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  • Review Article
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Molecular insights into the aetiology of female reproductive ageing

Nature Reviews Endocrinology volume 11, pages 725–734 (2015)Cite this article

Subjects

Key Points

  • The genetic architecture of pubertal timing and age at menopause involves hundreds of rare, low frequency and common variants, with allelic heterogeneity often apparent at the same loci

  • Progress in localizing these variants has shed light on the wide range of biological mechanisms that regulate these traits, including energy homeostasis, gene silencing and DNA repair

  • Population variability in age at menarche and menopause is associated with altered health outcomes in later life, notably earlier timings increase the risk of type 2 diabetes mellitus and cardiovascular disease

  • Mechanisms that link reproductive ageing to metabolic diseases involve both obesity-related pathways and pathways independent of BMI

  • Exposure to sex hormones is probably the overwhelming mechanism linking reproductive ageing to the risk of breast cancer and other hormone-sensitive cancers

Abstract

As age at pubertal onset declines and age at first pregnancy increases, the mechanisms that regulate female reproductive lifespan become increasingly relevant to population health. The timing of menarche and menopause can have profound effects not only on fertility but also on the risk of diseases such as type 2 diabetes mellitus, cardiovascular disease and breast cancer. Genetic studies have identified dozens of highly penetrant rare mutations associated with reproductive disorders, and also ∼175 common genetic variants associated with the timing of puberty or menopause. These findings, alongside other functional studies, have highlighted a diverse range of mechanisms involved in reproductive ageing, implicating core biological processes such as cell cycle regulation and energy homeostasis. The aim of this article is to review the contribution of such genetic findings to our understanding of the molecular regulation of reproductive timing, as well as the biological basis of the epidemiological links between reproductive ageing and disease risk.

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Figure 1: Genetic architecture of the female reproductive lifespan.
Figure 2: Genetic overlaps within and between menarche and menopause.
Figure 3: Aetiological mechanisms governing reproductive ageing in women.
Figure 4: Ovarian germ cell numbers throughout life and the mechanisms that influence the oocyte pool.

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Authors and Affiliations

  1. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK

    John R. B. Perry, Felix R. Day & Ken K. Ong

  2. Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK

    Anna Murray

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Correspondence to John R. B. Perry.

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Perry, J., Murray, A., Day, F. et al. Molecular insights into the aetiology of female reproductive ageing. Nat Rev Endocrinol 11, 725–734 (2015). https://doi.org/10.1038/nrendo.2015.167

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