For the past 70 years scientists have taught us that female mammals are born with a finite ovarian egg supply, and that this reserve steadily declines over the lifespan. In humans, that supply dwindles until menopause, when it goes bankrupt.
Yet a growing body of research is challenging that dogma. Over the past two decades, scientists have identified cells in the adult ovaries of mice, cows, pigs, non-human primates and humans that, under certain conditions, appear capable of generating new immature egg cells, known as oocytes. They aren’t certain whether these cells can produce viable eggs. Nevertheless, the findings are fueling a contentious debate in reproductive biology and raise a provocative, and controversial, possibility: Ovarian aging may be far more dynamic than we thought—and perhaps even reversible.
“Previous to this work, every response to questions about infertility or menopause was rooted in the concept that women only have a fixed number of eggs to work with,” says Jonathan Tilly, a biologist at Northeastern University. “But what if that wasn’t the case?”
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A New Understanding of the Ovaries
Scientists first proposed the idea that ovaries might generate new eggs through life as early as the 1920s. The idea lost steam after influential work in the mid-20th century by British scientist Solly Zuckerman, who counted oocytes in animals at different life stages. He didn’t detect the formation of any new oocytes during his experiments and so concluded that ovaries just couldn’t make new cells.
His conclusion went unchallenged until 2004, when Tilly and his team published a paper in Nature arguing that the “fixed egg pool” idea didn’t add up mathematically. The reason why has to do with a process called follicular atresia—the natural degeneration and death of oocytes before they can potentially become a mature egg. But the rate at which oocytes died off seemed inconsistent with the number that remained later in life. This discrepancy “pointed to the idea that there must be some kind of new egg production happening,” Tilly says.
Tilly proposed that specialized stem cells, called oogonial stem cells, or OSCs, must be producing new oocytes—just as spermatogonial cells continue to make sperm in testes. Stem cells are rare, unspecialized cells that can become a variety of cell types. They are incredibly useful for bodily repair and regeneration.
In 2009, researchers from Shanghai Jiao Tong University successfully isolated OSCs from adult mice and studied their oocyte-forming ability. Then, in 2012, Tilly and others showed the cells could be found in adult human ovaries.
In 2017, Tilly’s team used a genetic tool to engineer female mice so that any newly formed oocytes would glow fluorescent green under a microscope. The findings suggested that not only do newly generated oocytes keep adding new eggs to the mice’s ovarian reserve, but also that those new cells could be used to produce viable mouse offspring. In 2023, Tilly's team reported that while OSCs persist into old age in mice, they appear to lose their ability to generate new oocytes as key developmental genes become inactive—a pattern that was also seen in human ovarian tissue and may explain why OSCs still exist post-menopause.
Some scientists treat the entire idea of OSCs with fierce skepticism. They think Zuckerman’s work in the 1950s stands as the final word on whether the ovaries can create new egg cells.
Evelyn Telfer, chair of reproductive biology at the University of Edinburgh, notes that a scientific consensus, once formed, are difficult to overturn. “You’re part of a community, and that community holds these views, and if you’re going against those views, it’s difficult to get funding,” she says.
Telfer herself was initially cautious about Tilly’s findings. But after collaborating with him on research using human ovarian tissue, she has become convinced that cells exist within adult ovaries, and can, under certain circumstances, develop into oocyte-like structures. “These cells underwent a transformation within the tissue,” she says. “They formed what appeared to be follicles,” or small, fluid-filled sacs inside ovaries where eggs develop.
Some scientists still have doubts about whether OSCs exist. But, Telfer says, many have turned to the next question: If they exist, what can they do?
Aaron Hsueh, a professor of obstetrics and gynecology at Stanford University School of Medicine, says Tilly’s methods of using proprietary antibodies to prove these oocyte-forming cells exist are suspect. “I’m not completely against this idea [of ovarian stem cells], but I'm against Tilly’s approach,” Hsueh said. Tilly says that his antibodies are available from a commercial vendor, that Hsueh cherrypicked studies to support his ideas and “ignores the fact that nearly 100 peer-reviewed papers have been published by numerous labs around the world supporting the existence of OSCs and/or the occurrence of postnatal oocyte formation during adulthood since our initial 2004 Nature paper.”
For her part, Telfer says that while she is sure OSCs exist, it’s unclear whether they can produce viable human eggs.
Ultimately, the science is reshaping how some researchers think about the ovary itself. For decades, menopause has been viewed as the inevitable exhaustion of a fixed egg supply. But if that can be halted or reversed, the biology of reproductive aging may prove far less static than scientists once believed.
Eggs Are Part of a Larger System
Adult-generated oocytes could lead to treatments for infertility, Tilly says. He also hopes such OSCs could restore ovarian function in cancer patients—and one day treat symptoms of menopause or even delay it, extending women’s health span. The ovaries are complex systems, however, and it’s just not known if making new eggs would have those effects. “The ovary’s not just about the eggs,” Telfer points out.
Eggs do not exist in isolation; they are housed within follicles and supported by surrounding somatic (non-reproductive) cells that produce hormones and regulate egg development. As the ovaries age, those tissues become “increasingly fibrotic and mechanically altered,” according to Telfer, potentially disrupting the signals needed for OSCs to function properly.
Tilly compares the ovary to a house and the stem cells to its inhabitants. The stem cells, he says, may be present long after menopause, but “the house has fallen into disrepair,” he says. “The environment [the cells] exist in doesn’t function appropriately anymore to support their activity.”
But maybe the “house” isn’t always necessary. Tilly’s lab is working on platforms to grow engineered ovarian tissue; these “organoids” contain both a patient’s own OSCs and hormone-producing support cells. The initial goal is not to produce babies, but rather to work toward restoring natural hormone function in people who have lost it.
Scientists could one day take and store a person’s OSCs before or after menopause, grow them as organoids outside the body, and reimplant the tissue when needed. The organoids would not need to be placed into the ovary itself—they could be implanted in the arm, for example. The idea is that the reimplanted tissue would restore natural hormone production as an alternative for hormone replacement therapy, which can carry unwanted side effects, isn’t always effective, and isn’t recommended for some people.
Tilly’s lab has isolated “dormant” OSCs from ovarian tissue donated by women decades after menopause; but this work has not yet been published, he says. “It really changes [our] perspective on why ovaries fail,” he says. His team also hopes to investigate whether OSCs from women who have already gone through menopause can be “woken up” and coaxed to produce viable eggs again. “This early-stage research direction, albeit preliminary, looks promising,” he says.
As tantalizing as these results are, we are a long way from an approved OSC-based therapy for women. Researchers still need to determine whether the lab-grown ovarian tissue implants are safe and function reliably over time. “We need to do a lot more of the basic work,” Telfer says. If dormant regenerative cells can persist however, they could shape future fertility and menopause treatments.
