Tianjing Zelan formula improves polycystic ovary syndrome by regulating steroid biosynthesis and arachidonic acid metabolism.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Polycystic ovary syndrome (PCOS) is a set of symptoms related to menstrual irregularities that can cause infertility in women of reproductive age. Unfortunately, there are currently no authorized treatment medications for PCOS. The Tianjing Zelan (TJZL) formula, a herbal formulation developed from the ancient Chinese medical classic Beiji Qianjin Yaofang in Tang Dynasty, is employed in the clinical management of menstrual irregularities and amenorrhea. However, its clinical characteristics and mechanism have not been systematically evaluated. AIM OF THE STUDY: To reveal the clinical characteristics and mechanisms of TJZL in treating PCOS. MATERIALS AND METHODS: A multicenter and single-arm clinical trial, and two PCOS models were used to evaluate the effectiveness of TJZL. The chemical constituents of TJZL were analyzed by UHPLC-QTOF-MS/MS. In addition, a combination of untargeted metabolomics and transcriptomics was used to reveal the complex therapeutic mechanisms of TJZL on PCOS. Subsequently, a metabolite-gene network analysis was performed to reveal potential differentially expressed genes associated with metabolites in PCOS patients. Key targets and pathways were further validated using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry in PCOS mice. Finally, molecular docking analysis was employed to explore the potential active ingredients of TJZL. RESULTS: Clinical trials provided evidence that TJZL significantly improved the menstrual cycle, sex hormone levels, and hyperandrogenic phenotypes, and reduced insulin resistance in PCOS patients. TJZL significantly improved the fertility, estrous cycle, ovarian morphology, sex hormone levels, and oral glucose tolerance in PCOS model. Transcriptomic and metabolomics results show that TJZL has a significant regulatory effect on metabolites and gene expression profiles in pathways such as steroid synthesis, arachidonic acid metabolism, and fatty acid metabolism. Utilizing metabolite-gene association analysis, We further verified that TJZL significantly improved the expression of genes and proteins related to the ovarian steroidogenesis and arachidonic acid metabolism pathways, including CYP17A1, CYP19A1, HSD17B3 and PTGS2. Furthermore, molecular docking results showed that berberine, rosmarinic acid and glycyrrhizinic acid in TJZL had strong affinity with PTGS2 in arachidonic acid metabolism, and hesperidin, naringin and liquiritin have strong affinity with CYP19A1 in steroid synthesis. CONCLUSION: TJZL exerts beneficial therapeutic effects on PCOS in both clinical and laboratory studies. TJZL improves PCOS by regulating multiple endogenous metabolites and correcting abnormal steroid synthesis and arachidonic acid metabolism in the ovaries. Our research provides a promising therapeutic agent for PCOS patients.