Circulating plasma microRNAs as potential non-invasive biomarkers in infertile women with adenomyosis: an observational study

Corachán A, Ana Corachán, Mar Pérez-Ferrer, Pérez-Ferrer M, Faus A, Amparo Faus, Pilar Alamá, Alamá P, Vidal C, Carmen Vidal, Giles J, Juan Giles, Juan Gilés, António Pellicer, Pellicer A, Antonio Pellicer, Juan A. García-Velasco, García-Velasco JA, Juan Antonio García-Velasco, Hortensia Ferrero, Ferrero H
Reproductive biology and endocrinology : RB&E · 2026 · vol. 24(1) · doi:10.1186/s12958-026-01598-x · PMID:42823756 · PMC13629171 · W7172446065
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This study identified differentially expressed circulating plasma microRNAs, including miR-4433 and miR-652-5p, with diagnostic potential for adenomyosis in infertile women.

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This observational study investigated whether circulating plasma microRNAs could serve as non-invasive biomarkers for diagnosing adenomyosis in infertile women. Researchers compared miRNA profiles from women with adenomyosis, diagnosed via transvaginal ultrasound, against both infertile and healthy fertile controls using sequencing and quantitative PCR validation. The analysis identified specific differentially expressed miRNAs, such as miR-4433 and miR-652-5p, which demonstrated high diagnostic accuracy with area under the curve values exceeding 0.90 when distinguishing adenomyosis patients from infertile controls. Although the sample size was limited to ten participants per group in the initial sequencing phase, the findings suggest a strong link between systemic molecular alterations and endometrial pathology. This paper is centrally about adenomyosis — specifically the identification of circulating microRNAs as potential diagnostic biomarkers for the condition.

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Abstract

BACKGROUND: Despite advancements in imaging techniques, the non-invasive diagnosis of adenomyosis remains particularly challenging due to the overlap of imaging features with other uterine diseases, and the lack of consistent correlation with clinical presentation, with histological confirmation after hysterectomy still necessary. In this context, circulating miRNAs emerge as promising candidates for accurate non-invasive diagnosis. METHODS: To determine whether women with adenomyosis exhibit a distinct circulating plasma miRNA profile that can serve as a diagnostic marker, miRNA sequencing was performed to compare the plasma miRNA profile of women with adenomyosis with infertile and healthy fertile controls (n =  10/group). Adenomyosis was diagnosed by transvaginal ultrasound using Morphological Uterus Sonographic Assessment (MUSA) criteria. Plasma and endometrial biopsies were collected during the secretory phase from women undergoing hormone replacement therapy. Total RNA was extracted from plasma, libraries were prepared using NEXTFLEX® Small RNA-Seq v4 kits, and miRNAseq was performed on the NextSeq 550 NGS platform. Differentially expressed (DE) miRNAs were identified using the edgeR method (false discovery rate < 0.05). The discriminatory potential of DEmiRNAs was evaluated by receiver operating characteristic (ROC) curve analysis using the area under the curve (AUC). Validation was performed by quantitative PCR on plasma and endometrium (n =  15/group). The target genes of DEmiRNAs were retrieved from miRTarBase and subjected to functional enrichment analysis. RESULTS: A total of 11 disease-specific DEmiRNAs were identified in adenomyosis compared to infertile controls (5 up- and 6 downregulated), and 23 healthy control-referenced DEmiRNAs compared to fertile controls (19 up- and 4 downregulated). Among disease-specific DEmiRNAs, miR-4433 and miR-652-5p demonstrated strong diagnostic performance for adenomyosis compared to infertile controls (AUC = 0.92 and 0.91, respectively; p < 0.001). For healthy control-referenced DEmiRNAs, 11 miRNAs showed statistically significant diagnostic value (p < 0.01), with the highest AUCs observed for miR-3200-5p, miR-193b-5p, and miR-4732-5p (AUC = 0.88, 0.88 and 0.87, respectively). Validation experiments corroborated the upregulation of miR-4433 and miR-92a-3p upregulation in plasma and endometrium. CONCLUSIONS: This study supports the potential of circulating miRNAs as non-invasive biomarkers for adenomyosis and contributes to understanding its molecular basis. The concordance between circulating and endometrial miRNA expression suggests a possible link between systemic molecular alterations and endometrial pathology.
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Abstract

Background Despite advancements in imaging techniques, the non-invasive diagnosis of adenomyosis remains particularly challenging due to the overlap of imaging features with other uterine diseases, and the lack of consistent correlation with clinical presentation, with histological confirmation after hysterectomy still necessary. In this context, circulating miRNAs emerge as promising candidates for accurate non-invasive diagnosis.

Methods

To determine whether women with adenomyosis exhibit a distinct circulating plasma miRNA profile that can serve as a diagnostic marker, miRNA sequencing was performed to compare the plasma miRNA profile of women with adenomyosis with infertile and healthy fertile controls (n = 10/group). Adenomyosis was diagnosed by transvaginal ultrasound using Morphological Uterus Sonographic Assessment (MUSA) criteria. Plasma and endometrial biopsies were collected during the secretory phase from women undergoing hormone replacement therapy. Total RNA was extracted from plasma, libraries were prepared using NEXTFLEX® Small RNA-Seq v4 kits, and miRNAseq was performed on the NextSeq 550 NGS platform. Differentially expressed (DE) miRNAs were identified using the edgeR method (false discovery rate < 0.05). The discriminatory potential of DEmiRNAs was evaluated by receiver operating characteristic (ROC) curve analysis using the area under the curve (AUC). Validation was performed by quantitative PCR on plasma and endometrium (n = 15/group). The target genes of DEmiRNAs were retrieved from miRTarBase and subjected to functional enrichment analysis.

Results

A total of 11 disease-specific DEmiRNAs were identified in adenomyosis compared to infertile controls (5 up- and 6 downregulated), and 23 healthy control-referenced DEmiRNAs compared to fertile controls (19 up- and 4 downregulated). Among disease-specific DEmiRNAs, miR-4433 and miR-652-5p demonstrated strong diagnostic performance for adenomyosis compared to infertile controls (AUC = 0.92 and 0.91, respectively; p < 0.001). For healthy control-referenced DEmiRNAs, 11 miRNAs showed statistically significant diagnostic value (p < 0.01), with the highest AUCs observed for miR-3200-5p, miR-193b-5p, and miR-4732-5p (AUC = 0.88, 0.88 and 0.87, respectively). Validation experiments corroborated the upregulation of miR-4433 and miR-92a-3p upregulation in plasma and endometrium.

Conclusions

This study supports the potential of circulating miRNAs as non-invasive biomarkers for adenomyosis and contributes to understanding its molecular basis. The concordance between circulating and endometrial miRNA expression suggests a possible link between systemic molecular alterations and endometrial pathology. Similar content being viewed by others Abbreviations - AUC: - Area under the curve - BP: - Biological process - BMI: - Body mass index - CC: - Cellular component - DEmiRNAs: - Differentially expressed miRNAs - EMT: - Epithelial-to-mesenchymal transition - FDR: - False discovery rate - GO: - Gene Ontology - KEGG: - Kyoto Encyclopedia of Genes and Genomes pathways - MRI: - Magnetic resonance imaging - miRNAs: - MicroRNAs - MF: - Molecular function - MUSA: - Morphological Uterus Sonographic Assessment - ORA: - Over-Representation Analysis - ROC: - Receiver operating characteristic - TVUS: - Transvaginal ultrasound

Acknowledgements

We sincerely thank all the women who kindly agreed to participate in this study. We also acknowledge the IVIRMA Clinic staff for their assistance in sample collection, the Genomics Service of the University of Valencia for their technical assistance with miRNA sequencing, and EpiDisease for their support in data analysis. Funding This project was funded by the Conselleria de Educación, Universidades y Empleo (Generalitat Valenciana) (CIGE/2023/72 awarded to A.C.); the Health Institute Carlos III, co-funded by the European Social Fund (ESF) ‘Investing in your future’ (CP20/00120 awarded to H.F.; CD23/00157 awarded to A.C.). Author information Authors and Affiliations Corresponding authors Ethics declarations Ethics approval and consent to participate The collection and use of human samples was approved by the Clinical Research Ethics Committee at Hospital La Fe (2301-FIVI-008-HF) and informed written consent was obtained from all participants. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information 12958_2026_1598_MOESM1_ESM.xlsx (download XLSX ) Supplementary Material 1: Supplementary Table 1. Differentially expressed microRNAs in plasma from women with adenomyosis. 12958_2026_1598_MOESM2_ESM.xlsx (download XLSX ) Supplementary Material 2: Supplementary Table 2. Predicted target genes of the differentially expressed microRNAs in plasma from women with adenomyosis compared with infertile controls. 12958_2026_1598_MOESM3_ESM.xlsx (download XLSX ) Supplementary Material 3: Supplementary Table 3. Genes most commonly targeted by differentially expressed microRNAs in the adenomyosis group compared with the infertile control group. 12958_2026_1598_MOESM4_ESM.xlsx (download XLSX ) Supplementary Material 4: Supplementary Table 4. Kyoto Encyclopedia of Genes and Genomes pathway enrichment of predicted target genes of differentially expressed plasma microRNAs in adenomyosis compared with infertile controls. 12958_2026_1598_MOESM5_ESM.xlsx (download XLSX ) Supplementary Material 5: Supplementary Table 5. Gene Ontology enrichment analysis of predicted target genes of differentially expressed plasma microRNAs in adenomyosis compared with infertile controls. 12958_2026_1598_MOESM6_ESM.xlsx (download XLSX ) Supplementary Material 6: Supplementary Table 6. Predicted target genes of the differentially expressed microRNAs present in plasma from women with adenomyosis compared with fertile controls. 12958_2026_1598_MOESM7_ESM.xlsx (download XLSX ) Supplementary Material 7: Supplementary Table 7. Genes most commonly targeted by differentially expressed microRNAs in the adenomyosis group compared with the fertile control group. 12958_2026_1598_MOESM8_ESM.xlsx (download XLSX ) Supplementary Material 8: Supplementary Table 8. Kyoto Encyclopedia of Genes and Genomes pathway enrichment of predicted target genes of differentially expressed plasma microRNAs in adenomyosis compared with fertile controls. 12958_2026_1598_MOESM9_ESM.xlsx (download XLSX ) Supplementary Material 9: Supplementary Table 9. Gene Ontology enrichment analysis of predicted target genes of differentially expressed plasma microRNAs in adenomyosis compared with fertile controls. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Corachán, A., Pérez-Ferrer, M., Faus, A. et al. Circulating plasma microRNAs as potential non-invasive biomarkers in infertile women with adenomyosis: an observational study. Reprod Biol Endocrinol (2026). https://doi.org/10.1186/s12958-026-01598-x Received: Accepted: Published: DOI: https://doi.org/10.1186/s12958-026-01598-x

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MeSH descriptors

Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis

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