Severe gastrointestinal dysmotility developed after treatment with gonadotropin-releasing hormone analogs

Abstract

Background. Sporadic cases of abdominal pain and dysmotility has been described after treatment with gonadotropin-releasing hormone (GnRH) analogs. The aim of the present study was to scrutinize for patients with severe gastrointestinal complaints after treatment with GnRH analogs, to describe the expression of antibodies against progonadoliberin-2, GnRH1, GnRH receptor (GnRHR), luteinizing hormone (LH), and LH receptor in serum in these patients, and to search for possible triggers and genetic factors behind the development of this dysmotility. Methods. Patients suffering from prolonged gastrointestinal complaints after treatment with GnRH analogs at the Department of Gastroenterology, Skåne University Hospital, were included. GnRHR and LH receptor (LHCGR) genes were exome-sequenced. Serum was analyzed by enzyme-linked immune sorbent assays for the presence of antibodies. Healthy blood donors and women treated with GnRH analogs because of in vitro fertilization (IVF) were used as controls. Results. Seven patients with severe gastrointestinal complaints after GnRH treatment were identified, of whom six suffered from endometriosis. Several variants were found within the 11 exons of LHCGR. The minor allele G, at the single nucleotide polymorphism rs6755901, was detected in homozygosity in two patients (28.5%) who had developed chronic intestinal pseudo-obstruction and in 5.5% of the IVF controls. Three patients expressed IgM antibodies against progonadoliberin-2 and three against GnRH1 (42.9%) when cut off was set to a titer >97.5th percentile in blood donors. Conclusion. A high prevalence of endometriosis, polymorphism in the LHCGR and GnRH1 and progonadoliberin-2 antibodies in serum was found among the patients with severe dysmotility after treatment with GnRH analogs.

Key Words:

• chronic intestinal pseudo-obstruction
• enteric dysmotility
• gonadotropin-releasing hormone
• in vitro fertilization
• luteinizing hormone
• progonadoliberin-2

Acknowledgements

This study was supported by the Development Foundation of Region Skåne (BO), King Gustav V:s and Queen Victoria Free Mason´s Foundation (BO) and the Swedish Research Council (Vetenskapsrådet) (MD). Conceived and designed the experiments: LC, MB, MD, BO. Performed the experiments: LC, MB, ES, BR, EP, LL. Analyzed the data: LC, MB, EP, MD, BO. Contributed reagents/materials/analysis tools: BR BO. Wrote the paper: EP, MD, BO. Identified the patients included: BO. Collected the blood samples and data from the patients: BR, BO. Performed the statistical analyses: BO. Contributed to the manuscript with constructive criticism, and read and approved the final manuscript: LD, MB, ES, BR, EP, LL, MD, BO.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.