Unlocking the Diagnostic Potential: Noninvasive Biomarkers in Adolescent Endometriosis

Endometriosis is a chronic gynecological disorder characterized by endometrial-like tissue outside the uterine cavity. It is increasingly recognized in adult women and adolescents and often presents early in the reproductive years.[] The prevalence in this group is difficult to quantify precisely due to diagnostic challenges. Yet, estimates suggest that a significant proportion of adolescents with persistent pelvic pain or severe dysmenorrhea may have underlying endometriosis.[] The burden of the disease during adolescence extends beyond physical symptoms; it profoundly impacts daily functioning, academic performance, social engagement, and overall quality of life. Early onset of endometriosis can also influence future reproductive health, with risks of subfertility and chronic pelvic pain extending into adulthood.[] One of the greatest challenges in adolescent endometriosis is diagnostic delay. Symptoms are often dismissed as typical menstrual complaints, leading to years of untreated disease progression.[] This delay not only prolongs suffering but can also increase the risk of disease advancement, negatively affecting long-term outcomes such as fertility preservation and psychological well-being. Adolescents frequently endure repeated healthcare encounters before receiving a definitive diagnosis, contributing to frustration and a diminished trust in the healthcare system.[] The current gold standard for diagnosing endometriosis is laparoscopy, which allows direct visualization and histological confirmation of lesions. However, the invasiveness of this approach poses considerable limitations in adolescents.[] Concerns over surgical risks, the requirement for anesthesia, potential postoperative complications, and hesitancy to recommend invasive procedures in younger patients all contribute to underutilization of diagnostic laparoscopy in this group.[] These barriers underscore the pressing need for alternative strategies that are accurate, safe, and acceptable for adolescent populations.[] In recent years, there has been growing interest in developing and applying noninvasive biomarkers to diagnose endometriosis.[] Advances in molecular biology, immunology, and high-throughput technologies have expanded the pool of candidate biomarkers that may be detected in easily accessible biological fluids such as blood, urine, saliva, and menstrual effluent.[] Such biomarkers hold promise in reducing diagnostic delays, offering earlier detection, and facilitating disease monitoring without the risks associated with surgical procedures.[] Throughout this review, evidence derived from adolescent-specific cohorts is distinguished from findings extrapolated from adult populations, recognizing important biological, hormonal, and clinical differences between these groups. METHODOLOGY FOR LITERATURE SELECTION A narrative literature review was conducted to evaluate noninvasive biomarkers and imaging approaches relevant to the diagnosis of endometriosis in adolescents. Electronic searches were performed using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. The search included articles published between January 2000 and March 2025. Search terms included combinations of “endometriosis,” “adolescents,” “teenagers,” “young women,” “biomarkers,” “non-invasive diagnosis,” “ultrasound,” and “magnetic resonance imaging.” Original research articles, systematic reviews, and narrative reviews focusing on diagnostic biomarkers or imaging modalities in endometriosis were included. Studies that specifically enrolled adolescents or reported age-stratified data were prioritized. When adolescent-specific evidence was limited, relevant adult studies were included to provide biological and mechanistic context, with this extrapolation explicitly acknowledged. Case reports, animal studies, editorials, non-English publications, and studies without clear diagnostic confirmation of endometriosis were excluded. PATHOPHYSIOLOGY OF ENDOMETRIOSIS IN ADOLESCENTS Endometriosis in adolescents arises from a complex interplay of hormonal, inflammatory, genetic, and epigenetic mechanisms.[] The condition is strongly estrogen-dependent, with increased estrogen activity driving the proliferation of ectopic endometrial tissue, while progesterone resistance diminishes the normal inhibitory effect on growth.[] These hormonal influences are accompanied by a heightened inflammatory response, marked by macrophage activation, immune dysregulation, and the release of cytokines and prostaglandins, which sustain lesion survival and contribute to severe dysmenorrhea – often the earliest clinical symptom in adolescents.[] Genetic predisposition further plays a pivotal role, as suggested by familial clustering. At the same time, epigenetic modifications such as deoxyribonucleic acid methylation, histone changes, and dysregulated noncoding ribonucleic acids alter angiogenesis, immunity, and cell survival pathways.[] Together, these mechanisms create an environment that favors lesion establishment and persistence even at an early stage of disease.[] Distinct biological and clinical features separate adolescent endometriosis from adult-onset forms. In younger patients, lesions are frequently subtle, appearing as red or clear vesicles rather than older women’s typical black or blue lesions, making recognition at laparoscopy more difficult.[] Despite often having more superficial disease, adolescents may report severe pelvic pain, illustrating the complex relationship between lesion burden and symptom intensity. In addition, the interplay between the hormonal changes of puberty and a still-maturing immune system may create a unique disease environment not seen in adults.[] These differences highlight the importance of studying adolescent populations independently and underscore the potential for identifying age-specific, noninvasive biomarkers that can aid in timely diagnosis and management.[] DIAGNOSTIC CHALLENGES IN ADOLESCENTS Diagnosing endometriosis in adolescents is particularly complex because the clinical presentation is often nonspecific.[] Symptoms such as dysmenorrhea, chronic pelvic pain, and irregular menstrual cycles are frequently attributed to normal pubertal changes, primary dysmenorrhea, or psychosomatic complaints, leading to under-recognition of the disease.[] The intensity of pain may be dismissed as a common part of adolescence, and repeated use of analgesics or hormonal therapies without thorough evaluation can mask symptoms while delaying appropriate diagnosis.[] Furthermore, the variability in how adolescents describe or tolerate pain adds to the difficulty, as their experiences are often underestimated by healthcare providers, further contributing to diagnostic delays.[] The diagnostic process is further complicated by the overlap of symptoms with other adolescent gynecological or gastrointestinal conditions, such as polycystic ovary syndrome, pelvic inflammatory disease, irritable bowel syndrome, and urinary tract disorders.[] These similarities can mislead clinicians and result in inappropriate or fragmented care. Even when endometriosis is suspected, the gold standard of laparoscopy presents barriers in young patients due to concerns about surgical risks, anesthesia, and the invasiveness of the procedure at an early age.[] Parents and physicians may hesitate to pursue surgery, preferring conservative management despite the potential progression of the disease.[] These challenges underscore the need for reliable, noninvasive diagnostic tools that can provide early detection without subjecting adolescents to invasive procedures.[] BIOMARKER CATEGORIES FOR NONINVASIVE DIAGNOSIS Exploring noninvasive biomarkers for adolescent endometriosis is an evolving field that seeks to identify reliable, accessible, and cost-effective diagnostic tools.[] Biomarkers derived from blood, urine, saliva, and menstrual effluent offer the potential to overcome the limitations of invasive diagnostic methods and reduce the long delays commonly associated with this condition. Below is a detailed discussion of the major categories of biomarkers currently under investigation.[] Although numerous candidate biomarkers have been proposed, most available studies are exploratory in nature and limited by small sample sizes, heterogeneous study designs, and a lack of standardized assay methods. Few biomarkers have undergone external validation in independent adolescent cohorts, and reported diagnostic performance varies widely across studies. As a result, no single biomarker currently demonstrates sufficient robustness to serve as a standalone diagnostic test in adolescents. Noninvasive biomarker categories in adolescent endometriosis are shown in Table 1. IMAGING AS A NONINVASIVE ADJUNCT Imaging techniques remain a critical noninvasive tool in the evaluation of endometriosis, particularly in adolescents, where surgical diagnosis may be delayed or avoided.[] Ultrasound is often the first-line modality due to its safety, availability, and cost-effectiveness. In younger patients, transabdominal ultrasound is commonly used and can accurately detect ovarian endometriomas, though its sensitivity for subtle peritoneal or deep infiltrating lesions is limited.[] On the other hand, magnetic resonance imaging (MRI) provides superior visualization of pelvic anatomy and can identify deeply infiltrating lesions, rectovaginal nodules, and extrapelvic involvement. Its noninvasive nature and absence of ionizing radiation make MRI especially suitable for adolescents, though higher costs and the need for specialized expertise restrict its widespread use.[] There is growing interest in integrating imaging with biochemical biomarkers to enhance diagnostic precision. While biomarkers reflect systemic disease activity, imaging provides structural and anatomical localization, offering complementary insights.[] This combined approach has the potential to shorten diagnostic delays, improve disease staging, and support tailored treatment strategies.[] By minimizing reliance on laparoscopy, such multimodal strategies may provide adolescents a more comprehensive and acceptable diagnostic framework, ensuring earlier recognition and management of endometriosis.[] In adolescents, the complementary use of imaging and biomarkers is particularly valuable because early-stage disease often presents with subtle or atypical lesions and nonspecific symptoms. While biomarkers may reflect systemic inflammation or disease activity, imaging provides anatomical localization and exclusion of alternative pelvic pathology. This combined, noninvasive approach can improve diagnostic confidence while minimizing reliance on laparoscopy in young patients. CLINICAL UTILITY AND LIMITATIONS The clinical application of noninvasive biomarkers and imaging in adolescent endometriosis is shaped by their diagnostic accuracy, practicality, and acceptability.[] While individual biomarkers such as CA-125 or inflammatory cytokines often demonstrate modest sensitivity and specificity, combining multiple biomarkers or integrating them with imaging findings can enhance predictive value.[] This approach is especially relevant for adolescents, where early-stage disease and subtle lesion characteristics make diagnosis challenging.[] Despite promising results in pilot studies, most biomarkers require further validation in large, adolescent-specific cohorts before they can be incorporated into routine clinical practice.[] Another limitation lies in the variability across populations and disease stages. Differences in genetics, hormonal environment, and immune responses may influence biomarker levels, leading to inconsistent performance across diverse groups. In addition, the heterogeneity of endometriosis presentation – from minimal disease to deeply infiltrating lesions – affects diagnostic accuracy.[] Beyond scientific and technical barriers, ethical considerations must also be acknowledged in adolescents, particularly regarding repeated testing, the use of invasive confirmatory procedures, and disclosure of results with potential reproductive implications.[] These challenges highlight the need for standardized protocols, age-appropriate ethical frameworks, and carefully designed validation studies to ensure emerging diagnostic tools are effective and equitable for young patients.[] It is important to note that many promising biomarkers have been identified primarily in adult populations, and their applicability to adolescents remains uncertain due to differences in disease phenotype, hormonal milieu, and immune response. Future directions The future of noninvasive diagnostics for adolescent endometriosis lies in advancing beyond single-marker studies toward multi-omics approaches. Integrating proteomic, genomic, transcriptomic, and metabolomic data can generate comprehensive molecular signatures that reflect the complexity of the disease.[] Such integrative profiling can uncover novel biomarker combinations, improve sensitivity and specificity, and account for the heterogeneity observed across individuals and disease stages.[] In addition, these approaches may shed light on the biological pathways driving early-onset disease, helping to distinguish adolescent endometriosis from adult presentations and guiding tailored interventions.[] Alongside multi-omics, artificial intelligence (AI)–based algorithms offer exciting opportunities for combining biomarker data with imaging results. Machine learning models can detect subtle patterns invisible to traditional analysis, enhancing predictive accuracy and supporting individualized risk stratification.[] To achieve clinical translation, however, longitudinal adolescent cohorts must be established to validate candidate biomarkers over time, ensuring their reliability and reproducibility.[] The ultimate challenge will be bridging the gap between research and practice, developing standardized assays, and integrating these tools into routine clinical care.[] If achieved, such strategies hold the promise of earlier diagnosis, reduced reliance on invasive procedures, and improved quality of life for adolescents living with endometriosis.[] The overall level of evidence supporting noninvasive biomarkers in adolescent endometriosis remains low to moderate. Most studies are cross-sectional, involve limited participant numbers, and lack longitudinal follow-up. Additional challenges include population heterogeneity, variability in disease staging, and absence of universally accepted diagnostic thresholds. These limitations highlight the need for large, well-designed, adolescent-specific validation studies before clinical implementation.

Noninvasive biomarkers and imaging approaches are promising tools to overcome the longstanding challenges of diagnosing adolescent endometriosis. While individual markers and imaging modalities show limitations when used in isolation, their integration within multi-marker panels, multi-omics platforms, and AI-driven algorithms offers the potential for earlier, safer, and more accurate diagnosis. With further validation in adolescent-specific cohorts and careful attention to ethical considerations, these strategies could transform diagnostic pathways, reduce reliance on laparoscopy, and ultimately improve young patients’ outcomes and quality of life. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

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