In the PPCOSII trial comparing letrozole versus clomiphene citrate as first-line ovulation induction in anovulatory PCOS, letrozole demonstrated superior outcomes due to its mechanism of action. The mechanism of letrozole's superiority over clomiphene is:

• A Letrozole inhibits aromatase, reducing oestrogen feedback, allowing increased FSH release; anti-estrogenic effects on endometrium are absent due to its short half-life ✓
• B Letrozole directly stimulates FSH release from the pituitary, increasing folliculogenesis
• C Letrozole blocks oestrogen receptors in the hypothalamus permanently, causing a prolonged FSH surge
• D Letrozole has direct ovarian actions stimulating theca cell androgen production

Explanation

Letrozole is an aromatase inhibitor that blocks oestrogen synthesis in the follicle, reducing negative feedback on the hypothalamo-pituitary axis, thus increasing endogenous FSH — producing predominantly monofollicular development. Its short half-life (~48 hours) means the drug is cleared before implantation, so it does not have clomiphene's adverse anti-oestrogenic effects on the endometrium (thin endometrium) and cervical mucus. The PPCOSII trial confirmed higher cumulative live birth rates with letrozole vs. clomiphene in PCOS, making it the preferred first-line agent.

Reference: Shaw's Textbook of Gynaecology, 17th ed.

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