How does metformin help with Polycystic Ovary Syndrome (PCOS)?

How Metformin Helps with PCOS

Metformin improves PCOS primarily by reducing insulin resistance, which subsequently decreases ovarian androgen production and lowers testosterone levels, leading to improved menstrual regularity and ovulation rates. 1, 2

Primary Mechanism of Action

Metformin works through a metabolic pathway rather than direct hormonal suppression:

• Insulin sensitization is the core mechanism: Metformin improves how cells respond to insulin, reducing circulating insulin levels in hyperinsulinemic women with PCOS 1, 2
• Reduced insulin drives down androgen production: Lower insulin levels decrease ovarian stimulation, which reduces testosterone and other androgen production 1, 2
• Insulin sensitivity improves within 4 weeks of starting treatment, as demonstrated by improved glucose-to-insulin ratios 3

Metabolic Benefits

Metformin provides several cardiometabolic advantages beyond reproductive effects:

• Glucose metabolism improves: Metformin maintains or improves glucose tolerance over time, even when HbA1c is normal at baseline 1
• Lipid profile enhancement: Treatment decreases LDL cholesterol and triglyceride levels, providing cardiovascular protection 1
• Weight stabilization or modest reduction: Unlike thiazolidinediones which cause weight gain, metformin either maintains stable weight or produces modest decreases 1, 2
• Even 5% weight loss enhances metformin's effects on both metabolic and reproductive abnormalities 2

Reproductive and Hormonal Improvements

The reproductive benefits stem from the metabolic improvements:

• Menstrual cyclicity normalizes: Metformin restores regular menstrual cycles in approximately 67% of women, with all previously amenorrheic women resuming menses in clinical trials 1, 4
• Ovulation rates increase: About 67% of metformin-treated women achieve at least one ovulation compared to 45% with placebo 3
• Testosterone levels decrease significantly: Free androgen index drops from approximately 9.1 to 5.3, and total testosterone decreases from 2.9 to 1.8 nmol/L 4
• Clinical hyperandrogenic features improve: Acne improves dramatically (from 36% to 4% prevalence), and hirsutism scores decrease 4

Critical Clinical Caveat: Insulin Resistance Predicts Response

The presence of insulin resistance is the key predictor of metformin efficacy - this is a crucial clinical distinction:

• Women with insulin resistance respond well: 12 of 15 insulin-resistant women showed improved menstrual disturbances with metformin versus only 3 of 17 with placebo 3
• Women without insulin resistance show minimal benefit: Only 4 of 7 non-insulin-resistant women improved with metformin versus 4 of 6 with placebo (not statistically significant) 3
• Target population: Metformin is most appropriate for women with PCOS who demonstrate features of insulin resistance or metabolic syndrome, regardless of normal HbA1c values 1

Fertility and Pregnancy Considerations

Metformin has specific roles in fertility treatment:

• Not first-line for ovulation induction: Clomiphene citrate or letrozole remain first-line agents for ovulation induction 1
• Effective as combination therapy: Metformin combined with clomiphene citrate is more effective than either agent alone, particularly useful in clomiphene-resistant PCOS 5
• Pregnancy benefits: Continuing metformin through the first trimester at 1000-2000 mg/day may reduce early pregnancy loss, miscarriage, and preterm birth rates 1, 6, 5
• Preconception counseling is mandatory: Due to improved ovulation rates, unplanned pregnancy risk increases and requires discussion 1

Practical Dosing Algorithm

• Effective dose range: 1.5 to 2 grams daily (1500-2000 mg/day) 1, 5
• Typical regimen: 1000 mg twice daily has demonstrated significant improvements in hormonal and metabolic parameters over 12 weeks 1
• Extended-release formulation: Available in 500mg, 750mg, and 1000mg strengths for flexible twice-daily dosing 1
• Gastrointestinal side effects are the most common tolerability issue and may limit dose escalation 1

Absolute Contraindications

Metformin must be avoided in specific clinical scenarios:

• Impaired renal function (contraindicated) 1
• Known hepatic disease 1
• Hypoxemic conditions or severe infections 1
• Alcohol abuse 1
• Temporarily discontinue during acute illness with dehydration or hypoxemia 1
• Hold before radiocontrast administration 1

What Metformin Does NOT Do Well

Understanding limitations prevents inappropriate expectations:

• Not effective for first-line weight loss: Metformin alone is not a first-choice treatment for weight reduction in PCOS 6
• Limited efficacy for hirsutism and acne as monotherapy: While some improvement occurs, metformin is not first-line for treating clinical hyperandrogenic features 6
• Does not enhance letrozole: Combining metformin with letrozole (the current first-line ovulation induction agent) is not more effective than letrozole alone 5