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A grand challenge: slowing the biological clock

Yale Medicine Magazine, 2019 - Online


Why do women lose the ability to bear children at a certain age—and what, if anything, can medical science do about that arbitrary end?

Imagine you’re a 32-year-old woman. You recently finished an MD-PhD program, now you’re doing your residency, and you plan on completing a fellowship after that. You’re single. You want to have a baby someday, but you accept the fact that that day may be years off. Meanwhile, you’re concerned that if you wait too long, you might not be able to get pregnant.

That kind of scenario is driving a small but growing number of women to consider oocyte cryopreservation—freezing their eggs. At a time when more women than men receive graduate degrees and when women are increasingly engaged in professional careers, the option of freezing young eggs for use later is becoming mainstream.

The sad fact is that women’s ovaries begin aging much earlier than most people realize. In the past, it was commonly thought that a woman should aim to have her first child before age 40, but fertility experts now warn that the biological clock starts ticking much earlier than that. “Most women are infertile at 45, but many are infertile at 35,” said Emre Seli, MD, professor of obstetrics, gynecology & reproductive sciences at Yale School of Medicine.

When a female is born, she already possesses all of her eggs—more than one million of them nestled in the follicles of her ovaries. By the time she reaches puberty, most of the eggs have died, and egg mortality accelerates after that. At menopause, they are all gone.

In recent decades, medical science has made great progress in enabling people with fertility issues to have children. Thanks to in vitro fertilization and other techniques, and socioeconomic changes in society, the number of births to women in their late 30s in the United States more than doubled between 1980 and 2010 while the overall birthrate declined, according to the National Center for Health Statistics (NCHS). Yet medical researchers have made little progress in understanding—and slowing—the process of reproductive aging.

Seli and others at Yale are at the forefront of research into the mechanisms of reproductive aging, with a goal of slowing it. One of Seli’s most recent studies of mice showed that when mitochondria (the energy generators of all cells, including eggs) lose their ability to control stress, it causes ovarian aging. They believe they have found a technique for addressing it.

An important advance in measuring the number of eggs which naturally decrease with ovarian aging was produced by David Seifer, MD, professor of obstetrics, gynecology & reproductive sciences. His research over the past three decades has led to a simple blood test, measuring the antimullerian hormone (AMH), which helps determine the health of a woman’s ovaries, estimate her egg count and provide a real-time assessment of her biological clock. “I just stuck with it over years and made slow and steady progress, and it ended up being something that helps in the timing of creating families,” he said.

Back in the 1990s, Seifer was investigating ovarian follicular growth factors which were involved in ovarian cell aging and had discovered that AMH was present in women's follicular fluid who were undergoing IVF but was unclear about its exact physiological role. He read that when the AMH gene had been knocked out in female mice, their eggs aged prematurely and wondered if AMH might play a role in the human female egg response to medications given in IVF. Seifer focused on the possible measurement of AMH in the blood as a possible prognostic indicator of the number of eggs prior to women undergoing IVF treatment.

The test, finally approved by the U.S. Food and Drug Administration in 2018, can be performed in a doctor’s office in 20 minutes.

Seifer believes that in the next five to 10 years, medications based upon the chemical structure of AMH will be introduced that slow the ticking of the female ovarian biological clock. “These newly developed drugs could lead to further clinically relevant breakthroughs in the treatment and understanding of the ovarian aging process,” Seifer said. “Delaying ovarian aging would be just one of many potential applications of this new class of drugs for several reproductive disorders.”