The research team, co-led by Francesca Duncan, associate professor of reproductive science in medicine at Northwestern University Feinberg School of Medicine, and Birgit Schilling, professor and director of the Mass Spectrometry Center at the Buck Institute, set out to do something deceptively simple: look closely at what postmenopausal ovarian tissue is actually doing at the molecular level. Duncan herself admits she expected to find very little. “In the ovary, we reach a point of no return with respect to fertility in which it’s no longer producing eggs, and I would venture to say most people assume those ovaries are just sitting there doing nothing, similar to the appendix,” she said. “But that’s what makes this study very different.” Her initial prediction was that ovaries taken from 50-, 60-, 70- and 80-year-old women would all look essentially identical — egg-free and functionally dormant.

That prediction turned out to be wrong. To interrogate the tissue, the scientists moved beyond the hormones that have traditionally dominated ovarian research and instead analyzed the organ’s full protein composition at high resolution. Using advanced proteomic technologies paired with mass spectrometry — approaches capable of identifying and quantifying thousands of proteins simultaneously — Schilling’s team, spearheaded by staff scientist Mark Watson, profiled 5,812 protein groups in normal ovarian tissue from postmenopausal women between the ages of 50 and 75. This large-scale molecular census allowed the researchers to track how protein abundance shifts across the postmenopausal decades and to search for consistent patterns using multiple types of statistical analysis, rather than relying on any single analytical lens.

The picture that emerged was remarkably coherent. Ovaries from younger postmenopausal women carried a heavier complement of proteins involved in maintaining cells and tissue structure, while ovaries from older women showed increasing levels of proteins associated with inflammation, immune activity, and the ongoing breakdown and rebuilding of the extracellular matrix — the scaffolding that surrounds cells. The molecular differences were most pronounced when the researchers compared ovaries from women in their 50s with those from women aged 70 and older. “When we analyzed the data in multiple different statistical ways, what became clear across all these methodologies is that the ovary was not stagnant,” Schilling said. “In fact, over the decades, there were quite dramatic differences in terms of some proteins’ levels would go up with age and some proteins’ levels would go down, which tells us this organ is quite dynamic.”

The aging ovaries also displayed molecular signatures associated with cellular senescence, a state in which aging or damaged cells stop dividing but remain biologically active, secreting inflammatory signals and other molecules that can influence surrounding tissue. Senescent cells have been implicated in a wide range of age-related conditions, and their presence in postmenopausal ovarian tissue adds the ovary to the growing list of organs that appear to accumulate these problematic cell states over time. Taken together, the findings point to what Duncan describes as progressive aging features, in which the ovary seems to gradually lose its original reproductive identity and take on an altogether different biological character.

Human ovarian tissue is notoriously difficult to obtain, which makes the 28 ovaries in this study an unusually valuable scientific resource. The design of the research also matters: rather than comparing young ovaries with old ones across the entire human lifespan — an approach that inevitably conflates pre- and postmenopausal biology — the team deliberately focused on women within a relatively narrow 25-year age window after menopause. This strategy allowed them to isolate molecular changes that continue to unfold specifically during the postmenopausal years, a period of life that has expanded dramatically as women now routinely live for decades beyond the end of their reproductive capacity. Duncan’s group had previously documented similar continued remodeling in the postmenopausal ovaries of mice, and she notes that seeing the same phenomenon across species lends confidence that what they are observing is not a random artifact but a meaningful feature of ovarian biology.

Perhaps the most provocative finding concerns cancer. More than a decade ago, Duncan’s lab was the first to show that as ovaries age, they become increasingly inflamed, fibrotic and stiff — a process resembling scarring in other tissues. Because cancer cells are known to thrive in collagen-rich, stiff environments, her team has long investigated whether such age-related changes might make the ovary more hospitable to malignant cells. The new study offers a molecular view of that same remodeling process later in life: as postmenopausal ovaries aged, structural proteins declined while inflammation-related and tissue-reshaping proteins became more prominent. Although every tissue sample in the study appeared normal and cancer-free, several proteins previously linked to ovarian cancer were more abundant in the aging ovaries, with the strongest signal observed among women in their 60s. The researchers stress this does not mean the ovaries were cancerous or precancerous — only that healthy ovarian aging and ovarian cancer appear to share some of the same underlying biological processes.

Duncan frames the observation in terms of a broader model of cancer development. “It’s not that all postmenopausal women get ovarian cancer, but we know that that fibrotic inflammatory environment is certainly an environment that cancer cells prefer to home in on,” she said. “This is all consistent with the idea that the aging ovary is a potential third hit for ovarian cancer, with the first hit being genetic and the second hit being environmental. So can we target the aging ovary therapeutically to lower the risk of ovarian cancer, or can we develop novel biomarkers of ovarian cancer?” If the aging ovary’s microenvironment does indeed lower the barrier to malignancy, it could open entirely new avenues for prevention — from anti-inflammatory or anti-fibrotic interventions to early-detection markers rooted in the protein changes the study catalogued.

The work also raises a question that few clinicians have had reason to ask: should otherwise healthy ovaries ever be removed after menopause? “The ovary is not just a reproductive organ,” Schilling said. “It really influences how somebody ages because it speaks to all these other organs, such as the brain, and also to the bone, and women after menopause experience often a lot of bone problems. So, we think there is a connection between all these organs.” Duncan puts the stakes even more bluntly, asking whether the ovary might be “the canary in the coal mine in women” — an organ whose aging could set off a cascade of changes throughout the body. Much remains unknown, including whether the postmenopausal ovary’s activity is beneficial or harmful, and whether there is ever a point at which the organ stops helping and starts hurting. “Our data points to progressive aging features in which the ovary appears to lose its original identity and ends up doing something different,” Duncan said. “We do not yet know if there’s ever a point in a woman’s life when this organ is no longer beneficial and it’s actually harmful. These results really point to the need to ask this question.” The researchers emphasize that their findings do not answer whether healthy ovaries should be removed; instead, they open a new frontier of research into how this long-ignored organ shapes women’s health in the decades after reproduction ends.

Subject of Research: Molecular remodeling of the human ovary in the decades after menopause

Article Title: The ovary doesn’t retire after menopause

Article References: The ovary doesn’t retire after menopause. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: ovary, menopause, aging, proteomics, inflammation, fibrosis, ovarian cancer, cellular senescence, tissue remodeling, Northwestern University, Buck Institute, Aging Cell