*2.5. Growth Factor of the EGF Family*

Uterine receptivity is also regulated by members of the epidermal growth factor (EGF) family, whose expression pattern in the peri-implantation uterus has been widely investigated in murine models [155–162]. Among the EGF family members, amphiregulin (AREG) has been identified in the luminal epithelium exclusively at the site of blastocyst apposition and its expression appears to correlate initially with the increase of progesterone levels and then with the attachment reaction [157]. Similarly, the expression of heparin binding-EGF (HB-EGF), which is under the control of both estrogen and progesterone [160], requires the presence of a competent blastocyst and it occurs in the luminal epithelium when pinopodes are fully formed at the site of blastocyst apposition [155,161], while epiregulin (EREG) is expressed in both the luminal epithelium and stroma during blastocyst attachment [158]. This unique expression pattern suggests a role for AREG, HB-EGF, and EREG in uterine receptivity and subsequent embryo adhesion. The role of HB-EGF in blastocyst adhesion to the uterus has been further demonstrated in vitro in a co-culture of a mouse cell line synthesizing transmembrane human HB-EGF (TM HB-EGF) and mouse blastocysts. Cells synthesizing TM HB-EGF adhered to mouse blastocysts more than parental cells or cells synthesizing a constitutively secreted form of HB-EGF [163]. These results are confirmed by a more recent study using HB-EGF mutant mice, which demonstrates that maternal deficiency of HB-EGF limits pregnancy success [162].
