Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

Abstract

The endometrium maintains complex controls on proliferation and apoptosis as part of repetitive menstrual cycles that prepare the endometrium for the window of implantation and pregnancy. The reliance on inflammatory mechanisms for both implantation and menstruation creates the opportunity in the setting of endometriosis for establishment of chronic inflammation that is disruptive to endometrial receptivity, causing both infertility and abnormal bleeding. Clinically, there can be little doubt that the endometrium of women with endometriosis is less receptive to embryo implantation, and strong evidence exists to suggest that endometrial changes are associated with decreased cycle fecundity as a result of this disease. Here we provide unifying concepts regarding those changes and how they are coordinated to promote progesterone resistance and estrogen dominance through aberrant cell signaling pathways and reduced expression of key homeostatic proteins in eutopic endometrium of women with endometriosis.

Keywords: Endometriosis; endometrial receptivity; endometrium; implantation; progesterone resistance.

Figure 1

Timeline for major discoveries in endometriosis and related defects in endometrial receptivity. The history of discovery of endometrial changes associated with endometriosis is shown in this timeline. Pivotal research on endometriosis commenced with the work of Sampson, but the changes in endometrium were noted by representative investigators up to the present day. There are many other important contributions that may not be represented. (144-167)

Figure 2

The PI3K/AKT pathway is triggered when receptor tyrosine kinases are activated by ligand binding (GF) subsequently activating PI3K and adapter proteins (Grb2, SOS and SHC1). PI3K converts intracellular PtdIns-4,5-P2 (PIP2) to PtdIns-3,4,5-P3 (PIP3). In the absence of PTEN, which antagonizes PI3K, PIP3 activates AKT as a primary kinase downstream of PI3K. AKT moves to the plasma membrane, is phosphorylated and activated by mTORC2. PTEN antagonizes PI3K activity by dephosphorylating PIP3, leading to its conversion back to PIP2. Kras also contributes to PI3K activation and triggers generation of ERK pathway.