ESPE Yearbook of Paediatric Endocrinology

Nature. 2021;596(7872):393-7. doi: 10.1038/s41586-021-03779-7.PubMed ID: 34349265

Brief summary: This study analysed genome-wide association array (GWAS) data on ~200 000 women of European ancestry to identify 290 separate genetic signals associated with normal variation in age at natural menopause (ANM). Experimental alterations of key identified genes in mouse models confirmed their impacts on ovarian ageing, but also identified impacts across the life-course that shape fetal generation of the ovarian reserve as well as its rate of postnatal depletion.

Clinicians and scientists have long considered menopause to be a marker of biological aging, with little obvious relationship with childhood reproductive development or pubertal traits. Indeed this concept was reinforced by previous GWAS findings that various DNA damage response (DDR) processes contribute substantially to the genetic predisposition to earlier or later ANM. Apart from rare genetic causes of premature ovarian failure (Turner syndrome) or severe external perturbations (radiotherapy and chemotherapy), Paediatricians rarely consider the links between common childhood presentations and later menopause.

These researchers showed directionally-opposing effects of different DDR pathways on ANM. Disruption of DDR genes that repair damaged DNA led to a smaller oocyte pool, faster decline in oocyte numbers and earlier ANM (e.g. Chek1). By contrast, disruption of DDR genes (e.g. Chek2) that detect DNA damage and trigger cell apoptosis (i.e. trigger cell death instead of damage repair) led to more oocytes numbers and later ANM (albeit the oocyte retain DNA damage). Hence, female fertility in mice could be prolonged by Chek2 deletion or Chek1 overexpression. A key surprising observation was that Chek2 deletion and Chek1 overexpression increased ovarian oocyte pool size in infancy, as well as in later life.

These findings show that the same biological processes that protect and respond to cell damage in later life also have fundamental roles during early life development, when rates of cell replication and differentiation are high and cells are prone to external stressors, such as oxidative damage. Disruption of these processes may have impacts on reproductive development and functioning across the life-course.