Antibodies against gonadotropin-releasing hormone (GnRH) and destruction of enteric neurons in 3 patients suffering from gastrointestinal dysfunction

Background: Antibodies against gonadotropin-releasing hormone (GnRH) and gastrointestinal dysmotility have been found after treatment with GnRH analogues. The aim of this study was to examine the presence of such antibodies in patients with dysmotility not subjected to GnRH treatment and study the anti-GnRH antibody effect on enteric neurons viability in vitro. Methods: Plasma and sera from 3 patients suffering from either enteric dysmotility, irritable bowel syndrome (IBS) or gastroparesis were analysed for C-reactive protein (CRP), and for GnRH antibodies and soluble CD40 by ELISA methods. Primary cultures of small intestinal myenteric neurons were prepared from rats. Neuronal survival was determined after the addition of sera either from the patients with dysmotility, from healthy blood donors, antiserum raised against GnRH or the GnRH analogue buserelin. Only for case 1 a full-thickness bowel wall biopsy was available for immunohistochemical analysis. Results: All 3 patients expressed antibodies against GnRH. The antibody titer correlated to the levels of CD40 (r(s) = 1.000, p < 0.01), but not to CRP. Serum from case 3 with highest anti-GnRH antibody titer, and serum concentrations of sCD40 and CRP, when added to cultured rat myenteric neurons caused remarkable cell death. In contrast, serum from cases 1 and 2 having lower anti-GnRH antibody titer and lower sCD40 levels had no significant effect. Importantly, commercial antibodies against GnRH showed no effect on neuron viability whereas buserelin exerted a protective effect. The full-thickness biopsy from the bowel wall of case 1 showed ganglioneuritis and decrease of GnRH and GnRH receptor. Conclusion: Autoantibodies against GnRH can be detected independently on treatment of GnRH analogue. Whether the generation of the antibody is directly linked to neuron degeneration and chronic gastrointestinal symptoms in patients with intestinal dysmotility, remains to be answered.