Progesterone receptor in uterine glands is required for pregnancy establishment in mice

Embryo implantation is a critical event in the establishment of pregnancy, and implantation failure is a major cause of pregnancy loss in women. Coordinated, cell-type specific responses to the ovarian steroid hormones, estrogen, and progesterone, within the endometrium underlie successful embryo implantation and pregnancy establishment. In this study, we utilized a glandular epithelium (GE) specific Cre recombinase mouse line that is only active in the adult (Prss29-Cre) to determine the biological role of progesterone receptor (PGR) in uterine glands during pregnancy. Conditional ablation of PGR specifically in the GE compromised fertility due to defects in uterine receptivity and embryo implantation. Histological and transcriptomic analyses uncovered disruption of multiple PGR-regulated genes in the GE during the window of receptivity, including leukemia inhibitory factor (LIF), a cytokine produced specifically by the GE that is essential for embryo implantation. Interestingly, intraperitoneal injections of recombinant LIF in Pgr conditional knockout mice rescued embryo implantation and supported successful pregnancy to term. These findings underscore the vital role of PGR in regulating Lif expression in the GE, while suggesting that PGR in the glands of the uterus is unessential once pregnancy is established. Overall, these findings reveal a previously unrecognized role of PGR in uterine glands and support the hypothesis that glandular secretions, governed by PGR, are indispensable for pregnancy establishment.