Hypothalamic–Pituitary Relationships II Active Drills
Per-LO coverage of in-house lecture material with mechanism-focused active recall: GH signaling pathway, direct vs indirect effects, circadian/lifetime regulation, stimulators/inhibitors, and the four GH-axis disorders.
Lecture 03 · Endocrine Block · Growth Hormone Axis — LOs 1–5
GHRH & somatostatin: both use GPCRs on somatotropes — GHRH via Gs (↑cAMP); somatostatin via Gi (↓cAMP).
LO 1 · Carriers Lecture Notes · In House Anki
What carries GH and IGF-1 in the blood, and how does this affect their half-lives?
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Answer
GH: ~50% bound to GHBP (growth hormone binding protein — proteolytic fragment of the GH receptor). Despite binding, ½-life is short (~20 min) because GH is small enough to be filtered by the kidney.
IGF-1: nearly 100% bound to IGFBPs (IGFBP-1 through -6; mainly IGFBP-3) → ½-life ~12 HOURS (>30× longer than GH). IGFBP proteases free IGF-1 in target tissues to activate it.
Clinical: IGF-1 is stable and integrates GH exposure over 24h — ideal for screening acromegaly.
LO 2 · Direct vs Indirect GH Lecture Notes · In House Anki
Contrast the direct effects of GH vs. the indirect (IGF-1-mediated) effects.
Indirect effects (via IGF-1 — anabolic / growth): • ↑ protein synthesis (amino acid uptake, RNA translation) • ↑ chondrocyte proliferation in growth plates → LINEAR BONE GROWTH • ↑ cell proliferation, ↓ apoptosis in most tissues • ↑ organ size
LO 2 · Diabetogenic Effect Lecture Notes · In House Anki
Why is GH called a "diabetogenic" hormone, and how does this affect clinical populations?
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Answer
GH reduces insulin sensitivity in skeletal muscle and adipose → fewer GLUT4 transporters at membrane → glucose stays in blood → insulin resistance → hyperglycemia.
Useful between meals (keeps glucose available for CNS) but harmful when chronic.
Acromegaly: ~30–50% develop glucose intolerance / type 2 diabetes. Dieback in diabetes control is often the first clue to acromegaly in a pre-existing diabetic.
Insulin is PERMISSIVE for GH: insulin up-regulates hepatic GH receptors → needed to drive IGF-1 synthesis.
LO 2 · Tissue-Specific Effects Lecture Notes · In House Anki
For each: liver, adipose, skeletal muscle, bone/cartilage — list GH and IGF-1 effects.
Tx: recombinant human GH (somatropin) subcutaneous, daily. Most effective BEFORE epiphyseal closure. Also used for Turner syndrome, Prader-Willi, chronic kidney disease.
LO 5 · Laron Syndrome Lecture Notes · In House Anki
What is Laron syndrome, and how do labs differ from classic GH deficiency?
Phenotype: severe short stature (similar to dwarfism) + obesity + hypoglycemia + frontal bossing.
Labs:HIGH GH + LOW IGF-1 (pituitary makes GH, but liver can't respond → no IGF-1).
Treatment: recombinant IGF-1 (mecasermin) — replaces the downstream mediator. GH replacement does NOT work here (receptor defect).
Dramatically, people with Laron are PROTECTED from cancer and diabetes.
LO 5 · Gigantism vs Acromegaly Lecture Notes · In House Anki
What determines whether GH excess causes gigantism or acromegaly?
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Answer
Gigantism: GH excess BEFORE epiphyseal closure → linear bone growth → extreme tall stature + organ enlargement. Acromegaly: GH excess AFTER epiphyseal closure → long bones can't grow in length, but thicken. Results in jaw prognathism, frontal bossing, hand/foot enlargement, macroglossia, organomegaly, sleep apnea, cardiomegaly.
Both usually from a GH-secreting pituitary adenoma (somatotrope adenoma) — the 2nd most common functional pituitary tumor (after prolactinoma).
LO 5 · Dx Workup Lecture Notes · In House Anki
Best screening and confirmatory tests for acromegaly?
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Answer
Screen: serum IGF-1 (stable, integrates GH exposure over 24h; not pulsatile like GH itself)
Confirm:oral glucose tolerance test (OGTT) — give 75g glucose, measure GH at 0/30/60/90/120 min. Normal: GH suppresses <1 ng/mL. Acromegaly: GH does NOT suppress (tumor is feedback-independent).
Localize: MRI sella after biochemical confirmation (~95% have pituitary adenoma).
Also check other anterior pituitary hormones (co-secretion, mass effects).
LO 5 · Treatment Lecture Notes · In House Anki
List the treatment options for acromegaly in order of first to last choice.
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Answer
1. Surgery — transsphenoidal resection (first line; ~70% cure with microadenoma).
3. Radiation (stereotactic/gamma knife) — last resort; slow effect over years.
FIB 01 · LO 1 Lecture Notes · Study Guide
Growth hormone is a _____________-AA peptide released from _____________ cells (acidophils) of the anterior pituitary.
GH binds a _____________-type receptor on hepatocytes, which activates the _____________-STAT5 pathway to induce synthesis of IGF-1 (also called _____________ C).
FIB 03 · LO 1 Lecture Notes · Study Guide
GH has a short half-life of approximately _____________ minutes, while IGF-1 has a much longer half-life of approximately _____________ hours because it is bound to _____________.
FIB 04 · LO 2 Lecture Notes · Study Guide
GH has DIRECT effects (catabolic): ↑ lipolysis, ↑ gluconeogenesis, and _____________ on muscle/adipose — producing a _____________ (blood-sugar-raising) effect. INDIRECT effects via IGF-1 are _____________ (growth-promoting).
FIB 05 · LO 3 Lecture Notes · Study Guide
The largest physiological GH pulse occurs during _____________ sleep (stage 4). Across the lifespan, GH is HIGHEST during _____________, and declines in the elderly — a phenomenon called _____________.
The gastric hormone _____________ is a potent stimulator of GH release via the GHS-R receptor. Oral glucose SUPPRESSES GH in healthy subjects — the basis of the _____________ diagnostic test for acromegaly.
Instructions: Drag items into correct order, then click "Check Order." Use "Show Answer" if stuck.
Drill 1 · LO 1 — GH Signaling Cascade: Hypothalamus → Growing Bone Lecture Notes · Study Guide
Arrange the 6 steps from hypothalamic stimulus to cartilage proliferation.
⠿Somatotropes release GH into systemic circulation
⠿Ventromedial nucleus neurons release GHRH into the portal system
⠿IGF-1 released from liver, travels bound to IGFBP-3
⠿IGF-1 binds IGF-1R on chondrocytes → mitogenic signal → epiphyseal growth
⠿GHRH binds Gs-coupled receptor on somatotropes → ↑cAMP
IGF-1 → chondrocyte IGF-1R → mitogenesis → linear growth
Instructions: Click an item on the left, then click its match on the right. Correct pairs turn green; wrong pairs flash red.
Set 1 · LO 2 — Tissue → GH/IGF-1 Action
Match each tissue to the GH-axis action it experiences.
Tissue
Liver
Adipose
Skeletal muscle
Epiphyseal cartilage
Action
IGF-1-driven chondrocyte proliferation → linear growth
GH-stimulated IGF-1 synthesis + gluconeogenesis
IGF-1 → protein synthesis; GH → insulin resistance
GH → lipolysis + ↓ glucose uptake
Score: 0/4 correct
If-Then Cascade Drills: Ten cascades aligned to the four reference tables — GH Axis Big Picture, Direct vs Indirect Effects, Stimulators/Inhibitors, and Four GH-Axis Disorders. Click "Predict →" at each step to rehearse your GH-axis reasoning from hypothalamus → pituitary → liver → target tissues → clinical.
Cascade 1 · LO 1 — GH Axis Big Picture: Hypothalamus → Liver → Tissues Lecture Notes · Study Guide
Trigger
Healthy child. Trace a normal GH pulse from the hypothalamus all the way to bone/muscle growth — including every receptor type involved.
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Step 1 Hypothalamus
GHRH (from arcuate nucleus) binds Gs-coupled GHRH receptor on somatotrophs → ↑cAMP → ↑GH release. Somatostatin (SRIF) from periventricular/arcuate binds Gi → ↓cAMP → inhibits. Reciprocal pulsing creates crisp GH bursts ~every 4 hours, largest during slow-wave sleep. Ghrelin from stomach binds GHS-R on somatotrophs → synergizes with GHRH.
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Step 2 Pituitary → blood
Somatotrophs (ACIDOPHIL cells, ~50% of anterior pituitary — most abundant) release GH (peptide, 191 AA, same family as PRL and hPL). GH travels free in plasma with short t½ ~20 min. Some binds GHBP (cleaved ECD of GH receptor).
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Step 3 Liver — cytokine receptor
GH binds hepatic GH receptor — a CYTOKINE RECEPTOR (NOT a GPCR, NOT a RTK). Uses JAK2/STAT5 signaling → STAT5 translocates to nucleus → ↑ transcription of IGF-1. IGF-1 is the main growth-promoting mediator. Circulates bound to IGFBP-3 + ALS (ternary complex; long t½ ~12 hr vs free IGF-1 minutes).
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Step 4 Target tissues — RTK
IGF-1 binds IGF-1 receptor — a RECEPTOR TYROSINE KINASE (RTK), structurally similar to insulin receptor. Autophosphorylation → IRS → PI3K/Akt (anabolic) + RAS/MAPK (mitogenic). Drives chondrocyte proliferation at growth plates (linear growth), myocyte hypertrophy, tissue repair. Note the two DIFFERENT receptor classes in this pathway: cytokine receptor at liver, RTK at tissues.
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Step 5 Feedback
Long loop: IGF-1 inhibits somatotrophs AND stimulates hypothalamic somatostatin. Short loop: GH itself stimulates somatostatin release. Ultrashort loop: somatostatin autoinhibits. This creates sharp GH pulses.
Cascade 2 · LO 3 — GH Axis Big Picture: Circadian & Lifetime Rhythms Lecture Notes · Study Guide
Trigger
Healthy adolescent sleeps, wakes, exercises, skips lunch, eats dinner, returns to sleep. Track GH across this 24-hour cycle AND across the human lifetime.
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Step 1 Sleep onset
Entering slow-wave sleep (stage 3/4) ~60-90 min after sleep onset triggers the largest GH pulse of the day — 50-70% of daily GH output. This is why sleep deprivation in children blunts growth. Circadian cortisol peak occurs later (6-8 AM); they are OUT OF PHASE.
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Step 2 Meals & exercise
Fasting/exercise/hypoglycemia/amino acids (arginine) → ↑ GH. A meal brings hyperglycemia → ↓ GH. Chronic exercise and muscle building leverage pulsatile GH. Pulsatile delivery is REQUIRED — continuous GH desensitizes and loses efficacy.
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Step 3 Lifetime trajectory
Infancy/childhood: steady pulsatile GH + rising IGF-1. Puberty: sex steroids (E2, testosterone) amplify GH pulse amplitude → IGF-1 peaks → pubertal growth spurt. Young adulthood: epiphyseal plates close; GH/IGF-1 plateau. Middle-to-late age: GH/IGF-1 decline ~14% per decade (somatopause) → sarcopenia, ↑ visceral fat, bone loss.
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Step 4 Clinical consequences
Chronic sleep deprivation in children → blunted nocturnal GH → poor growth. Sex-steroid deficiency (Turner syndrome, hypogonadism) → missed pubertal IGF-1 surge → short stature. Somatopause is normal aging, NOT pathologic GH deficiency — GH replacement in elderly without documented GHD is NOT recommended.
Cascade 3 · LO 2 — Direct GH Effects: Fasting Metabolic Shift Lecture Notes · Study Guide
Trigger
Healthy adult on a prolonged fast (24+ hours). Glucose falling. Focus on GH's DIRECT effects (independent of IGF-1).
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Step 1 Insulin falls, GH rises
Fasting hypoglycemia stimulates GH. Insulin falls dramatically. Because insulin is PERMISSIVE for hepatic GH-R expression, low insulin → hepatic GH signaling blunted → LESS IGF-1 synthesized. GH's INDIRECT (IGF-1) effects are suppressed. But GH's DIRECT actions on muscle and adipose are UNOPPOSED.
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Step 2 Adipose direct effect
GH binds GH receptor on adipocytes → JAK2/STAT5 → ↑ hormone-sensitive lipase → LIPOLYSIS → free fatty acids released into circulation. FFAs become the major energy source for muscle and liver. Ketones rise (especially prolonged fast).
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Step 3 Muscle + liver direct
Muscle: GH → ↓ GLUT4 translocation → insulin resistance → muscle takes up LESS glucose. Liver: GH → ↑ hepatic gluconeogenesis → blood glucose PRESERVED. This is the "diabetogenic" face of GH.
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Step 4 Net: glucose sparing
Net effect: blood glucose is PRESERVED for CNS (which requires glucose). Muscle and adipose shift to fatty acid oxidation. This is GH's essential glucose-sparing physiologic role during fasting. The SAME direct effects become pathologic if chronic (acromegaly → T2DM).
Cascade 4 · LO 2 — Indirect (IGF-1) Effects: Fed State Protein Anabolism Lecture Notes · Study Guide
Insulin UP-REGULATES hepatic GH receptor expression. Without insulin, GH can't effectively drive IGF-1 synthesis. This is why the malnourished child with low insulin has LOW IGF-1 despite potentially NORMAL-or-HIGH GH — "functional GH resistance."
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Step 2 Hepatic IGF-1 synthesis
Postprandial GH pulse binds hepatic GH receptor (now plentiful thanks to insulin) → JAK2/STAT5 signaling → transcription of IGF-1 + IGFBP-3 + ALS. IGF-1 rises over hours and circulates bound to IGFBP-3 (t½ ~12 hr).
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Step 3 Target tissue growth
IGF-1 + amino acid substrate → chondrocyte proliferation at growth plates (LINEAR GROWTH), myocyte hypertrophy (muscle gain), osteoblast activity (bone deposition), fibroblast collagen synthesis (soft tissue). Amino acid availability is rate-limiting for IGF-1-driven protein synthesis.
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Step 4 Malnutrition case
Undernourished child: insulin LOW → hepatic GH-R LOW → IGF-1 LOW → GH rises (loss of IGF-1 feedback) but growth fails anyway. Biochemically similar to Laron syndrome (high GH, low IGF-1) but fully reversible with nutrition. Highlights how GH's growth effect absolutely requires the IGF-1 mediator.
Cascade 5 · LO 2/5 — Direct + Indirect Combined: Acromegaly (Chronic GH Excess) Lecture Notes · Study Guide
Trigger
Adult patient with a GH-secreting pituitary somatotroph adenoma. GH and IGF-1 chronically elevated. Observe how BOTH direct + indirect effects play out over years.
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Step 1 Indirect (IGF-1)
Chronic IGF-1 elevation drives appositional bone growth (epiphyses are closed → no linear growth): jaw prognathism, enlarged hands/feet (ring/shoe size ↑), frontal bossing. Soft tissue overgrowth: macroglossia, skin tags, carpal tunnel (median nerve compression), organomegaly (cardiomegaly, hepatomegaly).
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Step 2 Direct (metabolic)
Chronic GH direct effects: muscle/adipose insulin resistance + ↑ hepatic gluconeogenesis → T2DM in ~30-50% of acromegalics. OGTT fails to suppress GH (diagnostic). Lipolytic effect contributes to dyslipidemia. Sweating (eccrine gland stimulation) is often the earliest symptom.
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Step 3 Cardiovascular
Biventricular hypertrophy → diastolic dysfunction → CHF. HTN from Na retention. OSA from soft-tissue overgrowth (tongue, soft palate). Accelerated atherosclerosis. Cardiovascular disease = #1 cause of death in untreated acromegaly.
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Step 4 Treatment rationale
Surgery (transsphenoidal) first-line. Medical: somatostatin analogs (octreotide) suppress GH release (attacks source); pegvisomant is a GH-receptor antagonist blocking peripheral action (addresses direct + indirect at target tissues); cabergoline if PRL co-secretion. Normalizing IGF-1 restores near-normal life expectancy.
Cascade 6 · LO 4/5 — Stimulators Test: Insulin Tolerance Test (ITT) for GH Deficiency Lecture Notes · Study Guide
Trigger
Child with suspected GH deficiency. Insulin Tolerance Test (ITT) is performed: 0.15 U/kg insulin IV to induce hypoglycemia. Glucose drops to 35 mg/dL.
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Step 1 Physiologic stimulus
Hypoglycemia is one of the MOST POTENT physiologic stimulators of GH (and cortisol). Per the reference table: stimulators include ↓ glucose, ↓ FFA, ↑ amino acids (arginine), deep sleep, exercise, acute stress, sex steroids, ghrelin.
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Step 2 Expected response
In a NORMAL child: GH surges 10-fold within 30-60 min, peak usually > 10 ng/mL. ACTH → cortisol also rises (bonus test of HPA axis). Catecholamines rise (glucagon too) to counter the insulin.
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Step 3 Abnormal result
In GHD: peak GH < 5-10 ng/mL → confirms deficiency. Combined with low IGF-1 + low IGFBP-3 + delayed bone age → definite GHD. Alternative stimulation tests: arginine (amino acid), clonidine (central), macimorelin (oral ghrelin agonist, FDA-approved in adults).
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Step 4 Clinical follow-through
Confirmed GHD → MRI pituitary (rule out adenoma, craniopharyngioma) → recombinant GH (somatropin) daily SC injection until near-final height or plate closure. Don't confuse with OGTT: OGTT tests whether HYPERGLYCEMIA suppresses GH (diagnostic for acromegaly — EXCESS). Stim tests require the OPPOSITE stimulus.
Cascade 7 · LO 4/5 — Inhibitors Test: OGTT Fails to Suppress GH (Acromegaly) Lecture Notes · Study Guide
Trigger
Adult with soft-tissue overgrowth and elevated IGF-1. OGTT for GH: 75g oral glucose load given; GH measured at 0, 30, 60, 90, 120 min.
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Step 1 Normal physiologic inhibitor
Per the reference table, GH INHIBITORS include: hyperglycemia, ↑ FFA, hypercortisolemia, IGF-1 (long loop), GH itself (short loop), somatostatin, obesity (blunted stim response). Oral glucose → hyperglycemia → normally suppresses GH to < 1 ng/mL within 2 hours via somatostatin release.
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Step 2 Acromegaly paradox
Somatotroph adenoma secretes GH AUTONOMOUSLY — does not respond to normal negative-feedback signals. GH remains > 1 ng/mL throughout OGTT (and often RISES paradoxically in some cases). Failure to suppress confirms acromegaly.
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Step 3 Next steps
MRI sella turcica with contrast → locates and sizes the adenoma (micro < 1 cm vs macro ≥ 1 cm). Screen for: colon cancer (colonoscopy q5y — colonic polyps ↑), sleep apnea, T2DM, cardiomyopathy (echo), thyroid nodules.
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Step 4 Key contrast
Stim tests (ITT, arginine) use stimulating conditions (hypoglycemia, amino acids) to test for GH DEFICIENCY. OGTT uses inhibitory conditions (hyperglycemia) to test for GH EXCESS. Same axis, opposite tests — which direction you provoke depends on what you suspect.
Cascade 8 · LO 5 — Disorder: Laron Syndrome (GH Receptor Defect) Lecture Notes · Study Guide
Trigger
5-year-old from consanguineous family. Severe proportionate short stature, frontal bossing, saddle nose, episodic hypoglycemia. Labs: GH 22 ng/mL (HIGH), IGF-1 12 ng/mL (LOW).
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Step 1 Mechanism
Autosomal recessive loss-of-function mutation in the GH receptor (GHR). Liver cannot respond to GH → can't synthesize IGF-1. Because IGF-1 normally provides long-loop feedback on pituitary GH release, the loss of feedback → GH RISES (classic pattern: HIGH GH + LOW IGF-1 — inverse of classic GHD).
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Step 2 Phenotype
Severe proportionate dwarfism (adult height often 3-4 feet). Frontal bossing, saddle nose, truncal obesity. Delayed puberty. Episodic hypoglycemia because IGF-1 normally contributes to glucose homeostasis; without it, insulin requirement is reduced.
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Step 3 Treatment
Recombinant IGF-1 (mecasermin) — bypasses the defective receptor. Traditional recombinant GH DOES NOT WORK (no functional receptor to bind). This is the classic Step 1 distinction vs classic GHD.
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Step 4 Cancer protection
Observational studies in Ecuadorian Laron cohorts show dramatic reduction in cancer incidence and T2DM — consistent with the pro-mitogenic and pro-metabolic effects of IGF-1. A real-world demonstration of how central IGF-1 signaling is to both growth AND disease.
Cascade 9 · LO 5 — Disorder: Classic Pediatric GH Deficiency Lecture Notes · Study Guide
Trigger
7-year-old boy. Height below 1st percentile. Growth velocity 3 cm/year (normal ~5-7). Delayed bone age by 3 years. Labs: random GH 1.1 ng/mL; IGF-1 LOW.
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Step 1 Pattern recognition
Short stature + slow growth velocity + delayed bone age + LOW IGF-1 = suspicious for GHD. Need provocative testing because random GH is unreliable (pulsatile). Causes of pediatric GHD: idiopathic (most common), congenital (PROP1, PIT1, GHRH-R, GH1 mutations), brain tumors (especially craniopharyngioma), autoimmune hypophysitis.
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Step 2 Confirm diagnosis
Two provocative stimulation tests (ITT, arginine, clonidine, macimorelin). Peak GH < 10 ng/mL on both → confirmed GHD. MRI pituitary/sella to rule out structural causes. Consider additional axis testing (cortisol, T4, sex steroids) because multiple anterior pituitary deficiencies often coexist.
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Step 3 Pattern pattern
Classic pattern: LOW GH + LOW IGF-1 + intact GH receptor. This distinguishes from Laron (HIGH GH + LOW IGF-1, defective receptor) and from achondroplasia (NORMAL GH + NORMAL IGF-1, growth-plate FGFR3 defect — GH therapy wouldn't help achondroplasia either).
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Step 4 Treatment
Recombinant human GH (somatropin) daily SC injection. Titrate to IGF-1 in mid-normal range. Continue until near-final height or epiphyseal plate closure. Starting early maximizes final adult height. Monitor for slipped capital femoral epiphysis (GH side effect), idiopathic intracranial HTN, and carbohydrate intolerance.
Cascade 10 · LO 5 — Disorder: Gigantism vs Acromegaly (Same Biology, Different Timing) Lecture Notes · Study Guide
Trigger
12-year-old boy growing 22 cm/year with enlarging hands/feet. Contrast with adult who has same tumor biology. What is the single anatomic factor that differentiates gigantism from acromegaly?
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Step 1 Same pathobiology
Both conditions: somatotroph adenoma → autonomous GH secretion → high IGF-1 → target tissue overgrowth. Diagnostic workup identical: IGF-1 → OGTT → MRI. Treatment identical: surgery → SST analog → pegvisomant → radiation.
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Step 2 The discriminator
Epiphyseal plate status is the single distinguishing variable. OPEN plates (pre-pubertal/pubertal) → IGF-1 drives chondrocyte proliferation → LINEAR growth → GIGANTISM (tall stature + eventual soft-tissue features). CLOSED plates (adult) → no linear growth possible → periosteal + appositional bone growth → ACROMEGALY (jaw, hands, feet, viscera).
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Step 3 Syndromic associations
GH excess in children raises suspicion for underlying syndromes: MEN 1 (autosomal dominant — 3 P's: parathyroid/pancreas/pituitary); McCune-Albright (GNAS mosaic activation → precocious puberty + fibrous dysplasia + café-au-lait + acromegaly); Carney complex; FIPA (familial isolated pituitary adenoma) with AIP mutations.
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Step 4 Treatment note
Pediatric gigantism patients often need LARGER-than-adult doses of SST analogs (octreotide). Pegvisomant is used less frequently in children. Transsphenoidal surgery for microadenoma cures ~70%; macroadenoma cure rates fall to 30-50%. Timely diagnosis before plate closure prevents extreme final height.
Test Trap Mode: Each statement is TRUE or FALSE as written. Many reverse or mix facts that trip students up.
Trap 01 · LO 1 Lecture Notes
"Growth hormone exerts its anabolic, pro-growth effects on cartilage and muscle by binding directly to tissue cells without requiring a hepatic intermediate."
FALSE. GH's GROWTH-promoting effects are indirect — mediated by IGF-1 synthesized in the liver in response to GH. GH's direct tissue effects are largely CATABOLIC/diabetogenic (lipolysis, insulin resistance, gluconeogenesis). Without a functional liver IGF-1 response (Laron syndrome), GH cannot drive growth.
Trap 02 · LO 1 Lecture Notes
"The GH receptor is a classic G-protein-coupled receptor that activates adenylyl cyclase via Gs."
FALSE. The GH receptor is a single-pass CYTOKINE receptor that dimerizes on ligand binding and signals via JAK2 → STAT5. GHRH — the HYPOTHALAMIC releasing hormone — uses a Gs GPCR on somatotropes, but that's a different receptor. Prolactin and GH share similar cytokine-receptor biology (which is why GH can weakly cross-activate the PRL receptor at high levels).
Trap 03 · LO 2 Lecture Notes
"Growth hormone increases glucose uptake into skeletal muscle and adipose, thereby lowering serum glucose."
FALSE — opposite. GH is diabetogenic: it DECREASES glucose uptake into muscle and adipose (causes insulin resistance) and INCREASES hepatic gluconeogenesis → raises serum glucose. Useful during fasting, but pathologic in chronic GH excess (acromegaly → ~30–50% develop diabetes).
Trap 04 · LO 3 Lecture Notes
"The greatest physiologic pulse of growth hormone secretion occurs in the late afternoon, just before the largest meal of the day."
FALSE. The largest pulse occurs during slow-wave (stage 4) sleep, typically around midnight. Deep sleep + melatonin reinforce this surge. In fact, chronic sleep deprivation impairs GH secretion — one reason inadequate sleep blunts recovery from exercise and slows childhood growth.
"Oral glucose tolerance testing works as a confirmatory test for acromegaly because normal subjects show a rise in GH after glucose loading, while acromegalics show a fall."
FALSE — reversed. Normal subjects SUPPRESS GH after oral glucose (hyperglycemia inhibits GH). Acromegalics FAIL to suppress because the tumor is feedback-independent. So the pattern is: normal ↓ GH; acromegaly GH stays high or even rises paradoxically.
Reference MCQs: Ten questions directly testing the content of the four reference tables — GH Axis Big Picture, Direct vs Indirect Effects, Stimulators/Inhibitors, and Four GH-Axis Disorders.
Question 1 of 10 · LO 1 — GH Receptor Class Lecture Notes · Study Guide
A researcher generates a hepatocyte line in which JAK2 has been knocked out. When GH is added to the culture, which downstream event is MOST directly abolished?
AGH binding to the cell surface
BSTAT5 phosphorylation and IGF-1 transcription
CcAMP generation
DCa²⁺ release from the ER
EReceptor tyrosine kinase autophosphorylation
B. GH receptor is a cytokine receptor — NO intrinsic kinase. Activates JAK2 → STAT5 phosphorylation → IGF-1 gene transcription. Without JAK2, the cascade fails. Binding (A) is unaffected. GH-R is NOT an RTK (E) — that's IGF-1R.
Question 2 of 10 · LO 2 — Direct vs Indirect Lecture Notes · Study Guide
A patient fasting for 48 hours has high GH. Which effect is MEDIATED DIRECTLY by GH (not by IGF-1)?
AChondrocyte proliferation at growth plates
BMyocyte hypertrophy
CLipolysis in adipose tissue + hepatic gluconeogenesis
DFibroblast collagen synthesis
EOsteoblast bone deposition
C. Direct (GH alone) effects: lipolysis, insulin resistance in muscle/adipose, hepatic gluconeogenesis — collectively "diabetogenic" and "glucose-sparing." Indirect effects (via IGF-1): growth (chondrocytes, myocytes, osteoblasts, fibroblasts). Laron syndrome (no IGF-1) LOSES indirect effects but KEEPS direct.
Question 3 of 10 · LO 3 — Circadian Rhythm Lecture Notes · Study Guide
Over a 24-hour period in a healthy child, the LARGEST GH pulse occurs at which time and in which state?
A6-8 AM, coinciding with the cortisol peak
BWithin 60-90 min of sleep onset, during slow-wave (stage 3/4) sleep
CImmediately after a carbohydrate-rich meal
DDuring REM sleep
EMid-afternoon, at peak alertness
B. Slow-wave sleep drives 50-70% of daily GH output — the single biggest driver of growth. Chronic sleep deprivation in children → blunted nocturnal GH pulses → poor growth. Cortisol peak (A) is out of phase. Meals (C) suppress GH.
Question 4 of 10 · LO 4 — GH Stimulator Lecture Notes · Study Guide
Per the Stimulators/Inhibitors reference table, which of the following BEST STIMULATES GH release and can be used as a provocative test for GH deficiency?
AOral glucose load
BChronic hypercortisolemia
CInsulin-induced hypoglycemia
DElevated free fatty acids
EIGF-1 infusion
C. Hypoglycemia is one of the MOST POTENT GH stimulators. Basis of the Insulin Tolerance Test (ITT). Other stimulators: arginine, clonidine, exercise, macimorelin, deep sleep. Oral glucose (A) SUPPRESSES GH (basis of OGTT for acromegaly). Hypercortisolemia (B), elevated FFAs (D), and IGF-1 (E) all inhibit.
Question 5 of 10 · LO 4 — OGTT for Acromegaly Lecture Notes · Study Guide
A 41-year-old woman has IGF-1 840 ng/mL (ULN 260). OGTT is performed. At 120 min post-glucose, her GH is 2.8 ng/mL. Which statement best explains the finding?
ANormal physiologic response to oral glucose
BAutonomous GH secretion from a somatotrope adenoma unresponsive to negative feedback
CLaron syndrome
DIsolated IGF-1 overproduction from the liver
EExogenous GH use
B. Normal response to oral glucose: GH suppresses < 1 ng/mL. Failure to suppress = autonomous secretion = acromegaly. Laron (C) has HIGH GH + LOW IGF-1 — opposite pattern. Exogenous GH (E) would suppress endogenous GH via feedback.
Question 6 of 10 · LO 5 — Laron vs GHD Lecture Notes · Study Guide
A 5-year-old girl in a consanguineous family has severe short stature. Labs: GH 22 ng/mL (HIGH), IGF-1 12 ng/mL (LOW), homozygous GHR mutation. First-line treatment?
AHigh-dose recombinant human GH
BRecombinant IGF-1 (mecasermin)
COral glucose tolerance test and MRI sella
DRecombinant GHRH (tesamorelin)
EThyroxine replacement
B. Laron syndrome = GH RECEPTOR defect. GH therapy (A) useless — no working receptor. Treatment bypasses receptor by replacing the downstream mediator IGF-1 (mecasermin). Classic distinction from "classic GHD" (LOW GH + LOW IGF-1, intact receptor → use GH).
Question 7 of 10 · LO 2 — Acromegaly Diabetes Lecture Notes · Study Guide
A 52-year-old with acromegaly has fasting glucose 168 mg/dL and HbA1c 7.9%. No prior diabetes. Most specific mechanism?
APancreatic β-cell destruction
BGH-induced insulin resistance at muscle/adipose + ↑ hepatic gluconeogenesis
CAdrenal cortisol excess from co-secretion
DGlucagon overproduction
EAnti-insulin receptor antibodies
B. GH is diabetogenic — DIRECT effects include ↓ GLUT4 in muscle/adipose + ↑ hepatic gluconeogenesis. ~30-50% of acromegalics develop diabetes/glucose intolerance. Tumor control often improves but may not fully reverse long-standing diabetes.
Question 8 of 10 · LO 5 — Medical Therapy Lecture Notes · Study Guide
A 58-year-old with acromegaly starts monthly octreotide LAR. At 6 months IGF-1 is down 60%, tumor is 30% smaller, symptoms improved. Now develops RUQ pain; ultrasound = cholelithiasis. Best explanation?
ADirect octreotide toxicity on gallbladder epithelium
BSomatostatin analog suppresses CCK + gallbladder motility → bile stasis
COctreotide-induced hypercholesterolemia
DAutoimmune cholangitis
EVitamin D malabsorption
B. Octreotide = SST analog. Somatostatin inhibits many GI hormones including CCK → ↓ gallbladder contraction → bile stasis → cholelithiasis/sludge in 20-30%. Other side effects: hyperglycemia, steatorrhea, bradycardia, injection pain.
Question 9 of 10 · LO 3/4 — Permissiveness Lecture Notes · Study Guide
A malnourished child has LOW IGF-1 but NORMAL-to-HIGH GH. This biochemical pattern is MOST similar to which of the following?
AClassic pediatric GHD
BLaron syndrome (GH receptor defect)
CAcromegaly
DAchondroplasia
EHypothyroidism
B. Low insulin → hepatic GH-R under-expressed → functional GH resistance → HIGH GH + LOW IGF-1. Biochemically identical to Laron but reversible with nutrition. Insulin is PERMISSIVE for hepatic GH-R expression — a key teaching point.
Question 10 of 10 · LO 5 — Gigantism vs Acromegaly Lecture Notes · Study Guide
A 12-year-old has grown 22 cm in 18 months. Open epiphyseal plates. IGF-1 elevated, GH fails to suppress on OGTT. MRI: 1.6-cm pituitary macroadenoma. What single variable distinguishes gigantism from adult acromegaly in this case?
AThe diagnostic workup is entirely different
BEpiphyseal plate status: open → linear growth (gigantism) vs closed → appositional only (acromegaly)
CGigantism never causes soft-tissue overgrowth
DCardiovascular disease risk is lower in gigantism
EMedical therapy is contraindicated in pediatric patients
B. Same pathophysiology (somatotroph adenoma, ↑ GH, ↑ IGF-1), same workup (IGF-1 → OGTT → MRI), same treatment hierarchy (surgery → SST analog → pegvisomant). Epiphyseal plate status is the only discriminator — OPEN plates → linear growth (tall stature); CLOSED plates → soft-tissue + appositional bone thickening.
GH Axis — The Big Picture
Level
Source
Hormone
Receptor / Signaling
Hypothalamus (+)
Ventromedial nucleus
GHRH
Gs → ↑cAMP on somatotropes
Hypothalamus (−)
Periventricular nucleus
Somatostatin (GHIH)
Gi → ↓cAMP on somatotropes
Pituitary
Somatotrope (acidophil)
GH (191 AA)
Cytokine receptor → JAK2/STAT5
Liver
Hepatocytes
IGF-1 (somatomedin C, 70 AA)
Secreted; bound to IGFBP-3
Peripheral
Muscle, bone, fat
IGF-1 action
IGF-1R (RTK) → PI3K/Akt + MAPK
Direct (GH) vs. Indirect (IGF-1) Effects
Effect
Mediator
Tissue Action
Net Outcome
Linear bone growth
IGF-1
Chondrocyte proliferation at growth plates
↑ length (before epiphyseal closure)
Protein synthesis
IGF-1
↑ AA uptake + translation in muscle
↑ lean mass
Lipolysis
GH
Adipose lipase activation
↑ FFA release, weight redistribution
Glucose uptake
GH
↓ GLUT4 in muscle + adipose
INSULIN RESISTANCE → hyperglycemia
Gluconeogenesis
GH
↑ hepatic glucose output
↑ serum glucose
Organ / soft-tissue growth
IGF-1
Generalized mitogenesis
Cardiomegaly, macroglossia in excess
Stimulators vs. Inhibitors of GH Release
Stimulators (↑ GH)
Inhibitors (↓ GH)
↓ glucose / fasting
↑ glucose (basis of OGTT)
↓ FFA
↑ FFA
↑ amino acids (esp. arginine)
Hypercortisolemia (chronic)
Deep sleep (stage 4)
Pregnancy (hPL mimics GH)
Exercise
IGF-1 (long loop)
Acute stress / physiologic cortisol
GH itself (short loop)
Sex steroids (E2, testosterone)
Obesity, dopamine agonists (variably)
Ghrelin (GHS-R)
Somatostatin / somatostatin analogs
Four GH-Axis Disorders to Distinguish
Disorder
GH
IGF-1
Growth
Treatment
Classic GH deficiency
LOW
LOW
Short stature, proportionate
Recombinant GH (somatropin)
Laron (GH insensitivity)
HIGH
LOW
Short stature, protected from cancer/DM
Recombinant IGF-1 (mecasermin)
Gigantism (pre-closure)
HIGH (non-suppressible)
HIGH
Extreme tall stature, organomegaly
Surgery + SST analog + pegvisomant
Acromegaly (post-closure)
HIGH (non-suppressible)
HIGH
Jaw / hands / feet / organ thickening
Surgery + SST analog + pegvisomant
High-yield rule: "GH is diabetogenic; IGF-1 is anabolic." Most of what patients experience as "growth" comes from IGF-1. Most of what makes GH excess dangerous (glucose intolerance, cardiomegaly, insulin resistance) comes from the direct effects of GH itself.