What medications are used to treat infertility in women?

Medications for Women's Infertility

For anovulatory infertility, particularly in women with polycystic ovary syndrome (PCOS), letrozole is the preferred first-line medication, demonstrating superior pregnancy and live birth rates compared to clomiphene citrate. 1, 2, 3

First-Line Treatment: Letrozole

Letrozole 2.5 mg daily for 5 days (cycle days 3-7) should be the initial treatment for anovulatory infertility in women with PCOS. 1, 2

Key Advantages of Letrozole:

• Higher live birth rates: 30.3% vs. 18.9% with clomiphene in treatment-naïve PCOS women 3
• Superior clinical pregnancy rates: 38.5% vs. 22.0% with clomiphene 3
• Better endometrial development: Maintains adequate endometrial thickness even at higher doses, unlike clomiphene which can cause thin endometrium 2, 4
• Lower multiple pregnancy risk: Maintains estrogen levels near physiologic ranges, reducing ovarian hyperstimulation syndrome (OHSS) risk 2

Dosing Protocol:

• Start with 2.5 mg daily for 5 days (cycle days 3-7) 2, 5
• Increase dose if needed: Can escalate to 5 mg, then 7.5 mg in subsequent cycles for non-response 2, 5
• Treatment duration: Continue for 3-6 cycles before considering alternative interventions 2, 6
• Add intrauterine insemination (IUI) if pregnancy not achieved after 3-6 cycles 2, 6

Essential Monitoring:

• Regular ultrasound monitoring is mandatory to ensure appropriate follicular development and prevent multiple pregnancies 2
• Monitor follicle size and number during each treatment cycle 2
• Administer hCG trigger when at least one follicle reaches ≥18 mm mean diameter 4

Alternative First-Line: Clomiphene Citrate

Clomiphene citrate 50-100 mg daily for 5 days remains an acceptable alternative when letrozole is unavailable or contraindicated. 1

Clomiphene Protocol:

• Initial dose: 50 mg daily for 5 days (cycle days 3-7) 1
• Dose escalation: Increase to 100 mg, then 150 mg maximum for non-response 1
• Expected outcomes: Approximately 80% ovulation rate, 50% conception rate among those who ovulate 1

Important Limitations:

• Antiestrogenic effects on endometrium: Can cause thin endometrial lining, reducing implantation 4
• Higher non-response rate compared to letrozole 1
• Not recommended for functional hypothalamic amenorrhea (FHA): Limited evidence of efficacy in this population 7

Adjunctive Therapy: Metformin

For women with PCOS and insulin resistance, metformin improves ovulation rates and enhances response to ovulation induction agents. 8

Metformin Use:

• Mechanism: Reduces hyperinsulinemia, which contributes to anovulation in PCOS 8
• Combination therapy: Often used with letrozole or clomiphene to improve outcomes 8
• Weight loss synergy: Even 5% body weight reduction improves metabolic and reproductive outcomes in PCOS 1

Advanced Options for Refractory Cases

Gonadotropin Therapy:

• Low-dose FSH protocol recommended if oral agents fail after appropriate trials 7
• Goal: Induce monofollicular development to minimize hyperstimulation risk 7
• Requires intensive monitoring due to higher OHSS and multiple pregnancy risk 7

Pulsatile GnRH Therapy:

• Specifically for hypothalamic amenorrhea: Most effective treatment for FHA when fertility desired 7
• Not for PCOS: GnRH agonists do not preserve fertility or improve outcomes in PCOS 7

Laparoscopic Ovarian Drilling:

• Equally successful as FSH for ovulation induction in select patients 8
• Best candidates: Thin patients with high LH concentrations 8

Fertility Preservation Context

For Cancer Patients:

• Ovarian stimulation with letrozole is safe and effective for oocyte/embryo cryopreservation before gonadotoxic therapy 7
• Random start stimulation: Can begin at any point in menstrual cycle, not just cycle day 3 7
• Hormone-sensitive cancers: Letrozole preferred over traditional gonadotropins as it keeps estrogen levels near physiologic range 7

Critical Contraindications and Precautions

Letrozole Contraindications:

• Premenopausal women with breast cancer: Aromatase inhibitors alone are ineffective and contraindicated without ovarian suppression 2, 9
• Liver disease: Use with caution, particularly in decompensated cirrhosis 1

Clomiphene Contraindications:

• Liver disease: Absolutely contraindicated, especially in decompensated cirrhosis 1
• Insufficient endogenous estrogen: Not effective in hypogonadotropic hypogonadism 1

NSAIDs and Fertility:

• Continuous periovulatory NSAID exposure can induce luteinized unruptured follicle (LUF) syndrome, reducing fecundability 7
• Women with difficulty conceiving should discontinue NSAIDs 7

When to Refer for IVF

Refer for in vitro fertilization if letrozole treatment unsuccessful after 3-6 cycles with IUI. 2, 6

• IVF produces excellent results when all other treatments have failed 8
• Very few women with anovulatory PCOS cannot be successfully treated with available options 8

Common Pitfalls to Avoid

• Do not skip ultrasound monitoring: Essential for preventing multiple pregnancies and confirming appropriate follicular response 2
• Do not use GnRH agonists for fertility preservation in PCOS: No definitive data showing they preserve fertility 7
• Do not continue clomiphene beyond 6 cycles: Switch to alternative therapy if unsuccessful 1
• Do not ignore weight management: 5% weight loss significantly improves outcomes in PCOS 1