What medications can help increase fertility in a woman trying to conceive, particularly those with polycystic ovary syndrome (PCOS) or other ovulatory disorders?

Medications to Increase Female Fertility

Primary Recommendation

For women with polycystic ovary syndrome (PCOS) or ovulatory disorders attempting to conceive, begin with lifestyle modifications targeting 5-10% weight loss, then initiate clomiphene citrate 50-150 mg for 5 days starting on cycle day 5 as first-line pharmacological treatment, with letrozole 2.5-7.5 mg as an equally effective alternative that may offer superior pregnancy outcomes. 1, 2, 3

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Treatment Algorithm

Step 1: Mandatory Lifestyle Modifications (All Patients)

• Implement weight loss and exercise as the foundational treatment before any pharmacological intervention, targeting a 5% reduction in initial body weight through a 500-750 kcal/day energy deficit. 1, 4
• This approach significantly improves both metabolic and reproductive abnormalities, including ovulation and pregnancy rates, even in normal-weight patients. 1
• Exercise programs show positive effects independent of weight loss, with recommendations for at least 250 minutes/week of moderate-intensity activity for weight loss. 4

Step 2: First-Line Pharmacological Treatment

Option A: Clomiphene Citrate (Traditional First-Line)

• The American College of Obstetricians and Gynecologists recommends clomiphene citrate as first-line pharmacological treatment, with approximately 80% of PCOS patients ovulating and half of those who ovulate conceiving. 1, 2, 4
• Dosing per FDA labeling: Start 50 mg orally on cycle day 5 for 5 days, increase to 100-150 mg if ovulation does not occur, with treatment limited to approximately 6 total cycles (including 3 ovulatory cycles). 3
• Common pitfall: Clomiphene causes thin endometrium in up to 46% of patients, which can impair implantation despite successful ovulation. 5
• Side effects include blurred vision (20%), headache (18%), nausea (12%), and increased multiple pregnancy risk. 5

Option B: Letrozole (Evidence-Based Alternative with Superior Outcomes)

• Letrozole produces superior pregnancy outcomes compared to clomiphene, with higher ovulation rates (RR: 1.148), higher pregnancy rates, shorter time to conception, and more monofollicular development. 2, 6
• Dosing: 2.5 mg orally for 5 days starting cycle day 3, increase to maximum 7.5 mg if needed. 7, 8
• Key advantages over clomiphene: No antiestrogenic effects on endometrium (mean thickness 9.71 mm vs 6.08 mm with clomiphene), no reported side effects in clinical trials, reduced multiple pregnancy risk, and lower miscarriage rates. 5, 9, 7
• Important caveat: Letrozole use for ovulation induction is "off-label" (not FDA or EMA approved for this indication), though latest guidelines support it as first-line treatment. 6

Step 3: Adjunctive Metformin (When Indicated)

• Add metformin 500-2000 mg daily when insulin resistance or glucose intolerance is documented, when lifestyle modifications alone are insufficient, or when the patient has obesity or elevated cardiovascular risk factors. 4
• Metformin improves insulin sensitivity, reduces ovarian androgen production, and improves ovulation frequency. 1
• Metformin appears safe during pregnancy, though effects on early pregnancy outcomes are not fully established. 1

Step 4: Second-Line Options (If First-Line Fails)

• Low-dose gonadotropin therapy if clomiphene or letrozole treatment fails, due to lower risk of ovarian hyperstimulation compared to standard doses. 4
• Pulsatile GnRH therapy for functional hypothalamic amenorrhea with PCOM, showing 75-80% ovulation rates and 63-70% pregnancy rates per patient. 10

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Mandatory Pre-Treatment Requirements

Before Initiating Any Ovulation Induction

• Confirm patient is not pregnant and has no ovarian cysts (except polycystic ovaries). 3
• Perform pelvic examination prior to first and each subsequent treatment course. 3
• Rule out abnormal vaginal bleeding and ensure normal liver function. 3
• Screen for metabolic abnormalities: fasting glucose, 2-hour glucose tolerance test, and lipid profile. 1, 4
• Evaluate and treat other impediments to pregnancy: thyroid disorders, adrenal disorders, hyperprolactinemia, male factor infertility. 3

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Monitoring and Follow-Up

During Treatment

• Monitor ovulation with basal body temperature charting or other appropriate tests to time intercourse properly. 3
• Perform ultrasound on cycle day 14 to assess number and size of follicles and endometrial thickness. 5
• Discontinue clomiphene after 6 total cycles (including 3 ovulatory cycles) as long-term cyclic therapy is not recommended. 3

Once Pregnancy Achieved

• Women with PCOS require closer monitoring throughout pregnancy, including regular blood pressure monitoring, kidney function assessment, and proteinuria screening. 1
• Prescribe low-dose aspirin from week 12 to week 36 to reduce preeclampsia risk. 1

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Critical Clinical Pearls

Weighing clomiphene vs letrozole: While ACOG still recommends clomiphene as first-line based on its long-established safety profile, this recommendation predates the strongest letrozole data showing superior pregnancy outcomes. 2 The evidence demonstrates letrozole's higher ovulation rate (88% vs similar rates but better endometrial outcomes), absence of antiestrogenic effects, and lower complication rates. 6, 5, 9 In clinical practice, letrozole represents an equally valid or superior first-line choice, particularly for patients with prior clomiphene failure or thin endometrium. 9, 8

Avoid these common mistakes: Do not exceed recommended clomiphene dosage and duration, do not neglect metabolic screening even in normal-weight PCOS patients, and do not use clomiphene in patients with ovarian enlargement except those with PCOS. 4, 3