Ovarian reserve and exercise

Physical activity may be linked to mechanisms involved in ovarian aging. A study published in the scientific journal Nature Aging combined data from large human populations, genetic analyses and experiments in mice to investigate the relationship between exercise, adiponectin and ovarian reserve.

The experimental results are striking. In the animals, exercise was associated with the preservation of a larger number of primordial follicles and with changes in molecular pathways involved in follicle activation.

For women, however, the interpretation needs to be more cautious.

The human data show associations. They do not demonstrate that exercising preserves ovarian reserve, extends fertility or delays menopause.

For gynecologist and obstetrician Dr. Vanessa Cairolli, one of the most relevant contributions of the work lies precisely in moving from epidemiological observation to investigating the possible mechanisms involved.

According to her, combining large population databases with experimental models makes it possible to point to specific biological pathways, especially the role of adiponectin produced in the ovary itself and the modulation of the mTOR pathway. These are mechanisms that could guide new research on how the ovarian microenvironment responds to physical activity.

What showed up in the human data

The researchers analyzed 152,435 participants from the UK Biobank and another 12,418 from the National Health and Nutrition Examination Survey, or NHANES, in the United States.

In both databases, premenopausal women had higher levels of physical activity than postmenopausal women.

In the UK Biobank, among women who had already gone through menopause, higher levels of physical activity were also associated with a slightly later age at menopause.

The associations held after statistical adjustment for various factors.

This, however, does not establish a cause-and-effect relationship.

This part of the study has a cross-sectional design. As a result, it is not possible to tell from these data alone whether physical activity influences the timing of menopause or whether other differences between premenopausal and postmenopausal women contribute to the observed association.

So-called reverse causation also remains possible: women who have not yet gone through menopause may, for various reasons, be more physically active.

Vanessa Cairolli stresses that this type of study identifies correlations but does not allow anyone to claim that exercise, on its own, is responsible for delaying menopause.

That does not diminish the importance of physical activity for women’s health. Its benefits for body composition, muscle and bone mass, metabolism and quality of life during the menopausal transition are established regardless of any possible effect on the timing of menopause.

What happened in the mice

It was in the experimental phase that the researchers were able to test the hypothesis directly.

Adult mice exercised on a treadmill for 30 minutes a day, five days a week, for one month. At the end, the exercised animals had, on average, 1,110 primordial follicles, compared with 745 in the control group.

The total number of follicles was also higher, as were levels of anti-Müllerian hormone, or AMH.

In the animal model, therefore, exercise reduced the loss of primordial follicles and preserved markers of ovarian reserve.

This evidence is experimental, but it is still evidence obtained in mice.

The animals’ reproductive physiology differs from that of humans, which prevents the result from being applied directly to women.

Adiponectin may be part of the explanation

The researchers then investigated a possible biological mechanism for the phenomenon.

The focus fell on adiponectin, a protein best known for being produced in adipose tissue and for its role in metabolism.

The study showed that cells within the ovary itself also produce adiponectin, with particularly high expression in granulosa cells.

In the exercised mice, the researchers found higher levels of adiponectin both in the blood and in the ovaries. They also observed greater expression of the ADIPOR1 receptor in ovarian tissue.

These results suggested that the ovary is not merely a passive recipient of the metabolic changes triggered by exercise. The ovarian environment itself could take part in this signaling.

For Vanessa Cairolli, this is an important conceptual advance: the study provides concrete mechanistic targets for investigating how the ovarian microenvironment responds to the systemic changes associated with physical activity.

When adiponectin dropped, the protection also decreased

One of the most important experiments in the study was to specifically reduce adiponectin in the animals’ ovaries.

With this intervention, the protective effect associated with exercise on the loss of primordial follicles decreased by approximately 76% compared with animals without this reduction.

The result reinforces the role of ovarian adiponectin in the observed mechanism.

But there is an essential difference between this experimental demonstration and what is known in women.

In the human data, the researchers did not prospectively track adiponectin production in the ovaries or changes in follicular reserve over time. Nor did they demonstrate that adiponectin is the causal mechanism linking exercise and ovarian aging in humans.

Thus, the sequence exercise → adiponectin → reduced follicle activation → slower ovarian aging has strong support in the animal model but remains a translational hypothesis in women.

The mTOR pathway

Another piece investigated was the mTOR signaling pathway.

This pathway takes part in a range of cellular processes and is involved in the activation of primordial follicles.

In the ovaries of the exercised animals, there was lower activation of mTOR-related components. Complementary experiments indicated that adiponectin may help reduce follicle activation by modulating this pathway.

The hypothesis makes biological sense because the reserve of primordial follicles is limited. Slower activation could help conserve this population for longer.

That still does not mean, however, that this mechanism has been demonstrated clinically in women.

An experimental compound reinforced the hypothesis

The researchers also used AdipoRon, an experimental compound that activates adiponectin receptors.

In the treated mice, there was a larger number of primordial follicles and an extended reproductive lifespan compared with controls.

The experiment reinforces scientific interest in the adiponectin pathway and opens possibilities for further research.

It does not mean that there is currently an approved drug to slow ovarian aging in women.

Ovarian reserve is not fertility

This is one of the most important limits in interpreting the results.

“Ovarian reserve is not synonymous with fertility,” says Vanessa Cairolli.

Preserving a larger number of primordial follicles means, from a histological standpoint, that the quantitative stock of follicles was depleted less in a given experimental scenario.

Human fertility, however, depends on much more than quantity.

A key factor is oocyte quality — including genetic and cellular competence — which is strongly influenced by age.

For that reason, an ovary with more follicles will not necessarily have a greater capacity to produce a successful pregnancy.

According to Vanessa, directly extrapolating a higher follicle count to “greater fertility” is a conceptual error.

Can we say ovarian aging was delayed?

In clinical terms, not yet.

Vanessa Cairolli believes this limit should be treated strictly.

To claim that reproductive aging was actually delayed, it would be necessary to demonstrate, among other things, preserved oocyte competence, viable embryo development and relevant reproductive outcomes.

The current study does not provide these answers in women.

What the results do suggest is a favorable modulation of parameters of the ovarian microenvironment and of metabolic mechanisms associated with aging.

Turning this into a demonstration of ovarian rejuvenation or a clinical delay of the reproductive clock would go beyond the available evidence.

The animal protocol is not a prescription

It would also be incorrect to convert the mice’s 30 minutes on the treadmill, five times a week, into a specific recommendation for preserving women’s ovaries.

The study did not establish a dose–response relationship in humans and did not compare different types, volumes or intensities of exercise for this purpose.

In addition, metabolism, life expectancy and reproductive physiology vary substantially across species.

Endocrinologist Clayton Macedo, a sports medicine physician trained at UNIFESP and on staff at Einstein Hospital Israelita, notes that the biological plausibility observed is interesting, but the results do not justify an exercise prescription aimed specifically at preserving ovarian reserve or delaying menopause.

The experimental protocol serves to test a biological hypothesis. Not to establish clinical practice.

More exercise does not always mean more benefit

The relationship between physical activity and reproductive function itself depends on context.

Regular exercise is part of general health-promotion recommendations. But excessive training, especially when combined with low energy availability, can have the opposite effect on the reproductive system.

Menstrual changes, anovulation and amenorrhea are well known in situations of imbalance between energy demand, exercise and nutritional intake.

So there is no simple relationship in which more exercise necessarily means greater protection of ovarian function.

What would need to be demonstrated in women

To answer whether physical activity truly changes the pace of ovarian aging, prospective studies capable of following women over time would be needed.

These studies would have to assess not only quantitative markers of ovarian reserve but also parameters related to oocyte quality and, ideally, clinically relevant reproductive outcomes.

Vanessa Cairolli points out, however, that this does not mean waiting for some supposed formula capable of stopping the biological clock.

A woman is born with a finite stock of oocytes, which declines progressively over her lifetime. Exercise does not create new eggs and should not be presented as a way to freeze or reverse this process.

The best-established role of lifestyle lies in metabolic and systemic health.

Regular physical activity, a proper diet, less sedentary behavior and control of factors associated with inflammation contribute to a more favorable physiological environment and to a menopausal transition with better health and quality of life.

What the study really adds

The main contribution of the work is to show a possible connection between physical activity, metabolism and ovarian aging and to experimentally investigate a mechanism that could explain it.

Adiponectin emerges as an important piece of this hypothesis.

In mice, the chain of evidence is consistent: exercise, increased adiponectin-related signaling, modulation of the mTOR pathway and greater preservation of primordial follicles.

In women, the question remains open.

Prospective studies will be needed to determine whether different levels of physical activity truly change the trajectory of ovarian aging, whether they alter follicular reserve over the years and whether adiponectin plays a role in this process.

Until those answers exist, the research should be understood as promising translational evidence — and not as proof that exercising delays menopause or extends female fertility.

Source study
Li B, Zheng N, Luo T, et al. Physical activity delays ovarian aging in part through adiponectin-related signaling pathways. Nature Aging. DOI: 10.1038/s43587-026-01177-0.