Anovulation is the primary cause of infertility in PCOS (present in 70-80% of PCOS women trying to conceive). Fortunately, ovulation induction with oral agents is highly effective. The 2014 landmark PPCOS II trial established letrozole as superior to clomiphene as first-line ovulation induction in PCOS, with a live birth rate of 27.5% vs 19.1% in overweight women. This is now reflected in the International PCOS Guideline 2023 recommendations.
Letrozole (Femara): a third-generation aromatase inhibitor, originally developed for breast cancer. In ovulation induction, it inhibits estrogen production, releasing hypothalamic negative feedback, increasing FSH, and stimulating follicular development.
Letrozole dosing: Start 2.5 mg once daily on cycle days 3-7 (5 days). If no ovulation, escalate to 5 mg next cycle, then 7.5 mg if needed. Maximum 7.5 mg. Cycle monitoring with follicular tracking ultrasound around day 10-14 confirms ovulation and reduces multiple pregnancy risk. Ovulation rates are about 60-80% per cycle. Cumulative pregnancy rate over 3-6 cycles is 40-60%. Multiple pregnancy rate is 3-5% (mostly twins, lower than clomiphene).
Letrozole side effects: Hot flashes, fatigue, headache, muscle aches (usually mild). No negative effect on the endometrium, unlike clomiphene. Not associated with birth defects (a concern historically raised but disproven in large studies). Well tolerated overall.
Clomiphene citrate (Clomid): the historical first-line agent, still widely used. A selective estrogen receptor modulator that blocks estrogen receptors in the hypothalamus, releasing negative feedback and increasing FSH. Start 50 mg once daily on cycle days 3-7 (or 5-9). Escalate to 100 mg then 150 mg if no ovulation. Maximum 150 mg. Ovulation rates are 60-70% per cycle. Pregnancy rate is lower than letrozole in PCOS (per PPCOS II). Multiple pregnancy rate 7-8%.
Clomiphene side effects: Hot flashes, mood changes, breast tenderness, visual disturbances (rare, discontinue if they occur). Adverse effects on cervical mucus and endometrium may reduce pregnancy despite ovulation, one reason letrozole often outperforms it.
Metformin in ovulation induction: Metformin alone induces ovulation in about 30% of PCOS women but produces lower pregnancy rates than letrozole or clomiphene alone. Combined metformin + clomiphene is sometimes used for clomiphene-resistant patients (the PPCOS trial showed additional benefit in the obese subgroup). Metformin is also useful pre-conception to reduce gestational diabetes risk and possibly early miscarriage rates.
Gonadotropins (FSH injections: Gonal-F, Menopur, Puregon) are used if oral agents fail after 3-6 cycles. Highly effective but they need more monitoring (frequent ultrasounds, estradiol levels) and carry higher OHSS and multiple pregnancy risk. Costs significantly more. Usually initiated by a fertility specialist rather than a general gynecologist.
Ovarian drilling (laparoscopic ovarian diathermy) is a surgical option for clomiphene-resistant PCOS. It restores ovulation in about 50% of patients for 6-12 months. Now used less commonly given the effectiveness of letrozole and IVF alternatives. Small risk of adhesions and diminished ovarian reserve.
IVF for PCOS: When oral agents and gonadotropins fail, or if there are additional fertility factors (tubal disease, male factor), IVF is highly successful for PCOS women, who are among the best-responding groups. GnRH antagonist protocols are preferred (lower OHSS risk). Elective single embryo transfer is strongly recommended given the higher multiple pregnancy risk.
Pre-conception optimization for PCOS
- Folic acid 400-800 mcg (5 mg if BMI is over 30 or family history of neural tube defects)
- Achieve BMI under 30 if possible (5-10% weight loss can restore ovulation)
- Optimize HbA1c under 6.0% if pre-diabetic (GDM risk is 3 times higher in PCOS)
- Check TSH (target under 2.5 pre-conception), prolactin, vitamin D
- Rubella immunity confirmed
- Pap smear up to date
- Manage hypertension, address sleep apnea if severe
- Continue metformin during ovulation induction; stop after a positive pregnancy test unless specifically indicated
Success rates in perspective: With appropriate ovulation induction, about 70-80% of PCOS women achieve pregnancy within 6-12 cycles. Age remains the strongest determinant of success, with better outcomes in the 20s and early 30s than in the late 30s and 40s. Fertility discussions ideally begin BEFORE actively trying, not after 12 months of struggle.
