In a patient with polycystic ovary syndrome of reproductive age who is not pregnant or breastfeeding, what are the eligibility criteria and contraindications for initiating letrozole therapy?

Letrozole for PCOS: Eligibility Criteria and Contraindications

Letrozole is indicated for ovulation induction in women with PCOS who meet specific metabolic and reproductive criteria, but is absolutely contraindicated in pregnancy and requires careful screening for cardiovascular and hepatic conditions.

Essential Eligibility Criteria

Metabolic Prerequisites

• BMI must be ≥18.5 kg/m² before initiating letrozole therapy 1
• Complete metabolic screening is mandatory, including fasting glucose, 2-hour glucose tolerance test, and lipid profile 1
• All PCOS patients require glucose and lipid monitoring regardless of weight status 2

Reproductive Requirements

• Confirmed non-pregnant status through clinical criteria (within 7 days of menses onset or no intercourse since last menses) or urine pregnancy test 3
• At least one patent fallopian tube and normal uterine cavity 4
• Male partner with sperm concentration ≥14 million/mL 4
• Post-pubertal status (letrozole can be used when gonadotoxic treatment delays are needed) 3

Baseline Lifestyle Modifications

• All women with PCOS must begin with lifestyle modifications targeting 5-10% weight loss through diet (500-750 kcal/day deficit, total 1,200-1,500 kcal/day) and exercise (≥250 minutes/week moderate-intensity activity) before or concurrent with letrozole 1
• Even modest 5% weight loss significantly improves ovulation and pregnancy rates 3, 1

Absolute Contraindications

Pregnancy and Reproductive Status

• Pregnancy is an absolute contraindication - letrozole can cause fetal harm 5
• Breastfeeding ≤21 days postpartum 3
• Known hypersensitivity to letrozole or excipients 5

Cardiovascular Contraindications

• Age ≥35 years AND smoking ≥15 cigarettes daily 3
• Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 3
• Vascular disease 3
• Acute VTE or history of VTE with ≥1 risk factor for recurrence 3
• Major surgery with prolonged immobilization 3
• Known thrombogenic mutations (Factor V Leiden, prothrombin mutation, protein S/C deficiency, antithrombin deficiency) 3
• Current or history of ischemic heart disease or stroke 3
• Multiple risk factors for atherosclerosis 3

Hepatic Contraindications

• Acute or flare of viral hepatitis 3
• Severe or decompensated cirrhosis 3
• Hepatocellular adenoma or malignant liver tumor 3
• Note: Cirrhosis with severe hepatic dysfunction requires 50% dose reduction (2.5 mg every other day) 5

Other Absolute Contraindications

• Current breast cancer 3
• Migraine with aura 3
• Diabetes with nephropathy, retinopathy, neuropathy, other vascular disease, or duration ≥20 years 3
• Systemic lupus erythematosus with positive or unknown antiphospholipid antibodies 3

Relative Contraindications (Theoretical Risks Usually Outweigh Benefits)

• Age ≥35 years AND smoking <15 cigarettes daily 3
• Systolic BP 140-159 mmHg or diastolic BP 90-99 mmHg 3
• Adequately controlled hypertension 3
• VTE with no risk factors for recurrence 3
• Superficial venous thrombosis 3
• Past breast cancer with no evidence of disease for 5 years 3
• Breastfeeding 21-42 days postpartum with VTE risk factors 3

Special Considerations for PCOS Patients

Advantages Over Clomiphene

• Letrozole is superior to clomiphene citrate with higher ovulation rates (61.7% vs 48.3%), live birth rates (27.5% vs 19.1%), and better endometrial effects 4, 6, 2
• Maintains estrogen levels near physiologic ranges, reducing OHSS risk 7
• May be beneficial for patients with antiphospholipid antibodies or thrombophilia due to lower peak estrogen levels 7

Hormone-Sensitive Conditions

• Letrozole combined with standard fertility drugs keeps estrogen levels near physiologic levels, making it appropriate for women with estrogen-sensitive conditions 3
• Short-term follow-up indicates no impact on cancer-free survival when used for fertility preservation 3

Monitoring Requirements

• Ultrasound monitoring is mandatory during each treatment cycle to ensure appropriate follicular development and reduce multiple pregnancy risk 7
• Monitor follicle size, number, and endometrial thickness (target ≥7-8 mm) 7, 2
• Blood pressure measurement before initiating treatment 3
• Consider monitoring bone mineral density and serum cholesterol during extended use 5

Critical Pitfalls to Avoid

• Never skip ultrasound monitoring - essential for preventing multiple pregnancies and confirming appropriate follicular response 7
• Do not use aromatase inhibitors alone in premenopausal women for breast cancer treatment - they are ineffective without ovarian suppression and contraindicated 7
• Do not initiate ovulation induction in women with BMI <18.5 kg/m² 1
• Do not neglect metabolic screening even in normal-weight PCOS patients 1
• Do not attribute thin endometrium to prior procedures beyond 6 weeks, as the endometrium fully regenerates within one cycle 2
• Avoid exceeding recommended duration (3-6 cycles before considering alternatives) 7

Premenopausal Status Verification

• Letrozole should NOT be given to premenopausal women outside clinical trials for breast cancer treatment 3
• Women who become amenorrheic with chemotherapy may have continued ovarian estrogen production despite absent menses 3
• Serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to ensure true postmenopausal status if considering letrozole for breast cancer 3