Recommended Initial Treatment for PCOS-Related Infertility
Letrozole 2.5 mg daily for 5 days (cycle days 3-7) should be the first-line pharmacologic treatment for ovulation induction in this 35-year-old woman with PCOS and primary infertility, after initiating lifestyle modification targeting 5-10% weight loss. 1, 2
Foundation: Lifestyle Modification Must Come First
- Initiate a 500-750 kcal/day energy deficit immediately, as even 5% weight loss improves ovulation and pregnancy rates in PCOS patients 1, 2
- Prescribe at least 250 minutes/week of moderate-intensity exercise, which benefits PCOS even without weight loss 1
- Weight loss and exercise decrease androgen levels, improving the hormonal milieu for conception 1
First-Line Pharmacologic Treatment: Letrozole Over Clomiphene
Letrozole demonstrates superior live birth rates (30.3% vs 18.9%) and clinical pregnancy rates (38.5% vs 22.0%) compared to clomiphene citrate in treatment-naïve PCOS patients 3, with a significantly higher ovulation rate (RR: 1.148,95% CI: 1.077-1.223) 4. While the American College of Obstetricians and Gynecologists historically recommended clomiphene citrate as first-line therapy 1, 5, recent high-quality evidence has shifted practice toward letrozole as the preferred initial agent.
Letrozole Dosing Protocol
- Start letrozole 2.5 mg daily for 5 days (cycle days 3-7) 1, 6
- If no ovulation or poor ovulatory response occurs, escalate to 5 mg daily, then 7.5 mg daily in subsequent cycles 6
- Continue for up to 5 treatment cycles before considering second-line options 6
- Administer after progestin withdrawal if needed to induce menses 6
Why Letrozole Outperforms Clomiphene
- Letrozole produces fewer mature follicles but thicker endometrium, resulting in higher pregnancy rates 7
- The ovulation rate per woman is comparable (84.4% vs 77.2%), but conversion to pregnancy is significantly better with letrozole 3
- Letrozole avoids the anti-estrogenic endometrial effects that limit clomiphene's efficacy 7
Adjunctive Metabolic Management
- Add metformin 500-2000 mg daily as adjunct to lifestyle modification and letrozole, not as primary fertility treatment 2
- Metformin improves ovulation frequency, decreases circulating androgens, and may reduce miscarriage rates 1
- Metformin appears safe in pregnancy 1
Critical Pre-Treatment Metabolic Screening
All PCOS patients attempting conception require comprehensive metabolic surveillance regardless of weight or testosterone levels 1, 2:
- Screen for type 2 diabetes with fasting glucose followed by 2-hour glucose tolerance test 2
- Obtain fasting lipid profile 1, 2
- Calculate BMI and waist-hip ratio 2
If Letrozole Fails After 3-5 Cycles
- Proceed directly to low-dose gonadotropin therapy, which is preferred over high-dose protocols due to higher monofollicular development rates and lower OHSS risk 1
- The FASTT trial demonstrated that moving directly to IVF after three failed clomiphene cycles is the most cost-effective approach 8, and this principle likely applies to letrozole as well
Critical Pitfalls to Avoid
- Do not use spironolactone in patients attempting to conceive due to contraindication in pregnancy 1, 2
- Do not exceed recommended letrozole dosing (maximum 7.5 mg daily for 5 days) 6
- Do not delay lifestyle intervention—it must be the foundation, not an afterthought 1, 2
- PCOS patients are unusually sensitive to gonadotropins and at high risk for OHSS—start with the lowest dose and shortest duration 9
- If ovarian enlargement occurs, do not give additional medication until ovaries return to pretreatment size 9
- Cancel the cycle if more than two dominant follicles >15 mm develop to prevent high-order multiple gestations 8