What are the treatment options for Polycystic Ovary Syndrome (PCOS)-related infertility?

PCOS Infertility Treatment

For infertile women with PCOS, letrozole 2.5 mg daily for 5 days (cycle days 3-7) is the superior first-line pharmacological treatment, achieving higher live birth rates (27.5% vs 19.1%) and ovulation rates (61.7% vs 48.3%) compared to clomiphene citrate. 1

Initial Management: Lifestyle Modification First

Before any pharmacological intervention, all women with PCOS attempting pregnancy must begin with lifestyle modifications targeting 5-10% weight loss through diet and exercise. 2, 3

• Target an energy deficit of 500-750 kcal/day with total intake of 1,200-1,500 kcal/day 2
• Modest weight loss of just 5% of initial body weight significantly improves ovulation and pregnancy rates 3
• Perform at least 250 minutes/week of moderate-intensity activity for weight loss, plus muscle strengthening on 2 non-consecutive days/week 2
• Women should have BMI ≥18.5 kg/m² before ovulation induction is offered 4

First-Line Pharmacological Treatment: Letrozole

Letrozole is now the preferred first-line ovulation induction agent over clomiphene citrate based on the highest quality randomized controlled trial evidence. 1

Letrozole Dosing Protocol:

• Start with letrozole 2.5 mg orally daily for 5 days (cycle days 3-7) 5, 6
• Increase dose in subsequent cycles for non-response up to maximum of 7.5 mg daily for 5 days 7
• Continue for up to 5 treatment cycles 1

Evidence Supporting Letrozole Superiority:

• Live birth rate: 27.5% with letrozole vs 19.1% with clomiphene (rate ratio 1.44, P=0.007) 1
• Ovulation rate: 61.7% with letrozole vs 48.3% with clomiphene (P<0.001) 1
• Clinical pregnancy rate: 38.5% with letrozole vs 22.0% with clomiphene (P=0.004) in treatment-naïve women 8
• Letrozole avoids the unfavorable endometrial thinning effects frequently seen with clomiphene 6

Alternative: Clomiphene Citrate

If letrozole is unavailable or contraindicated, clomiphene citrate remains an acceptable alternative, though inferior. 2, 3

Clomiphene Dosing Protocol:

• Start with clomiphene citrate 50 mg orally daily for 5 days (cycle days 3-7) 5
• Increase dose in subsequent cycles for non-response up to maximum of 150 mg daily for 5 days 5, 7
• Do not exceed 6 total treatment cycles (including 3 ovulatory cycles) 5
• Approximately 80% of PCOS patients ovulate on clomiphene, with half of those conceiving 2, 3

Critical Clomiphene Pitfall:

• Clomiphene frequently causes endometrial thinning (≤0.5 cm), which impairs implantation despite achieving ovulation 6

Adjunctive Therapy: Metformin

Metformin improves insulin sensitivity and ovulation frequency but is not a first-line fertility treatment alone. 3

• Metformin reduces insulin levels, which decreases ovarian androgen production 3
• Consider adding metformin to ovulation induction agents, particularly in women with insulin resistance 2
• Metformin appears safe during pregnancy, though effects on early pregnancy outcomes are not fully established 3

Second-Line Treatment: Low-Dose Gonadotropins

If oral agents fail after appropriate trials, low-dose gonadotropin therapy is the next step, with lower risk of ovarian hyperstimulation compared to standard protocols. 2

• Reserve for patients who fail to ovulate or conceive after 5 cycles of letrozole 2
• Use low-dose protocols to minimize multiple pregnancy and ovarian hyperstimulation risks 2

Special Consideration: Immature Oocyte Retrieval

For PCOS patients unable to undergo controlled ovarian stimulation (risk of severe ovarian hyperstimulation), harvesting of immature oocytes by aspiration is an alternative option. 4

Preconception Requirements

Before initiating any fertility treatment, all women with PCOS must undergo metabolic screening and achieve appropriate BMI. 3

Required Preconception Evaluation:

• Fasting glucose and 2-hour glucose tolerance test 3
• Lipid profile 3
• Ensure BMI ≥18.5 kg/m² 4
• Confirm at least one patent fallopian tube and normal uterine cavity 1
• Confirm male partner has sperm concentration ≥14 million/mL 1

Preconception Counseling:

• Counsel about increased pregnancy risks including preeclampsia, gestational diabetes, and pregnancy loss 3
• Plan for closer monitoring throughout pregnancy with regular blood pressure, kidney function, and proteinuria checks 3
• Prescribe low-dose aspirin from week 12 to week 36 to reduce preeclampsia risk 3

Common Pitfalls to Avoid

• Do not use clomiphene citrate as first-line treatment in functional hypothalamic amenorrhea (FHA) - it is ineffective and not recommended 4
• Do not exceed recommended clomiphene dosage (150 mg/day) or duration (6 cycles total) 2, 5
• Do not neglect metabolic screening even in normal-weight PCOS patients 2
• Do not initiate ovulation induction in women with BMI <18.5 kg/m² 4

Monitoring During Treatment

• Use basal body temperature graphs or other appropriate tests to confirm ovulation 5
• Perform pelvic examination prior to first and each subsequent treatment cycle 5
• Monitor for ovarian enlargement, particularly with clomiphene 5
• Track endometrial thickness, especially with clomiphene therapy 6