Gastrointestinal motility and the role of gonadotropin-releasing hormone (GnRH)

Abstract: This thesis explores the relation between gonadotropin-releasing hormone (GnRH) and gastrointestinal symptoms and dysmotility. In primary Sjögren’s syndrome (pSS), a patient group with high levels of GnRH antibodies, associations between objective signs and symptoms of autonomic dysfunction (AD), impaired gastric emptying (IGE), and inflammatory and serological features were studied. Forty-three percent of pSS patients had objective signs of IGE, which was associated with increased levels of inflammatory markers and was more common in rheumatoid factor seropositive patients. No associations between IGE and objective and subjective AD variables or gastrointestinal symptoms were found. Gastrointestinal complaints in different patient populations with high levels of GnRH antibodies were investigated using the visual analog scale for irritable bowel syndrome (VAS-IBS) questionnaire. It was found that the VAS-IBS questionnaire can be used to assess gastrointestinal symptoms in individual patients, but does not aid clinicians in differentiating between different motility disorders. Patients with severe dysmotility, having had full-thickness biopsy, were investigated with the aim of describing expression of GnRH in the enteric nervous system (ENS) and antibodies against GnRH in serum. In a control group GnRH was present in about 50% of human myenteric neurons. A subgroup of patients with severe dysmotility expressed antibodies against GnRH and had reduced expression of GnRH-containing neurons in the ENS. Also, luteinizing hormone (LH) receptors were found in the gastrointestinal tract, in patients both with and without severe dysmotility, possibly providing a mechanism through which GnRH might affect the gastrointestinal tract. Gastrointestinal symptoms and presence of antibodies against GnRH and its receptor in serum in women before and after in vitro fertilization (IVF) treatment with buserelin was investigated. Buserelin treatment caused gastrointestinal symptoms during treatment, and the effect on symptoms in a five-year perspective varied; no severe dysmotility or production of antibodies against GnRH or its receptor was detected. Enteric neurodegeneration and titers of GnRH antibodies in rat in response to repeated administration of the GnRH analog buserelin was studied. Repeated administrations of buserelin were accompanied by up to 50% loss of enteric neurons in rat. However buserelin-treated rats do not display increased titers of GnRH antibodies in serum, nor do they lose weight compared to saline-treated control rats. Taken together, GnRH and LH receptors were expressed in about half of human enteric neurons. GnRH seems to affect gastrointestinal motility and function. Some patients with motility disorders express antibodies against GnRH in serum and display lower levels of the peptide in the bowel. Repeated treatment with the peptide in rat causes loss of myenteric neurons.