Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus

Infertility and reproductive-associated disease are global problems in the world today affecting millions of women. A successful pregnancy requires a healthy uterus ready to receive and support an implanting embryo. As an endocrine organ, the uterus is dependent on the secretions of the ovarian hormones estrogen and progesterone which signal via their cognate receptors, the estrogen and progesterone receptors. The progesterone receptor not only functions using classical nuclear receptor signaling, but also participates in non-genomic signaling at the cellular membrane. The complexity of progesterone signaling is further enhanced by the existence of multiple isoforms and post-translational regulation via kinases and transcription coregulators. This dynamic means of regulation of the progesterone receptor is evidenced in its necessary role in a successful pregnancy. Within early pregnancy, the progesterone receptor elicits activation of its target genes in a spatiotemporal manner in order to allow for successful embryo attachment and uterine decidualization. Additionally, appropriate progesterone signaling is important for the prevention of uterine disease such as endometrial cancer, endometriosis, and leiomyoma. The utilization of progesterone receptor modulators in the treatment of these devastating uterine diseases is promising. This review presents a general overview of progesterone receptor structure, function, and regulation and highlights its important role in the establishment of pregnancy and as a therapeutic target in uterine disease.