Hongliang Li1, Yankai Guo1, Jielin Deng1, Hayley Fischer1, Elizabeth A Weedin2, Heather R Burks2, LaTasha B Craig2, Xichun Yu3. 1. Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 2. Section of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 3. Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. xichun-yu@ouhsc.edu.
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.
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.
Authors: Ricardo Azziz; Enrico Carmina; ZiJiang Chen; Andrea Dunaif; Joop S E Laven; Richard S Legro; Daria Lizneva; Barbara Natterson-Horowtiz; Helena J Teede; Bulent O Yildiz Journal: Nat Rev Dis Primers Date: 2016-08-11 Impact factor: 52.329
Authors: Robert P Millar; Zhi-Liang Lu; Adam J Pawson; Colleen A Flanagan; Kevin Morgan; Stuart R Maudsley Journal: Endocr Rev Date: 2004-04 Impact factor: 19.871
Authors: David C Kem; Hongliang Li; Xichun Yu; Elizabeth Weedin; Anna C Reynolds; Elizabeth Forsythe; Marci Beel; Hayley Fischer; Brendon Hines; Yankai Guo; Jielin Deng; Jonathan T Liles; Zachary Nuss; Myriam Elkosseifi; Christopher E Aston; Heather R Burks; LaTasha B Craig Journal: J Endocr Soc Date: 2020-06-18