The Role of GnRH Receptor Autoantibodies in Polycystic Ovary Syndrome

Abstract

Objective Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? Design and Methods We retrospectively screened sera from 40 PCOS patients and 14 normal controls (NC) with regular menses by ELISA for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified IgG using a cell-based GnRHR bioassay. Results The mean ELISA value in the PCOS group was markedly higher than the NC (P=0.000036) and the OIC (P=0.0028) groups. IgG from a sample of five PCOS subjects, in contrast to a sample of five OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed (P<0.01) the elevated GnRHR activity induced by IgG from seven PCOS patients while the IgG activity levels from seven OIC subjects was unchanged. Five other OIC subjects had relatively high ELISA values at or above the 95% confidence limits. On further study, three had normal or low activity while two had elevated IgG-induced GnRHR activity. One suppressed with cetrorelix while the other did not. The co-presence of PCOS IgG increased the responsiveness to GnRH and shifted the dosage response curve to the left (P<0.01). Conclusions GnRHR-ECL2-AAb are significantly elevated in PCOS compared to normal controls. Their presence raises important etiological, diagnostic and therapeutic implications.

Elevated activity levels of activating autoantibodies to the GnRH receptor in patients with polycystic ovary syndrome

“…Because the GnRH receptor (GnRHR) is also a member of the family of seven transmembrane G-protein-coupled receptors (GPCRs) and is expressed primarily on the surface of the pituitary gonadotrope cells (as well as lymphocytes, breast, ovary, and prostate), it is certainly reasonable to consider an autoimmune process resulting in dysregulation of GnRH release from the hypothalamus. We have identified such an AAb, which was found to be markedly higher in patients with PCOS than in normal control subjects (13). Furthermore, we observed a stimulatory activity of this AAb in patients with PCOS as displayed by increasing the activation of transfected GnRHR cells (13).…”

“…We have identified such an AAb, which was found to be markedly higher in patients with PCOS than in normal control subjects (13). Furthermore, we observed a stimulatory activity of this AAb in patients with PCOS as displayed by increasing the activation of transfected GnRHR cells (13). This effect was significantly suppressed by the GnRHR antagonist cetrorelix.…”

“…The cell activity assay results from the present study provide promise in explaining the dysregulation of GnRH signaling associated with PCOS. While we originally examined the activating nature of the GnRHR AAbs in a small sample of patients (13), the expansion to include sera from 400 patients in the present study lends great strength to that finding.…”

“…This study confirms our previous findings. In our previous prospective case-control study of 40 infertile patients with PCOS, identified according to Rotterdam criteria, compared with 40 age-and BMI-matched infertile ovulatory controls, we identified the standardized optical density with the use of ELISA of GnRHR AAb levels in PCOS patients to be significantly higher than in ovulatory control subjects (P¼ .0032) and in normal control subjects (P¼ .0001) (13). With a subset of patient sera from that original study, we performed cell activity assays using transfected GnRHR cells with the addition of the GnRH antagonist cetrorelix to assess activity in both control samples (n ¼ 7) and those with PCOS (n ¼ 7).…”

“…We have previously demonstrated that the elevated levels of GnRHR AAbs in patients with PCOS can be suppressed with addition of cetrorelix to the cell assay (13). We have also demonstrated that the presence of the AAbs indirectly, in an allosteric fashion, enhances the effect of the natural ligand (GnRH) on the receptor activity (13). We think that this indirect effect may have significance along with the direct effect, although it is more difficult to measure and apply to the large number of samples in the present study.…”