Letrozole vs Clomid: Which Ovulation Medication Is Better?
For decades, Clomid was the default first-line fertility medication. That changed when head-to-head trials showed letrozole produces better outcomes for the most common ovulatory disorder.
The ASRM now recommends letrozole (Femara) over clomiphene (Clomid) as first-line ovulation induction for PCOS. Letrozole produces higher live birth rates, fewer multiples, and doesn't thin the uterine lining.
How They Work
Letrozole is an aromatase inhibitor. It temporarily blocks estrogen production, causing the brain to increase FSH release and stimulate follicle growth. Because the estrogen blockade is brief, the lining remains thick and receptive.
Clomiphene citrate is a selective estrogen receptor modulator (SERM). It blocks estrogen receptors in the hypothalamus, tricking the brain into producing more FSH. However, it also blocks estrogen receptors in the uterine lining, which can cause lining thinning — a disadvantage for implantation.
Head-to-Head: The Evidence
| Outcome | Letrozole | Clomiphene |
|---|---|---|
| Ovulation rate (PCOS) | ~62% | ~48% |
| Live birth rate (PCOS) | ~28% | ~19% |
| Multiple pregnancy rate | 3–4% | 7–8% |
| Endometrial thinning | No | Yes (30% of patients) |
| Cost (generic, per cycle) | $30–$80 | $10–$50 |
Data from the NICHD Reproductive Medicine Network trial (Legro et al., NEJM 2014), the landmark RCT comparing the two drugs.
Dosing and Monitoring
Letrozole: Typically 2.5–7.5mg daily for 5 days (cycle days 3–7 or 5–9). Starting dose is usually 2.5mg, increased in subsequent cycles if ovulation doesn't occur. Monitoring with ultrasound confirms follicle development.
Clomiphene: 50–150mg daily for 5 days (cycle days 3–7 or 5–9). Same escalation pattern. Maximum recommended duration: 6 cycles total (some studies link prolonged use to increased ovarian cancer risk, though evidence is conflicting).
When Clomid Is Still Used
Despite letrozole's superiority for PCOS, clomid remains relevant in some situations: unexplained infertility without PCOS (where the drugs perform more similarly), when letrozole isn't available or covered by insurance, and for patients who respond poorly to letrozole specifically.
When to Move Beyond Oral Medications
If 3–6 cycles of oral medications (with or without IUI) haven't achieved pregnancy, it's time to consider injectable gonadotropins or IVF. Continuing oral medications beyond 6 cycles has diminishing returns for most patients.