Molecular Determinants of Uterine Receptivity: Comparison of Successful Implantation, Recurrent Miscarriage, and Recurrent Implantation Failure

Abstract

Embryo implantation is one of the most remarkable phenomena in human reproduction and is not yet fully understood. Proper endometrial function as well as a dynamic interaction between the endometrium itself and the blastocyst-the so-called embryo-maternal dialog-are necessary for successful implantation. Several physiological and molecular processes are involved in the success of implantation. This review describes estrogen, progesterone and their receptors, as well as the role of the cytokines interleukin (IL)-6, IL-8, leukemia inhibitory factor (LIF), IL-11, IL-1, and the glycoprotein glycodelin in successful implantation, in cases of recurrent implantation failure (RIF) and in cases of recurrent pregnancy loss (RPL). Are there differences at the molecular level underlying RIF or RPL? Since implantation has already taken place in the case of RPL, it is conceivable that different molecular biological baseline situations underlie the respective problems.

Keywords: cytokines; implantation; recurrent implantation failure; recurrent pregnancy loss; uterine receptivity.

Figure 1

Function of hormones and molecular determinants in implantation and early pregnancy. Progesterone, LIF, IL-6, IL-11, IL-1β, and IL-1Ra are involved in regulating decidualization. LIF is increased under the influence of estrogen and hCG. LIF, IL-6, IL-8, glycodelin-A, IL-1β, and IL-1Ra are responsible for trophoblast invasion. As regards shifts in the immune system, IL-11 reduces TNF-α, glycodelin-A lowers the levels of NK cells, while glycodelin-A, IL-1β, and IL-1Ra are responsible for the shift within Th cells. LIF, IL-6, IL-8, IL-1β, and IL-1Ra are associated with embryo implantation. Furthermore, LIF, IL-6, IL-11, IL-1β, and IL-1Ra participate in placentation. Abbreviations: LIF (leukemia inhibitory factor), TNF-α (tumor necrosis factor-α), NK cells (natural killer cells), Th1/2 (type 1 T helper cells and type 2 T helper cells), IL-1Ra (IL-1 receptor antagonist), ↓ (down-regulated), ↑ (up-regulated).