Cell map offers insights into endometrial dysfunction in women with PCOS

Women with polycystic ovary syndrome (PCOS) find it harder to get pregnant, have more frequent miscarriages and have a higher risk of developing endometrial cancer. Now, in a new study published in Nature Medicine, Swedish researchers have shown that the uterine lining of these women differs in terms of both the composition of individual cells and gene expression. The results open the door to new drug treatments.

PCOS is the most common hormonal disorder affecting 11-13% of women of reproductive age. Women with the syndrome have difficulty getting pregnant and are at increased risk of miscarriage and uterine cancer, especially cancer of the endometrium. It is also common for affected women to be overweight and insulin resistant.

By studying endometrial tissue samples from five healthy women and 12 women with PCOS, the researchers created a cell map of individual cells. The women were all of similar age, weight and BMI and the tissue samples were taken at the same phase of the menstrual cycle to eliminate factors that could influence the analyses. In the study, all women were overweight, but only the women with PCOS were insulin resistant and had elevated levels of male sex hormones.

In total, almost 250,000 cell nuclei from the women's uterine linings were analyzed. The researchers found a clear difference in the composition of cell types with a higher proportion of so-called epithelial cells and a lower proportion of stromal cells in the uteruses of women with PCOS.

These results show that the growth of the cells is affected, which 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."

Elisabet Stener-Victorin, Professor of Reproductive Physiology at Karolinska Institutet and research leader of the current study

In the detailed cell map, the researchers can show that many genes in specific cell types have a disturbed expression in women with PCOS. A large proportion of the affected genes are linked to difficulties for the early embryo to attach to the uterus, miscarriage and endometrial cancer with functions affecting cell-to-cell attachment and communication.

"Our analyses show that certain cell types in the endometrium have disrupted communication and interaction specific to PCOS," says Gustaw Eriksson, one of the study's first authors and a doctoral student in Elisabet Stener-Victorin's research group.

The study also included a part where the women with PCOS underwent treatment with the diabetes drug metformin with or without lifestyle advice on diet and exercise. After 16 weeks of treatment, the researchers found that many gene expressions in specific cell types, especially in the epithelial and stromal cells, were normalised by metformin, but also by lifestyle changes, although not as pronounced.

"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," says Elisabet Stener-Victorin.

Another important finding was the correlation between gene expression in specific cell types and important clinical features of PCOS, such as elevated levels of male sex hormone and insulin resistance, highlighting the complex relationship between hormonal and metabolic factors and endometrial dysfunction.

"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," says Elisabet Stener-Victorin.

The study is a collaboration with Dr Congru Li as joint first author, and Associate Professor Qiaolin Deng and Associate Professor Sophie Petropoulos with joint senior and corresponding authorship.

The research was funded by the Swedish Research Council, the Novo Nordisk Foundation, the Diabetes Foundation and the Knut and Alice Wallenberg Foundation, among others.