miRNA serum testing for endometriosis: recent headway on the path to clinical utility

Endometriosis, defined as the presence of estrogen-responsive endometrial glands and stroma outside the uterus, remains a considerable health challenge. Affecting an estimated 10% of reproductive-aged women, the condition results in chronic inflammation that often leads to a reduced quality of life and sequelae such as infertility. Laparoscopic surgery is currently the only definitive diagnostic method for endometriosis [1]. An obstacle in its clinical management is its range of nonspecific symptoms at presentation. In avoiding the risks and costs of surgery, providers can feel blind as they initiate empiric treatment, reliant on symptom response for guidance. Further, there is an estimated 6- to 10-year delay in diagnosis, especially for women without insurance [2]. Meta-analyses of studies of biomarkers, imaging modalities, and physical exam findings have all found these strategies to be inadequate diagnostics tools [3–5]. One area of recent advancement in research is the potential for serum diagnosis via microRNA (miRNA) specific to endometriosis. Such a tool could potentially improve accessibility to earlier diagnosis and initiation of treatment. This technique has been scrutinized as less valuable for not having enough clinical utility, but there has been a recent stride in research to fill this gap.

miRNAs are short nucleotide sequences of non-coding RNA involved in regulatory pathways and are highly conserved across lineages. miRNA expression profiles are gaining appreciation as diagnostic measures, given the disparity in profiles between diseased and non-diseased patients, in a wide variety of illnesses [6]. Many contemporary experiments on cells of endometrial lesions have similarly found differences in the upregulation and downregulation of numerous miRNAs in patients with endometriosis versus controls.

A recent review highlights several miRNAs and describes the biologic plausibility and experimental evidence for their use as circulating biomarkers for endometriosis [7]. The authors also outline the data for improved diagnostic validity of panels of candidate miRNAs over use of single miRNA expression testing. With the rapid progress and contribution of many studies including functional miRNA experiments, the miRNAs most consistently demonstrated as predictive of endometriosis appear to be those known to be associated with pathophysiology described in endometriosis, such as epithelial-to-mesenchymal transition, angiogenesis, and cellular proliferation and invasion. Unfortunately, until recently, studies have shown poor sensitivity and specificity of plasma miRNAs, suggesting a limited clinical role as a diagnostic biomarker [8,9].

Additional deficiencies include design heterogeneities, in terms of degree and type of endometriosis, control group, and degree of up- or down-regulation defined as a significant change. Furthermore, there have been studies highlighting varying expression levels of specific miRNAs based on the type of endometriotic lesion [10]. Generally, clinicians provide the same treatment options for all types of endometriosis: hormonal suppression medications or surgical intervention, and thus there is no utility for signature testing specific to the type of lesion (ovarian, deep infiltrating, and peritoneal). Furthermore, is has been suggested that miRNA serum testing could be used as a biomarker to show response to hormonal therapy [11]. However clinically, response to therapy is determined by improvement of patients’ subjective symptoms. The degree of endometriosis found at a tissue level does not correlate with symptom severity, and so measuring tissue-level response to therapy would not change management.

Excitingly, in a recent prospective study by Mustafa et al, 100 patients undergoing gynecologic surgery for pelvic pain and/or infertility showed that a set of six miRNAs were able to accurately distinguish between endometriosis and other gynecologic conditions, regardless of current hormonal treatments or menstrual cycle phase [12]. This study was the first to apply expression testing of a panel of miRNAs previously determined as unique to endometriosis to predict the diagnosis of endometriosis in a patient with pelvic pain and/or infertility. What sets this study apart is not only the design, which looked at patients undergoing surgical exploration for pelvic pain, and thus patients ultimately confirmed to have endometriosis were compared to those with other gynecologic conditions, but also that the miRNA panel used: miR-125b, miR-150, miR-342, miR-451a, miR-3613, and let-7b, resulted in unparalleled sensitivity and specificity (∼90%).

While this trial represents real progress for miRNA serum testing, there are several steps remaining before it can begin to be applied in the clinic. The study claims that this panel could lead to earlier endometriosis care, but the study cohort does not necessarily represent the patient population that would benefit from such a test. It tested women already at the point of needing surgical exploration for diagnostic, but also treatment purposes. While this allowed for all patients to receive the gold standard in endometriosis diagnosis, ideal to investigate the prognostic value of the serum miRNA panel, it also likely selected for women who had already undergone empiric medical treatment for presumed endometriosis, i.e. were relatively late in their clinical course (average age of 34). In fact, this miRNA panel may be most predictive of women who will fail hormonal treatment and ultimately require surgery. Recently the preliminary and promising results of an ongoing study using the same panel of six miRNAs in adolescents (average age of 17) is underway [13]. This study will likely validate this panel in a patient population earlier in their disease course, undergoing surgery for diagnostic purposes in the setting of chronic pelvic pain. The next step would be a study using this miRNA panel in the office to evaluate women in the beginning of their pain symptoms. This would show if miRNA serum testing could more accurately identify women with endometriosis and lead to quicker implementation of effective medical management; following these women long-term would show if serum diagnosis means that fewer ultimately will require surgery.

Endometriosis is a prevalent condition with a serious impact on quality of life. We lack noninvasive testing, and thus diagnosis is often delayed. A more immediate and reliable test would certainly be of great clinical utility. Although we do not yet have evidence that the most recent and promising miRNA panel will lead to such outcomes, it surely lends optimism toward equipping gynecologists with this testing in our future.

Disclosure statement

No potential conflict of interest was reported by the author(s).