Predicting menopause: Is reproductive lifespan genetic?

Women may soon know their personal reproductive timeframe, as researchers have identified nearly 300 genes associated with the beginning of menopause.

A team of Aussie and international researchers conducted a genome-wide association study and identified 290 unique genes that were associated with reproductive lifespan (how long fertility lasts before menopause) in women of European descent.

The study, published in Nature, also showed that delayed menopause was associated with improved bone health and reduced likelihood of developing type 2 diabetes, but with increased risk of hormone-sensitive cancers.

The findings could help predict how long a woman is likely to be fertile for, so they can make informed decisions if planning for a family.

Females are born with all the eggs they will ever carry, which begin to mature monthly after puberty. When there are no eggs left, menopause occurs.

However, natural fertility can decline before menopause, because DNA in the eggs may be damaged before birth, or as the eggs mature later in life.

“It is clear that repairing damaged DNA in eggs is very important for establishing the pool of eggs women are born with and also for how quickly they are lost throughout life,” says co-author Eva Hoffmann of the University of Copenhagen, Denmark.

“Improved understanding of the biological processes involved in reproductive ageing could lead to improvements in fertility treatment options.”

The team also manipulated a few related genes in mice and found they were able to extend the creatures’ reproductive lifespan.

They identified two genes, called CHEK1 and CHEK2, that regulated a variety of DNA repair processes and changed how they were expressed in mice. They found that removing CHEK2 and over-expressing CHEK1 increased the reproductive lifespan of mice by 25%.

Mice are physiologically different to humans, and do not undergo menopause, but the team found that women who naturally lacked CHEK2 reached menopause on average 3.5 years later than other women.

“We saw that two of the genes which produce proteins involved in repairing damaged DNA work in opposite ways with respect to reproduction in mice,” says co-author Ignasi Roig, from the Autonomous University of Barcelona, Spain.

“Female mice with more of the CHEK1 protein are born with more eggs and they take longer to deplete naturally, so reproductive lifespan is extended.

“However, while the second gene, CHEK2, has a similar effect, allowing eggs to survive longer, in this case the gene has been knocked out so that no protein is produced, suggesting that CHEK2 activation may cause egg death in adult mice.”

The genomic data was collected from 201,323 women aged 40-60 from the UK BioBank and 23andMe. Subjects were predominantly of European descent, and so may not be representative of all women. Likewise, the association between genes and menopause (excluding CHEK1 and CHEK2) has not been experimentally confirmed to contribute to reproductive lifespans, and so does not show a causative association. But the research is still incredibly exciting, according to co-author John Perry of Cambridge University, UK.

“Although there’s still a long way to go, by combining genetic analysis in humans with studies in mice, plus examining when these genes are switched on in human eggs, we now know a lot more about human reproductive ageing,” he says.

“It also gives us insights into how to help avoid some health problems that are linked to the timing of menopause.”