Fertility is in the genes

Researchers already suspected that fertility must have something to do with genetics

The age at which a woman enters menopause is partly determined by her DNA. Genes for maintenance and repair of DNA are especially important. This is apparent from research in which Rotterdam scientists collaborated.

The researchers already suspected that fertility must have something to do with genetics, says gynecologist Prof. Joop Laven of Erasmus MC. But it was a surprise that the genes for repair and maintenance of DNA are especially important. ‘I thought: we must find genes that influence the maturation of the eggs. But nothing turned out to be less true.’

Menopause
The scientists examined the genetic material of more than 200,000 women, of whom it was known at what age they had entered the menopause. They found 290 genetic variants that affect the age at which menopause begins. Laven: ‘Because the menopause is preceded by a period of infertility and reduced fertility, we have therefore also found genes that are associated with fertility.’ Many of the genes found have a role in the maintenance and repair of DNA, in both sex cells and normal body cells.

As a check, the researchers tested the 290 variants in another population of nearly 300,000 women. There, the variants often showed the same effects on the menopausal age. Laven and six colleagues from Erasmus MC – all members of a large international consortium – published their findings in the leading scientific journal Nature .

Damage to eggs
The better DNA repair and maintenance works, the longer the fertile period. That’s how it works: a woman is born with a limited supply of eggs. Over the years, those eggs are damaged by smoking, obesity, other bad living habits and by exposure to all kinds of substances and radiation that cause DNA damage. This also explains the increased risk of a child with birth defects in older mothers. Their eggs have suffered damage that is too great to be properly repaired at a later age. If it is possible to repair the DNA damage properly, more ‘well-repaired’ eggs remain and the fertile period is therefore longer.

The onset of menopause is a tell-tale sign of how well DNA is being repaired and maintained
The new conclusions are in line with earlier findings among the Sami, the indigenous inhabitants of Lapland. Sami women do not use contraception, so are an ideal group to study natural aging and its relationship with fertility. What turned out? The women who had children at a later age – between 40 and 45 years – more often lived to be 90 years or older.

‘Apparently, the aging of your body partly determines how long the fertile period will last. This invalidates the old adage that you start to age after menopause. Rather, menopause is the result of aging and aging precedes menopause. The start of the menopause is, as it were, an indicator of how well DNA is being repaired and maintained’, says Laven.

PCOS fertile longer
Women with polycystic ovarian syndrome, or PCOS – a syndrome in which multiple ovarian cysts are present, were already known to be fertile for longer than women without PCOS. This also appears to have to do with DNA repair, according to previous research in which Laven’s research group collaborated. Women with PCOS have more of the better variants of the genes that ensure DNA repair and maintenance.

It turns out that women with PCOS also use those good genes. When the researchers looked at their embryos obtained through IVF, they were found to be much healthier and have less DNA damage than embryos from similar-aged women without PCOS. Laven: ‘That completely explained why women with PCOS can often still have children after the age of 40, while that seems almost impossible for women without PCOS.’

Early Transition
For women who enter the menopause early – roughly before their 40th birthday – the exact opposite applies to women with PCOS. Women with primary ovarian insufficiency (POI), as an early menopause is called, have many of the genetic variants that indicate poorer DNA repair. This not only shortens the fertile period, but also increases the risk of other aging-related diseases such as Alzheimer’s, diabetes and cardiovascular disease.

Laven therefore has some advice for women whose mothers entered the menopause early. ‘We don’t have a medicine to improve DNA repair. But we know that a healthy diet has a beneficial effect on aging in general. In the future, we could even use the genes we’ve found to advise women on healthier aging.’

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