Pregnancy comprises multiple stages with complex interactions of molecules and cells, and previous studies have clarified that progesterone (P4) is a key player in pregnancy. Several animal experimental models have been established to address the detailed mechanisms of P4, and genetically engineered mouse models have especially helped us understand its function. P4 receptor (PR)-null female mice show no ovulation, while PR co-chaperone FKBP52-null mice exhibit implantation failure with normal ovulation. Moderate supplementation of P4 rescues implantation failure in FKBP52-deficient mice but does not restore the capability for pregnancy up to full term, resulting in embryo resorption. Supplementation of a large amount of P4, however, can rescue pregnancy and provide normal reproductive outcomes until parturition. Mouse studies by our groups, and others, have also shown that epigenetic regulation of uterine P4-PR signaling, P4-induced molecular crosstalk between the epithelium and stroma and uterine proliferation-differentiation switching are indispensable for successful implantation. Collectively, P4 orchestrates the whole process of pregnancy in spatiotemporal manners, eventually integrating them toward successful parturition. In this review article, we review the literature on the uterine functions of P4 in pregnancy, with a special focus on the knowledge gained about embryo implantation by studies utilizing mouse models.
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