Gonadotropin-releasing hormone analog buserelin causes neuronal loss in rat gastrointestinal tract

Abstract

Gonadotropin-releasing hormone (GnRH) analogs are given to women undergoing in vitro fertilization. Case reports describing the development of chronic intestinal pseudo-obstruction and auto-antibodies against GnRH after such treatment suggest a strong association between intestinal dysfunction and GnRH analogs. No experimental model for studying such a relationship is currently at hand. Our main goal was to investigate possible enteric neurodegeneration and titers of GnRH antibodies in response to repeated administration of the GnRH analog buserelin in rat. Rats were treated for 1-4 sessions with daily subcutaneous injections of buserelin or saline for 5 days, followed by 3 weeks of recovery. Buserelin treatment caused significant loss of submucous and myenteric neurons in the fundus, ileum, and colon. The loss of enteric neurons can, at least partly, be explained by increased apoptosis. No GnRH- or GnRH-receptor-immunoreactive (IR) enteric neurons but numerous luteinizing hormone (LH)-receptor-IR neurons were detected. After buserelin treatment, the relative number of enteric LH-receptor-IR neurons decreased, whereas that of nitric-oxide-synthase-IR neurons increased. No intestinal inflammation or increased levels of circulating interleukins/cytokines were noted in response to buserelin treatment. Serum GnRH antibody titers were undetectable or extremely low in all rats. Thus, repeated administrations of buserelin induce neurodegeneration in rat gastrointestinal tract, possibly by way of LH-receptor hyperactivation. The present findings suggest that enteric neurodegenerative effects of GnRH analog treatment in man can be mimicked in rat. However, in contrast to man, no production of GnRH auto-antibodies has been noted in rat.

Expression and distribution of GnRH, LH, and FSH and their receptors in gastrointestinal tract of man and rat

“…LH-R has been demonstrated in submucous and myenteric neurons in small and large intestine, glia cells and endothelial cells in man [17], while in rat LH-R-IR was exclusively confined to enteric neurons [15]. In the former publication, no absorption controls were performed in man, but our present findings confirm LH-R on submucous and myenteric neurons.…”

“…Our present and previous findings of GnRH and LH-R in human and LH-R in rat gastrointestinal tract [12,15,17,18], may provide an explanation for the small intestinal dysmotility noted after administration of GnRH analogs or LH [9,10,11]. Patients with enteric dysmotility and chronic intestinal pseudo-obstruction exhibit disturbances in small intestinal motility patterns [26,27].…”

“…In rat, presence of GnRH and GnRH-R have been suggested in several cell types of the gastrointestinal tract [5,7,13,14], whereas such expression could not be confirmed by our group [15]. Notably, LH-R was found 4 to be expressed in enteric neurons in rat stomach, small and large intestine [15]. The aim of the present study was to study the possible expressions of GnRH, LH, and FSH as well as their receptors in man and rat, by retrieving microarray data from public repositories, by using quantitative Real-Time polymerase chain reaction (qRT-PCR), and by immunocytochemistry, with particular focus on the gastrointestinal tract.…”

“…Recently, our research group described GnRH expression in human submucous and myenteric neurons in both small and large intestine [12]. In rat, presence of GnRH and GnRH-R have been suggested in several cell types of the gastrointestinal tract [5,7,13,14], whereas such expression could not be confirmed by our group [15]. Notably, LH-R was found 4 to be expressed in enteric neurons in rat stomach, small and large intestine [15].…”

“…Previously, we reported expression of GnRH in submucous and myenteric neurons in human small and large intestine [12,18], while GnRH and GnRH-R-IR enteric neurons were absent in rat [15]. In contrast, other groups have found GnRH and GnRH-R immunoreactivity in rat enteric neurons, smooth muscle cells, and on parietal cells in the epithelium [5,6,7,13].…”