A 27-year-old woman with PCOS (Rotterdam criteria: oligomenorrhea, polycystic ovarian morphology on USG, hyperandrogenism) is being evaluated for infertility. AMH is 11.2 ng/mL. Antral follicle count is 28. Her BMI is 32 kg/m². Ovulation induction with letrozole is planned. What is the pharmacological mechanism of letrozole that makes it preferred over clomiphene citrate in PCOS-related anovulatory infertility?

• A Letrozole blocks estrogen receptors in the hypothalamus, providing positive feedback stimulation of FSH
• B Letrozole acts as a GnRH agonist, causing pituitary desensitization followed by FSH surge
• C Letrozole directly stimulates ovarian theca cells to produce androgens that are converted to estradiol for folliculogenesis
• D Letrozole inhibits aromatase (CYP19A1), transiently lowering estrogen, which removes negative feedback on hypothalamus and increases FSH pulse amplitude; shorter half-life prevents estrogen receptor downregulation seen with clomiphene ✓

Explanation

Letrozole is a third-generation aromatase inhibitor (AI) that competitively inhibits aromatase (CYP19A1), the enzyme that converts androgens (androstenedione, testosterone) to estrogens in peripheral tissues and the ovary. By transiently lowering circulating estradiol, letrozole removes negative feedback on the hypothalamus and pituitary, increasing endogenous FSH secretion. Unlike clomiphene citrate (which blocks hypothalamic estrogen receptors for prolonged periods, causing endometrial and cervical mucus thinning), letrozole has a much shorter half-life (~45 hours vs 5–7 days for clomiphene), so when it is cleared, estrogenic feedback is restored, limiting the FSH rise to a shorter interval and promoting monofollicular development. The LEGRO trial (NEJM 2014) showed letrozole achieves higher live birth rates than clomiphene in PCOS.

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

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Written and medically reviewed by the StethoPrep medical team.