Metformin use in women with polycystic ovary syndrome (PCOS): Opportunities, benefits, and clinical challenges

Abstract

Metformin, a synthetic biguanide, is widely used to manage type 2 diabetes, and is commonly prescribed in polycystic ovary syndrome (PCOS) to address insulin resistance and associated metabolic and reproductive disturbances. PCOS is characterised by hormonal imbalances such as hyperandrogenism and anovulation, metabolic abnormalities including insulin resistance and increased cardiometabolic risk, and higher rates of pregnancy complications. However, the role of metformin in the multifaceted nature of PCOS remains debated. This review synthesises the mechanisms of action of metformin and its effects on metabolic, hormonal, reproductive, and pregnancy-related outcomes in PCOS. In non-pregnant women, metformin improves insulin resistance, menstrual regularity, and androgen levels, particularly in those with obesity or insulin resistance, and may enhance fertility when combined with other treatments. However, it is not effective as a first-line therapy for weight loss, ovulation induction, or treatment of clinical hyperandrogenic features, including hirsutism or acne. In pregnancy, metformin may reduce early pregnancy loss, miscarriage, and preterm birth, though findings for gestational diabetes and preeclampsia are inconsistent. Evidence is limited by study heterogeneity, varying diagnostic criteria, and the use of aggregate data in meta-analyses, all of which make interpretation challenging. Future research should prioritise well-powered clinical trials, individual patient data meta-analyses, and longer-term follow-up studies, particularly in pregnancy, to better define the populations most likely to benefit from metformin use across the PCOS spectrum. PLAIN LANGUAGE SUMMARY: Polycystic ovary syndrome (PCOS) is a common condition that affects up to 1 in 10 women of reproductive age. It is characterised by irregular or absent periods, signs of elevated male hormones (high androgens or excess hair growth), and/or polycystic ovaries seen on ultrasound. These features can lead to fertility problems, acne, psychological distress, and an increased risk of various disorders such as depression, type 2 diabetes and heart disease. Many women with PCOS also experience challenges during pregnancy, including a higher risk of miscarriage, preterm birth, and gestational diabetes. Metformin is a medication most often used to manage diabetes. In women with PCOS, it can help improve how the body responds to insulin, which may also reduce male hormone levels, improve menstrual cycles, and support fertility. This review examines the role of metformin in treating PCOS-both before and during pregnancy-by summarising key findings from the available evidence. In women who are not pregnant, metformin can help improve insulin resistance, hormone levels, and menstrual regularity, particularly among those who are overweight or have signs of insulin resistance. However, metformin alone is not a first-choice treatment for weight loss, ovulation problems, or symptoms such as acne and unwanted hair growth. When combined with other treatments, such as hormone therapy or fertility medications, it may offer additional benefits. During pregnancy, metformin is considered safe for use in women with PCOS and may lower the risk of early pregnancy loss and preterm birth. However, its effects on preventing gestational diabetes or high blood pressure are less clear, with mixed results across studies. Some research suggests that babies exposed to metformin in the womb may have slightly larger head sizes or a higher risk of being overweight in early childhood, but the long-term health effects remain unknown. Overall, metformin can be a helpful part of treatment for some women with PCOS, especially those with insulin resistance or certain pregnancy risks. Still, it is not a one-size-fits-all solution. More high-quality research is needed to better understand which women benefit most and to assess any long-term effects on children exposed to metformin during pregnancy.

Keywords: efficacy; infertility; metformin; polycystic ovary syndrome; pregnancy; reproductive health; review; safety.

FIGURE 1

Molecular mechanisms of metformin and its role in PCOS. Dashed lines indicate indirect effects while solid lines suggest direct effects. Metformin is transported into the cytoplasm via the OCT1 channel across different tissues. Its primary action occurs in mitochondria, where it increases NADH:NAD+ and AMP levels while reducing ATP, leading to enhanced glycolysis and suppressed gluconeogenesis in the liver. Elevated AMP activates AMPK, which also undergoes direct activation by metformin through PEN2 binding and ATP6AP1 interaction. AMPK enhances glycolysis by reducing PEP levels, mediates inflammatory responses by inhibiting NF‐κB signalling, and lowers ROS levels, which play a key role in maintaining cellular health. Through its widespread effects, AMPK improves insulin sensitivity and increases glucose uptake systemically. In the liver, AMPK inhibits ACC, thereby suppressing de novo lipogenesis and promoting fatty acid oxidation (acetyl‐CoA carboxylase). In the intestine, metformin‐activated AMPK stimulates bile acid, mucin glycoprotein, and antimicrobial peptide production either directly or by suppressing mTORC1 activity. These changes influence gut microbiota composition and gut hormones (GLP‐1 and PYY), affecting the gut‐brain axis and glucose homeostasis. Additionally, microbiota alterations increase SCFAs, which further regulate metabolic functions. Metformin also inhibits mitochondrial complex I in enterocytes, increasing lactate production, which supports hepatic gluconeogenesis via gut–liver cross‐talk as part of a splanchnic glucose–lactate–glucose cycle. In the pancreas, elevated AMPK and GLP‐1 enhance insulin secretion. In adipose tissue, AMPK reduces lipolysis and lipogenesis by inhibiting HSL, ATGL, and SREBP1c activity. In skeletal muscle, metformin‐activated AMPK increases glucose uptake by promoting GLUT4 translocation to the membrane. In cardiomyocytes, AMPK facilitates FFA uptake by translocating the CD36 receptor. In the ovary, metformin directly modulates FSHR activity, reducing FSH levels. It also lowers androgen levels by inhibiting the HSD3B2 and CYP17‐lyase enzymes through mitochondrial‐mediated pathways. This reduction in androgens may alleviate symptoms of PCOS driven by hormonal imbalances. ACC, acetyl‐CoA carboxylase; AMPK, AMP‐activated protein kinase; ATGL, adipose triglyceride lipase; ATP6AP1, ATPase H+ transporting accessory protein 1; CD36, cluster of differentiation 36; CYP17, Cytochrome P450 17; FFA, free fatty acid; FSH, follicle‐stimulating hormone; FSHR, follicle‐stimulating hormone receptor; GLP‐1, glucagon‐like peptide‐1; GLUT4, glucose transporter type 4; HSD3B2, Hydroxy‐Delta‐5‐Steroid Dehydrogenase, 3 Beta‐ And Steroid Delta‐Isomerase 2; HSL, hormone‐sensitive lipase; mTORC1, mechanistic target of rapamycin complex 1; NADH:NAD+, nicotinamide adenine dinucleotide + hydrogen; NF‐κB, nuclear factor κ‐light‐chain‐enhancer of activated B cells; OCT1, Organic Cation Transporter 1; PEN2, presenilin enhancer 2; PEP, phosphoenolpyruvate; PYY, peptide tyrosine–tyrosine; ROS, reactive oxygen species; SCFAs, short‐chain fatty acids; SREBP1c, sterol regulatory element‐binding protein 1c.