Autoantibodies and gastrointestinal symptoms in infertile women in relation to in vitro fertilization.

BACKGROUND: Prior reports suggest a link between gonadotropin-releasing hormone (GnRH) and gastrointestinal function. The aim of the study was to prospectively investigate women subjected to in vitro fertilization (IVF) using the GnRH analog buserelin, taking into account gastrointestinal symptoms and antibody development against buserelin, GnRH, luteinizing hormone (LH), and their receptors. METHODS: Gastrointestinal symptoms were registered by the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS) before and after IVF treatment, and five years later. Health-related quality of life was evaluated by the 36-item Short-Form questionnaire (SF-36). ELISA was used for antibody analyses before and after treatment. Data were compared with women from the general population. RESULTS: In total, 124 patients were investigated before and after IVF, and 62 were re-evaluated after five years. Buserelin treatment led to significant impairment of constipation (p = 0.004), nausea and vomiting (p = 0.035), psychological well-being (p = 0.000), and the intestinal symptoms' influence on daily life (p = 0.027). At 5-year follow-up, abdominal pain was worsened (p = 0.041), but psychological well-being was improved (p = 0.036), compared to prior treatment, and 15% had an observable deterioration in gastrointestinal symptoms. None developed severe dysmotility. Patients had higher prevalence of IgG antibodies against LH (p = 0.001) and its receptor (p = 0.016), and IgM antibodies against the GnRH receptor (p = 0.001) prior treatment compared with controls, but no antibody development was observed after IVF. CONCLUSION: Patients experience gastrointestinal symptoms during buserelin treatment, and abdominal pain is still increased after five years, but buserelin does not increase antibody formation against GnRH, LH or their receptors.

Posterior laryngitis: a disease with different aetiologies affecting health-related quality of life: a prospective case-control study.

BACKGROUND: Laryngo-pharyngeal reflux (LPR) is assumed to be the most common cause of posterior laryngitis (PL). Since LPR is found in healthy subjects, and PL patients are not improved by acid-reducing therapy, other aetiologies to PL must be considered. The aims of this study in PL were to investigate the prevalence of acid reflux in the proximal oesophagus and functional gastrointestinal symptoms, to analyse motilin levels in plasma, and to assess health-related quality of life (HRQOL) before and after treatment. METHODS: Forty-six patients (26 women), with verified PL, median age 55 (IQR 41-68) years, were referred to oesophago-gastro-duodenoscopy and 24-h pH monitoring. Plasma motilin was analysed. The 36-item Short-Form questionnaire was completed at inclusion and at follow-up after 43±14 months, when also the Visual Analogue Scale for Irritable Bowel Syndrome was completed. Values were compared to controls. Treatment and relief of symptoms were noted from medical records. RESULTS: Thirty-four percent had proximal acid reflux and 40% showed signs of distal reflux. Ninety-four percent received acid-reducing treatment, with total relief of symptoms in 17%. Patients with reflux symptoms had lower plasma motilin levels compared to patients without reflux symptoms (p = 0.021). The HRQOL was impaired at inclusion, but improved over time. Patients, especially men, had more functional gastrointestinal symptoms than controls. CONCLUSIONS: This study indicates that a minority of patients with PL has LPR and is cured by acid-reducing therapy. Disturbed plasma motilin levels and presence of functional gastrointestinal symptoms are found in PL. The impaired HRQOL improves over time.

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

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.

Depletion of enteric gonadotropin-releasing hormone is found in a few patients suffering from severe gastrointestinal dysmotility.

OBJECTIVE: Many patients, especially women, suffer from severe gastrointestinal pain and dysmotility for several years without being diagnosed. Depletion of gonadotropin-releasing hormone (GnRH) in the enteric nervous system (ENS) has been described in some patients. The aim of this study was to examine the expression of GnRH in ENS and antibodies against GnRH in serum, in a dysmotility patient cohort of southern Sweden. MATERIALS AND METHODS: All consecutive patients (n = 35) referred for laparoscopic full-thickness biopsy because of symptoms or signs of severe dysmotility between 1998 and 2009, or patients with a severe dysmotility disorder having had a bowel resection within the time frame, were considered for inclusion. In 22 cases, representative biopsy material containing ganglia was available, and these patients were included. Medical records were scrutinized. The expression of GnRH was determined by immunohistochemistry in bowel biopsies from these patients and in patients with carcinoma or diverticulosis without ENS histopathology. Antibodies against GnRH in serum were determined by ELISA in patients and controls. RESULTS: 14 patients were diagnosed with enteric dysmotility (ED) and 8 with chronic intestinal pseudo-obstruction due to varying etiology. Immunostained biopsies showed expression of GnRH in the ENS. A reduced expression of GnRH-containing neurons was found in 5 patients, as well as antibodies against GnRH in serum. 3 of these patients had a history of in vitro fertilization (IVF) using GnRH analogs. CONCLUSIONS: A subgroup of patients with severe dysmotility had a reduced expression of GnRH-containing neurons in the ENS and expressed antibodies against GnRH in serum.

Expression of Luteinizing Hormone Receptor in the Gastrointestinal Tract in Patients with and without Dysmotility.

Leuprolide is a gonadotropin-releasing hormone (GnRH) analog which has been shown to reduce symptoms in patients with irritable bowel syndrome (IBS) and chronic intestinal pseudo-obstruction (CIPO). The mechanism is not known, but one hypothesis is through down-modulation of luteinizing hormone (LH) secretion, a hormone whith antagonistic effect on gastrointestinal motility. However, presence of LH receptors in the gastrointestinal tract has never been described. The aim of this study was to find one possible way of action for leuprolide by examining the presence of the LH receptor, and if present, to see whether there was different expression in patients with or without dysmotility. Full-thickness biopsies from the bowel wall of patients with and without severe dysmotility were examined using immunohistochemistry staining. Biopsies showed expression of LH receptors on myenteric neurons and in glial cells, neutrophils, endothelial cells and mast cells. There was no difference in expression between patient groups.

Evaluation of gastrointestinal symptoms in different patient groups using the visual analogue scale for irritable bowel syndrome (VAS-IBS).

BACKGROUND: Irritable bowel syndrome (IBS) and gastrointestinal (GI) dysmotility disorders have a similar clinical picture, although dysmotility disorders require the attention of a specialist. Patients with primary Sjögren's syndrome (pSS) have also been described to suffer from IBS-like symptoms. No objective marker is available to distinguish between the patients. A visual analogue scale has been developed for IBS patients (VAS-IBS) to measure treatment response of GI symptoms and well-being in patients with IBS. The aim of the present study was to examine if VAS-IBS could be used to compare the degree of GI complaints in different patient populations, to get an objective marker to differentiate between the patients. METHODS: The VAS-IBS consists of 7 VAS scales, namely, abdominal pain, diarrhoea, constipation, bloating and flatulence, vomiting and nausea, psychological well-being and the intestinal symptoms' influence on daily life. Consecutive female patients suffering from IBS, dysmotility disorders and pSS were asked to complete the VAS-IBS questionnaire when visiting the out-patient clinics. In addition, a control population consisting of healthy female volunteers was included. RESULTS: Healthy volunteers had almost no GI symptoms, whereas all 3 patient groups expressed symptoms. There was no statistical significant difference between IBS and dysmotility in any of the scales besides vomiting and nausea (p = 0.044). Except for constipation, patients with pSS had less severe symptoms than the others. CONCLUSION: The VAS-IBS questionnaire could be used to assess the level of GI symptoms. However, VAS scores do not help the clinicians to differentiate between IBS and other dysmotility disturbances.

Impaired gastric emptying in primary Sjogren's syndrome.

OBJECTIVE: To investigate the prevalence of impaired gastric emptying (IGE) and its relation to autonomic nervous dysfunction (AD), functional bowel syndrome, and inflammatory and serological variables in patients with primary Sjögren's syndrome (pSS). METHODS: Twenty-eight patients with pSS according to the American-European Consensus Criteria were included in the study. Gastric emptying was evaluated by the octanoate breath test from which half-time (t(half)) and lag-time (t(lag)) were determined and compared with the results from 50 healthy controls. Autonomic nervous function was evaluated by 5 objective autonomic reflex tests (ART) and by the Autonomic Symptom Profile (ASP) questionnaire evaluating AD symptoms. These results were compared with previously investigated healthy ART controls and population-based ASP controls. Patients were also assessed regarding symptoms of functional bowel syndrome. RESULTS: The t(half) and the t(lag) were significantly prolonged in patients compared to controls. Forty-three percent of patients with pSS presented signs of IGE and 29% fulfilled the criteria for gastroparesis. Significant correlations were found between t(lag) and increased levels of IgG (p = 0.02) and erythrocyte sedimentation rate (ESR; p = 0.01). In addition, rheumatoid factor (RF) seropositives showed objective signs of IGE to a greater extent than RF seronegatives. No associations between IGE, ART variables, ASP variables, or gastrointestinal symptoms were found. CONCLUSION: IGE was common in pSS. Associations with inflammatory and serological features of pSS could imply immunological mechanisms behind the IGE. Objective signs of IGE were not associated with objective signs or subjective symptoms of AD or functional bowel syndrome.

Autonomic nervous dysfunction development in patients with primary Sjogren's syndrome: a follow-up study.

OBJECTIVES: To investigate autonomic dysfunction (AD) development in patients with primary SS (pSS) and the associations between AD and clinical, inflammatory and serological features of pSS. METHODS: Twenty-seven patients with pSS, who had previously been evaluated for AD, were included in the study. The patients were studied at baseline and at follow-up by objective autonomic reflex tests (ARTs) and by the autonomic symptom profile (ASP) questionnaire, evaluating AD symptoms. The median follow-up time was 5 years for the ART and 4 years for the ASP variables. The results were compared with previously investigated healthy ART controls and population-based ASP controls. Fatigue, anxiety and depression were assessed by the profile of fatigue and by the Hospital Anxiety and Depression scale. RESULTS: Three of five ART variables as well as the ASP total score were significantly abnormal both at baseline and at follow-up in pSS patients in comparison with controls. When comparing ART and ASP results in pSS patients between baseline and follow-up, only the lowest diastolic blood pressure (lDBP) ratio significantly deteriorated during the follow-up period. The ART and ASP variables were not significantly correlated. However, the ASP total score significantly correlated with measurements of fatigue, anxiety and depression. CONCLUSIONS: Both objective signs and subjective symptoms of parasympathetic and sympathetic dysfunction were seen in pSS patients, both at baseline and at follow-up. During follow-up, only the lDBP ratio was found to significantly deteriorate. AD symptoms were significantly associated with fatigue, anxiety and depression.