A 32-year-old woman with WHO Group II anovulation (normal FSH, normal prolactin, normal thyroid function) presents with secondary infertility for 18 months. She has failed clomiphene citrate therapy (150 mg daily for 5 days) for two consecutive cycles with no follicular development. Her partner's semen analysis is normal. What is the most appropriate next step in management?

Explanation

## Clomiphene Resistance and Management Strategy **Key Point:** When a patient fails to respond to maximum tolerated doses of clomiphene citrate (150 mg/day), she is classified as clomiphene-resistant. The standard next step is NOT dose escalation beyond 150 mg, but rather switching to an alternative agent. **Why Letrozole is Preferred:** - Letrozole (an aromatase inhibitor) is now considered a first-line alternative to clomiphene for WHO Group II anovulation, particularly in clomiphene-resistant cases - It has a shorter half-life (45 hours vs. clomiphene's 30 days), reducing antiestrogenic effects on endometrium and cervical mucus - Studies show comparable or superior ovulation and pregnancy rates compared to clomiphene, especially in PCOS and non-PCOS anovulation - Letrozole does not deplete estrogen receptors, preserving endometrial thickness **Clinical Pearl:** In WHO Group II anovulation with normal FSH and normal prolactin, clomiphene or letrozole monotherapy is the first-line approach. Gonadotropins are reserved for clomiphene/letrozole-resistant cases after confirming adequate ovarian reserve and excluding other causes. **High-Yield:** The 2023 ASRM and ESHRE guidelines recommend letrozole as a reasonable first-line alternative to clomiphene, especially when clomiphene resistance is documented. **Mnemonic:** **CLOMIPHENE RESISTANCE → LETROZOLE FIRST** (before jumping to gonadotropins).