Polycystic ovary syndrome is the most common endocrine condition in women and anovulatory cause of female infertility. While a pro-inflammatory cytokines and leukocyte bias in systemic circulation is well-documented in PCOS, it is not known how this inflammation extends to or affects the ovary. Additionally, the relationship between ovulation and inflammation in PCOS is not well-defined. We hypothesize that the ovarian follicular immune environment in PCOS is uniquely dysregulated, and that resolving anovulation through ovulation induction is not sufficient to alleviate this dysregulation. Using single-cell RNA and surface protein analysis of peripheral blood and follicular fluid from patients undergoing in vitro fertilization, we discovered that both control and PCOS follicles were immunologically distinct from circulation. At a systemic level, we find that ovulation induction in PCOS does not alleviate systemic inflammation. In contrast, while healthy control ovaries experienced acute immune-directed ovulatory signaling, PCOS ovarian follicles were deficient in key pro-ovulatory cell to cell communication, and displayed instead a chronic low-grade inflammatory state with fibrotic features. Taken together, a picture emerges where acute ovulation demonstrates a well-ordered series of follicle-specific immune information flows, which are disrupted and replaced by low grade chronic inflammation in the PCOS follicle.

AKW has worked as a consultant for MFB Fertility, which was not involved in this study. All other authors have no competing interests to declare.

AKW was supported by NICHD T32HD1013840. This study was also supported by a grant from the American Society for Reproductive Medicine to LGC and AKS as well as UW-Madison OBGYN development funds and NICHD K12HD000849-28 to AKS.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

We selected 8 age and BMI matched control and PCOS patients from our consented and sampled patient pool University of Wisconsin-Madison IRB #2018-1247

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Sequencing data and count matrices are deposited in the NCBI Gene Expression Omnibus/Sequence Read Archive (Bioproject ID PRJNA1299291). Differential gene expression analysis results for main-text comparisons as well as scripts for all analyses are available at https://github.com/staniclab/PCOS-CITE-Seq2025

https://github.com/staniclab/PCOS-CITE-Seq2025