Metformin for PCOS
Metformin is recommended as a cornerstone medication for PCOS, particularly in women with cardiometabolic features such as abdominal obesity and insulin resistance, at doses of 1-2 grams daily, though it should NOT be used as first-line therapy for ovulation induction when fertility is the primary goal. 1
Treatment Algorithm Based on Primary Goal
For Metabolic and Androgenic Management (Not Seeking Pregnancy)
Metformin is the primary pharmacological intervention for women with PCOS who have metabolic abnormalities, working by improving insulin sensitivity, which subsequently reduces ovarian androgen production and lowers testosterone levels. 1
Dosing: Typical effective doses range from 1,000-2,000 mg daily (often 1g twice daily), with doses up to 1,700 mg/day used based on body weight. 2, 3
Metabolic benefits: Metformin improves insulin sensitivity within 4 weeks of initiation, as demonstrated by improved HOMA-IR (from 4.6 to 2.3), decreased 2-hour glucose (117 to 90 mg/dL), and reduced insulin area under the curve. 4, 3
Hormonal improvements: Treatment significantly decreases total testosterone (2.9 to 1.8 nmol/L), free androgen index (9.1 to 5.3), and DHEAS levels, while improving menstrual cyclicity in approximately 67% of women. 3, 5
Clinical improvements: Metformin ameliorates acne (36% to 4% prevalence), reduces hirsutism scores (11.2 to 9.7), and restores normal menstrual cycles in 66.7% of women, with all previously amenorrheic women achieving menses restoration. 3
Weight effects: Unlike thiazolidinediones which cause weight gain, metformin tends to decrease weight, making it preferable for PCOS patients who are often overweight. 2
For Fertility and Ovulation Induction
Clomiphene citrate (or letrozole) should be used as first-line therapy, NOT metformin, as it is significantly more effective for ovulation induction. 1, 6
Evidence hierarchy: Approximately 80% of PCOS patients ovulate with clomiphene, and half of those who ovulate will conceive—substantially better than metformin alone. 1, 6
Metformin's adjunctive role: Metformin may be added to clomiphene in women with clomiphene-resistant PCOS, as the combination is more effective than either agent alone. 7
Insulin resistance as predictor: Metformin's clinical efficacy for improving menstrual cyclicity and ovulatory function is significantly better in women WITH insulin resistance (12 of 15 responders) compared to those without IR (4 of 7 responders), making IR a baseline predictor of treatment success. 4
Pregnancy outcomes: When metformin does restore ovulation, 16 of 48 patients (33%) with infertility achieved pregnancy during therapy, with all delivering healthy infants. 3
Critical Safety Considerations During Pregnancy
Metformin readily crosses the placenta with umbilical cord levels equal to or higher than maternal levels, and emerging evidence shows concerning long-term metabolic effects in offspring. 6
Offspring metabolic risks: Follow-up studies at ages 4-10 years demonstrate children exposed to metformin in utero have higher BMI, increased obesity rates, higher weight-to-height ratios, and increased waist circumferences. 6
Pregnancy continuation: If pregnancy is achieved, continuing metformin to the end of the first trimester at effective doses (1,000-2,000 mg/day) may help reduce miscarriage rates, though this must be weighed against offspring metabolic risks. 7
Contraindications in pregnancy: Metformin should NOT be used in pregnant women with hypertension, preeclampsia, or those at risk for intrauterine growth restriction due to potential for growth restriction or acidosis with placental insufficiency. 6
Preconception counseling: Women of childbearing age must be counseled that metformin may restore ovulation in anovulatory women, potentially leading to unintended pregnancy. 8
Cardiovascular Risk Management
All women with PCOS should be screened for cardiovascular disease risk factors, as they have increased risk for metabolic syndrome, diabetes, dyslipidemia, and hypertension. 2
Screening protocol: Monitor weight changes every 6-12 months, check blood pressure at least annually, obtain fasting lipid panels, screen for glycemic control, and assess smoking status and physical activity. 2
Metformin's cardiovascular role: Interventions improving insulin sensitivity, including metformin, may positively impact risk factors for diabetes and cardiovascular disease, though the role in primary or secondary prevention remains incompletely defined. 2
Glucose tolerance: In women with PCOS using metformin, glucose tolerance improves or remains steady over time, providing metabolic protection. 2
Common Pitfalls to Avoid
Do not use metformin as first-line for fertility: Clomiphene citrate is significantly more effective and should be tried first. 1, 6
Do not ignore insulin resistance status: Metformin efficacy for menstrual cyclicity is substantially better in women WITH insulin resistance, making this a critical baseline assessment. 4
Do not continue metformin throughout pregnancy without clear indication: RCTs have not demonstrated benefit in preventing spontaneous abortion or gestational diabetes, and offspring metabolic concerns are emerging. 6
Do not use high-dose gonadotropin protocols: If clomiphene fails, use low-dose gonadotropin therapy to reduce ovarian hyperstimulation risk. 1
Monitoring Requirements
Renal function: Regular testing of renal function is essential, as patients with kidney problems should not take metformin. 8
Vitamin B12: Monitor hematological parameters regularly, as metformin can cause vitamin B12 deficiency. 8
Lactic acidosis risk: Patients must be counseled about lactic acidosis symptoms (unusual muscle pain, trouble breathing, unusual sleepiness, unexplained stomach problems, feeling cold, dizziness, slow/irregular heartbeat) and instructed to discontinue immediately if these occur. 8
Surgical/radiological procedures: Metformin should be temporarily discontinued prior to any surgical or radiological procedure with injectable dyes or contrast agents. 8