During the secretory phase of the menstrual cycle, progesterone acts on endometrial glands via progesterone receptor (PR). Progesterone withdrawal at the end of the cycle triggers menstruation. The initial molecular event connecting progesterone withdrawal to prostaglandin-mediated menstruation is:

• A Progesterone withdrawal directly activates matrix metalloproteinases (MMPs) without prostaglandin involvement
• B Falling progesterone allows estrogen-induced tissue factor expression, triggering local thrombosis in spiral arteries
• C Progesterone withdrawal removes inhibition of COX-2 and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) suppression, resulting in net PGF₂α and PGE₂ accumulation ✓
• D Progesterone withdrawal increases IL-15 secretion which activates NK cells to initiate tissue breakdown

Explanation

Progesterone maintains endometrial stability partly by inducing 15-PGDH (which degrades prostaglandins) and suppressing COX-2. When progesterone falls at luteolysis, the balance shifts: COX-2 is upregulated and 15-PGDH is downregressed, resulting in net accumulation of PGF₂α (causing vasoconstriction and myometrial contraction) and PGE₂ (causing vasodilation and vascular permeability). PGF₂α-induced spiral artery vasoconstriction leads to ischemia, followed by MMP activation for tissue breakdown. This cascade explains why NSAIDs (COX inhibitors) reduce menstrual blood loss in menorrhagia.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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