Skip to main content
SpringerLink
Log in

GnRH receptor-activating autoantibodies in polycystic ovary syndrome: identification of functional epitopes and development of epitope mimetic inhibitors

  • Research Letter
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

We have recently demonstrated that gonadotrophin-releasing hormone receptor-activating autoantibodies (GnRHR-AAb) are associated with polycystic ovary syndrome (PCOS). The aim of this study was to map the antigenic epitopes of GnRHR-AAb from PCOS patients, and develop retro-inverso peptide inhibitors that specifically target GnRHR-AAb.

Methods

Serum samples from ten GnRHR-AAb-positive PCOS patients and ten GnRHR-AAb-negative healthy controls were tested. Epitope mapping for GnRHR-AAb was performed using a set of 11 overlapping octapeptides spanning the second extracellular loop of GnRHR. Antibody-blocking effect of the designed retro-inverso peptide inhibitors was evaluated in a cell-based bioassay.

Results

Two peptide sequences, FSQCVTHC and HCSFSQWW, were found to react with all PCOS sera, but not with control sera. Two retro-inverso peptides that mimic the identified epitopes, d-CHTVCQSF and d-WWQSFSCH, significantly inhibited PCOS serum IgG-induced GnRHR activation. One of these two peptide inhibitors, d-CHTVCQSF, largely suppressed autoantibody-induced GnRHR activation, suggesting that the epitope sequence FSQCVTHC may be a major functional target of GnRHR-AAb.

Conclusion

We have identified a dominant functional epitope for GnRHR-AAb associated with PCOS, and demonstrated effective blocking of GnRHR-AAb activity with epitope-mimicking retro-inverso peptide inhibitors. These proteolytically stable decoy peptides may have important therapeutic implications in subjects who harbor these autoantibodies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. M.O. Goodarzi, D.A. Dumesic, G. Chazenbalk, R. Azziz, Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat. Rev. Endocrinol. 7(4), 219–231 (2011). https://doi.org/10.1038/nrendo.2010.217

    Article  CAS  PubMed  Google Scholar 

  2. J. Petrikova, I. Lazurova, S. Yehuda, Polycystic ovary syndrome and autoimmunity. Eur. J. Intern. Med. 21(5), 369–371 (2010). https://doi.org/10.1016/j.ejim.2010.06.008

    Article  PubMed  Google Scholar 

  3. D.C. Kem, H. Li, X. Yu, E. Weedin, A.C. Reynolds, E. Forsythe, M. Beel, H. Fischer, B. Hines, Y. Guo, J. Deng, J.T. Liles, Z. Nuss, M. Elkosseifi, C.E. Aston, H.R. Burks, L.B. Craig, The role of GnRH receptor autoantibodies in polycystic ovary syndrome. J. Endocr. Soc. 4(8), bvaa078 (2020). https://doi.org/10.1210/jendso/bvaa078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. E.A. Weedin, H.R. Burks, X. Yu, H. Li, C.E. Aston, D.C. Kem, L.B. Craig, Elevated activity levels of activating autoantibodies to the GnRH receptor in patients with polycystic ovary syndrome. Fertil. Steril. Rep. 1(3), 299–304 (2020). https://doi.org/10.1016/j.xfre.2020.09.015

    Article  Google Scholar 

  5. H. Li, Y. Guo, J. Deng, H. Fischer, E.A. Weedin, H.R. Burks, L.B. Craig, X. Yu, 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(1), 163–171 (2021). https://doi.org/10.1007/s12020-021-02761-7

    Article  CAS  PubMed  Google Scholar 

  6. D. Lizneva, L. Suturina, W. Walker, S. Brakta, L. Gavrilova-Jordan, R. Azziz, Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil. Steril. 106(1), 6–15 (2016). https://doi.org/10.1016/j.fertnstert.2016.05.003

    Article  PubMed  Google Scholar 

  7. H. Li, Y. Guo, G. Zhang, J. Deng, H. Fischer, L.B. Craig, X. Yu, D.C. Kem, Gonadotrophin-releasing hormone receptor autoantibodies induce polycystic ovary syndrome-like features in a rat model. Exp. Physiol. 106(4), 902–912 (2021). https://doi.org/10.1113/EP089109

    Article  CAS  PubMed  Google Scholar 

  8. P.M. Fischer, The design, synthesis and application of stereochemical and directional peptide isomers: a critical review. Curr. Protein Pept. Sci. 4(5), 339–356 (2003). https://doi.org/10.2174/1389203033487054

    Article  CAS  PubMed  Google Scholar 

  9. A.S. Kolaskar, P.C. Tongaonkar, A semi-empirical method for prediction of antigenic determinants on protein antigens. FEBS Lett. 276(1-2), 172–174 (1990). https://doi.org/10.1016/0014-5793(90)80535-q

    Article  CAS  PubMed  Google Scholar 

  10. J.M. Mason, Design and development of peptides and peptide mimetics as antagonists for therapeutic intervention. Future Med. Chem. 2(12), 1813–1822 (2010). https://doi.org/10.4155/fmc.10.259

    Article  CAS  PubMed  Google Scholar 

  11. H. Li, D.C. Kem, L. Zhang, B. Huang, C. Liles, A. Benbrook, H. Gali, V. Veitla, B.J. Scherlag, M.W. Cunningham, X. Yu, Novel retro-inverso peptide inhibitor reverses angiotensin receptor autoantibody-induced hypertension in the rabbit. Hypertension 65(4), 793–799 (2015). https://doi.org/10.1161/HYPERTENSIONAHA.114.05037

    Article  CAS  PubMed  Google Scholar 

  12. H. Li, L. Zhang, B. Huang, V. Veitla, B.J. Scherlag, M.W. Cunningham, C.E. Aston, D.C. Kem, X. Yu, A peptidomimetic inhibitor suppresses the inducibility of beta1-adrenergic autoantibody-mediated cardiac arrhythmias in the rabbit. J. Interv. Card Electrophysiol. 44(3), 205–212 (2015). https://doi.org/10.1007/s10840-015-0063-8

    Article  PubMed  PubMed Central  Google Scholar 

  13. H. Li, G. Zhang, L. Zhou, Z. Nuss, M. Beel, B. Hines, T. Murphy, J. Liles, L. Zhang, D.C. Kem, X. Yu, Adrenergic autoantibody-induced postural tachycardia syndrome in rabbits. J. Am. Heart Assoc. 8(19), e013006 (2019). https://doi.org/10.1161/JAHA.119.013006

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This manuscript is dedicated to the memory of our colleague Dr. David C. Kem, who passed away in 2020. He proposed the use of peptidomimetics as potential therapeutic agents for polycystic ovary syndrome associated with GnRH receptor autoimmunity.

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, and an Exploratory Grant award from Harold Hamm Diabetes Center at the University of Oklahoma.

Author information

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 & Xichun Yu

  2. Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Hariprasad Gali

  3. 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

Authors
  1. Hongliang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yankai Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jielin Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hariprasad Gali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth A. Weedin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heather R. Burks
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. LaTasha B. Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xichun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xichun Yu.

Ethics declarations

Conflict of interest

D.C.K., X.Y., H.L., and L.B.C. hold a US patent (10,975,124) and a US patent application (17/165,070, D.C.K.) regarding the retro-inverso peptides used in this manuscript. All other authors have no conflict of interest to disclose.

Ethical approval

This study was approved by the University of Oklahoma Health Sciences Center Institutional Review Board and conforms to the US Federal Policy for the Protection of Human Subjects.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, H., Guo, Y., Deng, J. et al. GnRH receptor-activating autoantibodies in polycystic ovary syndrome: identification of functional epitopes and development of epitope mimetic inhibitors. Endocrine 75, 959–963 (2022). https://doi.org/10.1007/s12020-021-02944-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-021-02944-2

Keywords

Search

Navigation