Photo Credit: iStock.com/Rasi Bhadramani

A new single-cell endometrium atlas shows how PCOS alters endometrial cell composition, disrupts hormone signaling, and impairs receptor signaling.

“Polycystic ovary syndrome (PCOS) has a negative effect on the receptivity of the endometrium to embryo implantation and increases the risk of miscarriage and endometrial cancer,” researchers wrote in Nature Medicine. “The cellular and molecular heterogeneity of the endometrium in women with PCOS has not been well studied.”

To address this research gap, Elisabet Stener-Victorin, PhD, applied single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics to create a detailed cellular and molecular map of the proliferative-phase endometrium in women with PCOS.

The researchers analyzed 247,791 nuclei from 27 biopsies in women with PCOS alongside matched controls.

“We identified cell-type-specific molecular disease signatures, variations in cellular composition, and spatial localization of PCOS-specific cells,” the authors wrote.

Endometrial Composition Alterations in PCOS

Compared with samples from controls, PCOS samples exhibited a higher proportion of epithelial cells and reduced numbers of stromal and lymphoid cells. Spatial transcriptomics confirmed these findings, showing distinct clustering of epithelial (EPCAM-positive) and stromal (IGF1-positive) populations.

Crucially, disease-specific gene expression patterns were linked to clinical features such as insulin resistance and hyperandrogenism.

“Our findings highlight that the PCOS endometrium exhibits an altered immune environment and impaired hormone receptor signaling,” Dr. Stener-Victorin and colleagues wrote.

Metformin and Lifestyle Interventions

In a subset of participants, 16 weeks of metformin therapy and lifestyle intervention partially restored normal endometrial gene signatures. Metformin-treated samples showed reductions in markers of hyperandrogenism and improvements in insulin sensitivity.

“Samples taken after metformin treatment showed extensive recovery of disease-specific endometrial signatures,” the authors wrote.

Lifestyle interventions improved menstrual cycle regularity in some participants, although the hormonal changes were less pronounced compared to those in the metformin group.

Epithelial and Stromal Disruptions

Detailed subcluster analysis revealed six distinct epithelial populations, including luminal cells, SOX9+ progenitors, and androgen receptor-positive cells. Among women with PCOS, downregulation of estrogen receptor-α (ESR1) was noted, along with dysregulation of genes tied to implantation failure (eg, PAEP) and endometrial cancer (eg, NEAT1).

Similarly, stromal cells in PCOS demonstrated downregulated ESR1 and disruptions in extracellular matrix organization. Metformin reversed dysregulation in pathways critical to collagen metabolism and the development of connective tissue. “These treatment-specific improvements reflect restoration of PCOS-specific endometrial dysfunction,” the authors concluded.

Immune Microenvironment: Persistent Challenges

Although the researchers determined that PCOS did not dramatically alter immune cell populations, gene expression profiling revealed significant changes in uterine natural killer cells and macrophages. Dysregulated pathways involved collagen metabolism, extracellular matrix organization, and integrin signaling.

Metformin reversed many of these abnormalities, whereas lifestyle interventions showed more modest effects. “Metformin treatment normalized collagen- and ECM-related gene expression in key immune subpopulations,” the study authors noted.

Toward Targeted Therapeutics

This high-resolution analysis reinforces the notion that cell-specific disruptions across epithelial, stromal, and immune compartments contribute to PCOS-related endometrial dysfunction. Moreover, it highlights metformin’s broader restorative capacity, extending beyond its metabolic benefits.

“Potential therapeutic targets, such as integrin inhibitors, were identified, laying the groundwork for future targeted therapies,” Dr. Stener-Victorin and colleagues wrote.