The GH-IGF Axis

Henry's Clinical Diagnosis and Management by Laboratory Methods - GH-IGF axis showing the hypothalamus, pituitary, and liver as the three key sites where GH deficiency can originate.

Level 1: Hypothalamic Causes (Tertiary Deficiency)

• Congenital/Idiopathic GHRH deficiency - the most common cause in children; reduced GHRH secretion from the hypothalamic nuclei (arcuate and paraventricular) with no identifiable structural lesion
• Hypothalamic tumors - craniopharyngioma is the classic culprit; also germinomas, gliomas, and ependymomas compressing the hypothalamus
• Head trauma / traumatic brain injury (TBI) - disrupts hypothalamic-pituitary connections; estimated 10-30% of TBI patients develop GHD
• Cranial irradiation - radiation damage to the hypothalamus; GHD is dose-dependent
• Infiltrative diseases - histiocytosis X (Langerhans cell histiocytosis), sarcoidosis, hemochromatosis, lymphocytic hypophysitis
• Infections - encephalitis, meningitis, tuberculosis
• Pituitary stalk disruption - any lesion compressing the pituitary stalk severs GHRH delivery ("stalk effect"); paradoxically prolactin rises while all other anterior pituitary hormones fall

Level 2: Pituitary Causes (Secondary Deficiency)

• Idiopathic GH deficiency (isolated GHD) - the most common form of nonfamilial deficiency; somatotroph dysfunction without identifiable cause; accounts for the majority of hypopituitarism cases in children
• Pituitary adenoma - the most common etiology in adult-onset GHD; destroys or compresses normal somatotrophs
• Craniopharyngioma - also directly compresses pituitary tissue (>70% of children with craniopharyngioma present with GHD)
• Congenital pituitary aplasia or hypoplasia - complete or partial failure of pituitary gland development (including septo-optic dysplasia)
• Pituitary apoplexy - sudden hemorrhage into or infarction of the pituitary gland; can arise spontaneously or in a pre-existing adenoma; causes acute hypopituitarism
• Sheehan syndrome - postpartum pituitary ischemic necrosis from obstetric hemorrhage and shock; presents as failure to lactate, then progressive panhypopituitarism
• Surgery / radiotherapy - postsurgical disruption of the hypothalamic-pituitary axis
• Genetic mutations - mutations in transcription factors (PIT1, PROP1) that control pituitary development result in combined pituitary hormone deficiency (CPHD)
• Panhypopituitarism (Simmonds syndrome) - loss of all anterior pituitary hormones including GH; patients are pale, lethargic, with dry skin and low BP

Level 3: Liver/Peripheral Causes (Primary IGF-1 Deficiency / GH Resistance)

• Laron syndrome (Laron dwarfism) - mutations in the GH receptor (GHR) gene → the receptor is defective or absent → GH cannot bind → no IGF-1 is produced by the liver despite high GH levels. Treatment with exogenous GH is ineffective; these patients require recombinant IGF-1 (mecasermin)
• Post-receptor signaling defects - mutations in the GH receptor signaling pathway (e.g., JAK2/STAT5 pathway) downstream of the receptor
• Neutralizing antibodies to GH - immune-mediated blockade of GH before it can act on the liver
• IGF-1 gene defects - rare mutations in the IGF-1 gene itself prevent production
• Severe liver disease - the liver is the primary source of circulating IGF-1; hepatic failure reduces IGF-1 synthesis even with normal GH levels
• Malnutrition / chronic illness / undernutrition - these states suppress hepatic IGF-1 production independently of GH levels
• IGF-1 receptor deficiency - the most distal defect; IGF-1 is produced but cannot signal in target tissues (e.g., African pygmy phenotype - normal/elevated GH and IGF-1 but receptor unresponsive)

Clinical Identification - Signs and Symptoms of GH Deficiency

In Children:

In Adults:

Key diagnostic clue: In hypothalamic and pituitary causes, serum GH is low. In liver/GH-resistance causes (e.g., Laron syndrome), serum GH is high but IGF-1 is low - this is the distinguishing laboratory finding.

• Costanzo Physiology, 7th Ed. - Pathophysiology of Growth Hormone section
• Goldman-Cecil Medicine - Growth Hormone Deficiency (Pathobiology, Clinical Manifestations)
• Bradley & Daroff's Neurology in Clinical Practice - Abnormalities of Anterior Pituitary Function
• Textbook of Family Medicine, 9e - GH Deficiency manifestations
• Guyton & Hall Medical Physiology - IGF-1 and Laron Syndrome
• Katzung's Basic & Clinical Pharmacology, 16th Ed. - GH Deficiency and Mecasermin

How to Identify Which Level is Causing GH Deficiency

Step 1 - Baseline Blood Tests (First Draw)

Key pattern already emerges here:

• Low GH + Low IGF-1 → problem is at hypothalamus OR pituitary (can't yet distinguish)
• High/Normal GH + Low IGF-1 → problem is at the liver/receptor level (GH resistance)

Step 2 - The GHRH Stimulation Test (Separates Hypothalamus from Pituitary)

This single test cleanly separates hypothalamic from pituitary GH deficiency. Repetitive GHRH administration can even therapeutically restore GH secretion in purely hypothalamic cases.

Step 3 - Gold Standard Provocative Tests (Confirm GH Deficiency Itself)

Step 4 - The IGF-1 Generation Test (Confirms Liver/GH Resistance)

Step 5 - Imaging (Find the Structural Cause)

The Complete Decision Algorithm

Child with short stature + low growth velocity
            ↓
Measure GH + IGF-1 + IGFBP-3
            ↓
    ┌────────────────────────────────────┐
    │                                    │
Low GH + Low IGF-1              High/Normal GH + Low IGF-1
    ↓                                    ↓
Do GHRH stimulation test         IGF-1 Generation Test + GHBP
    ↓                                    ↓
GH rises? → HYPOTHALAMIC         No rise + Low GHBP → LARON
GH no rise? → PITUITARY          No rise + Normal GHBP → post-receptor defect
    ↓
Confirm with ITT or Arginine test (×2)
    ↓
MRI brain/pituitary for structural cause

Summary Table - Distinguishing the 3 Levels

• Primary = Liver/target tissue failure (GH resistance)
• Secondary = Pituitary failure
• Tertiary = Hypothalamic failure

Differentiating Primary, Secondary, and Tertiary GH Deficiency

The Logic: Work Down the Axis

Hypothalamus → GHRH → Pituitary → GH → Liver → IGF-1 → Growth

Tertiary defect = broken here ↑
Secondary defect =             broken here ↑
Primary defect =                            broken here ↑

Step 1 - Two Blood Tests Tell You Almost Everything

This single pattern already identifies primary (GH resistance) vs the other two.

Step 2 - The GHRH Stimulation Test (Separates Tertiary from Secondary)

Step 3 - Confirm Primary with the IGF-1 Generation Test

Step 4 - MRI to Find the Structural Cause

Full Summary in One Table

Quick Mental Shortcut

• High GH + Low IGF-1 = Primary (GH is screaming but the liver is deaf)
• Low GH + GHRH test fixes it = Tertiary (pituitary was just waiting for the signal)
• Low GH + GHRH test does nothing = Secondary (pituitary is broken)

Step 3 - The IGF-1 Generation Test (Confirms Primary / GH Resistance)

When Do You Use This Test?

GH is HIGH or NORMAL + IGF-1 is LOW

The Problem It Detects

GH secreted → binds GH receptor on liver → liver produces IGF-1 → growth occurs

GH secreted ✓ → GH receptor BROKEN on liver ✗ → IGF-1 NOT produced → no growth

How the Test is Done

Reading the Result

Supporting Test - GH-Binding Protein (GHBP)

Variants of Primary GH Resistance

Why This Matters for Treatment

If primary GH resistance is confirmed - giving GH injections will do absolutely nothing. The liver cannot respond to GH, so IGF-1 will never be produced.

• Secondary and tertiary deficiencies respond to GH replacement
• Primary deficiency responds only to direct IGF-1 replacement

Summary of Step 3 in One Line

Inject high-dose GH for 4-7 days → if IGF-1 still doesn't rise + GHBP is low → the GH receptor on the liver is broken → Primary deficiency confirmed → treat with Mecasermin, NOT GH.

Mecasermin (Increlex)

What It Is

Who It Is For (Indications)

It can also stimulate linear growth in GH deficiency and idiopathic short stature, but it is less effective than GH replacement for those conditions, so GH is preferred when available.

How It Is Dosed

The Most Important Rule - Timing with Food

Must eat a carbohydrate-containing meal or snack within 20 minutes of each injection.

Expected Effect

• First year: Height velocity increases by approximately 4-5 cm/year above baseline
• After 2 years: Height SDS (standard deviation score) increases by about 0.5
• This is less than what GH replacement achieves in GH-deficient children (9-14 cm/year in year one), because IGF-1 alone does not trigger all the same anabolic pathways GH does

Side Effects

Contraindications

• Closed epiphyses - once growth plates are fused, there is no linear growth to stimulate, so using it for growth promotion is pointless
• Active or suspected cancer/neoplasia - IGF-1 is a potent growth factor and could accelerate tumor growth; stop if cancer develops during treatment

Pharmacokinetics (How the Body Handles It)

• Absorption: Virtually complete after subcutaneous injection
• Binding: More than 80% of circulating IGF-1 binds to a ternary complex with IGFBP-3 and the acid-labile subunit - this prolongs the half-life
• Half-life: Approximately 6 hours
• Metabolism: Both liver and kidney metabolize IGF-1

Quick Summary

Anterior Pituitary Hormones

• β-Lipotropin (β-LPH) - secreted alongside ACTH from the same POMC precursor; exact physiologic role is still not fully established

Important note about Prolactin: It is the only anterior pituitary hormone under predominant inhibitory control from the hypothalamus (via dopamine). All others are primarily stimulated by their hypothalamic releasing hormones. This is why a pituitary stalk cut causes all anterior hormones to fall except prolactin, which rises.

Posterior Pituitary Hormones

Critical concept: The posterior pituitary does NOT manufacture its own hormones. ADH and oxytocin are produced in hypothalamic neurons (supraoptic and paraventricular nuclei), travel down axons into the posterior pituitary, and are stored there until released into the bloodstream. The posterior pituitary is essentially a storage and release depot, not a secretory gland.

The Complete Picture Side by Side

Easy Memory Mnemonics

• FSH
• LH
• ACTH
• TSH
• Prolactin
• iGF (via GH)
• GH

• ADH (antidiuretic hormone)
• Oxytocin

Surfaces of the Palatine Tonsil

1. Medial Surface (Free Surface)

• This is the surface that faces into the oropharynx - it is visible when you open your mouth
• It is covered by stratified squamous epithelium (the same mucosa lining the oral cavity)
• It presents a pitted appearance - the pits are the openings of the tonsillar crypts
• These pits (usually 10-15 in number) lead into a system of blind-ending, often highly branching crypts that extend through the whole thickness of the tonsil
• The walls of the crypts are lined by epithelium that is heavily infiltrated by lymphocytes - so densely that the epithelial lining may be difficult to see microscopically
• The crypts trap debris, bacteria, and food particles - this is why the tonsil acts as a first-line immunological defense

2. Deep (Lateral) Surface

• This surface faces outward toward the pharyngeal wall and is not exposed to the pharyngeal lumen
• It is covered by a fibrous tissue hemicapsule (the tonsillar capsule)
• The capsule can be easily separated from the underlying superior constrictor muscle during tonsillectomy - this plane is the surgical dissection plane
• An important surgical landmark here is the external palatine vein (also called the paratonsillar vein) - it descends from the soft palate, runs lateral to the tonsillar hemicapsule, then pierces the pharyngeal wall. Hemorrhage from this vessel is a recognised complication of tonsillectomy.

Histological View

• SSE = Stratified Squamous Epithelium covering the free (medial) surface
• TC = Tonsillar Crypts - deep invaginations of the surface epithelium
• L = Lymphoid tissue (nodules with germinal centers)
• MG = Mucous glands at the base of the crypts
• Beneath all of this lies the submucosa of dense connective tissue, continuous with the capsule on the deep surface

Tonsil Bed Borders (Surgical Anatomy)

Size and Lifespan

• At puberty: approximately 10-15 mm transverse diameter, 20-25 mm vertical
• The tonsil begins to atrophy at puberty
• By old age, only a small remnant of lymphoid tissue remains

Summary: Two Surfaces at a Glance

Wheal and Flare - The Triple Response of Lewis

How It Is Triggered

Context 1 - Physical Injury (Dermatographism)

Context 2 - Allergic/Immunological (Skin Prick Test)

• The patient already has allergen-specific IgE bound to FcεRI receptors on dermal mast cells
• The allergen cross-links two adjacent IgE molecules on the mast cell surface
• This triggers mast cell degranulation - explosive release of preformed granule contents
• Histamine is the primary mediator of the wheal and flare response
• Other mediators released: tryptase, chymase, PGI₂, nitric oxide, leukotrienes

The Three Components

Component 1 - Red Reaction (within seconds)

• A small spot of reddening appears within a few seconds directly at the site of injury or injection
• Maximal at about 1 minute
• Caused by direct vasodilation of local capillaries and venules - a direct effect of histamine on capillary walls
• Mediated by H1 receptor activation → Ca²⁺-dependent activation of eNOS in endothelial cells → NO production → rapid vasodilation
• Independent of innervation - persists even after complete denervation

Component 2 - Flare (within 1-2 minutes)

• A bright red flush spreading ~1 cm beyond the original red spot
• Caused by arteriolar dilation in the surrounding skin
• The mechanism is the axon reflex - this is unique to the flare:

1. Injury stimulates a sensory C-fiber nerve ending in the skin
2. An action potential travels orthodromically toward the spinal cord
3. At the branch point of the nerve fiber, the signal also travels antidromically (backward) down collateral branches to nearby arterioles
4. These collateral branches release Substance P and CGRP (calcitonin gene-related peptide) from their terminals
5. Substance P and CGRP cause arteriolar dilation → the flare
6. This is why the flare is absent in:
   • Locally anesthetized skin (nerve blocked)
   • Denervated skin after sensory nerves have degenerated
   • BUT it IS present immediately after nerve block or section above the injury site (nerve still intact distally)

Component 3 - Wheal (within 1-5 minutes)

• A raised, pale, soft swelling at the exact injection/injury site
• This is edema - fluid and plasma proteins leaking out of the circulation into the skin
• Caused by increased capillary and venular permeability:
  1. Histamine binds H1 receptors on venular endothelial cells
  2. Activates RhoA/ROCK pathway → contracts endothelial cells → gaps open between them
  3. Plasma proteins and fluid leak through these gaps into the tissue → edema = wheal
• Substance P also contributes to the wheal by increasing vascular permeability
• The wheal replaces the initial red reaction as it develops

Summary of All Three Components

Key Clinical Points

• A wheal >3 mm greater than negative control = positive test
• It confirms allergen-specific IgE is present on dermal mast cells
• Antihistamines must be stopped before testing because they suppress the wheal and flare response:
  • First-generation antihistamines (e.g., diphenhydramine): suppress for 48-72 hours
  • Second-generation antihistamines (e.g., cetirizine, loratadine): suppress for 3-10 days
  • Tricyclic antidepressants (e.g., amitriptyline): suppress for up to 7 days

• Mast cell cytokines (TNF) upregulate endothelial adhesion molecules (E-selectin, ICAM-1)
• Influx of eosinophils, basophils, neutrophils, Th2 helper T cells
• Peaks at ~24 hours then subsides
• Responsible for the prolonged inflammation in conditions like chronic asthma and atopic dermatitis

• Urticaria (hives) - disseminated wheal-and-flare across the skin from systemic allergen exposure
• Dermographism - exaggerated physical wheal and flare on stroking the skin

How Inflammation Happens

Recognition → Recruitment → Removal → Regulation → Repair

Step 1 - Recognition of the Injurious Agent

• Toll-like receptors (TLRs) - detect bacterial cell wall components (LPS, peptidoglycan), viral RNA/DNA
• NOD-like receptors (NLRs) - detect intracellular pathogens
• Scavenger receptors - detect dead/necrotic cells
• Circulating plasma proteins - recognize microbes that enter the bloodstream

Step 2 - Vascular Changes (The Visible Signs of Inflammation)

2a. Vasodilation → Heat and Redness

• Histamine (from mast cells) and nitric oxide act on postcapillary venules
• Vessels dilate → blood flow increases dramatically
• This produces rubor (redness) and calor (heat)

2b. Increased Vascular Permeability → Swelling

• Histamine, bradykinin, leukotrienes bind endothelial H1 receptors
• Activates RhoA/ROCK pathway → endothelial cells contract and pull apart
• Gaps form between adjacent cells → plasma proteins and fluid pour out
• Rapid and short-lived (15-30 minutes)

• Burns, microbial toxins, activated neutrophils directly damage the endothelium
• Endothelial cells die and detach, creating large leaks
• Sustained for hours to days

Step 3 - Leukocyte Recruitment (The Cellular Response)

Phase 1 - Margination

• Normal blood flow keeps cells in the central axial column
• As blood slows, leukocytes drift to the vessel wall and start rolling along the endothelium

Phase 2 - Rolling (Selectin-mediated)

• Activated endothelium expresses E-selectin and P-selectin (induced by TNF, IL-1, histamine)
• Leukocytes carry sialylated carbohydrate ligands (e.g., sialyl-Lewis X) that bind selectins
• This creates a loose, tethering and rolling interaction - like velcro at low strength

Phase 3 - Firm Adhesion (Integrin-mediated)

• Chemokines (e.g., IL-8/CXCL8) are displayed on the endothelial surface
• They activate leukocyte integrins (LFA-1, MAC-1) → conformational change → high-affinity binding
• Integrins bind their endothelial ligands ICAM-1 and VCAM-1 (upregulated by TNF and IL-1)
• Leukocyte now stops firmly on the endothelial surface

Phase 4 - Transmigration / Diapedesis

• Leukocyte squeezes between endothelial cells (paracellular) at intercellular junctions
• Guided by CD31 (PECAM-1) homotypic interactions between the leukocyte and endothelial cell
• Once through the vessel wall, it crosses the basement membrane using collagenases

Phase 5 - Chemotaxis

• Now in the tissue, the leukocyte follows a gradient of chemoattractants toward the source:
  • Bacterial products (e.g., fMLP - formyl-met-leu-phe)
  • C5a (complement fragment)
  • Leukotriene B4 (LTB4)
  • IL-8 / CXCL8 (cytokine chemokine)
• The leukocyte reorganizes its cytoskeleton, extends filopodia at the leading edge, and migrates toward the highest concentration

Step 4 - Elimination (Phagocytosis and Killing)

1. Opsonins (IgG antibodies and C3b complement) coat the target
2. Leukocyte Fc receptors and complement receptors recognize the coated target
3. Pseudopods engulf it into a phagosome
4. Phagosome fuses with lysosome → phagolysosome
5. Killing by:
   • Reactive oxygen species (ROS) via NADPH oxidase (respiratory burst)
   • Nitric oxide (NO) via iNOS
   • Lysosomal enzymes (elastase, cathepsins, lysozyme)
   • Defensins - antimicrobial peptides

Key Chemical Mediators

Outcomes of Acute Inflammation

Injurious agent eliminated?
        ↓
      YES → Resolution → Tissue repair → Full restoration
        ↓
       NO → Persistent injury
        ↓
   Chronic inflammation (macrophages, lymphocytes, fibrosis)
        ↓
   OR Abscess formation (walled-off pus)
        ↓
   OR Systemic spread → Sepsis

The Classic 5 Signs (Cardinal Signs)