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Epigenetic inheritance of polycystic ovary syndrome — challenges and opportunities for treatment

Abstract

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and is associated with a substantially increased lifetime risk of comorbidities, including type 2 diabetes mellitus, psychiatric disorders and gynaecological cancers. Despite its high prevalence (~15%) and substantial economic burden, the aetiology of PCOS remains elusive. The genetic loci linked to PCOS so far account for only ~10% of its heritability, which is estimated at 70%. However, growing evidence suggests that altered epigenetic and developmental programming resulting from hormonal dysregulation of the maternal uterine environment contributes to the pathogenesis of PCOS. Male as well as female relatives of women with PCOS are also at an increased risk of developing PCOS-associated reproductive and metabolic disorders. Although PCOS phenotypes are highly heterogenous, hyperandrogenism is thought to be the principal driver of this condition. Current treatments for PCOS are suboptimal as they can only alleviate some of the symptoms; preventative and targeted treatments are sorely needed. This Review presents an overview of the current understanding of the aetiology of PCOS and focuses on the developmental origin and epigenetic inheritance of this syndrome.

Key points

  • Polycystic ovary syndrome (PCOS) is a common heritable disorder strongly linked to hyperandrogenism and hyperinsulinaemia.

  • Disentangling the genetic and non-genetic contributions to the transmission of PCOS will require further investigation.

  • PCOS-like phenotypic traits are transgenerationally inherited in female offspring of androgen-exposed or anti-Müllerian hormone-exposed dams up to the F3 generation, indicating long-lasting effects of an aberrant maternal–fetal environment.

  • Studies in mouse models of PCOS demonstrate that epigenetic modulation connects early-life exposures to subsequent phenotypes and contributes to the development and familial transmission of PCOS.

  • Inheritance through epigenetic mechanisms opens a path towards novel treatment strategies for PCOS-like phenotypic traits.

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Fig. 1: Pathophysiology of PCOS.
Fig. 2: Genetic and epigenetic mechanisms implicated in the inheritance of PCOS.
Fig. 3: Distinguishing between the effects of in utero environment and germline transmission.

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Acknowledgements

The authors’ research is supported by the Swedish Medical Research Council (Project No. 2018-02435: E.S.V., 2018-02557: Q.D.), Novo Nordisk Foundation (NNF19OC0056647: E.S.V.), the Strategic Research Programme in Diabetes at Karolinska Institutet (E.S.V.), Adlerbert Research Foundation (E.S.V.), Åke Wibergs Stiftelse (Q.D.) and faculty funding at Karolinska Institutet (Q.D.).

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E.S.V. and Q.D. contributed equally to all aspects of the article.

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Correspondence to Elisabet Stener-Victorin.

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Nature Reviews Endocrinology thanks E. Diamanti-Kandarakis, H. Teede, who co-reviewed with A. Johan, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Mendelian randomization analyses

A genetic approach that determines the causal effects of putative risk factors in disease by using genetic variants as instrumental variables to infer whether a risk factor causally affects a health outcome.

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Stener-Victorin, E., Deng, Q. Epigenetic inheritance of polycystic ovary syndrome — challenges and opportunities for treatment. Nat Rev Endocrinol 17, 521–533 (2021). https://doi.org/10.1038/s41574-021-00517-x

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