Molecular insights into the aetiology of female reproductive ageing

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.

Figure 1. The genetic architecture of female reproductive lifespan.

This schematic figure illustrates that variants with lower allele frequency (x-axis) have larger effect sizes (y-axis) on puberty or menopause timing. Font sizes of the names of the implicated genes is scaled to the relative effect size of the variant within the frequency categories.

Figure 2. Overlaps in implicated genes between menarche and menopause timing and between variant frequency groups.

Background colour shading indicates allele frequency of associated variants: red (rare), green (low-frequency) and blue (common). Lines indicate overlaps in the genes implicated by associated variants, between menarche and menopause traits, and also between variant frequency groups.

Figure 3. Schematic overview of the aetiological mechanisms governing reproductive ageing in women

Image credit: Wellcome Library, London (CC BY 4.0)

Figure 4. Changes in oocyte reserve throughout life.

This schematic figure indicates ovarian germ cell numbers throughout life and the mechanism that influence this. Histograms indicate the normal population variance in ages at menarche (puberty) and menopause.