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Distress response in granulosa cells of women affected by PCOS with or without insulin resistance

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Abstract

Purpose

In this study, we investigated whether metabolic dysfunction in women with Polycystic ovarian syndrome (PCOS) induces granulosa cell (GC) stress and activates in the endoplamatic reticulum and the mitochondria (UPRer and UPRmt, respectively).

Methods

Women who were diagnosed with PCOS (based on the Rotterdam criteria), were divided into two groups, PCOS with insulin resistance (PCOS-IR; n = 20) and PCOS with no insulin resistance (PCOS-nIR; n = 20), and compared to healthy oocyte donors (CONT; n = 20). Insulin resistance (IR) was assessed on the results of homeostasis model assessment (HOMA) that determines IR using the concentration of fasting plasma glucose and fasting insuline. Expression of UPRer genes (i.e., IRE1, ATF4, ATF6, XBP1, BIP, and CHOP), and UPRmt genes (i.e., HSP60, HSP10, CLPP, and HSP40) was assessed in cumulus GCs by qRT-PCR.

Results

We found that several genes involved in UPRer and UPRmt were overexpressed in the GCs of PCOS-IR and PCOS-nIR compared to CONT. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR compared to CONT. BIP and CHOP were overexpressed in PCOS groups compared to CONT. HSP10 and HSP40 were upregulated in PCOS-IR and PCOS-nIR groups compared to the CONT. HSP60 and CLPP showed no statistical different expression in PCOS-IR and PCOS-nIR compared to CONT group.

Conclusion

Our findings suggest that the GCs of women with PCOS (with or without IR) are metabolically distressed and upregulate UPRer and UPRmt genes. Our study contributes to the understanding of the molecular mechanisms underlying the pathological changes that occur in the follicular microenvironment of women with PCOS.

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Acknowledgements

The authors thank the participants of the study for making this work possible, as well as the medical staff that participated in sample collection and processing.

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA

    Mauro Cozzolino & Emre Seli

  2. IVIRMA, Roma, Italy

    Mauro Cozzolino & Antonio Pellicer

  3. Universidad Rey Juan Carlos, Madrid, Spain

    Mauro Cozzolino & Juan Antonio Garcia-Velasco

  4. Grupo de investigación en Medicina Reproductiva, Fundación IVI-Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain

    Mauro Cozzolino, Sonia Herraiz & Antonio Pellicer

  5. Acibadem Maslak Hospital Assisted Reproductive Technologies Unit, Istanbul, Turkey

    Yigit Cakiroglu & Bulent Tiras

  6. Department of Obstetrics and Gynecology, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

    Yigit Cakiroglu & Bulent Tiras

  7. IVIRMA, Madrid, Spain

    Juan Antonio Garcia-Velasco, Alberto Pacheco, Susana Rabadan, Graciela Kohls & Ana Isabel Barrio

  8. IVIRMA New Jersey, Basking Ridge, NJ, USA

    Emre Seli

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  1. Mauro Cozzolino
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Contributions

M.C. take primary responsibility for the paper, collected data, made statistical analysis, and write the paper; S.H. edited the final version of the paper; Y.C., J.A.G.V., B.T., A.P., S.R., G.K., AB, recruited patients and collected data and E.S. reviewed the final version of the paper.

Funding

This study was supported by a grant from Foundation for Embryonic Competence to E.S.

Corresponding author

Correspondence to Mauro Cozzolino.

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Conflict of interest

M.C., S.H., Y.C., J.A.G.V., B.T., A.P., S.R., G.K. A.B., A.P. declares no competing interests concerning this research. E.S. is a consultant for and receives research funding from the Foundation for Embryonic Competence.

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All patients were informed and gave written consent.

Ethical approval and consent to participate

All the procedures per- formed in the studies that involved human participants were made under the ethical standards of the Institutional and National Research Committee, and also with the 1964 Declaration of Helsinki as well as its later amendments, or comparable ethical standards. All study procedures were approved and conducted according to the Institutional Review Board of Hospital Universitario Puerta de Hierro, Madrid, Spain (1812-MAD-099-MC). Patients signed an informed consense.

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Cozzolino, M., Herraiz, S., Cakiroglu, Y. et al. Distress response in granulosa cells of women affected by PCOS with or without insulin resistance. Endocrine 79, 200–207 (2023). https://doi.org/10.1007/s12020-022-03192-8

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