Applicability of polygenic risk scores in endometriosis clinical presentation.

BACKGROUND: Risk prediction is an essential part of preventative medicine and in recent years genomic information has become an interesting factor in risk models. Polygenic risk scores (PRS) combine the effect of many genetic variations into a single score which has been shown to have predictive value for many diseases. This study aimed to investigate the association between PRS for endometriosis and the clinical presentation of the disease. METHODS: Women with endometriosis (N = 172) were identified at the Department of Gynecology. All participants answered questionnaires regarding sociodemographic factors, lifestyle habits and medical history, registered bowel symptoms on the Visual Analog Scale for Irritable Bowel Syndrome and passed blood samples. DNA was extracted and samples were genotyped, and a PRS was calculated based on previous genome-wide association studies of endometriosis. Inflammatory proteins and TSH receptor antibodies (TRAb) in serum were analyzed. RESULTS: Inverse associations were identified between PRS and spread of endometriosis, involvement of the gastrointestinal tract and hormone treatment. However, significance was lost when calculated as p for trend and the specificity and sensitivity were low. There were no correlations between PRS and TRAb or inflammatory proteins. CONCLUSION: The findings indicate that specific PRS should be developed to predict clinical presentations in patient with endometriosis.

AXIN1 in Plasma or Serum Is a Potential New Biomarker for Endometriosis.

Although endometriosis is considered an inflammatory disease, no reliable diagnostic biomarkers exist for use in clinical practice. The aim was to investigate the inflammatory profile in endometriosis using an exploratory approach of inflammation-related proteins. Patients with laparoscopy-verified endometriosis (N = 172), women with microscopic colitis (N = 50), healthy controls (N = 31), and age-matched controls from the general population (N = 100) were enrolled and questionnaires regarding socioeconomic factors, lifestyle habits, and medical history were completed. Sera from patients and healthy controls were analyzed for 92 inflammatory biomarkers using Proximity Extension Assay technology (PEA). Plasma AXIN1 levels were analyzed in patients with endometriosis and controls from the general population by ELISA. General linear model adjusted for age, Mann⁻Whitney U-test, and principal component analysis (PCA) were used for statistical calculations. Serum levels of AXIN1 and ST1A1 were increased in endometriosis compared with MC (p < 0.001) and healthy controls (p = 0.001), whereas CXCL9 levels were decreased. Plasma levels of AXIN1 were elevated in endometriosis compared with age-matched controls from the general population (30.0 (17.0⁻38.0) pg/mL vs. 19.5 (15.0⁻28.0) pg/mL, p < 0.001). PCA analysis identified four clusters of proteins, where one cluster differed between endometriosis and controls, with strong correlations for AXIN1 and ST1A1. Plasma/serum AXIN1 is an interesting biomarker to be further evaluated in endometriosis.

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin.

AIMS/HYPOTHESIS: In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. METHODS: Six-week-old male C57BL/6J wild-type and Adipoq -/- mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 µg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m2) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. RESULTS: AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8+ T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H2O2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq -/- mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq -/- mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients. CONCLUSIONS/INTERPRETATION: AICAR may promote metabolic health and protect against obesity-induced systemic diseases in an adiponectin-independent manner. Furthermore, AICAR reduced inflammation in human adipose tissue explants, suggesting by proof-of-principle that the drug may reduce obesity-induced complications in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT02322073.

Gastrointestinal symptoms among endometriosis patients--A case-cohort study.

BACKGROUND: Women with endometriosis often experience gastrointestinal symptoms. Gonadotropin-releasing hormone (GnRH) analogs are used to treat endometriosis; however, some patients develop gastrointestinal dysmotility following this treatment. The aims of the present study were to investigate gastrointestinal symptoms among patients with endometriosis and to examine whether symptoms were associated with menstruation, localization of endometriosis lesions, or treatment with either opioids or GnRH analogs, and if hormonal treatment affected the symptoms. METHODS: All patients with diagnosed endometriosis at the Department of Gynecology were invited to participate in the study. Gastrointestinal symptoms were registered using the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS); socioeconomic and medical histories were compiled using a clinical data survey. Data were compared to a control group from the general population. RESULTS: A total of 109 patients and 65 controls were investigated. Compared to controls, patients with endometriosis experienced significantly aggravated abdominal pain (P = 0.001), constipation (P = 0.009), bloating and flatulence (P = 0.000), defecation urgency (P = 0.010), and sensation of incomplete evacuation (P = 0.050), with impaired psychological well-being (P = 0.005) and greater intestinal symptom influence on their daily lives (P = 0.001). The symptoms were not associated with menstruation or localization of endometriosis lesions, except increased nausea and vomiting (P = 0.010) in patients with bowel-associated lesions. Half of the patients were able to differentiate between abdominal pain from endometriosis and from the gastrointestinal tract. Patients using opioids experienced more severe symptoms than patients not using opioids, and patients with current or previous use of GnRH analogs had more severe abdominal pain than the other patients (P = 0.024). Initiation of either combined oral contraceptives or progesterone for endometriosis had no effect on gastrointestinal symptoms when the patients were followed prospectively. CONCLUSIONS: The majority of endometriosis patients experience more severe gastrointestinal symptoms than controls. A poor association between symptoms and lesion localization was found, indicating existing comorbidity between endometriosis and irritable bowel syndrome (IBS). Treatment with opioids or GnRH analogs is associated with aggravated gastrointestinal symptoms.

Gastrointestinal Symptoms in Women With Endometriosis and Microscopic Colitis in Comparison to Irritable Bowel Syndrome: A Cross-Sectional Study.

BACKGROUND: Gastrointestinal (GI) symptoms similar to irritable bowel syndrome (IBS) are often present in women with endometriosis and microscopic colitis (MC). The objective of this study was to estimate GI symptoms in IBS, endometriosis, and MC, to compare the clinical expression of the diseases. METHODS: Women with IBS, endometriosis, and MC were identified by diagnosis codes at a tertiary center. The patients had to complete the visual analog scale for IBS to estimate specific GI symptoms. Women fulfilling Rome III criteria for IBS were diagnosed as IBS (n = 109) and divided into subgroups depending on predominating symptoms. Women diagnosed with endometriosis (n = 158) and MC (n = 88) were evaluated whether they also fulfilled the Rome III criteria for IBS. RESULTS: Women with IBS experienced aggravated abdominal pain, diarrhea, bloating and flatulence, nausea and vomiting, the urgency to defecate, the sensation of incomplete evacuation and intestinal symptom's influence on daily life, and impaired psychological wellbeing, compared to women with endometriosis. When patients with endometriosis also fulfilled the criteria for IBS, all symptoms in the 2 cohorts, except intestinal symptom's influence on daily life, were equal. Women with IBS or diarrhea-predominated IBS experienced aggravated abdominal pain, bloating and flatulence, intestinal symptom's influence on daily life, and impaired psychological well-being compared to MC, but at equal levels as MC with IBS-like symptoms. CONCLUSIONS: Women with IBS generally experience aggravated GI symptoms and impaired psychological well-being compared to endometriosis and MC. Patients with endometriosis or MC, in combination with IBS, express similar symptoms as patients with sole IBS.

Plasma AXIN1 expression exhibit negative correlations with inflammatory biomarkers and is associated with gastrointestinal symptoms in endometriosis.

The cytoplasmic protein AXIN1 is involved in the Wnt signalling pathway and its expression is increased in patients with endometriosis compared with healthy controls. The aim of the present cross-sectional study was to further assess the levels of AXIN1 and other inflammatory biomarkers in patients with endometriosis. Patients with laparoscopy-verified endometriosis were recruited (n=172) and completed a questionnaire regarding socioeconomic factors, lifestyle habits and medical history. Plasma AXIN1 and high-sensitivity C-reactive protein (hs-CRP) levels were analysed by ELISA. The levels of calprotectin were determined in the faeces, and the haemoglobin concentration and number of erythrocytes, leukocytes and platelets were determined in the blood in a subgroup of 64 patients during clinical routine procedures. F-calprotectin expression was detected in 18 women (28.1%), who had more severe constipation and more frequently experienced incomplete evacuation when defecating, and 5 women (7.8%) exhibited elevated levels. P-AXIN1 levels were higher in patients who received hormonal treatment, and correlated inversely with faecal-calprotectin levels (P=0.003), B-haemoglobin levels (P=0.030) and the numbers of B-erythrocytes (P=0.033) and B-platelets (P=0.017), but were not correlated with hs-CRP levels (P=0.818). Higher levels of AXIN1 were associated with the duration of the gastrointestinal symptoms and with diarrhoea, constipation, vomiting and nausea and the intestinal symptoms' effect on quality of life, and tended to be associated with the duration of endometriosis. Hs-CRP expression was not associated with the clinical characteristics or symptoms of endometriosis, but higher levels were associated with obesity (P=0.002) and hormonal treatment (P=0.011). In conclusion, P-AXIN1 expression was negatively correlated with certain inflammatory biomarkers and was positively associated with gastrointestinal symptoms. P-AXIN1 levels were increased in patients who received hormonal treatment, highlighting the importance of obtaining native samples for future studies regarding its role in the development and presentation of endometriosis. However, hs-CRP and other studied biomarkers seemed to be of no value for the assessment and diagnosis of endometriosis.

Autoantibodies common in patients with gastrointestinal diseases are not found in patients with endometriosis: A cross-sectional study.

OBJECTIVES: Gastrointestinal symptoms are common in endometriosis, but the mechanisms behind these symptoms are yet poorly understood. Associations between endometriosis and irritable bowel syndrome (IBS), celiac disease, and various autoimmune diseases have been reported. These diseases express characteristic autoantibodies. The aim of the current study was to investigate autoantibodies against gonadotropin-releasing hormone 1 (GnRH1) and luteinizing hormone (LH) and their receptors, tenascin-C, matrix metalloproteinase-9, deamidated gliadin peptide, and tissue transglutaminase in a cohort of women with endometriosis, compared to controls and women with IBS or enteric dysmotility. STUDY DESIGN: One hundred seventy-two women with laparoscopy-verified endometriosis completed questionnaires regarding socio-demographics, lifestyle habits, medical history, and gastrointestinal symptoms, and sera were analyzed with ELISA for the abovementioned antibodies. Healthy female blood donors (N = 100) served as controls, and women with IBS or enteric dysmotility (N = 29) were used for comparison. RESULTS: A non-significantly higher prevalence of IgM antibodies directed at tenascin-C (7.6% vs. 2.0%; p = 0.06) was the only observed difference in autoantibody levels in endometriosis compared to controls. Antibody presence was not associated with any clinical parameters. Patients with IBS or enteric dysmotility expressed higher levels of IgM antibodies against GnRH1 compared to both patients with endometriosis (p = 0.004) and healthy controls (p = 0.002), and higher levels of tenascin-C antibodies compared to healthy controls (17.2% vs. 2.0%; p = 0.006). CONCLUSIONS: Women with endometriosis do not express higher prevalence of autoantibodies found to be characteristic in other patient groups with gastrointestinal symptoms.

Characteristics of endometriosis: A case-cohort study showing elevated IgG titers against the TSH receptor (TRAb) and mental comorbidity.

OBJECTIVES: Endometriosis has been associated with a wide range of factors. The disease share immunological features with autoimmune diseases, and the prevalence of both hypo- and hyperthyroidism has been reported to be increased. However, the associations have to be confirmed and the mechanisms explored. The aim of this observational study was to investigate socioeconomic factors, lifestyle habits, and somatic and mental comorbidities in endometriosis compared to the general population. STUDY DESIGN: In all, 172 women with endometriosis completed a study questionnaire and were interviewed regarding socioeconomic factors, lifestyle habits, psychological well-being, and medical history. Bowel symptoms were measured by the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS). Serum was analyzed for IgG levels of TSH receptor antibodies (TRAb) and anti-thyroid peroxidase (TPO) antibodies. Women from the general population served as controls. Differences were calculated by logistic regression, adjusted for confounders. RESULTS: Alcohol intake, leisure time physical activity, body mass index and asthma were inversely, whereas IBS was positively associated with endometriosis. Hypothyroidism and anti-TPO antibodies did not associate, but elevated TRAb antibody titers were associated with endometriosis (odds ratio (OR): 539.26; 95% confidence interval (CI): 114.29-2544.32 for highest versus lowest tertile; p for trend < 0.001). Impaired psychological well-being (p for trend = 0.003) and current intake of antidepressant medication (OR: 3.54; 95% CI: 1.22-10.28; p = 0.020) associated with endometriosis, and impaired psychological well-being correlated with all gastrointestinal symptoms measured (all p < 0.001). CONCLUSIONS: Lifestyle habits and asthma are inversely associated, and IBS and impaired psychological well-being are positively associated with endometriosis. TRAb titers are associated with endometriosis, supporting a link between endometriosis, autoimmunity and thyroid pathophysiology, although overt thyroid diseases do not associate.