Clomiphene citrate induces changes in human fallopian tube secretory epithelial cells: An in vitro study

The fallopian tube microenvironment supports gamete transport, fertilization and early embryo development. Any disturbances in this microenvironment can lead to fertilization failure, infertility or ectopic pregnancy. In this study, we systematically investigated the effects of clomiphene citrate (CC) on human PAX8-positive fallopian tube secretory epithelial cells (hPFTSECs) to assess CC-induced alterations in the tubal microenvironment. Human fallopian tube tissues obtained from women undergoing postpartum tubectomy were enzymatically digested, and the isolated hPFTSECs were cultured with CC. CC exposure reduced hPFTSEC viability, clonogenicity, proliferation and organoid forming efficiency while inducing apoptosis, DNA damage, and senescence in a dose-dependent manner. Further, delayed cell-cycle progression and impaired DNA replication were observed in CC-exposed hPFTSECs. CC when administered to adult female Swiss albino mice, both single-dose (25, 50, and 100 mg/kg; intraperitoneally) and multiple-dose (10 mg/kg; intraperitoneally for four consecutive days) exposure caused several oviductal abnormalities, including epithelial disorganization, loss of ciliation, dysplasia, and hyperplasia. Our findings reveal that CC induces a spectrum of cytotoxic, genotoxic, and structural alterations in the fallopian tube epithelium, with potential implications for tubal function impairment and disruption of the optimal microenvironment essential for fertilization and early embryo development, which might negatively impact overall reproductive outcomes.