Single-nucleus profiling reveals age-associated remodeling opposed by parity in the postmenopausal human ovary

Abstract The postmenopausal ovary is commonly viewed as a passive organ, and its biology and cell composition remain incompletely characterized. Here, we generated a single-nucleus atlas of the aging postmenopausal human ovary comprising 439,011 nuclei across 64 ovarian samples from 28 donors. We resolved 37 fine cell states, revealing extensive stromal, vascular, and immune heterogeneity in the postmenopausal ovary. Aging was associated with stromal stress-state expansion, vascular and immune depletion, and enrichment of steroidogenic programs consistent with ovarian androgenization. Several major age-associated compositional shifts were supported in an independent GTEx ovary bulk RNA-seq cohort. Notably, the number of live births broadly opposed age-associated transcriptional and compositional remodeling. Together, our findings show that the postmenopausal ovary remains an actively remodeled aging tissue and that reproductive history leaves durable molecular and cellular imprints on ovarian aging. Competing Interest Statement The authors have declared no competing interest.