Hum Reprod Update. 2026 Jul 17. pii: dmag018. [Epub ahead of print]
BACKGROUND: With growing interest in ART, fertility preservation, and postmenopausal health of women, reproductive medicine is increasingly focused on characterizing oocytes and ovarian tissue composition, as well as understanding the molecular mechanisms that guide ovarian function throughout its lifecycle. High-throughput omics technologies have enabled the characterization of different molecular layers, leading to substantial advances in our understanding of their complex dynamics. However, not all molecular aspects are studied equally, and studies examining the same modalities often show inconsistencies, underscoring the need for data standardization and highlighting the potential for using transformative artificial intelligence and machine-learning (AI/ML) methods for ovary studies.
OBJECTIVE AND RATIONALE: This study aims to evaluate how multi-omic studies have advanced our understanding of the ovarian lifecycle from fetal development to postmenopause. We systematically reviewed published studies that have investigated molecular/omic layers, including the genome, methylome, transcriptome, and proteome throughout ovarian development and aging. Our analysis identified key molecular and cellular patterns, highlighted inconsistencies across studies and addressed gaps in data analysis, interpretation, and reproducibility to guide future research.
SEARCH METHODS: We conducted a systematic literature search of Medline (PubMed), Embase (Ovid), and Web of Science Core Collection (Clarivate) using a combination of controlled and free text terms for human ovary, oogenesis, folliculogenesis, ovary development and (epi)genome, transcriptome, proteome, and multi-omic mechanisms to find relevant articles published before August 2025. To focus the scope of the current review, studies of domesticated and farm animals, rodents and other model organisms, non-human primates, as well as those examining various human ovarian pathologies were excluded.
OUTCOMES: The search identified 23 546 studies for screening, of which 637 full-text studies were assessed for eligibility. Subsequently, we extracted data from 121 studies. Most studies analyzed the transcriptome of oocytes, granulosa cells, and ovarian tissue from reproductive-age individuals (n = 91), with fewer studies examining samples from individuals of advanced reproductive age (n = 45) and fetal (n = 16) samples. Transcriptome analyses were most common (n = 103, 85%), followed by proteome (n = 19, 16%) and epigenome (n = 14, 12%) studies. We found substantial variation in how studies defined and reported participants' groups as well as in their sequencing technologies and data analysis methods, with a lack of standardized reporting of background clinical information, data analysis methods, and pipeline details. The key findings underscore the prevailing consensus on genes defining major ovarian cell types and their roles throughout the ovarian lifespan, from prenatal development to postmenopausal transformation. This review highlighted the underrepresentation of certain patient groups, particularly prepubertal and peri-/postmenopausal individuals, among researched populations, due to obvious clinical and ethical reasons.
WIDER IMPLICATIONS: This scoping review offers a comprehensive overview and benchmark of the current state of high-throughput omics-based research on ovarian cellular composition and molecular dynamics. To address these shortcomings, we propose general recommendations for multi-omics ovary studies and emphasize the necessity for more thorough multi-omic data integration by effectively applying novel AI/ML approaches. They can potentially improve the quality of multi-omics analyses at both single-cell and tissue levels despite limited sample sizes and enable integration of molecular profiling data with clinical and radiology datasets, enabling a more comprehensive understanding of ovarian biology. Such advancements can enhance reproducibility of research findings and guide future research to deepen our understanding of ovarian biology and ultimately support the development of medical technologies for better preserving fertility and alleviating infertility.
REGISTRATION NUMBER: A protocol was published a priori on the Open Science Framework (https://osf.io/z38gb/).
Keywords: follicle development; genome; methylome; oocyte maturation; ovarian aging; ovarian development; ovarian multi-omics studies; postmenopause; proteome; transcriptome