Metabolomics changes in premature ovarian insufficiency: a systematic review

Premature ovarian insufficiency (POI) is a multifactorial disorder marked by the cessation of ovarian function prior to the age of 40. While its genetic and autoimmune causes have been somewhat investigated, the fundamental metabolic mechanisms are still inadequately characterized. Recent developments in metabolomics have created new avenues for identifying molecular biomarkers and clarifying the systemic metabolic disruptions linked to POI. This systematic review was conducted following PRISMA guidelines. An extensive search of the PubMed, Scopus, Web of Science, Cochrane, and Embase databases (up to July 2025) revealed all studies evaluating metabolomic alterations in POI. We included original observational, experimental, and Mendelian randomization studies without restrictions on species. Data regarding metabolomic platforms, alterations in metabolites, and impacted pathways were aggregated. A total of fifteen studies met the inclusion criteria, which comprised seven observational studies involving humans, four experimental studies conducted on animals, and four analyses utilizing Mendelian randomization. Various studies indicated ongoing dysregulation in the metabolism of lipids, amino acids, and energy. Altered pathways were identified, including mitochondrial oxidative phosphorylation, the synthesis of ubiquinone (CoQ₁₀), folate and vitamin metabolism, as well as sphingolipid pathways. Several metabolites, such as arachidonoyl amide, 18-HETE, ubiquinone, retinol, and 2-oxoarginine, have been recognized as potential noninvasive biomarkers for diagnosing and monitoring primary ovarian insufficiency (POI). Experimental research revealed that metabolic interventions, such as α-ketoglutarate, electro-acupuncture, Zishen Yutai pills, and human umbilical cord mesenchymal stem cells, could potentially alleviate ovarian issues by reestablishing energy balance and reducing oxidative stress. Metabolomic studies consistently reveal that primary ovarian insufficiency (POI) involves widespread metabolic alterations, especially in lipid and mitochondrial energy metabolism. These results suggest that POI is not merely a reproductive endocrine issue but a global metabolic disorder. Future research should verify potential biomarkers within large, multicenter groups and employ standardized metabolomic platforms along with multi-omics approaches to clarify causal pathways and identify therapeutic targets.