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Study of how genes influence menopause may improve fertility treatment

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A new way of treating infertility in women has been suggested by a study that investigated the genes controlling the age of menopause.

When one of the genes was blocked from having an effect in female mice, the animals responded more strongly to infertility drugs often used to induce the ovaries to release multiple eggs during IVF treatment.

Menopause usually happens around the age of 50, with infertility occurring several years beforehand, but there is wide variation, with the process being influenced by the number of eggs left in the ovaries. Girls are born with about a million eggs and by the time women reach menopause, this has fallen to about a thousand. Age at menopause is affected by both the starting number of eggs and the rate at which they die.

The new study, undertaken by a large international consortium of researchers, looked at genetic variants that influence the age of menopause. It used existing records of 200,000 women of European descent who have offered their DNA for sequencing and filled in health questionnaires, such as in the UK Biobank project.

The researchers found 290 regions of DNA that collectively cause about a third of the genetic variation in the age at which menopause occurs and about 12 per cent of the total variation – as lifestyle factors such as smoking and drinking also have an effect. The researchers also looked at records for nearly 80,000 women of East Asian ancestry and found similar results.

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Many of the genes identified are known to be linked to processes of DNA repair. Some are active before birth, when a fetus’s eggs are made, while others seem to affect the rate at which eggs die in adulthood, says John Perry at the University of Cambridge School of Clinical Medicine, a member of the research team.

The gene found to have the biggest effect is CHEK2, which was already known to be involved in a process of programmed cell death called apoptosis. Women with a variant that stops this gene from working go through menopause 3.5 years later than those with a working version, the study found.

When the team genetically modified female mice so that they had no CHEK2, their eggs died off more slowly as they aged. These mice also released more eggs when they were treated with gonadotrophin, which is used during IVF to stimulate egg development.

If we could develop a drug that blocks CHEK2, it could help women having IVF release more eggs, says Perry. “CHEK2 is probably causing viable eggs to die,” he says. “If you could slightly dial that down you could get more eggs. But you would need to be really sure you weren’t fertilising damaged eggs.”

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The team is currently adding more women to the genetic study and Perry says the results could in future be turned into a blood test to tell women if they are at high risk of early menopause and loss of fertility.

“The findings pave the way for more-detailed studies that could lead to women being able to predict their menopausal age and to consider options to extend their reproductive age span,” Krina Zondervan at the University of Oxford said in a commentary article published alongside the new research paper.

Journal references: Nature, DOI: 10.1038/s41586-021-03779-7; Zondervan’s commentary DOI: 10.1038/d41586-021-01710-8

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