Progesterone inhibition of oxytocin signaling in endometrium

Abstract

Expression of the oxytocin receptor (OXTR) in the endometrium of ruminant species is regulated by the ovarian steroids progesterone (P) and estradiol (E). Near the end of the estrous cycle, long-term exposure of endometrial epithelial cells to P results in loss of genomic P receptors (PGRs), leading to an increase in E receptors (ERs). Genomic regulation of the OXTR is mediated via suppression of ER signaling by P. Upon OT binding at the plasma membrane of endometrial cells, a signaling cascade is generated stimulating release of prostaglandin F2α (PGF2α). Transport of PGF2α to the ovary results in release of OT by luteal cells in a positive feedback loop leading to luteal regression. This signaling cascade can be rapidly blocked by exposing endometrial cells to physiologic levels of P. This mini review will focus on the mechanisms by which P may act to block OXTR signaling and the luteolytic cascade in the ruminant endometrium, with special focus on both non-genomic signaling pathways and non-receptor actions of P at the level of the plasma membrane. While this review focuses on ruminant species, non-classical blockage of OXTR signaling may be important for fertility in women.

Keywords: non-classical steroid hormone action; non-genomic steroid hormone action; oxytocin; oxytocin receptor; progesterone.

Figure 1

Progesterone (P) inhibition of oxytocin receptor (OXTR) signaling in endometrial cells. Binding of oxytocin (OT) to the OXTR activates the G-protein, G_αq/11. The activated G-protein phosphorylates the enzyme phospholipase Cβ (PLCβ), which cleaves phosphatidylinositol 4,5-bisphosphate into DAG and inositol 1,4,5-trisphosphate (IP₃). Released IP₃ induces intracellular calcium release (Ca²⁺) from the endoplasmic reticulum, and is then recycled into free inositol. Free arachadonic acid (AA) is cleaved from DAG by phospholipase A2 (PLA2) and then converted by cyclooxygenase 2 (COX2) into prostaglandin F_2α (PGF_2α). Blockage of this signaling cascade by P can occur by two mechanisms: (1) P binding to a membrane-associated binding protein that interacts with the OXTR, resulting in conformational changes to the receptor such that OT is not able to bind and/or the OXTR is unable to interact with the G-protein. (2) P overloading of the plasma membrane results in changes to membrane fluidity, preventing the OXTR from interacting with the G-protein. Both of these mechanisms of action would result in P-mediated decreased signaling of the OXTR.