Multi-omics analysis reveals steroid hormone biosynthesis as a key pathway in advanced maternal age threatened abortion.

BACKGROUND Advanced maternal age (AMA, ≥35 years) is increasingly common and is accompanied by rising threatened abortion (AMA-TA) rates, yet its molecular basis remains unclear.

OBJECTIVE To elucidate AMA-TA mechanisms by integrating metabolomics and transcriptomics, providing a foundation for biomarker and therapeutic discovery.

METHODS Untargeted serum metabolomics was performed in 9 AMA-TA patients and 7 age-matched healthy pregnant women. An AMA-TA mouse model was induced by mifepristone (4 mg/kg) to assess embryo resorption, placental morphology, and serum hormones (ELISA). Serum metabolomics and placental transcriptomic profiling (RNA-seq) were then conducted in AMA-TA mice to characterize metabolic and gene expression alterations. Cross-species and multi-omics integration was performed using HomoloGene and MetaboAnalyst 5.0. Key steroid biosynthesis-related genes were finally validated by RT-qPCR.

RESULTS Human serum metabolomics revealed the differential metabolites were mainly enriched in steroid hormone biosynthesis, lipid metabolism, and amino-acid metabolism. The AMA-TA model showed higher embryo resorption, abnormal placental architecture, and reduced progesterone and chorionic gonadotropin. RNA-seq revealed 111 up- and 1337 downregulated genes enriched in 68 pathways. Consistently, serum metabolomics in AMA-TA mice also showed significant metabolic disturbances, prominently involving steroid hormone biosynthesis. Integrated analysis converged on steroid hormone biosynthesis as a shared key dysregulated pathway. RT-qPCR further confirmed aberrant expression of steroid metabolism-related genes, including upregulation of Akr1d1 and Ugt family genes.

CONCLUSION Disruption of steroid hormone biosynthesis represents central molecular feature to AMA-TA. Integrated multi-omics analysis offers mechanistic insight and supports the development of biomarkers and therapeutic targets for AMA-TA.