The human ovary exhibits dynamic molecular remodeling in the decades post-menopause

The human ovary is among the first organs to show age-related functional decline, resulting in menopause. Beyond this transition, the postmenopausal ovary is often regarded as quiescent and remains poorly characterized. We analyzed the proteomes of healthy, non-pathological ovaries using mass spectrometry (data-independent acquisitions) from 28 postmenopausal women (50-75 years old), stratified into three age groups (50-59, 60-69, [≥]70). We quantified 5,812 protein groups and observed progressive age-associated shifts with 117 proteins significantly altered in the [≥]70 vs 50-59 age comparison. Multivariate analysis demonstrated clear separation between 50-59 and [≥]70-year-old age cohorts, with protein signatures shifting from RNA/gene-regulatory functions in younger ovaries to metabolic, trafficking, and innate immune/complement pathways in older ovaries. Across differential abundance, multivariate modelling, and covariate-adjusted linear modelling converged on a shared set of age-associated candidates, strengthening support for the gain of extracellular matrix remodeling, inflammatory signaling, and loss of structural/keratin components with age. Pathway enrichment further identified an increase in inflammatory, matrisome pathways, and increased abundance of damage-associated secretory factors decades following menopause. Secreted matrisome proteins WNT4 and Fibromodulin (FMOD) emerged as age-associated candidates and were validated by immunohistochemistry. These data fundamentally shift the notion of the postmenopausal ovary as an inert organ and instead demonstrate active and continuous molecular remodeling that has potential relevance to tissue signaling and implications for womens health.