Activation of the receptors for leukemia inhibitory factor (LIF) and IL-11 is 
essential for embryo attachment and decidualization in mice. Both receptors 
induce activation of the Stat family of signal transducers via the Jak/Stat 
pathway. Here, we aimed to establish whether activation of Stat3 in maternal 
endometrium is essential for successful implantation. Functional blockade of 
Stat3 before implantation, by injection into the uterine lumen of a 
cell-permeable Stat3 peptide inhibitor, reduced embryo implantation specifically 
by 70% (P < 0.001). Stat3 is phosphorylated in the luminal epithelium (LE) in 
response to LIF, and this phosphorylation was significantly reduced both in 
vitro and in vivo by the Stat3 inhibitor. The inhibitor also blocked induction 
by LIF of several LIF-regulated genes in the LE including Irg1, which has been 
shown previously to be essential for implantation. Successful implantation is 
therefore dependent on phosphorylation and activation of Stat3 in the 
endometrium before implantation. This finding provides a target for 
contraceptive development, based on selective blockade of signal transduction 
pathways essential for implantation. This study demonstrates that cell-permeable 
peptide inhibitors can be used effectively to target intracellular signaling 
pathways in the uterine LE.