Decidualization is a process in which endometrial stromal cells undergo morphological and functional changes from fibroblasts to decidual cells (Gellersen and Brosens, 2014; Rulli et al., 2018). This process is particularly important for the successful establishment and maintenance of human pregnancy (Akyaw et al., 2019). In slight contrast to mouse decidualization, human decidualization is tightly regulated by cyclic adenosine monophosphate (cAMP) and progesterone (Telgmann and Gellersen, 1998).

Prostaglandins (PGs) are closely involved in decidualization (Kang et al., 2006). Arachidonic acid is released from membrane lipids by phospholipase A2 and converted to prostaglandins, prostacyclin, and thromboxane by cyclooxygenases (COX-1 and COX-2) (Kirkby et al., 2015). Cytoplasmic phospholipase A2 (cPLA2) deficiency results in delayed implantation and abnormal embryo spacing (Song et al., 2002). COX-2 mutation leads to the failure of embryo implantation and decidualization (Lim et al., 1997; Li et al., 2018). Among the five prostaglandins, prostaglandin F2α (PGF2α) synthesis is catalyzed by AKR1B1, AKR1C1, AKR1C3 and CBR1 (Catalano et al., 2010; Bresson et al., 2011; Colombe et al., 2007; Sinreih et al., 2015). Therefore, AKR1B1 and AKR1C3 transform PGH2 into PGF2α and its analogues (Byrns et al., 2010). The interconversion of PGE2 and PGF2α is catalyzed by AKR1C1 (Dozier et al., 2008). CBR1 transforms PGE2 to PGF2α (Vilella et al., 2013). PGF2α is synthesized and released by the uterus and binds to prostaglandin receptor (PTGFR) to exert physiological effects (Li et al., 2021). In mice, PTGFR is markedly expressed in the circular myometrium on Days 3–5 of pregnancy (Yang et al., 1997). PTGFR-deficient mice are unable to undergo delivery (Sugimoto et al., 1997). The PGF2α level in human uterine fluid increases dramatically at the time of embryo implantation (Vilella et al., 2013). However, how uterine PGF2α is involved in embryo implantation and decidualization remains poorly understood.

The epidermal growth factor (EGF) family includes transforming growth factor α (TGFα), amphiregulin (AREG), epiregulin (EREG), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and betacellulin (BTC) (Wong and Guillaud, 2004). They are synthesized as precursors and shed by ADAM17 to produce mature proteins (John, 2013). In the mouse uterus, AREG, EREG, and HB-EGF are highly expressed during the preimplantation period and intimately participate in embryo implantation and decidualization (Akbalik and Ketani, 2013; Xie et al., 2007,Cui et al., 2019). In humans, AREG is expressed in the endometrial epithelium during early pregnancy and can promote embryo implantation and trophoblast growth (Berasain and Avila, 2014). Both EREG and HB-EGF promote human decidualization in vitro (Li et al., 2023a,b; Luo et al., 2023; Evers et al., 2002). However, whether human uterine PGF2α regulates AREG, EREG and HB-EGF is still unknown.

In our study, we demonstrated that hCG-stimulated the epithelial production of PGF2α to induce the decidualization of stromal cells through epithelium-stromal crosstalk.