Prostaglandins: Synthesis, Functions, and Clinical Roles
Introduction to Prostaglandins
Prostaglandins are a group of physiologically active lipid compounds that have diverse, hormone-like effects in animals. Unlike classical hormones, they are not secreted from a gland and do not travel to a distant site but are synthesized at the site where they are needed.
Discovered by: Ulf von Euler in 1935 in human semen, who thought they originated from the prostate gland (hence the name).
Classification: Prostaglandins belong to a broader group of bioactive lipids known as eicosanoids, which also includes thromboxanes and leukotrienes.
Chemical Structure
Prostaglandins are derived from 20-carbon essential fatty acids, primarily arachidonic acid.
Structure: All prostaglandins share a common skeleton of a 20-carbon fatty acid with a five-membered ring.
Various prostaglandins differ in:
The functional groups attached to the ring.
The degree of saturation of the side chains.
Biosynthesis of Prostaglandins
Step 1: Liberation of Arachidonic Acid
Arachidonic acid is released from membrane phospholipids by the action of the enzyme phospholipase A₂ (PLA₂).
Step 2: Conversion via the Cyclooxygenase Pathway
Enzyme: Cyclooxygenase (COX)
Two isoforms:
COX-1: Constitutively expressed; maintains normal physiological functions.
COX-2: An inducible enzyme; expressed during inflammation, injury, or infection.
Step 3: Formation of Prostaglandin Precursors
COX converts arachidonic acid to PGG₂ and then to PGH₂.
PGH₂ is the common precursor for various prostaglandins and thromboxanes.
Step 4: Conversion to Specific Prostaglandins
Tissue-specific synthases convert PGH₂ into:
PGE₂
PGI₂ (prostacyclin)
PGD₂
PGF₂α
TXA₂ (thromboxane A₂)
Major Types and Their Functions
| Prostaglandin | Site of Action | Major Functions |
|---|---|---|
| PGE₂ | Most tissues | Vasodilation, fever, pain sensitization, uterine contraction, gastric mucus secretion |
| PGI₂ (prostacyclin) | Endothelium | Inhibition of platelet aggregation, vasodilation |
| PGF₂α | Uterus, eye | Uterine contraction, increased intraocular pressure |
| PGD₂ | CNS, mast cells | Sleep regulation, bronchoconstriction, allergic responses |
| TXA₂ | Platelets | Promotion of platelet aggregation, vasoconstriction |
Physiological Roles of Prostaglandins
Inflammation and Immunity
PGE₂ and PGI₂ are produced during inflammation.
They increase vascular permeability, attract leukocytes, and induce pain and fever.
They are the primary target of NSAIDs to reduce symptoms of inflammation.
Reproductive System
PGF₂α and PGE₂ cause uterine contractions during menstruation and labor.
They are involved in ovulation and cervical ripening.
Cardiovascular System
PGI₂: A vasodilator and anti-thrombotic agent.
TXA₂: A vasoconstrictor and pro-thrombotic agent.
These two maintain the balance between coagulation and anticoagulation.
Gastrointestinal System
PGE₂ promotes mucus and bicarbonate secretion in the stomach.
It inhibits gastric acid secretion.
It protects the gastric mucosa.
Renal System
Prostaglandins maintain renal blood flow and glomerular filtration rate.
They regulate salt and water excretion.
Nervous System
PGE₂ is involved in pain perception and fever.
It acts on the hypothalamus to raise body temperature.
Clinical Relevance
NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
Examples: Aspirin, Ibuprofen, Naproxen.
Mechanism: Inhibit COX enzymes, which reduces prostaglandin synthesis.
Used to treat: Pain, inflammation, and fever.
COX-2 Inhibitors
Example: Celecoxib.
Mechanism: Selectively inhibit COX-2, resulting in less gastric irritation than non-selective NSAIDs.
Prostaglandin Analogues (Drugs)
| Drug | Analogue of | Used for |
|---|---|---|
| Misoprostol | PGE₁ | Preventing NSAID-induced ulcers, inducing labor |
| Dinoprostone | PGE₂ | Cervical ripening, labor induction |
| Latanoprost | PGF₂α | Treating glaucoma (reduces intraocular pressure) |
| Alprostadil | PGE₁ | Maintaining patent ductus arteriosus in neonates, treating erectile dysfunction |
Role in Pathology
Dysmenorrhea: Excess PGF₂α causes painful uterine contractions.
Asthma: PGD₂ contributes to bronchoconstriction.
Cancer: Overexpression of COX-2 is linked with tumorigenesis (e.g., angiogenesis, inhibition of apoptosis).
Summary of Key Points
Prostaglandins are locally acting lipid mediators derived from arachidonic acid.
They regulate a wide array of physiological functions, including inflammation, reproduction, cardiovascular health, and renal function.
Their synthesis is inhibited by NSAIDs, making them key targets in the treatment of pain, fever, and inflammation.
Synthetic prostaglandins and their analogues are used therapeutically in obstetrics, ophthalmology, and gastroenterology.
Prostaglandin Synthesis Pathway
Membrane Phospholipids
↓ (PLA₂)
Arachidonic Acid
↓ (COX-1 / COX-2)
PGG₂ → PGH₂
↓
PGE₂, PGI₂, PGF₂α, PGD₂, TXA₂