Circulating miRNAs in Women with Polycystic Ovary Syndrome: A Longitudinal Cohort Study

Abstract

Background: Women with polycystic ovary syndrome (PCOS) often change their metabolic profile over time to decrease levels of androgens while often gaining a propensity for the development of the metabolic syndrome. Recent discoveries indicate that microRNAs (miRNAs) play a role in the development of PCOS and constitute potential biomarkers for PCOS. We aimed to identify miRNAs associated with the development of an impaired metabolic profile in women with PCOS, in a follow-up study, compared with women without PCOS. Methods and materials: Clinical measurements of PCOS status and metabolic disease were obtained twice 6 years apart in a cohort of 46 women with PCOS and nine controls. All participants were evaluated for degree of metabolic disease (hypertension, dyslipidemia, central obesity, and impaired glucose tolerance). MiRNA levels were measured using Taqman® Array cards of 96 pre-selected miRNAs associated with PCOS and/or metabolic disease. Results: Women with PCOS decreased their levels of androgens during follow-up. Twenty-six of the miRNAs were significantly changed in circulation in women with PCOS during the follow-up, and twenty-four of them had decreased, while levels did not change in the control group. Four miRNAs were significantly different at baseline between healthy controls and women with PCOS; miR-103-3p, miR-139-5p, miR-28-3p, and miR-376a-3p, which were decreased in PCOS. After follow-up, miR-28-3p, miR-139-5p, and miR-376a-3p increased in PCOS women to the levels observed in healthy controls. Of these, miR-139-5p correlated with total testosterone levels (rho = 0.50, padj = 0.013), while miR-376-3p correlated significantly with the waist-hip ratio at follow-up (rho = 0.43, padj = 0.01). Predicted targets of miR-103-3p, miR-139-5p, miR-28-3p, and miR-376a-3p were enriched in pathways associated with Insulin/IGF signaling, interleukin signaling, the GNRH receptor pathways, and other signaling pathways. MiRNAs altered during follow-up in PCOS patients were enriched in pathways related to immune regulation, gonadotropin-releasing hormone signaling, tyrosine kinase signaling, and WNT signaling. Conclusions: These studies indicate that miRNAs associated with PCOS and androgen metabolism overall decrease during a 6-year follow-up, reflecting the phenotypic change in PCOS individuals towards a less hyperandrogenic profile.

A Comparative Analysis of Naïve Exosomes and Enhanced Exosomes with a Focus on the Treatment Potential in Ovarian Disorders

“…In estrogen-dependent tumors, this miRNA targets PFKFB3, regulating cancer cell proliferation through GLUT1, PFKFB3, and FAK [55]. Another study highlighted the antigrowth effect of miR-206 in ovarian cancer and its ability to increase chemotherapy sensitivity by targeting CDK4 [56]. which are downregulated in ovarian cancer, play pivotal roles in controlling cancer cell proliferation, reducing metastasis, and inhibiting invasion through the targeting of various genes and signaling pathways.…”

Serum Expression of miR-23a-3p and miR-424-5p Indicate Specific Polycystic Ovary Syndrome Phenotypes: A Pilot Study

“…The relative expression levels of all investigated miRNAs were calculated as the fold change [ 66 ]. For that, average Cq values were normalized to the mean of snU6 and miR-484, used as endogenous control [ 67 ], to calculate Δ (delta) Cq values. The fold change was calculated as 2 −ΔΔCq , where ΔΔCq was the ΔCq of PCOS phenotypes minus the ΔCq of controls.…”

The Role of MicroRNA, Long Non-Coding RNA and Circular RNA in the Pathogenesis of Polycystic Ovary Syndrome: A Literature Review

“…Likewise, certain miRNAs have been found to be altered during the course of followup of PCOS patients compared to healthy controls. While the control group had no changes in their miRNA during the follow-up, PCOS patients had twenty-six miRNAs that were altered in serum [88]. Four of these miRNAs were significantly decreased compared to healthy controls, including miR-376a-3p, miR-103-3p, miR-139-5p, and miR-28-5p.…”

“…Serum Reflect androgenic profile [88] miR-92b miR-92a Theca cells Correlate with hyperinsulinemia/IR and hyperandrogenism profile [45] miR-423 Granulosa cells and follicular fluid Downregulated, marker of PCOS [89] miR-142 miR-33b Granulosa cells and follicular fluid Upregulated, a marker of PCOS [89] miR-199b-5p Follicular fluid Correlates with anti-mullerian hormone [39] miR-382-5p Follicular fluid Correlates with free androgen index and age [39] miR-93-3p Follicular fluid Correlates with C-reactive protein [39] miR-490-5p miR-212-3p miR-4643 Follicular fluid and cumulus cells Identification of PCOS subtype [34] miR-647 Follicular fluid and cumulus cells Identification of PCOS subtype [34] Another study has demonstrated the use of serum miR-155 as a potential biomarker for monitoring estroprogestinic treatment in hyperandrogenic PCOS women [86]. Moreover, serum miR-339-5p was suggested as a marker of vascular endothelial health in PCOS [61], and plasma miR-93 could act as a useful biomarker for PCOS [31].…”