Perspective Chapter: Endometriosis – Challenges in Diagnosis and Treatment – Status and Future Perspectives

Endometriosis (EM) is a chronic, estrogen-dependent, inflammatory disease characterized by the presence of endometrial-like tissue outside the uterus. It is estimated that EM occurs in approximately 10% of women of the reproductive age and is associated with severe morbidity in the form of chronic pelvic pain and subfertility. Diagnosis is challenging due to nonspecific symptoms, long diagnosis-to-treatment times (4–11 years), the inability of imaging techniques to accurately locate superficial lesions, and the lack of validated noninvasive biomarkers. The latest European Society of Human Reproduction and Embryology (ESHRE) and American College of Obstetricians and Gynecologists (ACOG) guidelines no longer consider laparoscopy as the reference standard test. Presently, the management of EM is focused on symptom control using hormones (such as combined oral contraceptives, progestins, and gonadotropin-releasing hormone analogs) and surgery in non-responders or for fertility preservation. However, EM is highly recurrent, with recurrence rates of up to 50% at five years after treatment, associated with numerous side effects and limited improvement in fertility preservation rates. Precision medicine for EM will require the identification of multiomic biomarkers of the disease to develop non-invasive approaches for the diagnosis and management of EM using artificial intelligence-based imaging technologies and novel immunomodulatory drugs.

- endometriosis - clinic and symptoms - diagnostic - treatment - perspectives 1. Introduction Endometriosis (EM) is defined as the presence of endometrial-like epithelium and stroma outside the uterine cavity and myometrium, often accompanied by chronic inflammation, fibrosis, and adhesions. It affects 2–10% of reproductive-age women globally, with higher prevalence (up to 50%) among those with infertility, peaking in incidence among women aged 20–24 years. The condition exacts a profound toll, manifesting as debilitating dysmenorrhea, chronic pelvic pain, dyspareunia, and infertility in 30–50% of cases, alongside reduced quality of life, work productivity losses, and annual healthcare costs exceeding billions worldwide [1–3]. Endometriosis was traditionally viewed as simply a painful condition. The consensus today is that EM is an important contributor to subfertility because of the alterations that occur in the pelvis, such as, adhesions and scarring, a reduction in the quality of the egg, and the presence of an inflammatory response. However, what about the contribution of the other organs and systems affected by the disease? What about the impact of chronic nonreproductive symptoms? Advanced imaging and pharmacotherapy have not significantly improved the ability to diagnose and adequately treat women with EM. The reasons for this are multifactorial. Women with EM often have nonspecific symptoms that are identical to those of other disorders, such as, Irritable Bowel Syndrome (IBS), interstitial cystitis, or primary dysmenorrhea. The heterogeneity of the disease and lack of reliable biological markers also increase the difficulty of making a specific diagnosis. Finally, the treatment of EM remains a source of great controversy. Indeed, the fact that EM depends on the estrogen signal, is resistant to progesterone therapy, and has a high risk of recurrence postsurgically all emphasize the necessity of a multidisciplinary approach tailored to each individual patient [2–6]. 2. Pathogenesis and disease heterogeneity Endometriosis is a clinical condition characterized by the abnormal presence of endometrium-like tissue. Sampson (1897, 1927) proposed that EM results from the addition of this clinical condition to the basic pathogenic mechanisms of the disease. Retrograde menstruation, survival of retrograde-shed endometrium due to inadequate immune clearance, and adhesion and growth at the target site have been proposed as the pathogenic mechanisms that lead to the development of EM. The presence of an immune dysfunction at the EM sites, characterized by a decrease in natural killer cell activity, increased macrophage dysfunction, and an increased production of proinflammatory cytokines, such as, Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α), is observed. The survival of the endometriotic lesions and the neoangiogenesis are due to the increased expression of Vascular Endothelial Growth Factor (VEGF) [4, 5]. 3. Endocrine aspects Hormone dependency is a hallmark of EM and is sustained by: Local aromatase-dependent estrogen production, Progesterone receptor (PR) isoforms, and Target gene epigenetic modifications that promote endometriotic cell proliferation. Other contributing factors include: Genetics (first-degree relative risk 5–8 fold), MicroRNA (MiRNA)’s and Stem/progenitor cells deriving from the bone marrow or from menstruation, and Neuroangiogenesis contributing to the invasive and painful properties of endometriotic lesions. The heterogeneity of the disease is reflected by the wide range of possible peritoneal surface lesions, ovarian endometriomas, deep infiltrating endometriosis (DIE), and extrapelvic locations, which are not always correlated with the extent of the disease and with the intensity of the clinical symptoms. Furthermore, the therapeutic response is also highly variable. For example, DIE is often associated with severe and intractable pain that is poorly managed by the treatment of superficial EM lesions. The clinical heterogeneity of EM does not allow for the establishment of uniform clinical diagnostic and therapeutic criteria, and the identification of molecular subgroups is an issue of great priority [4–6]. 4. Clinical presentation and diagnostic challenges Endometriosis is a highly heterogeneous condition: the most commonly reported symptoms are cyclic dysmenorrhea (70–90%), chronic pelvic pain (40%), and deep dyspareunia (50%), as well as infertility in 30–50% of cases. Deep infiltrating endometriosis is also associated with a broader spectrum of catamenial symptoms depending on the organs involved. These include cyclic dyschezia, tenesmus, rectal bleeding, and bowel habit changes in cases of intestinal involvement; cyclic dysuria and hematuria in urinary tract disease; as well as less common manifestations such as, catamenial sciatica, hemoptysis, and hemothorax in extrapelvic disease. The 10–20% of EM cases that are asymptomatic are often diagnosed accidentally. Adolescents with EM complain of acyclic pain that is not responsive to analgesics [2, 3]. Diagnostic delay can be observed (range: 4–11 years) due to nonspecific and overlapping symptoms like IBS (present in 50% of cases), interstitial cystitis, adenomyosis, or musculoskeletal pain. In adolescents, the symptoms may disappear spontaneously, and the idea of possible future infertility acts as a stigmatizing barrier. A thorough medical history is not always reliable (sensitivity: 50–70%) since pain is cyclical and not always related to EM. A physical examination is also of little value for the diagnosis of DIE nodules or uterosacral ligament tenderness, as superficial lesions are often missed (prevalence: 30–50%) [6–9]. A diagnosis based on symptoms alone can usually be excluded, especially in the presence of coexisting anxiety and depression, which are found in more than half of women with these conditions. In such situations, the American College of Obstetricians and Gynecologists (ACOG) suggests empirical treatment, which is in keeping with the current evidence; however, it should be remembered that the definitive diagnosis will not be confirmed as long as a confirmatory test has not been performed [4, 8]. 5. Current diagnostic approaches: Status Transvaginal sonography (TVS) is highly sensitive and specific for endometriomas (sensitivity 95%, specificity 98%) and DIE (e.g., accuracy 90% in the case of rectosigmoid DIE with bowel preparation using the “sliding sign” and tender nodule mapping). Magnetic resonance imaging (MRI) is more accurate for DIE staging (sensitivity range 88–95% for pouch of Douglas obliteration) and allows better assessment of ureteral and bladder involvement using T2W sequences and fat-suppressed T1W for the detection of hemorrhage [1, 7]. The gold standard has been laparoscopy with histology; however, guidelines from European Society of Human Reproduction and Embryology (ESHRE) 2022 now recommend laparoscopy only when imaging tests are nondiagnostic and treatment does not provide relief, due to 20–40% of tests being false-negative for superficial EM and it being an invasive technique. Other studies on molecular biomarkers, such as, CA-125 in advanced EM, miRNAs, or cell-free DNA (cfDNA), are not used clinically in the diagnosis of EM due to low sensitivity (below 70%) and a lack of validation studies for this clinical condition [1]. An emerging biomarker with increasing clinical relevance is B-cell lymphoma 6 (BCL-6), a transcriptional repressor associated with endometrial inflammation and progesterone resistance. Overexpression of BCL-6 in eutopic endometrium, typically assessed via immunohistochemistry on endometrial biopsy, has been strongly correlated with the presence of EM, particularly in cases of unexplained infertility. Importantly, BCL-6 expression appears to reflect a functional endometrial defect rather than structural disease alone, thereby complementing imaging-based diagnostics. Although not yet incorporated into routine clinical guidelines, BCL-6 represents a promising adjunct in the noninvasive diagnostic workup of EM [10]. While invasive procedures can only confirm the nature of the mass, if an invasive procedure is required, there is a risk of complications (1–2%) [4]. The ESHRE/ACOG recommendations include ultrasound as a possible means of assessing the mass, thus enabling a more speedy initiation of the necessary therapy. The disadvantage of using ultrasound is that about 20 to 30% of superficial lesions will not be visualized [8, 9, 11]. A comprehensive comparison of the mentioned methods is included in Table 1. | Diagnostic method | Advantages | Limitations | |---|---|---| | Transvaginal ultrasound | High accuracy for endometriomas/DIE (90–95%), cost-effective, dynamic assessment | Operator-dependent, poor for superficial peritoneal lesions (sensitivity: 50–70%) | | MRI | Excellent DIE mapping (88–95%), multiplanar, ureter/bladder evaluation | Expensive, contraindicated in claustrophobia/renal failure, and misses superficial disease | | Laparoscopy + histology | Therapeutic potential, confirms superficial lesions | Invasive (complications 1–2%), general anesthesia, sampling error (20–40% false negative) | | Biomarkers (CA-125, miRNA, BCL-6) | Noninvasive potential | Low sensitivity/specificity (<70%); not validated for routine use | 6. Treatment of EM: Current standards Reduction of estrogen levels is a common strategy in the medical treatment of cyclical pain disorders. First-line management of dysmenorrhea and dyspareunia using first-generation combined hormonal contraceptives (CHC) reduces severity by 37% (RR 0.63). First-generation CHCs are commonly given on a continuous cycle to minimize breakthrough bleeding. The progestins dienogest and medroxyprogesterone achieve relief in 70–80% of women with dysmenorrhea through a decidualizing effect. The Levonorgestrel-Releasing Intrauterine System (LNG-IUS) is often used as a treatment choice for premenstrual pain and menstrual pain disorders [1, 3]. Gonadotropin-Releasing Hormone (GnRH) agonists (such as leuprolide 3.75 mg monthly) provide short-term pain relief of 70–90% but cause significant hypoestrogenia requiring add-back therapy (norethindrone/estrogen). GnRH antagonists (such as, elagolix and relugolix) are oral and have fewer side effects – Nonsteroidal Anti-inflammatory Drugs (NSAID)s provide an adjunctive benefit to pain management [7]. Surgery – excision rather than ablation for peritoneal lesions and cystectomy for endometriomas larger than 3 cm – is effective in reducing pain (OR 10 at six months) and in improving fertility in women with minimal EM. The ESHRE Core Committee treatment goals for EM include the reduction of pain and lesions, preservation of fertility using Endometriosis Fertility Index (EFI) to guide the choice of therapy to optimize the chance of pregnancy, prevention of recurrence using postoperative hormones, and, finally, an improved quality of life. Surgery should also include hysterectomy when nonfertility-preserving surgical options are chosen [1, 3, 12]. A comprehensive comparison of the listed treatment modalities can be found in Table 2. | Treatment modality | Key options | Strengths | Weaknesses | |---|---|---|---| | Medical: hormonal | CHC, progestins (dienogest, LNG-IUS), GnRH analogs | Noninvasive, 70–80% pain relief, fertility postponement | Side effects (bone loss, bleeding), recurrence upon cessation (40–50%) | | Surgical | Laparoscopic excision/cystectomy, DIE resection | Definitive pain relief (OR 10), fertility improvement (minimal disease) | Complications (2–5%), ovarian reserve loss (20–30% Anti-Müllerian Hormone (AMH) drop), recurrence (20–50%). | | Analgesics | NSAIDs | Rapid, Over-the-Counter (OTC) access | Gastrointestinal (GI) risks, incomplete control (50%) | 7. Challenges and limitations in current treatment Recurrence occurs in 40–50% of patients within five years of the initial surgical treatment and up to 60% when hormone adjuvant therapy is not administered, due to small residues and/or progesterone resistance. In any case, 20–30% of patients are not satisfied with the hormonal control of their symptoms, especially those who suffer from DIE. Potential long-term side effects of hormone therapy are: GnRH hypoestrogenism with bone loss of 5–10% per year. Endoscopic surgery is often performed in order to alleviate symptoms and to obtain a definitive diagnosis; however, it is known to decrease ovarian reserve by 20–38% postcystectomy, as shown in AMH decrease. The potential complications of endoscopic surgery include the risk of bowel and/or ureter injury, which occurs in about 1–3% of DIE cases. There was poor correlation between the extent of the endoscopic disease and the degree of symptoms experienced by patients with EM. Fertility management in the case of EM is equally challenging; the use of gonadal-toxic ovarian suppression for managing EM has been shown to negatively impact surgical outcomes, and the majority of women had limited success following surgery for EM due to only a few being classified with minimal disease [3, 12]. There is a set of other challenges surrounding the problem of EM: 8. Special considerations Endometriosis is a subfertile condition due to the inflammatory or oocyte-damaging pathway and is thus classified as, according to the revised American Society for Reproductive Medicine classification (rASRM), III/IV. Hence, there is a < 15%/cycle chance of spontaneous conception. In mild EM, surgery has been shown to increase the EFI to more than 4 (50–70% chance of conceiving). In severe EM, it is generally recommended to proceed with assisted reproductive technologies (ART), as the chance of having a live birth is between 30–40% [7, 13, 14]. In this context, BCL-6 overexpression has emerged as a clinically relevant prognostic marker in infertility associated with EM. Elevated BCL-6 levels have been associated with reduced implantation rates and poorer outcomes following in vitro fertilization (IVF). As a result, the assessment of BCL-6 expression may help stratify patients who would benefit from surgical management or pre-treatment with GnRH analogs prior to ART, thereby supporting a more individualized therapeutic approach [10]. Endometriosis during adolescence is responsible for 10–15% of cases and is generally characterized by cyclic pelvic pain. The initial management is empirical, with CHC or progestins, and surgery is proposed via laparoscopy in cases of failure, with a recurrence rate of 30–50%. The management of DIE requires highly specialized care, with increased efficacy of pain relief up to 70–80% through surgical excision and a risk of postoperative complications. Extrapelvic EM (5–12% occurrence) also requires a multidisciplinary approach [9, 11, 15, 16]. 9. Future perspectives Noninvasive diagnosis is being advanced using multi-omic biomarkers such as Interleukin-17F (IL-17F) / Platelet-Derived Growth Factor-AA (PDGF-AA) with an area under curve (AUC) of 0.84 for early disease diagnosis, Artificial Intelligence (AI)-multispectral laparoscopy (AUC > 0.90 for DIE), and polygenic risk scores. Molecular phenotyping using approaches such as, single-cell RNA-sequencing and spatial transcriptomics is elucidating the cellular composition of endometriotic lesions. Profiling the vaginal microbiome identifies a specific community at increased risk of developing EM, highlighting the possibility of using microbiota-based screening tools [8, 9, 11]. As emerging treatments, we can consider next-generation GnRH antagonists, immunomodulators (anti-IL-6/8), stem cell scaffolds for fibrosis regression, and lesion-targeted androgens. Improved pathogenesis insights (niche remodeling) will allow a broader range of nonhormonal options. AI-based patient stratification may be an option to address unmet needs, such as, adolescents with cancer or patients with relapse [13–16]. 10. Future Perspectives: Estrogen receptors and genetics The future role of estrogen receptors, genetics, and nutrigenetics in the diagnostics and treatment of the disease is experimental but promising, in order to obtain a more precise and individualized management of the disease [5, 6, 17]. 11. Diagnostic applications Estrogen Receptor alpha (ERα) / Estrogen Receptor beta (ERβ) expression profiling in the eutopic endometrium or in plasma by quantitative Polymerase Chain Reaction (qPCR) / Enzyme-Linked Immunosorbent Assay (ELISA) has been proposed as a new biomarker. ERβ overexpression is associated with Polyendocrine Metabolic Ovarian Syndrome (PMOS) (sensitivity ~ 80% according to a meta-analysis). Aromatase (an ER-linked enzyme) showed the highest diagnostic odds (OR > 10) among the hormonal markers. Polygenic risk scores (PRS) based on Single-Nucleotide Polymorphisms (SNPs) from 14 to 45 Genome-Wide Association Studies (GWAS) have been used to predict the risk of PMOS (AUC 0.65–0.75) and to stratify women with symptoms before undergoing further evaluations with imaging or laparoscopy, thereby potentially shortening the diagnostic period by half [5, 6, 12]. DNA tests for nutrigenetics (e.g., Estrogen Receptor 1 gene (ESR1) / Cytochrome P450 Family 19 Subfamily A Member 1 gene / aromatase gene (CYP19A1) variants) will determine the variants in the genes that are associated with the individual response to specific foods in your diet. The information obtained can be combined with the miR-200 and cfDNA multiomics tests to obtain a personal, individualized genetic risk score. It is to note that the DNA tests are considered research tools at the present time and will not be ready for widespread use as a clinical diagnostic test until the research studies are published [13–15]. 12. Therapeutic applications 12.1 Selective Estrogen Receptor Modulator (SERM) Selective Estrogen Receptor Modulators (SERMs) (raloxifene, SR-16,234) have the ability to selectively antagonize ERα in fibrotic lesions and can reduce pain by 40–60% in Randomized Controlled Trials (RCTs) postsurgery, with fewer systemic side effects, such as hypoestrogenism in comparison to GnRH analogs. Personalizing hormone therapy using a PRS-guided approach that accounts for individual genotypic risk, such as utilizing progestins in low Wnt Family Member 4 gene (WNT4) risk patients and timing of surgery, is recommended [17, 18]. 12.2 Adjuncts (nutrigenetics) – Omega-3 (fish oil) When an omega-3-rich diet was combined with supplementation, it was associated with a 30% reduction in inflammation in carriers of the variant (OR 0.7). A plant-based treatment (diet and/or supplements) resulted in regression of EM in the gut- EM axis in sensitive phenotypes. Ongoing work is investigating whether Fatty Acid Desaturase 1 gene (FADS1)-related metabolic phenotypes can be used, together with AI-based models, to stratify patients and enrich future clinical trials, including phase II trials of SERMs. Models are currently used for risk assessment and trial enrichment [17–19]. 12.3 Metabolomics in diagnostics and therapy Metabolomics provides comprehensive low-molecular-weight plasma, peritoneal fluid, urine, and endometrium (lipids and amino acids) metabolite information, including various aspects of EM -associated biochemistry, such as, inflammation, oxidative stress, and high energy demand, and has been shown to classify cases versus controls accurately (AUC 0.86–0.98) during the luteal phase. Furthermore, the multiomics approach (metabolomics and proteomics) demonstrated greater than 90% sensitivity and specificity compared to individual assays. It could also be used as a potential tool to identify the minimal and severe forms of EM and to monitor the effectiveness of treatment, given that the metabolome/proteome significantly changes following hormonal fluctuations [8, 9, 11]. Metabolomics is currently being investigated as a therapeutic tool to discover new drug targets, such as lipid peroxidation inhibitors and energy metabolism regulators, for the development of personalized or precision nutrition and drugs to be tested in human clinical trials [17–19]. 12.4 Exosomal markers in diagnostics and therapy Exosomal miRNAs, proteins, and lncRNAs that are stably present in serum/mucus have been identified, and thus their utility as potential biomarkers can be further evaluated. The results show that the expression levels of certain cargoes (up-regulated miR-22-3p and miR-320a, as WNK2 and CD44 proteins) are significantly altered in EM (AUC 0.82–0.86 for all combinations) and are not stage or cycle-phase-dependent. Therefore, saliva/vaginal exosomal miRNAs provide an easier, noninvasive method for sample collection. In comparison, the integrated serum proteomics/miRNAs have an AUC > 0.8 [14, 15]. Some lab-made exosomes are used in therapy. The exosomes carried either an antiinflammatory miRNA mimic or a drug, which was taken up by the plaque and inhibited atherosclerotic plaque growth in a mouse model [16]. 13. Clinical translation Data obtained by analyzing exosomes and integrated metabolomics using TVS/MRI can potentially achieve a noninvasive accuracy of 80–95% within a few weeks rather than months. Phase II validation is currently underway and is being investigated in a series of clinical trials that started in 2025 and will run through 2026. The only limitations of this technology are the standardization between platforms and the fact that the studies were based on a small number of patients. 14. Conclusion A new era in the management of EM started with the ESHRE/ACOG recommendations concerning clinical/imaging presumptive diagnosis and the use of hormones as a first line therapy and for surgical intervention in selected cases. Nevertheless, old symptoms concerning chronic EM, such as, long-standing medical delay, disease recurrence, and the fertility gap, are still seen in clinical practice. This reflects the multi-factorial nature of chronic EM. Despite recent progress in the field, the heterogeneity of the disease and the lack of validated biomarkers that would enable an exact diagnosis of EM and allow personalization of the optimal treatment modality for each patient can be improved by the use of multimodal noninvasive imaging approaches. Sustained research investment promises superior outcomes [1–3]. Key take-home messages Endometriosis should be considered in a patient with cyclic pelvic pain and/or infertility. Imaging/hormonals should be done before laparoscopy is even contemplated. Prioritize shared decision-making: CHC/progestins as the first-line; surgery for refractory/DIE/fertility. Counsel on recurrence (40–50%); post-op hormones reduce risk. ART trumps pre-ART surgery in advanced disease; monitor ovarian reserve. Future: biomarkers/AI for noninvasive, personalized care.

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