Is metformin indicated for treatment of polycystic ovary syndrome (PCOS) in women of reproductive age with insulin resistance or obesity?

Is Metformin Indicated for PCOS?

Yes, metformin is indicated for women with PCOS who demonstrate insulin resistance or metabolic syndrome features, regardless of normal blood glucose or HbA1c values, with typical effective dosing of 1.5-2 g daily. 1

Primary Indications

Metformin should be prescribed for PCOS patients with:

• Insulin resistance or metabolic syndrome features (elevated insulin, impaired glucose tolerance, dyslipidemia, central obesity), even when HbA1c and fasting glucose are normal 1
• Obesity or overweight status with metabolic abnormalities 1, 2
• Adolescents with PCOS, particularly when excess body weight is present 2
• Glucose intolerance states (prediabetes: fasting glucose 5.6-6.9 mmol/L or 2-hour post-glucose 7.8-11.0 mmol/L), especially if lifestyle modification fails 3, 1

Approximately 60% of PCOS women have insulin resistance regardless of BMI, and insulin resistance drives hyperandrogenism and anovulation even in normal-weight patients. 4

Metabolic Benefits

Metformin provides significant metabolic improvements:

• Reduces insulin resistance by decreasing hepatic gluconeogenesis and increasing peripheral glucose uptake, which subsequently lowers ovarian androgen production 1, 4
• Decreases LDL cholesterol and triglycerides, providing cardiovascular risk reduction beyond glucose control 1, 5
• Maintains or improves glucose tolerance over time, even when baseline HbA1c is normal 1
• Maintains stable weight or promotes modest weight loss, unlike some alternatives that cause weight gain 1

Even modest weight loss of 5% of initial body weight enhances metformin's metabolic and reproductive effects. 1, 5

Reproductive Benefits

Metformin normalizes ovulatory abnormalities in many PCOS patients:

• Improves menstrual regularity and restores ovulation in a subset of women 1, 2, 6
• May enhance fertility when combined with clomiphene citrate, particularly in clomiphene-resistant cases 1, 4
• However, clomiphene citrate remains first-line for ovulation induction (80% ovulation rate, 50% conception rate), and metformin should not be used as monotherapy for fertility alone 4

Dosing Algorithm

Start with 500 mg twice daily (1000 mg total) for better gastrointestinal tolerability, then titrate:

• Target dose: 1.5-2 g daily (typically 1 g twice daily) for optimal metabolic and reproductive effects 1, 5
• Treatment duration: minimum 12 weeks to assess response 3, 1
• For fertility: continue until pregnancy is achieved, then discontinue before conception or in early first trimester 5

Mandatory Contraindications

Do not prescribe metformin if:

• eGFR <30 mL/min/1.73m² (absolute contraindication) 1, 4
• eGFR 30-45 mL/min/1.73m² (not recommended to initiate) 4
• Known hepatic disease, alcohol abuse, or hypoxemic conditions 1, 4
• Acute illness with dehydration or hypoxemia (temporarily discontinue) 1
• Administration of radiocontrast material (discontinue temporarily) 1

Required Baseline Assessment and Monitoring

Before initiating metformin:

• Assess renal function (serum creatinine, eGFR) 4
• Screen for hepatic disease and alcohol use 4
• Obtain baseline weight and blood pressure 1
• Provide contraception counseling due to improved ovulation and unplanned pregnancy risk 1, 4, 5

Ongoing monitoring:

• Weight every 6-12 months 1, 5
• Blood pressure at least annually 1
• Lipid panel and menstrual regularity at 12-16 weeks to assess treatment response 5
• Screen periodically for smoking status and physical activity levels 1

Clinical Pitfalls to Avoid

Common mistakes in metformin prescribing for PCOS:

• Do not use metformin as first-line monotherapy for fertility in lean PCOS patients; clomiphene citrate is significantly more effective 4
• Do not use metformin as first-line for weight loss, hirsutism, or acne; it is not effective for these indications alone 7
• Do not continue metformin through pregnancy; metformin crosses the placenta and long-term offspring data show concerning trends including higher BMI and increased obesity rates in exposed children 1, 5
• Do not combine metformin with letrozole for ovulation induction; combination offers no advantage over letrozole alone 4

Alternative and Combination Therapies

If metformin alone provides insufficient benefit:

• GLP-1 receptor agonists (liraglutide 1.8 mg daily or semaglutide) may provide additional benefits for weight reduction and metabolic parameters when combined with metformin 1, 4, 5
• Combination with clomiphene citrate is more effective than either alone for clomiphene-resistant ovulation induction 4

The 2024 systematic review informing the 2023 International Evidence-based Guideline found limited data on anti-obesity agents in PCOS, with meta-analysis showing no differences between exenatide and metformin for most outcomes except slightly lower fasting glucose with metformin. 1

Special Populations

Lean/normal-weight PCOS patients:

• Metformin is indicated primarily when insulin resistance or metabolic syndrome features are present, even with normal BMI 4
• Prioritize lifestyle modification targeting 5% weight loss first 4
• For fertility concerns, use clomiphene citrate as first-line, not metformin monotherapy 4

Adolescents with PCOS:

• Metformin is recommended, particularly when excess body weight is present 2

Psychosocial Considerations

Address psychological and cultural factors:

• Screen for anxiety, depression, and eating-disorder behaviors, which are common in PCOS patients 1
• Incorporate cultural sensitivity and address weight-related stigma when counseling about lifestyle changes and pharmacotherapy to improve adherence 1