Letrozole for Ovulation Induction: Dosing and Protocols
The standard dose of letrozole for ovulation induction is 2.5 mg daily for 5 days, starting on cycle days 3-7, with dose escalation up to 7.5 mg daily in subsequent cycles for inadequate response. 1, 2
Standard Dosing Protocol
Initial dose: Start with 2.5 mg daily for 5 consecutive days (cycle days 3-7) 1, 2, 3
Dose escalation strategy:
- Increase to 5 mg daily (×5 days) in the next cycle if no follicular response or poor ovulatory response occurs 2, 3
- Further increase to 7.5 mg daily (×5 days) if response remains inadequate 2, 3
- Higher doses up to 12.5 mg daily have been studied and show increased follicular growth without detrimental effects on endometrial thickness, though this remains off-label 4
Ovulation trigger: Administer hCG 10,000 IU when at least one follicle reaches ≥18 mm mean diameter on transvaginal ultrasound 5
Treatment Duration and Next Steps
Continue letrozole for 3-6 cycles before considering alternative interventions 1, 6
If pregnancy not achieved after 3-6 cycles:
- Add intrauterine insemination (IUI) to letrozole treatment 1, 6
- Consider combination therapy with other fertility treatments for inadequate responders 6
Refer for IVF if letrozole treatment (with or without IUI) is unsuccessful after appropriate trial 1, 6
Essential Monitoring Requirements
Ultrasound monitoring is mandatory during each treatment cycle to ensure appropriate follicular development and reduce multiple pregnancy risk 1, 6
Monitor specifically:
- Follicle size and number during each cycle 1
- Endometrial thickness (letrozole maintains adequate endometrial development even at high doses) 1
Clinical Advantages
Letrozole offers several benefits over clomiphene citrate:
- Maintains estrogen levels near physiologic ranges, reducing OHSS risk 1
- No detrimental effect on endometrial receptivity 7
- Shorter half-life and fewer side effects than clomiphene 7
- Higher pregnancy rates in polycystic ovary patients (pregnancy rate 61.36% per patient across multiple cycles) 3, 5
Special populations:
- May be beneficial for patients with antiphospholipid antibodies or thrombophilia due to lower peak estrogen levels 1
- Can be used during ovarian stimulation without reducing mature oocyte yield or fertilization capacity 1
Critical Pitfalls to Avoid
Never skip ultrasound monitoring - it is essential for preventing multiple pregnancies and confirming appropriate follicular response 1
Do not use aromatase inhibitors alone in premenopausal women for breast cancer treatment - they are ineffective without ovarian suppression and are contraindicated in this population 1
Dose optimization approach: Start at 2.5 mg and increase based on sonographic results, antral follicular count, anti-Müllerian hormone, LH/FSH ratio, and estradiol levels rather than empirically escalating 3
Male Infertility Context
While the question focuses on female infertility, letrozole and other aromatase inhibitors are used off-label in male infertility to improve hormonal and semen parameters with a safe tolerability profile, though prospective RCTs are needed to better define efficacy 8