{"paper_id":"a34c42d5-9e27-4c9e-bef9-fae814b9e02f","body_text":"Endometriosis is a chronic inflammatory disease defined\nby the presence of endometrial-like tissue outside the uterine\ncavity ( 1 ,  2 ). It affects 5 to 10% of reproductive-age women\n( 1 ,  2 ), causing low quality of life, depression, and various pain\nsymptoms, including dysmenorrhea, dyspareunia, chronic\npelvic pain, dyschezia, and dysuria ( 3 ,  4 ). Many authors have\nstudied the association between this condition and infertility\n( 3 ,  5 ). Several theories have been proposed to try to clarify\nthe pathogenetic mechanisms underlying endometriosis. The\nmost common involves pelvic and systemic inflammation\nstimulating the activation of immune cells and the secretion\nof cytokines and chemokines. Alterations in concentrations\nof these inflammatory mediators have been extensively\ndescribed in women affected by this disease ( 6 ). Interleukin-6\n(IL-6) is the most studied interleukin in endometriosis ( 4 )\nand, considering its important functions in reproductive\nphysiology, altered concentrations in these patients may lead\nto fertility problems ( 7 ).\nGiven this, this study aims to review systematically the\navailable papers documenting IL-6 levels in serum (S),\nperitoneal fluid (PF), follicular fluid (FF), or endometrial\nbiopsy specimens (ES) in patients with endometriosisassociated infertility.\n\nA bibliographic search using Medline, Embase, Cochrane\ndatabase of Systematic Reviews, and ClinicalTrials.gov to\nDecember 2022 was performed querying for randomized\ncontrolled trials and prospective studies evaluating IL-6\nin patients with endometriosis-associated infertility.\nWe used the medical subject heading (MeSH) term\ninterleukin-6 (MeSH Unique ID: D015850) in combination with: Endometriosis (MeSH Unique ID: D004715); and\nInfertility (MeSH Unique ID: D007246).\nTo be included, each study had to measure IL-6 levels\nin S, PF, FF, or ES samples from endometriosis patients\nand compare the data with the presence of endometriosisrelated infertility. Only papers written in English were\nincluded. Commentaries, letters to editors, editorials, and\nconference abstracts were excluded.\nA systematic review was performed to find any statistically\nsignificant difference between groups evidenced by the\nresults of chi-squared tests, Student’s t tests, Mann-Whitney\nU-tests, Kruskal-Wallis tests, and Wilcoxon signed rank\ntests reported in the selected papers. Differences were\nexpressed as means/median ± standard deviation (SD)\nand a P<0.05 was considered statistically significant. The\nsystematic review was performed in accordance with the\nPreferred Reporting Items for Systematic Reviews and\nMeta-Analyses (PRISMA) guidelines ( 8 ) ( Fig .1 ).\nOne author (G.G.I.) independently screened titles and\nabstracts of each citation and included those for full-text\nreview. Each retrieved full-text article was independently\nevaluated for inclusion by another author (F.D.G.). Any\npotential disagreement was solved by discussion by a\nthird author (F.A.G.).\n\nOur systematic bibliographic research strategy\nidentified 656 articles. After screening of abstracts and\ntitles and removal of 73 duplicates, 107 full-text records\nwere assessed for eligibility. Finally, 15 studies were\nincluded in the systematic review ( Fig .1 ).\nPRISMA flowchart.\nIL-6 distribution among endometriosis-associated\ninfertility and infertility without endometriosis,\nendometriosis without infertility, and non-endometriosis\nwithout infertility, respectively are displayed in Tables 1\n( 9 - 20 ), 2 ( 21 ,  22 ) and 3 ( 15 ,  23 ).\nInterleukin-6 distribution among women with endometriosis-related infertility and without endometriosis\nInterluekin-6 (IL-6) levels for exposure groups were compared to those for controls reporting the higher or lower values between the two groups in case of statistical significance. αNA;\nα error not available, C; Control, E; Endometriosis, ES; Endometrial biopsy specimens, FF; Follicular fluid, ns; Non-significant, PF; Peritoneal fluid, S; Serum, and HCG; Human chorionic\ngonadotropin.\nInterleukin-6 distribution among women with endometriosis-related infertility and endometriosis without infertility\nInterluekin-6 (IL-6) levels for exposure groups were compared to those for controls reporting the higher or lower values between the two groups in case of statistical significance. C;\nControl, I; Infertility, n; Number, PF; Peritoneal fluid, and S; Serum.\nInterleukin-6 distribution among women with endometriosis-related infertility and non-endometriosis without infertility\nInterluekin-6 (IL-6) levels for exposure groups were compared to those for controls reporting the higher or lower values between the two groups in case of statistical significance. αNA;\nα error not available, C; Control, E; Endometriosis, n; Number, and PF; Peritoneal fluid.\nOne study reported higher values of S IL-6 in patients\nwith endometriosis-related infertility than controls ( 17 ).\nOther authors compared women with endometriosis and\ncontrols, studying some patients with endometriosis\nin natural cycles to others in stimulated cycles. They\nconcluded S IL-6 was increased in the natural cycles of\npatients with endometriosis and modulated by ovarian\nstimulation, showing a significant decrease in stimulated\ncycles and a significant increase just after human\nchorionic hormone administration ( 16 ). One study found\nno difference in S IL-6 levels between endometriosis associated infertility patients and the control group ( 13 )\nAll of the 6 included studies evaluating IL-6 concentration\nin PF found higher levels in the endometriosis-associated\ninfertility group than in controls ( 10 ,  11 ,  13 - 15 ,  18 ).\nInterestingly, Harada et al. ( 10 ) found a statistically\nsignificant correlation between the American Fertility\nSociety scoring system and the log-transformed IL-6\nlevels in PF from patients with endometriosis (r=0.723,\nP<0.01).\nHigher FF IL-6 concentrations were found in three\npapers in which infertile women with endometriosis were\ncompared to patients without endometriosis ( 11 ,  16 ,  17 ).\nTwo studies found no difference in FF IL-6 concentrations\nbetween endometriosis-associated infertility patients and\ncontrol groups ( 9 ,  20 ).\nThe only study evaluating IL-6 levels in ES between\ninfertile patients with endometriosis and a control group\nfailed to show any difference ( 12 ). Moreover, higher values\nof S ( 21 ) and PF ( 15 ) IL-6 were reported among patients\nwith endometriosis-associated infertility compared\nwith those who underwent diagnostic laparoscopy for\nendometriosis. Finally, higher values of PF IL-6 were\nshown among women with endometriosis-associated\ninfertility compared to women without endometriosis or\ninfertility ( 22 ,  23 ).\n\nThe present systematic review reinforces the hypothesis\nthat there is a correlation between elevated S and PF\nIL-6 concentrations and endometriosis-related infertility.\nHowever, there was no clear evidence of a correlation\nbetween FF and ES IL-6 concentrations and endometriosis associated infertility.\nNowadays 30 and 50% of patients with endometriosis\ndevelop infertility, and about 25 to 50% of infertile women\nare diagnosed with endometriosis ( 3 ,  21 ).\nSeveral theories have been proposed to explain this\npathogenesis and, currently, the chronic inflammation\ntheory seems to be the most plausible ( 6 ). Therefore,\nresearch into inflammatory factors as a cause of\nendometriosis is growing. Many authors have stated\nthat inflammatory markers are highly influential in\nendometriosis ( 21 ), and their evaluations represent noninvasive tests for this disease ( 24 )\nIL-6 is the most investigated interleukin concerning\nendometriosis and is an important pleiotropic cytokine for\nassisting with the diagnosis of this disease. It is secreted\nin response to injury by various immune cells ( 10 ), and\nparticipates in several immunological mechanisms ( 4 ,\n 25 ). Many studies have demonstrated higher S ( 26 ),\nPF ( 27 ) and FF ( 28 ) IL-6 concentrations in women\nwith endometriosis. IL6 also plays an important role in\nreproductive mechanisms, such as the production of\nsteroid hormones by the ovaries ( 10 ), folliculogenesis,\nand oocyte maturation by ovarian angiogenesis and\nenhancement of vascular permeability ( 7 ). IL-6 is an\nactivator of macrophages ( 29 ), which can amplify\nangiogenesis and regulate the immune environment of\nthe endometrium ( 5 ,  30 ). In this regard, IL-6 is felt to\ncontribute to infertility often associated with endometriosis\n( 3 ). IL-6 family proteins, especially leukemia inhibitory\nfactor (LIF), also play an important role in the early\nstages of embryonic implantation ( 15 ,  31 ) and therefore\none hypothesis is that their reduced expression may\ncause endometriosis-related infertility ( 15 ,  32 ). LIF, its\nreceptor LIFR, and the IL-6 family signaling molecule\nglycoprotein (gp)130 are predominantly expressed in the\nmid-secretory endometrium, where embryo implantation\noccurs ( 15 ,  33 ,  34 ). The binding of LIF to the high-affinity\nreceptor complex formed by LIFR and gp130 activates\nthe intracellular signaling transduced mainly through\nthe Janus kinase/signal transducer and activator of\ntranscription (JAK/STAT) pathway, which can be inhibited by suppression of cytokine signaling 1 (SOCS1) ( 15 ,  35 ).\nThe latter has been detected in the endometrium in both\nthe proliferative and secretory phases ( 15 ,  34 ). LIF also\nhas other functions in the endometrium, such as regulating\nthe immune environment during implantation, controlling\ninteractions between decidual leukocytes and the embryo,\nand altering the expression of glycans on the cell surface\n( 36 ,  37 ). In mice, the intrauterine administration of antiLIF has been shown to cause pregnancy blockage ( 38 ).\nIn accordance with this, some authors found a lower\nexpression of LIF in the mid-secretory endometrium of\ninfertile women with endometriosis than in fertile women\n( 32 ,  37 ), suggesting that altered endometrial expression\nof LIF, LIFR and gp130 may explain the higher rate of\ninfertility in women suffering from endometriosis ( 14 ,\n 15 ).\nPrima et al. ( 39 ) also showed a negative correlation\nbetween PF IL-6 levels and the Endometriosis Fertility\nIndex (EFI) score, an indicator to predict pregnancy in\npatients undergoing surgery that combines patient history\nfactors (age, duration of infertility and previous pregnancy\nhistory) and intraoperative findings (surgical factors).\nContrary to the discordant studies included in this review\nrelative to differences in FF IL-6 concentrations, Altun\net al. ( 40 ) reported an increased likelihood of clinical\npregnancies n women without endometriosis and with low\nFF IL-6 concentrations Therefore, evaluating local and\nsystemic IL-6 levels may be clinically useful to predict\nendometriosis-related infertility, especially in S and PF.\nFactors that may limit the conclusions of this review\nare that the control groups differed among the included\nstudies and that the results could have been influenced\nby the sample size, the presence of other inflammatory\npathological conditions, and the use of hormones and\ntherapies. The technical sensitivity of the assays used\ncan be an additional confounding factor and it is possible\nthat the IL-6 detected by some researchers may be nonfunctional or antagonized by anti-inflammatory cytokines\nor cytokine inhibitors. Another point to note is that\nIL-6 levels depend on the menstrual cycle phase, the\nendometriosis stage, and the type of lesion.\n\nLocal and systemic IL-6 levels may prove useful in\nthe future as diagnostic or biomarker tools to predict\nendometriosis-related infertility. However, the numerous\nbiases affecting the available studies, and challenges\nin endometriosis research reproducibility must be\nconsidered. Future investigations should pay attention\nto the choice of suitable control groups and carefully\nconsider other pathological conditions affecting the\npatients, the endometriosis stage, and the type of lesion as\nthese may affect the results.","source_license":"CC0","license_restricted":false}