What are the considerations for prescribing letrozole (aromatase inhibitor) for ovulation induction?

Letrozole for Ovulation Induction: Key Prescribing Considerations

Primary Recommendation

Letrozole is the preferred first-line agent for ovulation induction in women with PCOS-related anovulatory infertility, demonstrating superior live birth rates (27-35%) compared to clomiphene citrate (20%), with no increased risk of congenital malformations or ovarian hyperstimulation syndrome. 1

Patient Selection and Contraindications

Absolute Contraindications

• Pregnancy must be excluded before initiating treatment - letrozole causes fetal harm including skeletal malformations, incomplete ossification, and embryo-fetal toxicity in animal studies 2
• Premenopausal women with functioning ovaries should NOT receive letrozole for breast cancer treatment (aromatase inhibitors alone are ineffective and contraindicated in this population) 3
• Breastfeeding women - advise against breastfeeding during treatment and for at least 3 weeks after the last dose 2

Mandatory Pre-Treatment Assessment

• Pregnancy testing is required prior to starting letrozole 2
• Confirm anovulatory PCOS diagnosis as the indication
• Assess ovarian reserve markers (AMH, antral follicle count) to guide dosing expectations 4
• Baseline LH/FSH ratio and estradiol levels help predict response 4

Dosing Protocol

Starting Dose and Escalation

• Begin with letrozole 2.5 mg daily for 5 days (cycle days 3-7 or 5-9) 5, 4
• If no follicular response on ultrasound monitoring, increase to 5 mg daily for the next cycle 4
• For persistent non-responders, escalate to 7.5 mg daily 4
• Doses up to 12.5 mg daily have been studied and show increased follicular growth without detrimental effects on endometrial thickness 5
• Ovulation rates increase with higher doses: 22.9% at 2.5 mg, 42.1% at 5 mg, and 85.2% at 7.5 mg 4

Treatment Duration

• Continue for 3-6 cycles before considering alternative interventions 6
• If pregnancy not achieved after 3-6 cycles, add intrauterine insemination 6
• Refer for IVF if letrozole treatment unsuccessful after appropriate trial 6

Monitoring Requirements

Ultrasound Surveillance

• Regular ultrasound monitoring is essential to ensure appropriate follicular development and reduce multiple pregnancy risk 6
• Monitor follicle size and number during each treatment cycle
• Assess endometrial thickness (letrozole maintains adequate endometrial development even at high doses) 5

Cycle Monitoring

• Cycles of 38-40 days do not require intervention 7
• Concerning signs requiring evaluation: bleeding saturating a large pad hourly for ≥4 hours, hemodynamic instability, or abrupt change to heavy bleeding 7

Contraception and Fertility Counseling

Contraceptive Requirements

• Females of reproductive potential must use effective contraception during treatment and for at least 3 weeks after the last dose 2
• This applies when letrozole is used for non-fertility indications

Fertility Impact

• Letrozole may impair fertility in both males and females based on animal studies 2
• For fertility preservation in cancer patients, letrozole can be used during ovarian stimulation without reducing mature oocyte yield or fertilization capacity 3, 8

Safety Profile

Congenital Malformation Risk

• Overall congenital malformation rate with letrozole is 2.15% (95% CI 1.7-2.5%), which is NOT significantly increased compared to clomiphene or natural conception 9
• High-certainty evidence shows no increased risk versus clomiphene (risk difference 0.01,95% CI -0.02 to 0.03) 1
• Despite FDA warning label, systematic review of 46 studies found no evidence warranting restriction of letrozole use for fertility treatment 9

Ovarian Hyperstimulation Syndrome

• OHSS rates are identical between letrozole and clomiphene (0.5% in both groups) 1
• Letrozole maintains estrogen levels near physiologic ranges, reducing OHSS risk 7, 8

Pregnancy Outcomes

• Miscarriage rate: 24% with letrozole versus 25% with clomiphene (no significant difference) 1
• Multiple pregnancy rate: 1.6% with letrozole versus 2.2% with clomiphene (no significant difference) 1
• No increase in pregnancy loss compared to other fertility agents 9

Efficacy Data

Live Birth Rates

• Letrozole achieves 30-35% live birth rate versus 18-22% with clomiphene in treatment-naïve PCOS women 1, 10
• Number needed to treat = 10 (meaning one additional live birth for every 10 women treated with letrozole versus clomiphene) 1

Clinical Pregnancy Rates

• Clinical pregnancy rate: 32-39% with letrozole versus 24% with clomiphene 1
• Treatment-naïve women show 38.5% pregnancy rate with letrozole versus 22.0% with clomiphene 10

Ovulation Rates

• Ovulation occurs in 84.4% of women with letrozole versus 77.2% with clomiphene 10
• Dose-dependent response with higher ovulation rates at increased doses 4

Special Populations

Clomiphene-Resistant Patients

• Letrozole is effective in women who failed clomiphene treatment 4
• Consider starting at 5 mg rather than 2.5 mg in this population based on prior non-response 4

Breast Cancer Patients Requiring Fertility Preservation

• Letrozole reduces peak estradiol to near-physiologic levels while maintaining oocyte yield 3, 8
• Can be combined with gonadotropins for ovarian stimulation 3
• No adverse effect on survival in women with breast cancer undergoing fertility preservation 3

Patients with Thrombophilia

• Letrozole may be beneficial for patients with antiphospholipid antibodies or thrombophilia due to lower peak estrogen levels 8

Common Pitfalls to Avoid

• Do not use aromatase inhibitors alone in premenopausal women for breast cancer treatment - they are ineffective without ovarian suppression 3
• Do not delay dose escalation in non-responders - adjust based on ultrasound findings rather than waiting multiple cycles at subtherapeutic doses 4
• Do not withhold letrozole due to FDA warning label concerns about teratogenicity - high-quality evidence demonstrates safety comparable to other fertility agents 9, 1
• Do not skip ultrasound monitoring - essential for preventing multiple pregnancies and confirming appropriate follicular response 6