Infertility workup: identifying endometriosis
2022; Elsevier BV; Volume: 118; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2022.03.015
ISSN1556-5653
AutoresPaul Pirtea, Nicolas Vulliemoz, Dominique de Ziegler, Jean Marc Ayoubi,
Tópico(s)Gynecological conditions and treatments
ResumoEndometriosis was classically diagnosed during diagnostic laparoscopies, which used to be routinely performed up until a decade ago or so. This practice fitted with the long-held belief that surgery was the gold standard for diagnosing endometriosis. Today, the abandon of routine diagnostic laparoscopies—in favor of assisted reproductive technology-first therapeutic approaches—has created a void for diagnosing endometriosis. Modern-day imaging techniques—ultrasound and magnetic resonance imaging—when used with a systematic approach have offered a reliable replacement option for diagnosing endometriosis. In infertility, endometriosis should be identified or excluded on the basis of past history or confirmation or exclusion suspicion on the basis of history and/or physical examination. Endometriosis was classically diagnosed during diagnostic laparoscopies, which used to be routinely performed up until a decade ago or so. This practice fitted with the long-held belief that surgery was the gold standard for diagnosing endometriosis. Today, the abandon of routine diagnostic laparoscopies—in favor of assisted reproductive technology-first therapeutic approaches—has created a void for diagnosing endometriosis. Modern-day imaging techniques—ultrasound and magnetic resonance imaging—when used with a systematic approach have offered a reliable replacement option for diagnosing endometriosis. In infertility, endometriosis should be identified or excluded on the basis of past history or confirmation or exclusion suspicion on the basis of history and/or physical examination. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34774 DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34774 Classically, endometriosis was a surgical diagnosis, ideally with histologic confirmation of the lesions removed (1de Ziegler D. Borghese B. Chapron C. Endometriosis and infertility: pathophysiology and management.Lancet. 2010; 376: 730-738Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar, 2Kennedy S. Bergqvist A. Chapron C. D'Hooghe T. Dunselman G. Greb R. et al.ESHRE guideline for the diagnosis and treatment of endometriosis.Hum Reprod. 2005; 20: 2698-2704Crossref PubMed Scopus (1277) Google Scholar). The high efficacy of modern-day assisted reproductive technology (ART) has led to progressively adopt ART-first approaches, particularly for women in their 30s. These new characteristics of infertility management lead, therefore, to raise the following practical questions:•How should endometriosis be diagnosed today in women with infertility?•What is the impact of endometriosis on oocyte quality and ART outcome?•What is the impact of endometriosis on endometrial receptivity?•Is there still a place for surgery in the management of infertility associated with endometriosis? The present review article addresses in practical terms the management of infertility associated with endometriosis with particular emphasis on its diagnosis and the consequences for clinical management. Not too long ago, diagnostic laparoscopies were still routinely performed in infertility workups notably (3Tanahatoe S. Hompes P.G. Lambalk C.B. Accuracy of diagnostic laparoscopy in the infertility work-up before intrauterine insemination.Fertil Steril. 2003; 79: 361-366Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) for diagnosing and treating endometriosis found in 35%–40% of women with infertility (4Evans M.B. Decherney A.H. Fertility and endometriosis.Clin Obstet Gynecol. 2017; 60: 497-502Crossref PubMed Scopus (54) Google Scholar). Today, ART achieves live birth rates in excess of 40% in women aged <35 years (https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2019) and similar results in older women provided that only euploid embryos are transferred (5Pirtea P. De Ziegler D. Tao X. Sun L. Zhan Y. Ayoubi J.M. et al.Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.Fertil Steril. 2021; 115: 45-53Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). These remarkable results together with the fact that women seek infertility treatments at an ever-increasing age have led infertility specialists to more and more often offer ART-first approaches, at least when women are in their 30s. The progressive abandon of diagnostic laparoscopies follows the accumulation of evidence that surgery for endometriosis—including endometriomas—does not improve ART outcome (6Brink Laursen J. Schroll J.B. Macklon K.T. Rudnicki M. Surgery versus conservative management of endometriomas in subfertile women. A systematic review.Acta Obstet Gynecol Scand. 2017; 96: 727-735Crossref PubMed Scopus (31) Google Scholar, 7Wu C.Q. Albert A. Alfaraj S. Taskin O. Alkusayer G.M. Havelock J. et al.Live birth rate after surgical and expectant management of endometriomas after in vitro fertilization: a systematic review, meta-analysis, and critical appraisal of current guidelines and previous meta-analyses.J Minim Invasive Gynecol. 2019; 26 (e3): 299-311Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 8Khan S. Lee C.L. Treating deep endometriosis in infertile patients before assisted reproductive technology.Gynecol Minim Invasive Ther. 2021; 10: 197-202Crossref PubMed Scopus (5) Google Scholar). On the contrary, reports have accumulated to indicate that surgery may actually cause more harm by impairing ovarian reserve (9Benaglia L. Castiglioni M. Paffoni A. Sarais V. Vercellini P. Somigliana E. Is endometrioma-associated damage to ovarian reserve progressive? Insights from IVF cycles.Eur J Obstet Gynecol Reprod Biol. 2017; 217: 101-105Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar) than endometriosis itself (10Streuli I. de Ziegler D. Gayet V. Santulli P. Bijaoui G. de Mouzon J. et al.In women with endometriosis anti-Mullerian hormone levels are decreased only in those with previous endometrioma surgery.Hum Reprod. 2012; 27: 3294-3303Crossref PubMed Scopus (138) Google Scholar). Furthermore, contrary to observations made in ovarian stimulation and insemination, ART does not worsen endometriosis symptoms and has no impact on ovarian endometriomas or deep infiltrating endometriosis (11Somigliana E. Vigano P. Benaglia L. Busnelli A. Paffoni A. Vercellini P. Ovarian stimulation and endometriosis progression or recurrence: a systematic review.Reprod Biomed Online. 2019; 38: 185-194Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). While widely predominant, the no-surgery-before-ART view is challenged by a few, however, notably, in the case of colorectal endometriosis (12Casals G. Carrera M. Dominguez J.A. Abrao M.S. Carmona F. Impact of surgery for deep infiltrative endometriosis before in vitro fertilization: a systematic review and meta-analysis.J Minim Invasive Gynecol. 2021; 28 (1303–12.e5)Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 13Bendifallah S. Roman H. Mathieu d'Argent E. Touleimat S. Cohen J. Darai E. et al.Colorectal endometriosis-associated infertility: should surgery precede ART?.Fertil Steril. 2017; 108 (525–31.e4)Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). The remaining indication for surgery in the case of infertility associated with endometriosis is for enhancing the chances of conceiving naturally in the 12–18 months after surgery. In a seminal article, Vercellini et al. (14Vercellini P. Somigliana E. Vigano P. Abbiati A. Barbara G. Crosignani P.G. Surgery for endometriosis-associated infertility: a pragmatic approach.Hum Reprod. 2009; 24: 254-269Crossref PubMed Scopus (213) Google Scholar) reported that surgery for pelvic endometriosis increased the chances of conceiving naturally in the 18 months after surgery by approximately 50%. These data were later confirmed by others (15Muzii L. DI Tucci C. Galati G. Mattei G. Chine A. Cascialli G. et al.Endometriosis-associated infertility: surgery or IVF?.Minerva Obstet Gynecol. 2021; 73: 226-232Crossref PubMed Scopus (7) Google Scholar, 16Duckelmann A.M. Taube E. Abesadze E. Chiantera V. Sehouli J. Mechsner S. When and how should peritoneal endometriosis be operated on in order to improve fertility rates and symptoms? The experience and outcomes of nearly 100 cases.Arch Gynecol Obstet. 2021; 304: 143-155Crossref PubMed Scopus (20) Google Scholar). Before considering surgery for infertility associated with endometriosis, one needs to verify that natural conception is possible—normal sperm and patent tubes—and that time and ovarian reserve exist for dedicating 12–18 months to attempt to conceive naturally (16Duckelmann A.M. Taube E. Abesadze E. Chiantera V. Sehouli J. Mechsner S. When and how should peritoneal endometriosis be operated on in order to improve fertility rates and symptoms? The experience and outcomes of nearly 100 cases.Arch Gynecol Obstet. 2021; 304: 143-155Crossref PubMed Scopus (20) Google Scholar). Practically, surgery is primarily envisioned in women in their 20s. One important new parameter is that the possible benefit from surgery should be established preoperatively, not during the procedure itself. Indeed, determining beforehand—before surgery—whether a person is likely to benefit from surgery differs from prior practices that established the chance of conceiving during the surgical procedure (17Adamson G.D. Pasta D.J. Endometriosis fertility index: the new, validated endometriosis staging system.Fertil Steril. 2010; 94: 1609-1615Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar). The progressive abandon of diagnostic laparoscopies had 2 practical consequences. First, recent data have reported a decreased prevalence of endometriosis in women with infertility over a 10-year study interval (18Christ J.P. Yu O. Schulze-Rath R. Grafton J. Hansen K. Reed S.D. Incidence, prevalence, and trends in endometriosis diagnosis: a United States population-based study from 2006 to 2015.Am J Obstet Gynecol. 2021; 225 (500.e1–9)Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). This is in keeping with the data of a study conducted using the Society for Assisted Reproductive Technology database reporting an abnormally low incidence of endometriosis in only 11% in a cohort of 400,059 ART cycles (19Senapati S. Sammel M.D. Morse C. Barnhart K.T. Impact of endometriosis on in vitro fertilization outcomes: an evaluation of the Society for Assisted Reproductive Technologies Database.Fertil Steril. 2016; 106 (164–71.e1)Abstract Full Text Full Text PDF Scopus (124) Google Scholar). Second, the demise of diagnostic laparoscopies has created a void for diagnosing endometriosis. This is now being filled in part by imaging-based approaches, using ultrasound or magnetic resonance imaging (MRI) for diagnosing ovarian and deep infiltrating endometriosis. Unfortunately, imaging-based approaches are poor at diagnosing superficial endometriosis. One landmark publication on the use of ultrasound for diagnosing endometriosis has emphasized the role of systematic analysis of all areas where endometriosis is likely to develop, an approach defined as the mapping technique (20Exacoustos C. Malzoni M. Di Giovanni A. Lazzeri L. Tosti C. Petraglia F. et al.Ultrasound mapping system for the surgical management of deep infiltrating endometriosis.Fertil Steril. 2014; 102 (143–50.e2)Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). These results were then confronted with findings made at laparoscopies (20Exacoustos C. Malzoni M. Di Giovanni A. Lazzeri L. Tosti C. Petraglia F. et al.Ultrasound mapping system for the surgical management of deep infiltrating endometriosis.Fertil Steril. 2014; 102 (143–50.e2)Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar) and later refined (21Van den Bosch T. Van Schoubroeck D. Ultrasound diagnosis of endometriosis and adenomyosis: state of the art.Best Pract Res Clin Obstet Gynaecol. 2018; 51: 16-24Crossref PubMed Scopus (109) Google Scholar, 22Chapron C. Marcellin L. Borghese B. Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis.Nat Rev Endocrinol. 2019; 15: 666-682Crossref PubMed Scopus (428) Google Scholar, 23Piessens S. Edwards A. Sonographic evaluation for endometriosis in routine pelvic ultrasound.J Minim Invasive Gynecol. 2020; 27: 265-266Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Magnetic resonance imaging, using a similar mapping technique, likewise allows to precisely characterize and diagnose endometriosis (24Jaramillo-Cardoso A. Shenoy-Bhangle A. Garces-Descovich A. Glickman J. King L. Mortele K.J. Pelvic MRI in the diagnosis and staging of pelvic endometriosis: added value of structured reporting and expertise.Abdom Radiol (NY). 2020; 45: 1623-1636Crossref PubMed Scopus (15) Google Scholar) as well as adenomyosis (25Chapron C. Vannuccini S. Santulli P. Abrao M.S. Carmona F. Fraser I.S. et al.Diagnosing adenomyosis: an integrated clinical and imaging approach.Hum Reprod Update. 2020; 26: 392-411Crossref PubMed Scopus (176) Google Scholar). Recently, it was concluded that transvaginal ultrasound with bowel preparation was equivalent to diagnostic laparoscopy, except for its inability to identify superficial endometriosis (26Goncalves M.O. Siufi Neto J. Andres M.P. Siufi D. de Mattos L.A. Abrao M.S. Systematic evaluation of endometriosis by transvaginal ultrasound can accurately replace diagnostic laparoscopy, mainly for deep and ovarian endometriosis.Hum Reprod. 2021; 36: 1492-1500Crossref PubMed Scopus (32) Google Scholar). Superficial endometriosis, indeed, escapes diagnosis by imaging (26Goncalves M.O. Siufi Neto J. Andres M.P. Siufi D. de Mattos L.A. Abrao M.S. Systematic evaluation of endometriosis by transvaginal ultrasound can accurately replace diagnostic laparoscopy, mainly for deep and ovarian endometriosis.Hum Reprod. 2021; 36: 1492-1500Crossref PubMed Scopus (32) Google Scholar). In the future, truly noninvasive markers of endometriosis on the basis of a panel of microribonucleic acids may serve for singling out women affected with endometriosis (27Bendifallah S. Dabi Y. Suisse S. Jornea L. Bouteiller D. Touboul C. et al.MicroRNome analysis generates a blood-based signature for endometriosis.Sci Rep. 2022; 12: 4051Crossref PubMed Scopus (15) Google Scholar). Like for other noninvasive biomarkers of endometriosis (28Lessey B.A. Lebovic D.I. Taylor R.N. Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects.Semin Reprod Med. 2013; 31: 109-124Crossref PubMed Scopus (95) Google Scholar, 29Nisenblat V. Bossuyt P.M. Shaikh R. Farquhar C. Jordan V. Scheffers C.S. et al.Blood biomarkers for the non-invasive diagnosis of endometriosis.Cochrane Database Syst Rev. 2016; 2016: CD012179PubMed Google Scholar, 30Coutinho L.M. Ferreira M.C. Rocha A.L.L. Carneiro M.M. Reis F.M. New biomarkers in endometriosis.Adv Clin Chem. 2019; 89: 59-77Crossref PubMed Scopus (42) Google Scholar, 31Chen T. Wei J.L. Leng T. Gao F. Hou S.Y. The diagnostic value of the combination of hemoglobin, CA199, CA125, and HE4 in endometriosis.J Clin Lab Anal. 2021; 35e23947Crossref Scopus (12) Google Scholar), these data remain at research stage for the time being. As discussed in the following, to avoid underreporting endometriosis and failing to apply proper approaches while undertaking ART, proper imaging-based approaches for diagnosis ought to be deployed once endometriosis is clinically suspected. The classic view portrayed endometriosis as being responsible for altering oocyte quality and, thereby, altering ART outcome. Our judgment is more subtle now, realizing that endometriosis may affect ovarian response to gonadotropin. While this effect may not impact the actual implantation rates (32Matalliotakis I.M. Cakmak H. Mahutte N. Fragouli Y. Arici A. Sakkas D. Women with advanced-stage endometriosis and previous surgery respond less well to gonadotropin stimulation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility.Fertil Steril. 2007; 88: 1568-1572Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar), even in the presence of endometriomas (33Hamdan M. Dunselman G. Li T.C. Cheong Y. The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis.Hum Reprod Update. 2015; 21: 809-825Crossref PubMed Scopus (228) Google Scholar), it is likely, however, to diminish the ultimate cumulative pregnancy rate. The actual details proffering that endometriosis altered oocyte quality were all indirect. These were either based on granulosa cell or follicular fluid markers (34Carlberg M. Nejaty J. Froysa B. Guan Y. Soder O. Bergqvist A. Elevated expression of tumour necrosis factor alpha in cultured granulosa cells from women with endometriosis.Hum Reprod. 2000; 15: 1250-1255Crossref PubMed Scopus (108) Google Scholar) or using an animal model on the basis of in vivo fertilization (35Bilotas M.A. Olivares C.N. Ricci A.G. Baston J.I. Bengochea T.S. Meresman G.F. et al.Interplay between endometriosis and pregnancy in a mouse model.PLoS One. 2015; 10e0124900Crossref PubMed Scopus (27) Google Scholar, 36Cohen J. Ziyyat A. Naoura I. Chabbert-Buffet N. Aractingi S. Darai E. et al.Effect of induced peritoneal endometriosis on oocyte and embryo quality in a mouse model.J Assist Reprod Genet. 2015; 32: 263-270Crossref PubMed Scopus (34) Google Scholar). Contrary to these views of altered oocyte quality in in vivo-derived conditions, there is now evidence that ART by sparing contact between the oocyte and the toxic environment of the pelvic cavity (37Agostinis C. Balduit A. Mangogna A. Zito G. Romano F. Ricci G. et al.Immunological basis of the endometriosis: the complement system as a potential therapeutic target.Front Immunol. 2020; 11: 599117Crossref PubMed Scopus (38) Google Scholar, 38Lee Y.H. Yang J.X. Allen J.C. Tan C.S. Chern B.S.M. Tan T.Y. et al.Elevated peritoneal fluid ceramides in human endometriosis-associated infertility and their effects on mouse oocyte maturation.Fertil Steril. 2018; 110 (767–77.e5)Abstract Full Text Full Text PDF Scopus (15) Google Scholar) provides oocytes of unaltered quality. Indeed, oocytes obtained by ART develop into embryos that have similar euploidy and implantation rates as those of age-matched controls (39Juneau C. Kraus E. Werner M. Franasiak J. Morin S. Patounakis G. et al.Patients with endometriosis have aneuploidy rates equivalent to their age-matched peers in the in vitro fertilization population.Fertil Steril. 2017; 108: 284-288Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 40Bishop L.A. Gunn J. Jahandideh S. Devine K. Decherney A.H. Hill M.J. Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts.Fertil Steril. 2021; 115: 416-422Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Today, therefore, we are confronted with a dichotomy when it comes to oocyte quality in the case of infertility associated with endometriosis. On the one side, oocytes ovulated in vivo and, therefore, exposed even transitorily to the toxic characteristics of the pelvic cavity are of altered quality (36Cohen J. Ziyyat A. Naoura I. Chabbert-Buffet N. Aractingi S. Darai E. et al.Effect of induced peritoneal endometriosis on oocyte and embryo quality in a mouse model.J Assist Reprod Genet. 2015; 32: 263-270Crossref PubMed Scopus (34) Google Scholar), whereas those obtained by ART are functionally normal (39Juneau C. Kraus E. Werner M. Franasiak J. Morin S. Patounakis G. et al.Patients with endometriosis have aneuploidy rates equivalent to their age-matched peers in the in vitro fertilization population.Fertil Steril. 2017; 108: 284-288Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 40Bishop L.A. Gunn J. Jahandideh S. Devine K. Decherney A.H. Hill M.J. Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts.Fertil Steril. 2021; 115: 416-422Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). This duality explains the reduced natural conception chances encountered in women with endometriosis, whereas recent ART studies indicated that the implantation and live birth rates are most often normal (41Metzemaekers J. Lust E. Rhemrev J. Van Geloven N. Twijnstra A. Van Der Westerlaken L. et al.Prognosis in fertilisation rate and outcome in IVF cycles in patients with and without endometriosis: a population-based comparative cohort study with controls.Facts Views Vis Obgyn. 2021; 13: 27-34Crossref PubMed Google Scholar). To account for the improved pregnancy chances observed after surgery for endometriosis (14Vercellini P. Somigliana E. Vigano P. Abbiati A. Barbara G. Crosignani P.G. Surgery for endometriosis-associated infertility: a pragmatic approach.Hum Reprod. 2009; 24: 254-269Crossref PubMed Scopus (213) Google Scholar, 15Muzii L. DI Tucci C. Galati G. Mattei G. Chine A. Cascialli G. et al.Endometriosis-associated infertility: surgery or IVF?.Minerva Obstet Gynecol. 2021; 73: 226-232Crossref PubMed Scopus (7) Google Scholar), one is inclined to postulate that surgery decreases—if only for a time—the toxic pelvic environment (37Agostinis C. Balduit A. Mangogna A. Zito G. Romano F. Ricci G. et al.Immunological basis of the endometriosis: the complement system as a potential therapeutic target.Front Immunol. 2020; 11: 599117Crossref PubMed Scopus (38) Google Scholar, 38Lee Y.H. Yang J.X. Allen J.C. Tan C.S. Chern B.S.M. Tan T.Y. et al.Elevated peritoneal fluid ceramides in human endometriosis-associated infertility and their effects on mouse oocyte maturation.Fertil Steril. 2018; 110 (767–77.e5)Abstract Full Text Full Text PDF Scopus (15) Google Scholar) prevailing in endometriosis. On the contrary, clinical evidence suggests that this is not the case after the medical treatment of endometriosis. Indeed, medical treatments of endometriosis, which all block ovulation and are, therefore, contraceptive (42Archer D.F. Ng J. Chwalisz K. Chiu Y.L. Feinberg E.C. Miller C.E. et al.Elagolix suppresses ovulation in a dose-dependent manner: results from a 3-month, randomized study in ovulatory women.J Clin Endocrinol Metab. 2020; 105: dgz086Crossref PubMed Scopus (14) Google Scholar, 43Vercellini P. Vigano P. Barbara G. Buggio L. Somigliana E. Luigi Mangiagalli' Endometriosis Study GroupElagolix for endometriosis: all that glitters is not gold.Hum Reprod. 2019; 34: 193-199Crossref PubMed Scopus (34) Google Scholar), reduce symptoms and the risk of recurrence. Yet, the pelvic effects of these treatments, contrary to surgery, are not associated with a rebound of fertility upon stopping (44Vercellini P. Crosignani P. Somigliana E. Vigano P. Frattaruolo M.P. Fedele L. 'Waiting for Godot': a commonsense approach to the medical treatment of endometriosis.Hum Reprod. 2011; 26: 3-13Crossref PubMed Scopus (150) Google Scholar). Hence, medical treatment holds no place in the management of infertility associated with endometriosis. The eutopic endometrium—in the uterus itself—is altered in the case of endometriosis, a fact that is believed to affect endometrial receptivity to embryo implantation (45Benaglia L. Cardellicchio L. Guarneri C. Paffoni A. Restelli L. Somigliana E. et al.IVF outcome in women with accidental contamination of follicular fluid with endometrioma content.Eur J Obstet Gynecol Reprod Biol. 2014; 181: 130-134Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). These alterations have been incriminated in the presumed decreased embryo implantation rates once related in the case of endometriosis. In an extensive review of the topic, Bulun et al. (46Bulun S.E. Yilmaz B.D. Sison C. Miyazaki K. Bernardi L. Liu S. et al.Endometriosis. Endocr Rev. 2019; 40: 1048-1079Crossref PubMed Scopus (375) Google Scholar) report that the eutopic endometrium displays numerous cellular and molecular abnormalities. These include the activation of oncogenic pathways or biosynthetic cascades that favor increased production of estrogen, cytokines, prostaglandins, and metalloproteinases (47Noble L.S. Takayama K. Zeitoun K.M. Putman J.M. Johns D.A. Hinshelwood M.M. et al.Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells.J Clin Endocrinol Metab. 1997; 82: 600-606Crossref PubMed Scopus (412) Google Scholar). This in turn causes an improper transformation of decidualized cells, as studied in vitro (48Barragan F. Irwin J.C. Balayan S. Erikson D.W. Chen J.C. Houshdaran S. et al.Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis.Biol Reprod. 2016; 94: 118Crossref PubMed Scopus (103) Google Scholar). In endometrial stromal cells, the estrogen receptor-β levels are 142-fold higher and the estrogen receptor-α levels are ninefold lower than those in the normal endometrium (49Xue Q. Lin Z. Cheng Y.H. Huang C.C. Marsh E. Yin P. et al.Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis.Biol Reprod. 2007; 77: 681-687Crossref PubMed Scopus (276) Google Scholar), as a result of epigenetic changes (46Bulun S.E. Yilmaz B.D. Sison C. Miyazaki K. Bernardi L. Liu S. et al.Endometriosis. Endocr Rev. 2019; 40: 1048-1079Crossref PubMed Scopus (375) Google Scholar, 50Dyson M.T. Roqueiro D. Monsivais D. Ercan C.M. Pavone M.E. Brooks D.C. et al.Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis.PLoS Genet. 2014; 10e1004158Crossref PubMed Scopus (146) Google Scholar). The resulting abnormally high ratio of receptor-β over receptor-α affects the normal activation of the progesterone receptor gene. This in turn causes the characteristic progesterone resistance, which is emblematic of the endometrial changes encountered in endometriosis (51Aghajanova L. Tatsumi K. Horcajadas J.A. Zamah A.M. Esteban F.J. Herndon C.N. et al.Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis.Biol Reprod. 2011; 84: 801-815Crossref PubMed Scopus (83) Google Scholar). Moreover, nerve tissue has been immunohistochemically identified in the functional layer of eutopic endometrial tissue in all women with endometriosis but not in the eutopic endometrium of disease-free women (52Tokushige N. Markham R. Russell P. Fraser I.S. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis.Hum Reprod. 2006; 21: 782-787Crossref PubMed Scopus (180) Google Scholar, 53Tokushige N. Markham R. Russell P. Fraser I.S. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis.Fertil Steril. 2007; 88: 795-803Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). The resulting inflammation of the eutopic endometrium has been hypothesized to generate or perpetuate the disease itself by disseminating activated endometrial progenitor cells through retrograde menstruation (54Wang Y. Nicholes K. Shih I.M. The origin and pathogenesis of endometriosis.Annu Rev Pathol. 2020; 15: 71-95Crossref PubMed Scopus (175) Google Scholar). Practically, the alterations of the eutopic endometrium have been claimed to alter endometrial receptivity to embryo implantation, including in ART (28Lessey B.A. Lebovic D.I. Taylor R.N. Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects.Semin Reprod Med. 2013; 31: 109-124Crossref PubMed Scopus (95) Google Scholar, 55Brosens I. Brosens J.J. Benagiano G. The eutopic endometrium in endometriosis: are the changes of clinical significance?.Reprod Biomed Online. 2012; 24: 496-502Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Ovarian suppression by hormone treatment appears to reverse the effects of endometriosis on the eutopic endometrium notably on nerve fibers (56Tokushige N. Markham R. Russell P. Fraser I.S. Effects of hormonal treatment on nerve fibers in endometrium and myometrium in women with endometriosis.Fertil Steril. 2008; 90: 1589-1598Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar), markers of inflammation (57Matson B.C. Quinn K.E. Lessey B.A. Young S.L. Caron K.M. Elevated levels of adrenomedullin in eutopic endometrium and plasma from women with endometriosis.Fertil Steril. 2018; 109: 1072-1078Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar), local production of estradiol (E2) (58Maia Jr., H. Casoy J. Correia T. Freitas L.A. Pimentel K. Athayde C. The effect of oral contraceptives on aromatase expression in the eutopic endometrium of patients with endometriosis.Gynecol Endocrinol. 2008; 24: 123-128Crossref PubMed Scopus (25) Google Scholar), and progesterone resistance (59Patel B.G. Rudnicki M. Yu J. Shu Y. Taylor R.N. Progesterone resistance in endometriosis: origins, consequences and interventions.Acta Obstet Gynecol Scand. 2017; 96: 623-632Crossref PubMed Scopus (208) Google Scholar). Recent ART data suggest that the ovarian suppression induced by the E2 and progesterone treatments used for timing frozen embryo transfers exerts a similar beneficial effect (40Bishop L.A. Gunn J. Jahandideh S. Devine K. Decherney A.H. Hill M.J. Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts.Fertil Steril. 2021; 115: 416-422Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Indeed, Bishop et al. (40Bishop L.A. Gunn J. Jahandideh S. Devine K. Decherney A.H. Hill M.J. Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts.Fertil Steril. 2021; 115: 416-422Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) reported that the transfers of euploid blastocysts timed with E2 and progesterone hormone replacement cycles had similar implantation rates in endometriosis and age-matched control women. This approach—freeze-all and deferred embryo transfer—will likely replace the old approach that recommended prolonged ovarian suppression using either the gonadotropin-releasing hormone agonist (GnRH-a) (60Surrey E.S. Silverberg K.M. Surrey M.W. Schoolcraft W.B. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis.Fertil Steril. 2002; 78: 699-704Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar) or the contraceptive pill before ART cycles (61de Ziegler D. Gayet V. Aubriot F.X. Fauque P. Streuli I. Wolf J.P. et al.Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes.Fertil Steril. 2010; 94: 2796-2799Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). At the onset of the infertility workup, one has to establish whether endometriosis exists, as per past surgery or ad hoc imaging procedures, or when suspected on the basis of symptoms and/or pelvic examination (62Chapron C. Lafay-Pillet M.C. Santulli P. Bourdon M. Maignien C. Gaudet-Chardonnet A. et al.A new validated screening method for endometriosis diagnosis based on patient questionnaires.EClinicalMedicine. 2022; 44: 101263Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). In the case of clinical suspicion, appropriate imaging-based screening—ultrasound and/or MRI—ought to be undertaken. While in expert hands, ultrasound and MRI appear equivalent in their ability to diagnose ovarian and deep infiltrating endometriosis, MR images are operator independent and can be reassessed by a different radiologist. A recent systematic review and meta-analysis concluded that ultrasound and MRI were equivalent for diagnosing deep infiltrating endometriosis (63Guerriero S. Saba L. Pascual M.A. Ajossa S. Rodriguez I. Mais V. et al.Transvaginal ultrasound vs magnetic resonance imaging for diagnosing deep infiltrating endometriosis: systematic review and meta-analysis.Ultrasound Obstet Gynecol. 2018; 51: 586-595Crossref PubMed Scopus (154) Google Scholar), as illustrated in Figure 1. If endometriosis is diagnosed, the choice is between surgery for enhancing the chances of natural conception and ART. The ART-first approaches are generally preferred today in women in their 30s. Indeed, in these women, delaying management by expecting to conceive naturally for 12–18 months after surgery may impair their overall prospect for pregnancy. This is also the cases if other elements compound infertility, such as ovulatory, male factor, or tubal issues or a sense of urgency from the side of the couple. If ART is opted for—whatever the reason—surgery is unnecessary, and in general, one proceeds directly to ART, following a new no-surgery-before-ART rule. If endometriosis is diagnosed—either by prior history or because the clinical suspicion is confirmed—and ART is opted for, the following precautions are recommended. The exclusive use of antagonist ovarian stimulation protocols is recommended as a measure to avoid the risk of frank ovarian hyperstimulation syndrome with similar overall efficacy (64Drakopoulos P. Rosetti J. Pluchino N. Blockeel C. Santos-Ribeiro S. de Brucker M. et al.Does the type of GnRH analogue used, affect live birth rates in women with endometriosis undergoing IVF/ICSI treatment, according to the rAFS stage?.Gynecol Endocrinol. 2018; 34: 884-889Crossref PubMed Scopus (13) Google Scholar). Triggering of ovulation with GnRH-a is also recommended. Not only using GnRH-a for inducing the final stage of oocyte maturation is preferred for avoiding ovarian hyperstimulation syndrome, but it also decreases the risk of cyst formation—not desired in the case of endometriosis. Differed embryo is in all cases preferred as ovarian suppression by hormone replacement cycles used for timing frozen embryo transfers quells the effects of endometriosis on the eutopic endometrium (40Bishop L.A. Gunn J. Jahandideh S. Devine K. Decherney A.H. Hill M.J. Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts.Fertil Steril. 2021; 115: 416-422Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar), as previously shown with GnRH-a treatment. Freeze-all and deferred embryo transfer using E2 and progesterone replacement cycle optimizes the implantation rates (40Bishop L.A. Gunn J. Jahandideh S. Devine K. Decherney A.H. Hill M.J. Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts.Fertil Steril. 2021; 115: 416-422Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) compared with fresh transfer (65Bourdon M. Santulli P. Maignien C. Gayet V. Pocate-Cheriet K. Marcellin L. et al.The deferred embryo transfer strategy improves cumulative pregnancy rates in endometriosis-related infertility: a retrospective matched cohort study.PLoS One. 2018; 13e0194800Crossref Scopus (41) Google Scholar), even if this view is not shared by all (66Tan J. Cerrillo M. Cruz M. Cecchino G.N. Garcia-Velasco J.A. Early pregnancy outcomes in fresh versus deferred embryo transfer cycles for endometriosis-associated infertility: a retrospective cohort study.J Clin Med. 2021; 10: 344Crossref PubMed Scopus (6) Google Scholar). In conclusion, the workup of infertile women has been drastically changed over the past decade or so, notably by the abandon of diagnostic laparoscopies, which were nearly routinely performed in yesteryears. Today, the ART-first approaches are most often preferred in women in their 30s, and overwhelming data indicate that their results are not altered in the case of endometriosis including endometriomas. In these cases, the novel no-surgery-before-ART is prone by most unless unmanageable pelvic pain exists and/or hydrosalpinges are present. In a few cases, however—for women in their 20s—surgery may be preferred for enhancing the chances of conceiving naturally provided that there is time (age and ovarian reserve) to dedicate for natural conception. In the latter case, the sperm tubes and ovulatory functions need to be normal.
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