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These findings might lead to ways to help predict the timing of menopause, which marks the end of a woman's reproductive phase of life.
"Genetics only explains about half of the variability with the other half due to factors such as smoking. So, genetics will never be able to precisely predict a woman's age at menopause," said study co-author Anna Murray, senior lecturer in human genetics at the University of Exeter Medical School in Exeter, England.
The study appears in the Sept. 28 issue of Nature Genetics.
On average, menopause occurs around age 50 -- that's when the majority of the eggs in a woman's ovaries have been lost, Murray said.
"There is considerable variation in menopause timing, though, with the normal range spanning about 20 years. About 1 percent of women go through menopause before they are 40 years old. We do not fully understand the processes that control the loss of eggs throughout a women's life and thus leads to menopause," she said.
In the new study, researchers from 177 institutions worldwide analyzed the DNA of about 70,000 women of European ancestry. They found more than 50 genetic variations -- including 18 previously discovered ones -- that seem to be linked to the age a woman reaches menopause.
"We found that a large number of them are important for repairing damage to DNA," Murray said. "We therefore think that the main way in which eggs are lost throughout life, leading to menopause, is by damage to DNA within the eggs. This could happen before a woman is born and continue throughout life."
The researchers also found genetic links between late menopause and a higher risk of breast cancer. And they discovered genetic links to delayed puberty.
Murray cautioned that the genetic variations don't seem to have a huge effect on the timing of menopause. "This is why the genetic changes only alter the age at menopause by a few months, at most a year." But as more related genes are discovered, she said, scientists may get a better handle on predicting when a woman will enter menopause.
The researchers noted that environment plays a significant role. For example, the genes that repair DNA may be able to help repair some of the damage caused by an environmental factor, such as smoking. But when too much damage accumulates, it causes cells to die, the researchers said. Previous research has shown that women who smoke enter menopause an average of one to two years earlier, the researchers noted.
Dr. Kutluk Oktay, director of the Division of Reproductive Medicine and Institute for Fertility Preservation at New York Medical College in Valhalla, N.Y., called the research significant, and said it expands on previous studies by his team that provided insight into genes and childbearing in women.
The new findings confirm and expand the roles of genetic mutations and DNA's ability to fix itself in the aging of ovaries, he said. "Up until now, no good explanation existed as to why reproductive life span is limited as it is and why women's eggs tend to be of lower quality with advancing age," he said.
Better understanding of the system "is likely to lead to discoveries that can delay menopause and extend reproductive life," Oktay said. "It is also likely to enable strategies to prevent decline in egg quality, possibly reducing the risk of pregnancy losses and declining fertility seen in older women."
The study also offers insight into the link between menopause timing and breast cancer, said Dr. David Keefe, chair of Obstetrics and Gynecology at New York University School of Medicine in New York City.
"Early menopause could be a double-edged sword when it comes to breast cancer risk. On the one hand, early menopause reduces exposure to progesterone, an ovarian hormone which seems to increase the risk of breast cancer. On the other hand, early menopause may be a symptom of a compromised DNA damage-response system, which also contributes to cancer risk," Keefe said.
And what about the potential for predicting when a woman will enter menopause? Scientist Karla Hutt of the department of Anatomy and Developmental Biology at Monash University in Melbourne, Australia, said, "it would be hugely desirable to have a test that could accurately predict fertile lifespan and age at menopause.
"This would empower women by enabling them to plan for the future and make decisions about when to start a family without the risk of leaving it too late," said Hutt.
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