====== Glucocorticoid Signaling Pathway ======

Glucocorticoids (e.g., cortisol, prednisone, dexamethasone) exert their effects primarily through intracellular receptor-mediated gene regulation.

They influence metabolism, immune response, and inflammation.

See drug class:
  * [[endocrine:drug_classes:corticosteroids|Corticosteroids]]

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===== Step 1 – Cell Entry =====

Glucocorticoids are lipid-soluble.

  * Diffuse freely across cell membranes
  * No surface receptor required

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===== Step 2 – Cytoplasmic Receptor Binding =====

Inside the cytoplasm:

  * Glucocorticoid binds to the glucocorticoid receptor (GR)
  * Receptor is normally bound to heat shock proteins (HSP90)
  * Binding causes conformational change
  * Heat shock proteins dissociate

Now activated GR–steroid complex forms.

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===== Step 3 – Nuclear Translocation =====

The activated glucocorticoid-receptor complex:

  * Translocates into the nucleus
  * Binds glucocorticoid response elements (GREs) on DNA

This alters gene transcription.

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===== Genomic Effects =====

==== Upregulated (Anti-Inflammatory Genes) ====

  * Annexin-1 (inhibits phospholipase A2)
  * IkB (inhibits NF-kB)
  * Anti-inflammatory proteins

==== Downregulated (Pro-Inflammatory Genes) ====

  * IL-1
  * IL-2
  * IL-4
  * IL-5
  * IL-6
  * TNF-α
  * COX-2
  * Adhesion molecules

Net effect:
  ↓ Inflammation
  ↓ Immune cell activation
  ↓ Eosinophil survival

Onset:
  Hours to days (requires gene transcription)

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===== Non-Genomic Effects =====

Some rapid effects occur within minutes.

Mechanisms may include:

  * Membrane-associated glucocorticoid receptors
  * Interaction with intracellular signaling pathways
  * Direct suppression of immune cell activation

These effects are less well defined but clinically relevant in acute settings.

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===== Inflammatory Pathway Suppression =====

Key downstream effect:

  ↓ Phospholipase A2 activity
  ↓ Arachidonic acid production
  ↓ Prostaglandins
  ↓ Leukotrienes

This explains synergy with:
  * [[allergy:drugs:loratadine|Antihistamines]]
  * [[respiratory:drugs:Leukotriene Modifiers]]

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===== Immune System Impact =====

Glucocorticoids:

  * Suppress Th1 and Th2 responses
  * Reduce cytokine production
  * Reduce T-cell proliferation
  * Decrease macrophage activation
  * Promote lymphocyte apoptosis (dose dependent)

Clinical implication:
  Broad immunosuppression.

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===== Metabolic Effects =====

Glucocorticoids also:

  * Increase gluconeogenesis
  * Promote protein catabolism
  * Increase lipolysis
  * Decrease peripheral glucose uptake

Explains:
  * Hyperglycemia
  * Muscle wasting
  * Cushingoid appearance

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===== HPA Axis Regulation =====

Endogenous cortisol secretion is regulated by:

  Hypothalamus → CRH  
  Pituitary → ACTH  
  Adrenal cortex → Cortisol  

Cortisol provides negative feedback at hypothalamus and pituitary.

Exogenous glucocorticoids suppress ACTH production → adrenal atrophy.

See:
  * [[endocrine:physiology:hpa_axis|HPA Axis Physiology]]

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===== Clinical Integration =====

Glucocorticoid signaling explains therapeutic use in:

  * [[allergy:clinical:allergic_rhinitis|Allergic Rhinitis]]
  * [[respiratory:clinical:asthma|Asthma]]
  * [[dermatology:clinical:atopic_dermatitis|Atopic Dermatitis]]
  * [[rheumatology:clinical:rheumatoid_arthritis|Rheumatoid Arthritis]]
  * [[gastroenterology:clinical:ibd|Inflammatory Bowel Disease]]

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===== High-Yield Pearls =====

  * Glucocorticoids act through intracellular receptors.
  * Effects are primarily genomic (slow onset).
  * They suppress both cytokine production and eicosanoid synthesis.
  * Long-term use suppresses the HPA axis.
  * They are broad anti-inflammatory agents — not targeted therapies.