Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process

Cell Metab. 2021 Mar 2;33(3):513-530.e8. doi: 10.1016/j.cmet.2021.01.004. Epub 2021 Feb 3.


Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects. These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy.

Keywords: AMH; PCOS; developmental programming; epigenetics; fertility; inheritance; metabolic disorder; methylation; neuroendocrine; transgenerational.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Mullerian Hormone / pharmacology
  • Anti-Mullerian Hormone / therapeutic use
  • Case-Control Studies
  • DNA Methylation / drug effects
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Luteinizing Hormone / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mixed Function Oxygenases / genetics
  • Ovary / metabolism
  • Polycystic Ovary Syndrome / drug therapy
  • Polycystic Ovary Syndrome / genetics*
  • Polycystic Ovary Syndrome / pathology
  • Prenatal Care
  • Proto-Oncogene Proteins / genetics
  • S-Adenosylmethionine / pharmacology
  • S-Adenosylmethionine / therapeutic use
  • Transcriptome / drug effects


  • Proto-Oncogene Proteins
  • S-Adenosylmethionine
  • Anti-Mullerian Hormone
  • Luteinizing Hormone
  • Mixed Function Oxygenases
  • TET1 protein, human