Gonadotrophin‐releasing hormone receptor autoantibodies induce polycystic ovary syndrome‐like features in a rat model

Abstract

Gonadotrophin-releasing hormone receptor-activating autoantibodies (GnRHR-AAb) are associated with polycystic ovary syndrome (PCOS). In the present study, we examined the impact of GnRHR-AAb on reproductive function in GnRHR-immunized female rats. All immunized rats produced high titres of GnRHR-AAb targeting a dominant epitope located in the central region of the second extracellular loop of the GnRHR. Increased pulsatile luteinizing hormone secretion and testosterone concentrations were found in immunized rats. These rats exhibited disrupted oestrous cycles, increased ovarian follicular atresia, and activation of insulin signalling in the pituitary and ovary, as indicated by increased mRNA expressions of insulin receptor substrate, phosphatidylinositol 3-kinase and glucose transporter 1. No significant changes in inflammatory cytokines were detected in the ovarian tissue. These features mimic those observed in humans with PCOS. Our findings support the concept that chronic stimulation of the GnRHR by GnRHR-AAb, with an associated increase in pituitary luteinizing hormone secretion and ovarian androgen overproduction, might represent a new aetiological mechanism for PCOS.

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

“…One of these two peptide analogs, d-CHTVCQSF, largely suppressed autoantibody-induced GnRHR activation, indicating that the epitope sequence FSQCVTHC (amino acids 193-200) may be a major functional target of GnRHR-AAb. The same epitope was recognized by experimentally produced antibodies to GnRHR ECL2 in a rat model of autoimmune PCOS [7]. These antibodies share functional similarities with GnRHR-AAb from PCOS patients.…”

“…Compared to other peptidomimetics, the retro-inverso construct is relatively simple and can be administered orally as well as parenterally. Studies are underway to investigate the antibody blocking effect of the GnRHR-derived retro-inverso peptides in a recently developed animal model of autoimmune PCOS [7].…”

“…Epitope mapping for GnRHR-AAb was performed with multipin solid phase peptides as previously described [7]. Briefly, a set of 11 overlapping 8-mer peptides (each offset by two amino acids) spanning the ECL2 of human GnRHR (DSSGQTKVFSQCVTHCSFSQWWHQAFYN) [3] was synthesized onto polyethylene pins in a 96-well format (Mimotopes, Melbourne, Australia).…”

The effect of adding exogenous LH to IVF/ICSI cycles on pregnancy outcomes in elderly women with PCOS: a retrospective cohort study

“…The high LH levels were associated with the endocrine pro le of PCOS patients [20]- [21] . High insulin growth factor levels promote LH receptor expression [22]- [23] and the presence of GnRH receptor-activating autoantibodies (GnRHR-AAb) in the body causes chronic stimulation of the GnRH receptor (GnRHR) in PCOS [24]- [25]. The addition of GnRH-ant counteracts the early LH peak to some extent and signi cantly reduces the incidence of OHSS, which is now widely used in IVF/ICSI cycles in PCOS patients.…”