Long after their reproductive role ends, ovaries continue to undergo molecular changes linked to inflammation, tissue remodeling, and cellular signaling, raising new questions about their potential influence on women's health as they age.
Study: The human ovary exhibits dynamic molecular remodeling in the decades post-menopause. Image credit: Toey Andante/Shutterstock.com
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
A recent study on the preprint server bioRxiv suggests that the postmenopausal ovary remains biologically active, undergoing tissue remodeling and showing changes in proteins associated with secretory signaling that could have implications for women’s health and ovarian cancer research.
Rethinking the role of ovaries after menopause
The ovaries are among the first organs in the body to show signs of aging, often decades before other organs. Women are born with a limited supply of eggs, which gradually declines with age until menopause marks the end of their reproductive years.
Menopause is associated with an increased risk of several long-term health conditions, including heart disease, osteoporosis, and neurodegenerative disorders. Ovarian cancer risk also rises with age. As women live longer, many now spend several decades after menopause, making it increasingly important to understand how their bodies continue to change.
For years, scientists largely viewed the postmenopausal ovary as inactive tissue, made up mainly of fibrous material. However, emerging research suggests that the ovaries remain biologically active after menopause, continuing to produce hormones such as androgens and molecules that help cells communicate. These substances may also influence processes elsewhere in the body.
Previous studies have found that aging ovaries undergo changes in gene activity, including changes linked to metabolism, cellular stress, and communication between cells. However, much of this research has involved relatively small studies or focused on women before or around menopause.
To address this gap, the researchers examined healthy ovarian tissue from women aged 50 to 75, looking at how protein levels and biological processes differ across the decades following menopause.
Researchers analyze 28 ovaries across three age groups
The investigators examined histologically normal ovarian tissue from 28 women aged 50-75 years, stratified into three age groups: 50-59 (n = 11), 60-69 (n = 10), and ≥ 70 years (n = 7).
Using data-independent acquisition mass spectrometry with parallel accumulation-serial fragmentation (diaPASEF), they examined the proteome of the ovarian tissue. They quantified 5,812 protein groups to identify age-associated shifts between the age groups. They also searched for overlap with proteins previously associated with ovarian cellular senescence and ovarian cancer.
Using multiple complementary analytical approaches, they developed a 26-protein signature of postmenopausal ovarian aging, called the Buck Postmenopausal Ovary Molecular Signature (BuckPOMS).
Older ovaries show increasing inflammatory and remodeling signatures
The researchers found clear differences in protein levels between the age groups, suggesting that the ovaries continue to change long after menopause.
Compared with women aged 50–59, those aged 60–69 had significant changes in 40 protein groups. Of these, 34 increased, and six decreased. The increases included proteins involved in immune responses, inflammation, and tissue remodeling, suggesting that these processes become more prominent as the ovaries age.
The differences were even greater among women aged 70 and older, with 117 protein groups showing significant changes compared with the youngest group. Of these, 84 declined, including many proteins that help maintain the structure and shape of ovarian cells and tissues. Meanwhile, 33 proteins increased, including those involved in tissue remodeling and cellular responses to damage.
Overall, younger postmenopausal ovaries had more proteins involved in regulating gene activity, while older ovaries showed greater activity in pathways linked to metabolism, immune responses, and the movement of substances within cells.
Seventeen proteins reveal shared changes across aging groups
Both pairwise comparisons identified a common set of 17 proteins with significant alterations, reflecting shared biological processes associated with aging across these decades. The overall protein pattern suggests a late postmenopausal shift in ovarian protein expression away from structural and epithelial-associated programs and toward extracellular remodeling and signaling.
The altered proteins were mapped to inflammatory and matrisome/extracellular matrix (ECM) remodeling pathways, with higher abundance of proteins associated with damage-related secretory responses in the oldest ovaries.
Protein signatures distinguish younger and older postmenopausal ovaries
Age-associated differences in protein signatures were greater between the 50-59 years age group and the ≥70 years group, though differences between adjacent groups were modest. The ability of the multivariate model to distinguish the youngest from the oldest group was moderate. These differences were driven most strongly by 20 proteins elevated in the youngest group but reduced in the oldest group, and another 20 showing the opposite pattern.
Younger postmenopausal ovaries were characterized by proteostasis and transcription-regulation pathways. Conversely, the oldest postmenopausal ovaries had a protein signature reflecting changes in lipid metabolism and innate immune pathways. The signaling molecule WNT4 became progressively more abundant with age, suggesting that signaling capacity may persist in the oldest postmenopausal ovaries. Increased WNT4 abundance was also supported by immunohistochemical staining of ovarian tissue.
Two proteins show significant age-related abundance changes
Linear regression analysis revealed two proteins that changed progressively with age after adjustment for body mass index and race/ethnicity. Fatty acid-binding protein 5 (FABP5) decreased with age by approximately 29% per decade. Conversely, heparan-sulfate 6-O-sulfotransferase 2 (HS6ST2) increased by approximately 58% per decade.
More broadly, they examined the top 30 age-linked protein shifts. These involved extracellular matrix remodeling, lipid metabolism, secretory molecule movement, movement across cell membranes, gene regulation, and cytoskeletal changes. These changes map to increased inflammatory and matrisome programs with age, accompanied by the loss of structural and keratin-associated programs.
Aging ovaries show changes in collagen-related pathways
The proteomic pathway analyses suggest reduced abundance of proteins associated with epithelial structure and keratinization, alongside changes in collagen-related pathways that may reflect alterations in ovarian tissue organization. At the same time, there is evidence of greater inflammatory signaling and extracellular matrix remodeling in older ovarian tissue.
Notably, the collagen organizer molecule FMOD was downregulated with age across the ovarian cortex and medulla. Reduced FMOD abundance is consistent with molecular changes implicated in disordered matrix organization and fibrotic remodeling.
Aging ovaries share some features with senescent tissue
Cellular senescence refers to the loss of the cell’s ability to divide because of damage or aging, with retained signaling and biological activity that could potentially affect adjacent tissue.
The researchers found partial overlap between previously reported induced-senescence proteomic and transcriptomic datasets and their own age-associated ovarian proteomic findings. The overlapping signatures included proteins associated with the ovarian cortex, medulla, and stromal remodeling. However, only a subset of overlapping proteins changed in the same direction, indicating limited concordance.
Healthy aging ovaries share proteins linked to cancer
From current literature, the investigators compiled a set of 35 proteins associated with or implicated in ovarian cancer. Comparing them with the current dataset, they found 21 of these proteins were detected in postmenopausal ovarian tissue. Their combined abundance patterns showed age-group differences, with several proteins showing their highest levels in the 60-69 years group. The strongest enrichment was in the 60-69 years age group, which includes the reported median age of approximately 63 years at ovarian cancer diagnosis.
The researchers also calculated ovarian cancer-associated scores across participants, again finding the highest average scores in the 60-69 cohort compared with the younger and oldest groups.
“Our data support the view that, even in the absence of malignancy, the aging postmenopausal ovary moves toward a more “cancer-ready” niche.” However, the clinical implications remain unclear, pending future research.
Importantly, this does not constitute evidence of cancerous changes. Instead, it shows overlap between proteins associated with normal aging and ovarian cancer.
The BuckPOMS score
The BuckPOMS score comprised 26 proteins most strongly associated with age. In this study population, the score increased progressively across participants’ ages and across age groups. These changes are consistent with some molecular processes reported in other aging tissues. However, BuckPOMS was developed and assessed using the same 28 participants, and its performance has not yet been independently validated or established for clinical use.
Small sample size limits broader clinical conclusions
The investigators did not record age at natural menopause, years since menopause, or history of menopausal hormone therapy. Surgical menopause may induce a different trajectory of changes. However, the researchers characterized molecular changes across multiple postmenopausal decades, capturing a broad picture of remodeling across this period.
Postmenopausal ovaries remain molecularly active decades after menopause
The findings suggest that active molecular remodeling continues in the postmenopausal ovary. This is characterized by a shift towards inflammatory, matrisome-associated, and damage-associated pathways along with metabolic alterations.
This ongoing molecular remodeling that occurs in the postmenopausal ovary challenges the notion that the ovary is an innocent bystander in the post reproductive period and instead suggests a potentially more active role in systemic aging and chronic disease risk in women.
Although the results raise the possibility of wider effects on aging and disease, such systemic consequences were not directly demonstrated in this study.
The BuckPOMS framework provides a basis for future studies into the mechanisms and clinical implications of ovarian aging postmenopause, and associated ovarian disease.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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