Growth Hormone - Detailed Endocrine Physiology

1. OVERVIEW

2. HYPOTHALAMIC CONTROL - THE AXIS

HYPOTHALAMUS
    │
    ├──► Arcuate nucleus → GHRH (43-aa peptide) ──────────────► (+) GH secretion
    │
    └──► Periventricular region → Somatostatin (SS-14) ─────► (−) GH secretion

        ↑ Also: Ghrelin (28-aa peptide from STOMACH) ────────► (+) GH secretion
                [via GH secretagogue receptor 1a, GHSR1a]

GHRH Mechanism (at somatotrophs)

GHRH → GHRHR (GPCR) → Gαs → Adenylyl cyclase → ↑ cAMP
                                        │
                               ↓        ▼
                           ↑ [Ca²⁺]i  PKA activation
                               │        │
                               └────────┴──► GH SYNTHESIS + RELEASE

Somatostatin Mechanism (at somatotrophs)

SS → SS receptor (GPCR) → Gαi → ↓ Adenylyl cyclase → ↓ cAMP
                                                         │
                                                   ↓ [Ca²⁺]i
                                                         │
                                                   ↓ GH RELEASE (inhibited)

3. HYPOTHALAMIC-PITUITARY-TARGET TISSUE DIAGRAM

The arcuate nucleus releases GHRH; the periventricular region releases somatostatin (SS). GHRH raises cAMP and Ca²+ in somatotrophs to release GH; SS inhibits adenylyl cyclase and lowers Ca²+ to block GH release.

4. PULSATILE SECRETION AND DIURNAL VARIATION

Key point: The largest secretory burst occurs within 1 hour of falling asleep, during slow-wave sleep (stages III and IV). Over 70% of total daily GH secretion occurs during these nocturnal pulses. The pattern depends on sleep-wake cycles, not light-dark cycles.

Lifecycle Pattern of GH Secretion

Birth ──► Childhood (stable) ──► Puberty (massive surge) ──► Adulthood (stable, lower) ──► Senescence (lowest)
                                        ↑
                            Estrogen (females) / Testosterone (males)
                            increase frequency + magnitude of pulses
                            → GROWTH SPURT of puberty

5. FACTORS AFFECTING GH SECRETION

6. FEEDBACK CONTROL LOOPS

Feedback Flowchart

GH secretion ──► ↑ Circulating GH
                        │
          ┌─────────────┴──────────────────────┐
          │                                    │
    Direct SHORT LOOP:                    Stimulates LIVER
    GH → antagonizes GHRH                  → produces IGF-1
    release from hypothalamus                   │
                                   LONG LOOP with IGF-1:
                                   1) IGF-1 directly inhibits somatotroph
                                   2) IGF-1 suppresses GHRH release
                                   3) IGF-1 stimulates SS secretion
                                   → ALL THREE ↓ GH secretion

7. GH RECEPTOR AND SIGNAL TRANSDUCTION

• Large extracellular domain
• Single transmembrane domain
• Large intracellular domain associated with JAK2 kinase

Receptor Activation

One GH molecule has TWO receptor-binding domains:
   GH binds first receptor ──► second receptor recruited ──► HOMODIMERIZATION
                                                                    │
                                                           Essential for activation

JAK2-STAT Signaling (Primary Pathway)

GH–GHR dimer
      │
      ▼
JAK2 transphosphorylation (tyrosine kinase activation)
      │
   ┌──┴──────────────────────────────────────────────┐
   │                                                  │
STATs (inactive monomers) phosphorylated           IRS-1/IRS-2 phosphorylated
→ STAT1 dimer → SIE element → gene transcription     → Insulin-like metabolic effects
→ STAT5 → GLE-1/GLE-2 elements
→ c-fos via SRE/SRF/TCF                          Also: PLC → DAG → PKC
                                                        Ca²+ channels open
                                                        MAP kinase activated
                                                        PLA₂ activated

8. ACTIONS OF GROWTH HORMONE

1. Direct effects on target cells via GH receptor (JAK2-STAT)
2. Indirect effects via IGF-1 (somatomedin C) produced mainly by the liver

Complete Actions Flowchart

                    GROWTH HORMONE
                         │
          ┌──────────────┴──────────────────┐
     DIRECT EFFECTS                   INDIRECT (via IGF-1)
          │                                 │
   ┌──────┼──────────┐           ┌──────────┴──────────┐
   │      │          │       BONE GROWTH           SOFT TISSUE GROWTH
   ▼      ▼          ▼           │                     │
MUSCLE   FAT      LIVER      Chondrocytes         DNA/RNA/protein
 │         │        │        proliferate          synthesis in
↓Glucose ↑Lipolysis ↑Gluco-  Epiphyseal plates   all organs
 uptake    ↑FFA    neogenesis  widen → linear      ↑ lean body mass
 (insulin   →↑BG    ↑BG       growth (+before      ↑ organ size
resistance)                    puberty closure)

Metabolic Effects Summary

Protein/Electrolyte Effects:

• Positive nitrogen and phosphorus balance
• ↓ Blood urea nitrogen and plasma amino acids (taken up for synthesis)
• ↑ Gastrointestinal Ca²+ absorption
• ↓ Na+ and K+ excretion (diverted to growing tissues)
• ↑ Plasma phosphorus
• ↑ Urinary excretion of 4-hydroxyproline (marker of collagen turnover in growth)

9. IGF-1 (SOMATOMEDIN C) - The Key Mediator

GH → acts on LIVER (primarily) and other tissues (kidney, muscle, cartilage, bone)
                 │
                 ▼
         IGF-1 PRODUCED
                 │
    ┌────────────┼───────────────────────┐
    │            │                      │
Binds IGF-1   Binds to                Circulates
receptor      IGFBPs (6 types)        bound to IGFBP-3
(similar to   → prolongs half-life      (90% of circulating IGF-1)
insulin R,    → modulates activity
tyrosine
kinase)
    │
    ▼
EFFECTS:
- Linear bone growth (chondrocyte proliferation and differentiation)
- ↑ DNA, RNA, protein synthesis in virtually all tissues
- Insulin-like metabolic effects at high concentrations
   (can cause hypoglycemia)
- FEEDBACK: inhibits GH secretion (long loop)

• IGF-1: GH-dependent, mirrors GH secretion, mainly post-natal growth
• IGF-2: Less GH-dependent, important for fetal growth
• Both structurally similar to proinsulin, with A, B, C domains + unique D domain (C peptide NOT cleaved, unlike insulin)

10. COMPLETE REGULATORY FLOWCHART

╔═══════════════════════════════════════════════════════════════╗
║                    HYPOTHALAMUS                               ║
║   Arcuate nucleus → GHRH (+)    Periventricular → SS (−)     ║
╚══════════════╤════════════════════════════════╤══════════════╝
               │ Portal veins                  │ Portal veins
               ▼                               ▼
╔═══════════════════════════════════════════════════════════════╗
║              ANTERIOR PITUITARY (Somatotrophs)                ║
║   GHRH → cAMP ↑ → PKA → Ca²+ ↑ → GH release                 ║
║   SS → cAMP ↓ → Ca²+ ↓ → GH release inhibited               ║
║   Ghrelin (stomach) → GHSR1a → GH release (+)                ║
╚══════════════════════════╤════════════════════════════════════╝
                           │
                     GH released
                           │
          ┌────────────────┼─────────────────────────────┐
          ▼                ▼                             ▼
     SHORT-LOOP        TARGET TISSUES              LIVER + others
     FEEDBACK          (direct effects)           → IGF-1 produced
    GH → ↓GHRH    muscle/fat/liver/bone                 │
                  (insulin resistance,             LONG-LOOP FEEDBACK:
                  lipolysis, gluconeogenesis)     IGF-1 → ↑ SS
                  JAK2-STAT signaling             IGF-1 → ↓ GHRH
                                                  IGF-1 → direct ↓ pituitary

11. PATHOPHYSIOLOGY

GH Deficiency

Deficiency BEFORE puberty:
→ Pituitary dwarfism (growth failure, short stature)
→ Mild obesity, delayed puberty
→ Normal size at birth (GH not needed for fetal growth)

Deficiency AFTER puberty:
→ No major clinical illness
→ ↓ Lean body mass, ↑ body fat
→ Reduced sense of well-being
→ Treatment with recombinant GH restores lean mass, reduces fat

• GH levels are ELEVATED (normal pituitary)
• GH receptors are defective
• IGF-1 cannot be produced
• Treatment with GH is ineffective - must use recombinant IGF-1

Hypothalamus → ↓ GHRH secretion
Pituitary → Primary ↓ GH production
Liver → Failure to generate IGF-1
Receptor → GH receptor defect (Laron) or IGF-1 receptor defect

GH Excess

Before puberty (epiphyses OPEN):
→ GIGANTISM
→ Extraordinary height (Tom Thumb's inverse: Alton giant >2.7 m)
→ Linear + soft tissue growth

After puberty (epiphyses CLOSED):
→ ACROMEGALY
→ No increase in height (no linear growth)
→ Periosteal thickening: hands, feet, jaw, brow, skull
→ Soft tissue swelling, hirsutism
→ Enlarged viscera (heart, liver, spleen, GI tract)
→ Hypertension, joint deformity, pulmonary insufficiency, heart failure
→ Insulin resistance / secondary diabetes mellitus
→ 20-40% have concurrent hyperprolactinemia (mixed adenomas)
→ Most common cause: GH-secreting pituitary adenoma

12. CLINICAL CORRELATIONS

Key Points to Remember

1. GH is a 191-aa polypeptide from somatotrophs of anterior pituitary
2. Regulated by GHRH (+), SS (−), Ghrelin (+) from hypothalamus/stomach
3. Secreted in pulses - largest burst in stage III/IV sleep; >70% secreted nocturnally
4. Acts via JAK2-STAT pathway (cytokine receptor superfamily, homodimerization required)
5. Direct effects: diabetogenic (↑ blood glucose via insulin resistance, lipolysis, gluconeogenesis)
6. Indirect effects via IGF-1: anabolic, promotes linear growth via chondrocyte proliferation
7. Feedback: short loop (GH → ↓GHRH), long loop (IGF-1 → ↑SS, ↓GHRH, direct pituitary inhibition)
8. Deficiency before puberty → dwarfism; excess before puberty → gigantism; excess after puberty → acromegaly
9. Laron dwarfism = GH receptor defect → high GH, low IGF-1, GH treatment ineffective
10. GH peak secretion is at puberty (estrogen in females, testosterone in males)