{"paper_id":"0c3974b0-8aef-41c5-b701-61892082be0f","body_text":"Copyright@ Xiaopan Chen, Jing Shu | Biomed J Sci & Tech Res | BJSTR. MS.ID.004129.\n18728\nMini Review\nISSN: 2574 -1241\nPotential Involvement of Iron Overload in the \nPathogenesis of Endometriosis-Associated Infertility\nYier Zhou1#, Chongyi Shu2#, Dandan Wu3, Jianxin Lv2, Xiaopan Chen1,2,4* and Jing Shu1-4*\n1The First Clinical Medical School of Wenzhou Medical University, P .R. China\n2School of Laboratory Medicine and Life Science, Wenzhou Medical University, P .R. China\n3School of Medicine, Bengbu Medical College, P .R. China\n4Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, P .R. China\n#These authors contributed equally to this work\n*Corresponding author: Xiaopan Chen, The First Clinical Medical School of Wenzhou Medical University, School of Laboratory \nMedicine and Life Science, Wenzhou Medical University, Department of Reproductive Endocrinology, Zhejiang Provincial People’s \nHospital, P .R. China\nJing Shu, The First Clinical Medical School of Wenzhou Medical University, School of Laboratory Medicine and Life Science, Wenzhou \nMedical University, School of Medicine, Bengbu Medical College, P .R. China, Department of Reproductive Endocrinology, Zhejiang \nProvincial People’s Hospital, P .R. China\n      DOI: 10.26717/BJSTR.2020.24.004129\nReceived: \n  January 19, 2020\nPublished: \n   January 27, 2020\nCitation: Yier Zhou, Chongyi Shu, Dandan \nWu, Jianxin Lv, Xiaopan Chen, Jing Shu. \nPotential Involvement of Iron Overload \nin the Pathogenesis of Endometriosis-\nAssociated Infertility. Biomed J Sci & Tech \nRes 24(5)-2020. BJSTR. MS.ID.004129.\nARTICLE INFO Abstract\nEndometriosis is a common gynecological disease affecting women of childbearing \nage and closely related to infertility. Pelvic iron overload caused by ectopic periodic \nbleeding is one of the typical pathological features of endometriosis. Endometriosis-\nrelated pelvic iron overload may mediate infertility by affecting the microenvironment \nof gametes and zygotes and causing defective endometrial receptivity. The aim of this \nstudy is to review the current literature associating iron overload with endometriosis-\nassociated infertility and to discuss the potential damage of iron overload on the \nfunctionality of key cells during the reproductive process, thereby contributing to the \ndevelopment of the infertility. \nKeywords: Endometriosis; Infertility; Iron-Overload; Spermatozoa Quality; Ovarian \nFunction; Embryo Development; Endometrial Receptivity\nMini Review\nEndometriosis is defined as the appearance of intimal tissue, \nincluding both endometrial glands and stroma, outside the \nuterine, the main symptoms of which includes dysmenorrhea, \nabnormal menstruation, infertility and sexual intercourse pain. \nEndometriosis is an estrogen-dependent condition, primarily \nfound in women of childbearing age and is highly correlated with \ninfertility [1]. Epidemiology study revealed that the incidence \nof endometriosis in women of reproductive age is 10%~15%, \nwhereas the incidence is as high as 30%~50% in infertile patients \n[2]. Women with endometriosis tend to have a lower monthly \nfecundity rate compared to normal women [3]. In addition, there \nis also a link between endometriosis and lower live birth rates \n[4]. Despite an increasing number of studies on endometriosis-  \n \nassociated infertility, its etiopathology remains largely unknown. \nIndeed, a growing body of evidences suggests that mechanisms \nsuch as distorted pelvic anatomy, endocrine abnormalities, and \naltered cell-mediated functions in the endometrium may play a role \nin the pathogenesis of endometriosis-associated infertility [5].\nIron is an important metal for virtually all living organisms \ndue to its presence in a large number of iron-containing proteins \n[6]. Excess accumulation of iron within tissues or cells, however, \ncan contribute to toxicity and is associated with the pathogenesis \nof a variety of diseases such as thalassemia, hemochromatosis, \ncardiovascular or neurodegenerative diseases [7]. Moreover, \nin the case of hemorrhage, lysis of iron-rich erythrocytes leads \nto excess iron, which is directly toxic to target tissues and cells, \n\n\nCopyright@ Xiaopan Chen, Jing Shu | Biomed J Sci & Tech Res | BJSTR. MS.ID.004129.\nVolume 24- Issue 5\nDOI: 10.26717/BJSTR.2020.24.004129\n18729\ncausing iron-mediated oxidative damage and inflammation [8]. \nIt was recently suggested that iron-overload could be associated \nwith endometriosis-associated infertility [9]. In this manuscript, \npresence of excess iron in peritoneal fluid from patients with \nendometriosis are summarized, emphasizing the origin of iron \noverload in this disease. Current literature on iron involvement \nin endometriosis-associated infertility is reviewed and potential \ndamage of iron overload on reproductive processes are reported \non the basis of current data collected from both clinical study and \nbiological models.\nPresence of Excess Iron in Peritoneal Fluid from Patients \nwith Endometriosis\nIron deposits are typical features of endometrial lesions and \nincreased iron concentration are observed in the pelvic cavity of \npatients with endometriosis [10-12], and the concentration of iron \nis related to the severity of disease [11-13]. It has been reported \nthat the concentration of free iron in endometriotic cysts was \nhigher than that in non-endometriotic benign cysts, suggesting that \nendometriosis lesion may be the source of increased pelvic iron \n[14]. The periodic shedding and bleeding of lesions by the cyclic \nvariation of estrogen and progesterone accumulates a large number \nof red blood cells, part of which are swallowed up by macrophages, \nstored in the pelvic cavity in the form of hemosiderin, and the \nrest was breaks down and leads to the release of hemoglobin8. \nDigestion of hemoglobin leads to releasing a large amount of free \niron, which is suggested to excess the iron-binding ability of ferritin \nand transferrin [15]. When decompensation occurs, the excess free \niron which cannot be completely bound by transferrin and ferritin \nwas released into pelvic fluid, resulting in iron overload in pelvic \nfluid of patients with endometriosis [8].\nEvidences of Adverse Effects of Iron Overload on \nReproduction\nPelvic fluid closely participates in the formation of \nmicroenvironment for oocyte maturation, fertilization and embryo \nimplantation and development [16]. Langendonckt et al. reported \nthat compared to controls, the significantly increased pelvic iron \nconcentration found in patients with endometriosis was only \nobserved in secretory phase, but not in proliferative phase or \nmenstrual period [12]. The secretory phase coincides with the \ntiming of ovulation, fertilization, and implantation and development \nof early embryo, which means that any adverse alteration occurred \nduring this process, including overload of iron in pelvic cavity, \nshould be detrimental to the reproductive outcome.\nSpermatozoa Quality: High dose of iron found in the patients \nwith endometriosis may hinder the process of fertilization. A study \nby Arumugam et al. investigated the association between iron \nconcentration in peritoneal fluid from patients with endometriosis \nand acrosome reaction rates of spermatozoa [17]. This study \nfound that an increased iron concentration is responsible to the \ndecreased acrosome reaction rate, suggesting the increased iron \nconcentrations found in patients with endometriosis may have \nadverse effects on the fertilization [17]. More recent data suggest \nthat iron could produce biphasic effects on spermatozoa quality. In \nthis study, low concentration of iron prompts spermatozoa motility \nand DNA integrity whereas high concentration of iron exerts toxic \neffects [18]. In addition, iron uptake by peritoneal macrophages \nmay prompt the spermiophagy and lead to the subfertility found in \npatients with endometriosis [19].\nOvarian Function: Endometriosis, especially at the ovarian \nsite has been reported to have detrimental effects on ovarian \nfunction. Sonographic, histologic, and biochemical data have shown \nthat patients with endometriosis tend to have diminished ovarian \nreserve [20,21]. Moreover, this tendency of diminishing ovarian \nreserve also accompanied by a decrease in oocyte quality [22]. \nThis deleterious effect on ovarian reserve together with the decline \nin oocyte quality suggest a general decrease in ovarian function \nin patients with endometriosis, which has been proposed to be \nassociated with the iron-mediated toxic damage to the surrounding \nfollicles, as higher levels of iron was observed in the follicular \nfluid from follicles growing close to the lesion compared to that \nin contralateral unaffected ovaries [23]. However, despite these \nfindings, it remains uncertain whether iron overload may exert \nadverse effect on ovarian function, with one study concluding that \niron diffusion from endometriosis lesion into the adjacent ovarian \ntissue does not markedly affect ovarian function [24].\nEmbryo Development:  Potential effect of iron on \npreimplantation embryo development has also been reported. \nStudies using in vitro mouse embryo found that iron at very low \nconcentration was beneficial to elicit an improved blastulation \nrate and support preimplantation embryo development [25,26]. \nZhao et al. recently found that iron is essential for porcine \nembryonic development, but redundant iron impair the embryonic \ndevelopment [27]. This finding was compatible with the study by \nNaes et al. who noted that the high non-physiological levels of iron \nhad toxic effect of embryonic development [18]. Nonetheless, it \nworth noting that still some other studies do not tend to support \nthe idea that iron overload could compromise preimplantation \nembryo development [23,24].\nEndometrium Receptivity: It has long been well accepted \nthat changes in the receptivity of endometriosis affected embryo \nimplantation [16]. Deferred histologic maturation, biochemical \ndisturbances or immune disorders may contribute to dysfunction \nof endometrium [28]. However, to the best of our knowledge, \nthere is only one study linked the iron overload to the defective \nendometrium receptivity. In this study, haemosiderin deposition \nin the endometrial glandular epithelium in the patients with beta-\nthalassaemia major has been considered to be a potential cause \nof the defective endometrial receptivity and associated with the \ninfertility of these patients [29]. \n\nCopyright@ Xiaopan Chen, Jing Shu | Biomed J Sci & Tech Res | BJSTR. MS.ID.004129.\nVolume 24- Issue 5\nDOI: 10.26717/BJSTR.2020.24.004129\n18730\nSummary and Prospect\nAlthough increasing evidences on the association between \niron-overload and endometriosis-related infertility are available, \nthoughtful research is still lacking and some unresolved aspects \nshould be considered. First, conflicting results have been reported \nfor some of the aforementioned observations, especially in the \nstudy of association of iron overlord with ovarian function and \npreimplantation embryo development. Second, future study \nincluding both randomized controlled clinical trials and biological \ninvestigations are necessary to elucidate the precise mechanisms \nthrough which iron exert adverse effects on reproductive processes \nand will facilitate further explorations of the possible benefits of \niron chelation therapy to treat endometriosis associated infertility.\nAcknowledgement\nThis work was supported by grants from National Natural \nScience Foundation of China [81701460 (X. C.)] & [81200251 (J. S.)], \nNatural Science Foundation of Zhejiang Province [LY17H040014 (J. \nS)], General Research Program for Medicine and Health of Zhejiang \nProvince [ 2019KY033 (J. S.)], [ 2020KY414 (J. S.)], [2020KY448 \n(X. C.)] & [ 2019KY021 (R. W.)], and Excellent Young Scientist \nFoundation of Zhejiang Provincial People’s Hospital [ZRY2016A002 \n(X. C.)].\nConflict of Interest\nThe authors declare no conflict of interest.\nReferences\n1. 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MS.ID.004129.\nVolume 24- Issue 5\nDOI: 10.26717/BJSTR.2020.24.004129\n18731\nSubmission Link: https://biomedres.us/submit-manuscript.php\nAssets of Publishing with us\n• Global archiving of articles\n• Immediate, unrestricted online access\n• Rigorous Peer Review Process\n• Authors Retain Copyrights\n• Unique DOI for all articles\nhttps://biomedres.us/\nThis work is licensed under Creative\nCommons Attribution 4.0 License\nISSN: 2574-1241\nDOI: 10.26717/BJSTR.2020.24.004129\nXiaopan Chen, Jing Shu. Biomed J Sci & Tech Res","source_license":"CC0","license_restricted":false}