title: 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.
authors.affiliation: Department of Experimental Medical Sciences, Neurogastroenterology Unit, Lund University, BMC B11, 22184, Lund, Sweden. elin.sand@med.lu.se
authors.forename: Elin
authors.initials: E
authors.lastname: Sand
authors.forename: Ulrikke
authors.initials: U
authors.lastname: Voss
authors.forename: Oskar
authors.initials: O
authors.lastname: Hammar
authors.forename: Ragnar
authors.initials: R
authors.lastname: Alm
authors.forename: Gunilla Nordin
authors.initials: GN
authors.lastname: Fredrikson
authors.forename: Bodil
authors.initials: B
authors.lastname: Ohlsson
authors.forename: Eva
authors.initials: E
authors.lastname: Ekblad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002064:Buserelin / Q000494:pharmacology*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D003106:Colon / Q000166:cytology; D005260:Female; D041981:Gastrointestinal Tract / Q000166:cytology*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives*; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011974:Receptors, LH / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
chemical_list: D011974:Receptors, LH; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D014660:Vasoactive Intestinal Peptide; D052248:Nitric Oxide Synthase Type I; D002064:Buserelin