest pulse follows sleep onset and occurs during deep slow-wave sleep (stage N3). This is why sleep deprivation blunts GH secretion and why a single random GH level is uninformative. For this reason, IGF-1 (stable, long half-life, integrates 24-hour GH exposure) is preferred for screening, and OGTT for confirmation.

Q5. A 6-year-old boy with short stature (well below 3rd percentile) has delayed bone age, chubby appearance, and central adiposity. Serum GH is markedly ELEVATED; IGF-1 is LOW. Exogenous GH injection does NOT raise IGF-1 or stimulate growth. The MOST likely diagnosis is:

A. Isolated GHRH receptor mutation
B. Pituitary somatotroph destruction from craniopharyngioma
C. GH receptor mutation (Laron syndrome)
D. Congenital hypothyroidism
E. Constitutional growth delay

C — Laron syndrome (GH receptor mutation).
GH-receptor insensitivity: GH is normal or HIGH (no IGF-1 feedback), but IGF-1 is LOW because GH can't signal through its receptor → no hepatic IGF-1 production → short stature with normal proportions, chubby appearance, delayed bone age. Exogenous GH does not help. Treatment: recombinant IGF-1 (mecasermin). Laron patients paradoxically have low rates of cancer and diabetes because GH/IGF-1 signaling is blunted.

Q6. A 54-year-old man with acromegaly has persistent IGF-1 elevation three months after transsphenoidal resection of a somatotroph adenoma. Octreotide has not achieved biochemical control. The physician adds pegvisomant. Which BEST describes its mechanism?

A. Somatostatin receptor 2/5 agonist that inhibits GH release
B. Dopamine D₂ agonist that paradoxically suppresses GH in some adenomas
C. GH receptor ANTAGONIST that blocks dimerization and downstream JAK-STAT signaling
D. GHRH receptor antagonist at the pituitary
E. Recombinant IGF-1 for substitution therapy

C — GH receptor antagonist.
Pegvisomant is a PEGylated, mutated analog of GH that binds the receptor but blocks functional dimerization → no JAK2-STAT5 signaling → hepatic IGF-1 production falls. Follow IGF-1 (not GH, which paradoxically rises because feedback is lost). Use for patients not controlled by surgery or somatostatin analogs. Octreotide (A), cabergoline (B), and mecasermin (E) work through different mechanisms.

Q7. A 28-year-old woman presents with fatigue, central adiposity, and decreased exercise tolerance. She had transsphenoidal surgery and pituitary radiation for a macroadenoma 4 years ago. Morning cortisol and T₄ are replaced. GH deficiency is suspected. Which is the MOST appropriate diagnostic test?

A. Random single GH level
B. 24-hour urinary GH excretion
C. Insulin tolerance test (induced hypoglycemia provokes GH release)
D. OGTT GH suppression
E. CT pituitary

C — Insulin tolerance test (ITT).
ITT is the gold-standard provocative test for GH deficiency: induced hypoglycemia (<40 mg/dL) normally triggers a robust GH surge (>5 ng/mL in adults). Failure to respond = GHD. Alternative (safer in patients with cardiac/seizure risk): GHRH + arginine stimulation. Random GH (A) is useless; OGTT (D) is for suspected GH EXCESS, not deficiency. IGF-1 alone can be normal in up to 40% of adult GHD, so provocative testing is needed for diagnosis.

Q8. During a fasting state, GH counter-regulates insulin. Which of the following BEST describes the direct metabolic effects of GH on peripheral tissues?

A. Promotes glucose uptake in muscle and stimulates hepatic glycogenesis
B. Inhibits lipolysis and promotes triglyceride storage in adipose tissue
C. Stimulates lipolysis in adipose, decreases glucose uptake in muscle, and increases hepatic gluconeogenesis (→ raises serum glucose & FFA)
D. Stimulates pancreatic β-cell insulin secretion
E. Cross-reacts with the insulin receptor to produce anabolic effects

C — Lipolytic, anti-insulin, gluconeogenic.
GH's direct metabolic effects are opposite to insulin: ↑ lipolysis in adipose (→ ↑ FFA), ↓ glucose uptake in muscle and fat, ↑ hepatic gluconeogenesis → net hyperglycemia + hyperlipidemia. This is why chronic GH excess causes glucose intolerance and diabetes in acromegaly. The indirect, growth-promoting effects (via IGF-1) are separate — anabolic, insulin-like, and drive linear growth, muscle protein synthesis, and chondrogenesis. "GH keeps glucose HIGH; IGF-1 grows the tissues."

Hypothalamic-Pituitary Relationships II (GH Axis) — Active Recall