I-24: The Role of Interleukins, Integrins and Other Proteins in Recurrent Implantation Failure

Embryo implantation represents the most critical step of the reproductive process in many species. Inadequate uterine receptivity is responsible for approximately two-thirds of implantation failures. The cell adhesion molecule (CAM) such as integrins, cadherins, selectins and immunoglobulins intervene to ensure adhesiveness between the embryo and the endometrium. Some recent studies indicate that women with unexplained RPL had significantly reduced integrin expression compared to that of control group. Co-expression of osteopontin (OPN) and b3 integrin is a biological marker for good endometrial receptivity and that both proteins play a critical role in blastocyst implantation. Homeobox A10 (HOXA10), a key transcription factor, does a vital part in endometrial receptivity by regulating the expression of downstream target genes, such as β3-integrin (ITGB3). Findings clearly support roles for hCG-regulated factor, and fibroblast growth factor 2 (FGF2), in the blastocyst-endometrial cross-talk important for endometrial receptivity and blastocyst implantation. Regarding the key role of interleukines, an altered expression of leukemia inhibitory factor (LIF) and IL-15 was shown in the endometrium of women with RIF. Changes in endometrial IL-1R throughout early gestation in vivo, suggests a deep modulation of endometrial receptivity. It is also found that human endometrial stromal cells (HESCs) rapidly release IL-33, which controls the temporal expression of receptivity genes. Recently, evaluation of the bone marrow mesenchymal stem cell (BMSC), revealed their positive role in improving the regeneration of endometrium and endometrial receptivity.Researches on in vitro fertilization indicate that failure to achieve a clinical pregnancy after the transfer of at least four good-quality embryos in three transfer cycles, is not associated with abnormal endometrial integrin expression. In addition, the expression of integrins a1, a4, and aVb3 appears to bear no prognostic value in subsequent IVF treatment. It is also found that lower follicular fluid IL-6 levels in IVF patients are associated with the increased likelihood of clinical pregnancy. The endometrial receptivity array (ERA) consists of a customized array containing 238 genes expressed at different stages of the endometrial cycle, and is coupled to a computational predictor that is able to identify the receptivity status of an endometrial sample and diagnose the personalized windows of implantation. The accuracy of the ERA test is superior to endometrial histology, and results were reproducible in the same patients 29-40 months after the first test.