ArticleReproduction (Cambridge, England)2016
Reproductive age-associated fibrosis in the stroma of the mammalian ovary.
Article in Reproduction (Cambridge, England), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 243 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
243 citing papers in PubMed, 2 syntheses or guidelines pooled it, 367 citations in OpenAlex.
- Beyond apoptosis: evidence of other regulated cell death pathways in the ovary throughout development and life.Human reproduction update · 2023Pooled it
- Age-associated changes in cumulus cells and follicular fluid: the local oocyte microenvironment as a determinant of gamete quality.Biology of reproduction · 2022Pooled it
- Standardizing Cell Ontology terms for cross-study integration in the female reproductive tract.Science advances · 2026Review
- Modulating the Gut-Ovarian Axis: Mechanistic Rationale and the Limits of Current Evidence for Probiotics in Female Reproductive Aging.Food science & nutrition · 2026Review
- The Human Ovary Exhibits Dynamic Molecular Remodeling in the Decades Post-Menopause.Aging cell · 2026Article
- Dietary composition and metabolic stress differentially affect the ovarian microenvironment in mice.GeroScience · 2026Article
- Multimodal profiling establishes ovarian fibrosis as a measurable and targetable hallmark of human reproductive aging.Research square · 2026Article
- Postnatal ketone deficiency impairs adult oocyte quality via enhancing histone acetylation in malnourished mice.The Journal of biological chemistry · 2026Article
- The Fibro-Inflammatory Ovary: Stromal Fibrosis, Extracellular Matrix Remodeling, and Mechanotransduction in Female Infertility.Current issues in molecular biology · 2026Review
- New Hyaluronic Acid-Based Bioengineered 3D Scaffold: Fabrication and Potential for Oocyte In Vitro Maturation.Biotechnology and bioengineering · 2026Article
- Mitochondrial Haplotype Shapes the Trajectory of Ovarian Aging in Genetically Heterogeneous Rats.Aging cell · 2026Article
- Ovarian Extracellular Matrix Mechanics Regulate Oocyte-Follicle Interactions During Female Reproductive Aging.Aging cell · 2026Article
- Aging increases ovarian cancer growth, metastasis, and immunosuppression that can be alleviated by inhibiting hedgehog signaling.bioRxiv : the preprint server for biology · 2026Article
- Modulating IL-11-dependent matrix stiffness to delay ovarian aging.Nature aging · 2026Article
- Mechanism and Intervention of the NPY1R/CREB Signaling Axis in Regulating Inflammatory Response in Aged Ovarian Granulosa Cells and Ovarian Senescence.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Mice lacking NF-ĸB1 undergo premature ovarian aging.Reproductive biology and endocrinology : RB&E · 2026Article
- Cumulus Expansion and Oocyte Quality Across the Pubertal Transition in Mice: Implications for Modeling Fertility Preservation in Adolescents.Research square · 2026Article
- Aging disrupts spatiotemporal coordination in the cycling murine ovary.Nature aging · 2026Article
- Single-nucleus profiling reveals age-associated remodeling opposed by parity in the postmenopausal human ovary.bioRxiv : the preprint server for biology · 2026Article
- Senescent cells in systemic aging: SASP heterogeneity, immune escape, and endocrine modulation.Biogerontology · 2026Review
183 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Under normal physiological conditions, tissue remodeling in response to injury leads to tissue regeneration without permanent damage. However, if homeostasis between synthesis and degradation of extracellular matrix (ECM) components is altered, fibrosis - or the excess accumulation of ECM - can disrupt tissue architecture and function. Several organs, including the heart, lung and kidney, exhibit age-associated fibrosis. Here we investigated whether fibrosis underlies aging in the ovary - an organ that ages chronologically before other organs. We used Picrosirius Red (PSR), a connective tissue stain specific for collagen I and III fibers, to evaluate ovarian fibrosis. Using bright-field, epifluorescence, confocal and polarized light microscopy, we validated the specific staining of highly ordered PSR-stained fibers in the ovary. We next examined ovarian PSR staining in two mouse strains (CD1 and CB6F1) across an aging continuum and found that PSR staining was minimal in ovaries from reproductively young adult animals, increased in distinct foci in animals of mid-to-advanced reproductive age, and was prominent throughout the stroma of the oldest animals. Consistent with fibrosis, there was a reproductive age-associated increase in ovarian hydroxyproline content. We also observed a unique population of multinucleated macrophage giant cells, which are associated with chronic inflammation, within the ovarian stroma exclusively in reproductively old mice. In fact, several genes central to inflammation had significantly higher levels of expression in ovaries from reproductively old mice relative to young mice. These results establish fibrosis as an early hallmark of the aging ovarian stroma, and this altered microenvironment may contribute to the age-associated decline in gamete quality.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.