{"paper_id":"fbbcedfb-e17a-48aa-a0b6-b271bcc61670","body_text":"Mini Review\nVolume 3 Issue 3 -March 2017\nDOI: 10.19080/JGWH.2017.03.555612\nJ Gynecol Women’s Health\nCopyright © All rights are reserved by Rudy Leon De Wilde\nRole of Endometriosis in Infertility and Embryonic \nLoss: More than Anatomical Reasons\nLuz Angela Torres-de la Roche, Hugo Verhoeven and Rudy Leon De Wilde*\nClinic of Gynecology, Obstetrics and Gynecological Oncology, University Hospital for Gynecology, Pius-Hospital, Medical Campus University of Oldenburg, \nGermany\nSubmission: March 06, 2017; Published: March 21, 2017\n*Corresponding author: Rudy Leon De Wilde, MD PhD, Clinic of Gynecology, Obstetrics and Gynecological Oncology, University Hospital for \nGynecology, Pius-Hospital, Medical Campus University of Oldenburg, Germany, Tel: ; Fax:   \nEmail: \nJ Gynecol Women’s Health 3(3): JGWH.MS.ID.555612 (2017)\nMini Review\nThe association between endometriosis and infertility \nis widely recognized, but several studies demonstrate that \nendometriosis also affects pregnancy rates in different ways \nother than anatomical distortion of internal reproductive \norgans; however the evoking mechanisms are complex. In \nmild to advanced stages of disease, peritoneal adhesions, tubal \nobstruction, destruction of ovarian tissue or distortion of the \nuterine wall are evident originating factors of infertility or \nmiscarriage. In contrast, in 17% of all cases of endometriosis, \nthe reason of infertility is not clear [1], especially in women \nless than 35 years-old, who have a 2-fold increased risk of \nunexplained infertility (HR= 2.12, 95% CI= 1.76-2.56) [2],  \n \nalthough miscarriage rate after ICSI is not age dependent (<35 \nyears-old vs.> 35 years-old women; OR 0,4; 95% CI 0,1-2,1) \n[3]. The underlying abnormalities could explain the modest \npregnancy rates achieved by currently available medical and \nsurgical treatments, estimated in 52.9-83% in mild disease and \n0-6,7% insevere disease [1]. \nSome of the known pathophysiologic factors implied in \nendometriosis-associated infertility are irreversible (Table 1). \nThey generate functional and structural abnormalities of the \nhypothalamic-pituitary-ovary-endometrium axis, which in turn \nlead to retardation of sperm, oocyte and blastocyst transport, \nalteration of endometrial receptivity and, finally, embryonic loss. \n001\nJournal of\nGynecology and Women’s Health\nISSN 2474-7602\nTable 1: Proposed mechanisms of infertility and embryonic loss associated with endometriosis.\nMechanism Effect\nPituitary-ovarian axis dysfunction\nAltered feedback pathways.\nAbnormal cyclic changes in the ovary.\nImpaired folliculogenesis.\nPoor quality oocytes.\nImmunological alterations Alterations in humoral and cell-mediated immunity during luteal phase.\nAltered peritoneal milieu\nElevated level of prostaglandins, haptoglobin, cytokines, cellular remodeling enzymes, growth factors.\nSperm dysfunction.\nImpaired interaction sperm-endosalpinx epithelium.\nImpaired fertilization.\nGenetic mutations\nEndometrial cells polymorphisms.\nLess uterine receptivity.\nAbnormal uterine receptivity\nAltered steroid hormone pathways.\nDecreased or absent expression of implantation regulators and biomarkers.\nDelayed blastocyst hatching.\nImplantation failure.\nPoor quality embryo development\n\n\nHow to cite this article: Torres-de la Roche LA, Verhoeven H, De Wilde RL. Role of Endometriosis in infertility and Embryonic Loss: More than Anatomical \nReasons. J Gynecol Women’s Health. 2017; 3(3): 555612. DOI: 10.19080/JGWH.2017.03.555612002\nJournal of Gynecology and Women’s Health\nHormonal dysfunction in endometriosis includes [4,5]: \nextended follicular phase with aberrant patterns of LH-secretion, \nlower levels of circulating estrogen, androgen and progesterone, \nand increased intrafollicuaractivin, cytokines and growth \nfactors. This in turn induces premature apoptosis of cumulus \ncells, alteration of the morphology, maturation and liberation of \noocytes, and impairsoocyte fertilization potential. At ultrasound, \nimpairment of follicular growth and low dominant follicle size \ncould be observed. It is also possible to observe trapped oocytes \nin a luteinizing corpus hemorragicum as a signal of anovulation \nand altered corpus luteum development, defined as luteinized \nunruptured follicle syndrome (LUFs). \nThe local immunologic alteration induced by endometriosis \nresults in an inappropriate milieu for sperm, oocytes, embryo \ndevelopment and uterine receptivity [5]. This milieu is \ncharacterized by a high concentration of inflammatory cytokines, \noxidative stress products and reactive oxygen species (ROS). \nThese substances affect spermatozoa membrane, leading to an \nimpaired sperm function or rupture, including abnormal sperm-\nendosalpinx and sperm-oocyte interaction, low number of free \nspermatozoa in tubal ampulla, and loss of sperm fertilization \npotential. \nWomen with endometriosis also have six-times more nuclear \nand cytoplasmic aberrations than other women and have been \nassociated with disease severity [6]. These aberrations include \npolymorphisms, dysregulated micro-RNAs and epigenetic \nfactors. Such factors are able to induce DNA hypomethylation \nwith subsequent alteration of endometrial receptivity mediators \nand implantation failure [7]. \nDefects in blastocyst implantation could result due to altered \nhormonal levels, embryo anomalies orprogesterone-target genes \ndysregulation [7]. The last leads to a local progesterone resistance \nand to an inhospitable environment, which in turn impairs \nblastocyst implantation. This environment is characterized by   a \ndecreased or absent expression of implantation and regulators \nmarkers of endometrial receptivity, such as integrins, glycodelin \nA, leukemia inhibitory factor, osteopontin and lysophosphatidic \nacid receptor. Although hormone and inflammatory marker \nlevels, and uterine cavity anatomy can easily be studied, there is \ninsufficient evidence to recommend an appropriate assessment \nof endometrial receptivity.\nSome studies report that progesterone supplementation and \nendometrial biopsy may improve endometrial receptivity and \npregnancy rates, especially in IVF-embryo transfer cycles [8]. \nHowever, the analysis of published evidence is difficult given the \nquality of the studies and the diversity of proposed treatments, \nespecially those involving assisted- reproductive techniques. \nProgesterone administration for luteal phase support in embryo \ntransfer protocols is effective when given on the day or the day-\nafter oocyte pick-up (OR 1.87; 95% CI 1.13 to 3.08). On the other \nhand, increased endometrial implantation competency after \nendometrial biopsy are based on endometrial wound healing \nmechanisms, including secretion of cytokines and growth \nfactors accompanied of stem cells recruitment, which are free \nof epigeneticdefects, favoring embryo implantation. Treatments \nwith not conclusive efficacy are systemic administration of \nheparin, aspirin, prednisone, immunoglobulins or recombinant \nfollicle-stimulant hormones. Future therapies involving \nimmunomodulators or hormonal suppressive therapies could be \nuseful to improve fertility and pregnancy rates [9]. \nConclusion\nAs physicians and gynecologists, the better we understand the \nunderlying causes of infertility, failure of uterine receptivity and \nimpaired embryonic implantation associated to endometriosis, \nthe more appropriate and secured therapies we can provide, \nalthough many of these pathophysiological mechanisms are right \nnow not influenceable. Therefore more research is needed to \ndesign specific therapies capable of modulating the changeable \nones, to improve fertility rates, and to reduce embryonic loss \nrates, especially when we are facing patients undergoing \nassisted-reproductive treatments.\nReferences\n1. Johnson NP , Proctor M, Farquhar (2003) Gaps in the evidence for \nfertility treatment. Analysis of the Cochrane Menstrual Disorders and \nSubfertility Group. Hum Rep 18(5): 947-954. \n2. Prescott J, Farland LV, Tobias DK, Gaskins AJ, Spiegelman D, et al. (2016) \nA prospective cohort study of endometriosis and subsequent risk of \ninfertility. Hum Reprod 31(7): 1475-1482. \n3. Bahceci M, Ulug U (2005) Does underlying infertility aetiology impact \non first trimester miscarriage rate following ICSI? A preliminary report \nfrom 1244 singleton gestations. Hum Reprod 20(3): 717-721. \n4. Stilley JA, Birt JA, Sharpe-Timms KL (2012) Cellular and molecular \nbasis for endometriosis-associated infertility. Cell Tissue Res 349(3): \n849-862. \n5. Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, et al. (2008) \nPathogenic mechanisms in endometriosis-associated infertility. Fertil \nSteril 90(2): 247-257. \n6. Tomassetti C, Meuleman C, Pexsters A, Mihalyi A, Kyama C, et al. (2006) \nEndometriosis, recurrent miscarriage and implantation failure: Is \nthere an immunological link? Reprod Bio Medicine Online 13(1):58-64. \n7. Cakmak H, Taylor HS (2011) Implantation failure: molecular \nmechanisms and clinical treatment. Hum Reprod Update 17(2): 242-\n253. \n8. Glujovsky D, Pesce R, Fiszbajn G, Sueldo C, Hart RJ, et al. (2010) \nEndometrial preparation for women undergoing embryo transfer with \nfrozen embryos or embryos derived from donor oocytes. Cochrane \nDatabase of Systematic Reviews 1: CD006359. \n9. Brown J, Farquhar C (2014) Endometriosis: an overview of Cochrane \nReviews. Cochrane Database of Systematic Reviews 3: CD009590. \n\nHow to cite this article: Torres-de la Roche LA, Verhoeven H, De Wilde RL. Role of Endometriosis in infertility and Embryonic Loss: More than Anatomical \nReasons. J Gynecol Women’s Health. 2017; 3(3): 555612. DOI: 10.19080/JGWH.2017.03.555612003\nJournal of Gynecology and Women’s Health\nYour next submission with Juniper Publishers    \n      will reach you the below assets\n• Quality Editorial service\n• Swift Peer Review\n• Reprints availability\n• E-prints Service\n• Manuscript Podcast for convenient understanding\n• Global attainment for your research\n• Manuscript accessibility in different formats \n         ( Pdf, E-pub, Full Text, Audio) \n• Unceasing customer service\n                      Track the below URL for one-step submission \n               https://juniperpublishers.com/online-submission.php\nThis work is licensed under Creative\nCommons Attribution 4.0 Licens\nDOI: 10.19080/JGWH.2017.03.555612","source_license":"CC0","license_restricted":false}