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Endometrial biomarkers for the non-invasive diagnosis of endometriosis

  • Review
  • Diagnostic

Authors

  • Devashana Gupta,

    1. Auckland District Health Board, Auckland, New Zealand
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  • M Louise Hull,

    1. The University of Adelaide, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, Adelaide, South Austraila, Australia
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  • Ian Fraser,

    1. University of New South Wales, School of Women's and Children's Health, Royal Hospital for Women, Sydney, NSW, Australia
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  • Laura Miller,

    1. Fertility Plus, Department of Obstetrics and Gynaecology, Auckland, New Zealand
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  • Patrick MM Bossuyt,

    1. Academic Medical Center, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam, Netherlands
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  • Neil Johnson,

    1. The University of Adelaide, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, Adelaide, South Austraila, Australia
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  • Vicki Nisenblat

    Corresponding author
    1. The University of Adelaide, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, Adelaide, South Austraila, Australia
    • Vicki Nisenblat, Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, King William Road, Adelaide, South Austraila, Australia. vnisenblat@gmail.com.

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Abstract

Background

About 10% of reproductive-aged women suffer from endometriosis, which is a costly, chronic disease that causes pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but it is expensive and carries surgical risks. Currently, there are no non-invasive tests available in clinical practice that accurately diagnose endometriosis. This is the first diagnostic test accuracy review of endometrial biomarkers for endometriosis that utilises Cochrane methodologies, providing an update on the rapidly expanding literature in this field.

Objectives

To determine the diagnostic accuracy of the endometrial biomarkers for pelvic endometriosis, using a surgical diagnosis as the reference standard. We evaluated the tests as replacement tests for diagnostic surgery and as triage tests to inform decisions to undertake surgery for endometriosis.

Search methods

We did not restrict the searches to particular study designs, language or publication dates. To identify trials, we searched the following databases: CENTRAL (2015, July), MEDLINE (inception to May 2015), EMBASE (inception to May 2015), CINAHL (inception to April 2015), PsycINFO (inception to April 2015), Web of Science (inception to April 2015), LILACS (inception to April 2015), OAIster (inception to April 2015), TRIP (inception to April 2015) and ClinicalTrials.gov (inception to April 2015). We searched DARE and PubMed databases up to April 2015 to identify reviews and guidelines as sources of references to potentially relevant studies. We also performed searches for papers recently published and not yet indexed in the major databases. The search strategies incorporated words in the title, abstract, text words across the record and the medical subject headings (MeSH).

Selection criteria

We considered published peer-reviewed, randomised controlled or cross-sectional studies of any size that included prospectively collected samples from any population of reproductive-aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE).

Data collection and analysis

Two authors independently extracted data from each study and performed a quality assessment. For each endometrial diagnostic test, we classified the data as positive or negative for the surgical detection of endometriosis and calculated the estimates of sensitivity and specificity. We considered two or more tests evaluated in the same cohort as separate data sets. We used the bivariate model to obtain pooled estimates of sensitivity and specificity whenever sufficient data were available. The predetermined criteria for a clinically useful test to replace diagnostic surgery was one with a sensitivity of 94% and a specificity of 79%. The criteria for triage tests were set at sensitivity at or above 95% and specificity at or above 50%, which in case of negative results rules out the diagnosis (SnOUT test) or sensitivity at or above 50% with specificity at or above 95%, which in case of positive result rules in the diagnosis (SpIN test).

Main results

We included 54 studies involving 2729 participants, most of which were of poor methodological quality. The studies evaluated endometrial biomarkers either in specific phases of the menstrual cycle or outside of it, and the studies tested the biomarkers either in menstrual fluid, in whole endometrial tissue or in separate endometrial components. Twenty-seven studies evaluated the diagnostic performance of 22 endometrial biomarkers for endometriosis. These were angiogenesis and growth factors (PROK-1), cell-adhesion molecules (integrins α3β1, α4β1, β1 and α6), DNA-repair molecules (hTERT), endometrial and mitochondrial proteome, hormonal markers (CYP19, 17βHSD2, ER-α, ER-β), inflammatory markers (IL-1R2), myogenic markers (caldesmon, CALD-1), neural markers (PGP 9.5, VIP, CGRP, SP, NPY, NF) and tumour markers (CA-125). Most of these biomarkers were assessed in single studies, whilst only data for PGP 9.5 and CYP19 were available for meta-analysis. These two biomarkers demonstrated significant diversity for the diagnostic estimates between the studies; however, the data were too limited to reliably determine the sources of heterogeneity. The mean sensitivities and specificities of PGP 9.5 (7 studies, 361 women) were 0.96 (95% confidence interval (CI) 0.91 to 1.00) and 0.86 (95% CI 0.70 to 1.00), after excluding one outlier study, and for CYP19 (8 studies, 444 women), they were were 0.77 (95% CI 0.70 to 0.85) and 0.74 (95% CI 0.65 to 84), respectively. We could not statistically evaluate other biomarkers in a meaningful way. An additional 31 studies evaluated 77 biomarkers that showed no evidence of differences in expression levels between the groups of women with and without endometriosis.

Authors' conclusions

We could not statistically evaluate most of the biomarkers assessed in this review in a meaningful way. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Although PGP 9.5 met the criteria for a replacement test, it demonstrated considerable inter study heterogeneity in diagnostic estimates, the source of which could not be determined. Several endometrial biomarkers, such as endometrial proteome, 17βHSD2, IL-1R2, caldesmon and other neural markers (VIP, CGRP, SP, NPY and combination of VIP, PGP 9.5 and SP) showed promising evidence of diagnostic accuracy, but there was insufficient or poor quality evidence for any clinical recommendations. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and using any non-invasive tests should only be undertaken in a research setting. We have also identified a number of biomarkers that demonstrated no diagnostic value for endometriosis. We recommend that researchers direct future studies towards biomarkers with high diagnostic potential in good quality diagnostic studies.

Plain language summary

Endometrial biomarkers for the non-invasive diagnosis of endometriosis

Review question

Can physicians use biomarkers (distinctive molecules, genes or other characteristics that appear in certain conditions) to reduce the need to surgically diagnose endometriosis?

Background

The endometrium refers to the tissue that lines the womb and is shed during menstruation. Women with endometriosis have endometrial tissue growing outside the womb, within the pelvic cavity. This tissue responds to reproductive hormones causing painful periods, chronic lower abdominal pain and difficulty conceiving. Currently the only reliable way of diagnosing endometriosis is to perform keyhole surgery and visualise the endometriotic deposits inside the abdomen. Because surgery is risky and expensive, various tests within the endometrium that can be obtained during an in-office womb sampling procedure have been assessed for their ability to detect endometriosis non-invasively or with minimal invasion. An accurate test could lead to the diagnosis of endometriosis without the need for surgery, or it could reduce the need for diagnostic surgery so only women who were most likely to have endometriosis would require it. Review teams have also evaluated other non-invasive ways of diagnosing endometriosis using blood, urine and imaging tests as well as a combination of several testing methods in separate Cochrane reviews within this series.

Study characteristics

The evidence in this review is current to April 2015. We included 54 studies involving 2729 participants. All studies evaluated reproductive-aged women who were undertaking diagnostic surgery to investigate symptoms of endometriosis or for other indications. Twenty-six studies evaluated the role of 22 different biomarkers in diagnosing endometriosis, and 31 studies identified 77 additional biomarkers that had no value in differentiating between women with and without the disease.

Key results and quality of evidence

Only two of the assessed biomarkers, a neural fibre marker PGP 9.5 and hormonal marker CYP19, were assessed in sufficient number of studies to obtain meaningful results. PGP 9.5 identified endometriosis with enough accuracy to replace surgical diagnosis. Several additional biomarkers (endometrial proteome, 17βHSD2, IL-1R2, caldesmon and other neural markers) show promise in detecting endometriosis, but there are too few studies to be sure of their diagnostic value.

The studies differed in how they were conducted, which groups of women were studied and how the surgery was undertaken. The reports were of low methodological quality, which is why readers cannot consider these results to be reliable unless confirmed in large, high quality studies. Overall, there is not enough evidence to recommend any endometrial test for use in clinical practice for the diagnosis of endometriosis.

Future research

Further high quality research is necessary to accurately evaluate the diagnostic potential of the endometrial biomarkers for the diagnosis of endometriosis.

Резюме на простом языке

Эндометриальные биомаркеры для не-инвазивной диагностики эндометриоза

Вопрос обзора

Могут ли врачи использовать биомаркеры (отличительные молекулы, гены или другие характеристики, которые появляются в определенных условиях), чтобы уменьшить необходимость хирургической диагностики эндометриоза?

Актуальность

Эндометрий относится к ткани, выстилающей матку и которая теряется во время менструации. У женщин с эндометриозом, эндометрий растёт не в матке, а внутри полости малого таза. Эта ткань реагирует на половые гормоны, вызывая болезненные менструации, хронические боли внизу живота и трудности с зачатием. В настоящее время наиболее надёжным способом диагностики эндометриоза является проведение лапароскопической операции для визуального определения эндометриальных узлов в брюшной полости. В связи с тем, что операция является дорогостоящей и рискованной, различные тесты в эндометрии, которые можно осуществить в условиях больницы с помощью отбора образцов были оценены на их способность обнаруживать эндометриоз неинвазивно или с минимальным вторжением. Точный метод визуализации мог бы диагностировать эндометриоз без необходимости операции, или уменьшить необходимость в оперативном вмешательстве таким образом, что оно требовалось бы только тем женщинам, у которых наиболее высокая вероятность эндометриоза. Группы обзора также оценили другие неинвазивные способы диагностики эндометриоза с использованием крови, анализа мочи и изображений, а также сочетание нескольких методов тестирования в отдельных Кокрейновских обзорах этой серии.

Характеристика исследований

Доказательства в этом обзоре актуальны по 26 апреля 2015 года. Мы включили 54 исследований с участием 2729 женщин. Все исследования включали женщин детородного возраста, которым проводились диагностические операции, чтобы исследовать симптомы эндометриоза или по другим показаниям. Двадцать шесть исследований оценили роль 22 различных биомаркеров в диагностике эндометриоза, и 31 исследование выявило 77 дополнительных биомаркеров, которые не имели значения в дифференциации между женщинами не играли роли в дифференциации (различении) женщин, больных эндометриозом, и здоровых женщин.

Основные результаты и качество доказательств

Только два из оцениваемых биомаркеров, маркер нейронных волокон PGP 9,5 и гормональный маркер CYP19, были оценены в достаточном числе исследований для получения значимых результатов. PGP 9.5 определил эндометриоз с достаточной точностью, чтобы заменить хирургическую диагностику. Несколько дополнительных биомаркеров (внутриматочный протеом, 17βHSD2, IL-1R2, кальдесмон и другие нейронные маркеры) являются обещающими для обнаружения эндометриоза, но существует слишком мало исследований, чтобы быть уверенными в их диагностической ценности.

Исследования различались тем, как они были проведены, какие группы женщин были изучены, и как была проведена операция. Отчёты были низкого методологического качества, поэтому читатели не могут рассматривать эти результаты, как надежные, пока они не будут подтверждены в больших исследованиях высокого качества. В целом, не существует достаточно доказательств, чтобы рекомендовать какой-либо один тест на наличие эндометриоза для использования в клинической практике для его диагностики.

Будущие исследования

Требуются дополнительные исследования высокого качества для оценки диагностического потенциала эндометриальных биомаркеров для диагностики эндометриоза.

Заметки по переводу

Перевод: Гараева Айзяра Фаниловна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Laienverständliche Zusammenfassung

Endometriale Biomarker zur nichtinvasiven Diagnose von Endometriose

Fragestellung

Können Ärzte Biomarker (typische Moleküle, Gene oder andere Merkmale, die unter bestimmten Bedingungen auftreten) einsetzen, um die Notwendigkeit einer chirurgischen Diagnose der Endometriose zu verringern?

Hintergrund

Endometrium nennt man das Gewebe, das die Gebärmutter auskleidet und das während der Menstruation abgestoßen wird. Bei Frauen mit Endometriose wächst endometriales Gewebe außerhalb der Gebärmutter in der Beckenhöhle. Dieses Gewebe reagiert auf Fortpflanzungshormone, was zu Regelschmerzen, chronischen Unterbauchschmerzen und Schwierigkeiten bei der Empfängnis führt. Derzeit kann Endometriose zuverlässig nur durch einen minimalinvasiven Eingriff („Schlüssellochchirurgie“) diagnostiziert werden, bei dem die Endometrioseherde im Bauchraum sichtbar gemacht werden. Da ein chirurgischer Eingriff immer mit Risiken behaftet und kostspielig ist, wurden verschiedene Tests am Endometrium bewertet, die sich anhand einer Probenahme in der gynäkologischen Praxis durchführen lassen. Auf diese Weise könnte eine Endometriose nichtinvasiv oder minimalinvasiv festgestellt werden. Ein genauer Test könnte die Diagnose von Endometriose ohne die Notwendigkeit eines chirurgischen Eingriffs ermöglichen oder die Notwendigkeit eines solchen Eingriffs derart verringern, dass er nur bei Frauen mit der höchsten Wahrscheinlichkeit für Endometriose nötig wäre. Andere Review-Teams haben in weiteren Cochrane-Reviews dieser Reihe weitere nichtinvasive Möglichkeiten der Endometriose-Diagnose mithilfe von Blut, Urin und Bildgebungsverfahren sowie eine Kombination mehrerer Testmethoden ausgewertet.

Studienmerkmale

Die Evidenz in diesem Review ist auf dem Stand vom April 2015. Wir schlossen 54 Studien mit 2729 Teilnehmerinnen ein. Alle Studien wurden mit Frauen im gebärfähigen Alter durchgeführt, die sich einem diagnostischen Eingriff unterzogen, entweder um Endometriose-Symptome abzuklären oder aufgrund anderer Indikationen. 26 Studien bewerteten die Rolle von 22 verschiedenen Biomarkern bei der Diagnose der Endometriose und in 31 Studien wurden 77 zusätzliche Biomarker identifiziert, die nicht zur Unterscheidung zwischen Frauen mit dieser und ohne diese Erkrankung beitrugen.

Hauptergebnisse und Qualität der Evidenz

Nur zwei der untersuchten Biomarker, der Nervenfasermarker PGP9.5 und der Hormonmarker CYP19, wurden in einer ausreichenden Anzahl von Studien bewertet, um relevante Ergebnisse zu liefern. PGP9.5 identifizierte Endometriose mit ausreichender Genauigkeit, um eine chirurgische Diagnose zu ersetzen. Mehrere weitere Biomarker (endometriales Proteom, 17βHSD2, IL-1R2, Caldesmon und andere neurale Marker) lieferten vielversprechende Ergebnisse bei der Erkennung von Endometriose, für gesicherte Erkenntnisse über ihren diagnostischen Wert liegen jedoch zu wenige Studien vor.

Die Studien unterschieden sich in ihrer Durchführung, den Gruppen der untersuchten Frauen und der Durchführung des chirurgischen Eingriffs. Die Berichte waren von niedriger methodischer Qualität; diese Ergebnisse können daher nicht als zuverlässig angesehen werden, bis sie in großen, hochwertigen Studien bestätigt werden. Insgesamt gibt es keine ausreichende Evidenz, um einen Test am Endometrium zur Diagnose von Endometriose in der klinischen Praxis empfehlen zu können.

Zukünftige Forschungsarbeiten

Es sind weitere hochwertige Forschungsarbeiten erforderlich, um das diagnostische Potenzial der endometrialen Biomarker in der Diagnose der Endometriose genau zu bewerten.

Anmerkungen zur Übersetzung

S. Schmidt-Wussow, freigegeben durch Cochrane Schweiz.