Dataset Information

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

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.

SUBMITTER: Li H

PROVIDER: S-EPMC8891032 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Li Hongliang H Guo Yankai Y Deng Jielin J Gali Hariprasad H Weedin Elizabeth A EA Burks Heather R HR Craig LaTasha B LB Yu Xichun X

Endocrine 20211122 3

<h4>Purpose</h4>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.<h4>Methods</h4>Serum samples from ten GnRHR-AAb-positive PCOS patients and ten GnRHR-AAb-negative healthy controls were tested. Epitope mapping fo ...[more]

PMID: 34807394

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Project description:BackgroundPolycystic ovary syndrome (PCOS) is a complex neuroendocrine disorder characterized by dysregulation of the hypothalamus. Both electroacupuncture (EA) and manual acupuncture (MA) have demonstrated therapeutic efficacy in the treatment of PCOS through improvements in hypothalamic function. However, the underlying mechanisms remain poorly understood. Gonadotropin-releasing hormone (GnRH) neurons are pivotal in regulating hypothalamic endocrine function, whereas tanycyte, a specialized glial cell type, potentially contribute to this process.MethodsA dihydrotestosterone (DHT)-induced PCOS-like mouse model was used to investigate the effects of acupuncture. Tissue clearing and three-dimensional (3D) imaging were employed to visualize the hypothalamic GnRH neuronal network and assess postacupuncture modifications. Transcriptome sequencing was performed to identify changes in the gene profiles associated with EA and MA. Rax-CreERT2 transgenic mice were utilized to investigate the molecular targets of EA in tanycytes.ResultsEA significantly alleviated neuroendocrine dysfunction in PCOS-like mice by restoring the density and coverage of GnRH axonal projections. MA displayed similar therapeutic effects but had less pronounced effects on GnRH axons. Transcriptome analysis revealed distinct mechanisms for these two approaches: EA primarily regulates neuroglial plasticity, whereas MA predominantly targets neurotransmitter regulation. Both EA and MA share a common therapeutic target in the integrin family. Functional studies in Rax-CreERT2 transgenic mice confirmed that Itgb1 plays a critical role in maintaining the balance of hypothalamic GnRH-tanycyte unit during EA treatment.ConclusionsEA exerts therapeutic effects on PCOS by targeting hypothalamic GnRH-tanycyte unit, with Itgb1 identified as a key factor. MA primarily functions through neurotransmitter regulation. These findings highlight potential hypothalamic targets and provide new insights into the distinct mechanisms of EA and MA.

Project description:Gonadotropin-releasing hormone (GnRH) analogues are commonly used in clinical practice to prevent premature luteinizing hormone (LH) surge during In-Vitro Fertilization/ Intra-Cytoplasmic Sperm Injection (IVF/ICSI) cycles. This review aimed to summarize the available evidence comparing the effects of conventional GnRH antagonist protocols, the most commonly used GnRH antagonist protocols, and GnRH agonist protocols on IVF/ICSI outcomes in women with polycystic ovary syndrome (PCOS). A comprehensive electronic search was carried out in Pubmed, Cochrane CENTRAL, Scopus, Web of Science, CINAHL, TRIP, ClinicalTrials.gov and ISRCTN registry from inception until 24 November 2020 without any language or date restrictions. In addition, reference lists of eligible studies and previous meta-analyses were hand-searched to identify relevant studies. Eligible randomized controlled trials were those designed to compare the effects of conventional GnRH antagonist protocols and GnRH agonist protocols on IVF/ICSI outcomes in PCOS subjects. The Cochrane ROB 2.0 tool was used to assess the risk of bias of each study, and the GRADE assessment was used to evaluate the overall quality of evidence. Data synthesis and analyses were done using Review Manager 5.3 with the assistance of Revman Web. A random-effects model was used for all meta-analysis. Dichotomous outcomes were reported as Relative Risk (RR) and continuous outcomes as Weighted Mean Difference (WMD), both with 95% CIs. The primary outcomes were Live birth rate, Ongoing pregnancy rate, and Ovarian hyperstimulation syndrome (OHSS) rate. Other IVF outcomes were considered secondary outcomes. We included ten studies with 1214 randomized PCOS women. Using GnRH antagonist protocols led to a significantly lower OHSS rate (RR = 0.58; 95% CI: [0.44 to 0.77], P = 0.0002), shorter stimulation duration (WMD = - 0.91; 95% CI: [-1.45 to - 0.37] day, P = 0.0009), lower gonadotropin consumption (WMD = - 221.36; 95% CI: [- 332.28 to - 110.45] IU, P < 0.0001), lower E2 levels on hCG day (WMD = - 259.21; 95% CI: [- 485.81 to - 32.60] pg/ml, P = 0.02), thinner endometrial thickness on hCG day (WMD = - 0.73; 95% CI: [- 1.17 to - 0.29] mm, P = 0.001), and lower number of retrieved oocytes (WMD = - 1.82; 95% CI: [- 3.48 to - 0.15] oocytes, P = 0.03). However, no significant differences in live birth rate, ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, miscarriage rate and cycle cancellation rate were seen between the GnRH antagonist protocols and the long GnRH agonist one. Although more cycles were cancelled due to poor ovarian response in the GnRH antagonist protocol (RR = 4.63; 95% CI: [1.49 to 14.41], P = 0.008), similar rates of cancellation due to risk of OHSS were noticed in both groups. The differences in IVF/ICSI outcomes may arise from the different patterns of gonadotropins suppression that the GnRH analogues exhibit during the early follicular phase of IVF/ICSI cycles and the divergent direct impacts of these analogues on ovaries and endometrial receptivity. The main evidence limitation was Imprecision. Conventional GnRH antagonist protocols represent a safer and more cost-effective treatment choice for PCOS women undergoing IVF/ICSI cycles than the standard long GnRH agonist protocol without compromising the IVF/ICSI clinical outcomes. The study had no sources of financial support and was prospectively registered at PROSPERO (International Prospective Register of Systematic Reviews) under registration number (CRD42021242476).

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

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