{"paper_id":"bb55e083-6403-4d5e-a2cf-f916382348f8","body_text":"Endometriosis is a disease defined as the presence of endometrial tissue outside the\nuterine cavity ( Burney & Giudice, 2012 ;\n Gupta  et al ., 2006 ). It\nis highly prevalent among women of reproductive age ( Burney & Giudice, 2012 ), which is very alarming, since endometriosis\nis also frequently associated to infertility ( ASRM,\n2012 ). It affects approximately 25 to 50% of infertile women, and 30 to\n50% of endometriosis patients have difficulties to become pregnant ( ASRM, 2012 ). Although the literature widely\naddresses the association between the disease and infertility ( Akande  et al ., 2004 ;  Carvalho  et al ., 2012 ;  Da Broi & Navarro, 2016b ;  Gupta  et al ., 2008 ;  Marcoux  et al ., 1997 ; Parazzini, 1999), the\netiopathogenic mechanisms involved in this relation have not yet been fully\nunderstood.\nHere, we review and discuss on the role of some possible mechanisms underlying this\ncondition, including anatomical changes of the reproductive tract and smaller\novarian reserve possibly involved in advanced disease infertility, and also the role\nof peritoneal and follicular microenvironments, cumulus cells (CC), sperm function,\nand endometrial receptivity as possible mechanisms involved in the fertility\nimpairment in patients with early endometriosis.\nAlthough endometriosis is frequently associated to infertility ( ASRM, 2012 ), the mechanisms underlying this\ncondition are still not completely known. Several studies have been conducted in\norder to elucidate this question, and authors have suggested different\nmechanisms potentially involved in infertility impairment, including anatomical\nand microenvironmental conditions that may negatively impact the oocyte\ncompetence acquisition, egg fertilization, zygote transport within the tube and\nembryo implantation.\nIn cases of advanced disease (rAFS III and IV), anatomical changes of the\nreproductive tract such as peritubal and periovarian adhesions and pelvic\ndistortions are indicated as limiting factors, which could impair the oocyte\ncapture by the fimbriae, its passage through the tuba, as well as the gametic\ninteraction and the embryonic path to the uterine cavity ( ASRM, 2012 ;  Catenacci &\nFalcone, 2008 ;  Schenken  et\nal ., 1984 ). It has also been suggested a smaller ovarian\nreserve in women with advanced endometriosis ( Seyhan  et al ., 2015 ), especially in cases of\nendometrioma ( Hock  et al .,\n2001 ;  Sanchez  et\nal ., 2014 ;  Uncu  et\nal ., 2013 ). In this sense, some authors defend that\novarian endometrioma  per  se may affect ovarian reserve ( Goodman  et al ., 2016 ;\n Uncu  et al ., 2013 ).\nIt is believed that ovarian tissue may be target of toxic substances contained\nin the endometrioma, which could diffuse in the adjacent tissue and culminate\nwith the reduced ovarian reserve ( Sanchez\n et al ., 2014 ). On the other hand, some\nresearchers believe that surgical treatment of endometriomas promotes the damage\non ovarian tissue, predisposing to low follicle count ( Cranney  et al ., 2017 ;  Goodman  et al ., 2016 ;\n Mehdizadeh Kashi  et al .,\n2017 ).\nHowever, infertility presented by women with early endometriosis (rAFS I and II),\nwhere pelvic anatomical distortions are not present, raises questions about the\ninvolvement of other mechanisms in the impairment of fertility in patients with\nthe disease ( Da Broi & Navarro,\n2016b ;  Holoch & Lessey, 2010 ).\nIn this sense, it is believed that the peritoneal, follicular and endometrial\nmicroenvironments are altered in these women, with consequent damages to\nfolliculogenesis, ovulation, oocyte quality, endometrial receptivity and, even,\nsperm function ( Agarwal  et al .,\n2012 ;  Gupta  et al .,\n2008 ).\nEvidence from literature suggest that the immune function is possibly\ndysregulated in endometriosis patients ( Gupta\n et al ., 2008 ;  Miller  et al ., 2017 ). It is questioned if women\nwith endometriosis have immunological dysfunction preventing the removal of\nendometrial implants and leading to tissue adhesion in the peritoneal cavity\n( Ahn  et al ., 2015a ).\nIt is also believed that peritoneal endometrial lesions are responsible for the\nactivation of macrophages, with consequent increase in the generation of\ninflammatory factors, reactive oxygen and nitrogen species, cytokines, growth\nfactors, and prostaglandins. A marked inflammatory response, with exacerbation\nof reactive species and cytokines, would make the pelvic environment adverse,\nwhich would be reflected in the peritoneal fluid (PF) of these women ( Agarwal  et al ., 2003 ;  Gupta  et al ., 2006 ;  Ruder  et al ., 2008 ;  Szczepańska  et al ., 2003 ).\nCorroborating this reasoning, studies have shown changes in the PF composition\nof women with endometriosis, including changes in cellular and humoral mediators\n( Cheong  et al .,\n2002 ;  Eisermann  et al .,\n1988 ;  Jørgensen  et\nal ., 2017 ;  Keenan\n et al ., 1995 ), including pro-inflammatory\ncytokines such as tumor necrosis factor (TNF)-α, interleukin\n(IL)-1β, IL-6, IL-8, IL-10, IL-13, IL-17, IL-33, monocyte chemoattractant\nprotein (MCP)-1, macrophage migration inhibitory factor (MIF) and Regulated on\nActivation, Normal T Cell Expressed and Secreted (RANTES) ( Ahn  et al ., 2015b ;  Bersinger  et al ., 2006 ;  Harada  et al ., 1997 ;\nPunnonen  et al ., 1996;  Sikora\n et al ., 2012 ;  Wang  et al ., 2018 ;  Yoshino  et al ., 2003 ), chemokines ( Margari  et al ., 2013 ),\nangiogenic factors ( Ahn  et al .,\n2015b ;  Kianpour  et\nal ., 2013 ;  Yoshino\n et al ., 2003 ), and increased activated\nmacrophages, T-lymphocytes and natural killer cells ( Lebovic  et al ., 2001 ). These alterations\nmay lead to chronic inflammation, proliferation of lesions, local hormonal\nimbalance, what may lead to poor oocyte quality, poor sperm motility, embryo\ntoxicity and reduced endometrial receptivity ( Miller  et al ., 2017 ). In addition, there is\nevidence of altered oxidative stress (OS) markers in the PF of these women\n(Polak  et al ., 2013;  Santulli\n et al ., 2015 ;  Shanti  et al ., 1999 ). As a consequence of these\nalterations, studies have suggested an adverse effect of PF on the reproductive\ncapacity of the patients ( Jianini  et\nal ., 2017 ;  Gupta\n et al ., 2008 ;  Mansour  et al ., 2009a ;  Mansour  et al ., 2010 ).\nBecause the PF bathes the ovaries and maintains direct contact with the oocyte\nduring ovulation and in its initial course through the uterine tube, changes in\nthis microenvironment may culminate in oocyte damage and be involved in the\nimpairment of oocyte quality in endometriosis patients. Accordingly, studies\nwith murine model indicate damage to spindle and chromosomes after incubation of\noocytes in metaphase II with PF from women with the disease ( Mansour  et al ., 2009a ;\n Mansour  et al .,\n2010 ) which were reduced with the addition of an antioxidant, suggesting\nthe role of OS in promoting the oocyte alterations ( Mansour  et al ., 2009a ). In addition, in a\nrecent study, meiotic damage to bovine oocytes was evidenced after  in\nvitro  oocyte maturation in the presence of PF from infertile\npatients with endometriosis, suggesting changes in this fluid could also\ncompromise oocyte development during maturation and possibly affect oocyte\nquality of these patients ( Jianini  et\nal ., 2017 ).\nEvidences have suggested the occurrence of systemic OS in women with the disease\n( Andrade  et al .,\n2010 ;  Da Broi  et al .,\n2016 ;  Liu  et al .,\n2013 ;  Nasiri  et al .,\n2017 ;  Singh  et al .,\n2013 ), which could consequently reach the ovaries and affect\nintrafollicular oocyte development, since the ovarian cortex is highly\nvascularized, especially in the final period of folliculogenesis ( Tamanini & De Ambrogi, 2004 ).\nDifferent studies have investigated changes in the follicular fluid (FF)\ncomposition of women with endometriosis, such as cytokines ( Singh  et al ., 2016 ;  Wu  et al. , 2017 ) OS\nmarkers ( Choi  et al .,\n2015 ;  Da Broi  et\nal ., 2016a ;  Huang  et\nal ., 2014 ;  Liu\n et al ., 2013 ;  Nasiri  et al ., 2017 ; Prieto  et\nal ., 2012;  Singh  et\nal ., 2013 ), growth factors ( Choi  et al ., 2015 ), metals ( Singh  et al ., 2013 ), prostaglandins ( Du  et al ., 2013 ),\nmacrophages activation pattern ( Lamaita\n et al ., 2012 ), lipidic ( Cordeiro  et al ., 2015 ) and proteic\nprofiles ( Lo Turco  et al .,\n2013 ). In this sense, the evidences of OS in the follicular\nmicroenvironment of these women ( Choi  et\nal ., 2015 ;  Da Broi\n et al ., 2016a ;  Huang  et al ., 2014 ;  Liu  et al ., 2013 ;  Nasiri  et al ., 2017 ; Prieto  et\nal ., 2012;  Singh  et\nal ., 2013 ), suggest that not only their PF, but also their\nFF may contain substances harmful to the acquisition of oocyte competence. In\nthis regards, studies evaluating the effect of FF of infertile women with\nendometriosis on  in vitro  maturation of bovine oocytes showed\nspindle and chromosomal damage ( Da Broi\n et al ., 2014 ), which were prevented by the\naddition of antioxidants to the maturation medium, suggesting a pro-oxidant\nmicroenvironment in the ovarian follicles of these women ( Giorgi  et al ., 2016 ). Possibly, these\nalterations are consequence of OS damage on oocyte cell structures. Recently, it\nwas evidenced the presence of higher levels of eight-hydroxy-2-deoxyguanosine\n(8OHdG) in the FF of infertile women with endometriosis, suggesting oxidative\nDNA damage in cumulus-oocyte complexes, being a possible mechanism involved in\nthe impairment of oocyte quality in these patients ( Da Broi  et al ., 2016a ).\nThe CC are considered indirect markers of oocyte quality ( Assou  et al ., 2006 ;  Hamamah  et al ., 2006 ;  Hamel  et al ., 2008 ;  Haouzi & Hamamah, 2009 ), since they are\nresponsible for energetic metabolism ( Downs\n& Utecht, 1999 ;  Monniaux,\n2016 ; Paczkowski  et al ., 2013;  Saito  et al ., 1994 ), ions support ( FitzHarris  et al ., 2007 ),\ntranscriptional maintenance ( Albertini  et\nal ., 2001 ), maturation ( Li & Albertini, 2013 ;  Tanghe\n et al ., 2002 ) and defense ( Albertini  et al ., 2001 ;  Lolicato  et al ., 2015 ;\n Shaeib  et al. , 2016 ;\n Tanghe  et al ., 2002 )\nof the female gamete, so that changes in these cells can harm follicular\ndevelopment and indicate damage to the oocyte.\nStudies comparing the expression of genes related to steroidogenesis, acquisition\nof oocyte competence, and OS in CC of infertile women with and without\nendometriosis have been performed. Accordingly, the aromatase-encoding gene\n( CYP19A1)  ( Barcelos\n et al ., 2015 ;  Hosseini  et al ., 2016 ) ,  and the\ncyclooxygenase 2 (COX-2)-encoding gene ( PTGS2)  ( Donabela  et al ., 2011 )\nthat may mediate  CYP19A1  induction, seem to be both lower in CC\nof infertile women with endometriosis compared to infertile controls undergoing\ncontrolled ovarian stimulation for intracytoplasmic sperm injection (ICSI). In\nthis regards, it has been suggested an epigenetic alteration may be involved in\n CYP19A1  gene deregulation in CC of these patients ( Hosseini  et al ., 2016 ).\nAltogether, these data suggest reduced aromatase and, consequently, possibly\naltered follicular steroidogenesis and impaired oocyte quality in infertile\nwomen with endometriosis, what requires confirmation by further studies.\nThe evaluation of enzymatic antioxidants gene expression in CC of infertile women\nwith and without endometriosis evidenced increased superoxide dismutase 1\n( SOD1 ) expression in the moderate/severe endometriosis\ngroup compared to women with minimal/mild endometriosis and controls. It\nsuggests that advanced disease may induce pronounced OS and stimulate increased\nexpression of this antioxidant as an attempt to prevent oxidative damage to\noocytes ( Donabela  et al .,\n2015 ).\nMoreover, alterations in mitochondrial function of CC from infertile women with\nendometriosis have also been suggested as a possible mechanism involved in\noocyte damage ( Hsu  et al .,\n2015 ). Some authors have also evidenced alterations in CC's cell\ncycle of infertile women with advanced disease ( Toya  et al ., 2000 ), which may justify the increased\napoptosis observed by others in their CC ( Díaz-Fontdevila  et al ., 2009 ) and,\nconsequently, lead to abnormal folliculogenesis in these women ( Toya  et al ., 2000 ).\nLikewise, endometriosis has been identified as a disease related to changes in\nthe hypothalamic-pituitary-ovarian axis, with abnormal luteinizing hormone (LH)\nand prolactin secretion ( Cahill & Hull,\n2000 ;  Cunha-Filho  et\nal ., 2001 ), which may result in ovary dysfunction in\nwomen with the disease. Moreover, granulosa cells of infertile women with early\nendometriosis seem to be less sensitive to LH stimulation ( Cahill  et al ., 2003 ). In this sense,\nstudies point to the occurrence of an abnormal luteal phase ( Cunha-Filho  et al ., 2001 ;\n 2003 ;  Schenken  et al ., 1984 ) and a longer follicular\nphase ( Cahill  et al .,\n1997 ) in these patients, what may affect the patterns of estrogen and\nprogesterone secretion ( Cahill & Hull,\n2000 ;  Cunha-Filho  et\nal ., 2003 ). Accordingly, reduced estrogen, androgen and\nprogesterone, and increased activin were found in the follicular fluid of\npatients with endometriosis ( Cahill & Hull,\n2000 ). Consequently, these alterations may, directly or indirectly,\ndamage follicular growth, reduce dominant follicle size, affect follicles\nmaturation, and compromise ovulation in women with endometriosis ( Doody  et al ., 1988 ;  Schenken  et al ., 1984 ;\n Tummon  et al .,\n1988 ).\nIn addition, high growth factors, cytokines, activated macrophages, TNF-α\nconcentrations and OS present in the PF from infertile women with endometriosis\nmay be toxic to sperm function ( Aeby  et\nal ., 1996 ;  Liu\n et al ., 2000 ;  Mansour  et al. , 2009b ). These altered factors may\ninduce sperm DNA fragmentation ( Mansour\n et al ., 2009b ), disrupt sperm membrane\npermeability or integrity ( Said  et\nal ., 2005 ), reduce sperm motility ( Liu  et al ., 2000 ;  Oral  et al ., 1996 ), impair the interaction\nbetween the sperm and the epithelium of the uterine tube ( Reeve  et al ., 2005 ), promote abnormal\nsperm acrosome reaction ( Arumugam, 1994 )\nand impair sperm-oocyte fusion ( Aeby  et\nal ., 1996 ), representing another possible mechanism\ninvolved in endometriosis-related infertility.\nSome authors have also considered the role of the endometrium in infertility\nrelated to endometriosis, so that alterations in endometrial receptivity due to\nlate histological maturation or biochemical disturbances in the eutopic\nendometrium may compromise embryo implantation in women with the disease ( Bulletti  et al ., 2010 ;\n Giudice & Kao, 2004 ).\nStudies suggest that the endometrium may be functionally altered during the\nimplantation window in these patients ( Wei\n et al ., 2009 ). Among the molecules identified\nwith aberrant expression during the window of implantation in the eutopic\nendometrium of women with endometriosis there are receptors of progesterone and\nestrogen ( Young, 2013 ), integrins ( Giudice & Kao, 2004 ), leukemia\ninhibitory factor (LIF), glicodelin A, (GdA), osteopontin (OPN),\nlipolysophosphatidic acid receptor 3 (LPA3), HOXA10 ( Revel, 2012 ), which are related to the establishment of\nendometrial receptivity and/or to the interaction between the endometrium and\nthe embryo ( Giudice  et al .,\n2002 ).\nOn the other hand, recent studies have discussed the relevance of endometrial\nfactor for endometriosis-related infertility ( Broi  et al ., 2017 ;  Da Broi  et al ., 2017 ;  Garcia-Velasco  et al ., 2015 ). Simultaneous\nexpression of crucial genes for endometrial receptivity does not appear to\nundergo significant changes in infertile women with endometriosis during the\nimplantation window ( Broi  et\nal ., 2017 ). Likewise, the presence and stage of development\nof pinopods, which were once considered classic biomarkers of the implantation\nwindow in the human endometrial epithelium (Achache & Revel, 2006;  Aghajanova  et al ., 2003 ;\n Nikas, 1999 ;  Nikas & Makrigiannakis, 2003 ;  Nikas & Psychoyos, 1997 ;  Xu  et al ., 2012 ), also appear to be\nsimilar in women with the disease and controls ( Da Broi  et al ., 2017 ;  Ordi  et al ., 2003 ).\nRecently,  Garcia-Velasco  et al .\n(2015)  published a pilot study in which samples of eutopic\nendometrium from infertile women with endometriosis and infertile controls were\nevaluated using a molecular diagnostic tool (ERA), and showed no difference in\nthe expression of the genes predicted for receptivity between the groups.\n\nAlthough the mechanisms involved in endometriosis-related infertility are still not\ncompletely understood, some evidences suggest multiple factors that may potentially\naffect patient's fertility. In addition to the pelvic anatomical alterations likely\nto compromise the gametic interaction and the altered steroidogenesis, ovulation and\ndisrupted ovarian function, peritoneal changes seem to promote a harmful and\npro-oxidative microenvironment, which may compromise the CC and the follicular\nmicroenvironment, affecting folliculogenesis and, possibly, the oocyte competence in\nwomen with endometriosis. Peritoneal alterations may also damage the spermatozoa and\ndifficult gametes interaction. The role of compromised endometrial receptivity is\nstill controversial; however, recent evidence points to a major role of the oocyte\nfactor in impaired fertility of infertile women with endometriosis.","source_license":"CC-BY-4.0","license_restricted":false}