Study highlights how PCOS alters uterine lining

Study highlights how PCOS alters uterine lining | Image Credit: © Pakorn - © Pakorn - stock.adobe.com.

Differences in uterine lining composition

The composition of cells and gene expression in uterine lining differ between women with polycystic ovary syndrome (PCOS) vs those without PCOS, according to a recent study published in Nature Medicine.¹

Investigators developed a cell map by studying endometrial tissue samples in women with and without PCOS. This allowed them to identify several genes with disturbed expression among women with PCOS.¹

“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,” said Elisabet Stener-Victorin, MD, professor of reproductive physiology at Karolinska Institutet.¹

Study participants and design

Participants included women aged 18 to 40 years with a body mass index of 25 or higher.² Revised 2003 Rotterdam criteria was referenced when diagnosing PCOS among these individuals, and hirsutism was assessed using the Ferriman–Gallwey score.

The number of antral follicles, ovarian volume, and endometrial thickness were measured through transvaginal ultrasound. Controls included patients with under 12 antral follicles, and ovarian volume under 10 cm³, regular menstrual cycles, and a Ferriman–Gallwey score of 4 or less.²

Sex steroids were collected for serum analyses, including dehydroepiandrosterone (DHEA), androstenedione, testosterone, estradiol, and progesterone. An endometrial suction curette was used to collect endometrial tissue biopsies.²

Study results

There were 12 women with PCOS and 5 healthy controls included in the final analysis, with similar age, weight, and body mass index reported between groups. Elevated Ferrima–Gallwey scores, DHEA, and androstenedione were reported in PCOS patients, as well as insulin resistance.²

Of PCOS patients, 10 received a 16-week randomized trial, with 7 receiving metformin and 3 lifestyle interventions. No significant hormonal changes were reported in patients with lifestyle interventions, while metformin led to a decreased antral follicle count, androstenedione, testosterone, and a free androgen index.²

Using the single-nuclei map of endometrial biopsies from all participants, investigators identified compositional variations, cell-type-specific disease signatures, and transcriptomic changes following the 16-week intervention. The 10x Genomics protocol was utilized to perform single-nuclei RNA sequencing.²

Findings on cell types and proportions

There were 247,791 nuclei analyzed, 99,482 from PCOS baseline cases, 78,664 PCOS-metformin, 25,309 PCOS-lifestyle, and 44,336 controls. When evaluating these samples, investigators identified 7 main cell clusters, including stromal cell in 124,055, smooth muscle cells in 2737, epithelial cells in 105,095, lymphoid and myeloid immune cells in 13,596, endothelial cells in 2308, and lymphatic cell in 2308.²

When compared with controls, more epithelial cells and less stromal and lymphoid cells were observed in samples from PCOS patients. These differences did not significantly change following the intervention.²

Similar patterns were reported when comparing the cell-type proportions with proliferative endometrium from both groups. This highlights a detailed map of endometrial alterations among PCOS patients.²

Gene expression

The proportion of epithelial nuclei was increased in PCOS patients vs controls, though proportions did not differ between epithelial subpopulations vs controls. Additionally, certain epithelial subpopulations among PCOS women had downregulated estrogen-α, but this was partially reversed by metformin.²

“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.

References

1. Cell atlas of the endometrium in women with PCOS may lead to better treatment. Karolinska Institutet. March 20, 2025. Accessed March 21, 2025. https://www.eurekalert.org/news-releases/1077156?
2. 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