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Increased testosterone and proinflammatory cytokines in patients with polycystic ovary syndrome correlate with elevated GnRH receptor autoantibody activity assessed by a fluorescence resonance energy transfer-based bioassay

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Abstract

Purpose

The recently identified agonistic autoantibodies (AAb) to the gonadotropin-releasing hormone receptor (GnRHR) are a novel investigative and therapeutic target for polycystic ovary syndrome (PCOS). In this study, we used a new cell-based fluorescence resonance energy transfer (FRET) bioassay to analyze serum GnRHR-AAb activity and examine its relationship with testosterone and proinflammatory cytokines in patients with PCOS.

Methods

Serum samples from 33 PCOS patients, 39 non-PCOS ovulatory infertile controls and 30 normal controls were tested for GnRHR-AAb activity and proinflammatory cytokines in a FRET-based bioassay and multiplex bead-based immunoassay, respectively. Correlation was analyzed using the Spearman’s correlation test.

Results

Serum GnRHR-AAb activity was significantly higher in the PCOS patients than for the ovulatory infertile (p < 0.05) and normal (p < 0.01) controls. GnRHR-AAb were positive in 39% of PCOS patients, 10% of ovulatory infertile controls, and 0% of normal controls. PCOS IgG-induced GnRHR activation was specifically blocked by the GnRHR antagonist cetrorelix. Serum levels of proinflammatory cytokines interleukin-2, interleukin-6, interferon-γ, and tumor necrosis factor-α were significantly increased in PCOS patients compared with ovulatory infertile and normal controls (p < 0.01). Correlation analysis demonstrated positive correlations of GnRHR-AAb activity with testosterone and proinflammatory cytokine levels in the PCOS group.

Conclusions

Elevated GnRHR-AAb activity, as assessed by a new FRET assay, is associated with increased testosterone and proinflammatory cytokines in PCOS, suggesting autoimmune activation of GnRHR may contribute to the pathogenesis of this common disorder.

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Acknowledgements

We gratefully acknowledge the contributions of our colleague Dr. David Kem, who recently passed away. He pioneered the concept of GnRH receptor autoimmunity as a potential pathogenic mechanism for polycystic ovary syndrome.

Funding

This work was supported in part by funding from the National Heart, Lung, and Blood Institute (R01HL128393), Oklahoma Center for the Advancement of Science and Technology (OCAST), University of Oklahoma College of Medicine Alumni Association Research Fund, an Exploratory Grant award from Harold Hamm Diabetes Center at the University of Oklahoma, and individual grants from the Oklahoma University Foundation Webster Fund.

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Authors and Affiliations

  1. Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Hongliang Li, Yankai Guo, Jielin Deng, Hayley Fischer & Xichun Yu

  2. Section of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Elizabeth A. Weedin, Heather R. Burks & LaTasha B. Craig

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  1. Hongliang Li
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  2. Yankai Guo
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Correspondence to Xichun Yu.

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Li, H., Guo, Y., Deng, J. et al. Increased testosterone and proinflammatory cytokines in patients with polycystic ovary syndrome correlate with elevated GnRH receptor autoantibody activity assessed by a fluorescence resonance energy transfer-based bioassay. Endocrine 74, 163–171 (2021). https://doi.org/10.1007/s12020-021-02761-7

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