Endometrial Shedding Triggers Prostaglandin Release
Falling progesterone triggers endometrial breakdown and prostaglandin release.
- Day 1: Cycle day of onset (menstruation starts)
- ~90%: Progesterone drop (luteal phase ends)
- 2–5 mm: Endometrium shed (functional layer)
- 50–90%: Women affected (some menstrual pain)
Progesterone withdrawal
Corpus luteum regresses, progesterone falls sharply.
Endometrial breakdown
Lysosomal enzymes degrade endometrial tissue rapidly.
Prostaglandin trigger
Damaged cells free arachidonic acid for synthesis.
Primary dysmenorrhea affects up to 90% of menstruating women.
COX Enzymes Convert Arachidonic Acid Into PGF2α
COX-1 and COX-2 rapidly synthesize PGF2α from membrane lipids.
- ~10×: COX-2 upregulation (secretory endometrium)
- First 48h: PGF2α peak (of menstruation)
- 3: Synthesis steps (PLA2, COX, PGF synthase)
- 3–10×: Menstrual PGF2α (higher than luteal phase)
Arachidonic acid release
Phospholipase A2 frees membrane arachidonic acid.
COX conversion
COX-1/COX-2 oxidize arachidonic acid into PGH2.
PGF2α synthase
PGH2 is converted into potent PGF2α.
Dysmenorrheic women show 3–10× higher endometrial PGF2α.
High PGF2α Drives Painful Uterine Contractions
Excess PGF2α overstimulates the myometrium, forcing strong contractions.
- ≤400 mmHg: Intrauterine pressure (vs 50–80 normal)
- >5/10min: Contraction frequency (hypercontractile pattern)
- Reduced: Uterine blood flow (ischemia occurs)
- Hours before: Pain onset (bleeding starts)
Myometrial overstimulation
PGF2α binds FP receptors, triggers calcium influx.
Ischemic pain
Sustained contractions restrict uterine blood flow.
Sensitized nerves
Ischemia and prostaglandins activate pain fibers.
Contractions can exceed 400 mmHg, cutting uterine blood supply.
Ibuprofen And Naproxen Block COX Enzyme Activity
NSAIDs competitively inhibit COX, cutting new PGF2α production.
- ~2 h: Ibuprofen half-life (dosed every 4–6h)
- 12–17 h: Naproxen half-life (longer acting)
- 30–60 min: Inhibition onset (after oral dose)
- 1–2 h: Peak plasma level (post-dose)
Competitive inhibition
NSAIDs block the COX enzyme active site.
Dose dependence
Higher doses inhibit a larger share of COX.
Pharmacokinetics
Absorption, peak, and elimination shape the effect.
Early dosing before pain peaks blocks more prostaglandin synthesis.
Suppressed PGF2α Relaxes The Uterus And Cuts Pain
Lower PGF2α reduces contraction strength and reported pain scores.
- ≤80%: Pain reduction (with adequate NSAID dosing)
- ~2–3: Number needed to treat (for pain relief)
- Within hours: Contraction normalizes (of effective dosing)
- 80–90%: Treatment success (of primary dysmenorrhea)
Contraction relaxation
Less PGF2α means weaker, less frequent contractions.
Blood flow restored
Reduced ischemia lowers pain-fiber signaling.
Clinical response
Most patients respond well to adequate dosing.
NSAIDs outperform placebo for menstrual pain in most women.