What is the role of letrozole (aromatase inhibitor) in treating infertility, particularly in women with Polycystic Ovary Syndrome (PCOS)?

Letrozole in Treating Infertility in Women with PCOS

Letrozole is superior to clomiphene citrate as first-line treatment for ovulation induction in women with PCOS, offering higher live birth rates and better endometrial outcomes. 1

Mechanism and Efficacy

Letrozole is an aromatase inhibitor that works by:

• Inhibiting estrogen production
• Increasing follicle-stimulating hormone (FSH) secretion
• Promoting follicular development
• Maintaining more physiologic estrogen levels compared to clomiphene citrate

Evidence of Superiority

• High-quality evidence shows letrozole produces higher live birth rates compared to selective estrogen receptor modulators (SERMs) like clomiphene citrate (OR 1.72,95% CI 1.40 to 2.11) 1
• Clinical pregnancy rates are significantly higher with letrozole (38.5% vs. 22.0%) 2
• Ovulation rates are higher with letrozole compared to clomiphene citrate (RR: 1.148,95% CI: 1.077 to 1.223) 3

Dosing and Administration

• Standard dosing: 2.5 mg daily for 5 days starting on day 3 of the menstrual cycle 2
• Can be initiated on day 3 of menstrual cycle for consistent follicular development 4
• "Random start" stimulation can also be successful according to newer evidence 4

Advantages Over Clomiphene Citrate

1. Better Endometrial Outcomes: Letrozole causes significantly less endometrial thinning compared to clomiphene (2% vs. 46% of patients) 5
2. Fewer Side Effects: Patients on letrozole report fewer side effects compared to those on clomiphene citrate 5
3. Similar OHSS Risk: Ovarian hyperstimulation syndrome rates are similar between letrozole and clomiphene (0.5% in both) 1
4. Similar Multiple Pregnancy Risk: Multiple pregnancy rates are comparable (1.6% with letrozole vs. 2.2% with clomiphene) 1

Special Considerations

• Letrozole is particularly valuable for patients with estrogen-sensitive conditions (like breast cancer) as it keeps estrogen levels near physiologic levels 4
• Letrozole can be effective in patients who have failed clomiphene citrate treatment, with studies showing 75% ovulation rates in previous clomiphene non-responders 6
• Long-term use may be associated with musculoskeletal symptoms (arthralgia 53%, myalgia 28%) and vasomotor symptoms (hot flashes 38%, fatigue 36%) 4

Clinical Algorithm for PCOS-Related Infertility

1. First-line: Letrozole 2.5 mg daily for 5 days (days 3-7 of cycle)
2. If unsuccessful after 3-6 cycles: Consider increasing dose or adding adjuncts
3. If still unsuccessful: Consider gonadotropin therapy or laparoscopic ovarian drilling
4. Monitor: Follicular development with transvaginal ultrasound on day 14 of cycle

Important Caveats

• Despite strong evidence supporting its use, letrozole is not FDA-approved for ovulation induction and is used "off-label" 3
• The American College of Obstetricians and Gynecologists (ACOG) has historically recommended clomiphene citrate as first-line treatment, but newer evidence supports letrozole's superiority 7, 1
• Weight loss (as little as 5% of initial weight) should be encouraged alongside medication as it improves ovulation and pregnancy rates in women with PCOS 7

Letrozole represents a significant advancement in treating infertility in women with PCOS, offering better outcomes with similar safety profiles compared to traditional treatments.