Abstract
This meta-analysis assessed the association between gonadotropin hormone-releasing hormone (GnRH) antibodies and irritable bowel syndrome (IBS). We defined a search strategy and implemented it with PubMed, Ovid, Scopus, and Web of Science databases for English language publications. The data were evaluated for acceptability, and randomized controlled studies as well as case-control, cross-sectional, and cohort studies reporting the prevalence of GnRH antibodies in IBS patients were included. The total number of patients in the included studies was 1095: 270 patients in the IBS group and 825 patients in the control group. By comparing the IBS group and the control group, we found a statistically significant association between IBS and the increased prevalence of GnRH IgM antibodies (risk ratio = 2.29, 95% confidence interval = 1.58 to 3.31, P < 0.0001). We also found a statistically significant association between IBS and increased prevalence of GnRH receptor IgM antibodies compared with controls (risk ratio = 3.80, 95% confidence interval = 1.72 to 8.38, P = 0.001). The meta-analysis revealed a statistically significant association between IBS and increased prevalence of GnRH IgM and GnRH receptor IgM antibodies.
Keywords: Endogenous gonadotropin-releasing hormone, GnRH antibodies, irritable bowel syndrome, metaanalysis
Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder described by bloating, abdominal discomfort, and disturbed excretion.1 It has been shown to affect 10% to 15% of the population, with women being 1.5 to 3 times more likely to have it than men.2 The absence of any recognizable physical, radiologic, or laboratory abnormalities indicative of organic disease is a distinguishing factor of IBS.1 Causes of IBS have not been recognized, but it has been proposed that in IBS, the epithelial barrier, bile acids, food antigens, and gut microbes produce abnormal responses in the main controllers of sensorimotor functions, including the hypothalamus-pituitary-adrenal axis, gut axis, enteric nervous system, and immune system.3 One possible explanation for IBS is antibodies against the gonadotropin hormone-releasing hormone (GnRH) receptors. GnRH is considered the primary controller of reproduction4 and is found within the enteric nervous system.5 It regulates secretion of follicle-stimulating hormone and luteinizing hormone (LH), which then control both endocrine and gonadal function.4 Connections between sex hormones, notably progesterone, and gastrointestinal function have been hypothesized to explain why women are affected to a greater extent than men.6,7 Here, we introduce the first meta-analysis to investigate a link between IBS and GnRH autoantibodies and discuss the current literature on the relation between anti-GnRH antibodies and IBS.
METHODS
We conducted this meta-analysis according to the Preferred Reporting for Systematic Review (PRISMA) guidelines and checklist. We searched PubMed, Ovid, Scopus, and Web of Science for English-language publications using the search strategy of (gonadotropin-releasing hormone) AND (irritable bowel syndrome) AND (autoantibodies). No filters were used. An additional manual search was done through the “related articles” function. Exported results from databases were placed in the Covidence platform. Two investigators (M.G., K.M.) screened the studies independently and then resolved conflicts together. We included any randomized controlled studies as well as prospective cohort, cross-sectional, and case-control studies that reported GnRH autoantibodies or GnRH receptor autoantibodies in IBS patients. We excluded case reports, editorials, reviews, animal studies, and studies unavailable in English. Two investigators (F.M., K.S.A.) independently extracted data and then reached consensus on the reported items. Quality assessment was performed using the New Castle–Ottawa Scale tool. Each study was given a score and ranked good, fair, or poor quality.
We used Review Manager version 5.4 to perform the meta-analysis. The continuous outcomes were measured as mean difference and standard deviation (SD), and the dichotomous outcomes as risk ratios (RR) with 95% confidence interval (CI). In case of heterogeneity (chi-square P < 0.05), a random effect model was used, and a fixed-effect model was used if no heterogeneity was detected. The results were considered significant if the P value was <0.05.
RESULTS
Our search yielded 931studies, which was reduced to 911 studies eligible for title and abstract screening after removal of duplicates. Of the 911, 902 were irrelevant and 9 studies were eligible for full-text screening. Finally, eight studies were included in the systematic review (Table 1),8–15 and four studies were included in the meta-analysis after full-text screening8,9,11,15 (Figure 1). All four studies included in the meta-analysis were of good quality (Table 2).
Table 1.
Baseline characteristics of the studies eligible for systematic review
| Study | Study design | Age (years) Mean (SD) |
Females, n (%) |
Current treatment | ||
|---|---|---|---|---|---|---|
| IBS | Control | IBS | Control | |||
| Ohlsson 20118 | Case control | 41 (16) | – | 33 (82.5%) | 216 (47.4%) | – |
| Hammar 201311 | Prospective cohort | 34 (4.5) | 43.3 (17.2) | 123 (100%) | 169 (100%) | In vitro fertilization |
| Ek 20199 | Cross-sectional | 37 (20.3) | 41.8 (17.3) | 29 (100%) | 100 (100%) | – |
| Saidi 202115 | RCT | 46.1 (13.1) | 43.6 (12.4) | 82 (78%) | 51 (51%) | Starch- and sucrose-reduced diet |
| Roth 201410 | Cross-sectional | – | – | 87 (55%) | 71 (45%) | – |
| Berntorp 201314 | Cross-sectional | 52.4 (12.5) | – | 27 (69.2%) | – | – |
| Ohlsson 200912 | Cross-sectional | 49 (10) | – | 43 (100%) | – | – |
| Ohlsson 201013 | Case series | 49.3 (21.7) | – | 1 (33.3%) | – | Histamine receptor blockers and proton pump inhibitors / analgesics and metoclopramide / methotrexate and radiation therapy |
RCT indicates randomized controlled study.
Figure 1.
PRISMA flow diagram.
Table 2.
Newcastle–Ottawa Quality Assessment Scale of risk bias of the included studies
A total of 1095 patients were included in the studies: 270 patients in the IBS group and 825 patients in the control group. Baseline data are shown in Table 1. The prevalence of GnRH IgM antibodies, GnRH IgG antibodies, and GnRH receptor IgM antibodies were reported in four, two, and three studies, respectively.
For GnRH IgM antibodies, the pooled analysis showed a statistically significant association between IBS and increased prevalence of GnRH IgM antibodies compared with controls (RR = 2.29, 95% CI = 1.58 to 3.31, P < 0.0001). No heterogeneity was observed among the studies (P = 0.20, I2 = 36%) (Figure 2a).
Figure 2.
Prevalence of outcome for (a) GnRH IgM antibodies, (b) GnRH IgG antibodies, and (c) GnRH receptor IgM antibodies.
For GnRH IgG antibodies, the pooled analysis showed no statistically significant difference between IBS and controls (RR = 2.11, 95% CI = 0.91 to 4.91, P = 0.08). No heterogeneity was observed among studies (P = 0.85, I2 = 0%) (Figure 2b).
For GnRH receptor IgM antibodies, the pooled analysis showed a statistically significant association between IBS and increased prevalence of GnRH receptor IgM antibodies compared with controls (RR = 3.80, 95% CI = 1.72 to 8.38, P = 0.0010). No heterogeneity was observed among studies (P = 0.17, I2 = 44%) (Figure 2c).
DISCUSSION
We found a statistically significant association between IBS and increased prevalence of IgM antibodies against GnRH and its receptor compared with controls. No statistically significant association was detected between IBS and an increased prevalence of IgG antibodies against GnRH.
Little research has been done on the role of GnRH in gastrointestinal function. In a study using immunochemistry, Huang et al16 discovered that GnRH-R and leuprolide acetate, which do not act through GnRH receptors, were detectable in the intestinal epithelium and myenteric ganglia of small and large rats. This revealed enhanced motor activity in the rodents’ gut muscle cells.17 GnRH is known as a 9-residue gonadotropin-releasing hormone analog. GnRH could explain why IBS is an immunological disease, with patients developing autoantibodies against endogenous GnRH located in intestinal neurons, resulting in IBS.8 According to some studies, antibodies to GnRH have been associated with autoimmune diseases such as primary Sjögren’s syndrome, inflammatory bowel disease, celiac disease, and diabetes, as the antibodies were found in sera.9 The presence of GnRH was revealed in the human enteric nervous system.18
Patients with IBS and intestinal dysmotility developed IgM antibodies against GnRH1 and its receptors.10 Also, an interesting association between IBS and intestinal dysmotility and GnRH autoantibodies was reported.8,9 IgM and IgG antibodies against GnRH were found in patients with IBS when compared to healthy controls. In 2019, researchers found that patients with IBS or enteric dysmotility had greater frequencies of increased IgM antibodies against GnRH1 tenascin-C antibodies when compared to a healthy control group.9
Furthermore, sporadic occurrences of severe gastrointestinal symptoms associated with IgM antibodies against GnRH1 have been documented.19 Antibodies against this hormone are commonly reported in patients with gastrointestinal dysmotility and IBS compared to control groups.8 The question has been raised of whether these symptoms are due to medication usage. The lack of antibody formation during therapy suggests that the antibodies seen in women with GnRH-induced dysmotility were caused by the disease rather than the drug.18,20 Another explanation for the increased severity of GnRH dysmotility may be related to other factors such as genetics, infection, or prior susceptibility.5
Endometriosis treated with GnRH and GnRH analogs is associated with gastrointestinal tract function.10,19 One study found that some women treated with GnRH analogs for endometriosis developed GnRH antibodies and gastrointestinal dysmotility. This led to the loss of nearly all GnRH neurons of their enteric system.19 During treatment with buserelin, gastrointestinal side effects were reported,21 including constipation, nausea, and vomiting, reaffirming past ideas about the enteric nervous system and gastrointestinal motor control regulated by GnRH.22 The levels of stomach discomfort 5 years after buserelin medication were higher than they were throughout treatment. Buserelin, on the other hand, does not increase the formation of antibodies against GnRH, LH, or receptors.11 Additionally, LH receptor expression was recently discovered on human enteric neurons,20 and it was found to be lowered in rats following recurrent buserelin treatment.23
In vitro fertilization is related to several psychological factors that could potentially impact gastrointestinal function.24 Despite the fact that many patients experienced gastrointestinal side effects while using the GnRH analog buserelin, stomach pain and psychological well-being improved after 5 years, and no severe dysmotility instances were observed. Buserelin administration was also not linked to antibodies against buserelin, GnRH, LH, or receptors. The findings support previous significant epidemiological research that shows that in vitro fertilization treatment is relatively safe.25 However, it has to be determined which patients are at risk of developing substantial, long-lasting gastrointestinal adverse effects due to GnRH therapy.18 Culturally stimulating culture promotes cell proliferation, but brief stimulation limits gastric smooth muscle cells.26 A probable explanation for the gastrointestinal side effects is that GnRH is secreted into the portal system in a pulsatile form as released from the pituitary gland. It quickly disappears from the bloodstream before it can be detected in the periphery. GnRH analogs that are systemically given increase the half-life and include additional peripheral tissue exposure.
The inhibition of gonadotropins and gonadal sex hormones may explain the favorable benefits of continuous GnRH analogue treatment on individuals with IBS,27,28 as these hormones have a detrimental effect on gastrointestinal motility.29,30 Further research regarding the relationship between gastrointestinal symptoms and antibody expression is needed. However, the expression of LH receptor in both the genital organs and the gastrointestinal system,23,31 the down-regulation of LH receptor following buserelin treatment,23 and the development of serum antibodies against LH and LH receptor all point to LH and its receptor as one possible explanation for the gut-genital organ relationship reported in women.6,7
In conclusion, IBS is associated with the increased prevalence of IgM antibodies against GnRH and its receptor compared with healthy controls. GnRH IgM antibodies may play a role in the pathogenesis of IBS.
References
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