For decades, scientists have largely viewed the ovary as a passive storage system containing a limited supply of eggs that gradually disappears with age. A new study published in Nature Aging challenges that idea.
Researchers from the Centre for Genomic Regulation (CRG) and Radboud University Medical Center have discovered that mouse ovaries appear to actively regulate how many dormant eggs begin growing at any given time. Surprisingly, even as the total egg reserve falls dramatically with age, the proportion of eggs entering the growth phase remains almost exactly the same—about 14%.
According to senior author Dr. Elvan Böke, this suggests that the ovary may somehow sense the size of its remaining egg reserve and adjust egg activation accordingly. The mechanism responsible for this control is still unknown, but the finding reveals a previously unrecognized form of ovarian biology.
The Ovary May Be Monitoring Its Own Egg Supply
Female mammals are born with a limited number of immature egg cells, known as oocytes. Most remain dormant inside structures called follicles. Throughout reproductive life, only a small fraction of these eggs begin developing, while the majority eventually disappear without ever being ovulated.
The new research suggests this process may not happen randomly.
Researchers found that approximately 14% of the ovarian reserve was consistently located in the transitional stage between dormancy and growth, regardless of the mouse's age. In other words, when the total number of eggs decreased, the number entering this stage decreased proportionally.
This raises an important question: How does the ovary know how many eggs it has left?
The researchers suspect that an unknown hormonal or neuronal signaling system could be involved. Such a system might allow the ovary to monitor its reserve and maintain a stable fraction of eggs ready to enter the growth process.
If confirmed, this would fundamentally change how scientists understand the aging ovary.
A 3D Map Reveals the Ovary Across a Lifetime
The discovery was made possible by an ambitious effort to create a complete three-dimensional map of mouse ovaries throughout their reproductive lifespan.
Researchers examined more than 100 intact ovaries from mice at different ages. Using advanced tissue-clearing techniques, high-resolution microscopy and artificial intelligence, they were able to identify, count and classify individual oocytes throughout the entire organ.
In total, the team tracked more than 85,000 cells.
This approach allowed scientists to study the ovarian reserve in three dimensions rather than examining small sections of tissue under a microscope. It provided an unprecedented view of how eggs are distributed, activated and lost over time.
The researchers also developed AI-based image analysis tools capable of automatically identifying and classifying ovarian cells, making it possible to analyze an enormous amount of biological information.
Identical Mice Can Have Very Different Egg Reserves
Another unexpected discovery was the enormous variation between individual mice.
By the time mice reached puberty, some had up to three times more oocytes than other genetically identical mice raised under the same environmental conditions.
This was particularly surprising because the animals had essentially the same genes and lived in the same conditions.
The difference was not caused by genetic variation. Instead, the researchers found that the variation was already present before puberty, suggesting that events occurring very early in life—even during embryonic development—could influence the size of an individual's ovarian reserve.
Mice with smaller reserves also tended to have smaller ovaries and fewer growing eggs.
This suggests that the conditions established early in life may influence ovarian function for the rest of an animal's reproductive lifespan.
More Eggs Together May Mean More Activity
The study also challenges another long-standing idea about how dormant eggs interact with one another.
Scientists have previously suggested that dormant oocytes packed closely together might suppress each other's activation. If this were true, regions containing many dormant eggs should have relatively low levels of egg activation.
The researchers found the opposite.
Areas with the highest concentration of dormant oocytes were also the areas where the greatest number of eggs emerged from dormancy.
This finding suggests that densely packed eggs may not inhibit activation as previously thought. Instead, the local organization of the ovary could play a more complicated role in controlling which eggs begin developing.
Researchers Identify a Developmental Bottleneck
The team also discovered a previously unrecognized checkpoint during egg development.
At around 60 micrometers in diameter, many growing follicles appeared to pause before progressing to the stage where they become responsive to hormonal signals.
This developmental bottleneck could be especially important because it represents a potential point where egg survival or loss is determined.
Understanding why some follicles pass this checkpoint while others stop could eventually help researchers understand why ovarian reserves decline with age.
Could This Help Delay Menopause?
The findings could have major implications for reproductive aging, although researchers emphasize that much more work is needed.
Humans are estimated to begin life with roughly one million oocytes. The number falls to around 400,000 by puberty and eventually reaches only about 1,000 near menopause. Only a small fraction—around 400—are typically ovulated during a woman's reproductive lifetime.
Most eggs are lost naturally without ever being released.
If scientists eventually discover why so many eggs are lost and how the ovary regulates the rate of egg activation, it could open new possibilities for reproductive medicine.
One future goal could be finding ways to slow unnecessary egg loss or carefully modify the ovarian system to preserve reproductive function for longer.
However, this does not mean that a treatment to delay menopause is currently available. The present findings are an important biological discovery, not a medical therapy.
Important Differences Between Mice and Humans
The researchers also caution against directly applying the mouse findings to humans.
Mice and humans have major differences in reproductive biology. A mouse can ovulate from both ovaries every four to five days, while humans typically release one egg approximately every 28 days.
Mice also begin life with a much smaller ovarian reserve—around 5,000 oocytes compared with roughly one million in humans.
These differences mean that the timing and scale of egg depletion are not identical between the two species.
Human ovarian reserves also vary widely because people differ genetically and experience different environmental conditions throughout life. Therefore, much larger human studies will be necessary to determine whether the same 14% activation pattern exists in women.
A New Tool for Future Research
The researchers have already demonstrated that their imaging and analysis approach can be applied to human ovarian cortex tissue.
They have also made their AI-based analysis workflow, microscopy images and trained model available to other researchers through the open-source BiaPy platform.
This could make it easier for scientists around the world to study ovarian tissue using similar methods.
The ability to map individual oocytes in three dimensions could eventually help researchers investigate fertility, reproductive aging, ovarian diseases and the biological processes behind menopause.
A New View of Reproductive Aging
The biggest message from the study is that the ovary may be far more active and sophisticated than previously believed.
Rather than simply being a storage container in which eggs gradually disappear, the ovary appears to maintain a carefully regulated system that controls how many eggs remain ready to grow—even as its total reserve declines dramatically.
The discovery of a stable 14% activation fraction, striking differences between genetically identical animals and a previously unknown developmental bottleneck all point toward a complex regulatory system that scientists are only beginning to understand.
The next major challenge is to identify the biological signals that allow the ovary to monitor and regulate its egg supply.
If researchers can uncover that mechanism, it could provide a completely new framework for understanding female reproductive aging—and potentially open new avenues for preserving ovarian function in the future.
Reference: D’Angelo, A., Franco-Barranco, D., Musy, M. et al. Three-dimensional mapping of intact ovaries reveals the aging dynamics of the ovarian reserve. Nat Aging 6, 1580–1591 (2026). https://doi.org/10.1038/s43587-026-01178-z
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