Why does female fertility decline so quickly? A question that seemingly concerns only egg cells is now gaining a whole new dimension: the key lies in the ovary as a complete ecosystem — the nerves, support cells, blood vessels, and connective tissue that surround each egg and codetermine its fate. New research, published on October 9, 2025, reveals that the speed of ovarian aging and the decline in fertility do not only depend on the quality and number of egg cells but also on changes in the surrounding cellular niches that, with age, remodel the way follicles are recruited and mature.

The biological clock ticks loudest in the ovary

In the period between the mid-twenties and age 40, the probability of conception in a single cycle significantly decreases. The reasons are multifaceted: from slower follicle maturation and loss of follicular reserve to more frequent chromosomal abnormalities in egg cells that occur with age. Numerous demographic and clinical observations confirm this trend and show that with increasingly delayed family planning, the need for solutions that preserve reproductive health increases.

From the "egg cell problem" to a story about the entire tissue

It has long been believed that the decline in fertility was almost exclusively a consequence of the weakening quality of oocytes and their increasingly rapid disappearance. However, detailed 3D visualizations of human and mouse ovaries, along with single-cell analyses, now show that the egg cell microenvironment — including glial cells, sympathetic nerves, and fibroblasts — undergoes systematic, age-related changes. These changes alter the way follicles are recruited, mature, and ovulate, as well as how the tissue heals and responds to stress. In this sense, the ovary is shown to be a dynamic network of intercellular conversations, not just a mere "drawer" of egg cells.

"Pockets" of egg cells and an uneven map of the ovary

In whole sections and transparent 3D views of human ovaries, egg cells are not found in a homogeneous distribution but are grouped into clusters or "pockets" surrounded by areas without egg cells. With age, the density in these pockets thins out, suggesting that local conditions — e.g., blood supply, the presence of nerve fibers, or the state of the extracellular matrix — can determine how long an individual follicle survives in dormancy and whether it will even begin to grow.

A new player: the nervous system in the ovary

One of the most intriguing findings is the dense network of sympathetic nerves that becomes even denser with age. In experiments on mice, targeted weakening of these nerves increased the number of "sleeping" follicles but at the same time reduced the number of those that begin to mature — as if the nerve signals serve as a regulator that signals when it's "time to grow." In addition to sympathetic fibers, glial cells have also been identified in the ovary, known from the brain as "guardians" and metabolic support for neurons; their presence within the ovarian niche opens up a whole new field of research on the connection between the nervous system and reproduction.

Inflammation, fibrosis, and "stiffening" with aging

As ovaries age, fibroblasts and other stromal cells change their work program: they promote the creation of collagen and other extracellular matrix proteins, which leads to scarring (fibrosis) and an increase in tissue stiffness. These changes, along with low-grade inflammation, occur in the ovary earlier than in many other organs and can disrupt the finely tuned mechanical and biochemical signals necessary for proper follicle maturation. Clinical and preclinical work increasingly highlights the importance of the stromal microenvironment in the decline of fertility and points to fibroinflammatory axes as potential therapeutic targets.

What actually happens with "reserve" over the years

A woman is born with millions of primordial follicles, but most disappear even before puberty. During the reproductive years, a portion of follicles is recruited each month, while most die by natural selection. Anti-Müllerian hormone (AMH), secreted by the granulocytes of small growing follicles, serves in clinical practice as a practical and relatively stable marker of ovarian reserve — its serum concentration, on average, falls as age increases. Although AMH is not a "fertility test," it can help assess the potential response of the ovaries to stimulation in assisted reproductive technology procedures and identify women with an accelerated loss of reserve. The latest studies emphasize the need for age-specific nomograms and standardization of measurements to avoid misinterpretations.

Aneuploidies and pregnancy risks with age

In addition to the decline in the number of follicles, the proportion of aneuploid egg cells increases with age, mainly due to spindle division disorders and chromosome nondisjunction. This increases the risk of spontaneous miscarriage and reduces the likelihood of a healthy pregnancy, even if embryos are selected based on appearance. These insights are important for counseling couples who are planning a pregnancy later in life and for planning personalized IVF protocols.

Technologies that opened the "black box" of the ovary

The revolution in understanding the ovary came with a combination of 3D clearing and optical imaging of the entire organ — without slicing into thin sections — and single-cell and single-nucleus multiomic analyses that map active genes and regulatory elements in each cell. These approaches create reference atlases of the human and mouse ovary throughout age, reveal cell subtypes that were not previously recorded, and point to signaling pathways specific to ovarian aging, such as mTOR signaling and an imbalance in the communication between immune and stromal cells.

Glycosylation and proteomic changes

In addition to transcriptomic insights, there is growing interest in changes in glycosylation of protein transporters and receptors during ovarian aging, which can alter signaling between cells and their sensitivity to hormones and cytokines. Catalogs of the mouse N-glycoproteome throughout its lifespan offer a starting point for understanding how the biochemical "decorative" features of proteins change as the ovary ages.

What this means for everyday clinical practice

For gynecologists, reproductive endocrinologists, and embryologists, the new picture of the ovary has practical consequences: fertility assessment and treatment planning should not rely solely on the number of follicles or age but should also take into account signs of stromal inflammation and fibrosis, innervation patterns, and possible metabolic and vascular disorders. This also explains why sometimes "mismatched" profiles are encountered — for example, a normal AMH but a poor response to stimulation, or vice versa — because the microenvironment can limit or enhance the ovary's ability to respond to gonadotropic signals.

Triggers that accelerate ovarian aging

The dynamics of ovarian aging are also influenced by factors outside of genetics: smoking, some forms of therapy, and possible exposure to environmental toxins and heavy metals that act as endocrine disruptors. The connection between such exposures and lower AMH and earlier menopause encourages public health measures to reduce risk, especially in mid-life.

Comparison of humans and mice: how reliable is the model?

Although humans and mice have different reproductive windows, comparative maps show a surprising similarity in the organization of the ovary with age. This opens the way for faster preclinical testing of interventions that target nerve pathways, immune interactions, and matrix remodeling in the ovary. It also helps explain why certain drugs and genetic manipulations produce similar phenotypes of reduced reserve and oocyte quality in both species.

Fertility by age: what to realistically expect

Regardless of technology, biological trends remain relentless: fertility is highest in the late teens and twenties, and it noticeably declines after age 35. Around age 40, the chance of pregnancy in a single cycle can drop to a single digit, while the risks of miscarriage and complications increase. These numbers vary among populations, but the message for family planning remains similar: the older a woman is, the more difficult it is to achieve pregnancy naturally, so informed and timely counseling has increasing importance.

Why AMH and antral follicle count are not a crystal ball

Although AMH and ultrasound antral follicle count are indispensable tools, their interpretation requires caution. AMH is better at predicting the ovarian response to stimulation than the chances of spontaneous conception or the exact timing of menopause. Informing patients about these limitations reduces the misuse of the test and exaggerated expectations. Because of this, more work is being done on creating age-specific nomograms and standardizing measurement methods.

What tomorrow's therapies will bring

The understanding that the ovary is a neuro-immuno-vascular ecosystem opens up the possibility of new therapeutic strategies: modulation of sympathetic signaling, antifibrotic and pro-regenerative approaches, targeted anti-inflammatory interventions, and even soft tissue biomaterials for favorable "pre-programming" of the microenvironment. In clinical research, approaches are already being considered that target tissue stiffness and excessive matrix accumulation. At the same time, multiomic maps help identify signaling axes specific to the ovary — e.g., metabolism and mTOR — that could be modulated by drugs developed for other indications.

Implications beyond fertility

Accelerated ovarian aging is linked to a higher risk of cardiovascular, metabolic, and bone diseases after menopause. If the physiological "aging of the ovary" could be slowed down — even without extending the reproductive period — the health benefits could be tangible and widespread. The concept that the "fountain of youth" might be in the ovary is no longer just a metaphor but a research program that can now be measured, mapped, and systematically tested.

What readers can concretely do today

• Talk to a doctor about individual goals and a timeline for having children, taking into account age and personal history.


• Understand what AMH is — and what it isn't — and view the results in the context of an ultrasound and clinical picture, not as an independent "judgment on fertility."


• Be mindful of lifestyle factors and exposures that can accelerate ovarian aging, including quitting smoking and reducing contact with potential endocrine disruptors whenever it is reasonably feasible.


• Inform yourself about the options for fertility preservation in cases where family planning is realistically delayed or medical procedures are anticipated that could affect ovarian reserve.