Analysis of heart and neural crest derivatives-expressed protein 2 (HAND2)-progesterone interactions in peri-implantation endometrium†.

Implantation is restricted to a narrow window when the local endometrial microenvironment is supportive of the invading embryo. The ovarian steroid hormones estrogen (E) and progesterone (P) are principal regulators of uterine receptivity. Suppression of E-dependent proliferation of luminal epithelium (LE) by P is mandatory for embryo implantation. Here, we report that the balance of E receptor α (ERα) and P receptors (PR) activity controls HAND2 expression, a key transcription factor that determines the fate of the implanting embryo and thereby pregnancy outcome. As a model, we used wild-type mice as well as mice in which either both PR isoforms or the A-isoform was genetically ablated (PRKO and PRAKO, respectively). Detailed spatiotemporal analyses of PR, HAND2, and ERα expression at implantation site demonstrated co-expression of HAND2 and PR but not ERα. Furthermore, in hormonally treated ovariectomized WT, PRAKO and PRKO mice, E suppresses endometrial HAND2 expression. Adding P together with E partially rescues HAND2 expression in WT, but not PRAKO and PRKO animals. Therefore, infertility in PRAKO mice is at least in part associated with the loss of PR-A-regulated HAND2 expression.