Hypothalamic–Pituitary Relationships II Step 1 Extensions
Per-LO coverage of in-house lecture material on the GH axis integrated with mapped 3rd-party resources. Each drill cites its source; every item is tagged by LO.
Other excess-mortality contributors: T2DM, colon cancer, stroke. Treatment that normalizes IGF-1 restores near-normal life expectancy.
LO 5 · Acromegaly Workup FA 3.02 · Bootcamp 3.04
A patient has clinical suspicion for acromegaly. Sequence: screening → confirmation → localization.
Answer
Step 1 (screen): serum IGF-1 (elevated for age-matched reference) Step 2 (confirm): oral glucose tolerance test — give 75g glucose; measure GH at 0/30/60/90/120 min. Normal: GH suppresses <1 ng/mL. Acromegaly: GH FAILS to suppress. Step 3 (localize): MRI sella turcica with contrast (~95% have a pituitary macroadenoma; some have microadenomas).
Also screen for: prolactin (co-secretion common), TFTs, ACTH/cortisol, FSH/LH — mass effects.
LO 5 · First-Line Treatment FA 3.02 · Bootcamp 3.04
Why is transsphenoidal surgery first-line for acromegaly and not for prolactinoma?
Answer
Prolactinoma: highly responsive to dopamine D2 agonists (cabergoline) → drug shrinks tumor AND normalizes PRL → SURGERY RARELY NEEDED.
GH-secreting adenoma: NO equally effective medical therapy. Somatostatin analogs (octreotide) + pegvisomant can CONTROL hormone effects but rarely shrink the tumor to cure. Surgery offers the best chance of biochemical cure, especially for microadenomas (~70%).
Radiation is last-line (slow effect, high rate of hypopituitarism).
LO 5 · Medical Therapy Options FA 3.02 · Bootcamp 3.04
Compare octreotide, pegvisomant, and cabergoline for acromegaly treatment.
Pegvisomant: recombinant modified GH that binds GH receptor but BLOCKS signal transduction → peripheral GH effects blocked. Does NOT shrink tumor (monitor MRI).
Cabergoline: D2 agonist — useful when tumor co-secretes prolactin (25% of somatotrope adenomas). Modest GH-lowering effect.
LO 5 · Laron Syndrome FA 3.02 · In House
Mechanism, phenotype, labs, treatment — and why patients are protected from cancer?
Answer
Mechanism: autosomal recessive loss-of-function mutation in GH receptor → liver cannot respond to GH → very low IGF-1. Phenotype: severe proportionate short stature, frontal bossing, saddle nose, obesity, hypoglycemia (IGF-1 drops insulin requirements), delayed puberty. Labs: HIGH GH + LOW IGF-1 (hallmark; flipped from classic GH deficiency). Tx: recombinant IGF-1 (mecasermin) — bypasses the receptor.
Cancer protection: IGF-1 is pro-mitogenic + anti-apoptotic. Chronic IGF-1 deficiency in Laron dramatically reduces cancer incidence (observational Ecuadorian cohort studies).
LO 5 · Pituitary Dwarfism FA 4.03 · Bootcamp 3.05
Typical causes in children, testing algorithm, and treatment?
Testing: random GH is unreliable → use provocative tests — arginine, insulin tolerance test (induces hypoglycemia), clonidine, exercise. Healthy patient responds with GH surge; deficient patient does not. Low IGF-1 + IGFBP-3 are supporting.
Tx:recombinant human GH (somatropin), daily SC injection until near-final height or epiphyseal closure. Maximal benefit if started early.
LO 5 · Achondroplasia FA 4.03 · In House
Why is achondroplasia NOT treated with GH, and what molecular defect causes it?
Answer
Mechanism: autosomal dominant GAIN-of-function mutation in FGFR3 — constitutively active fibroblast growth factor receptor 3 INHIBITS chondrocyte proliferation at growth plates. Growth plate is defective, not GH/IGF-1 signaling.
Phenotype: short LIMBS (disproportionate — short arms/legs, normal trunk), large head with frontal bossing, trident hand, midface hypoplasia.
Labs: NORMAL GH, NORMAL IGF-1. GH therapy does NOT help — the growth plate can't respond.
Emerging therapy: vosoritide (C-type natriuretic peptide analog) for growth promotion.
LO 5 · Turner Syndrome & GH FA · BnB
Why is recombinant GH indicated in Turner syndrome despite normal GH axis function?
Answer
Turner (45,X) girls are NOT classically GH-deficient, but short stature is one of the most prominent features due to SHOX gene haploinsufficiency + gonadal failure (estrogen-deficient puberty growth spurt).
GH therapy (off-label-to-approved): starting in early childhood can add 5–8 cm to final adult height. Used in combination with estrogen replacement at puberty. Similar empirical benefit in Prader-Willi, SHOX deficiency, SGA-without-catch-up, idiopathic short stature.
NOT effective in achondroplasia (growth plate problem), Laron (use IGF-1), or normal-variant short stature.
LO 5 · MEN1 Association FA 4.25 · In House
What is MEN1, how does it relate to GH excess, and what's the classic triad?
Answer
MEN1 (autosomal dominant, tumor suppressor MEN1 gene) — classic "3 P's": • Parathyroid hyperplasia → primary hyperparathyroidism (95% of MEN1) • Pancreatic islet tumors (gastrinoma, insulinoma) • Pituitary adenoma (30–40%; most commonly PROLACTINOMA but GH-secreting adenomas cause acromegaly at higher-than-background rates)
How does McCune-Albright syndrome sometimes cause GH excess?
Answer
McCune-Albright = post-zygotic activating GNAS mutation → constitutively active Gsα in affected tissues.
If somatotropes are part of the mutation mosaic, they make GH independently of GHRH (Gsα is always "on") → GH excess → acromegaly or gigantism (depending on age).
Clinical triad: polyostotic fibrous dysplasia + coast-of-Maine café-au-lait + endocrine hyperfunction (precocious puberty most common; acromegaly + hyperthyroidism + Cushing also possible). All stem from the SAME GPCR defect affecting different Gs-coupled hormones in different tissues.
LO 5 · GH Doping In House
Why do athletes abuse GH, and how is GH doping detected?
Answer
Sought effects: claimed ↑ lean mass, faster recovery, fat loss. Evidence for athletic performance benefit in adults is surprisingly weak, but cardiovascular/metabolic risks are real.
Detection challenges: • Recombinant GH is identical to endogenous (22kDa isoform dominant; natural mix includes 20kDa). • Isoform ratio test: exogenous GH shifts the ratio toward 22kDa • GH biomarkers: IGF-1, P-III-NP — elevated persistently
Side effects: diabetes, carpal tunnel, joint pain, OSA, cardiomyopathy, theoretical cancer risk.
LO 4 · Ghrelin In House · FA 3.02
How does ghrelin connect nutrition to the GH axis, and what is its clinical relevance?
Answer
Ghrelin: 28-AA peptide from stomach (X/A-like cells). Sole endogenous ligand for GHS-R (growth hormone secretagogue receptor).
Clinical: • Ghrelin falls after bariatric surgery (gastric bypass) → ↓ appetite • Prader-Willi syndrome has HIGH ghrelin → hyperphagia • Ghrelin-receptor agonists (e.g., macimorelin) used as GH stimulation test for deficiency diagnosis.
LO 5 · Prader-Willi Syndrome FA · BnB
How does Prader-Willi relate to the GH axis, and why do patients benefit from GH therapy?
Answer
Prader-Willi: loss of paternal 15q11–13 expression (maternal-deletion; uniparental disomy; or imprinting error). Features: • Neonatal hypotonia → feeding problems • After age 1–2: insatiable hyperphagia → severe obesity • Short stature (functional GH deficiency) • Hypogonadotropic hypogonadism • Intellectual disability, behavioral issues
GH therapy: improves height, body composition (↓ fat mass, ↑ lean mass), muscle tone, bone density. FDA-approved indication — one of the landmark non-GHD pediatric uses.
LO 2 · GH — Fed vs Fasted In House · BnB 5.01
Explain the "dual role of GH": what does GH do in a FED state vs a FASTED state, and why?
Answer
Fed state (balanced meal — insulin high, AAs high): • Insulin UP-REGULATES hepatic GH receptors (insulin is PERMISSIVE for IGF-1 synthesis). • GH + IGF-1 → protein anabolism → net tissue growth. • Carb-heavy but protein-POOR meals: insulin spikes but AA substrate is limited → energy storage (fat) WITHOUT growth.
Fasted state (glucose low, insulin low): • GH is elevated and acts directly on adipose and muscle. • Effects: lipolysis (↑ FFA), insulin resistance (↓ glucose uptake), hepatic gluconeogenesis → glucose-sparing for CNS.
Useful between meals. Pathological when chronic (acromegaly → T2DM).
LO 2/4 · Pregnancy & hPL In House · FA 3.01
Why does pregnancy SUPPRESS endogenous GH release, and what metabolic picture does this create?
Answer
The placenta secretes human placental lactogen (hPL) — also called human chorionic somatomammotropin (hCS) — which has partial structural homology to GH and prolactin (all belong to the same cytokine/hormone family).
hPL binds the GH receptor at physiologic levels → long-loop feedback suppresses endogenous GHRH and GH release from the anterior pituitary.
Metabolic consequence: hPL mimics GH's diabetogenic effect — insulin resistance in muscle/adipose + lipolysis → spares glucose for the fetus. This is the physiologic basis for gestational diabetes, which typically emerges in the 2nd–3rd trimester as hPL rises. Resolves after delivery as placental hPL falls to zero.
LO 2 · Insulin Permissiveness In House
Why is insulin considered "permissive" for GH's growth effects, and what does this mean for the malnourished child?
Answer
Permissiveness: Insulin up-regulates hepatic GH receptor expression. Without insulin, hepatocytes cannot respond fully to GH → IGF-1 production is low even when GH is high.
Consequence for the malnourished child: chronic caloric/protein deprivation → low insulin → functional hepatic GH resistance → ↓ IGF-1 → growth failure — despite HIGH GH levels (loss of IGF-1-mediated long-loop feedback + no substrate).
Analogous to Laron syndrome biochemically (high GH + low IGF-1) but reversible with nutrition. Also: T1DM with poor insulin control → subnormal IGF-1; restoring insulin restores IGF-1 and growth.
LO 4 · GHRH / Somatostatin Convergence In House · BnB 5.01
How do GHRH and somatostatin produce opposing effects on the same somatotrope, and why does this create SHARP pulsatile GH release?
Answer
Both hypothalamic hormones converge on the SAME intracellular target — adenylyl cyclase / cAMP — in somatotropes: • GHRH → Gs → ↑ AC → ↑ cAMP → ↑ GH release • Somatostatin → Gi → ↓ AC → ↓ cAMP → ↓ GH release
Because they hit the same node with opposite signs, hypothalamic control is competitive and RECIPROCAL — when one is on, the other is off. Ultra-short-loop autoinhibition by each adds temporal sharpness.
Net result: clean, high-amplitude GH pulses every ~4 hours with low-GH troughs between them (largest pulse during deep sleep). Pulsatility protects target receptors from desensitization — much like pulsatile GnRH for LH/FSH.
LO 1 · IGFBPs & Proteases In House · FA 3.02
What is the role of IGF-binding proteins (IGFBPs) and their proteases in modulating IGF-1 activity?
Answer
Nearly all circulating IGF-1 travels bound to IGFBPs (mainly IGFBP-3), which dramatically extends its half-life (~12 hours vs seconds if free).
Bound IGF-1 is inactive — it cannot bind the IGF-1 receptor. Activation requires liberation from the carrier: • Tissue IGFBP proteases (e.g., PAPP-A, prostate-specific antigen/PSA) cleave IGFBPs → release free IGF-1 → binds IGF-1R on target cells
Clinical implications: • Pregnancy ↑ PAPP-A (used in first-trimester Down syndrome screening) → modulates IGF-1 availability • Some cancers overexpress IGFBP proteases → high local free IGF-1 → autocrine/paracrine mitogenesis • IGFBP-3 is a cleaner readout of GH/IGF-1 status than total IGF-1 in some clinical settings
LO 1/5 · GH/PRL Receptor Homology In House · FA 3.04
GH and prolactin share receptor similarity. What clinical manifestation appears in untreated severe acromegaly because of this?
Answer
GH and prolactin (PRL) belong to the same cytokine/hormone family with primary-sequence homology. Their receptors are structurally similar cytokine receptors (JAK2-STAT5).
At normal physiologic GH levels, cross-reactivity with the PRL receptor is negligible. But at the very high GH levels of untreated acromegaly, GH can weakly activate the PRL receptor on mammary epithelium → galactorrhea without elevated serum prolactin.
This is also why some somatotrope adenomas co-secrete both GH and PRL (~25%) — explaining why dopamine agonists (cabergoline) can have modest efficacy even in pure GH-secreting tumors. Always measure prolactin in acromegaly workup.
LO 4 · Hypercortisolism & Growth In House
Why does chronic hypercortisolism (endogenous Cushing or exogenous steroids) cause growth failure in children, and how does it affect GH in adults?
Answer
Chronic high cortisol has THREE mechanisms that suppress growth: 1. Central suppression of GH release — cortisol stimulates somatostatin and inhibits GHRH. 2. Direct inhibition of chondrocyte proliferation at growth plates. 3. Antagonism of IGF-1's anabolic effects on muscle and bone.
Pediatric Cushing: growth velocity falls, bone age is delayed, obesity WITHOUT the usual height-acceleration-with-weight-gain pattern — a counterintuitive and high-yield clue.
Indirect (IGF-1-mediated): • Bone/cartilage: chondrocyte proliferation → linear growth • Muscle: protein anabolism, myocyte hypertrophy • Most "growth" effects
Clinical relevance: Laron syndrome loses INDIRECT effects (no IGF-1) while keeping DIRECT effects (high GH acts on adipose/muscle) → severe short stature with preserved or exaggerated insulin resistance. Pegvisomant blocks DIRECT effects at GH-R but doesn't affect adenoma GH output.
LO 4 · Stimulators / Inhibitors In House · FA 3.02
List the major physiologic stimulators and inhibitors of GH release.
What is the pattern of GH release across 24 hours, and what sleep stage drives the largest pulse?
Answer
GH is secreted in discrete pulses every ~4 hours (6–8 pulses/24h) with near-undetectable troughs between.
The largest pulse occurs during slow-wave (stage 3/4) sleep, typically within the first 1–2 hours after sleep onset (often near midnight for conventional schedules). This accounts for 50–70% of the day's total GH output.
Clinical implications: • Chronic sleep deprivation → ↓ nocturnal GH pulse → can contribute to growth failure in children. • Random GH in daytime is usually low and unreliable for diagnosis. • 24-hour urinary or serial GH sampling is historic; modern practice uses IGF-1 instead. • Cortisol's circadian peak is EARLY MORNING (6–8 AM) — out of phase with GH.
LO 3 · Lifetime GH Trajectory In House
How do GH and IGF-1 levels change across the human lifespan?
Answer
Childhood: steady pulsatile GH + rising IGF-1 driving linear growth. GH does not rise dramatically at birth. Puberty: sex steroids (E2, testosterone) amplify GH pulse amplitude → IGF-1 PEAKS → pubertal growth spurt. This is one of the major justifications for adding estrogen in Turner syndrome and watching timing of GH initiation. Young adulthood: epiphyseal plates close. GH/IGF-1 plateau; linear growth ends. Anabolic role shifts to tissue maintenance. Midlife → older adulthood: steady decline in GH and IGF-1 (~14% per decade after age 30) known as somatopause. Contributes to sarcopenia, ↑ visceral fat, bone loss. NOT equivalent to pathologic GHD — routine replacement is not indicated.
LO 5 · Gigantism vs Acromegaly Bootcamp 3.04 · FA 3.02
What single variable determines whether GH excess presents as gigantism or acromegaly?
Answer
Epiphyseal plate status is the single distinguishing variable.
CLOSED plates (adult): no linear growth possible → appositional bone growth + soft-tissue overgrowth → acromegaly (jaw, hands, feet, viscera).
Same pathophysiology: GH-secreting pituitary adenoma (± MEN1, McCune-Albright). Same workup (IGF-1 → OGTT → MRI). Same treatment hierarchy (surgery → SST analog → pegvisomant → radiation). The ONLY phenotypic difference comes from the skeletal substrate available when excess begins.
LO 5 · Adult GH Deficiency FA 4.03 · Bootcamp 3.05
What features distinguish adult GH deficiency, and when is replacement therapy indicated?
Answer
Features: • ↑ visceral adiposity, ↓ lean body mass • ↓ bone mineral density • Dyslipidemia (↑ LDL, ↓ HDL) • ↓ exercise capacity, fatigue • Impaired QoL, mood • Insulin resistance (mild)
Causes: most commonly a pituitary adenoma treatment history (surgery/radiation), traumatic brain injury, Sheehan, autoimmune hypophysitis, craniopharyngioma.
Diagnosis: at least ONE stimulation test (ITT or macimorelin) showing blunted GH + low IGF-1. Often in context of other pituitary axis deficiencies.
Tx: recombinant GH (lower dose than pediatric). Titrate to IGF-1 mid-normal. Monitor glucose, lipids, cardiac function. Not indicated for isolated somatopause or anti-aging.
Step 1-Style MCQs: Single best answer. Explanations display automatically after your choice.
Question 1 of 10 · LO 5 — Acromegaly Screening FA 3.02 · BnB 5.01
A 44-year-old man complains of increased ring size (over 3 years), worsening headaches, and new-onset obstructive sleep apnea. Exam: prominent jaw, wide nasal bridge, enlarged hands and feet, soft doughy palms. You suspect acromegaly. Which single initial test has the best combination of availability, sensitivity, and specificity?
ARandom morning serum growth hormone
BSerum IGF-1 (age and sex adjusted)
C24-hour urine growth hormone
DMRI of the pituitary gland
EArginine stimulation test
B — Serum IGF-1. GH is pulsatile and has a short ½-life (~20 min) → random GH can be normal in an acromegalic. IGF-1 is stable (t½ ~12h, bound to IGFBP) and integrates GH exposure → best SCREEN. MRI (D) is for LOCALIZATION after biochemical confirmation. OGTT confirms by showing non-suppressibility. Arginine stim (E) is for SUSPECTED GH DEFICIENCY, not excess.
Question 2 of 10 · LO 5 — Acromegaly Confirmation Bootcamp 3.04 · FA 3.02
A 41-year-old woman has IGF-1 of 840 ng/mL (ULN 260). An oral glucose tolerance test is performed. At 120 minutes post-glucose, her GH remains at 2.8 ng/mL. Which of the following best explains this finding?
ANormal physiologic response to oral glucose
BAutonomous GH secretion from a somatotrope adenoma unresponsive to physiologic feedback
CLaron syndrome
DIsolated IGF-1 overproduction from the liver
EExogenous GH use
B. Normal physiology: oral glucose suppresses GH below 1 ng/mL via long-loop feedback. Failure to suppress confirms autonomous secretion — i.e., acromegaly from a pituitary adenoma. Laron syndrome (C) has HIGH GH (because of the receptor defect) but LOW IGF-1 — opposite biochemical pattern. Exogenous GH (E) would suppress endogenous GH via feedback, though it could confuse the assay. Direct LO 5 test.
Question 3 of 10 · LO 5 — GH Deficiency in Child Bootcamp 3.05 · FA 4.03
A 7-year-old boy has height below the 1st percentile and growth velocity of 3 cm/year (normal ~5–7 cm/year). Bone age is delayed by 3 years. Random GH is 1.1 ng/mL; IGF-1 is 40 ng/mL (below age-matched reference). Insulin tolerance test: after inducing hypoglycemia (serum glucose 38 mg/dL), peak GH reaches only 3 ng/mL (normal response >10 ng/mL). MRI is normal. Which of the following is the best next step?
AInitiate recombinant human GH (somatropin)
BInitiate recombinant IGF-1 (mecasermin)
CInitiate octreotide
DReassure and observe — normal variant short stature
EStart pegvisomant
A — Recombinant GH. Classic GH deficiency: low growth velocity, delayed bone age, low IGF-1, and blunted GH response to provocative stimulation. Intact GH receptor (no features of Laron; normal family history) means somatropin works well. Earlier initiation → better final adult height. Mecasermin (B) is for Laron (GH-receptor resistance). Octreotide (C) and pegvisomant (E) are for acromegaly.
Question 4 of 10 · LO 1/5 — Laron Syndrome In House
A 5-year-old girl in a consanguineous family has severe proportionate short stature (height <3 SD below the mean), frontal bossing, saddle nose, truncal obesity, and episodic hypoglycemia. Labs: GH 22 ng/mL (HIGH), IGF-1 12 ng/mL (LOW), IGFBP-3 very low. Genetic testing reveals a homozygous inactivating mutation in GHR. Which of the following is the most appropriate treatment?
AHigh-dose recombinant human GH
BRecombinant IGF-1 (mecasermin)
COral glucose tolerance test and MRI sella
DRecombinant GHRH (tesamorelin)
EThyroxine replacement
B — Mecasermin (recombinant IGF-1). Laron syndrome is a GH RECEPTOR defect. The pituitary makes GH normally (or more, because long-loop feedback is lost with low IGF-1) but the liver cannot respond. GH therapy (A) is useless — there's no functioning receptor. Treatment bypasses the receptor by replacing the downstream mediator IGF-1. Tests LO 5 and clinical distinction from classic GHD.
Question 5 of 10 · LO 2 — Diabetes in Acromegaly Bootcamp 3.04 · BnB 5.01
A 52-year-old woman with newly diagnosed acromegaly has fasting glucose of 168 mg/dL and HbA1c 7.9%. She had no prior diabetes. Which of the following is the most specific mechanism explaining her hyperglycemia?
APancreatic β-cell destruction
BGH-induced insulin resistance at muscle and adipose tissue with ↑ hepatic gluconeogenesis
CAdrenal cortisol excess from co-secretion
DGlucagon overproduction by α-cells
EAnti-insulin receptor antibodies
B. GH is diabetogenic: DIRECT effects include ↓ GLUT4 translocation in muscle/adipose (insulin resistance) and ↑ hepatic gluconeogenesis. This is distinct from IGF-1's anabolic growth effects. ~30–50% of acromegalics develop diabetes/glucose intolerance. Treatment (tumor removal) often improves but may not fully reverse the diabetes if it's been long-standing. Directly tests LO 2.
Question 6 of 10 · LO 5 — Medical Therapy Side Effects FA 3.02 · Bootcamp 3.04
A 58-year-old man with acromegaly cannot undergo transsphenoidal surgery due to cardiopulmonary comorbidities. He is started on monthly octreotide LAR (long-acting release). At 6 months, IGF-1 has decreased 60%, symptoms have improved, and tumor volume is ~30% smaller. However, he develops right upper quadrant pain and ultrasound reveals cholelithiasis. Which of the following best explains this side effect?
ADirect toxic effect of octreotide on gallbladder epithelium
BSomatostatin analog suppression of CCK and gallbladder motility, promoting bile stasis
COctreotide-induced hypercholesterolemia
DAutoimmune cholangitis triggered by the peptide
ESecondary hyperparathyroidism from vitamin D malabsorption
B. Octreotide is a somatostatin analog. Somatostatin INHIBITS many GI hormones and motility, including CCK → ↓ gallbladder contraction → bile stasis → cholelithiasis/sludge (20–30% of patients on long-term therapy). Other side effects: hyperglycemia or hypoglycemia, injection-site pain, steatorrhea, bradycardia, B12 deficiency. Integrates with LO 5 treatment pharmacology.
Question 7 of 10 · LO 1 — GH Signal Transduction In House · BnB 5.01
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 nuclear translocation → IGF-1 transcription
CcAMP generation
DCa²⁺ release from ER
EReceptor tyrosine kinase autophosphorylation
B. GH receptor is a cytokine receptor — has NO intrinsic kinase. Dimerization recruits JAK2, which phosphorylates the receptor and activates STAT5. STAT5 dimerizes, translocates to nucleus, and drives transcription of IGF-1 (and other anabolic genes). Binding itself (A) is unaffected. GH-R is NOT an RTK (E) — that's the IGF-1R. Tests LO 1 directly.
Question 8 of 10 · LO 1 — IGF-1 Half-Life In House · FA 3.02
A pharmacology student asks why IGF-1 has a half-life of ~12 hours in circulation while GH has a half-life of ~20 minutes. Which of the following provides the most specific explanation?
AIGF-1 is a larger protein than GH and cleared more slowly by the kidney
BIGF-1 circulates bound to IGFBP-3 (+ ALS) as a ternary complex, prolonging its half-life
CGH is rapidly degraded by hepatic JAK2
DIGF-1 is glycosylated while GH is not
EIGF-1 is degraded only inside target cells
B. IGF-1 travels almost exclusively bound to IGFBP-3 plus the acid-labile subunit (ALS), forming a ~150-kDa ternary complex that cannot cross endothelial barriers → reservoir function + protection from proteases → t½ ~12h. GH binds GHBP (a cleaved fragment of GHR ECD) weakly → modest t½ extension (~20 min). Free IGF-1 is cleared in minutes (similar to free GH). This is why IGF-1 is a better integrated screen for acromegaly than random GH — tests LO 1.
Question 9 of 10 · LO 5 — Pegvisomant Monitoring FA 3.02 · Bootcamp 3.04
A 47-year-old woman with residual acromegaly after surgery is started on pegvisomant. After 6 months, her IGF-1 has normalized and her symptoms are markedly improved. Which monitoring strategy is MOST important in this patient?
ASerial serum GH levels (expect GH to fall)
BSerial MRI of the pituitary to monitor tumor size, plus LFTs
CSerial ACTH levels
DDaily fasting glucose (risk of hypoglycemia)
ESerum calcium
B — MRI + LFTs. Pegvisomant is a GH-receptor ANTAGONIST — it blocks peripheral GH action but does not treat the tumor. Paradoxically, serum GH RISES on pegvisomant (loss of IGF-1 negative feedback), so tracking GH is useless. You must follow IGF-1 for efficacy and MRI for tumor growth (rare but reported). Pegvisomant can cause LFT elevations (hepatotoxicity) and lipoatrophy at injection sites. Tests LO 5 drug-specific pharmacology.
Question 10 of 10 · LO 2/4 — GH in Pregnancy In House
A 29-year-old G2P1 woman at 28 weeks' gestation has fasting glucose of 112 mg/dL and a 1-hour post-load glucose of 198 mg/dL. Her pre-pregnancy A1c was 5.2%. Serum GH (pituitary) is LOW; hPL is markedly elevated. Which of the following best explains her hyperglycemia?
COveractive pituitary GH secretion during pregnancy
DMaternal cortisol deficiency
EGestational thyrotoxicosis
B — hPL-driven gestational diabetes.Human placental lactogen (hCS) is a GH/PRL-family hormone. It rises through pregnancy, binds the GH receptor, and mimics GH's diabetogenic effects (muscle/adipose insulin resistance + lipolysis). This spares glucose + AAs for the fetus. Pituitary GH is SUPPRESSED by long-loop feedback from hPL. The combination is physiologically normal but unmasks gestational diabetes in predisposed patients. Resolves within hours of delivery. Tests LO 2/4.
Vignette 1 of 6 · LO 5 — MEN1 Acromegaly FA 3.02 · Bootcamp 3.04
A 36-year-old man presents with recurrent peptic ulcers (4 in the last 2 years) despite high-dose PPI therapy. His father died at 40 of acromegaly complications. Exam: enlarged jaw, coarse features, shoe size increased two full sizes over 6 years. Labs: Ca²⁺ 11.8 mg/dL (high), PTH 110 pg/mL (inappropriately normal-high), IGF-1 4× ULN, fasting gastrin 850 pg/mL. Ca²⁺ rises further after calcium infusion (Paradoxical Ca infusion test). Which genetic syndrome most likely unifies these findings?
C — MEN 1. Classic "3 P's": Parathyroid hyperplasia (hypercalcemia, ↑PTH) + Pancreatic endocrine tumor (gastrinoma → Zollinger-Ellison → recurrent ulcers) + Pituitary adenoma (GH-secreting → acromegaly). Autosomal dominant, tumor suppressor MEN1 gene on 11q13. Family history makes this near-certain. Screen relatives. MEN 2A/2B (A, B) are RET-associated and feature MEDULLARY thyroid cancer and pheo — not acromegaly or gastrinomas.
Vignette 2 of 6 · LO 5 — McCune-Albright with Acromegaly FA 4.03
A 14-year-old girl has history of precocious puberty (menarche at age 4), large "coast of Maine"–bordered café-au-lait patch across her left flank, and a left femoral fibrous dysplasia lesion. Over the past 2 years she has grown 30 cm and developed prominent jaw and enlarged hands and feet. Labs: IGF-1 markedly elevated, GH fails to suppress with OGTT. MRI shows no discrete pituitary adenoma but diffuse pituitary enlargement. Genetic testing on affected bone biopsy reveals a postzygotic activating GNAS mutation. Which of the following best explains the GH excess?
ATraditional somatotrope adenoma
BConstitutive activation of Gsα in mosaic somatotrope tissue → tonic cAMP → autonomous GH release
CLoss-of-function mutation in somatostatin receptor
DEctopic GHRH production from the bone lesion
EGermline STAT5 activating mutation
B — McCune-Albright GH excess. The same post-zygotic activating GNAS mutation that drives precocious puberty, fibrous dysplasia, and café-au-lait can affect somatotropes. GHRH binds a Gs-coupled receptor → normally requires GHRH ligand. Constitutively active Gsα → tonic cAMP → autonomous GH secretion without GHRH. Diffuse enlargement (not a discrete adenoma) is characteristic. Treatment is harder than typical acromegaly (no focal target for surgery); medical therapy with SST analogs / pegvisomant is often needed.
Vignette 3 of 6 · LO 5 — Achondroplasia Differential In House
A 3-year-old boy is referred for short stature. He is below the 1st percentile for height. Exam: disproportionate short stature with short limbs, normal trunk length, large head with frontal bossing, midface hypoplasia, trident hand. Both parents are of normal height. Labs: normal GH provocative response, normal IGF-1, normal TSH. Genetic testing reveals a heterozygous FGFR3 p.G380R variant. Which treatment approach is most appropriate?
C. Buzzwords: disproportionate short limbs, frontal bossing, trident hand, FGFR3 activating mutation. Achondroplasia is a GROWTH PLATE disease — constitutively active FGFR3 INHIBITS chondrocyte proliferation. GH/IGF-1 axis is NORMAL, and GH therapy is not effective because the plate itself can't respond to IGF-1. Vosoritide (FDA-approved CNP analog) antagonizes the FGFR3 pathway → improves growth. Important board distinction: GH deficiency / Laron / Turner → GH or IGF-1 helps. Achondroplasia → a different biology altogether.
Vignette 4 of 6 · LO 3/5 — Somatopause vs. Pathologic GHD In House
A 68-year-old man feels increasingly fatigued, has lost 4 kg of muscle mass despite exercise, and has gained 5 kg of visceral fat. A marketing campaign is advertising "anti-aging GH therapy." His labs: IGF-1 at the lower limit of adult normal, TSH normal, morning cortisol normal, testosterone at the low end of normal. Which of the following statements best reflects the appropriate medical approach?
AInitiate recombinant GH; physiologic decline is pathologic and reversible
BStart pegvisomant to block excessive GH-mediated aging
CDecline GH therapy: age-related GH decline ("somatopause") is not equivalent to pathologic GH deficiency; risks of GH (insulin resistance, edema, cardiomegaly, possible cancer) outweigh benefits
DInitiate IGF-1 therapy
EInitiate cabergoline
C. Age-related decline in GH/IGF-1 (somatopause) is a normal biological phenomenon — NOT the same as documented hypopituitary GH deficiency. Trials of GH in older adults show modest body-composition benefits but significant rates of insulin resistance, edema, arthralgias, cardiomegaly, and theoretical cancer risk. Organ-system aging is multifactorial; hormone therapy doesn't reverse it. GH is FDA-approved ONLY for documented GH deficiency — not anti-aging. Practical LO 3/5 application.
Vignette 5 of 6 · LO 5 — Post-Traumatic Hypopituitarism FA 4.03 · Bootcamp 3.05
A 28-year-old man presents 8 months after a severe traumatic brain injury. He reports fatigue, 9-kg weight gain, loss of libido, and reduced exercise tolerance. Labs: low free T4 with low-normal TSH, AM cortisol 4 mcg/dL with low ACTH, testosterone low with low LH/FSH, IGF-1 at ~0.3× age-matched mean. Insulin tolerance test: peak GH 2.4 ng/mL (normal >10). MRI shows a partially empty sella. Regarding GH replacement, which statement is most correct?
AGH replacement is contraindicated in post-traumatic hypopituitarism
BReplace GH FIRST; thyroxine and cortisol are less urgent
CReplace glucocorticoid FIRST, then thyroxine, then consider GH replacement once other axes are stable
DGH replacement in adults is never indicated — wait for spontaneous recovery
EStart pegvisomant to block peripheral GH insensitivity
C — adrenal first, always. In panhypopituitarism (especially traumatic), glucocorticoid replacement must precede thyroxine — giving thyroxine first in a cortisol-deficient patient can precipitate adrenal crisis by accelerating cortisol clearance. After glucocorticoid + thyroxine, sex steroids and GH can be considered. Adult GHD replacement improves body composition, bone density, and QoL; monitor IGF-1 (titrate to mid-normal), lipids, glucose, and cardiac function. Integrates LO 5 with broader pituitary pathophysiology.
Vignette 6 of 6 · LO 5 — Gigantism vs. Acromegaly Bootcamp 3.04 · BnB 5.01
A 12-year-old boy has grown 22 cm in the past 18 months. His parents note enlarging hands and feet, coarsening features, and recent headaches with peripheral vision changes. Height is at the 99th percentile. Bone age imaging shows open epiphyseal plates. Labs: IGF-1 markedly elevated; GH fails to suppress on OGTT; prolactin mildly elevated. MRI: 1.6-cm pituitary macroadenoma with suprasellar extension. Which of the following statements best distinguishes this presentation from classic adult acromegaly?
AThe diagnostic workup is entirely different
BGH excess BEFORE epiphyseal closure produces linear gigantism; the same adenoma biology drives acromegaly after closure
CGigantism never causes soft-tissue overgrowth
DCardiovascular disease risk is lower in gigantism
EMedical therapy is contraindicated in pediatric patients
B. Same pathophysiology, different skeletal substrate: GH excess BEFORE epiphyseal plate closure → IGF-1 drives LINEAR growth at the plates → gigantism (tall stature). AFTER closure → no linear growth possible → periosteal and soft-tissue thickening → acromegaly (jaw, hands, feet, viscera). Workup (IGF-1 → OGTT → MRI) and treatment (surgery → SST analog → pegvisomant) are essentially the same. Open vs closed epiphyseal plates is the single distinguishing factor. Note visual symptoms hint at mass effect on optic chiasm — urgent for surgical planning. Tests LO 5 + integrates peds physiology.
Step 1 Traps: Each statement is TRUE or FALSE — many reverse or mix facts that routinely trip students up.
Trap 01 · LO 1 — GH Mechanism In House
"Growth hormone exerts its effects on cartilage and bone by binding directly to receptors on chondrocytes to induce cell division."
FALSE. GH stimulates the LIVER to produce IGF-1; it's IGF-1 that binds IGF-1R on chondrocytes to drive proliferation. This is why Laron syndrome (GH receptor on hepatocytes broken) produces short stature despite high GH — the mediator IGF-1 is missing.
Trap 02 · LO 2 — GH Glucose Effect In House · BnB 5.01
"Growth hormone improves glycemic control by enhancing insulin sensitivity in skeletal muscle and adipose tissue."
FALSE — opposite. GH is diabetogenic: it INDUCES insulin resistance in muscle/adipose and RAISES serum glucose via ↑ hepatic gluconeogenesis. Long-term GH excess causes T2DM. This is the key reason oral glucose is used to diagnose acromegaly (normal → GH suppresses; acromegaly → no suppression).
Trap 03 · LO 5 — OGTT Interpretation In House · FA 3.02
"In a healthy subject, oral glucose administration STIMULATES GH release — which is why it is used as a provocation test for GH deficiency."
FALSE. Oral glucose SUPPRESSES GH in healthy subjects. It's used to DIAGNOSE acromegaly — failure to suppress indicates autonomous secretion. For GH DEFICIENCY, provocation tests INDUCE hypoglycemia or use AMINO ACIDS (e.g., arginine, insulin tolerance test, clonidine, exercise) to STIMULATE GH.
Trap 04 · LO 5 — Laron Syndrome FA 3.02
"A child with Laron syndrome should be treated with high-dose recombinant GH because this overcomes the partial GH receptor defect."
FALSE. Laron = COMPLETE loss of GH receptor function. Giving more GH makes no difference — there's nothing for GH to bind. Treatment is recombinant IGF-1 (mecasermin), which bypasses the defective receptor. Classic board distinction from "classic" GH deficiency (intact receptor, responds to somatropin).
Trap 05 · LO 5 — Achondroplasia FA 4.03
"Achondroplasia results from GH deficiency; recombinant GH therapy is the mainstay of treatment."
FALSE. Achondroplasia = GAIN-of-function mutation in FGFR3 that INHIBITS chondrocyte proliferation at growth plates. GH and IGF-1 levels are NORMAL — the growth plate can't respond. GH therapy doesn't work. Newer therapy: vosoritide (CNP analog). Classic disproportionate short stature (short limbs, normal trunk, frontal bossing, trident hand).
Trap 06 · LO 3 — GH Pulsatility In House
"The peak physiologic GH pulse occurs in the morning shortly after waking, as cortisol also peaks."
FALSE. The peak GH pulse occurs during stage 4 slow-wave sleep, typically around midnight. Cortisol's circadian peak is in the EARLY MORNING (6–8 AM), so they are out of phase. Children with chronic sleep deprivation can develop growth failure in part from inadequate nocturnal GH pulses.
Trap 07 · LO 5 — GH Doping Detection In House
"Exogenous GH cannot be detected in athletes because recombinant GH is biochemically identical to all endogenous GH isoforms."
FALSE. Endogenous GH exists as a mix of isoforms (22 kDa — dominant, and 20 kDa plus minor variants). Recombinant GH is pure 22 kDa. The isoform-ratio test detects the shifted ratio. Biomarker tests (persistently elevated IGF-1 + P-III-NP) also improve detection sensitivity. Both are used in anti-doping protocols.
Trap 08 · LO 2 — Fed/Fasted GH Role In House
"Growth hormone is an anabolic hormone in ALL physiologic states — it promotes protein synthesis and fat deposition whether the patient is fed or fasted."
FALSE. GH's role is CONTEXT-DEPENDENT. In the FED state (insulin high, AAs high), GH drives protein ANABOLISM and growth via IGF-1. In the FASTED state (insulin low, glucose low), GH acts directly on peripheral tissues to cause LIPOLYSIS, insulin resistance, and hepatic gluconeogenesis — glucose-sparing effects that preserve CNS fuel. Insulin is permissive for hepatic GH-R expression: without insulin, GH can't effectively drive IGF-1 synthesis.
Trap 09 · LO 2/4 — Pregnancy & GH In House · FA 3.01
"Pregnancy raises endogenous pituitary growth hormone secretion, which is why pregnant patients are at risk for glucose intolerance."
FALSE. Pregnancy SUPPRESSES endogenous pituitary GH. The placenta makes human placental lactogen (hPL / hCS), which is structurally similar to GH, binds the GH receptor, and exerts long-loop feedback on the hypothalamus → pituitary GH release falls. However, hPL itself mimics GH's diabetogenic effects (insulin resistance, lipolysis) → spares glucose for the fetus → this drives the insulin resistance of pregnancy and, in susceptible patients, gestational diabetes. Resolves after delivery as hPL falls to zero.
Trap 10 · LO 1 — IGFBP Function In House · FA 3.02
"Free IGF-1 has a longer half-life than IGFBP-bound IGF-1, which is why carrier proteins are not important for IGF-1 signaling."
FALSE — reversed. Nearly all circulating IGF-1 is IGFBP-BOUND, with a half-life of ~12 HOURS. Free IGF-1 is cleared in minutes. Carrier binding DRAMATICALLY extends IGF-1 half-life (by >30×) and provides a circulating reservoir. But bound IGF-1 is INACTIVE — tissue IGFBP proteases (PAPP-A, PSA, etc.) cleave the carrier at target tissues to release active IGF-1 locally. Pregnancy uses PAPP-A (1st-trimester Down syndrome screening marker) for this purpose.
Trap 11 · LO 1 — GH Receptor Class In House · BnB 5.01
"The GH receptor is a receptor tyrosine kinase that autophosphorylates on ligand binding."
FALSE. The GH receptor is a cytokine receptor — it has NO intrinsic kinase activity. It uses associated JAK2 kinase to phosphorylate STAT5, which dimerizes and translocates to the nucleus. Confusingly, IGF-1's receptor (IGF-1R) IS a true RTK with intrinsic kinase activity (similar architecture to insulin receptor). Don't mix them up.
Trap 12 · LO 4 — Ghrelin Source In House · FA 3.02
"Ghrelin is secreted by the hypothalamic arcuate nucleus and acts as the body's primary GH-releasing hormone."
FALSE. Ghrelin is secreted primarily from the stomach (X/A-like cells of oxyntic glands), not the hypothalamus. It binds GHS-R on somatotropes and arcuate NPY/AgRP neurons → ↑ GH release + ↑ appetite. The "primary" hypothalamic GH-releasing hormone is GHRH; ghrelin SYNERGIZES with GHRH but is not the primary releaser. Macimorelin (oral GHS-R agonist) is FDA-approved for adult GH deficiency testing.
Trap 13 · LO 5 — Pegvisomant Effect on GH FA 3.02 · Bootcamp 3.04
"Successful pegvisomant therapy in acromegaly is monitored by serial measurement of serum GH, which should fall to undetectable levels."
FALSE — opposite. Pegvisomant is a peripheral GH-receptor ANTAGONIST. It blocks GH from generating IGF-1 in the liver, so IGF-1 falls. But because IGF-1 normally provides long-loop negative feedback to the pituitary, removing that feedback causes pituitary GH to RISE. Therefore, pegvisomant therapy is monitored by IGF-1 normalization (efficacy) and MRI tumor surveillance + LFTs (safety) — never by GH levels.
Trap 14 · LO 4 — Cortisol & Growth In House
"Children with chronic hypercortisolism (Cushing) typically have ACCELERATED linear growth in addition to weight gain."
FALSE. Pediatric Cushing causes weight gain WITH growth FAILURE — a counterintuitive but high-yield clue. Cortisol suppresses GH release centrally, inhibits chondrocyte proliferation directly, and antagonizes IGF-1 effects on bone/muscle. The unusual obesity-without-height-gain pattern should always trigger a Cushing workup (vs. simple obesity, which usually accelerates linear growth and bone age). Long-term exogenous steroids in children require GH-axis monitoring.
Matching Drills: Click a left item, then its right pair. Correct → green; wrong → red flash. Set 1 stays in pure GH-axis biology; later sets weave in disease, drug, and clinical-test associations.
Drill 1 · LO 1 — Hormone / Carrier / Half-Life
Match each circulating molecule to its dominant carrier protein and approximate half-life.
Clinical Correlates + HY Testing Notes: Signature GH-axis diseases with mechanism details, followed by buzzwords, rules, mnemonics, and common traps. Click "Expand" on each case for deeper mechanism context.
LO 5 · GH Excess FA 3.02 · Bootcamp 3.04 · BnB 5.01
Acromegaly — The Post-Epiphyseal GH Excess
Insidious onset over years → classical features: jaw prognathism, macroglossia, soft-tissue overgrowth, cardiomegaly, T2DM, OSA. Cardiovascular disease is the leading cause of death; timely diagnosis & treatment restore life expectancy.
Dx: IGF-1 screen → OGTT confirms (GH fails to suppress) → MRI sella for localization. Tx hierarchy: • Surgery (transsphenoidal) — first line; 70–90% microadenoma cure rate; ~30–50% macroadenoma cure. • Somatostatin analogs (octreotide LAR, lanreotide, pasireotide) — reduce GH and shrink tumor in ~50%. • Pegvisomant — GH receptor antagonist; normalizes IGF-1 in 90% but doesn't shrink tumor. • Cabergoline — useful if PRL co-secretion or modest GH elevations. • Radiation — last line; slow response, high rate of hypopituitarism. Screen for co-existing colonic polyps (colonoscopy q5y), OSA, diabetes, cardiomyopathy.
LO 5 · GH Deficiency FA 4.03 · Bootcamp 3.05
Pituitary Dwarfism — Classic GH Deficiency
Short stature with proportionate body segments, delayed bone age, normal birth size → growth velocity drops after age 1–2. Causes range from idiopathic to tumor/radiation to genetic defects (PROP1, PIT1, GHRH-R).
Treatment: recombinant human GH (somatropin), daily SC injection, titrated to IGF-1 in the mid-normal range. Continue until near-final height or epiphyseal closure. Adult GH deficiency: consider replacement if quality-of-life / metabolic risk warrants.
LO 5 · GH Receptor Defect FA 3.02 · In House
Laron Syndrome — The Cancer-Protective Dwarfism
Autosomal recessive GHR mutation → severe short stature despite HIGH GH. Observational cohorts in Ecuador demonstrate striking protection against malignancy and T2DM — consistent with the cancer-promoting effects of IGF-1.
Research implication: IGF-1 signaling is a classic longevity/cancer axis. Lower lifetime IGF-1 correlates with lower cancer and diabetes incidence (but also smaller body size and potential sarcopenia). Calorie restriction reduces IGF-1 in animals and may contribute to longevity effects.
LO 5 · Syndromic FA 4.25 · In House
MEN 1 — The "3 P's" With Acromegaly
Parathyroid hyperplasia + Pancreatic endocrine tumor (gastrinoma most common) + Pituitary adenoma. ~30% of pituitary adenomas in MEN 1 are GH-secreting. Family history is key.
Autosomal dominant loss of MEN1 tumor suppressor (menin) on 11q13. Anyone presenting with acromegaly plus either recurrent peptic ulcers/hypercalcemia should prompt screening (MEN1 genetics + family). Compare MEN2A/2B (RET gene, features MEDULLARY thyroid + pheo — NOT acromegaly).
Two classic pediatric short-stature syndromes with completely different biology. Distinguishing them is a core Step 1 skill.
Pituitary dwarfism: PROPORTIONATE short stature; ↓GH, ↓IGF-1; growth plate is normal but understimulated. Treatment: recombinant GH.
Achondroplasia: DISPROPORTIONATE short stature (short limbs, normal trunk); trident hand; frontal bossing; midface hypoplasia. Normal GH, normal IGF-1. Growth plate can't respond. FGFR3 mutation. Treatment: vosoritide (CNP analog).
Other short-stature scenarios on Step 1: • Turner (45,X): short stature + streak gonads + webbed neck + coarctation. GH therapy indicated. • Prader-Willi: hypotonic infant → obese hyperphagic child + GH deficiency. GH therapy indicated. • Constitutional delay: delayed bone age, delayed puberty, family history of "late bloomers." Catches up. Reassure. • Familial short stature: normal bone age, both parents short. Normal variant.
LO 3 · Lifetime Trajectory In House · BnB 5.01
Somatopause — Aging of the GH Axis
GH and IGF-1 decline with age. Associated with sarcopenia, ↑ visceral adiposity, bone loss. Tempting to "treat" — but GH replacement in elderly adults without documented deficiency causes more harm than benefit.
Mechanisms: decreased GHRH pulse amplitude, increased somatostatin tone, declining sex steroids. Lifestyle interventions (resistance exercise, adequate protein, good sleep) can partially offset sarcopenia without hormone therapy.
Adult GH deficiency (true): post-pituitary surgery / radiation / tumor / hemorrhage → replacement may improve QoL, body composition, bone density — but cardiac effects must be monitored. NOT the same as somatopause.
Ethical note: "Anti-aging" GH therapy is not evidence-based and is illegal to market as such in the United States.
LO 2/4 · hPL in Pregnancy In House · FA 3.01
Human Placental Lactogen — Pregnancy's "Built-In Acromegaly"
The placenta produces hPL (human chorionic somatomammotropin, hCS) — a GH-family hormone with partial structural homology to both GH and prolactin. It rises through pregnancy and mimics GH's diabetogenic effects, driving the physiologic insulin resistance of pregnancy and, in susceptible patients, gestational diabetes.
Clinical implications:
• Gestational diabetes: usually emerges 2nd–3rd trimester as hPL peaks; screen at 24–28 weeks with OGTT. Resolves after delivery.
• Women with pre-existing acromegaly often experience worsened symptoms during pregnancy as hPL adds to endogenous GH action.
• Postpartum: hPL falls to zero within hours → insulin resistance resolves. If the woman also had pituitary lesion/Sheehan, baseline GH axis should be reassessed.
Fun fact: hPL was named "human placental lactogen" because of its weak lactogenic activity — stemming from GH/PRL receptor family homology.
LO 5 · GH Excess (Pediatric) Bootcamp 3.04 · FA 3.02
Gigantism — Pre-Epiphyseal GH Excess
Same somatotrope-adenoma biology as acromegaly but presenting BEFORE epiphyseal plate closure → extreme linear growth. Classic clue: accelerated growth velocity + macroadenoma on MRI + headaches / visual field defects.
Pathophysiology: A GH-secreting pituitary adenoma in a child/adolescent drives IGF-1-mediated linear bone growth at still-open epiphyseal plates → abnormally tall stature. Once plates close (usually late teens), further GH excess shifts to the acromegalic phenotype (soft tissue + appositional bone overgrowth without linear growth).
Workup: identical to acromegaly — IGF-1 screen → OGTT → MRI sella. Pediatric patients often need larger-than-adult somatostatin analog doses; pegvisomant is used less frequently in children.
Key distinguishing features vs constitutional tall stature: the ADENOMA (mass symptoms, elevated IGF-1), the PLATEAU absence (continued acceleration rather than normal tempo), and any associated soft-tissue overgrowth (jaw, hands, feet) developing during late adolescence.
High-Yield Testing Notes — Pattern-matching, buzzwords, rules, and trap corners that recur on Step 1.
Buzzword → Diagnosis Pattern Bank
"Enlarged ring size + shoe size + jaw": Acromegaly. "Adult + new-onset diabetes + OSA + soft tissue overgrowth": Acromegaly (screen IGF-1). "High GH + LOW IGF-1 + severe short stature": Laron syndrome — use mecasermin. "Short limbs, normal trunk, frontal bossing, FGFR3": Achondroplasia — NOT a GH disorder. "Recurrent PUD + hypercalcemia + acromegaly": MEN 1. "Precocious puberty + café-au-lait + fibrous dysplasia + acromegaly": McCune-Albright (GNAS). "Neonatal hypotonia → obese child, short stature": Prader-Willi (GH therapy indicated). "Short girl, webbed neck, coarctation, primary amenorrhea": Turner (GH + estrogen). "Child with obesity but NO height gain": suspect Cushing (cortisol suppresses growth).
Rules of the GH Axis High-Yield
Screen acromegaly with IGF-1, not random GH (pulsatile). Confirm acromegaly with OGTT — GH fails to suppress <1 ng/mL. Test GHD with provocation (ITT, arginine, macimorelin), NOT OGTT. Laron uses mecasermin, not GH. Achondroplasia is NOT a GH problem — FGFR3 / growth plate issue. GH is diabetogenic — screen acromegalics for T2DM; monitor glucose in all on GH therapy. Cardiovascular disease is the #1 cause of death in acromegaly. SST analogs cause cholelithiasis. Pegvisomant is monitored by IGF-1 + MRI + LFTs — NOT GH levels. Somatopause is normal — no "anti-aging" GH.
Mnemonics Memory Hooks
"GH Releases Up in the night": peak secretion during deep sleep. "GH-IGF: Growth Happens Indirectly via Factor-1": growth effects are IGF-1 mediated. "LaRon has a Receptor problem": GH receptor mutation → HIGH GH, LOW IGF-1. "Acromegaly kills through the Heart": leading cause of death = cardiovascular. "3 P's of MEN1": Parathyroid, Pancreas, Pituitary. "Octreotide's GIFt": Gallstones, Intestinal problems, blocks Flow of hormones. "JAK-STAT for cytokines, RTK for insulin-family": GH-R → JAK2/STAT5; IGF-1R → intrinsic tyrosine kinase.
Traps Corner Common Errors
Do NOT give GH for Laron (use IGF-1). Do NOT give GH for achondroplasia (use vosoritide). Do NOT confuse OGTT (acromegaly test) with ITT/arginine (GHD tests). Do NOT confuse MEN1 (Parathyroid/Pancreas/Pituitary) with MEN2 (Medullary thyroid/Pheo). Do NOT interpret somatopause as pathologic GHD. Do NOT reverse: GH is DIABETOGENIC; IGF-1 is anabolic/hypoglycemic. Do NOT forget to screen acromegalics for colon cancer (colonoscopy q5y). Do NOT monitor pegvisomant by GH (it RISES on therapy — follow IGF-1 + MRI + LFTs). Do NOT replace thyroxine before glucocorticoids in panhypopituitarism (risk of adrenal crisis).
GH-Axis Disorders — Rapid Comparison
Condition
Cause
GH
IGF-1
Height
First-Line Treatment
Classic GH deficiency
Pituitary failure (idiopathic, genetic, tumor)
LOW
LOW
Short, proportionate
Recombinant GH
Laron syndrome
GH receptor mutation
HIGH
LOW
Short, proportionate
Recombinant IGF-1 (mecasermin)
Gigantism
GH adenoma (pre-epiphyseal closure)
HIGH
HIGH
Tall, linear growth
Surgery ± SST analog
Acromegaly
GH adenoma (post-closure)
HIGH
HIGH
Jaw/hand/feet thickening
Surgery ± SST analog / pegvisomant
Achondroplasia
FGFR3 gain-of-function
Normal
Normal
Short, DISPROPORTIONATE limbs
Vosoritide (CNP analog)
Turner syndrome
45,X (SHOX + estrogen deficit)
Normal
Normal
Short, + stigmata
Recombinant GH + estrogen replacement
Prader-Willi
Paternal 15q11–13 loss
Low (functional)
Low-normal
Short + hyperphagic obesity
Recombinant GH
Medical Therapy for GH Excess
Drug
Mechanism
Effect on Tumor
Effect on IGF-1
Key Side Effects
Octreotide / Lanreotide
SSTR-2/5 agonist → ↓ GH release
~30–50% shrinkage
↓ 50–70%
Cholelithiasis, hyperglycemia, bradycardia
Pasireotide
Pan-SSTR (including SSTR-5)
Similar shrinkage
↓ more potent
WORSE hyperglycemia than octreotide
Pegvisomant
GH receptor antagonist (peripheral)
No shrinkage (monitor MRI)
Normalizes in ~90%
LFT elevations, lipoatrophy at injection
Cabergoline
D2 agonist → variable ↓ GH
Variable
Modest ↓
Nausea, orthostasis; cardiac valvulopathy at high doses
Tests for GH-Axis Dysfunction
Test
What It Measures
Indication
Serum IGF-1
Integrated GH exposure (age-adjusted)
Screen for acromegaly OR GHD (both directions)
OGTT for GH
Suppression of GH after 75g oral glucose
Confirm acromegaly (failure to suppress <1 ng/mL)
Insulin tolerance test
Induces hypoglycemia → should stimulate GH + cortisol
Confirm GH deficiency (failure to respond); ALSO HPA assessment
Arginine stimulation
Arginine ↑ GH release
GHD testing (especially if ITT contraindicated)
Macimorelin (oral GHS-R agonist)
Simulates ghrelin — robust GH release
Adult GHD diagnosis (FDA-approved)
MRI sella
Anatomic localization
After biochemical confirmation of acromegaly or GHD
Key teaching point: GH is not "just anabolic." It is context-dependent. Acromegaly reproduces the fasted-state effects chronically (insulin resistance), on top of continuous IGF-1–driven growth. Treating acromegaly normalizes both.