(171) Progesterone Receptor Signaling in Uterine Glands is Required for Pregnancy Establishment in Mice

Greeshma Sai Bayammagari¹, Sai Goutham Reddy Yeddula¹, Sarayut Winuthayanon¹, Francesco J. Demayo³, John P. Lydon⁴, Thomas E. Spencer^1,2, and Andrew M. Kelleher^1,2

1. Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.

2. Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, Missouri, USA.

3. Reproductive and Development Biology Laboratory, National Institute of Environment Health Sciences, Durham, North Carolina, USA.

4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.

 


Abstract Text:

Embryo implantation is a highly orchestrated and critical event that marks the establishment of pregnancy, and its failure is a major cause of pregnancy loss in women. Successful implantation requires precise, cell type-specific responses to ovarian steroid hormones, primarily estrogen (E2) and progesterone (P4), within the endometrium. These hormonal signals coordinate the molecular and cellular changes necessary for uterine receptivity, embryo attachment, and subsequent pregnancy progression. In this study, we investigated the biological role of the progesterone receptor (PGR) in uterine glands during pregnancy using a glandular epithelium (GE)-specific Cre recombinase mouse model (Prss29-Cre). This Cre driver is active in the adult uterus following implantation, allowing for targeted genetic manipulation of PGR specifically within the GE. Conditional ablation of PGR in the GE resulted in parity-dependent decline in fertility, with an average of 1.2 ± 1.82 pups per litter from the second litter onward, compared to 6.55 ± 2.77 pups in controls over a six-month breeding trial. Compromised pregnancy in Prss29^Cre/CrePgr^f/f (Pgr gecKO) mice was attributed to defects in uterine receptivity and embryo implantation. Surprisingly, loss of PGR in glands did not alter artificial decidual response in PgrgecKO mice. Histological and transcriptomic analyses revealed dysregulation of multiple PGR-regulated genes (Prss29, Prss28, Ihh, Spink1) in the GE during the critical window of receptivity, including Leukemia Inhibitory Factor (Lif), a cytokine exclusively produced by the GE and essential for embryo implantation. Of note, there was no differences in GE abundance or expression of ESR1 and FOXA2, two established regulators of Lif expression during the acquisition of endometrial receptivity, in the GE of Pgr gecKO mice. This finding indicates novel role of PGR in regulating E2-induced Lif expression in the GE during early pregnancy. Remarkably, intraperitoneal administration of recombinant LIF in PGR conditional knockout females rescued implantation failure, enabling embryo attachment and supporting pregnancy to term without apparent defects in decidual or placental development. This finding underscores the indispensable role of P4-PGR signaling in regulating Lif expression within the GE, while also suggesting that glandular PGR is not required beyond implantation. Overall, these findings uncover a previously unrecognized function of PGR in the uterine glands, highlighting its involvement in regulating glandular secretions necessary for pregnancy establishment. Supported by NIH Grant R01HD112315 and NIH Grant 1R37HD114609.