Letrozole (Femara) works by temporarily lowering estrogen, triggering the brain to produce more FSH and stimulate follicle growth. For PCOS patients, it produces significantly higher live birth rates than Clomid (27.5% vs 19.1%). It's also better tolerated with fewer effects on the uterine lining and cervical mucus. The standard dose is 2.5–7.5 mg on cycle days 3–7.
How Letrozole Differs from Clomid
Letrozole is an aromatase inhibitor — it temporarily blocks the enzyme that converts androgens to estrogen. With estrogen production lowered, the hypothalamus senses the deficit and ramps up GnRH and FSH production, stimulating follicle development. The key difference from Clomid: Letrozole doesn't block estrogen receptors in the uterus and cervix, so it doesn't thin the endometrial lining or dry out cervical mucus the way Clomid can.
| Letrozole | Clomid | |
|---|---|---|
| Mechanism | Aromatase inhibitor (reduces estrogen production) | SERM (blocks estrogen receptors) |
| Live birth rate (PCOS) | 27.5% | 19.1% |
| Multiple pregnancy risk | 3.4% | 7.4% |
| Effect on endometrium | Neutral to positive | Can thin lining (anti-estrogenic) |
| Effect on cervical mucus | Neutral | Can reduce and dry out |
| Half-life | ~45 hours (clears quickly) | ~5–7 days (lingers longer) |
| Side effects | Fatigue, headache, mild hot flashes | Hot flashes, mood swings, visual changes |
| FDA-approved for fertility? | No (off-label use) | Yes |
Letrozole data from Legro et al. 2014, NEJM.
Despite being used off-label, Letrozole has become the recommended first-line ovulation induction agent for PCOS by multiple international fertility guidelines, including ESHRE and many US-based RE practices.
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