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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.

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