Reconsidering IVF/ICSI outcomes in endometriosis: phenotype variability, confounding factors, and clinical interpretation

Background Endometriosis is a biologically heterogeneous disorder frequently encountered in women undergoing assisted reproductive technology (ART). Reported effects on in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) outcomes remain inconsistent across studies, partly due to variations in disease phenotype, prior surgical treatment, ovarian reserve, and concomitant uterine pathology.

To critically evaluate contemporary evidence regarding IVF/ICSI outcomes in women with endometriosis, with emphasis on phenotype-related reproductive variability, sources of evidence heterogeneity, and implications for individualized reproductive management.

A structured narrative review was performed using PubMed/MEDLINE, Embase, and Scopus databases. Literature published between January 2015 and March 2026 was screened, with particular focus on contemporary studies evaluating ovarian response, embryological parameters, implantation, live birth, cumulative reproductive outcomes, and the potential confounding role of adenomyosis.

Current evidence suggests that the reproductive impact of endometriosis is not uniform across patient populations. Ovarian endometrioma and previous ovarian surgery are most consistently associated with reduced ovarian reserve and lower oocyte yield, whereas superficial peritoneal disease appears to exert less pronounced effects on ovarian responsiveness. Embryological outcomes are frequently preserved despite impaired ovarian response, although substantial heterogeneity exists among studies. Implantation and live birth outcomes may additionally be influenced by uterine factors, particularly adenomyosis, which may independently impair reproductive efficiency. Differences in study design, patient selection, disease classification, and outcome reporting contribute significantly to variability in the available literature.

IVF/ICSI prognosis in women with endometriosis should be interpreted within a phenotype-specific and multifactorial clinical context rather than through a single generalized disease model. Contemporary evidence Page 2 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56

Endometriosis is a chronic estrogen-dependent inflam - matory disorder characterized by the presence of endometrial-like tissue outside the uterine cavity and associated with complex alterations involving immune regulation, inflammatory signaling, angiogenesis, fibrosis, oxidative stress, and progesterone resistance [ 1– 4]. The disease affects approximately 10% of women of repro - ductive age and is detected in up to 30–50% of women presenting with infertility [ 1, 2]. Beyond pelvic pain and anatomical distortion, endometriosis has increasingly been recognized as a heterogeneous systemic disorder with variable reproductive implications depending on disease phenotype, ovarian involvement, previous surgi - cal treatment, and coexisting uterine pathology [1– 5]. Assisted reproductive technology (ART), particularly in vitro fertilization and intracytoplasmic sperm injec - tion (IVF/ICSI), represents an important therapeutic option for many women with endometriosis-associated infertility. However, the precise impact of endometrio - sis on ART outcomes remains incompletely understood and continues to generate substantial controversy within reproductive medicine. Earlier studies frequently sug - gested generalized impairment across multiple repro - ductive domains, including ovarian reserve, oocyte competence, embryo development, implantation, and live birth [6– 8]. More recent evidence, however, indicates that reproductive impairment is neither uniform nor bio- logically identical across different endometriosis pheno - types [9– 12]. Contemporary data increasingly support the concept that ovarian endometrioma and previous ovarian sur - gery are among the principal determinants of reduced ovarian reserve and diminished ovarian response dur - ing IVF/ICSI cycles [ 11– 15]. In contrast, several studies demonstrate relatively preserved fertilization, blastocyst development, and live birth per embryo transfer once good-quality embryos are available [ 12, 16– 18]. These findings suggest that the reproductive impact of endo - metriosis may predominantly involve quantitative rather than universal qualitative impairment, with cumulative treatment efficiency being influenced mainly through reduced oocyte yield and smaller embryo cohorts. At the same time, the pathophysiological mechanisms potentially affecting implantation and endometrial recep- tivity remain complex and incompletely resolved. Deep infiltrating endometriosis (DIE), chronic inflammatory activation, altered pelvic immune microenvironment, progesterone resistance, and concomitant adenomyo - sis have all been proposed as contributors to impaired implantation potential in selected patient subgroups [ 3, 4, 19– 22]. Increasing recognition of adenomyosis as an independent uterine confounder has further complicated interpretation of IVF/ICSI outcomes in women with endometriosis, particularly regarding cumulative live birth and embryo transfer strategy [20– 22]. Interpretation of the literature is additionally limited by major heterogeneity in study design, disease classifi - cation, surgical history, ovarian reserve profiles, stimula - tion protocols, embryo transfer strategies, and reported outcome measures. Many available studies remain ret - rospective and combine biologically distinct phenotypes under a single diagnostic category, potentially obscur - ing clinically relevant phenotype-specific effects [ 9, 11, 23– 25]. Consequently, simplistic interpretation of endo - metriosis as either uniformly detrimental or clinically negligible in IVF/ICSI is unlikely to accurately reflect the biological complexity of the disease. The aim of this review is therefore to provide a pheno - type-oriented and evidence-informed synthesis of con - temporary data regarding IVF/ICSI outcomes in women with endometriosis, with particular emphasis on patho - physiological mechanisms, ovarian reserve dynamics, embryological competence, implantation, cumulative live birth, and sources of evidence heterogeneity relevant to individualized reproductive management strategies.

This manuscript was designed as a structured narrative review intended to provide a clinically and biologically integrated synthesis of contemporary evidence regard - ing IVF/ICSI outcomes in women with endometriosis. Because of substantial heterogeneity in disease pheno - type, study design, ovarian reserve profiles, surgical his - tory, stimulation protocols, embryo transfer strategies, and reported reproductive endpoints, a formal quantita - tive meta-analysis was considered inappropriate for the

of the present review [9– 12, 23– 25]. A comprehensive literature search was performed using PubMed/MEDLINE, Embase, and Scopus data - bases. The search focused primarily on studies published between January 2015 and March 2026, while selected landmark earlier studies of major mechanistic or clini - cal relevance were also included when necessary to con - textualize contemporary evidence. Greater emphasis was placed on systematic reviews, meta-analyses, large supports individualized reproductive assessment integrating ovarian reserve, surgical history, adenomyosis evaluation, and cumulative treatment trajectory when counselling and managing women with endometriosis undergoing ART.

Endometriosis, IVF, ICSI, Assisted reproductive technology, Ovarian reserve, Endometrioma, Adenomyosis, Cumulative live birth, Reproductive outcomes Page 3 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 cohort studies, guideline statements, and clinically rel - evant translational studies published from 2020 onward. The search strategy incorporated combinations of Medical Subject Headings (MeSH) terms and free- text keywords including “endometriosis” , “IVF” , “ICSI” , “assisted reproductive technology” , “ovarian reserve” , “ AMH” , “antral follicle count” , “endometrioma” , “deep infiltrating endometriosis” , “adenomyosis” , “embryo qual- ity” , “blastocyst” , “implantation” , “frozen embryo transfer” , “live birth” , and “cumulative live birth” . Eligible publications included randomized controlled trials, prospective and retrospective cohort studies, reg - istry-based analyses, systematic reviews, meta-analyses, guideline papers, and clinically relevant mechanistic investigations addressing ovarian response, embryologi - cal outcomes, implantation, pregnancy, live birth, cumu - lative live birth, or phenotype-specific reproductive outcomes in women with endometriosis undergoing IVF/ ICSI treatment. Particular attention was given to studies evaluating ovarian endometrioma, prior ovarian surgery, adeno - myosis, deep infiltrating endometriosis (DIE), embryo transfer strategy, and cumulative reproductive outcomes. Studies were preferentially included when they provided phenotype-stratified analysis, contemporary IVF labora - tory data, or clinically applicable interpretation relevant to individualized treatment planning. Case reports, very small uncontrolled case series, dupli- cate datasets, and studies lacking sufficient methodologi - cal clarity or clearly defined reproductive outcomes were not prioritized. Due to substantial heterogeneity across the available literature, evidence synthesis was performed narratively with emphasis on biological plausibility, phenotype-specific interpretation, methodological limi - tations, and clinically meaningful outcome integration rather than pooled statistical estimates alone. In addition to reproductive outcomes, the review also incorporated selected translational and pathophysiological studies addressing inflammatory signaling, oxidative stress, pro - gesterone resistance, follicular microenvironment altera - tions, adenomyosis-associated implantation impairment, and emerging molecular mechanisms potentially relevant to reproductive dysfunction in endometriosis [26– 40]. Pathophysiological and phenotype-specific framework Endometriosis is increasingly recognized as a multifacto - rial systemic disorder characterized by complex interac - tions among inflammatory, immunological, endocrine, genetic, angiogenic, and fibrotic pathways. The biologi - cal heterogeneity of the disease may partly explain the marked variability observed in reproductive outcomes among women undergoing IVF/ICSI treatment [ 3, 4, 26– 30]. One of the central pathophysiological features of endo - metriosis is chronic inflammatory activation within the pelvic microenvironment. Elevated concentrations of activated macrophages, pro-inflammatory cytokines, chemokines, prostaglandins, and reactive oxygen species have been consistently demonstrated in peritoneal fluid and ectopic lesions [ 26, 30]. These inflammatory altera - tions may contribute to impaired folliculogenesis, altered oocyte maturation, mitochondrial dysfunction, abnormal granulosa-cell signaling, and disturbances in embryo- endometrial interaction. Oxidative stress appears to represent another impor - tant mechanism potentially influencing reproductive competence in endometriosis. Increased reactive oxygen species and reduced antioxidant capacity within follicu - lar fluid have been associated with altered meiotic spin - dle formation, mitochondrial injury, DNA damage, and impaired cellular metabolism [ 18, 31, 32]. Although the precise clinical significance of these molecular alterations remains incompletely established, they may contribute to the biological heterogeneity observed across IVF/ICSI studies. Progesterone resistance has also emerged as a major mechanistic concept in endometriosis-associated infer - tility. Altered progesterone receptor expression and dys - regulated downstream signaling pathways may impair decidualization and endometrial receptivity, potentially affecting implantation in selected patient subgroups [ 33, 34]. These mechanisms may be particularly relevant in women with coexisting adenomyosis, where abnormali - ties in uterine contractility, inflammatory signaling, junc- tional zone architecture, and local estrogen metabolism may further compromise implantation potential and cumulative reproductive outcomes [20– 22, 35]. Genetic and epigenetic factors are increasingly impli - cated in the pathogenesis of endometriosis and may partly explain phenotype-specific reproductive variabil - ity. Several studies have identified associations involving inflammatory signaling pathways, estrogen metabolism, progesterone resistance, KRAS activation, PI3K/AKT pathway dysregulation, ARID1A alterations, and epigen - etic modifications affecting endometrial function and cellular proliferation [27, 28, 36, 37]. However, the direct translational relevance of these molecular findings to IVF/ICSI outcomes remains incompletely clarified. Importantly, the biological consequences of endo - metriosis are not uniform across disease phenotypes. Superficial peritoneal disease may predominantly involve inflammatory and immune-mediated mecha - nisms, whereas ovarian endometrioma is more strongly associated with quantitative ovarian damage, mechani - cal cortical compression, altered vascularization, fibro - sis, and progressive follicular depletion [ 13– 18, 31, 38]. Deep infiltrating endometriosis (DIE) may additionally Page 4 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 interpreted as a major determinant of poor IVF/ICSI prognosis. Considerable variability between studies may additionally reflect differences in patient selection, dis - ease classification, and coexistence of other endometrio - sis phenotypes [9– 12, 23– 25]. Ovarian endometrioma, ovarian reserve, and embryo availability Ovarian endometrioma represents the phenotype most consistently associated with impaired ovarian reserve and reduced ovarian responsiveness during IVF/ICSI treat - ment [ 11– 15, 38]. Multiple studies demonstrate lower anti-Müllerian hormone (AMH) concentrations, reduced antral follicle count (AFC), fewer retrieved oocytes, and higher risk of suboptimal ovarian response in women with ovarian endometrioma, particularly in bilateral dis - ease and after previous ovarian cystectomy [13– 15, 38]. Histological and mechanistic studies further suggest that chronic inflammatory exposure, fibrosis, altered vas- cularization, and cortical compression adjacent to the endometrioma may contribute to progressive follicular depletion [ 31, 38]. Previous ovarian surgery may addi - tionally exacerbate ovarian damage through inadvertent removal of healthy cortical tissue and compromised vas - cular supply. Importantly, although ovarian endometrioma fre - quently reduces oocyte quantity, evidence regarding oocyte and embryo competence remains less consistent. Several contemporary studies suggest that fertilization, blastocyst development, and pregnancy rates per embryo transfer may remain relatively preserved once good- quality embryos are obtained [ 12, 16, 17]. Consequently, cumulative live birth may be influenced predominantly through smaller embryo cohorts and lower overall treat - ment efficiency rather than universal impairment of embryo developmental competence. Deep infiltrating endometriosis and complex pelvic disease Deep infiltrating endometriosis (DIE) represents a more anatomically and surgically complex phenotype char - acterized by fibrotic lesions infiltrating pelvic struc - tures including the rectovaginal septum, bowel, bladder, uterosacral ligaments, and pelvic sidewall. In addition to chronic pelvic pain and distorted pelvic anatomy, DIE may be associated with extensive inflammatory activa - tion and altered uterine signaling pathways [35, 40, 41]. However, the independent reproductive impact of DIE remains difficult to determine because this phenotype frequently coexists with ovarian endometrioma, adeno - myosis, and previous pelvic surgery. Surgical treatment of extensive DIE may itself influence ovarian reserve, pel - vic vascularization, and reproductive outcomes, thereby further complicating interpretation of IVF/ICSI studies. influence pelvic anatomy, chronic pain burden, inflam - matory uterine signaling pathways, and cumulative treat - ment complexity. Ovarian endometrioma represents one of the most clinically relevant phenotypes in reproductive medi - cine. Histological and molecular studies suggest that chronic exposure of adjacent ovarian cortex to inflam - matory mediators, iron-induced oxidative stress, fibrosis, and altered angiogenesis may contribute to progressive reduction in ovarian reserve [ 13– 15, 31]. In addition, surgical excision of endometriomas may further acceler - ate follicular depletion through inadvertent removal of healthy ovarian cortex and vascular compromise [ 14, 15, 38]. Despite these mechanistic alterations, contemporary evidence suggests that endometriosis does not uniformly impair embryo developmental competence. Fertilization, cleavage, and blastocyst development are often relatively preserved, particularly when adequate ovarian response is achieved [ 12, 16, 17]. This apparent discrepancy between biological abnormalities and relatively preserved embryological outcomes further supports the concept that the principal reproductive impact of endometriosis in IVF/ICSI may involve treatment efficiency and embryo cohort size rather than universal embryo incompetence. Overall, current evidence supports a phenotype- dependent biological model in which ovarian reserve impairment, inflammatory activation, uterine receptivity alterations, and cumulative treatment dynamics interact variably across different patient populations. Recognition of this biological heterogeneity is essential for interpreta - tion of IVF/ICSI outcomes and development of individu - alized reproductive treatment strategies. Phenotype-specific reproductive implications in IVF/ICSI Superficial peritoneal endometriosis and pelvic inflammatory mechanisms Superficial peritoneal endometriosis is generally consid - ered the least destructive phenotype from a reproduc - tive perspective, although important inflammatory and immunological alterations may still be present. Perito - neal lesions are associated with increased concentra - tions of inflammatory mediators, activated macrophages, prostaglandins, and oxidative stress markers within the pelvic microenvironment [ 26, 30]. These abnormalities may potentially influence gamete interaction, follicular signaling, tubal transport, and endometrial receptivity. However, many women with isolated superficial disease maintain relatively preserved ovarian reserve and accept - able IVF/ICSI outcomes, particularly in the absence of adenomyosis or previous ovarian surgery [9, 11, 23]. Current evidence therefore suggests that superfi - cial peritoneal disease should not automatically be Page 5 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 Available evidence therefore supports cautious inter - pretation of IVF/ICSI outcomes in women with DIE, par- ticularly when retrospective analyses fail to adequately control for concomitant adenomyosis, ovarian surgery, and baseline ovarian reserve status. Adenomyosis as a uterine confounding factor Adenomyosis deserves particular consideration as a dis - tinct uterine phenotype frequently coexisting with endo - metriosis. Increasing evidence suggests that adenomyosis may independently impair implantation, clinical preg - nancy, and live birth rates, particularly in frozen embryo transfer cycles [20– 22, 35]. Proposed biological mechanisms include abnor - mal uterine peristalsis, chronic inflammatory activa - tion, impaired decidualization, progesterone resistance, altered junctional zone architecture, and disturbed endo - metrial receptivity [ 33– 35]. Importantly, adenomyosis should not simply be considered an extension of endo - metriosis, but rather an independent uterine factor capa - ble of modifying reproductive prognosis. Recognition of adenomyosis as a confounding variable is therefore essential when interpreting reproductive out- comes in women with endometriosis, especially in stud - ies evaluating implantation and live birth outcomes. Biological heterogeneity and interpretation of IVF/ICSI outcomes The coexistence of multiple endometriosis phenotypes further complicates interpretation of IVF/ICSI outcomes. Women presenting with combined ovarian endome - trioma, adenomyosis, and DIE may demonstrate sub - stantially different reproductive profiles compared with women with isolated superficial peritoneal disease. This biological heterogeneity likely contributes to the incon - sistent findings observed across many retrospective IVF/ ICSI studies and meta-analyses [9– 11, 23– 25]. Overall, contemporary evidence supports individual - ized interpretation of reproductive prognosis according to disease phenotype, ovarian reserve profile, uterine involvement, previous surgical treatment, patient age, and cumulative reproductive strategy rather than gener - alized assumptions regarding endometriosis-associated infertility (Fig. 1). Ovarian reserve and ovarian response in women with endometriosis Among all reproductive domains potentially affected by endometriosis, impairment of ovarian reserve and dimin- ished ovarian responsiveness during IVF/ICSI treatment represent the most consistently supported findings in the contemporary literature [ 11– 15, 38]. However, the magnitude and clinical significance of this effect appear strongly dependent on disease phenotype, bilateral ovarian involvement, patient age, and previous surgical treatment. Ovarian endometrioma has been repeatedly associated with lower serum anti-Müllerian hormone (AMH) con - centrations, reduced antral follicle count (AFC), fewer retrieved oocytes, and increased likelihood of suboptimal ovarian response during controlled ovarian stimulation [13– 15, 38, 42]. Several mechanisms have been proposed to explain this association, including chronic inflamma - tory exposure, oxidative stress, cortical fibrosis, altered ovarian vascularization, follicular compression, and pro - gressive loss of primordial follicles adjacent to the cyst wall [31, 38, 42]. The negative impact on ovarian reserve appears partic - ularly pronounced in women with bilateral endometrio - mas and in those undergoing repeated ovarian surgery [13– 15, 42, 43]. Surgical excision of endometriomas may inadvertently remove healthy ovarian cortex and com - promise ovarian blood supply, thereby accelerating fol - licular depletion [ 14, 15, 43]. Although cystectomy may improve pain symptoms, reduce inflammatory burden, or facilitate oocyte retrieval in selected patients, current evidence does not consistently demonstrate improved live birth outcomes following routine pre-IVF surgery for asymptomatic ovarian endometrioma [11, 14, 44]. Importantly, diminished ovarian reserve does not nec - essarily imply uniformly impaired embryo developmen - tal competence. Several studies suggest that women with endometriosis may achieve fertilization, blastocyst for - mation, and implantation rates comparable to controls once adequate numbers of mature oocytes and transfer - able embryos are obtained [ 12, 16, 17]. This distinction between quantitative ovarian impairment and preserved embryo competence has important implications for interpretation of IVF/ICSI prognosis. The concept of suboptimal ovarian response may be particularly relevant in women with endometriosis-asso - ciated infertility. Even modest reductions in oocyte yield may substantially influence cumulative treatment effi - ciency because each stage of laboratory attrition, includ - ing failed fertilization, impaired blastocyst development, cryosurvival loss, and transfer cancellation, becomes proportionally more clinically significant when embryo cohorts are limited [ 11, 15, 42]. Consequently, cumula - tive live birth per initiated retrieval cycle may represent a more informative endpoint than isolated per-transfer pregnancy rates in this patient population. The relationship between ovarian reserve and dis - ease severity nevertheless remains complex. Some women with advanced endometriosis maintain satisfac - tory ovarian reserve parameters, whereas others with apparently limited ovarian disease demonstrate unex - pectedly diminished ovarian response [ 27, 40]. This vari- ability likely reflects the multifactorial biological nature Page 6 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 of endometriosis and the interaction among inflamma - tory activity, genetic susceptibility, surgical history, age- related ovarian decline, and individual follicular reserve. Interpretation of ovarian reserve markers in endome - triosis also requires caution. Anti-Müllerian hormone concentrations may decline progressively over time even in the absence of surgery, suggesting that the dis - ease itself may contribute to ongoing ovarian injury [ 13, 15, 42]. However, AMH reduction alone does not fully predict reproductive potential, embryo competence, or probability of live birth. Clinical prognosis should there - fore integrate ovarian reserve markers with patient age, embryo availability, uterine factors, disease phenotype, and overall cumulative reproductive strategy. Overall, current evidence supports the concept that the principal reproductive impact of ovarian endometriosis during IVF/ICSI treatment is predominantly quantitative, characterized mainly by reduced ovarian reserve, dimin - ished oocyte yield, and decreased treatment efficiency Fig. 1 Phenotype-specific biological pathways influencing IVF/ICSI outcomes in endometriosis. The figure summarizes how different endometriosis phenotypes may influence ART outcomes through distinct ovarian, inflammatory, embryological, and uterine mechanisms. Ovarian endometrioma and prior ovarian surgery primarily affect ovarian reserve and oocyte yield, whereas adenomyosis may act mainly through impaired uterine receptivity and implantation. DIE, deep infiltrating endometriosis; AMH, anti-Müllerian hormone; AFC, antral follicle count; IVF/ICSI, in vitro fertilization/intracytoplasmic sperm injection Page 7 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 rather than universal failure of embryo developmental competence (Table 1). Embryological outcomes and embryo competence The effect of endometriosis on oocyte competence, fer - tilization, embryo development, and blastocyst formation remains one of the most debated areas in reproductive medicine. Although multiple biological mechanisms potentially capable of impairing oocyte and embryo quality have been described, clinical IVF/ICSI studies continue to demonstrate heterogeneous and sometimes conflicting findings [6, 8– 12, 16– 18, 44]. Several pathophysiological mechanisms have been proposed to explain possible embryological impairment in women with endometriosis. Chronic inflammatory activation, oxidative stress, altered follicular cytokine profiles, mitochondrial dysfunction, and abnormal granulosa-cell signaling may theoretically compromise meiotic spindle integrity, chromosomal segregation, cellular metabolism, and developmental competence of the oocyte [ 18, 26, 30– 32]. In addition, the follicular microenvironment surrounding ovarian endometriomas may contain elevated concentrations of reactive oxygen species, inflammatory mediators, free iron, and toxic degradation products capable of influencing folliculogen- esis and oocyte maturation [31, 32]. Despite these biological observations, clinical evidence regarding embryo competence remains inconsistent. Ear- lier studies frequently suggested lower fertilization rates, impaired embryo quality, reduced blastocyst develop - ment, and decreased implantation rates in women with endometriosis [ 6– 8]. However, more recent analyses increasingly indicate that embryological competence may remain relatively preserved once adequate numbers of mature oocytes are obtained [9– 12, 16, 17]. Several contemporary studies have demonstrated comparable fertilization rates, cleavage-stage develop - ment, blastocyst formation, and euploid embryo poten - tial between women with endometriosis and control populations undergoing IVF/ICSI treatment [ 12 , 16, 17, 45]. Donor-oocyte studies have also provided important insight by suggesting that implantation and pregnancy outcomes may be more strongly influenced by uterine or cumulative treatment factors than by universal intrinsic oocyte incompetence alone [16, 46]. Importantly, interpretation of embryological outcomes is complicated by major heterogeneity across studies. Differences in disease phenotype, ovarian reserve, patient age, surgical history, stimulation protocols, embryo cul - ture conditions, embryo grading systems, and transfer policies may substantially influence reported results [ 9– 11, 23– 25]. Many earlier studies also combined biologi - cally distinct phenotypes into single analytical groups, potentially obscuring phenotype-specific embryological effects. Ovarian endometrioma appears to primarily affect oocyte quantity rather than universally impair embryo developmental competence [ 12, 16, 17, 44]. In many patients, acceptable blastocyst development and implan - tation rates can still be achieved when sufficient numbers of mature oocytes are retrieved. Consequently, reduced cumulative live birth in endometriosis populations may frequently reflect diminished embryo cohort size rather than catastrophic embryological failure. The growing use of time-lapse embryo monitoring, pre- implantation genetic testing (PGT-A), metabolomic anal- ysis, and artificial intelligence-based embryo selection may provide further insight into subtle embryological dif- ferences associated with endometriosis in future studies [47, 48]. However, current evidence remains insufficient to support the concept of uniformly impaired embryo competence across all endometriosis phenotypes. Overall, contemporary data suggest that the embryo - logical consequences of endometriosis are heterogeneous and strongly phenotype-dependent. Although inflam - matory and oxidative mechanisms may influence oocyte biology in selected patients, current evidence does not support generalized assumptions of severe universal Table 1 Biological mechanisms potentially influencing ovarian reserve and ovarian response in women with endometriosis undergoing IVF/ICSI Mechanism Biological effect Clinical biomarker Clinical implication Chronic pelvic inflammation Cytokine-me- diated follicular impairment Reduced AMH and AFC Reduced ovar- ian reserve and variable ovarian response Oxidative stress Reactive oxygen species-mediated cellular and mito- chondrial damage within the follicular environment Not routinely measurable Potential impairment of oocyte competence in selected patients Ovarian endometrioma Cortical compres- sion, fibrosis, and altered vascularization Reduced AMH and AFC Lower oocyte yield and tech- nically more difficult oocyte retrieval Altered ovarian vascularization Reduced follicular perfusion and oxygenation AFC variability Possible subop- timal follicular recruitment Surgical excision of endometrioma Unintentional loss of healthy ovarian cortex and vascular compromise Significant AMH decline Iatrogenic reduction in ovarian reserve Repeated ovar- ian surgery Progressive follicu- lar depletion Marked AMH decline Increased risk of poor ovarian response Abbreviations : IVF/ICSI in vitro fertilization/intracytoplasmic sperm injection, AMH anti-Müllerian hormone, AFC antral follicle count Page 8 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 embryo developmental impairment in women undergo - ing IVF/ICSI treatment for endometriosis-associated infertility. Implantation, endometrial receptivity, and adenomyosis The potential effect of endometriosis on implantation and endometrial receptivity remains controversial and substantially more complex than isolated assessment of ovarian reserve or oocyte yield. While some women with endometriosis achieve satisfactory implantation and live birth rates following transfer of good-quality embryos, others experience recurrent implantation failure or reduced cumulative reproductive success despite appar - ently adequate embryological outcomes [19– 22, 33– 35]. Several mechanisms have been proposed to explain impaired implantation potential in endometriosis-associ- ated infertility. Chronic inflammatory activation, altered cytokine signaling, progesterone resistance, oxidative stress, disturbed decidualization, and abnormal expres - sion of receptivity-associated molecules may contribute to impaired embryo-endometrial interaction in selected patients [ 19, 33, 34]. Molecular abnormalities involving integrins, HOXA10 expression, inflammatory media - tors, and progesterone-regulated pathways have all been implicated in impaired endometrial receptivity associ - ated with endometriosis [19, 34, 49]. At the same time, interpretation of implantation out - comes in endometriosis is complicated by substantial heterogeneity across published studies. Implantation rates may be influenced not only by disease phenotype but also by embryo quality, ovarian reserve, transfer strategy, embryo stage, cryopreservation protocols, prior surgery, and particularly the presence of concomitant adenomyosis [ 20– 22, 35]. Many earlier studies failed to adequately distinguish isolated endometriosis from com - bined endometriosis-adenomyosis phenotypes, poten - tially contributing to inconsistent findings across the literature. Adenomyosis has increasingly emerged as one of the most important uterine confounders in women with endometriosis undergoing IVF/ICSI treatment. Contem - porary evidence suggests that adenomyosis may inde - pendently reduce implantation, clinical pregnancy, and live birth rates while increasing miscarriage risk [ 20– 22, 35, 50]. Proposed mechanisms include abnormal uterine peristalsis, chronic inflammatory activation, junctional zone disruption, altered estrogen metabolism, progester - one resistance, impaired decidualization, and defective endometrial receptivity [33– 35, 50]. Importantly, the coexistence of adenomyosis may partly explain why some studies report apparently impaired implantation despite relatively preserved embryo devel - opmental competence [ 16, 17, 20– 22]. In this context, uterine factors rather than intrinsic embryo quality may become dominant determinants of reproductive outcome (Table 2). Frozen embryo transfer (FET) strategies have therefore gained increasing interest in women with adenomyosis and severe endometriosis phenotypes. Some studies sug - gest that prolonged pituitary suppression using long-act - ing GnRH agonists prior to embryo transfer may improve implantation and pregnancy outcomes in selected adeno- myosis populations by reducing inflammatory activity and improving endometrial receptivity [ 50– 52]. Never - theless, available evidence remains heterogeneous, and the optimal transfer strategy in women with coexisting endometriosis and adenomyosis has not yet been defini - tively established. The independent contribution of deep infiltrating endometriosis (DIE) to implantation failure also remains uncertain. DIE frequently coexists with adenomyosis, severe pelvic inflammation, fibrosis, and previous pel - vic surgery, making isolation of its specific reproductive impact methodologically difficult [ 35, 41]. Consequently, current evidence does not support uniform assumptions regarding implantation impairment across all endome - triosis phenotypes. Overall, contemporary data suggest that implantation dysfunction in endometriosis-associated infertility is multifactorial and strongly phenotype-dependent. While many women maintain acceptable implantation potential following transfer of good-quality embryos, concomi - tant adenomyosis, progesterone resistance, inflammatory activation, and altered endometrial receptivity may sub - stantially influence reproductive outcomes in selected patient populations. Table 2 Phenotype-specific reproductive implications and IVF/ ICSI management considerations in women with endometriosis Phenotype Dominant reproductive issue Main IVF/ ICSI impact Clinical interpretation Superficial perito- neal disease Inflamma- tory pelvic environment Usually preserved ovarian response Often favorable prognosis when ovarian reserve preserved Ovarian endometrioma Reduced ovar- ian reserve Lower oo- cyte yield Quantitative rather than uni- versal qualita- tive impairment Deep infiltrating endometriosis Pelvic fibrosis and complex anatomy Potential cumulative treatment complexity Frequently asso- ciated with ad- enomyosis and prior surgery Adenomyosis Impaired recep- tivity and uter- ine dysfunction Reduced implanta- tion and live birth Important inde- pendent uterine confounder Page 9 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 Cumulative live birth and treatment efficiency Cumulative live birth has increasingly emerged as one of the most clinically meaningful endpoints in contempo - rary reproductive medicine because it reflects the over - all probability of achieving a live birth from a complete ovarian stimulation cycle, including all fresh and frozen embryo transfers derived from a single retrieval [ 53, 54]. This endpoint may be particularly relevant in women with endometriosis, where ovarian reserve impairment and reduced embryo cohort size can substantially influ - ence long-term treatment efficiency despite apparently acceptable per-transfer outcomes. Historically, many studies evaluating IVF/ICSI out - comes in endometriosis focused primarily on isolated fresh transfer pregnancy rates. However, such endpoints may incompletely reflect the true reproductive burden associated with diminished ovarian response, repeated stimulation cycles, embryo attrition, and transfer cancel - lation [11, 23, 24, 53]. Increasing emphasis on cumulative live birth therefore allows more biologically and clinically integrated interpretation of reproductive prognosis. Several contemporary studies suggest that women with endometriosis, particularly those with ovarian endome - trioma or previous ovarian surgery, may demonstrate reduced cumulative live birth rates primarily because of lower oocyte yield and fewer available embryos rather than universal implantation failure or catastrophic embryo incompetence [ 11– 15, 44, 53]. Even when preg - nancy rates per embryo transfer remain relatively pre - served, the probability of ultimately achieving transfer may decline because of reduced embryo availability across the entire treatment pathway. This distinction between per-transfer outcomes and cumulative reproductive efficiency is especially impor - tant in women with suboptimal ovarian response. In patients generating limited numbers of oocytes, each stage of biological and laboratory attrition—including failed fertilization, impaired blastocyst development, cryosurvival loss, and cycle cancellation—may carry proportionally greater clinical significance [ 11, 42, 53]. Consequently, apparently reassuring transfer-based suc - cess rates may mask reduced cumulative probability of live birth per initiated retrieval cycle.The role of embryo cryopreservation and frozen embryo transfer strategies in women with endometriosis remains similarly complex. Freeze-all approaches may theoretically optimize endo - metrial receptivity, reduce supraphysiologic hormonal exposure, and facilitate individualized transfer timing. However, in women with limited embryo cohorts, man - datory transfer deferral and potential cryopreservation- associated attrition may also prolong time to pregnancy and reduce overall treatment efficiency [53– 55] (Table 3). Adenomyosis may further influence cumulative repro - ductive outcomes independently of ovarian reserve or embryo competence. Several studies suggest that implan- tation failure, miscarriage risk, and reduced live birth may be more pronounced in women with combined endometriosis-adenomyosis phenotypes than in women with isolated ovarian disease [ 20– 22, 50]. Consequently, cumulative live birth interpretation requires simultane - ous consideration of ovarian, embryological, and uterine factors rather than isolated analysis of a single reproduc - tive domain. Importantly, heterogeneity among published stud - ies remains substantial. Differences in disease pheno - type, age distribution, surgical history, embryo transfer policies, ovarian stimulation protocols, and inclusion of adenomyosis significantly complicate comparison of cumulative outcome data across studies [ 9– 11, 23– 25]. Furthermore, many retrospective analyses exclude patients who fail to reach embryo transfer, thereby poten- tially overestimating apparent reproductive success. Overall, current evidence supports the concept that cumulative live birth in women with endometriosis is influenced predominantly by treatment efficiency, embryo cohort dynamics, ovarian reserve, and uterine Table 3 Sources of heterogeneity and interpretation challenges in studies evaluating IVF/ICSI outcomes in endometriosis Outcome domain Major source of heterogeneity/confounding Clinical interpretation challenge Ovarian response Prior ovarian surgery, bilateral endometrioma, reduced ovarian reserve Difficulty distinguishing the independent effect of endo- metriosis from surgically mediated ovarian damage Oocyte and embryo quality Laboratory variability, stimulation protocols, embryo culture sistems Differences in embryological methodology may contribute to inconsistent findings regarding embryo competence Implantation and endome- trial receptivity Coexisting adenomyosis and uterine dysfunction Variable diagnosis and reporting of adenomyosis may confound implantation and pregnancy outcomes Live birth per transfer Selection bias and transfer-stage inclusion Many retrospective studies exclude patients who fail to reach embryo transfer, potentially overestimating success Cumulative live birth Variable follow-up duration and embryo availability Incomplete cumulative datasets may underestimate the impact of reduced embryo cohort size Comparative phenotype analysis Heterogeneous disease classification and mixed patient populations Different phenotypes are frequently analyzed together despite distinct biological characteristics Interpretation of reproduc- tive prognosis Differences in age, ovarian reserve, and prior treatment exposure Patient-level variability limits direct comparison between studies and reduces generalizability Page 10 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 comorbidity rather than isolated impairment of a single reproductive mechanism. Individualized interpreta - tion of cumulative prognosis is therefore essential when counselling patients and designing IVF/ICSI treatment strategies. Clinical interpretation and individualized reproductive management The substantial biological and clinical heterogeneity of endometriosis makes simplistic interpretation of IVF/ ICSI prognosis increasingly inadequate in contempo - rary reproductive medicine. Current evidence suggests that reproductive outcomes are influenced by a complex interaction among disease phenotype, ovarian reserve, adenomyosis, patient age, surgical history, embryo avail - ability, and cumulative treatment strategy rather than by the mere presence or absence of endometriosis alone [9– 15, 20– 25, 40]. One of the most clinically important concepts emerg - ing from contemporary evidence is the distinction between quantitative ovarian impairment and universal embryo incompetence. Women with ovarian endome - trioma frequently demonstrate reduced ovarian reserve, lower oocyte yield, and increased risk of suboptimal ovarian response, yet many retain acceptable fertilization, blastocyst development, and implantation potential once transferable embryos are achieved [ 11– 17, 42– 44]. This distinction has important implications for both prognos - tic interpretation and treatment planning. Current evidence therefore does not support uniform assumptions that all women with endometriosis experi - ence severely compromised IVF/ICSI outcomes. Instead, reproductive prognosis appears highly phenotype-depen- dent. Women with isolated superficial peritoneal disease may maintain relatively preserved reproductive poten - tial, whereas those with bilateral ovarian endometrioma, repeated ovarian surgery, diminished ovarian reserve, adenomyosis, or combined severe phenotypes may expe - rience substantially more complex reproductive chal - lenges [13– 15, 20– 22, 35, 41]. Interpretation of ovarian reserve markers also requires clinical nuance. Reduced anti-Müllerian hormone (AMH) concentrations and diminished oocyte yield should not automatically be interpreted as evidence of complete reproductive futility, particularly in younger women who may still achieve satisfactory embryo com - petence and live birth following individualized IVF/ ICSI treatment [ 13– 15, 42, 43]. Conversely, apparently reassuring per-transfer pregnancy rates may underes - timate the cumulative reproductive burden associated with repeated stimulation cycles and reduced embryo availability. The role of surgery before IVF/ICSI remains similarly individualized. Although cystectomy may be indicated in selected women with severe pain symptoms, suspi - cious ovarian morphology, technical difficulties during oocyte retrieval, or rapidly enlarging cysts, routine pre- IVF surgical excision of asymptomatic endometriomas is not consistently supported by evidence demonstrating improved live birth outcomes [ 11, 14, 44, 56]. Preserva - tion of ovarian reserve therefore represents a major con - sideration during individualized treatment planning. Adenomyosis deserves particular attention during reproductive counselling and treatment strategy selec - tion. Increasing evidence suggests that implantation fail - ure, miscarriage, and reduced cumulative live birth may be more strongly associated with concomitant adeno - myosis than with isolated ovarian disease alone [ 20– 22, 50]. In selected patients, prolonged pituitary suppression prior to embryo transfer, individualized frozen embryo transfer strategies, or modified stimulation approaches may therefore be considered, although evidence remains heterogeneous and optimal management remains incom- pletely established [50– 52]. Importantly, many published IVF/ICSI studies con - tinue to combine biologically distinct patient populations under the broad diagnosis of “endometriosis, ” thereby potentially obscuring clinically meaningful phenotype- specific effects [ 9– 11, 23– 25]. Consequently, individual - ized interpretation of prognosis should integrate disease phenotype, ovarian reserve profile, uterine factors, age, previous treatment history, and cumulative reproductive strategy rather than relying solely on generalized popula - tion-level outcome statistics. Overall, contemporary evidence supports a personal - ized and phenotype-oriented approach to IVF/ICSI man - agement in women with endometriosis. Recognition of biological heterogeneity, ovarian reserve dynamics, uter - ine comorbidity, and cumulative treatment efficiency is essential for realistic prognostic interpretation and indi - vidualized reproductive decision-making. Future perspectives Despite major advances in reproductive medicine, sev - eral important uncertainties regarding endometriosis- associated infertility and IVF/ICSI outcomes remain unresolved. Future research will likely require more bio - logically integrated and phenotype-specific approaches capable of addressing the substantial heterogeneity that currently limits interpretation of available evidence [ 9– 11, 23– 25]. One of the most important future directions involves improved phenotype stratification. Many existing studies continue to combine superficial peritoneal disease, ovar - ian endometrioma, deep infiltrating endometriosis (DIE), and adenomyosis within a single diagnostic category despite their potentially distinct biological and reproduc - tive implications [ 35, 40, 41]. Future prospective studies Page 11 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 incorporating standardized phenotype classification, ovarian reserve assessment, adenomyosis imaging crite - ria, and cumulative live birth endpoints may substantially improve clinical interpretation. Increasing interest also surrounds the identification of molecular and inflammatory biomarkers associated with reproductive prognosis in women with endometriosis. Altered cytokine signaling, oxidative stress pathways, progesterone resistance markers, epigenetic modifica - tions, and inflammatory mediators may potentially con - tribute to individualized prediction of ovarian response, implantation potential, and cumulative treatment success [27, 30, 33, 34, 37]. However, most currently proposed biomarkers remain investigational and lack sufficient val- idation for routine clinical application. Artificial intelligence (AI), machine learning, and advanced embryo assessment technologies may also play an expanding role in future reproductive management. Time-lapse imaging systems, AI-assisted embryo selec - tion, metabolomic profiling, and non-invasive embryo assessment strategies may improve evaluation of embryo developmental competence and treatment efficiency in women with complex reproductive disorders, includ - ing endometriosis [ 47, 48, 57]. Nevertheless, prospective validation specifically within endometriosis populations remains limited. Further investigation is also needed regarding optimal embryo transfer strategies in women with coexisting ade- nomyosis and severe endometriosis phenotypes. The role of prolonged GnRH agonist suppression, personalized frozen embryo transfer protocols, endometrial receptiv - ity assessment, and individualized luteal support strate - gies remains incompletely established [ 50– 52]. Future randomized studies specifically addressing phenotype- stratified transfer strategies may therefore be particularly valuable. The long-term reproductive implications of repeated ovarian surgery also require further clarification. Although ovarian reserve decline following endometri - oma cystectomy is well recognized, the balance between surgical symptom control and preservation of reproduc - tive potential remains clinically challenging [ 14, 15, 43, 56]. Future fertility-preserving surgical strategies and individualized decision algorithms may therefore become increasingly important. Importantly, future studies should prioritize cumula - tive live birth and time-to-pregnancy endpoints rather than isolated fresh transfer outcomes alone [ 53, 54]. Such approaches may better reflect the true reproductive burden experienced by women with endometriosis and provide more clinically meaningful information for indi - vidualized treatment planning. Overall, future progress in endometriosis-associated reproductive medicine will likely depend on integration of phenotype-specific classification, translational biol - ogy, molecular biomarkers, advanced embryology tech - nologies, and individualized cumulative reproductive strategies capable of addressing the complex biological heterogeneity of the disease.

Several important limitations should be considered when interpreting the available evidence regarding IVF/ICSI outcomes in women with endometriosis. First, substan - tial heterogeneity exists across published studies in rela - tion to disease classification, patient selection, ovarian reserve profiles, adenomyosis prevalence, prior surgical treatment, stimulation protocols, embryo transfer poli - cies, and reported reproductive endpoints [ 9– 11, 23– 25]. This heterogeneity significantly complicates direct com - parison among studies and limits the generalizability of pooled conclusions. Second, many available studies remain retrospective in design and are therefore inherently vulnerable to selec - tion bias, incomplete confounder adjustment, inconsis - tent diagnostic criteria, and variable reporting quality [9– 11, 23– 25]. In particular, earlier studies frequently combined biologically distinct phenotypes—including superficial peritoneal disease, ovarian endometrioma, deep infiltrating endometriosis (DIE), and adenomyo - sis—within a single diagnostic category, potentially obscuring clinically meaningful phenotype-specific reproductive differences. Third, interpretation of implantation and live birth out- comes remains complicated by the frequent coexistence of adenomyosis, which may independently influence endometrial receptivity, miscarriage risk, and cumula - tive reproductive success [20– 22, 35, 50]. Many historical IVF/ICSI datasets lacked systematic adenomyosis assess - ment, thereby limiting accurate evaluation of isolated endometriosis-associated reproductive effects. Fourth, available evidence regarding embryo compe - tence remains inconsistent because of major variability in laboratory methodologies, embryo grading systems, embryo culture conditions, transfer strategies, and use of contemporary technologies such as time-lapse imag - ing or preimplantation genetic testing [16– 18, 45, 47, 48]. In addition, cumulative live birth and time-to-pregnancy endpoints remain underreported in many studies despite their important clinical relevance. The present review itself also has methodological limi - tations. As a structured narrative review rather than a formal systematic review or meta-analysis, the study may be subject to selective interpretation bias despite efforts to incorporate a broad and balanced synthesis of con - temporary literature. Nevertheless, a narrative frame - work was intentionally selected because of the marked Page 12 of 13 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 biological and methodological heterogeneity currently characterizing the available evidence base. Finally, although increasing translational evidence implicates inflammatory signaling, oxidative stress, pro - gesterone resistance, genetic susceptibility, and molecu - lar pathway dysregulation in endometriosis-associated infertility, the direct clinical relevance of many mechanis- tic findings remains incompletely established [ 26, 27, 30, 33, 37]. Further prospective phenotype-stratified studies integrating molecular biology with clinically meaningful reproductive endpoints are therefore required.

Endometriosis-associated infertility represents a bio - logically heterogeneous condition in which reproductive outcomes during IVF/ICSI treatment are influenced by complex interactions among disease phenotype, ovarian reserve, inflammatory activation, uterine involvement, previous surgical treatment, and cumulative treatment dynamics. Contemporary evidence increasingly suggests that the reproductive impact of endometriosis is not bio - logically uniform and should not be interpreted through generalized assumptions alone. Among the various disease phenotypes, ovarian endo - metrioma appears most consistently associated with reduced ovarian reserve, diminished oocyte yield, and lower treatment efficiency, whereas embryo develop - mental competence may remain relatively preserved once transferable embryos are achieved [ 11– 17, 42– 44]. In contrast, adenomyosis may independently contribute to implantation impairment, miscarriage risk, and reduced cumulative live birth through alterations in endometrial receptivity and uterine function [20– 22, 35, 50]. Current evidence therefore supports a phenotype- oriented and individualized approach to reproductive management rather than uniform treatment algorithms for all women with endometriosis. Interpretation of IVF/ ICSI prognosis should integrate ovarian reserve pro - file, disease phenotype, uterine comorbidity, patient age, prior surgical history, embryo availability, and cumulative reproductive strategy. Importantly, cumulative live birth and overall treat - ment efficiency may represent more clinically meaningful outcome measures than isolated per-transfer pregnancy rates alone, particularly in women with reduced ovarian reserve or limited embryo cohorts [ 53, 54]. Recognition of biological heterogeneity is therefore essential for real - istic prognostic assessment and individualized reproduc - tive counselling. Future progress in the field will likely depend on improved phenotype stratification, integration of trans - lational biology and molecular biomarkers, standard - ized reporting of cumulative reproductive outcomes, and development of individualized embryo transfer and fertility-preservation strategies. Further prospective phe - notype-specific studies are needed to clarify the complex relationship between endometriosis and reproductive outcomes in contemporary IVF/ICSI practice.

Not applicable. Authors' contributions MD conceived the study and drafted the manuscript. TTP , ATL, DH, MK, SC and NM contributed to literature interpretation, critical revision of the manuscript and improvement of the clinical framework. All authors read and approved the final manuscript. Funding Not applicable. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. This study is a narrative review based exclusively on previously published studies and does not involve human participants, human data, or human tissue directly collected by the authors. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Author details 1Department of Obstetrics and Gynecology, Unit of Reproductive Medicine, University Hospital Sveti Duh, Zagreb, Croatia 2Department of Obstetrics and Gynecology, Clinical Embryology Laboratory, University Hospital Sveti Duh, Zagreb, Croatia Received: 14 March 2026 / Accepted: 2 June 2026

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