GROWTH HORMONE PHYSIOLOGY

1. Introduction

• Costanzo Physiology, 7th Edition

2. Chemistry and Structure

• GH is synthesized in the somatotrophs, which are specialized cells of the anterior pituitary gland. These cells are distributed throughout the anterior pituitary.
• Human GH is a straight-chain polypeptide containing 191 amino acids, with 2 internal disulfide bridges.
• Like other peptide hormones, GH is initially synthesized as a larger precursor called a "prehormone". During processing through the endoplasmic reticulum and Golgi system, several small peptides are cleaved off.
• GH exists in at least three molecular forms in the circulation. The predominant form has a molecular weight of approximately 22,000 daltons (22 kDa).
• GH is structurally similar to two other hormones: prolactin (198 amino acids, 3 disulfide bridges, 75% homology with GH) and human placental lactogen (191 amino acids, 2 disulfide bridges, 80% homology). These three hormones belong to the same gene family.
• The gene for GH is a member of this family of genes for related peptides.
• Costanzo Physiology, 7th Edition; Medical Physiology (Boron & Boulpaep)

3. Secretion and Secretory Pattern

3.1 Pulsatile Secretion

3.2 Sleep and Secretion

3.3 Age-Related Changes in Secretion

• Secretion increases steadily from birth into early childhood.
• During childhood, secretion remains relatively stable at a moderate level.
• At puberty, there is an enormous secretory burst - induced by estrogen in females and testosterone in males. This puberty-related GH surge is responsible for the well-known pubertal growth spurt (increased frequency AND magnitude of secretory pulses).
• After puberty, GH secretion declines to a stable level.
• In senescence (old age), secretory rates and pulsatility decline to their lowest levels.
• Costanzo Physiology, 7th Edition

4. Regulation of GH Secretion

4.1 Hypothalamic Hormones

• Produced in the arcuate nucleus of the hypothalamus.
• Released into the hypophyseal portal blood, reaches the anterior pituitary, and binds to GHRH receptors (GHRHR) on somatotrophs.
• Activates adenylyl cyclase (via Gs protein), raising intracellular cAMP, which increases intracellular Ca²+ and triggers GH release.
• The pulsatile pattern of GH secretion is primarily driven by pulsatile GHRH secretion.

• A 14-amino acid neuropeptide produced in the periventricular region of the hypothalamus.
• Acts as a potent inhibitor of GH secretion by blocking the action of GHRH on somatotrophs.
• Binds to SSTR (a GPCR) on somatotrophs, activates Gαi, inhibits adenylyl cyclase, lowers cAMP and Ca²+, thus reducing GH release.
• When somatotrophs are exposed to both GHRH and SS simultaneously, the inhibitory action of SS prevails.
• SS is also made in pancreatic islet delta cells and GI tract D cells, where it plays additional roles.

• A peptide hormone produced mainly by endocrine cells in the gastric fundus (stomach), with smaller amounts from the hypothalamic arcuate nucleus.
• Released during fasting and appears to be involved in postmeal stimulation of GH secretion.
• Binds to GHSR1a (GH Secretagogue Receptor 1a).
• Infusion of ghrelin markedly increases GH secretion and is also orexigenic (stimulates appetite), contributing to body mass regulation.
• Medical Physiology (Boron & Boulpaep)

4.2 Factors Affecting GH Secretion

• Costanzo Physiology, 7th Edition

4.3 Negative Feedback Control

1. Long-loop feedback: IGF-1 (produced in liver in response to GH) feeds back to the hypothalamus and pituitary to decrease GHRH and increase somatostatin, thereby suppressing further GH secretion.
2. Short-loop feedback: GH itself feeds back on the hypothalamus to reduce its own secretion.
3. Ultra-short loop: GHRH and SS interact locally within the hypothalamus.

• Costanzo Physiology, 7th Edition; Medical Physiology

5. Mechanism of GH Action - The IGF-1 Axis

5.1 GH Receptor and Signal Transduction

• GH binds to a specific GH receptor (GHR) on target cells.
• GHR is a member of the cytokine receptor superfamily. GH simultaneously binds to two GHR molecules, causing receptor dimerization.
• This activates JAK2 (Janus kinase 2), which leads to phosphorylation of STAT proteins (STAT5b).
• Phosphorylated STAT5b enters the nucleus, acts as a transcription factor, and stimulates the expression of IGF-1 and other GH target genes.

5.2 IGF-1 (Insulin-Like Growth Factor-1) - The Key Mediator

• GH exerts most of its growth-promoting effects indirectly through stimulating the production of IGF-1 (also called Somatomedin C) in the liver and other target tissues (muscle, cartilage, bone).
• IGF-1 is structurally similar to insulin - it shares three domains (A, B, C) with insulin, but unlike insulin, the C peptide is NOT cleaved from IGF-1 during processing.
• IGF-1 acts via a specific receptor tyrosine kinase (IGF1R), structurally related to the insulin receptor (two extracellular alpha chains + two transmembrane beta chains with intrinsic tyrosine kinase activity).
• Over 90% of plasma IGF-1 is bound to IGF-binding proteins (IGFBPs), primarily made in the liver. These maintain a relatively stable plasma level of IGF-1 despite the pulsatile GH secretion. The plasma IGF-1 level effectively integrates pulsatile GH secretion over 24 hours.
• IGF-1 can act:
  • Endocrine - reaches target tissues via the bloodstream (mainly hepatic secretion).
  • Paracrine - acts on neighboring cells in the same tissue.
  • Autocrine - acts on the same cell that secreted it.
• Medical Physiology (Boron & Boulpaep)

6. Physiological Actions of Growth Hormone

6.1 Effects on Linear Bone Growth (Skeletal Effects)

• GH promotes longitudinal bone growth by stimulating the epiphyseal growth plates (cartilage plates).
• This is largely mediated by IGF-1, which promotes:
  • Chondrocyte proliferation and differentiation in growth plates.
  • Bone matrix formation (collagen synthesis, osteoblast activity).
• Once epiphyseal plates close at puberty, GH can no longer cause bone elongation (hence, GH excess after puberty causes acromegaly, not gigantism).

6.2 Effects on Protein Metabolism (Anabolic Effects)

• GH is strongly anabolic for protein:
  • Increases amino acid uptake into cells.
  • Stimulates protein synthesis (increases ribosomal activity).
  • Decreases protein catabolism (anti-catabolic).
• Results in increased lean body mass (more muscle, less fat).
• These effects are largely mediated by IGF-1 acting on muscle and connective tissue.

6.3 Effects on Carbohydrate Metabolism (Diabetogenic Effects)

• GH has anti-insulin (diabetogenic) effects:
  • Decreases glucose uptake by peripheral tissues.
  • Decreases glucose oxidation.
  • Promotes hepatic gluconeogenesis.
  • Causes insulin resistance in muscle and adipose tissue.
• Net result: raises blood glucose levels (opposite to insulin).
• Excess GH can cause secondary diabetes mellitus (sometimes called "pituitary diabetes").
• This is a direct action of GH, not mediated by IGF-1.

6.4 Effects on Fat Metabolism (Lipolytic Effects)

• GH stimulates lipolysis - breakdown of stored triglycerides in adipose tissue.
• Releases free fatty acids and glycerol into the blood.
• These free fatty acids serve as an alternative fuel source, sparing glucose for vital organs like the brain.
• GH decreases body fat mass.

6.5 Effects on Organ Growth

• GH promotes growth of virtually all organs and tissues including:
  • Skeletal muscle
  • Heart, liver, kidneys, spleen (organomegaly)
  • Skin and connective tissue
  • The GI tract
• The lengthening of long bones is specific to pre-pubertal life; post-pubertal GH excess causes thickening of bones and soft tissues.

6.6 Other Actions

• Immune stimulation - GH is an immune stimulant (important bridge between endocrine and immune systems).
• Sodium and water retention - GH mildly promotes sodium retention.
• Mineral homeostasis - promotes calcium absorption from the gut and retention in bone; increases phosphate reabsorption in the kidney.
• Medical Physiology (Boron & Boulpaep); Costanzo Physiology, 7th Edition

7. Growth Hormone and Other Hormones in Growth

• Medical Physiology (Boron & Boulpaep)

8. Clinical Correlations (Disorders of GH)

8.1 GH Deficiency in Childhood - Pituitary Dwarfism

• Children with GH deficiency are born of normal size (GH is not required for fetal growth; that is driven by insulin and IGF-2).
• They subsequently fall behind their peers in stature.
• The deficiency results in pituitary dwarfism - short stature with normal body proportions.
• Classic example: General Tom Thumb (Charles Stratton), who had GH deficiency and reached an adult height of approximately 1.0 m.

8.2 GH Excess in Childhood - Gigantism

• GH-secreting pituitary adenoma before epiphyseal closure causes gigantism (excessive linear growth).
• Example: The Alton Giant had a GH-secreting pituitary tumor from early childhood and reached an adult height of over 2.7 m.

8.3 GH Excess in Adults - Acromegaly

• GH excess after puberty (after epiphyseal closure) causes acromegaly (from Greek: akron = extremity, megas = large).
• Features: progressive thickening and coarsening of bones and soft tissues of the face (frontal bossing, enlarged nose, jaw prognathism), hands, and feet; macroglossia, skin thickening.
• Complications: joint deformity, hypertension, cardiomegaly (heart failure), pulmonary insufficiency, glucose intolerance.
• If untreated, acromegaly significantly increases morbidity and shortens life expectancy.

8.4 GH Deficiency in Adults

• Does not cause major clinical illness.
• However, GH replacement in deficient adults leads to increased lean body mass, decreased body fat, and improved sense of well-being.
• Medical Physiology (Boron & Boulpaep)

9. Assessment of Growth Hormone Status

Laboratory

• Plasma GH levels alone are not reliable due to pulsatile secretion (a single random GH level may be very low even in normal individuals, between pulses).
• Plasma IGF-1 is a better index as it integrates pulsatile GH secretion over 24 hours and remains relatively stable.
• Stimulation tests (e.g., insulin-induced hypoglycemia, arginine infusion) are used to test GH reserve.
• Suppression test (oral glucose tolerance test - OGTT): In normal individuals, glucose ingestion suppresses GH to very low levels. In acromegaly, GH is NOT suppressed by glucose.

10. Summary Diagram - GH Axis

HYPOTHALAMUS
    |                    |
  GHRH (+)          Somatostatin (-)
  Ghrelin (+)
    |                    |
    ↓                    ↓
ANTERIOR PITUITARY (Somatotrophs)
    |
    ↓
GROWTH HORMONE (GH)
    |
    +----→ Direct effects (carbohydrate ↑ glucose, lipolysis)
    |
    ↓
TARGET TISSUES (especially Liver, Muscle, Bone, Cartilage)
    |
    ↓
IGF-1 (Insulin-like Growth Factor-1)
    |
    +----→ Bone lengthening (epiphyseal plates)
    +----→ Protein synthesis ↑ (muscle growth)
    +----→ Cell proliferation
    |
    ↓
NEGATIVE FEEDBACK ←── IGF-1 & GH feed back to hypothalamus & pituitary

11. Conclusion

References

1. Costanzo LS. Physiology, 7th Edition. Elsevier; 2022. pp. 388-400.
2. Boron WF, Boulpaep EL. Medical Physiology, 3rd Edition. Elsevier; 2017. Chapter 48.
3. Brunton LL, et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition. McGraw-Hill; 2023. Chapter on Growth Hormone and Prolactin.
4. Goldman L, Schafer AI. Goldman-Cecil Medicine, 27th Edition. Elsevier; 2024.