Growth Hormone and Growth Factors

GH Synthesis & Secretion - Pituitary Powerhouse

• Source: Somatotrophs (acidophil cells) in anterior pituitary; comprise ~50% of its cells.
• Structure: Single-chain peptide hormone, 191 amino acids, species-specific.
• Synthesis: PreproGH → proGH → active GH; stored in cytoplasmic granules.
• Secretion: Pulsatile (surges approx. every 2 hours); largest burst occurs 1-2 hours after deep sleep onset (NREM stage 3/4).
  • Key Stimulators: GHRH (primary hypothalamic releasing hormone), ghrelin (stomach), hypoglycemia, exercise, sleep, stress, amino acids (e.g., arginine), estrogens.
  • Key Inhibitors: Somatostatin (GHIH, hypothalamic inhibiting hormone), IGF-1 (Insulin-like Growth Factor 1, via negative feedback), hyperglycemia, ↑Free Fatty Acids, chronic glucocorticoids, obesity.
• Transport: Circulates ~50% bound to GH-Binding Protein (GHBP), which is derived from the extracellular domain of the GH receptor.

⭐ Laron dwarfism results from defective GH receptors, leading to ↓IGF-1 despite normal or ↑GH levels. (📌 Mnemonic: Laron = Low Action of GH Receptor ON target tissues).

GH Actions & Regulation - Growth Spurt Signals

• GH Actions:
  • Direct: Anti-insulin effects (↑ lipolysis, ↓ glucose uptake, ↑ gluconeogenesis).
  • Indirect (via IGF-1/Somatomedin C from liver):
    • Growth promotion: Cartilage, bone (linear growth at epiphyses), muscle, viscera.
    • ↑ Protein synthesis, ↑ cell division.
• Regulation of GH Release:
  • Stimulated by:
    • Hypothalamus: GHRH.
    • Stomach: Ghrelin.
    • Physiological: Deep sleep, exercise, hypoglycemia, stress, ↑ amino acids.
    • Pubertal Growth Spurt: Sex steroids (androgens, estrogens) synergize with GH.
  • Inhibited by:
    • Hypothalamus: Somatostatin (GHIH).
    • Feedback: ↑ GH, ↑ IGF-1 (negative feedback).
    • Metabolic: Hyperglycemia, ↑ Free Fatty Acids (FFAs), obesity.
    • Chronic glucocorticoid excess.
• Epiphyseal Closure: Primarily by estrogens, terminating linear growth.

⭐ Laron dwarfism results from GH receptor defects, leading to ↓ IGF-1 despite normal/high GH levels, causing severe short stature but often with normal intelligence and longevity features similar to calorie restriction models due to low IGF-1 signaling. This highlights IGF-1's crucial role in mediating GH's growth effects and the distinct consequences of GH resistance versus GH deficiency. The condition is autosomal recessive and more common in consanguineous populations. Treatment involves recombinant IGF-1 therapy, which can improve growth if started early. This contrasts with pituitary dwarfism (GH deficiency), where GH replacement is effective. Understanding Laron syndrome underscores the importance of the entire GH-IGF-1 axis, not just GH levels, in assessing growth disorders. The characteristic facial features include a prominent forehead, saddle nose, and small chin. Patients may also exhibit hypoglycemia in infancy due to unopposed insulin action (as GH's diabetogenic effects are absent) and reduced muscle mass. Despite low IGF-1, some cellular processes might be affected differently, leading to ongoing research into the broader implications of this pathway on aging and metabolism. The discovery of Laron syndrome was pivotal in elucidating the physiological role of IGF-1.

IGFs & Binding Proteins - Growth's Go-Betweens

• Insulin-like Growth Factors (IGFs/Somatomedins): Mediate GH's anabolic effects.
  • IGF-1 (Somatomedin C): GH-dependent. Liver (main), local tissues. Key for postnatal growth.
  • IGF-2 (Somatomedin A): Largely GH-independent. Crucial for fetal development.
  • Actions: ↑protein synthesis, ↑cell proliferation & differentiation. Weak insulin-like activity.
• IGF Binding Proteins (IGFBPs): Family of 6 (IGFBP-1 to -6).
  • IGFBP-3: Most abundant (≈75% of circulating IGFs). Forms ternary complex with IGF & Acid-Labile Subunit (ALS). GH stimulates IGFBP-3 & ALS production.
  • Functions: Prolong IGF half-life, transport IGFs, modulate IGF bioavailability & activity.
  • IGFBP-1: Levels ↑ during fasting/hypoglycemia, ↓ by insulin.

⭐ IGF-1 levels are a key diagnostic marker for GH deficiency and acromegaly, reflecting integrated GH secretion over time rather than pulsatile GH release.

GH Pathophysiology - Size Matters Clinically

• GH Deficiency (GHD):

  • Causes: Congenital, pituitary tumors, trauma.
  • Children: Dwarfism (↓growth velocity < 4 cm/yr), delayed puberty, hypoglycemia.
  • Adults: ↓Lean mass, ↑adiposity, ↓bone density, ↓QoL, ↑CV risk.
  • Diagnosis: ↓IGF-1, ↓IGFBP-3; provocative tests (ITT gold standard), peak GH < 5-10 ng/mL.

• GH Excess (Usually Pituitary Adenoma):

  • Gigantism (Children): ↑Linear growth before epiphyseal fusion.
  • Acromegaly (Adults): Coarse facies, prognathism, large hands/feet (spade-like), organomegaly (cardiomyopathy), DM, HTN.
  • Diagnosis: ↑IGF-1 (best initial); OGTT: GH not suppressed.

  ⭐ Acromegaly diagnosis: GH fails to suppress < 1 ng/mL (or < 0.4 ng/mL with ultrasensitive assays) after 75g OGTT.

• Laron Syndrome (GH Insensitivity):

  • Autosomal Recessive GH receptor (GHR) defect.
  • Features: Severe dwarfism, ↑GH, ↓IGF-1.
  • 📌 L.A.R.O.N: Low IGF-1, Autosomal Recessive, Often ↑GH, No response.

High‑Yield Points - ⚡ Biggest Takeaways

• Growth Hormone (GH) is secreted by anterior pituitary somatotrophs; regulated by GHRH (stimulates) and Somatostatin (inhibits).
• IGF-1 (Somatomedin C), mainly from the liver, mediates most of GH's anabolic and growth-promoting effects.
• GH exhibits pulsatile secretion, with peak levels during deep sleep (Stage N3).
• Excess GH leads to Gigantism in children and Acromegaly in adults.
• GH deficiency or insensitivity causes Dwarfism; Laron dwarfism is due to defective GH receptors.
• Direct GH effects include lipolysis and diabetogenic (anti-insulin) actions, increasing blood glucose.
• Ghrelin also stimulates GH secretion directly from the pituitary and via GHRH neurons.