What is the recommended dosage and frequency of letrozole (aromatase inhibitor) for ovulation induction and how is the dose adjusted in subsequent cycles?

Letrozole Dosing Protocol for Ovulation Induction

For ovulation induction, letrozole should be administered at an initial dose of 2.5 mg daily for 5 days starting on day 3-7 of the menstrual cycle, with dose increases up to 7.5 mg daily in subsequent cycles if ovulation is not achieved.

Initial Dosing Regimen

• Start with 2.5 mg letrozole daily for 5 consecutive days
• Begin on cycle days 3-7 (typically day 3) of the menstrual cycle
• Monitor follicular development with transvaginal ultrasound
• Time intercourse or intrauterine insemination appropriately based on follicular maturity

Dose Adjustment Protocol

If no adequate response is observed (inadequate follicular development or no ovulation):

1. First cycle: 2.5 mg daily for 5 days
2. Second cycle: Increase to 5 mg daily for 5 days if no ovulation occurs
3. Third cycle: Increase to 7.5 mg daily for 5 days if still no response
4. Fourth cycle: Consider higher doses up to 12.5 mg daily for 5 days in select cases 1

Monitoring Response

• Transvaginal ultrasound to assess follicular development (typically day 12-14)
• Endometrial thickness measurement (optimal >7mm)
• Serum estradiol levels may be measured but are not mandatory
• Ovulation can be confirmed by progesterone level or ultrasound evidence of follicular collapse

Effectiveness and Outcomes

Letrozole has demonstrated superior outcomes compared to clomiphene citrate:

• Higher live birth rates (30.3% vs 18.9%) 2
• Higher clinical pregnancy rates (38.5% vs 22.0%) 2
• Similar ovulation rates but better endometrial development 3

Special Considerations

• For women with PCOS who are treatment-naïve, letrozole is now considered a first-line agent 4
• For women with previous clomiphene resistance, higher starting doses (5 mg) may be considered
• Letrozole appears particularly valuable for women who had thin endometrium (<5mm) with clomiphene 3

Factors Associated with Poor Response

Be aware of factors that may predict poor response to standard letrozole dosing:

• History of clomiphene resistance (10-fold higher risk of letrozole resistance) 5
• Presence of hirsutism 5
• Higher baseline LH levels 5

Important Caveats

• Standard 2.5 mg dosing may be insufficient for women with clomiphene resistance 5
• When used for fertility preservation in cancer patients, letrozole can be combined with standard fertility drugs to enhance ovarian stimulation while keeping estrogen levels near physiologic levels 6
• Random-start stimulation protocols can be used regardless of cycle day, which is particularly valuable when time is limited 6

Letrozole's effectiveness in improving live birth rates compared to other ovulation induction methods is supported by high-certainty evidence, making it an excellent first-choice agent for ovulation induction in women with anovulatory infertility, particularly those with PCOS 4.