How Letrozole Helps You Get Pregnant
Letrozole works by temporarily blocking estrogen production in your body, which tricks your brain into releasing more follicle-stimulating hormone (FSH), causing your ovaries to develop and release eggs—a process called ovulation induction. 1
Mechanism of Action
Letrozole is an aromatase inhibitor that blocks the enzyme responsible for converting androgens to estrogen 2. This temporary reduction in estrogen levels causes your hypothalamus and pituitary gland to respond by increasing FSH secretion 2. The elevated FSH then stimulates follicle development in your ovaries, leading to ovulation 2.
The key advantage is that letrozole doesn't deplete estrogen receptors like clomiphene citrate does, meaning you avoid the anti-estrogenic side effects such as thin uterine lining and poor cervical mucus that can actually prevent pregnancy 2. Because estrogen receptors in the brain remain intact, normal negative feedback occurs, which typically results in single egg ovulation rather than multiple eggs 2.
Evidence for Effectiveness in PCOS
Letrozole is superior to clomiphene citrate (the traditional first-line treatment) for women with PCOS seeking pregnancy. 1
Live Birth Rates
- Letrozole increases live birth rates by 72% compared to clomiphene citrate 1
- If your chance of live birth with clomiphene is 20%, letrozole increases it to 27-35% 1
- In treatment-naïve PCOS women, letrozole achieved 30.3% live birth rate versus 18.9% with clomiphene 3
Ovulation Rates
- Letrozole achieves significantly higher ovulation rates than clomiphene (84.4% vs 77.2% per woman) 3, 4
- The probability of ovulation is 14.8% higher with letrozole compared to clomiphene 4
Pregnancy Rates
- Clinical pregnancy rates are 69% higher with letrozole versus clomiphene 1
- If your pregnancy chance with clomiphene is 24%, letrozole increases it to 32-39% 1
- Letrozole achieved 38.5% clinical pregnancy rate versus 22.0% with clomiphene in treatment-naïve women 3
Safety Profile
Letrozole has an excellent safety profile with no increased risk of serious complications. 1
- Ovarian hyperstimulation syndrome (OHSS) occurs at the same low rate (0.5%) as with clomiphene 1
- Miscarriage rates are identical between letrozole and clomiphene (24% vs 25%) 1
- Multiple pregnancy rates are similar (1.6% with letrozole vs 2.2% with clomiphene) 1
- Congenital anomaly rates are comparable to clomiphene-treated pregnancies 2
Dosing Strategies
Starting with higher doses or extended duration achieves ovulation faster without increasing complications. 5
The standard starting regimen is 2.5 mg daily for 5 days 3, but evidence shows:
- 5 mg for 5 days achieves ovulation 3.4 times faster than 2.5 mg for 5 days 5
- 2.5 mg for 10 days achieves ovulation 9.1 times faster than the standard regimen 5
- 5 mg for 10 days achieves ovulation 5.9 times faster than the standard regimen 5
- Higher doses and extended courses shorten time to pregnancy without increasing multifollicular development 5
Clinical Context
Letrozole is particularly valuable in fertility preservation for women with hormone-sensitive cancers because when combined with standard fertility drugs, it enhances ovarian stimulation while keeping estrogen levels near physiologic levels, resulting in similar numbers of eggs and embryos with no impact on cancer-free survival 6.
Important Caveats
- Letrozole use for ovulation induction is "off-label" (not FDA-approved for this indication), though it is recommended by recent guidelines 4
- The American College of Obstetricians and Gynecologists recommends clomiphene citrate as first-line treatment in their guidelines 7, 8, though this predates the high-quality evidence showing letrozole superiority 1
- When gonadotropins are needed after letrozole failure, use low-dose protocols (75 IU or lower) to minimize multiple pregnancy risk 6