delaying marriage even longer
Study Casts Doubt on Limits to Fertility

By Rick Weiss
Washington Post Staff Writer
Thursday, March 11, 2004; Page A01

For more than half a century textbooks have taught that female mammals -- be they mice, cows or women -- are born with all the eggs they will ever have.

The result is one of the great sexual disparities: Males, who make fresh sperm daily, can sire children at virtually any age, whereas females gradually deplete their limited supply of eggs to the ticking of the biological clock.

Now Harvard researchers have come to the radical conclusion that female mice produce a constant stream of new egg cells as adults -- challenging a central dogma of reproductive biology and raising the heretical possibility that women, too, clandestinely produce fresh eggs for at least the first half of life.

The findings suggest the possibility of extending fertility much longer than was thought possible and even restoring fertility in women whose ovaries have shut down.

"I'd regard this as one of the most significant discoveries in the reproductive field in the past several decades," said Duke University developmental biologist Haifan Lin, who studies egg development. "It provides a new potential opportunity for prolonging the reproductive span of females."

After all, Lin and others said, if women are busily making eggs for their first 40 or 50 years -- rather than simply spending down a nonrenewable endowment -- then it may be possible to tweak that egg-production machinery in ways that can keep it going a decade or two longer.

It may even be possible to transplant into older or chemotherapy-damaged ovaries some egg-producing cells that have been frozen since youth, restoring a woman's lost fertility.

Those options could have profound social impact by granting women more freedom with regard to the timing of careers and parenthood. Even if women chose not to have children later in life, an extended period of fertility could have significant health implications -- perhaps delaying the onset of heart disease, osteoporosis and other ailments that become more prevalent after menopause but also possibly increasing the risk of other diseases, such as breast cancer, that have been linked to years of exposure to the hormones the ovaries churn out.

Experts warned that the study, led by Harvard developmental biologist Jonathan Tilly and published in today's issue of the journal Nature, will have to be confirmed by others.

"At this point I'm agnostic," said John Eppig, a reproductive biologist at the Jackson Laboratory in Bar Harbor, Maine. "My mind is racing."

But Tilly said his group already has completed an added study that supports the idea that women, too, are still making eggs as young adults.

If doctors can learn how to tap that egg-making capacity to delay menopause, said Marian Damewood, president of the American Society for Reproductive Medicine, "that could be the most significant advance in reproductive medicine since the advent of in vitro fertilization more than 25 years ago."

Scientists in the early part of the 20th century went back and forth on the question of whether mammals could make fresh eggs after birth, but a 1951 journal article seemed to settle the issue in the negative, and few revisited the question after that. By examining ovaries retrieved from experimental animals -- or from cadavers and surgical patients of various ages -- scientists documented a declining number of egg cells with age.

In humans that decline starts just five months into fetal life, when the number of eggs -- each nestled in a hormone-secreting niche called a follicle -- peaks at about 7 million. The vast majority are gone by birth, and the last typically disappears in a woman's 40s or 50s, prompting menopause.

Tilly's work shows that the daily rate of egg loss is actually much higher than scientists knew -- at least in mice -- but the loss is largely masked by simultaneous production of new eggs.

"As much as we still ourselves are in disbelief that the dogma is wrong, it's very real," said Tilly, director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital in Boston. "The dogma is wrong."

The new view that eggs are being made every day even as a somewhat larger number of them shrivel and die could resolve some seeming contradictions.

For one thing, Tilly said, "it makes no sense to have a fixed population of eggs that have to sit around for decades until they are used," accumulating mutations and other problems along the way. In less complex animals, including insects, females as well as males make sex cells into adulthood. It is gratifying, Tilly said, to see mice following that sensible pattern.

In one set of tests, Tilly's group showed that on a single day as many as 1,200 egg-encasing follicles were dying in the ovaries of young adult mice -- far too many for the initial supply to last a reproductive lifetime. The group also identified a population of what appear to be egg stem cells -- the self-replenishing kind of cell that makes egg cells -- in one region of the ovary. Each ovary seems to have about 63 such cells -- few enough to have been missed by early ovary gazers.

Another experiment showed that meiosis, a process unique to the production of sperm and eggs, was occurring in the ovaries of adult mice. The team also used molecular markers to show that some stem cells in adult mouse ovaries seemed to be growing into new eggs.

For one strain of mouse, the team calculated that about 77 new eggs are produced every day -- not a huge number, but infinitely bigger than zero.

"Seventy seven eggs a day! That's just unbelievable," said Hans Scholer, a University of Pennsylvania mouse stem cell expert. "That's really a major finding."

To get a sense of whether women may also be making eggs, Tilly looked at the incidence of premature menopause in cancer patients treated with various cancer drugs. In results not published in the Nature paper, he found that 106 of 107 women treated with busulphan, which specifically knocks out cells making eggs or sperm, went into premature menopause, compared with only 69 of 140 treated with different drugs. That difference suggests that egg production was indeed going on in the women's ovaries, Tilly said.

The new thinking has quickly raised new questions, including why egg stem cells die or shut down in middle age and whether drugs or other stimuli might keep them going. Scientists already know some of the hormones that insects use to maintain egg production in adulthood, and similar hormones have been identified in mice and humans. Scientists said they were now eager to test the effects of those hormones on mammals.

Extended fertility would have its ups and downs, said Judith Houck, a historian of medicine at the University of Wisconsin at Madison. "Historically, in the 20th century, menopause has been seen as the moment when women finally get to live for themselves . . . a time when women could look more carefully at intellectual interests, take up painting, go back to school," Houck said. Delaying of menopause could mean delaying that transition, she warned.

"On the other hand," Houck said, "more and more women are choosing to have careers, and the most convenient way to do that is to leave childbearing until at least their 30s. So it may help them replicate the male model of success."