{"paper_id":"f179ae08-de79-4218-b8bd-22db790f81fd","body_text":"Editorial\nInfertility Associated to Endometriosis: Clarifying Some\nImportant Controversies\nPaula Andrea Navarro 1\n1 Department of Obstetrics and Gynecology, Faculdade de Medicina\nde Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP,\nBrazil\nRev Bras Ginecol Obstet 2019;41:523 –524.\nEndometriosis is an estrogen-dependent gynecological dis-\nease characterized by the presence and growth of endometrial\ntissue (glands and/or stroma) outside the uterine cavity.1 The\ndisease affects /C24 10% of women of reproductive age 2 and is\nstrongly associated with infertility.3 It is estimated that more\nthan 30% of infertile women have endometriosis2 and that 30\nto 50% of these women report difficulties in getting pregnant.4\nOpinion remains divided as to whether minor endometriosis\n(minimal and mild endometriosis—stages I and II, respectively)\nhas an adverse effect on the likelihood of conception.5–9 In 1998,\na study demonstrated that the fecundity of infertile women\nwith minimal or mild endometriosis is not significantly lower\nthan that of women with unexplained infertility, suggesting that\nthe initial stage of the disease is just afinding and not the cause\nof infertility.\n6 Otherwise, the findings of a randomized\ncontrolled trial showing improved natural conception rates\nfollowing surgical treatment of visible endometriotic lesions\nsuggest that the presence of visible minor lesions alone may\nhave an adverse effect on natural conception.\n7 Additionally, a\nretrospective study of 192 fully investigated infertile couples\n(117 women with unexplained infertility and 75 with\nminimal/mild endometriosis without adhesive disease, both\nmanaged conservatively after diagnostic laparoscopy) evaluated\ncumulative pregnancy rates in both groups followed up for up to\n3 years following laparoscopy.\n8 This study demonstrated that\nwomen with endometriosis had a lower probability of preg-\nnancy compared with women with unexplained infertility (36%\nv e r s u s5 5 % ,r e s p e c t i v e l y ) ,w h i c hc o nfirmed the presence of\nlower cumulative pregnancy rates in women in the early stages\nof endometriosis compared with women with infertility of\nunknown cause,\n9 thus supporting the association between\ninfertility and endometriosis in the early stages.\nInfertility presented by women with early endometriosis,\nin whom pelvic anatomical distortions are not present, raises\nquestions about the mechanisms involved in the impairment\nof fertility in patients with the disease. The research group\nunder my supervision has extensively performed studies in\nthis subject and published recent review articles approach-\ning this topic.\n10–12 Although the mechanisms involved in\nendometriosis-related infertility are still not completely\nunderstood, in summary, there are studies suggesting the\nperitoneal, follicular, systemic, and endometrial microenvir-\nonments may be altered in these women, with consequent\ndamages to folliculogenesis, oocyte quality, endometrial\nreceptivity, and, even, sperm function.\n10–12\nAnother very controversial point is whether the indica-\ntion of in-vitro fertilization (IVF) in infertile women with\nendometriosis is associated with a worse gestational prog-\nnosis after the procedure, and if the progression in disease\nstaging further worsens the results of the IVF.\nA systematic review published in 2002\n13 showed that\npatients with endometriosis who underwent ovarian stimula-\ntion for IVF had lower pregnancy rates when compared with\ninfertile patients with tubal factor (relative risk (RR) 0.56, 95%\nconfidence interval [95% CI] 0.44–0.70). However, when divid-\ning endometriosis patients according to the staging of the\ndisease (minimal/mild endometriosis—stages I/II and moder-\nate/severe endometriosis—stages III/IV), it was observed that\npatients with endometriosis I/II presented pregnancy rates\nsimilar to those with tubal factor (RR 0.79, 95% CI 0.6 –1.03),\nand patients with endometriosis III/IV had significantly lower\nrates than those without the disease (RR 0.46, 95% CI\n0.28–0.74). Despite being a relevant review, its main limitation\nis that most of the included studies were published between\n1980 and 1999, a period in which ovarian stimulation and\ntechnical conditions were quite different from the current ones.\nHowever, more recent studies contradict the results of this\nmeta-analysis published in 2002. Data from the latest pub-\nlished meta-analysis,\n14 which analyzed 36 cohort studies and\nrandomized controlled trials, show that compared with wom-\nen without endometriosis, women with endometriosis under-\ngoing IVF and intracytoplasmic sperm injection (ICSI) had a\nPaula Andrea Navarro ’s ORCID is https://orcid.org/0000-0003-\n2368-4188.\nAddress for correspondence\nP a u l aA n d r e aN a v a r r o ,A v .\nBandeirantes 3900, 14049-900,\nVila Monte Alegre, Ribeirão Preto,\nSP, Brazil (e-mail: drapaulanavarro\n@gmail.com).\nDOI https://doi.org/\n10.1055/s-0039-1697638.\nISSN 0100-7203.\nCopyright © 2019 by Thieme Revinter\nPublicações Ltda, Rio de Janeiro, Brazil\nTHIEME\nEditorial 523\nPublished online: 2019-09-23\n\nsimilar live birth rate per woman (RR¼ 0,94, 95% CI 0.84–1.06,\n13 studies, 12,682 patients, I2¼ 35%), lower clinical pregnancy\nrate per woman (RR ¼ 0.78, 95% CI 0.65 –0.94) (mean differ-\nence of -1.98, 95% CI, 22.87 –21.09, 17 studies, 17.593 cycles,\nI2 ¼ 97), a lower mean number of oocyte retrieved per cycle\n(mean difference - 1,98, 95% CI - 2.87 to - 1.09, 17 studies,\n17,593 cycles, I2 ¼ 97%). When compared with women with-\nout endometriosis, women with more advanced disease\n(stages III-IV) have lower rates of live births, clinical pregnancy\nrates, and mean number of retrieved oocytes. Briefly, data from\nthis meta-analysis show a lower number of oocytes captured in\nwomen with endometriosis compared with women without\nendometriosis, and lower live birth rates only in women with\nstage III/IV endometriosis when compared with women with-\nout endometriosis.\nIt is important to state that women with advanced endo-\nmetriosis have higher risk of presenting lower ovarian reserve\nthan women without endometriosis, which may be related to\nthe worse live birth rates demonstrated by this meta-analysis.\nCorroborating this hypothesis, a study published by our group\nevaluated 787 women who underwent IVF/ICSI (241 with\nendometriosis and 546 without) and demonstrated that\nalthough the mean age was similar between women with\nand without the diagnosis of endometriosis (33.8 /C6 4 versus\n33.7 /C6 4.4 years, respectively), poor ovarian reserve, defined as\nan antral follicle count /C20 6 before the beginning of ovarian\nstimulation, was more common in women with endometriosis\n(39.8% versus 22.7%).\n15 The chance of achieving live birth was\nsimilar between women with the diagnosis of endometriosis\nand those without it (19.1% versus 22.5%), and also when\nconsidering only women with a poor ovarian reserve (9.4%\nversus 8.9%) and only those with a normal ovarian reserve\n(25.5 versus 26.5%). Thus, we concluded that women diag-\nnosed with endometriosis are more likely to have a poor\novarian reserve; however, their chance of conceiving by\nIVF/ICSI is similar to the one observed in patients without\nendometriosis and with a comparable ovarian reserve.\nIn conclusion, although still a controversial theme, it\nseems even minor endometriosis has an adverse effect on\nthe likelihood of natural conception. The treatment of\ninfertility associated with endometriosis has to be individ-\nualized, taking into consideration some important aspects,\nsuch as the age of the patient, her ovarian reserve, the stage\nof the disease, the presence of pelvic pain, endometrioma\nand previous surgical intervention, the presence or absence\nof tubal abnormality, and the seminal quality of the part-\nner. When IVF is indicated, recent data show that the\nchance of conceiving is similar to the one observed in\npatients without endometriosis and with a comparable\novarian reserve.\nConflicts of Interest\nThe authors have no con flicts of interest to declare.\nReferences\n1 Giudice LC, Kao LC. Endometriosis. Lancet 2004;364(9447):1789-\n–1799. Doi: 10.1016/S0140-6736(04)17403-5\n2 Augoulea A, Alexandrou A, Creatsa M, Vrachnis N, Lambrinoudaki\nI. Pathogenesis of endometriosis: the role of genetics, in flamma-\ntion and oxidative stress. Arch Gynecol Obstet 2012;286(01):\n99–103. Doi: 10.1007/s00404-012-2357-8\n3 Sensky TE, Liu DT. Endometriosis: associations with menorrhagia,\ninfertility and oral contraceptives. Int J Gynaecol Obstet 1980;17\n(06):573–576. Doi: 10.1002/j.1879-3479.1980.tb00210.x\n4 Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and\ninfertility. J Assist Reprod Genet 2010;27(08):441 –447. Doi:\n10.1007/s10815-010-9436-1\n5 Revised American Society for Reproductive Medicine classi fica-\ntion of endometriosis: 1996. Fertil Steril 1997;67(05):817 –821.\nDoi: 10.1016/S0015-0282(97)81391-X\n6 Bérubé S, Marcoux S, Langevin M, Maheux R; The Canadian\nCollaborative Group on Endometriosis. Fecundity of infertile\nwomen with minimal or mild endometriosis and women with\nunexplained infertility. Fertil Steril 1998;69(06):1034 –1041. Doi:\n10.1016/S0015-0282(98)00081-8\n7 Marcoux S, Maheux R, Bérubé S; Canadian Collaborative Group on\nEndometriosis. Laparoscopic surgery in infertile women with\nminimal or mild endometriosis. N Engl J Med 1997;337(04):\n217–222. Doi: 10.1056/NEJM199707243370401\n8 Akande VA, Hunt LP, Cahill DJ, Jenkins JM. Differences in time to\nnatural conception between women with unexplained infertility\nand infertile women with minor endometriosis. Hum Reprod\n2004;19(01):96–103. Doi: 10.1093/humrep/deh045\n9 D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and\nsubfertility: is the relationship resolved? Semin Reprod Med\n2003;21(02):243–254. Doi: 10.1055/s-2003-41330\n10 Da Broi MG, Navarro PA. Oxidative stress and oocyte quality: ethio-\npathogenic mechanisms of minimal/mild endometriosis-related\ninfertility. Cell Tissue Res 2016;364(01):1–7. Doi: 10.1007/s00441-\n015-2339-9\n11 Da Broi MG, Giorgi VSI, Wang F, Keefe DL, Albertini D, Navarro PA.\nInfluence of follicular fluid and cumulus cells on oocyte quality:\nclinical implications. J Assist Reprod Genet 2018;35(05):735–751.\nDoi: 10.1007/s10815-018-1143-3\n12 Broi MGD, Ferriani RA, Navarro PA. Ethiopathogenic mechanisms\nof endometriosis-related infertility. JBRA Assist Reprod 2019;23\n(03):273–280. Doi: 10.5935/1518-0557.20190029\n13 Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis\non in vitro fertilization. Fertil Steril 2002;77(06):1148 –1155\n14 Hamdan M, Omar SZ, Dunselman G, Cheong Y. In fluence of\nendometriosis on assisted reproductive technology outcomes: a\nsystematic review and meta-analysis. Obstet Gynecol 2015;125\n(01):79–88. Doi: 10.1097/AOG.0000000000000592\n15 Coelho Neto MA, Martins WdeP, Luz CM, Jianini BT, Ferriani RA,\nNavarro PA. Endometriosis, ovarian reserve and live birth rate\nfollowing in vitro fertilization/intracytoplasmic sperm injection.\nRev Bras Ginecol Obstet 2016;38(05):218 –224. Doi: 10.1055/s-\n0036-1584126\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nInfertility Associated to Endometriosis Navarro524","source_license":"CC0","license_restricted":false}