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Cited by 243Endometriosis Research and TreatmentEctopic Pregnancy Diagnosis and ManagementGynecological conditions and treatments

Biomarkers in endometriosis: Challenges and opportunities

Open access
Ahn, Soo Hyun, Singh, Vinay, Tayade, Chandrakant·2017·Fertility and Sterility
DOI 10.1016/j.fertnstert.2017.01.009
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Abstract

Endometriosis is a debilitating gynecologic disease affecting millions of women across the world, with symptoms including dysmenorrhea, chronic pelvic pain, and infertility. Theorized to stem from the phenomenon of retrograde menstruation, the diagnosis of endometriosis is typically delayed by 8-10 years owing to misinterpretation of symptoms as common menstrual cramps in adolescent girls and young women. With increased incidence of endometriosis in young girls correlated with earlier menarche, the development of diagnostic biomarkers is imperative for diagnosing and treating women afflicted with endometriosis as early as we can. In the past few years, multiple reviews highlighted the list of potential diagnostic candidates in peritoneal fluid, blood, urine, and endometrial biopsies from endometriosis patients in different stages of disease and menstrual cycle. In this review, we explore the opportunities and challenges facing the field of diagnostic biomarkers for endometriosis. We highlight the importance of eutopic endometrium as a source of potential diagnostic biomarkers by looking at the expression levels of noncoding RNA in tissue as well as in blood. Finally, we discuss some of the challenges that hinder our efforts in validating candidate diagnostic biomarkers for endometriosis.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that noninvasive diagnostic biomarkers for endometriosis are urgently needed because diagnosis is typically delayed by 8–10 years, but disease heterogeneity, comorbidities, and nonstandardized sample collection hinder validation. It highlights eutopic endometrium and circulating/tissue noncoding RNAs as promising candidates, while cautioning that inflammatory cytokines and endometrial DNA methylome have not proven sufficiently specific.

Key findings

  • Diagnostic delay is substantial: adolescent girls delay seeking medical attention by 4.6 years, and it takes another 4.7 years until diagnosis; overall diagnosis is typically delayed by 8–10 years.
  • Endometriosis symptoms are more common than in women without endometriosis: nonmenstrual pelvic pain 38.7% vs. 14.3%, dyspareunia 29.5% vs. 13.4%, and infertility 11.6% vs. 3.4%; economic burden is $1.8 billion in Canada and $18–22 billion in the United States.
  • Candidate noncoding RNA biomarkers show diagnostic potential: plasma brain-derived neurotropic factor for stage I–II disease had 91.7% sensitivity and 69.4% specificity; circulating let-7b had 83.3% sensitivity and 100% specificity; miR-17-5p, miR-20a, and miR-22 discriminated severe endometriosis with an AUC of 0.90; a five-lncRNA combination had 89.7% sensitivity and 73.2% specificity.
  • Cytokine panels have been tested but are limited: one six-marker panel showed 60%–71% specificity and 87%–92% sensitivity, and a 28-biomarker panel showed 63%–81% specificity and 81%–90% sensitivity, but control selection and nonendometriotic pelvic inflammation can confound results.

Methods

  • Design: narrative review of diagnostic biomarkers for endometriosis, focused on opportunities and challenges in validation.
  • Data/sample: literature on candidate biomarkers from peritoneal fluid, blood, urine, endometrial biopsies, eutopic endometrium, and epigenetic markers, including miRNA and lncRNA; no primary cohort or new experimental data are reported.
  • Main analysis: synthesizes prior reviews, meta-analyses, and selected studies to evaluate biomarker specificity/sensitivity and discuss barriers to clinical validation; evident from the text that this is not a systematic review or meta-analysis.

Limitations

  • The paper states that endometriosis is heterogeneous in phenotype and symptoms, with endopelvic and extrapelvic manifestations, and that comorbidities such as autoimmune disorders, migraines, gastrointestinal problems, and adenomyosis can mask or confound biomarker signals.
  • The paper states that biomarker studies are limited by unstandardized sample collection, storage, and phenotyping; small sample sizes; lack of representation across all disease stages and menstrual stages; and discrepancies between tissue and blood miRNA expression.
  • Evident from the text: as a narrative review, it does not provide a systematic search strategy, quantitative synthesis, or primary validation data, so its conclusions depend on selected published literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.fertnstert.2017.01.009

Cites

121 of 121 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 73 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    For decades, basic and clinical research have lumped different phenotypes of endometriosis (ovarian, peritoneal, deep infiltrating) as one entity.

    “For decades, both basic and clinical research have been much focused on elucidating the pathogenesis of endometriosis, but they have lumped different phenotypes of the disease, including ovarian, peritoneal, and deep infiltrating endometriosis, as one entity.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The endometrium of endometriosis patients displays aberrant molecular expression patterns that give it the ability to implant, invade, and develop into endometriotic foci.

    “which have demonstrated that the endometrium of endometriosis patients displays aberrant molecular expression patterns that give it the ability to implant, invade, and develop into endometriotic foci (27)(28)(29)(30).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Burney, 2007, Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis, Endocrinology source

      Not checked in the free run.

    • cites [28] Bulun, 2006, Progesterone resistance in endometriosis: link to failure to metabolize estradiol, Mol Cell Endocrinol source

      Not checked in the free run.

    • cites [29] Mehasseb, 2011, Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis, Fertil Steril source

      Not checked in the free run.

  • Premisecitation

    Naqvi et al. observed five hypermethylated (MGMT, DUSP22, CDCA2, ID2, RBBP7) and five hypomethylated (TNFRSF1B, MBPR1B, ZNF681, IGSF21, TP73) genes in eutopic endometrium of endometriosis patients compared with endometriosis-free controls.

    “For example, Naqvi et al. (26) observed five hypermethylated (MGMT, DUSP22, CDCA2, ID2, and RBBP7) and five hypomethylated (TNFRSF1B, MBPR1B, ZNF681, IGSF21, and TP73) genes in eutopic endometrium of patients compared with endometriosis-free control subjects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Naqvi, 2014, Altered genome-wide methylation in endometriosis, Reprod Sci source

      Not checked in the free run.

  • Interpretationreasoning

    Heterogeneity of disease phenotype increases the potential of false-negative laparoscopic surgery in symptomatic women, such that a clean pelvic cavity does not necessarily indicate absence of endometriosis elsewhere.

    “Such heterogeneity of disease phenotype also increases the potential of false-negative laparoscopic surgery in symptomatic women, wherein a ''clean'' pelvic cavity might not necessarily indicate the absence of endometriosis in other areas of the body (Table 1).”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Accurate differential diagnosis of endometriosis based on symptoms alone is difficult without explorative laparoscopic surgery.

    “Unless accompanied by explorative laparoscopic surgery for complete diagnosis, accurate differential diagnosis in potential endometriosis patients based on symptoms proves to be a difficult challenge.”
    Quote in the paperSubstantial claim
  • May combine two claims. 8
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    Diagnosis of endometriosis is typically delayed by 8-10 years, with adolescent girls delaying seeking medical attention by 4.6 years and a further 4.7 years until diagnosis.

    “Owing to the common misinterpretation of endometriosis-induced pain as menstrualrelated abdominal pain, the diagnosis of endometriosis is typically delayed by 8-10 years: Adolescent girls who suffer from the symptoms of endome-triosis delay seeking medical attention by 4.6 years, and by the time they seek medical attention, it takes another 4.7 years until diagnosis (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Greene, 2009, Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis, Fertil Steril source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased concentration of glutamine and glutamate within the anterior insula and greater neuronal connectivity from the anterior insula to the medial prefrontal cortex positively correlate with pain intensity, clinical anxiety, and depression in endometriosis patients.

    “Furthermore, As-Sanie et al. demonstrated that increased concentration of glutamine and glutamate within the anterior insula and greater neuronal connectivity from the anterior insula to the medial prefrontal cortex positively correlated with not only pain intensity, but also clinical anxiety and depression in patients (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] As-Sanie, 2016, Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain, J Pain source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Endometriosis is a complex disease with variable phenotypic and symptomatic presentation in women.

    “Endometriosis is a complex disease with variable phenotypic and symptomatic presentation in women (14,15).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Vercellini, 2007, Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients, Hum Reprod source

      Not checked in the free run.

    • cites [15] Acién, 2013, Endometriosis: a disease that remains enigmatic, Int Sch Res Not Obstet Gynecol

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Basic scientific research on the pathogenesis of extrapelvic endometriosis is limited.

    “Furthermore, basic scientific research on the pathogenesis of extrapelvic endometriosis is limited.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Endometrial biopsy by pipelle or curette is minimally invasive and can be useful to test endometrial receptivity in infertile women and as a diagnostic tool for endometriosis in an outpatient setting.

    “The method of obtaining endometrial sample by either pipelle or curette is minimally invasive; however, aside from minimal discomfort for the patient, biopsy can prove to be a useful not only to test endometrial receptivity in infertile women with or without endometriosis (81), but also as a diagnostic tool for endometriosis in an outpatient setting (82).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Garcia-Velasco, 2015, Is endometrial receptivity transcriptomics affected in women with endometriosis? A pilot study, Reprod Biomed Online source

      Not checked in the free run.

    • cites [82] Saare, 2016, The influence of menstrual cycle and endometriosis on endometrial methylome, Clin Epigenetics source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because endometriosis can be found in asymptomatic women, the biochemical pathway of nerve stimulation by menstrual debris does not apply to asymptomatic women, suggesting inflammation from menstruating ectopic foci and menstrual debris may not be the sole cause of pelvic pain.

    “Because endometriosis can be found in asymptomatic women, however, the biochemical pathway of nerve stimulation by the release of damage-associated molecular patterns and pathogen-associated molecular patterns by the menstrual debris (58) does not apply to the asymptomatic women, suggesting that the inflammation caused by ''menstruating'' ectopic foci and menstrual debris may not be the sole cause”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Laux-Biehlmann, 2015, Menstruation pulls the trigger for inflammation and pain in endometriosis, Trends Pharmacol Sci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The strengths of GWAS studies are affected by unstandardized methods of biologic sample collection, storage, and phenotyping across studies, which may lead to heterogeneous interpretations and findings.

    “Even though GWASs have identified numerous SNPs associated with endometriosis risk across multiple populations, the strengths of the studies are affected by unstandardized methods of biologic sample collection, storage, and phenotyping of samples across studies, which may invariably lead to heterogeneous interpretations and findings (24).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Rahmioglu, 2014, Genetic variants underlying risk of endometriosis: Insights from meta-analysis of eight genome-wide association and replication datasets, Hum Reprod Update source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A panel of cytokines, rather than a single biomarker, improves sensitivity and specificity values, with some panels showing the ability to discriminate between different stages of disease.

    “The studies showed that a panel of cytokines, rather than a single biomarker, improve sensitivity and specificity values, with some panels showing the ability to discriminate between different stages of disease.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Fassbender, 2015, Update on biomarkers for the detection of endometriosis, Biomed Res Int source

      Not checked in the free run.

    • cites [69] May, 2010, Peripheral biomarkers of endometriosis: a systematic review, Hum Reprod Update source

      Not checked in the free run.

    • Rests on an assumption: The physiologic process of menstruation is an inflammatory event.

  • May combine two claims.

    Study design and conductcitation

    A limiting factor hindering the exploration of miRNA as biomarkers in clinical trials is the small sample sizes of patients and lack of representation of all stages of endometriosis, stratified by menstrual stage.

    “However, one limiting factor hindering the exploration of miRNA as biomarkers in clinical trials is the small sample sizes of patients and lack of representation of all stages of endometriosis, which are also stratified by menstrual stage (85, 109, 110).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [85] Burney, 2009, MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis, Mol Hum Reprod source

      Not checked in the free run.

    • cites [109] Cho, 2015, Circulating microRNAs as potential biomarkers for endometriosis, Fertil Steril source

      Not checked in the free run.

    • cites [110] Jia, 2013, Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis, Hum Reprod source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    miRNA profiling of eutopic endometrium in endometriosis patients would provide pathophysiologic molecular fingerprints for understanding disease pathogenesis and as potential noninvasive biomarkers.

    “Therefore, miRNA profiling of eutopic endometrium in endometriosis patients would provide pathophysiologic molecular fingerprints that we can use to further understand disease pathogenesis and as potential noninvasive biomarkers for endometriosis.”
    Quote in the paperSubstantial claim
10 of 10

  • The paper relies on this without support.

    Laparoscopic surgery remains the current criterion-standard diagnostic tool for endometriosis.

    “Laparoscopic surgery remains the current criterion-standard diagnostic tool; however, it is unlikely that women of reproductive age would subject themselves to such an invasive surgery when they can opt to temporarily diminish pain symptoms by means of other therapeutic mechanisms.”

  • The paper relies on this without support.

    Women of reproductive age would be unlikely to subject themselves to laparoscopic surgery when they can opt to temporarily diminish pain symptoms by other therapeutic mechanisms.

    “Laparoscopic surgery remains the current criterion-standard diagnostic tool; however, it is unlikely that women of reproductive age would subject themselves to such an invasive surgery when they can opt to temporarily diminish pain symptoms by means of other therapeutic mechanisms.”

  • The paper relies on this without support.

    Only 10% of women develop endometriosis.

    “This is critical to elucidate why only 10% of women develop endometriosis although the phenomenon of retrograde menstruation occurs in 76%-90% of reproductive-age women (94)(95)(96).”

  • The paper relies on this without support.

    The physiologic process of menstruation is an inflammatory event.

    “The physiologic process of menstruation is an inflammatory event, as is the pathophysiologic process of endometriosis.”

  • The paper relies on this without support.

    There is a need for a diagnostic biomarker for endometriosis.

    “Along with the need to better understand the pathophysiology of endometriosis, the need for a diagnostic biomarker for endometriosis has been equally recognized.”
5 of 5

Claims other papers make about this one

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Peritoneal endometriosis classified as both pelvic and extrapelvic

    Minor

    The paper first places peritoneal implants in the pelvis, then lists typical peritoneal endometriosis among extrapelvic manifestations.

1 of 1

Cites

Flagged first, then by citations

11 of the 132 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Liu, 2015, Urinary biomarkers for the noninvasive diagnosis of endometriosis, Cochrane Database Syst Rev, CD012019
  2. Nisenblat, 2016, Imaging modalities for the noninvasive diagnosis of endometriosis, Cochrane Database Syst Rev, CD009591
  3. Nisenblat, 2016, Combination of the noninvasive tests for the diagnosis of endometriosis, Cochrane Database Syst Rev, CD012281

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Related

Authors
Ahn, S. H., Singh, V., & Tayade, C.
Affiliations
Queen's University (CA)
Corresponding author
Tayade, Chandrakant
ORCID
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2017-03
Volume
107
Issue
3
Pages
523-532
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/j.fertnstert.2017.01.009
OpenAlex
W2586274172
Cited by
242
References
132
Citations by year
2026: 20 · 2025: 32 · 2024: 35 · 2023: 21 · 2022: 18 · 2021: 29 · 2020: 33 · 2019: 27 · 2018: 23 · 2017: 3 · 2016: 1
FWCI
3.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research (394924)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gynecological conditions and treatments
Keywords
endometriosis, diagnostic biomarkers, eutopic endometrium, non-coding RNA, peritoneal fluid, blood biomarkers, urinary biomarkers, endometrial biopsy, biomarker validation, delayed diagnosis, retrograde menstruation, infertility, dysmenorrhea, chronic pelvic pain
MeSH terms
Biopsy, Endometriosis, Endometrium, Female, Genetic Markers, Humans, Menstrual Cycle, Predictive Value of Tests, Prognosis, Reproducibility of Results, Biomarkers, Comorbidity, Cytokines, Inflammation Mediators, MicroRNAs, RNA, Long Noncoding

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