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

Cells. 2023 Mar 23;12(7):983. doi: 10.3390/cells12070983.

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.

Trial registration: ClinicalTrials.gov NCT03142633.

Keywords: PCOS; biomarker; circulation; clinical trial; metabolic syndrome; microRNA; non-coding RNA; ovary; polycystic ovary syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens
  • Circulating MicroRNA* / genetics
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Humans
  • Longitudinal Studies
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Polycystic Ovary Syndrome* / genetics
  • Polycystic Ovary Syndrome* / metabolism

Substances

  • Circulating MicroRNA
  • MicroRNAs
  • Androgens
  • MIRN139 microRNA, human

Associated data

  • ClinicalTrials.gov/NCT03142633

Grants and funding

This work was funded by ReproUnion and the Danish Diabetes Academy. This article is part of a ReproUnion collaborative study, co-financed by the European Union, Interreg V ÔKS. The salary for PBU is funded by a grant from ReproUnion. AES was funded by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation.