First-Line Fertility Treatment for PCOS
Lifestyle modification targeting 5-10% weight loss through diet and exercise is the mandatory first-line treatment for all women with PCOS seeking fertility, followed by letrozole as the preferred first-line pharmacological agent for ovulation induction, which demonstrates superior live birth rates compared to clomiphene citrate. 1, 2
Foundational Lifestyle Intervention (Required First Step)
All women with PCOS attempting conception must begin with structured lifestyle modification, regardless of body weight, as this improves metabolic, reproductive, and psychological outcomes and is positioned at the top of the intervention hierarchy 3, 1
Target an energy deficit of 500-750 kcal/day with total intake of 1,200-1,500 kcal/day, adjusted for individual requirements 1
Perform at least 250 minutes/week of moderate-intensity activity or 150 minutes/week of vigorous activity, plus muscle strengthening on 2 non-consecutive days/week for weight loss 1
Even modest weight loss of 5% improves ovulation and pregnancy rates in overweight women with PCOS, making this intervention highly effective before pharmacotherapy 3, 4
Incorporate behavioral strategies including goal-setting, self-monitoring, stimulus control, and relapse prevention to optimize adherence 1
First-Line Pharmacological Treatment: Letrozole
Letrozole should be the preferred first-line pharmacological agent for ovulation induction in women with PCOS based on the highest quality evidence:
Letrozole increases live birth rates by 43% compared to clomiphene citrate (RR 1.43,95% CI 1.17-1.75) in the most recent and comprehensive individual participant data meta-analysis of 1,043 women 2
Letrozole improves clinical pregnancy rates by 45% (RR 1.45,95% CI 1.23-1.70) and reduces time-to-pregnancy by 72% (HR 1.72,95% CI 1.38-2.15) compared to clomiphene 2
Letrozole is particularly effective in women with higher baseline testosterone levels, with a positive interaction showing enhanced treatment effects in hyperandrogenic phenotypes (interaction RR 1.29,95% CI 1.01-1.65) 2
Letrozole produces more monofollicular development, reducing multiple pregnancy risk compared to clomiphene 5
Mechanism and Practical Advantages
Letrozole blocks aromatase, reducing estrogen and increasing FSH secretion to stimulate follicular development without the anti-estrogenic peripheral effects of clomiphene 5
Unlike clomiphene, letrozole does not adversely affect endometrial thickness or cervical mucus, contributing to superior pregnancy outcomes 5, 6
Alternative First-Line Option: Clomiphene Citrate
While letrozole is superior, clomiphene citrate remains an acceptable first-line option based on long-established safety and FDA approval:
Clomiphene induces ovulation in approximately 80% of women with PCOS, with half of those who ovulate achieving conception 3, 1, 7
Start clomiphene on cycle day 5 and limit to 6 total cycles (including 3 ovulatory cycles) to avoid diminishing returns 7
The main limitation is that ACOG's recommendation for clomiphene as first-line predates the strongest letrozole evidence from 2019, representing a lag in guideline updates 5, 2
When to Consider Clomiphene Plus Metformin
Adding metformin to clomiphene may improve clinical pregnancy rates (RR 1.18,95% CI 1.00-1.39) and reduce time-to-pregnancy (HR 1.25,95% CI 1.00-1.57), though evidence for improved live birth is insufficient 2
This combination is most beneficial in women with documented insulin resistance or elevated baseline insulin levels (interaction RR 1.03,95% CI 1.01-1.06), particularly those who are older with visceral obesity 4, 2
Metformin alone has limited benefits for live birth and should not be used as monotherapy for ovulation induction 8
Critical Implementation Points
Pre-Treatment Requirements
Confirm the patient is not pregnant and has no ovarian cysts (except polycystic ovaries) before starting ovulation induction 7
Evaluate for adequate endogenous estrogen levels and exclude primary pituitary or ovarian failure 7
Screen for and treat other impediments to pregnancy including thyroid disorders, hyperprolactinemia, and male factor infertility 7
Perform endometrial biopsy in women over 35 or with abnormal bleeding to exclude endometrial hyperplasia or carcinoma 7
Monitoring and Safety
Properly timed intercourse in relationship to ovulation is essential; use basal body temperature charting or ovulation predictor kits 7
Counsel patients about the 5-10% risk of multiple pregnancy with clomiphene and the need for ultrasound monitoring 4, 8
Pelvic examination is required before each treatment cycle to detect ovarian enlargement 7
Common Pitfalls to Avoid
Do not skip lifestyle modification even in normal-weight women, as metabolic improvements occur independent of BMI 3, 1
Do not use metformin as monotherapy for ovulation induction, as it does not significantly improve live birth rates compared to placebo 8
Do not exceed 6 cycles of clomiphene or continue beyond 3 ovulatory cycles without reassessment 7
Do not neglect metabolic screening (fasting glucose, lipids, blood pressure) even when focusing on fertility, as PCOS carries long-term cardiovascular and diabetes risk 1