{"paper_id":"7d27ef15-1a04-45b4-83be-c80ec8424230","body_text":"REVIEW Open Access\nMiddle East Fertility\nSociety Journal\nDubovečak et al. Middle East Fertility Society Journal           (2026) 31:56 \nhttps://doi.org/10.1186/s43043-026-00346-w\nReconsidering IVF/ICSI outcomes \nin endometriosis: phenotype variability, \nconfounding factors, and clinical \ninterpretation\nMiroslav Dubovečak1* , Tatjana Turudić Pavelić1, Ana Tikvica Luetić1, Daria Hafner2, Mia Klenkar2, Sanja Cvrtila1 and \nNina Medić1\n  * C o r r e s p o n d e n c e :  \nMiroslav Dubovečak\nmiroslav.dubovecak@gmail.com\nFull list of author information is available at the end of the article\n© The Author(s) 2026. Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, \nsharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and \nthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included \nin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit  h t    t p : / / c r e  a   t i v e  c  o  m m o n s . o r g / l i c e n s e s / b y / 4 . 0 /     .    \nAbstract\nBackground Endometriosis is a biologically heterogeneous disorder frequently encountered in women undergoing \nassisted reproductive technology (ART). Reported effects on in vitro fertilization and intracytoplasmic sperm injection \n(IVF/ICSI) outcomes remain inconsistent across studies, partly due to variations in disease phenotype, prior surgical \ntreatment, ovarian reserve, and concomitant uterine pathology.\nObjective To critically evaluate contemporary evidence regarding IVF/ICSI outcomes in women with endometriosis, \nwith emphasis on phenotype-related reproductive variability, sources of evidence heterogeneity, and implications for \nindividualized reproductive management.\nMethods A structured narrative review was performed using PubMed/MEDLINE, Embase, and Scopus databases. \nLiterature published between January 2015 and March 2026 was screened, with particular focus on contemporary \nstudies evaluating ovarian response, embryological parameters, implantation, live birth, cumulative reproductive \noutcomes, and the potential confounding role of adenomyosis.\nResults Current evidence suggests that the reproductive impact of endometriosis is not uniform across patient \npopulations. Ovarian endometrioma and previous ovarian surgery are most consistently associated with reduced \novarian reserve and lower oocyte yield, whereas superficial peritoneal disease appears to exert less pronounced \neffects on ovarian responsiveness. Embryological outcomes are frequently preserved despite impaired ovarian \nresponse, although substantial heterogeneity exists among studies. Implantation and live birth outcomes may \nadditionally be influenced by uterine factors, particularly adenomyosis, which may independently impair reproductive \nefficiency. Differences in study design, patient selection, disease classification, and outcome reporting contribute \nsignificantly to variability in the available literature.\nConclusions IVF/ICSI prognosis in women with endometriosis should be interpreted within a phenotype-specific \nand multifactorial clinical context rather than through a single generalized disease model. Contemporary evidence \n\nPage 2 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \n  Introduction\nEndometriosis is a chronic estrogen-dependent inflam -\nmatory disorder characterized by the presence of \nendometrial-like tissue outside the uterine cavity and \nassociated with complex alterations involving immune \nregulation, inflammatory signaling, angiogenesis, fibrosis, \noxidative stress, and progesterone resistance [ 1– 4]. The \ndisease affects approximately 10% of women of repro -\nductive age and is detected in up to 30–50% of women \npresenting with infertility [ 1, 2]. Beyond pelvic pain and \nanatomical distortion, endometriosis has increasingly \nbeen recognized as a heterogeneous systemic disorder \nwith variable reproductive implications depending on \ndisease phenotype, ovarian involvement, previous surgi -\ncal treatment, and coexisting uterine pathology [1– 5].\nAssisted reproductive technology (ART), particularly \nin vitro fertilization and intracytoplasmic sperm injec -\ntion (IVF/ICSI), represents an important therapeutic \noption for many women with endometriosis-associated \ninfertility. However, the precise impact of endometrio -\nsis on ART outcomes remains incompletely understood \nand continues to generate substantial controversy within \nreproductive medicine. Earlier studies frequently sug -\ngested generalized impairment across multiple repro -\nductive domains, including ovarian reserve, oocyte \ncompetence, embryo development, implantation, and \nlive birth [6– 8]. More recent evidence, however, indicates \nthat reproductive impairment is neither uniform nor bio-\nlogically identical across different endometriosis pheno -\ntypes [9– 12].\nContemporary data increasingly support the concept \nthat ovarian endometrioma and previous ovarian sur -\ngery are among the principal determinants of reduced \novarian reserve and diminished ovarian response dur -\ning IVF/ICSI cycles [ 11– 15]. In contrast, several studies \ndemonstrate relatively preserved fertilization, blastocyst \ndevelopment, and live birth per embryo transfer once \ngood-quality embryos are available [ 12, 16– 18]. These \nfindings suggest that the reproductive impact of endo -\nmetriosis may predominantly involve quantitative rather \nthan universal qualitative impairment, with cumulative \ntreatment efficiency being influenced mainly through \nreduced oocyte yield and smaller embryo cohorts.\nAt the same time, the pathophysiological mechanisms \npotentially affecting implantation and endometrial recep-\ntivity remain complex and incompletely resolved. Deep \ninfiltrating endometriosis (DIE), chronic inflammatory \nactivation, altered pelvic immune microenvironment, \nprogesterone resistance, and concomitant adenomyo -\nsis have all been proposed as contributors to impaired \nimplantation potential in selected patient subgroups [ 3, \n4, 19– 22]. Increasing recognition of adenomyosis as an \nindependent uterine confounder has further complicated \ninterpretation of IVF/ICSI outcomes in women with \nendometriosis, particularly regarding cumulative live \nbirth and embryo transfer strategy [20– 22].\nInterpretation of the literature is additionally limited \nby major heterogeneity in study design, disease classifi -\ncation, surgical history, ovarian reserve profiles, stimula -\ntion protocols, embryo transfer strategies, and reported \noutcome measures. Many available studies remain ret -\nrospective and combine biologically distinct phenotypes \nunder a single diagnostic category, potentially obscur -\ning clinically relevant phenotype-specific effects [ 9, 11, \n23– 25]. Consequently, simplistic interpretation of endo -\nmetriosis as either uniformly detrimental or clinically \nnegligible in IVF/ICSI is unlikely to accurately reflect the \nbiological complexity of the disease.\nThe aim of this review is therefore to provide a pheno -\ntype-oriented and evidence-informed synthesis of con -\ntemporary data regarding IVF/ICSI outcomes in women \nwith endometriosis, with particular emphasis on patho -\nphysiological mechanisms, ovarian reserve dynamics, \nembryological competence, implantation, cumulative live \nbirth, and sources of evidence heterogeneity relevant to \nindividualized reproductive management strategies.\nMethods\nThis manuscript was designed as a structured narrative \nreview intended to provide a clinically and biologically \nintegrated synthesis of contemporary evidence regard -\ning IVF/ICSI outcomes in women with endometriosis. \nBecause of substantial heterogeneity in disease pheno -\ntype, study design, ovarian reserve profiles, surgical his -\ntory, stimulation protocols, embryo transfer strategies, \nand reported reproductive endpoints, a formal quantita -\ntive meta-analysis was considered inappropriate for the \nobjectives of the present review [9– 12, 23– 25].\nA comprehensive literature search was performed \nusing PubMed/MEDLINE, Embase, and Scopus data -\nbases. The search focused primarily on studies published \nbetween January 2015 and March 2026, while selected \nlandmark earlier studies of major mechanistic or clini -\ncal relevance were also included when necessary to con -\ntextualize contemporary evidence. Greater emphasis \nwas placed on systematic reviews, meta-analyses, large \nsupports individualized reproductive assessment integrating ovarian reserve, surgical history, adenomyosis evaluation, \nand cumulative treatment trajectory when counselling and managing women with endometriosis undergoing ART.\nKeywords Endometriosis, IVF, ICSI, Assisted reproductive technology, Ovarian reserve, Endometrioma, Adenomyosis, \nCumulative live birth, Reproductive outcomes\n\nPage 3 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \ncohort studies, guideline statements, and clinically rel -\nevant translational studies published from 2020 onward.\nThe search strategy incorporated combinations of \nMedical Subject Headings (MeSH) terms and free-\ntext keywords including “endometriosis” , “IVF” , “ICSI” , \n“assisted reproductive technology” , “ovarian reserve” , \n“ AMH” , “antral follicle count” , “endometrioma” , “deep \ninfiltrating endometriosis” , “adenomyosis” , “embryo qual-\nity” , “blastocyst” , “implantation” , “frozen embryo transfer” , \n“live birth” , and “cumulative live birth” .\nEligible publications included randomized controlled \ntrials, prospective and retrospective cohort studies, reg -\nistry-based analyses, systematic reviews, meta-analyses, \nguideline papers, and clinically relevant mechanistic \ninvestigations addressing ovarian response, embryologi -\ncal outcomes, implantation, pregnancy, live birth, cumu -\nlative live birth, or phenotype-specific reproductive \noutcomes in women with endometriosis undergoing IVF/\nICSI treatment.\nParticular attention was given to studies evaluating \novarian endometrioma, prior ovarian surgery, adeno -\nmyosis, deep infiltrating endometriosis (DIE), embryo \ntransfer strategy, and cumulative reproductive outcomes. \nStudies were preferentially included when they provided \nphenotype-stratified analysis, contemporary IVF labora -\ntory data, or clinically applicable interpretation relevant \nto individualized treatment planning.\nCase reports, very small uncontrolled case series, dupli-\ncate datasets, and studies lacking sufficient methodologi -\ncal clarity or clearly defined reproductive outcomes were \nnot prioritized. Due to substantial heterogeneity across \nthe available literature, evidence synthesis was performed \nnarratively with emphasis on biological plausibility, \nphenotype-specific interpretation, methodological limi -\ntations, and clinically meaningful outcome integration \nrather than pooled statistical estimates alone. In addition \nto reproductive outcomes, the review also incorporated \nselected translational and pathophysiological studies \naddressing inflammatory signaling, oxidative stress, pro -\ngesterone resistance, follicular microenvironment altera -\ntions, adenomyosis-associated implantation impairment, \nand emerging molecular mechanisms potentially relevant \nto reproductive dysfunction in endometriosis [26– 40].\nPathophysiological and phenotype-specific \nframework\nEndometriosis is increasingly recognized as a multifacto -\nrial systemic disorder characterized by complex interac -\ntions among inflammatory, immunological, endocrine, \ngenetic, angiogenic, and fibrotic pathways. The biologi -\ncal heterogeneity of the disease may partly explain the \nmarked variability observed in reproductive outcomes \namong women undergoing IVF/ICSI treatment [ 3, 4, \n26– 30].\nOne of the central pathophysiological features of endo -\nmetriosis is chronic inflammatory activation within the \npelvic microenvironment. Elevated concentrations of \nactivated macrophages, pro-inflammatory cytokines, \nchemokines, prostaglandins, and reactive oxygen species \nhave been consistently demonstrated in peritoneal fluid \nand ectopic lesions [ 26, 30]. These inflammatory altera -\ntions may contribute to impaired folliculogenesis, altered \noocyte maturation, mitochondrial dysfunction, abnormal \ngranulosa-cell signaling, and disturbances in embryo-\nendometrial interaction.\nOxidative stress appears to represent another impor -\ntant mechanism potentially influencing reproductive \ncompetence in endometriosis. Increased reactive oxygen \nspecies and reduced antioxidant capacity within follicu -\nlar fluid have been associated with altered meiotic spin -\ndle formation, mitochondrial injury, DNA damage, and \nimpaired cellular metabolism [ 18, 31, 32]. Although the \nprecise clinical significance of these molecular alterations \nremains incompletely established, they may contribute \nto the biological heterogeneity observed across IVF/ICSI \nstudies.\nProgesterone resistance has also emerged as a major \nmechanistic concept in endometriosis-associated infer -\ntility. Altered progesterone receptor expression and dys -\nregulated downstream signaling pathways may impair \ndecidualization and endometrial receptivity, potentially \naffecting implantation in selected patient subgroups [ 33, \n34]. These mechanisms may be particularly relevant in \nwomen with coexisting adenomyosis, where abnormali -\nties in uterine contractility, inflammatory signaling, junc-\ntional zone architecture, and local estrogen metabolism \nmay further compromise implantation potential and \ncumulative reproductive outcomes [20– 22, 35].\nGenetic and epigenetic factors are increasingly impli -\ncated in the pathogenesis of endometriosis and may \npartly explain phenotype-specific reproductive variabil -\nity. Several studies have identified associations involving \ninflammatory signaling pathways, estrogen metabolism, \nprogesterone resistance, KRAS activation, PI3K/AKT \npathway dysregulation, ARID1A alterations, and epigen -\netic modifications affecting endometrial function and \ncellular proliferation [27, 28, 36, 37]. However, the direct \ntranslational relevance of these molecular findings to \nIVF/ICSI outcomes remains incompletely clarified.\nImportantly, the biological consequences of endo -\nmetriosis are not uniform across disease phenotypes. \nSuperficial peritoneal disease may predominantly \ninvolve inflammatory and immune-mediated mecha -\nnisms, whereas ovarian endometrioma is more strongly \nassociated with quantitative ovarian damage, mechani -\ncal cortical compression, altered vascularization, fibro -\nsis, and progressive follicular depletion [ 13– 18, 31, 38]. \nDeep infiltrating endometriosis (DIE) may additionally \n\nPage 4 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \ninterpreted as a major determinant of poor IVF/ICSI \nprognosis. Considerable variability between studies may \nadditionally reflect differences in patient selection, dis -\nease classification, and coexistence of other endometrio -\nsis phenotypes [9– 12, 23– 25].\nOvarian endometrioma, ovarian reserve, and embryo \navailability\nOvarian endometrioma represents the phenotype most \nconsistently associated with impaired ovarian reserve and \nreduced ovarian responsiveness during IVF/ICSI treat -\nment [ 11– 15, 38]. Multiple studies demonstrate lower \nanti-Müllerian hormone (AMH) concentrations, reduced \nantral follicle count (AFC), fewer retrieved oocytes, and \nhigher risk of suboptimal ovarian response in women \nwith ovarian endometrioma, particularly in bilateral dis -\nease and after previous ovarian cystectomy [13– 15, 38].\nHistological and mechanistic studies further suggest \nthat chronic inflammatory exposure, fibrosis, altered vas-\ncularization, and cortical compression adjacent to the \nendometrioma may contribute to progressive follicular \ndepletion [ 31, 38]. Previous ovarian surgery may addi -\ntionally exacerbate ovarian damage through inadvertent \nremoval of healthy cortical tissue and compromised vas -\ncular supply.\nImportantly, although ovarian endometrioma fre -\nquently reduces oocyte quantity, evidence regarding \noocyte and embryo competence remains less consistent. \nSeveral contemporary studies suggest that fertilization, \nblastocyst development, and pregnancy rates per embryo \ntransfer may remain relatively preserved once good-\nquality embryos are obtained [ 12, 16, 17]. Consequently, \ncumulative live birth may be influenced predominantly \nthrough smaller embryo cohorts and lower overall treat -\nment efficiency rather than universal impairment of \nembryo developmental competence.\nDeep infiltrating endometriosis and complex pelvic \ndisease\nDeep infiltrating endometriosis (DIE) represents a more \nanatomically and surgically complex phenotype char -\nacterized by fibrotic lesions infiltrating pelvic struc -\ntures including the rectovaginal septum, bowel, bladder, \nuterosacral ligaments, and pelvic sidewall. In addition \nto chronic pelvic pain and distorted pelvic anatomy, DIE \nmay be associated with extensive inflammatory activa -\ntion and altered uterine signaling pathways [35, 40, 41].\nHowever, the independent reproductive impact of DIE \nremains difficult to determine because this phenotype \nfrequently coexists with ovarian endometrioma, adeno -\nmyosis, and previous pelvic surgery. Surgical treatment \nof extensive DIE may itself influence ovarian reserve, pel -\nvic vascularization, and reproductive outcomes, thereby \nfurther complicating interpretation of IVF/ICSI studies.\ninfluence pelvic anatomy, chronic pain burden, inflam -\nmatory uterine signaling pathways, and cumulative treat -\nment complexity.\nOvarian endometrioma represents one of the most \nclinically relevant phenotypes in reproductive medi -\ncine. Histological and molecular studies suggest that \nchronic exposure of adjacent ovarian cortex to inflam -\nmatory mediators, iron-induced oxidative stress, fibrosis, \nand altered angiogenesis may contribute to progressive \nreduction in ovarian reserve [ 13– 15, 31]. In addition, \nsurgical excision of endometriomas may further acceler -\nate follicular depletion through inadvertent removal of \nhealthy ovarian cortex and vascular compromise [ 14, 15, \n38].\nDespite these mechanistic alterations, contemporary \nevidence suggests that endometriosis does not uniformly \nimpair embryo developmental competence. Fertilization, \ncleavage, and blastocyst development are often relatively \npreserved, particularly when adequate ovarian response \nis achieved [ 12, 16, 17]. This apparent discrepancy \nbetween biological abnormalities and relatively preserved \nembryological outcomes further supports the concept \nthat the principal reproductive impact of endometriosis \nin IVF/ICSI may involve treatment efficiency and embryo \ncohort size rather than universal embryo incompetence.\nOverall, current evidence supports a phenotype-\ndependent biological model in which ovarian reserve \nimpairment, inflammatory activation, uterine receptivity \nalterations, and cumulative treatment dynamics interact \nvariably across different patient populations. Recognition \nof this biological heterogeneity is essential for interpreta -\ntion of IVF/ICSI outcomes and development of individu -\nalized reproductive treatment strategies.\nPhenotype-specific reproductive implications in \nIVF/ICSI\nSuperficial peritoneal endometriosis and pelvic \ninflammatory mechanisms\nSuperficial peritoneal endometriosis is generally consid -\nered the least destructive phenotype from a reproduc -\ntive perspective, although important inflammatory and \nimmunological alterations may still be present. Perito -\nneal lesions are associated with increased concentra -\ntions of inflammatory mediators, activated macrophages, \nprostaglandins, and oxidative stress markers within the \npelvic microenvironment [ 26, 30]. These abnormalities \nmay potentially influence gamete interaction, follicular \nsignaling, tubal transport, and endometrial receptivity. \nHowever, many women with isolated superficial disease \nmaintain relatively preserved ovarian reserve and accept -\nable IVF/ICSI outcomes, particularly in the absence of \nadenomyosis or previous ovarian surgery [9, 11, 23].\nCurrent evidence therefore suggests that superfi -\ncial peritoneal disease should not automatically be \n\nPage 5 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \nAvailable evidence therefore supports cautious inter -\npretation of IVF/ICSI outcomes in women with DIE, par-\nticularly when retrospective analyses fail to adequately \ncontrol for concomitant adenomyosis, ovarian surgery, \nand baseline ovarian reserve status.\nAdenomyosis as a uterine confounding factor\nAdenomyosis deserves particular consideration as a dis -\ntinct uterine phenotype frequently coexisting with endo -\nmetriosis. Increasing evidence suggests that adenomyosis \nmay independently impair implantation, clinical preg -\nnancy, and live birth rates, particularly in frozen embryo \ntransfer cycles [20– 22, 35].\nProposed biological mechanisms include abnor -\nmal uterine peristalsis, chronic inflammatory activa -\ntion, impaired decidualization, progesterone resistance, \naltered junctional zone architecture, and disturbed endo -\nmetrial receptivity [ 33– 35]. Importantly, adenomyosis \nshould not simply be considered an extension of endo -\nmetriosis, but rather an independent uterine factor capa -\nble of modifying reproductive prognosis.\nRecognition of adenomyosis as a confounding variable \nis therefore essential when interpreting reproductive out-\ncomes in women with endometriosis, especially in stud -\nies evaluating implantation and live birth outcomes.\nBiological heterogeneity and interpretation of IVF/ICSI \noutcomes\nThe coexistence of multiple endometriosis phenotypes \nfurther complicates interpretation of IVF/ICSI outcomes. \nWomen presenting with combined ovarian endome -\ntrioma, adenomyosis, and DIE may demonstrate sub -\nstantially different reproductive profiles compared with \nwomen with isolated superficial peritoneal disease. This \nbiological heterogeneity likely contributes to the incon -\nsistent findings observed across many retrospective IVF/\nICSI studies and meta-analyses [9– 11, 23– 25].\nOverall, contemporary evidence supports individual -\nized interpretation of reproductive prognosis according \nto disease phenotype, ovarian reserve profile, uterine \ninvolvement, previous surgical treatment, patient age, \nand cumulative reproductive strategy rather than gener -\nalized assumptions regarding endometriosis-associated \ninfertility (Fig. 1).\nOvarian reserve and ovarian response in women \nwith endometriosis\nAmong all reproductive domains potentially affected by \nendometriosis, impairment of ovarian reserve and dimin-\nished ovarian responsiveness during IVF/ICSI treatment \nrepresent the most consistently supported findings in \nthe contemporary literature [ 11– 15, 38]. However, the \nmagnitude and clinical significance of this effect appear \nstrongly dependent on disease phenotype, bilateral \novarian involvement, patient age, and previous surgical \ntreatment.\nOvarian endometrioma has been repeatedly associated \nwith lower serum anti-Müllerian hormone (AMH) con -\ncentrations, reduced antral follicle count (AFC), fewer \nretrieved oocytes, and increased likelihood of suboptimal \novarian response during controlled ovarian stimulation \n[13– 15, 38, 42]. Several mechanisms have been proposed \nto explain this association, including chronic inflamma -\ntory exposure, oxidative stress, cortical fibrosis, altered \novarian vascularization, follicular compression, and pro -\ngressive loss of primordial follicles adjacent to the cyst \nwall [31, 38, 42].\nThe negative impact on ovarian reserve appears partic -\nularly pronounced in women with bilateral endometrio -\nmas and in those undergoing repeated ovarian surgery \n[13– 15, 42, 43]. Surgical excision of endometriomas may \ninadvertently remove healthy ovarian cortex and com -\npromise ovarian blood supply, thereby accelerating fol -\nlicular depletion [ 14, 15, 43]. Although cystectomy may \nimprove pain symptoms, reduce inflammatory burden, \nor facilitate oocyte retrieval in selected patients, current \nevidence does not consistently demonstrate improved \nlive birth outcomes following routine pre-IVF surgery for \nasymptomatic ovarian endometrioma [11, 14, 44].\nImportantly, diminished ovarian reserve does not nec -\nessarily imply uniformly impaired embryo developmen -\ntal competence. Several studies suggest that women with \nendometriosis may achieve fertilization, blastocyst for -\nmation, and implantation rates comparable to controls \nonce adequate numbers of mature oocytes and transfer -\nable embryos are obtained [ 12, 16, 17]. This distinction \nbetween quantitative ovarian impairment and preserved \nembryo competence has important implications for \ninterpretation of IVF/ICSI prognosis.\nThe concept of suboptimal ovarian response may be \nparticularly relevant in women with endometriosis-asso -\nciated infertility. Even modest reductions in oocyte yield \nmay substantially influence cumulative treatment effi -\nciency because each stage of laboratory attrition, includ -\ning failed fertilization, impaired blastocyst development, \ncryosurvival loss, and transfer cancellation, becomes \nproportionally more clinically significant when embryo \ncohorts are limited [ 11, 15, 42]. Consequently, cumula -\ntive live birth per initiated retrieval cycle may represent \na more informative endpoint than isolated per-transfer \npregnancy rates in this patient population.\nThe relationship between ovarian reserve and dis -\nease severity nevertheless remains complex. Some \nwomen with advanced endometriosis maintain satisfac -\ntory ovarian reserve parameters, whereas others with \napparently limited ovarian disease demonstrate unex -\npectedly diminished ovarian response [ 27, 40]. This vari-\nability likely reflects the multifactorial biological nature \n\nPage 6 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \nof endometriosis and the interaction among inflamma -\ntory activity, genetic susceptibility, surgical history, age-\nrelated ovarian decline, and individual follicular reserve.\nInterpretation of ovarian reserve markers in endome -\ntriosis also requires caution. Anti-Müllerian hormone \nconcentrations may decline progressively over time \neven in the absence of surgery, suggesting that the dis -\nease itself may contribute to ongoing ovarian injury [ 13, \n15, 42]. However, AMH reduction alone does not fully \npredict reproductive potential, embryo competence, or \nprobability of live birth. Clinical prognosis should there -\nfore integrate ovarian reserve markers with patient age, \nembryo availability, uterine factors, disease phenotype, \nand overall cumulative reproductive strategy.\nOverall, current evidence supports the concept that the \nprincipal reproductive impact of ovarian endometriosis \nduring IVF/ICSI treatment is predominantly quantitative, \ncharacterized mainly by reduced ovarian reserve, dimin -\nished oocyte yield, and decreased treatment efficiency \nFig. 1 Phenotype-specific biological pathways influencing IVF/ICSI outcomes in endometriosis. The figure summarizes how different endometriosis \nphenotypes may influence ART outcomes through distinct ovarian, inflammatory, embryological, and uterine mechanisms. Ovarian endometrioma and \nprior ovarian surgery primarily affect ovarian reserve and oocyte yield, whereas adenomyosis may act mainly through impaired uterine receptivity and \nimplantation. DIE, deep infiltrating endometriosis; AMH, anti-Müllerian hormone; AFC, antral follicle count; IVF/ICSI, in vitro fertilization/intracytoplasmic \nsperm injection\n \n\nPage 7 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \nrather than universal failure of embryo developmental \ncompetence (Table 1).\nEmbryological outcomes and embryo competence\nThe effect of endometriosis on oocyte competence, fer -\ntilization, embryo development, and blastocyst formation \nremains one of the most debated areas in reproductive \nmedicine. Although multiple biological mechanisms \npotentially capable of impairing oocyte and embryo \nquality have been described, clinical IVF/ICSI studies \ncontinue to demonstrate heterogeneous and sometimes \nconflicting findings [6, 8– 12, 16– 18, 44].\nSeveral pathophysiological mechanisms have been \nproposed to explain possible embryological impairment \nin women with endometriosis. Chronic inflammatory \nactivation, oxidative stress, altered follicular cytokine \nprofiles, mitochondrial dysfunction, and abnormal \ngranulosa-cell signaling may theoretically compromise \nmeiotic spindle integrity, chromosomal segregation, \ncellular metabolism, and developmental competence \nof the oocyte [ 18, 26, 30– 32]. In addition, the follicular \nmicroenvironment surrounding ovarian endometriomas \nmay contain elevated concentrations of reactive oxygen \nspecies, inflammatory mediators, free iron, and toxic \ndegradation products capable of influencing folliculogen-\nesis and oocyte maturation [31, 32].\nDespite these biological observations, clinical evidence \nregarding embryo competence remains inconsistent. Ear-\nlier studies frequently suggested lower fertilization rates, \nimpaired embryo quality, reduced blastocyst develop -\nment, and decreased implantation rates in women with \nendometriosis [ 6– 8]. However, more recent analyses \nincreasingly indicate that embryological competence may \nremain relatively preserved once adequate numbers of \nmature oocytes are obtained [9– 12, 16, 17].\nSeveral contemporary studies have demonstrated \ncomparable fertilization rates, cleavage-stage develop -\nment, blastocyst formation, and euploid embryo poten -\ntial between women with endometriosis and control \npopulations undergoing IVF/ICSI treatment [ 12 , 16, 17, \n45]. Donor-oocyte studies have also provided important \ninsight by suggesting that implantation and pregnancy \noutcomes may be more strongly influenced by uterine or \ncumulative treatment factors than by universal intrinsic \noocyte incompetence alone [16, 46].\nImportantly, interpretation of embryological outcomes \nis complicated by major heterogeneity across studies. \nDifferences in disease phenotype, ovarian reserve, patient \nage, surgical history, stimulation protocols, embryo cul -\nture conditions, embryo grading systems, and transfer \npolicies may substantially influence reported results [ 9–\n11, 23– 25]. Many earlier studies also combined biologi -\ncally distinct phenotypes into single analytical groups, \npotentially obscuring phenotype-specific embryological \neffects.\nOvarian endometrioma appears to primarily affect \noocyte quantity rather than universally impair embryo \ndevelopmental competence [ 12, 16, 17, 44]. In many \npatients, acceptable blastocyst development and implan -\ntation rates can still be achieved when sufficient numbers \nof mature oocytes are retrieved. Consequently, reduced \ncumulative live birth in endometriosis populations may \nfrequently reflect diminished embryo cohort size rather \nthan catastrophic embryological failure.\nThe growing use of time-lapse embryo monitoring, pre-\nimplantation genetic testing (PGT-A), metabolomic anal-\nysis, and artificial intelligence-based embryo selection \nmay provide further insight into subtle embryological dif-\nferences associated with endometriosis in future studies \n[47, 48]. However, current evidence remains insufficient \nto support the concept of uniformly impaired embryo \ncompetence across all endometriosis phenotypes.\nOverall, contemporary data suggest that the embryo -\nlogical consequences of endometriosis are heterogeneous \nand strongly phenotype-dependent. Although inflam -\nmatory and oxidative mechanisms may influence oocyte \nbiology in selected patients, current evidence does not \nsupport generalized assumptions of severe universal \nTable 1 Biological mechanisms potentially influencing ovarian \nreserve and ovarian response in women with endometriosis \nundergoing IVF/ICSI\nMechanism Biological effect Clinical \nbiomarker\nClinical \nimplication\nChronic pelvic \ninflammation\nCytokine-me-\ndiated follicular \nimpairment\nReduced \nAMH and \nAFC\nReduced ovar-\nian reserve and \nvariable ovarian \nresponse\nOxidative stress Reactive oxygen \nspecies-mediated \ncellular and mito-\nchondrial damage \nwithin the follicular \nenvironment\nNot routinely \nmeasurable\nPotential \nimpairment \nof oocyte \ncompetence \nin selected \npatients\nOvarian \nendometrioma\nCortical compres-\nsion, fibrosis, \nand altered \nvascularization\nReduced \nAMH and \nAFC\nLower oocyte \nyield and tech-\nnically more \ndifficult oocyte \nretrieval\nAltered ovarian \nvascularization\nReduced follicular \nperfusion and \noxygenation\nAFC \nvariability\nPossible subop-\ntimal follicular \nrecruitment\nSurgical \nexcision of \nendometrioma\nUnintentional loss \nof healthy ovarian \ncortex and vascular \ncompromise\nSignificant \nAMH decline\nIatrogenic \nreduction in \novarian reserve\nRepeated ovar-\nian surgery\nProgressive follicu-\nlar depletion\nMarked AMH \ndecline\nIncreased risk \nof poor ovarian \nresponse\nAbbreviations : IVF/ICSI in vitro fertilization/intracytoplasmic sperm injection, \nAMH anti-Müllerian hormone, AFC antral follicle count\n\nPage 8 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \nembryo developmental impairment in women undergo -\ning IVF/ICSI treatment for endometriosis-associated \ninfertility.\nImplantation, endometrial receptivity, and \nadenomyosis\nThe potential effect of endometriosis on implantation \nand endometrial receptivity remains controversial and \nsubstantially more complex than isolated assessment of \novarian reserve or oocyte yield. While some women with \nendometriosis achieve satisfactory implantation and live \nbirth rates following transfer of good-quality embryos, \nothers experience recurrent implantation failure or \nreduced cumulative reproductive success despite appar -\nently adequate embryological outcomes [19– 22, 33– 35].\nSeveral mechanisms have been proposed to explain \nimpaired implantation potential in endometriosis-associ-\nated infertility. Chronic inflammatory activation, altered \ncytokine signaling, progesterone resistance, oxidative \nstress, disturbed decidualization, and abnormal expres -\nsion of receptivity-associated molecules may contribute \nto impaired embryo-endometrial interaction in selected \npatients [ 19, 33, 34]. Molecular abnormalities involving \nintegrins, HOXA10 expression, inflammatory media -\ntors, and progesterone-regulated pathways have all been \nimplicated in impaired endometrial receptivity associ -\nated with endometriosis [19, 34, 49].\nAt the same time, interpretation of implantation out -\ncomes in endometriosis is complicated by substantial \nheterogeneity across published studies. Implantation \nrates may be influenced not only by disease phenotype \nbut also by embryo quality, ovarian reserve, transfer \nstrategy, embryo stage, cryopreservation protocols, prior \nsurgery, and particularly the presence of concomitant \nadenomyosis [ 20– 22, 35]. Many earlier studies failed to \nadequately distinguish isolated endometriosis from com -\nbined endometriosis-adenomyosis phenotypes, poten -\ntially contributing to inconsistent findings across the \nliterature.\nAdenomyosis has increasingly emerged as one of the \nmost important uterine confounders in women with \nendometriosis undergoing IVF/ICSI treatment. Contem -\nporary evidence suggests that adenomyosis may inde -\npendently reduce implantation, clinical pregnancy, and \nlive birth rates while increasing miscarriage risk [ 20– 22, \n35, 50]. Proposed mechanisms include abnormal uterine \nperistalsis, chronic inflammatory activation, junctional \nzone disruption, altered estrogen metabolism, progester -\none resistance, impaired decidualization, and defective \nendometrial receptivity [33– 35, 50].\nImportantly, the coexistence of adenomyosis may partly \nexplain why some studies report apparently impaired \nimplantation despite relatively preserved embryo devel -\nopmental competence [ 16, 17, 20– 22]. In this context, \nuterine factors rather than intrinsic embryo quality may \nbecome dominant determinants of reproductive outcome \n(Table 2).\nFrozen embryo transfer (FET) strategies have therefore \ngained increasing interest in women with adenomyosis \nand severe endometriosis phenotypes. Some studies sug -\ngest that prolonged pituitary suppression using long-act -\ning GnRH agonists prior to embryo transfer may improve \nimplantation and pregnancy outcomes in selected adeno-\nmyosis populations by reducing inflammatory activity \nand improving endometrial receptivity [ 50– 52]. Never -\ntheless, available evidence remains heterogeneous, and \nthe optimal transfer strategy in women with coexisting \nendometriosis and adenomyosis has not yet been defini -\ntively established.\nThe independent contribution of deep infiltrating \nendometriosis (DIE) to implantation failure also remains \nuncertain. DIE frequently coexists with adenomyosis, \nsevere pelvic inflammation, fibrosis, and previous pel -\nvic surgery, making isolation of its specific reproductive \nimpact methodologically difficult [ 35, 41]. Consequently, \ncurrent evidence does not support uniform assumptions \nregarding implantation impairment across all endome -\ntriosis phenotypes.\nOverall, contemporary data suggest that implantation \ndysfunction in endometriosis-associated infertility is \nmultifactorial and strongly phenotype-dependent. While \nmany women maintain acceptable implantation potential \nfollowing transfer of good-quality embryos, concomi -\ntant adenomyosis, progesterone resistance, inflammatory \nactivation, and altered endometrial receptivity may sub -\nstantially influence reproductive outcomes in selected \npatient populations.\nTable 2 Phenotype-specific reproductive implications and IVF/\nICSI management considerations in women with endometriosis\nPhenotype Dominant \nreproductive \nissue\nMain IVF/\nICSI impact\nClinical \ninterpretation\nSuperficial perito-\nneal disease\nInflamma-\ntory pelvic \nenvironment\nUsually \npreserved \novarian \nresponse\nOften favorable \nprognosis when \novarian reserve \npreserved\nOvarian \nendometrioma\nReduced ovar-\nian reserve\nLower oo-\ncyte yield\nQuantitative \nrather than uni-\nversal qualita-\ntive impairment\nDeep infiltrating \nendometriosis\nPelvic fibrosis \nand complex \nanatomy\nPotential \ncumulative \ntreatment \ncomplexity\nFrequently asso-\nciated with ad-\nenomyosis and \nprior surgery\nAdenomyosis Impaired recep-\ntivity and uter-\nine dysfunction\nReduced \nimplanta-\ntion and live \nbirth\nImportant inde-\npendent uterine \nconfounder\n\nPage 9 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \nCumulative live birth and treatment efficiency\nCumulative live birth has increasingly emerged as one of \nthe most clinically meaningful endpoints in contempo -\nrary reproductive medicine because it reflects the over -\nall probability of achieving a live birth from a complete \novarian stimulation cycle, including all fresh and frozen \nembryo transfers derived from a single retrieval [ 53, 54]. \nThis endpoint may be particularly relevant in women \nwith endometriosis, where ovarian reserve impairment \nand reduced embryo cohort size can substantially influ -\nence long-term treatment efficiency despite apparently \nacceptable per-transfer outcomes.\nHistorically, many studies evaluating IVF/ICSI out -\ncomes in endometriosis focused primarily on isolated \nfresh transfer pregnancy rates. However, such endpoints \nmay incompletely reflect the true reproductive burden \nassociated with diminished ovarian response, repeated \nstimulation cycles, embryo attrition, and transfer cancel -\nlation [11, 23, 24, 53]. Increasing emphasis on cumulative \nlive birth therefore allows more biologically and clinically \nintegrated interpretation of reproductive prognosis.\nSeveral contemporary studies suggest that women with \nendometriosis, particularly those with ovarian endome -\ntrioma or previous ovarian surgery, may demonstrate \nreduced cumulative live birth rates primarily because of \nlower oocyte yield and fewer available embryos rather \nthan universal implantation failure or catastrophic \nembryo incompetence [ 11– 15, 44, 53]. Even when preg -\nnancy rates per embryo transfer remain relatively pre -\nserved, the probability of ultimately achieving transfer \nmay decline because of reduced embryo availability \nacross the entire treatment pathway.\nThis distinction between per-transfer outcomes and \ncumulative reproductive efficiency is especially impor -\ntant in women with suboptimal ovarian response. In \npatients generating limited numbers of oocytes, each \nstage of biological and laboratory attrition—including \nfailed fertilization, impaired blastocyst development, \ncryosurvival loss, and cycle cancellation—may carry \nproportionally greater clinical significance [ 11, 42, 53]. \nConsequently, apparently reassuring transfer-based suc -\ncess rates may mask reduced cumulative probability of \nlive birth per initiated retrieval cycle.The role of embryo \ncryopreservation and frozen embryo transfer strategies \nin women with endometriosis remains similarly complex. \nFreeze-all approaches may theoretically optimize endo -\nmetrial receptivity, reduce supraphysiologic hormonal \nexposure, and facilitate individualized transfer timing. \nHowever, in women with limited embryo cohorts, man -\ndatory transfer deferral and potential cryopreservation-\nassociated attrition may also prolong time to pregnancy \nand reduce overall treatment efficiency [53– 55] (Table 3).\nAdenomyosis may further influence cumulative repro -\nductive outcomes independently of ovarian reserve or \nembryo competence. Several studies suggest that implan-\ntation failure, miscarriage risk, and reduced live birth \nmay be more pronounced in women with combined \nendometriosis-adenomyosis phenotypes than in women \nwith isolated ovarian disease [ 20– 22, 50]. Consequently, \ncumulative live birth interpretation requires simultane -\nous consideration of ovarian, embryological, and uterine \nfactors rather than isolated analysis of a single reproduc -\ntive domain.\nImportantly, heterogeneity among published stud -\nies remains substantial. Differences in disease pheno -\ntype, age distribution, surgical history, embryo transfer \npolicies, ovarian stimulation protocols, and inclusion \nof adenomyosis significantly complicate comparison of \ncumulative outcome data across studies [ 9– 11, 23– 25]. \nFurthermore, many retrospective analyses exclude \npatients who fail to reach embryo transfer, thereby poten-\ntially overestimating apparent reproductive success.\nOverall, current evidence supports the concept that \ncumulative live birth in women with endometriosis \nis influenced predominantly by treatment efficiency, \nembryo cohort dynamics, ovarian reserve, and uterine \nTable 3 Sources of heterogeneity and interpretation challenges in studies evaluating IVF/ICSI outcomes in endometriosis\nOutcome domain Major source of heterogeneity/confounding Clinical interpretation challenge\nOvarian response Prior ovarian surgery, bilateral endometrioma, reduced \novarian reserve\nDifficulty distinguishing the independent effect of endo-\nmetriosis from surgically mediated ovarian damage\nOocyte and embryo quality Laboratory variability, stimulation protocols, embryo \nculture sistems\nDifferences in embryological methodology may contribute \nto inconsistent findings regarding embryo competence\nImplantation and endome-\ntrial receptivity\nCoexisting adenomyosis and uterine dysfunction Variable diagnosis and reporting of adenomyosis may \nconfound implantation and pregnancy outcomes\nLive birth per transfer Selection bias and transfer-stage inclusion Many retrospective studies exclude patients who fail to \nreach embryo transfer, potentially overestimating success\nCumulative live birth Variable follow-up duration and embryo availability Incomplete cumulative datasets may underestimate the \nimpact of reduced embryo cohort size\nComparative phenotype \nanalysis\nHeterogeneous disease classification and mixed patient \npopulations\nDifferent phenotypes are frequently analyzed together \ndespite distinct biological characteristics\nInterpretation of reproduc-\ntive prognosis\nDifferences in age, ovarian reserve, and prior treatment \nexposure\nPatient-level variability limits direct comparison between \nstudies and reduces generalizability\n\nPage 10 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \ncomorbidity rather than isolated impairment of a single \nreproductive mechanism. Individualized interpreta -\ntion of cumulative prognosis is therefore essential when \ncounselling patients and designing IVF/ICSI treatment \nstrategies.\nClinical interpretation and individualized \nreproductive management\nThe substantial biological and clinical heterogeneity of \nendometriosis makes simplistic interpretation of IVF/\nICSI prognosis increasingly inadequate in contempo -\nrary reproductive medicine. Current evidence suggests \nthat reproductive outcomes are influenced by a complex \ninteraction among disease phenotype, ovarian reserve, \nadenomyosis, patient age, surgical history, embryo avail -\nability, and cumulative treatment strategy rather than \nby the mere presence or absence of endometriosis alone \n[9– 15, 20– 25, 40].\nOne of the most clinically important concepts emerg -\ning from contemporary evidence is the distinction \nbetween quantitative ovarian impairment and universal \nembryo incompetence. Women with ovarian endome -\ntrioma frequently demonstrate reduced ovarian reserve, \nlower oocyte yield, and increased risk of suboptimal \novarian response, yet many retain acceptable fertilization, \nblastocyst development, and implantation potential once \ntransferable embryos are achieved [ 11– 17, 42– 44]. This \ndistinction has important implications for both prognos -\ntic interpretation and treatment planning.\nCurrent evidence therefore does not support uniform \nassumptions that all women with endometriosis experi -\nence severely compromised IVF/ICSI outcomes. Instead, \nreproductive prognosis appears highly phenotype-depen-\ndent. Women with isolated superficial peritoneal disease \nmay maintain relatively preserved reproductive poten -\ntial, whereas those with bilateral ovarian endometrioma, \nrepeated ovarian surgery, diminished ovarian reserve, \nadenomyosis, or combined severe phenotypes may expe -\nrience substantially more complex reproductive chal -\nlenges [13– 15, 20– 22, 35, 41].\nInterpretation of ovarian reserve markers also requires \nclinical nuance. Reduced anti-Müllerian hormone \n(AMH) concentrations and diminished oocyte yield \nshould not automatically be interpreted as evidence of \ncomplete reproductive futility, particularly in younger \nwomen who may still achieve satisfactory embryo com -\npetence and live birth following individualized IVF/\nICSI treatment [ 13– 15, 42, 43]. Conversely, apparently \nreassuring per-transfer pregnancy rates may underes -\ntimate the cumulative reproductive burden associated \nwith repeated stimulation cycles and reduced embryo \navailability.\nThe role of surgery before IVF/ICSI remains similarly \nindividualized. Although cystectomy may be indicated \nin selected women with severe pain symptoms, suspi -\ncious ovarian morphology, technical difficulties during \noocyte retrieval, or rapidly enlarging cysts, routine pre-\nIVF surgical excision of asymptomatic endometriomas \nis not consistently supported by evidence demonstrating \nimproved live birth outcomes [ 11, 14, 44, 56]. Preserva -\ntion of ovarian reserve therefore represents a major con -\nsideration during individualized treatment planning.\nAdenomyosis deserves particular attention during \nreproductive counselling and treatment strategy selec -\ntion. Increasing evidence suggests that implantation fail -\nure, miscarriage, and reduced cumulative live birth may \nbe more strongly associated with concomitant adeno -\nmyosis than with isolated ovarian disease alone [ 20– 22, \n50]. In selected patients, prolonged pituitary suppression \nprior to embryo transfer, individualized frozen embryo \ntransfer strategies, or modified stimulation approaches \nmay therefore be considered, although evidence remains \nheterogeneous and optimal management remains incom-\npletely established [50– 52].\nImportantly, many published IVF/ICSI studies con -\ntinue to combine biologically distinct patient populations \nunder the broad diagnosis of “endometriosis, ” thereby \npotentially obscuring clinically meaningful phenotype-\nspecific effects [ 9– 11, 23– 25]. Consequently, individual -\nized interpretation of prognosis should integrate disease \nphenotype, ovarian reserve profile, uterine factors, age, \nprevious treatment history, and cumulative reproductive \nstrategy rather than relying solely on generalized popula -\ntion-level outcome statistics.\nOverall, contemporary evidence supports a personal -\nized and phenotype-oriented approach to IVF/ICSI man -\nagement in women with endometriosis. Recognition of \nbiological heterogeneity, ovarian reserve dynamics, uter -\nine comorbidity, and cumulative treatment efficiency is \nessential for realistic prognostic interpretation and indi -\nvidualized reproductive decision-making.\nFuture perspectives\nDespite major advances in reproductive medicine, sev -\neral important uncertainties regarding endometriosis-\nassociated infertility and IVF/ICSI outcomes remain \nunresolved. Future research will likely require more bio -\nlogically integrated and phenotype-specific approaches \ncapable of addressing the substantial heterogeneity that \ncurrently limits interpretation of available evidence [ 9–\n11, 23– 25].\nOne of the most important future directions involves \nimproved phenotype stratification. Many existing studies \ncontinue to combine superficial peritoneal disease, ovar -\nian endometrioma, deep infiltrating endometriosis (DIE), \nand adenomyosis within a single diagnostic category \ndespite their potentially distinct biological and reproduc -\ntive implications [ 35, 40, 41]. Future prospective studies \n\nPage 11 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \nincorporating standardized phenotype classification, \novarian reserve assessment, adenomyosis imaging crite -\nria, and cumulative live birth endpoints may substantially \nimprove clinical interpretation.\nIncreasing interest also surrounds the identification of \nmolecular and inflammatory biomarkers associated with \nreproductive prognosis in women with endometriosis. \nAltered cytokine signaling, oxidative stress pathways, \nprogesterone resistance markers, epigenetic modifica -\ntions, and inflammatory mediators may potentially con -\ntribute to individualized prediction of ovarian response, \nimplantation potential, and cumulative treatment success \n[27, 30, 33, 34, 37]. However, most currently proposed \nbiomarkers remain investigational and lack sufficient val-\nidation for routine clinical application.\nArtificial intelligence (AI), machine learning, and \nadvanced embryo assessment technologies may also play \nan expanding role in future reproductive management. \nTime-lapse imaging systems, AI-assisted embryo selec -\ntion, metabolomic profiling, and non-invasive embryo \nassessment strategies may improve evaluation of embryo \ndevelopmental competence and treatment efficiency in \nwomen with complex reproductive disorders, includ -\ning endometriosis [ 47, 48, 57]. Nevertheless, prospective \nvalidation specifically within endometriosis populations \nremains limited.\nFurther investigation is also needed regarding optimal \nembryo transfer strategies in women with coexisting ade-\nnomyosis and severe endometriosis phenotypes. The role \nof prolonged GnRH agonist suppression, personalized \nfrozen embryo transfer protocols, endometrial receptiv -\nity assessment, and individualized luteal support strate -\ngies remains incompletely established [ 50– 52]. Future \nrandomized studies specifically addressing phenotype-\nstratified transfer strategies may therefore be particularly \nvaluable.\nThe long-term reproductive implications of repeated \novarian surgery also require further clarification. \nAlthough ovarian reserve decline following endometri -\noma cystectomy is well recognized, the balance between \nsurgical symptom control and preservation of reproduc -\ntive potential remains clinically challenging [ 14, 15, 43, \n56]. Future fertility-preserving surgical strategies and \nindividualized decision algorithms may therefore become \nincreasingly important.\nImportantly, future studies should prioritize cumula -\ntive live birth and time-to-pregnancy endpoints rather \nthan isolated fresh transfer outcomes alone [ 53, 54]. \nSuch approaches may better reflect the true reproductive \nburden experienced by women with endometriosis and \nprovide more clinically meaningful information for indi -\nvidualized treatment planning.\nOverall, future progress in endometriosis-associated \nreproductive medicine will likely depend on integration \nof phenotype-specific classification, translational biol -\nogy, molecular biomarkers, advanced embryology tech -\nnologies, and individualized cumulative reproductive \nstrategies capable of addressing the complex biological \nheterogeneity of the disease.\nLimitations\nSeveral important limitations should be considered when \ninterpreting the available evidence regarding IVF/ICSI \noutcomes in women with endometriosis. First, substan -\ntial heterogeneity exists across published studies in rela -\ntion to disease classification, patient selection, ovarian \nreserve profiles, adenomyosis prevalence, prior surgical \ntreatment, stimulation protocols, embryo transfer poli -\ncies, and reported reproductive endpoints [ 9– 11, 23– 25]. \nThis heterogeneity significantly complicates direct com -\nparison among studies and limits the generalizability of \npooled conclusions.\nSecond, many available studies remain retrospective in \ndesign and are therefore inherently vulnerable to selec -\ntion bias, incomplete confounder adjustment, inconsis -\ntent diagnostic criteria, and variable reporting quality \n[9– 11, 23– 25]. In particular, earlier studies frequently \ncombined biologically distinct phenotypes—including \nsuperficial peritoneal disease, ovarian endometrioma, \ndeep infiltrating endometriosis (DIE), and adenomyo -\nsis—within a single diagnostic category, potentially \nobscuring clinically meaningful phenotype-specific \nreproductive differences.\nThird, interpretation of implantation and live birth out-\ncomes remains complicated by the frequent coexistence \nof adenomyosis, which may independently influence \nendometrial receptivity, miscarriage risk, and cumula -\ntive reproductive success [20– 22, 35, 50]. Many historical \nIVF/ICSI datasets lacked systematic adenomyosis assess -\nment, thereby limiting accurate evaluation of isolated \nendometriosis-associated reproductive effects.\nFourth, available evidence regarding embryo compe -\ntence remains inconsistent because of major variability \nin laboratory methodologies, embryo grading systems, \nembryo culture conditions, transfer strategies, and use \nof contemporary technologies such as time-lapse imag -\ning or preimplantation genetic testing [16– 18, 45, 47, 48]. \nIn addition, cumulative live birth and time-to-pregnancy \nendpoints remain underreported in many studies despite \ntheir important clinical relevance.\nThe present review itself also has methodological limi -\ntations. As a structured narrative review rather than a \nformal systematic review or meta-analysis, the study may \nbe subject to selective interpretation bias despite efforts \nto incorporate a broad and balanced synthesis of con -\ntemporary literature. Nevertheless, a narrative frame -\nwork was intentionally selected because of the marked \n\nPage 12 of 13\nDubovečak et al. Middle East Fertility Society Journal            (2026) 31:56 \nbiological and methodological heterogeneity currently \ncharacterizing the available evidence base.\n Finally, although increasing translational evidence \nimplicates inflammatory signaling, oxidative stress, pro -\ngesterone resistance, genetic susceptibility, and molecu -\nlar pathway dysregulation in endometriosis-associated \ninfertility, the direct clinical relevance of many mechanis-\ntic findings remains incompletely established [ 26, 27, 30, \n33, 37]. Further prospective phenotype-stratified studies \nintegrating molecular biology with clinically meaningful \nreproductive endpoints are therefore required.\nConclusion\nEndometriosis-associated infertility represents a bio -\nlogically heterogeneous condition in which reproductive \noutcomes during IVF/ICSI treatment are influenced by \ncomplex interactions among disease phenotype, ovarian \nreserve, inflammatory activation, uterine involvement, \nprevious surgical treatment, and cumulative treatment \ndynamics. Contemporary evidence increasingly suggests \nthat the reproductive impact of endometriosis is not bio -\nlogically uniform and should not be interpreted through \ngeneralized assumptions alone.\nAmong the various disease phenotypes, ovarian endo -\nmetrioma appears most consistently associated with \nreduced ovarian reserve, diminished oocyte yield, and \nlower treatment efficiency, whereas embryo develop -\nmental competence may remain relatively preserved once \ntransferable embryos are achieved [ 11– 17, 42– 44]. In \ncontrast, adenomyosis may independently contribute to \nimplantation impairment, miscarriage risk, and reduced \ncumulative live birth through alterations in endometrial \nreceptivity and uterine function [20– 22, 35, 50].\nCurrent evidence therefore supports a phenotype-\noriented and individualized approach to reproductive \nmanagement rather than uniform treatment algorithms \nfor all women with endometriosis. Interpretation of IVF/\nICSI prognosis should integrate ovarian reserve pro -\nfile, disease phenotype, uterine comorbidity, patient age, \nprior surgical history, embryo availability, and cumulative \nreproductive strategy.\nImportantly, cumulative live birth and overall treat -\nment efficiency may represent more clinically meaningful \noutcome measures than isolated per-transfer pregnancy \nrates alone, particularly in women with reduced ovarian \nreserve or limited embryo cohorts [ 53, 54]. Recognition \nof biological heterogeneity is therefore essential for real -\nistic prognostic assessment and individualized reproduc -\ntive counselling.\nFuture progress in the field will likely depend on \nimproved phenotype stratification, integration of trans -\nlational biology and molecular biomarkers, standard -\nized reporting of cumulative reproductive outcomes, \nand development of individualized embryo transfer and \nfertility-preservation strategies. Further prospective phe -\nnotype-specific studies are needed to clarify the complex \nrelationship between endometriosis and reproductive \noutcomes in contemporary IVF/ICSI practice.\nAcknowledgements\nNot applicable.\nAuthors' contributions\nMD conceived the study and drafted the manuscript. TTP , ATL, DH, MK, SC and \nNM contributed to literature interpretation, critical revision of the manuscript \nand improvement of the clinical framework. All authors read and approved \nthe final manuscript.\nFunding\nNot applicable.\nThis research received no specific grant from any funding agency in the \npublic, commercial, or not-for-profit sectors.\nData availability\nNo datasets were generated or analysed during the current study.\nDeclarations\nEthics approval and consent to participate\nNot applicable. This study is a narrative review based exclusively on previously \npublished studies and does not involve human participants, human data, or \nhuman tissue directly collected by the authors.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nAuthor details\n1Department of Obstetrics and Gynecology, Unit of Reproductive \nMedicine, University Hospital Sveti Duh, Zagreb, Croatia\n2Department of Obstetrics and Gynecology, Clinical Embryology \nLaboratory, University Hospital Sveti Duh, Zagreb, Croatia\nReceived: 14 March 2026 / Accepted: 2 June 2026\nReferences\n1. Zondervan KT, Becker CM, Missmer SA, Endometriosis (2020) N Engl J Med \n382:1244–1256\n2. Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L et al (2022) \nESHRE guideline: endometriosis. Hum Reprod Open 2022:hoac009\n3. Burney RO, Giudice LC (2012) Pathogenesis and pathophysiology of endome-\ntriosis. Fertil Steril 98:511–519\n4. 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