Medical College Researcher Discovers Why Women Lose Fertility as they Age

Date: February 13, 2013
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Donna Moriarty
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Valhalla, N.Y.— A team led by a New York Medical College physicianresearcher has discovered the factors that decrease female fertility as a woman ages.

The findings, which were published today in the journal Science Translational Medicine, could lead to new research that could potentially boost a woman’s fertility in her later years.

Led by Kutluk Oktay, M.D., a clinician scientist specializing in preserving the fertility of female cancer patients, a research teamexamined eggs collected from women aged 24-41 undergoing in vitro fertilization and fertility preservation procedures. The researchers found that as eggs get older, they lose their ability to repair DNA double-strand breaks.

By measuring the level of DNA repair enzymes in the collected eggs, Oktay and his team found that older eggs are less able to repair DNA damage, resulting in the accumulation of DNA breaks, hence creating a growing fraction of faulty eggs. The body usually rids itself of these faulty eggs with increasing speed (explaining the sharp drop in fertility after ages 36-37). Those faulty eggs the body cannot shed result in abnormal embryos, explaining why pregnancy losses and birth defects increase with age, and why women have a hard time conceiving past their mid-thirties.

“Our bodies and cells are constantly exposed to environmental forces that damage our DNA,” said Dr. Oktay. “When it comes to a woman’s eggs, the inability to repair this damage decreases fertility, and also leads to chromosomal anomalies.”

The findings help explain why women rapidly lose both increasing numbers of eggs as well as their reproductive capacity as they age. “We found that as women age, they increasingly lose their natural ability to guard against DNA damage to their eggs,” said Dr. Oktay. “As a result, fewer and fewer eggs are left in a woman’s ovaries. Moreover, those that remain are increasingly faulty, explaining why older women have a difficult time becoming pregnant, remaining pregnant, and having healthy babies.”

Some DNA-damaged eggs may result in pregnancies, but developing embryos may be more susceptible to chromosomal abnormalities. This is because the same genes and molecules that play a role in fixing DNA damage may also play a role in making sure chromosomes are stable.

One of these genes is BRCA1, widely known as the “breast cancer gene.” Previous work by Dr. Oktay and his team found that women with BRCA1 mutations produce fewer eggs in response to fertility drugs compared with women lacking the mutation.

In the clinical portion of the study released today, Dr. Oktay and his colleagues assessed fertility in a group of 80 women tested for BRCA1 mutations. By measuring the levels of anti-Mullerian hormone in blood samples, the researchers were able to estimate how many eggs a woman has left in her ovaries. They found that women with BRCA1 mutations had a lower ovarian reserve than women without the mutation. Working with animals whose BRCA1 gene and other DNA-repair genes were “silenced” (their gene expression capacity reduced) showed more DNA damage than was found in the egg cells of the controls.

The researchers concluded that the proteins responsible for repairing DNA damage in egg cells work less efficiently with age. In instances where DNA damage cannot be repaired, egg cells may die off through a “cell suicide” mechanism. Eggs unable to repair double-strand breaks are also less likely to be fertilized—another clue to understanding why fertility declines with age.

The results of the study, “Impairment of BRCA1-Related DNA Double Strand Break Repair Leads to Ovarian Aging in Mouse and Human,” suggest that BRCA1 and other DNA-repair genes may contribute to decreased fertility in aging women. The authors argue that these findings could conceivably lead to treatments that might delay reproductive aging and the aging process itself.

Kutluk Oktay, M.D., is professor of obstetrics and gynecology, cell biology and anatomy, medicine and pathology at New York Medical College. He is director of the medical college’s Division of Reproductive Medicine and Infertility. In addition, Dr. Oktay is director of the Laboratory of Molecular Reproduction and Fertility Preservation in the Department of Obstetrics and Gynecology.He is also the medical director of the Institute for Reproductive Medicine and Fertility Preservation in Rye, N.Y.