Long-term ovarian function risks associated with combined oral contraceptive administration in polycystic ovary syndrome: multisource data integration and protective mechanisms of metformin.

BackgroundPolycystic ovarian syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. Furthermore, the potential risks of long-term use of combined oral contraceptives (COCs) on ovarian reserve function remain unclear. We aimed to assess the association systematically between COC use and ovarian function decline in patients with PCOS and to explore potential mechanisms associated with metformin.MethodsWe analyzed 336 patients with PCOS and evaluated the association between COC use and ovarian function decline. A disproportionality analysis was performed to assess 3,424 COC-related ovarian-function adverse event reports in FAERS. Datasets of potential targets for ovarian function risk were constructed, and ovarian toxicity-related targets were screened. Intersection genes from the datasets were used to construct a protein-protein interaction (PPI) network. We identified core targets and pathways and predicted drug-target co-folded structures, while molecular dynamics simulations evaluated the binding stability and explored the potential regulatory effects of metformin.ResultsProlonged COC use was significantly associated with an increased risk of premature ovarian insufficiency and premature ovarian failure. A history of metformin use was associated with lower odds of the broader ovarian function decline outcome. Computational analyses suggested that COCs may be linked to ovarian toxicity-related pathways, whereas metformin may modulate these predicted interactions through competitive binding and conformational alterations.ConclusionsThis study represents the first integration of multisource data to systematically characterize potential ovarian-function risks associated with long-term COC therapy in patients with PCOS and to explore putative mechanisms that may underlie these associations. The findings suggest that a history of metformin use may be associated with attenuated risks, but future prospective or randomized investigations are warranted to validate these clinical associations and hypothesized mechanisms, thereby optimizing individualized management of PCOS.