Metformin Restores Endometrial Health in PCOS

New research from the Karolinska Institutet has uncovered a surprising new role for metformin in women with polycystic ovary syndrome (PCOS). Beyond managing blood sugar, the diabetes drug appears to restore the health of the uterine lining, potentially reducing miscarriage risk and improving fertility.

The study was published in Nature Medicine.

Beyond blood sugar: A new role for metformin

PCOS is one of the most common hormonal disorders affecting 11-13% of women of reproductive age. It is characterized by irregular menstrual cycles, elevated levels of male hormones (androgens) and polycystic ovaries. PCOS not only complicates fertility – leading to challenges with conception and a higher risk of miscarriage – but also increases the risk of endometrial cancer.

Current treatments for PCOS primarily focus on managing symptoms through lifestyle changes – such as diet and exercise – and medication to control blood sugar and hormone levels.

One of the key underlying issues in PCOS is insulin resistance, a condition where the body’s cells become less responsive to insulin, causing elevated blood sugar levels. This insulin resistance is often managed with metformin, a drug commonly prescribed for type 2 diabetes. Metformin helps lower blood glucose by improving insulin sensitivity and reducing liver glucose production. While its role in managing metabolic dysfunction is well known, its effects on reproductive health – especially the endometrium – are less clear.

Emerging evidence suggests that the endometrium itself undergoes profound changes in women with PCOS, which may explain their higher rates of miscarriage and uterine cancer. Previous research has indicated that PCOS endometrium exhibits altered cellular composition and gene expression, but most studies have focused on bulk tissue analysis, overlooking the diversity of individual cell types​. Developing single-cell atlases of the endometrium is crucial for identifying cell-specific dysfunctions and revealing targeted treatment strategies.

To fill this gap, researchers from the Karolinska Institutet conducted the first single-cell transcriptomic study of the endometrium in women with PCOS, using advanced techniques like single-nuclei RNA sequencing and spatial transcriptomics.

Metformin restores endometrial health in PCOS

The researchers analyzed endometrial tissue samples from 12 women with PCOS and 5 healthy controls. The women were of similar age, weight and BMI and tissue samples were collected during the same phase of the menstrual cycle to ensure consistency.

The team mapped ~250,000 individual cell nuclei from the collected tissues to create a detailed cellular atlas of the endometrium.

In the PCOS samples, there was a higher proportion of epithelial cells and a reduced proportion of stromal cells compared to the healthy controls.

“These results may explain why it can take longer for affected women to become pregnant and why they are more likely to miscarry, as well as contributing to the increased risk of endometrial cancer,” said corresponding author Dr. Elisabet Stener-Victorin, a principal investigator of the research group Reproductive Endocrinology and Metabolism at the Department of Physiology and Pharmacology at Karolinska Institutet.

The team identified changes in immune-related gene expression, including genes like SLPI and CXCL14, which are linked to inflammation and implantation failure.

They also found correlations between gene expression changes in specific cell types and clinical features of PCOS, such as elevated androgen levels and insulin resistance.

“Our analyses show that certain cell types in the endometrium have disrupted communication and interaction specific to PCOS,” said lead author Gustaw Eriksson, a PhD student in Stener-Victorin's research group.

After initial baseline assessments, 10 of the women with PCOS underwent a 16-week randomized trial. Seven of the participants received metformin treatment, while the remaining three were advised on lifestyle changes, including diet and exercise.

In the participants that underwent metformin treatment, disrupted gene expression related to cell adhesion, extracellular matrix signaling and integrin pathways were restored. This was seen in several genes including ITGA2 and ITGA3, which are linked to abnormal cell proliferation and heightened cancer risk. Metformin treatment also improved cell-to-cell attachment and communication by restoring molecular pathways crucial for maintaining a healthy uterine lining, which may help reduce miscarriage risk and improve fertility.

While lifestyle changes also showed some positive effects on gene expression, the impact was less pronounced compared to metformin. This highlights the drug's unique ability to address not just metabolic dysfunction but also the underlying reproductive health issues associated with PCOS, however, further studies are needed to assess this effect in a larger cohort.

Moving toward personalized treatment

The findings from this study could change future treatment strategies for PCOS, moving the focus from managing metabolic symptoms to targeting endometrial dysfunction directly. By improving cell adhesion and reducing inflammation, metformin may help reduce miscarriage risk and improve pregnancy outcomes in affected women.

“We can show that metformin seems to have many more functions in women with PCOS than lowering blood sugar. In the study, all the women were overweight, but it is likely that metformin has similar effects in affected women who are not overweight but insulin resistant if they have problems getting pregnant or have repeated miscarriages,” said Stener-Victorin.

The authors also note targeting integrin pathways beyond metformin, may offer a new therapeutic pathway. Given their role in cell proliferation and increased cancer risk, developing drugs that specifically modulate integrin signaling could complement metformin’s effects and offer new ways to improve endometrial health in women with PCOS.

“As we identified changes in gene expression in specific cell types, this study provides crucial guidance for developing more targeted treatments for PCOS-related endometrial dysfunction,” said Stener-Victorin.

Reference: Eriksson G, Li C, Sparovec TG, et al. Single-cell profiling of the human endometrium in polycystic ovary syndrome. Nat Med. 2025. doi: 10.1038/s41591-025-03592-z

This article is a rework of a press release issued by the Karolinska Institutet. Material has been edited for length and content.