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Human Reproduction Open 2023What is the role of iron in the pathophysiology of endometriosis?
STUDY QUESTION
What is the role of iron in the pathophysiology of endometriosis?
SUMMARY ANSWER
Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory micro-environment, and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity, and malignant transformation.
WHAT IS KNOWN ALREADY
Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarize our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field.
STUDY DESIGN SIZE DURATION
This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science, and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms ('Iron' and 'Endometriosis') and free-text search terms ('Iron', 'Ferric', 'Ferrous', 'Endometriosis', 'Endometrioma').
PARTICIPANTS/MATERIALS SETTING METHODS
This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle-Ottawa scoring system.
MAIN RESULTS AND THE ROLE OF CHANCE
There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions, and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity, and, possibly, malignant transformation.
LIMITATIONS REASONS FOR CAUTION
A minority of the included studies were of objectively low quality with a high risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterize the included patients by known confounding variables, such as menstrual cycle phase, which may introduce bias to the findings.
WIDER IMPLICATIONS OF THE FINDINGS
Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localized hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation.
STUDY FUNDING/COMPETING INTERESTS
J.W. and S.G.P. are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and an MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare.
REGISTRATION NUMBER
A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818).
PubMed: 37638130
DOI: 10.1093/hropen/hoad033 -
Reproduction (Cambridge, England) Jul 2019The objective is to study the significance of altered interleukin levels in endometriosis-related infertility or pelvic pain. The present systematic review and... (Meta-Analysis)
Meta-Analysis
The objective is to study the significance of altered interleukin levels in endometriosis-related infertility or pelvic pain. The present systematic review and meta-analysis includes a discussion on the roles of interleukin in the physiopathology of endometriosis-associated infertility and/or pelvic pain. We included all studies in which interleukins in peritoneal fluid, follicular fluid or serum from patients were measured and that correlated the findings with either peritoneal or deep endometriosis-associated infertility or pelvic pain. For the meta-analysis, we selected studies on the following cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8). Endometriosis is a chronic inflammatory disease. Inflammatory processes clearly participate in the etiology of endometriosis. Cytokines are mediators of inflammation, and increase in their concentration in plasma or other body fluids signals the presence and extent of tissue lesions. A number of studies have reported on the association between higher cytokine levels and progression or maintenance of endometriosis and coexisting infertility or pelvic pain. The results of the analyses support that an association exists between elevated serum IL-6 and/or IL-8 concentrations and the occurrence of endometriosis-associated infertility. Such association was not found for endometriosis-associated pain. In spite of accumulated evidence on the association of pro-inflammatory cytokines and endometriosis, it still is not clear if and how these mediators participate in the physiopathology of endometriosis-associated infertility or pelvic pain, in part due to poor quality of the evidence established in the vast majority of interleukins and challenges in endometriosis research reproducibility. In summary, the results of the analyses support that an association exists between elevated serum IL-6 and/or IL-8 concentrations and the occurrence of endometriosis-associated infertility.
Topics: Endometriosis; Female; Humans; Infertility, Female; Interleukins; Pelvic Pain
PubMed: 30933927
DOI: 10.1530/REP-18-0618 -
Frontiers in Oncology 2021Postoperative colorectal anastomotic leakage (CAL) is a devastating complication following colorectal resection. However, the diagnosis of anastomotic leakage is often...
BACKGROUND
Postoperative colorectal anastomotic leakage (CAL) is a devastating complication following colorectal resection. However, the diagnosis of anastomotic leakage is often delayed because the current methods of identification are unable to achieve 100% clinical sensitivity and specificity. This meta-analysis aimed to evaluate the predictive value of peritoneal fluid cytokines in the detection of CAL following colorectal surgery.
METHODS
A comprehensive search was conducted on PubMed, Embase, Cochrane Library, and Web of Science before June 2021 to retrieve studies regarding peritoneal fluid cytokines as early markers of CAL. Pooled analyses of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF) were performed. The means (MD) and standard deviations (SD) of the peritoneal fluid cytokines were extracted from the included studies. Review Manager Software 5.3 was used for data analysis.
RESULTS
We included eight studies with 580 patients, among which 85 (14.7%) and 522 (44.5%) were evaluated as the CAL and non-CAL groups, respectively. Compared to the non-CAL group, the CAL group had significantly higher peritoneal IL-6 levels on postoperative day (POD) 1-3 (P = 0.0006, 0.0002, and 0.002, respectively) and slightly higher TNF levels on POD 4 (P = 0.0002). Peritoneal levels of IL-1β and IL-10 were not significantly different between the two groups in this study.
CONCLUSION
Peritoneal IL-6 levels can be a diagnostic marker for CAL following colorectal surgery, whereas the value of TNF needs further exploration in the future.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/#myprospero], PROSPERO (CRD42021274973).
PubMed: 35127496
DOI: 10.3389/fonc.2021.791462 -
PloS One 2022Changes in endothelial function are implicated in the spread of tuberculosis (TB). Studies suggest a role for the vascular endothelial growth factor (VEGF) in TB-related... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Changes in endothelial function are implicated in the spread of tuberculosis (TB). Studies suggest a role for the vascular endothelial growth factor (VEGF) in TB-related endothelial function changes. However, the findings of studies investigating the VGEF profile in TB are not consistent, and no formal systematic review and meta-analysis exists summarizing these studies.
METHODS
We did a meta-analysis of studies assessing VEGF levels in patients with TB. A systematic search on June 25, 2021, was conducted for eligible studies that made VEGF measurements in an unstimulated sample, e.g., a blood fraction (plasma or serum), cerebrospinal fluid (CSF), pleural effusion (PE), or bronchoalveolar lavage fluid, and ascites or pericardial fluid for patients with TB and controls without TB. Also, studies that made simultaneous measurements of VEGF in blood and PE or CSF in the same patients with TB were included. Longitudinal studies that provided these data at baseline or compared pre-post anti-tuberculosis treatment (ATT) levels of VEGF were included. The primary outcome was the standardized mean difference (SMD) of VEGF levels between the comparison groups.
RESULTS
52 studies were included in the meta-analysis. There were 1787 patients with TB and 3352 control subjects of eight categories: 107 patients with transudative pleural effusion, 228 patients with congestive heart failure (CHF)/chronic renal failure (CRF), 261 patients with empyema and parapneumonic effusion (PPE), 241 patients with cirrhosis, 694 healthy controls (with latent TB infection or uninfected individuals), 20 patients with inactive tuberculous meningitis (TBM), 123 patients with non-TBM, and 1678 patients with malignancy. The main findings are as follows: (1) serum levels of VEGF are higher in patients with active TB compared with healthy controls without other respiratory diseases, including those with latent TB infection or uninfected individuals; (2) both serum and pleural levels of VEGF are increased in patients with TPE compared with patients with transudative, CHF/CRF, or cirrhotic pleural effusion; (3) ascitic/pericardial fluid, serum, and pleural levels of VEGF are decreased in patients with TB compared with patients with malignancy; (4) pleural levels of VEGF are lower in patients with TPE compared with those with empyema and PPE, whereas serum levels of VEGF are not different between these patients; (5) both CSF and serum levels of VEGF are increased in patients with active TBM compared with controls, including patients with inactive TBM or non-TBM subjects; (6) post-ATT levels of VEGF are increased compared with pre-ATT levels of VEGF; and (7) the mean age and male percentage of the TB group explained large and total amount of heterogeneity for the meta-analysis of blood and pleural VEGF levels compared with healthy controls and patients with PPE, respectively, whereas these moderators did not show any significant interaction with the effect size for other analyses.
DISCUSSION
The important limitation of the study is that we could not address the high heterogeneity among studies. There might be unmeasured factors behind this heterogeneity that need to be explored in future research. Meta-analysis findings align with the hypothesis that TB may be associated with abnormal vascular function, and both local and systemic levels of VEGF can be used to trace this abnormality.
Topics: Exudates and Transudates; Humans; Latent Tuberculosis; Male; Pleural Effusion; Tuberculosis, Meningeal; Tuberculosis, Pleural; Vascular Endothelial Growth Factor A
PubMed: 35613134
DOI: 10.1371/journal.pone.0268543 -
Pediatric Critical Care Medicine : a... Jun 2024The objective of this Prospective Register of Systematic Reviews (CRD42022384192) registered systematic review and meta-analysis was to determine whether prophylactic... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The objective of this Prospective Register of Systematic Reviews (CRD42022384192) registered systematic review and meta-analysis was to determine whether prophylactic peritoneal dialysis (PD) catheter insertion at the time of pediatric cardiac surgery is associated with improved short-term outcomes.
DATA SOURCES
Databases search of the MEDLINE, EMBASE, CINAHL, and Cochrane Library completed in April 2021 and updated October 2023.
STUDY SELECTION
Two reviewers independently completed study selection, data extraction, and bias assessment. Inclusion criteria were randomized controlled trials (RCTs) and observational studies of children (≤ 18 yr) undergoing cardiac surgery with cardiopulmonary bypass. We evaluated use of prophylactic PD catheter versus not.
DATA EXTRACTION
The primary outcome was in-hospital mortality, as well as secondary short-term outcomes. Pooled random-effect meta-analysis odds ratio with 95% CI are reported.
DATA SYNTHESIS
Seventeen studies met inclusion criteria, including four RCTs. The non-PD catheter group received supportive care that included diuretics and late placement of PD catheters in the ICU. Most study populations included children younger than 1 year and weight less than 10 kg. Cardiac surgery was most commonly used for arterial switch operation. In-hospital mortality was reported in 13 studies; pooled analysis showed no association between prophylactic PD catheter placement and in-hospital mortality. There were mixed results for ICU length of stay and time to negative fluid balance, with some studies showing shortened duration associated with use of prophylactic PD catheter insertion and others showing no difference. Overall, the studies had high risk for bias, mainly due to small sample size and lack of generalizability.
CONCLUSIONS
In this meta-analysis, we have failed to demonstrate an association between prophylactic PD catheter insertion in children and infants undergoing cardiac surgery and reduced in-hospital mortality. Other relevant short-term outcomes, including markers of fluid overload, require further study.
Topics: Child; Child, Preschool; Humans; Infant; Infant, Newborn; Cardiac Surgical Procedures; Hospital Mortality; Peritoneal Dialysis; Postoperative Complications; Adolescent
PubMed: 38334438
DOI: 10.1097/PCC.0000000000003465 -
The Cochrane Database of Systematic... Mar 2014The longevity of peritoneal dialysis (PD) is limited by high rates of technique failure, some of which stem from peritoneal membrane injury. 'Biocompatible' PD solutions... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The longevity of peritoneal dialysis (PD) is limited by high rates of technique failure, some of which stem from peritoneal membrane injury. 'Biocompatible' PD solutions have been developed to reduce damage to the peritoneal membrane.
OBJECTIVES
This review aimed to look at the benefits and harms of biocompatible PD solutions in comparison to standard PD solutions in patients receiving PD.
SEARCH METHODS
We searched the Cochrane Renal Group's Specialised Register (28 February 2013), through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE, and handsearching conference proceedings.
SELECTION CRITERIA
All randomised controlled trials (RCTs) and quasi-RCTs in adults and children comparing the effects of biocompatible PD solutions (neutral pH, lactate-buffered, low glucose degradation product (GDP); neutral pH, bicarbonate (± lactate)-buffered, low GDP; glucose polymer (icodextrin)) in PD were included. Studies of amino acid-based PD solutions were excluded.
DATA COLLECTION AND ANALYSIS
Two authors extracted data on study quality and outcomes (including adverse effects). The authors contacted investigators to obtain missing information. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for categorical variables, and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous variables.
MAIN RESULTS
Thirty-six eligible studies (2719 patients) were identified: Neutral pH, lactate-buffered/bicarbonate (± lactate)-buffered, low GDP PD solution (24); icodextrin (12). Allocation methods and concealment were generally incompletely reported, and adequate in only ten studies (27.8%). Patients lost to follow-up ranged from 0% to 83.4%. Neutral pH, low GDP versus conventional glucose PD solutionBased on generally sub-optimal quality evidence, the use of neutral pH, low GDP PD solutions was associated with larger urine volumes at the end of the studies, up to three years of therapy duration (7 studies, 520 patients: MD 126.39 mL/d, 95% CI 26.73 to 226.05). Improved preservation of residual renal function was evident in studies with greater than 12 month follow-up (6 studies, 360 patients: SMD 0.31, 95% CI 0.10 to 0.52). There was no significant effect on peritonitis, technique failure or adverse events with the use of neutral pH, low GDP PD solutions. Glucose polymer (icodextrin) versus conventional glucose PD solutionThere was a significant reduction in episodes of uncontrolled fluid overload (2 studies, 100 patients: RR 0.30, 95% CI 0.15 to 0.59) and improvement in peritoneal ultrafiltration (4 studies, 102 patients, MD 448.54 mL/d, 95% CI 289.28 to 607.80) without compromising residual renal function (4 studies, 114 patients: SMD 0.12, 95% CI -0.26 to 0.49) or urine output (3 studies, 69 patients: MD -88.88 mL/d, 95% CI -356.88 to 179.12) with icodextrin use. A comparable incidence of adverse events with the icodextrin (four studies) was reported.
AUTHORS' CONCLUSIONS
Based on generally sub-optimal quality studies, use of neutral pH, low GDP PD solution led to greater urine output and higher residual renal function after use exceeded 12 months. Icodextrin prescription improved peritoneal ultrafiltration and mitigated uncontrolled fluid overload. There were no significant effects on peritonitis, technique survival, patient survival or harms identified with their use. Based on the best available evidence, the use of these 'biocompatible' PD solutions resulted in clinically relevant benefits without added risks of harm.
Topics: Adult; Child; Dialysis Solutions; Glucose; Humans; Hydrogen-Ion Concentration; Kidney; Peritoneal Dialysis; Peritoneum; Randomized Controlled Trials as Topic; Solutions; Urine
PubMed: 24671928
DOI: 10.1002/14651858.CD007554.pub2 -
Nephrology, Dialysis, Transplantation :... Apr 2012Peritonitis caused by nontuberculous mycobacterium (NTM) is an important complication in peritoneal dialysis (PD) patients. (Review)
Review
BACKGROUND
Peritonitis caused by nontuberculous mycobacterium (NTM) is an important complication in peritoneal dialysis (PD) patients.
METHODS
Cases of PD complicated by NTM peritonitis reported in the English language literature were identified in the PubMed database. The characteristics of these cases were reviewed.
RESULTS
In 41 articles, we identified 57 cases of PD-associated NTM peritonitis in patients ranging from 5 to 82 years. The prevalent clinical findings of these cases were fever, abdominal pain, cloudy fluid and an elevated leukocyte count in peritoneal fluid. These findings were non-specific and could not be differentiated from symptoms caused by Mycobacterium tuberculosis or other bacteria. The majority of these cases received empirical antibacterial therapy before diagnosis of NTM peritonitis. Isolates in more than half of the peritonitis cases were the rapidly growing Mycobacterium, Mycobacterium fortuitum (38.6%) and Mycobacterium chelonae (14.0%). In most cases, PD catheters were removed and experience with non-removal was limited.
CONCLUSION
Diagnosis of NTM infection should be considered in PD patients with peritonitis that are culture negative or refractory to empirical antibiotic therapy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Child, Preschool; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Peritoneal Dialysis; Peritonitis; Prognosis; Young Adult
PubMed: 21891775
DOI: 10.1093/ndt/gfr504 -
Human Fertility (Cambridge, England) Jun 2018Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of assisted reproductive treatment. Management of women with severe OHSS has traditionally... (Review)
Review
Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of assisted reproductive treatment. Management of women with severe OHSS has traditionally included hospitalisation for close monitoring and supportive treatment. The aim of this review is to assess the evidence for safety and efficacy of outpatient management of severe OHSS. A systematic review of studies describing outpatient management options was performed. Current guidance from advisory bodies was also reviewed. Outpatient management has been found in observational studies to be safe and cost-effective compared to inpatient management. Paracentesis of ascitic fluid seems to be effective treatment for severe OHSS along with supportive management including maintenance of fluid balance and preventative measures against thrombo-embolism. GnRH antagonist was shown in few studies to be effective in treatment of early severe OHSS although further research is required to assess its role in this context. Appropriate outpatient set up and protocols are essential to provide safe outpatient management for women with severe OHSS.
Topics: Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Outpatients; Ovarian Hyperstimulation Syndrome; Paracentesis; Practice Guidelines as Topic; Pregnancy; Treatment Outcome
PubMed: 28554223
DOI: 10.1080/14647273.2017.1331048 -
Translational Gastroenterology and... 2022Spontaneous bacterial peritonitis (SBP) is a common bacterial infection in cirrhotic patients associated with a high mortality rate. Prompt diagnosis and early...
BACKGROUND
Spontaneous bacterial peritonitis (SBP) is a common bacterial infection in cirrhotic patients associated with a high mortality rate. Prompt diagnosis and early antibiotic administration are crucial in minimizing adverse outcomes. Although detection of ≥250 polymorphonuclear leukocytes (PMN) in ascitic fluid is the current gold standard to diagnose SBP, consideration for rapid detection with biomarkers is warranted.
METHODS
A literature search for studies evaluating ascitic calprotectin and lactoferrin for detection of SBP was performed using PubMed, Embase, Scopus, Google Scholar, Cochrane library, and Clinical Trial Registries. Summary sensitivity, specificity, log diagnostic odds ratio (LDOR), and area under the summary receiver operating curve (AUC) were calculated.
RESULTS
In total, 12 and 13 studies evaluated ascitic calprotectin and lactoferrin, respectively, for detection of SBP. Summary sensitivity, specificity, and LDOR for calprotectin were 0.942 (95% CI, 0.916, 0.967), 0.860 (95% CI, 0.799, 0.935), and 4.250 (95% CI, 3.504, 4.990), respectively. AUC for calprotectin was 0.91. Summary sensitivity, specificity, and LDOR for lactoferrin were 0.954 (95% CI, 0.930, 0.979), 0.890 (95% CI, 0.836, 0.945), and 4.630 (95% CI, 3.800, 5.452), respectively. AUC for lactoferrin was 0.958.
CONCLUSIONS
The overall performance of ascitic calprotectin and lactoferrin was substantial, potentially serving as a screening tool or an alternative to manual cell count. However, a variety of manufacturers, cut-off values, and significant heterogeneity between studies should be noted. Point-of-care testing for calprotectin and lactoferrin may resolve disadvantages associated with the current methods. Future studies on this topic are, therefore, needed.
PubMed: 36300150
DOI: 10.21037/tgh-20-323 -
Alimentary Pharmacology & Therapeutics Oct 2005The peritoneum is one of the most common extrapulmonary sites of tuberculous infection. Peritoneal tuberculosis remains a significant problem in parts of the world where... (Review)
Review
The peritoneum is one of the most common extrapulmonary sites of tuberculous infection. Peritoneal tuberculosis remains a significant problem in parts of the world where tuberculosis is prevalent. Increasing population migration, usage of more potent immunosuppressant therapy and the acquired immunodeficiency syndrome epidemic has contributed to a resurgence of this disease in regions where it had previously been largely controlled. Tuberculous peritonitis frequently complicates patients with underlying end-stage renal or liver disease that further adds to the diagnostic difficulty. The diagnosis of this disease, however, remains a challenge because of its insidious nature, the variability of its presentation and the limitations of available diagnostic tests. A high index of suspicion is needed whenever confronted with unexplained ascites, particularly in high-risk patients. Based on a systematic review of the literature, we recommend: tuberculous peritonitis should be considered in the differential diagnosis of all patients presenting with unexplained lymphocytic ascites and those with a serum-ascites albumin gradient (SAAG) of <11 g/L; culture growth of Mycobacterium of the ascitic fluid or peritoneal biopsy as the gold standard test; further studies to determine the role of polymerase chain reaction, ascitic adenosine deaminase and the BACTEC radiometric system for acceleration of mycobacterial identification as means of improving the diagnostic yield; increasing utilization of ultrasound and computerized tomographic scan for the diagnosis and as a guidance to obtain peritoneal biopsies; low threshold for diagnostic laparoscopy; treatment for 6 months with the first-line antituberculous drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) in uncomplicated cases.
Topics: Adolescent; Adult; Algorithms; Antitubercular Agents; Female; Humans; Laparoscopy; Male; Peritonitis, Tuberculous; Tomography, X-Ray Computed
PubMed: 16197489
DOI: 10.1111/j.1365-2036.2005.02645.x