Across this set, endometriosis-associated cancer risk

The gap

Evidence profile

Sourced from the future work and limitations and stated challenges and synthesized of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 4 representative gaps

• Reconsidering IVF/ICSI outcomes in endometriosis: phenotype variability, confounding factors, and clinical interpretation (2026) · Middle East Fertility Society Journal · doi

  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 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 Page 11 of 13 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.

  generalfuture workevidence 5/5
  Keywords: reproductive endometriosis future embryo phenotype strategies ovarian assessment women individualized transfer important associated addressing tive
• Reconsidering IVF/ICSI outcomes in endometriosis: phenotype variability, confounding factors, and clinical interpretation (2026) · Middle East Fertility Society Journal · doi

  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 Dubovečak et al. Middle East Fertility Society Journal (2026) 31:56 Page 12 of 13 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.

  generallimitationsevidence 5/5
  Keywords: reproductive endometriosis embryo available icsi adenomyosis review important evidence regarding outcomes heterogeneity tion disease ovarian
• Hippo pathway in endometriosis pathogenesis: from cellular dysregulation to therapeutic opportunities (2026) · Frontiers in Pharmacology · doi

  One challenge is the complexity of endometriosis, which arises from a complex interplay of genetic susceptibility, environmental influences, hormonal dysregulation, and altered immune responses. Another challenge is the need for further subtype-resolved mechanistic studies, robust preclinical validation, and clinical safety assessment. The paper also highlights the challenge of translating experimental findings into clinical practice.

  generalstated challengesevidence 5/5
  Keywords: one challenge complexity endometriosis arises complex interplay genetic
• From deep infiltrating endometriosis to endometriosis-associated cancer: current aspects of differential diagnosis (2026) · Obstetrics, Gynecology and Reproduction · doi

  Across this set, endometriosis-associated cancer risk stratification is evaluated only descriptively in one paper; none of the studies applies molecular profiling datasets, genomic biomarkers, or machine-learning approaches to predict malignant transformation risk in endometriosis cohorts, despite the stated need for 'standardized integrative approaches to improve diagnostic accuracy and stratification of oncological risk.'

  generalsynthesizedevidence 5/5
  Keywords: across set endometriosis-associated cancer risk stratification evaluated only

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