From the Guidelines
Metformin treats polycystic ovary syndrome (PCOS) primarily by improving insulin sensitivity, as supported by the most recent guidelines from 2023 1. In PCOS, many women experience insulin resistance, where cells don't respond properly to insulin, leading to higher insulin levels that stimulate excess androgen production by the ovaries. Metformin works by activating AMP-activated protein kinase (AMPK), which reduces hepatic glucose production, increases peripheral glucose uptake in muscles, and decreases intestinal glucose absorption. This lowers circulating insulin levels, which consequently reduces ovarian androgen production. Additionally, metformin directly inhibits ovarian androgen synthesis independent of its insulin-sensitizing effects. By addressing these underlying hormonal imbalances, metformin helps restore ovulation in many women with PCOS, improves menstrual regularity, reduces hirsutism and acne, and may assist with weight loss. The typical starting dose is 500 mg once daily with meals, gradually increasing to 1500-2000 mg daily in divided doses to minimize gastrointestinal side effects, as noted in previous studies 1. Therapeutic benefits may take 3-6 months to become fully apparent, and metformin is often used as part of a comprehensive approach that includes lifestyle modifications, as recommended in recent standards of care 1.
Key Points
- Metformin improves insulin sensitivity in PCOS patients
- It reduces hepatic glucose production and increases peripheral glucose uptake
- Metformin decreases ovarian androgen production and improves menstrual regularity
- The typical starting dose is 500 mg once daily, increasing to 1500-2000 mg daily
- Therapeutic benefits may take 3-6 months to become fully apparent
Mechanism of Action
Metformin's mechanism of action involves the activation of AMP-activated protein kinase (AMPK), which plays a key role in regulating glucose and lipid metabolism. By activating AMPK, metformin reduces hepatic glucose production, increases peripheral glucose uptake in muscles, and decreases intestinal glucose absorption. This results in lower circulating insulin levels, which consequently reduces ovarian androgen production. Additionally, metformin directly inhibits ovarian androgen synthesis independent of its insulin-sensitizing effects.
Clinical Recommendations
Recent guidelines recommend evaluating for polycystic ovary syndrome in female adolescents with type 2 diabetes, including laboratory studies when indicated 1. Metformin, in addition to lifestyle modification, is likely to improve menstrual cyclicity and hyperandrogenism in female individuals with type 2 diabetes 1. Oral contraceptive pills for treatment of polycystic ovary syndrome are not contraindicated for female individuals with type 2 diabetes 1.
From the Research
Mechanism of Action of Metformin in PCOS
- Metformin ameliorates insulin resistance, which helps to resolve hormonal and metabolic disturbances in PCOS 2, 3, 4, 5.
- The metabolic action of metformin involves increasing glucose uptake, thus inducing lower synthesis/secretion of insulin, which permits the possible restoration of normal biological functions affected by compensatory hyperinsulinemia reactive to increased peripheral insulin resistance 3.
- Metformin improves impairments typically observed in hyperinsulinemic PCOS patients, reducing the possible evolution towards metabolic syndrome and Type 2 diabetes 3.
- Metformin can decrease levels of androgen and LH and increase levels of SHBG in women with PCOS 4.
Effects of Metformin on PCOS Symptoms
- Metformin restores cyclic pituitary-gonadal function and improves fertility in women with PCOS 2, 3, 4, 5.
- Metformin improves ovulation and menstrual cyclicity in women with PCOS 2, 3, 4, 5.
- Metformin may reduce the risk of gestational diabetes, eclampsia, and hypertension in pregnant women with PCOS 3.
Controversies and Limitations
- One study found that metformin does not decrease insulin resistance in PCOS, suggesting that the cellular mechanism of insulin resistance in PCOS may be different from other common insulin-resistant states 6.
- The optimal dosage and times to initiate and discontinue metformin in women with PCOS who achieve pregnancy need to be defined with greater precision 2.