Genes associated with embryonic attachment and implantation and the role of progesterone

Abstract

Implantation in humans is a complex process that involves embryo apposition and attachment to the maternal endometrial epithelium, traversing adjacent cells of the epithelial lining and invasion into the endometrial stroma. These processes involve a variety of molecules that are not unique in themselves but play unique roles in the process of implantation. Genes important to embryonic attachment include the epidermal growth factor (EGF) family (EGF, heparin-binding EGF-like growth factor and amphiregulin) and the cytokines (colony-stimulating factor, leukemia inhibitory factor and interleukin-1), as well as a variety of cell adhesion molecules and other glycoproteins. Epithelial factors important in attachment may be regulated by paracrine interactions via the endometrial epithelium and the endometrial stroma, which is a progesterone-responsive tissue. Investigations into genetic knockout animal models and natural mutations in the mouse have demonstrated that genes important to the implantation process affect both embryo attachment and decidualization and include cyclooxygenase-2 and the homeobox gene HOXA-10. Calcitonin is believed to play a role in preparing the apical cell pole for contact with the trophoblast. A number of factors contribute to endometrial regulation by progesterone; some are important in embryo attachment as well as in the invasive phase of implantation. Four specific factors regulated in the endometrial stroma by progesterone are transforming growth factor-beta, interleukin-1 and insulin-like growth factor binding protein-1, tissue inhibitors of metalloproteinases (TIMPs) (especially TIMP-3) and fibronectin, all of which have been demonstrated to inhibit trophoblast invasiveness. Current research should provide answers regarding the effects of various levels of progesterone on the implantation process.