A critical appraisal of the circulating levels of differentially expressed microRNA in endometriosis

Abstract

Endometriosis is a common gynaecological condition characterized by estrogen dependence, chronic pelvic pain, infertility and diagnostic delay of between 5.4 and 12 years. Despite extensive study, no biomarker, either alone or in combination with other markers, has proven superior to laparoscopy for the diagnosis of endometriosis. Recent studies report that circulating levels of differentially expressed microRNA (miRNA) in women with endometriosis compared to controls are potential diagnostic tools. However, the lack of replication and absence of validated differential expression in novel study populations have led some to question the diagnostic value of miRNA. To elucidate potential reasons for the lack of replication of study results and explore future directions to enhance replicability of circulating miRNA results, we carried out an electronic search of the miRNA literature published between 2000 and 2020. Eighteen studies were identified in which 63 different miRNAs were differentially expressed in the circulation of women with endometriosis compared to controls. However, the differential expression of only 14 miRNAs were duplicated in one or more studies. While individual miRNAs lacked diagnostic value, miRNA panels yielded sensitivity and specificity equal to or better than laparoscopy in five studies. Important differences in study design, sample processing and analytical methods were identified rendering direct comparisons across studies problematic and could account for the lack of reproducibility of study results. We conclude that while the results of miRNA studies to date are encouraging, refinements to study design and analytical methods should enhance the reliability of circulating miRNA for the diagnosis of endometriosis.

Endometriosis-associated infertility: From pathophysiology to tailored treatment

“…To date, more than 60 miRNAs were found to be differentially expressed in the circulation (plasma and/or serum) of women with endometriosis ( 313 ). Very few (20%) miRNAs have been replicated in more than one study ( 314 ). While generally miRNAs are not highly evolutionarily conserved, serum let-7 family miRNA showed similar dysregulation in a murine model of endometriosis ( 315 ).…”

Plasma microRNA expression in adolescents and young adults with endometriosis: the importance of hormone use

“…Previous studies investigating miRNA levels in blood samples from endometriosis patients have reported varying results (10)(11)(12). Of the more recent studies, multiple blood-based miRNAs have been included in diagnostic models of endometriosis; however, none of the potential diagnostic miRNAs identified overlapped between studies (17-20, 22, 53-56) (54) reported that 42 miRNAs were differentially expressed between endometriosis patients and surgically-disconfirmed controls in their discovery phase; however, none of the associations were significant after correcting for multiple testing.…”

“…Unfortunately, considerable heterogeneity has been reported across studies in terms of the diagnostic potential of individual miRNAs. A recent review by Leonova et al (2021), noted that 63 miRNAs were reported to be differentially expressed between women with and without endometriosis across 18 studies; however, only 14 of those miRNAs were reported in more than one study (10).…”

“…Compared to other RNA species, miRNAs are relatively RNAase-resistant, rendering them more stable against degradation ( 9 ). Recently research has expanded into elucidating miRNA profiles of endometriosis ( 10 – 12 ), and investigating how changes in miRNA expression may impact gene expression in ectopic endometrial tissue ( 13 , 14 ). While recent studies have reported promising results for the use of miRNA signatures in endometriosis diagnosis ( 15 – 19 ), gaps remain in our understanding of the relationship between miRNAs and endometriosis etiology ( 12 ).…”

“…Unfortunately, considerable heterogeneity has been reported across studies in terms of the diagnostic potential of individual miRNAs. A recent review by Leonova et al (2021), noted that 63 miRNAs were reported to be differentially expressed between women with and without endometriosis across 18 studies; however, only 14 of those miRNAs were reported in more than one study ( 10 ). Currently, miRNA-based diagnostic tests are in active development for use in patient care across a variety of disease outcomes, and some are already available for clinical use including a saliva-based miRNA test for endometriosis that showed promising interim results ( 16 , 23 , 24 ).…”