Open research questions in Endometriosis Research and Treatment

What the literature leaves open

• To date, no studies have demonstrated the capacity to directly reverse suppression of signaling pathways such as the GZMA-PARD3 axis or to restore depleted regenerative stromal subpopulations, including IGFBP3⁺ cells.

  Endometrial Repair and Regenerative Medicine: From Broad-Spectrum Regeneration to Precision Intervention · 2026 · DOI

• In summary, surgical treatment of endometriosis for fertility enhancement is complex and depends on multiple clinical factors, including but not limited to the patient’s age, ovarian reserve, fertility goals (infertility history, ideal family size, desire/ability to do IVF), semen parameters, tubal status, and presence of any uterine pathology such as leiomyoma or adenomyosis (2, 39).

  Endometriosis: surgical management for fertility enhancement · 2026 · DOI

• Abstract Endometriosis affects an estimated 10% of reproductive-age women and girls worldwide, approximately 190 million individuals, yet its molecular pathogenesis remains incompletely understood and current treatments rely largely on hormonal suppression, surgery, and symptom management.

  Abstract A044: Decoding the endometriosis immune–pain axis: A single-cell pipeline for neuroimmune hub discovery and drug prioritization · 2026 · DOI

• Increasing evidence indicates that lower urinary tract symptoms (LUTS) are more common in women with endometriosis, even in the absence of direct urinary tract involvement; however, the underlying mechanisms remain poorly understood.

  Lower Urinary Tract Symptoms in Women with Surgically Confirmed Endometriosis: Association with Urethral Ultrasonographic Findings · 2026 · DOI

• Endometriosis remains a complex reproductive disorder. Diagnostic delays and limited therapeutic options frequently com- promise patients’ quality of life and fertility. The impact of this disease goes beyond physical symptoms, negatively affecting women’s mental health and their social and professional lives. Therefore, it is urgent to investigate the basis of endometriosis, because early diagnosis and targeted treatment can mitigate pain, prevent progression, and ultimately improve quality of life and preserve fertility. Current pharmacological interventions, largely based on hor- monal suppression, are often incompatible with pregnancy and carry significant side effects, highlighting the urgent need for non- hormonal targets (84). The opioid system emerges as a promising yet dual-natured candidate in this landscape. Our review under- scores its fundamental role in endometrial physiology, including its influence on inflammation, angiogenesis, and apoptosis—processes that are systematically dysregulated in endometriosis. However, a critical “opioid paradox” exists: while these molecules offer a pathway for pain management and the possibility of modulating disease progression, their systemic and chronic use may inadver- tently impair ovarian steroidogenesis, oocyte quality, and endome- trial receptivity (85). Beyond their palliative role in pain management, we propose that opioids are putative modulators of the underlying mechanisms that drive endometriosis-associated subfertility. In this regard, miRNAs may offer new insights into the modulation of opioid pathways, representing a promising avenue for the future exploration of non- invasive biomarkers to assess pain signaling and therapeutic response. Furthermore, the feasibility of prospective clinical analyses on human subjects should be prioritized to evaluate the role of the opioid system within the landscape of infertility and ARTs. Investigating how opioid signaling correlates with oocyte quality and embryo implantation rates could determine whether site-specific modulation can improve both pain management and pregnancy outcomes. We hypothesize that a targeted approach to the opioid system could provide a novel dual-action framework: serving as a diagnos- tic biomarker for impaired endometrial receptivity and as a non- hormonal therapeutic strategy to restore ovulatory and menstrual regularity. It is imperative to transition from systemic analgesia to site-specific modulation to ensure that managing chronic pain does not compromise the reproductive capacity of these patients. Future research should prioritize the functional characterization of opioid receptors within the endometriotic microenvironment to transform them into precision tools for fertility preservation.

  The opioid system in endometriosis: implications for endometrial receptivity and reproductive outcomes · 2026 · DOI

• Endometriosis management relies on hormonal suppression (GnRH agonists, progestogens, and contraceptives) or surgical excision. However, hormonal therapies are inherently incompatible with patients seeking immediate pregnancy, as they inhibit ovulation and alter endometrial receptivity (18, 19). While surgery and Assisted Reproductive Technologies (ART) remain the primary options for restoring fertility, chronic pain often persists due to centralized nociceptive processing and inflammatory sensitization processes (20). Although they are not first-line therapies, opioids are frequently prescribed for uncontrolled or post-surgical pain associated with this condition (21).

  The opioid system in endometriosis: implications for endometrial receptivity and reproductive outcomes · 2026 · DOI

• This study analyzed data about 339,718 German women aged 10 years and older with statutory health insurance diagnosed with endometriosis between 2012 and 2022 to estimate age-specific incidence and, for the first time, the remission rate of endometriosis. Using a large pop- ulation-based dataset and the illness–death model with a related PDE framework, our approach provides robust and reliable estimates of disease dynamics in the German population. Our findings highlight the continued challenge of delayed diagnosis of endometriosis, which contributes to prolonged symptoms and adverse outcomes such as infertility. The diagnostic delay of approximately 7–10 years between symptom onset and diagnosis ulti- mately creates a cycle of persistent pain that is difficult to interrupt [21]. Earlier recognition through increased awareness and targeted physician training could reduce diagnostic delays and improve timely access to appro- priate surgical or conservative treatment. In addition, the substantial financial burden associated with long- term treatment and monitoring underscores the need to address economic as well as medical aspects of care. The observed prevalence suggests that endometriosis may still be underdiagnosed, reinforcing the importance of improving early detection, particularly among younger women. By providing precise epidemiological estimates of inci- dence and remission, this study offers valuable informa- tion for healthcare professionals and policymakers to develop more effective management strategies and allo- cate resources more efficiently. Increased awareness of these disease dynamics may also empower women to bet- ter understand and manage their condition. Future research should examine the influence of life- style factors, medical interventions, and genetic or epi- genetic mechanisms on the incidence and remission of endometriosis. Expanding analyses to include data from privately insured populations could further enhance the accuracy and generalizability of these estimates.

  Incidence and remission of endometriosis in Germany based on prevalence data from 35 million patients from the statutory health insurance · 2026 · DOI

• Our study had some strengths and limitations. One strength was its large sample size, which allows for more precise and reliable estimates of measures such as inci- dence and remission rates. A larger sample size enhances the representativeness of the study population and reduces random error, thereby improving the precision of estimated incidence and remission rates. incorporating Another strength was its use of a statistical method designed to accurately capture real-world dynamics. It utilized the IDM, a powerful tool for analyzing chronic diseases [19, 20]. By its mathemati- cal framework, specifically PDEs, the IDM enabled us to establish precise relationships between prevalence, incidence, and remission rates for endometriosis. One notable advantage of this approach is its ability to pre- dict disease paths and estimate key disease parameters. Therefore, the IDM is particularly valuable for project- ing future trends and understanding the components of chronic disease progression. The other key advantage of the IDM over other methods, such as cohort or longi- tudinal studies, is its cost-effectiveness [8]. Unlike these methods, which can be expensive and resource-intensive, the IDM offers a more affordable alternative as it can be performed based on cross-sections. The IDM is also less time-consuming, as it does not require long-term follow- up, allowing for efficient estimation of trends and future outcomes within large populations, making it a valuable tool for studying chronic diseases. Schütte Saem et al. BMC Women's Health (2026) 26:318 Page 8 of 9 Besides these strengths, our study and the method it used to estimate the incidence and remission rates based on the IDM and a related PDE had some limitations that could impact the estimations. Firstly, incomplete or inac- curate data can undermine the reliability of the IDM, such as missing information on patient demographics (age, sex, socioeconomic status); disease status (diagnosis, severity, remission periods); transitions between illness, remission, and relapse; or healthcare utilization (medical visits, treatments, comorbidities). Such issues can lead to biased or invalid estimates of disease incidence, pro- gression, and remission, ultimately affecting the model’s accuracy in chronic disease analysis. Secondly, estimat- ing certain parameters, such as remission rate or specific mortality risks, can be difficult in this method, particu- larly when these events are rare or poorly documented in the available datasets. Thirdly, the incidence and remis- sion were inferred from cross-sectional prevalence data. Differences in prevalence across age groups may partly reflect cohort effects (e.g., changes in environmental exposures or diagnostic practices across generations), which could influence the estimated transition rates. Moreover, datasets often only include information on patients who have utilized services from SHI-affiliated physicians and received a confirmed diagnosis through this system; those covered by private health insurance are not included. This exclusion may lead to gaps in data coverage. Given the diagnostic challenges discussed, it is reasonable to infer that the prevalence of endometriosis is considerably underreported. Fourthly, the remission rate peaking towards the end of the estimated age range might be explained by the delay in confirming recovery after menopause. Altogether, these limitations contribute to potential inaccuracies in estimating the remission rate, undermining the reliability of our results.

  Incidence and remission of endometriosis in Germany based on prevalence data from 35 million patients from the statutory health insurance · 2026 · DOI

• Future investigations incorporating extended follow-up, quantitative lesion burden analysis, and functional endpoints are warranted to further define the durability of these effects and facilitate the clinical translation of DP-MSCs therapy for endometriosis.

  Dental pulp–derived mesenchymal stem cells reduce lesion progression in a rat model of endometriosis · 2026 · DOI

• In superficial disease, animal models demonstrate that peritoneal inflammatory mediators and ROS can impair oocyte maturation, though direct causal evidence in humans is lacking.

  Endometriosis-Associated Infertility: A Review of Pathophysiological Mechanisms and Current Treatment Strategies · 2026 · DOI

• Objective: Though numerous studies have explored the immunological profile in endometriosis cases, limited information exists about the potential role of TIGIT/CD155 interaction.

  Endometrial expression of T-cell immunoreceptor with Ig and ITIM domains and cluster of differentiation 155: A case-control study of a novel immunomodulatory axis in endometriosis · 2026 · 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.

  Reconsidering IVF/ICSI outcomes in endometriosis: phenotype variability, confounding factors, and clinical interpretation · 2026 · 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.

  Reconsidering IVF/ICSI outcomes in endometriosis: phenotype variability, confounding factors, and clinical interpretation · 2026 · DOI

• This study has several limitations. First, it was conducted in a single tertiary hospital, which may not the wider population. Second, the sample size was relatively small, limiting the statistical power of the findings. Third, the study period was short, restricting long-term observation Finally, participants were selected using a non- (purposive) sampling method, random which may selection bias. Therefore, the findings of this study cannot be generalized to the entire population. follow-up. introduce and REFERENCES 1. Viganò P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2018;51:1-12. 2. Gałczyński K, Jóźwik M, Lewkowicz D, Semczuk A. Ovarian endometrioma – a possible finding in adolescent girls and young women. Prz Menopauzalny. 2019;18(2):104-108.

  Association of Serum Anti-Mullerian Hormone Level with Size of Ovarian Endometrioma · 2026 · DOI

• Although the exact mechanism of the disease remains unclear, substantial evidence supports its multifactorial nature, influenced by anatomical, hormonal, immunological, estrogenic, genetic, epigenetic, and environmental factors [14].

  Elucidating the role of transcription factors in molecular pathways underlying infertility in endometriosis: a bioinformatics approach · 2026 · DOI

• SHAP values represent statistical associations, not biological causation. Underlying confounders or complex patterns may influence observed associations, requiring future causal research to test generated clinical hypotheses.

  Identifying key determinants of cumulative live birth in women with ovarian endometrioma undergoing ethanol sclerotherapy followed by in vitro fertilization or intracytoplasmic sperm injection: an interpretable machine learning analysis · 2026 · DOI

• The study showed that there are objective grounds for the use of gonadotropin-releasing hormone analogues in women with endometrial hyperplasia without atypia, in whom progestogen therapy was insufficiently effective, as well as as a first-line therapy in women with low expression of PGR in glandular cells at the stage of primary histological screening.

  Progestogen-resistant forms of endometrial hyperplasia without atypia. Molecular diagnostic criteria and pathogenetic therapy strategy · 2025 · DOI

• CONCLUSIONS: The significant correlation between LVSI and lymph node metastasis in LUSI-positive cases indicates that pathologists should also focus on LVSI findings in the frozen examination required for the decision of staging surgery in patients with endometrioid endometrial cancer limited to the uterus.

  Lower uterine segment involvement in lymphovascular space invasion and lymph node metastasis in endometrioid endometrial cancer · 2019 · DOI

• WHAT IS KNOWN ALREADY: The literature suggests an inverse relation between endometriosis and BMI, although few studies have specifically explored this association in depth.

  Body size and endometriosis: results from 20 years of follow-up within the Nurses' Health Study II prospective cohort · 2013 · DOI

• Current stem cell-based interventions are largely characterized by a broad reparative profile, yet precise targeting of key molecular mechanisms remains insufficient.

  Endometrial Repair and Regenerative Medicine: From Broad-Spectrum Regeneration to Precision Intervention · 2026 · DOI

• In addition, the actual delivery efficiency of microneedle-based systems within the enclosed and humid uterine environment has not yet been fully clarified.

  Endometrial Repair and Regenerative Medicine: From Broad-Spectrum Regeneration to Precision Intervention · 2026 · DOI

• Relatively little is known about the genetic drivers of endometriosis even though its heritability is around 50%.

  Identification and Reproducibility of Novel Combinatorial Genetic Risk Factors for Endometriosis across UK and US Patient Cohorts · 2026 · DOI

• Studies reporting on Antral Follicle Count (AFC) gave conflicting results and all were assessed as at high or critical risk of bias.

  Ethanol sclerotherapy versus cystectomy in the management of endometriomata: a systematic review and meta-analysis · 2026 · DOI

• Further prospective multicenter studies incorporating standardized pain assessment, urodynamic evaluation, and longitudinal follow-up are warranted to better elucidate the mechanisms underlying lower urinary tract symptoms in this population.

  Lower Urinary Tract Symptoms in Women with Surgically Confirmed Endometriosis: Association with Urethral Ultrasonographic Findings · 2026 · DOI

• Diagnostic delay is a global problem, but its consequences are amplified where specialist imaging, high-quality endometriosis surgery, assisted reproduction, and fertility preservation are scarce or unaffordable.

  Maximising and Maintaining Fertility in Suspected or Confirmed Endometriosis: A Structured Narrative Review for Clinical Practice · 2026 · DOI

Most-cited papers in Endometriosis Research and Treatment

• ESHRE guideline: management of women with endometriosis · Human Reproduction · 2014 · 1,781 citations
• ESHRE guideline for the diagnosis and treatment of endometriosis · Human Reproduction · 2005 · 1,219 citations
• Endometriosis is a chronic systemic disease: clinical challenges and novel innovations · The Lancet · 2021 · 1,176 citations
• Diagnostic delay for endometriosis in Austria and Germany: causes and possible consequences · Human Reproduction · 2012 · 411 citations
• Endometriosis‐associated infertility: aspects of pathophysiological mechanisms and treatment options · Acta Obstetricia Et Gynecologica Scandinavica · 2016 · 316 citations
• The #Enzian classification: A comprehensive non‐invasive and surgical description system for endometriosis · Acta Obstetricia Et Gynecologica Scandinavica · 2021 · 279 citations
• Diagnosis and management of endometriosis · Canadian Medical Association Journal · 2023 · 260 citations
• Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease · Human Reproduction · 2003 · 259 citations
• Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes · Human Reproduction · 2017 · 259 citations
• Nerve fibres in peritoneal endometriosis · Human Reproduction · 2006 · 249 citations

Most recent work

• Expanding the genetic landscape of endometriosis: Integrative -omics analyses implicate key genes and pathways in a multi-ancestry study of over 1,000,000 women · medRxiv · 2026
• Risk of congenital anomalies among infants of patients with endometriosis: a population-based cohort study · Canadian Medical Association Journal · 2026
• The impact of adenomyosis localization in myometrium on fertility and pregnancy outcomes: a narrative systematic review of the literature · Frontiers in Reproductive Health · 2026
• Elucidating the role of transcription factors in molecular pathways underlying infertility in endometriosis: a bioinformatics approach · Middle East Fertility Society Journal · 2026
• How are workplace policies, organizational dysfunction, and lack of accommodations for employees with endometriosis associated with fertility-related needs, absenteeism, and productivity in the workforce? A scoping review · International Journal of Industrial Ergonomics · 2026
• A scoping review of alterations in sensory and motor function, and body perception in women with chronic pelvic pain · Journal of Pain · 2026
• Identifying key determinants of cumulative live birth in women with ovarian endometrioma undergoing ethanol sclerotherapy followed by in vitro fertilization or intracytoplasmic sperm injection: an interpretable machine learning analysis · Frontiers in Cell and Developmental Biology · 2026
• What the Body Knows: A Plain English Guide to Endometriosis as a Systemic Condition, and a Direct Address to the Profession That Has the Power to Change It · Zenodo (CERN European Organization for Nuclear Research) · 2026
• A novel magnetic resonance imaging index to evaluate ovarian reserve in endometrioma patients: the ovary to endometrioma volume index · Frontiers in Medicine · 2026
• Stem cell therapy-based approaches in experimental endometriosis: a systematic review · Reproductive Biology and Endocrinology · 2026

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