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Aberrant H19 Expression Disrupts Ovarian Cyp17 and Testosterone Production and Is Associated with Polycystic Ovary Syndrome in Women

Abstract

As one of the most common endocrine disorders affecting women, polycystic ovary syndrome (PCOS) is associated with serious conditions including anovulation, endometrial cancer, infertility, hyperandrogenemia, and an increased risk for obesity and metabolic derangements. One contributing etiology to the pathophysiology of hyperandrogenemia associated with PCOS is an intrinsic alteration in ovarian steroidogenesis, leading to enhanced synthesis of androgens including testosterone. Studies have suggested that the increased testosterone synthesis seen in PCOS is driven in part by increased activity of CYP17A1, the rate-limiting enzyme for the formation of androgens in the gonads and adrenal cortex, which represents a critical factor driving enhanced testosterone secretion in PCOS. In this work, we evaluated the hypothesis that dysregulation of the noncoding RNA H19 results in aberrant CYP17 and testosterone production. To achieve this, we measured Cyp17 in ovarian tissues of H19 knockout mice, and quantified serum testosterone levels, in comparison with wild-type controls. We also evaluated circulating and ovarian H19 expression and correlated results with the presence or absence of PCOS in a group of women undergoing evaluation and treatment for infertility. We found that the loss of H19 in a mouse model results in decreased ovarian Cyp17, along with decreased serum testosterone in female mice. Moreover, utilizing serum samples and cumulus cells from women with PCOS, we showed that circulating and ovarian levels of H19 are increased in women with PCOS compared to controls. Findings from our multimodal experimental strategy, involving both a mouse model of dysregulated H19 expression and clinical serum and ovarian cellular samples from women with PCOS, suggest that the loss of H19 may disrupt androgen production via a Cyp17-mediated mechanism. Conversely, excess H19 may play a role in the pathogenesis of PCOS-associated hyperandrogenemia.

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Data Availability

The raw data used to support the findings of this study are available upon request.

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Acknowledgements

H19KO mice were provided by Luisa Dandolo, PhD, and Stefan Muljo, PhD. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core (used for serum steroid hormone analysis) is supported by the Eunice Kennedy Shriver NICHD Grant R24 HD102061. We thank Ms. Meirav Sela for her assistance with manuscript proofreading.

Funding

Dr Kallen received funding and research support provided by the NIH-NICHD (R01HD101475), the Reproductive Scientist Development Program (NIH-NICHD Project #2K12HD000849-26), the American Society for Reproductive Medicine, and the NIH Loan Repayment Program. Dr Kallen and Dr Xi received funding and support from the Milstein Medical Asian American partnership Foundation (MMAAPF). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core (used for serum steroid hormone analysis) is supported by the Eunice Kennedy Shriver NICHD Grant R24 HD102061.

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Authors

Contributions

AK, XX, and LL conceived and planned the experiments. XX, LL, ZC, and CK carried out the experiments. XX and CK contributed to sample collection and preparation. XX, ZC, LL, and MB contributed to the interpretation of the results. AK and ZC took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Corresponding author

Correspondence to Amanda N. Kallen.

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Ethics Approvals

Studies involving mice were approved by the Yale University Institutional Animal Care and Use Committee (IACUC protocol #2021–20018). Studies utilizing patient samples were approved by the Gazi University Institutional Review Board committee (IRB protocol #131/11.05.2011) and the Yale University Institutional Review Board (IRB protocol #1606017946).

Conflict of Interest

The authors declare no competing interests.

Additional information

Zhaojuan Chen and Lan Liu are co-first authors.

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Chen, Z., Liu, L., Xi, X. et al. Aberrant H19 Expression Disrupts Ovarian Cyp17 and Testosterone Production and Is Associated with Polycystic Ovary Syndrome in Women. Reprod. Sci. (2021). https://doi.org/10.1007/s43032-021-00700-5

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Keywords

  • H19
  • Noncoding RNA
  • ncRNA
  • PCOS