Circulating microRNAs show promise as non-invasive biomarkers for adenomyosis.

A recent study by Corachán and colleagues investigated whether microRNAs (miRNAs) circulating in blood plasma could provide a molecular signature of adenomyosis1. miRNAs are short regulatory RNA molecules involved in controlling gene expression and can be detected in biological fluids, making them attractive candidates for biomarker development.

The researchers compared infertile women with adenomyosis with two control populations: infertile women without adenomyosis and healthy fertile women. This design allowed them to distinguish changes potentially associated specifically with adenomyosis from those related more generally to infertility or reproductive status. Plasma miRNAs were profiled by small RNA sequencing, with libraries prepared using the NEXTFLEX™ Small RNA-Seq v4 Kit. Selected findings were subsequently evaluated by qPCR in plasma and endometrial tissue.

A distinct plasma miRNA signature emerges in adenomyosis

The study found that infertile women with adenomyosis displayed a distinct circulating miRNA profile compared with both control groups.

-When adenomyosis patients were compared with infertile controls, the researchers identified 11 differentially expressed miRNAs, including five that were increased and six that were decreased. This comparison was particularly informative because it reduced the potential influence of infertility itself and therefore highlighted changes more specifically associated with adenomyosis. Among these candidates, miR-4433 and miR-652-5p showed particularly strong discriminatory performance in this cohort, with areas under the ROC curve of 0.92 and 0.91, respectively.

Compared with healthy fertile women, 23 differentially expressed miRNAs were identified. Several showed promising ability to distinguish adenomyosis from healthy controls in this cohort, including miR-3200-5p, miR-193b-5p and miR-4732-5p, which achieved AUC values of 0.88, 0.88 and 0.87, respectively.

miR-4433 was significantly increased in plasma from women with adenomyosis compared with infertile controls, supporting its potential as a disease-associated circulating marker. qPCR analysis also supported elevated plasma expression of miR-92a-3p in women with adenomyosis. This miRNA had previously been associated with adenomyosis in studies of exosomes and endometrial models.

The researchers then examined whether some of these circulating changes were also detectable in the endometrium. miR-92a-3p was significantly elevated in endometrial tissue from women with adenomyosis, while miR-4433 showed a similar direction of change to that observed in plasma, although the difference in endometrium did not reach statistical significance. These findings provide preliminary support for a relationship between circulating and endometrial miRNA profiles, although the tissue source of the circulating miRNAs cannot be determined from this study.

The study also explored what these altered miRNAs might reveal about disease biology. Their predicted target genes were enriched in pathways including PI3K-AKT, mTOR, MAPK, AMPK, p53 and prolactin signaling, as well as biological processes involving cell adhesion, inflammation, epithelial-to-mesenchymal transition, migration, cell-cycle regulation and apoptosis. Genes including CDKN1A, CCND1 and IGF1R appeared repeatedly across these analyses. Many of these pathways have previously been implicated in adenomyosis, providing hypotheses for how the altered miRNAs may relate to disease biology in addition to their potential value as biomarkers.

Toward less-invasive approaches to adenomyosis diagnosis

This study provides evidence that circulating plasma miRNAs could eventually complement existing approaches such as ultrasound or MRI in adenomyosis assessment. Candidates including miR-4433 and miR-652-5p showed strong ability to distinguish women with adenomyosis from infertile women without the condition in this cohort, while miR-92a-3p was supported by both plasma and endometrial measurements.

Overall, the study identifies a set of circulating miRNAs associated with adenomyosis and uses follow-up plasma and endometrial measurements to prioritize candidates for further investigation. The study included a relatively small sequencing cohort, and larger studies will now be needed to determine whether these signals are reproducible and sufficiently robust to contribute to future biomarker-based approaches for adenomyosis.