Closer to the Reality-Proteome Changes Evoked by Endometrial Scratching in Fertile Females.

Endometrial scratching (ES) has been widely used in assisted reproductive technology to possibly improve pregnancy rates, but its exact mechanism is still not understood or investigated, and its benefits are controversially discussed. Hypothetically, ES may trigger a local immune response, leading to an improved endometrial receptivity. So far, it has been shown that ES affects the gene expression of cytokines, growth factors, and adhesive proteins, potentially modulating inflammatory pathways and adhesion molecule expression. Our pilot study applying proteomic analysis reveals that ES probably has an impact on the proteins involved in immune response pathways and cytoskeleton formation, which could potentially increase endometrial receptivity. Specifically, proteins that are involved in the immune response and cytoskeleton regulation showed a trend toward higher abundance after the first ES. On the other hand, proteins with a decreasing abundance after the first ES play roles in the regulation of the actin cytoskeleton and cellular processes such as intracellular transport, apoptosis, and autophagy. These trends in protein changes suggest that ES may affect endometrial tissue stiffness and extracellular matrix remodeling, potentially enhancing the embryos' implantation. To our knowledge, this pilot study provides, for the first time, data investigating potential changes in the endometrium due to the scratching procedure that might explain its possible benefit for patients in infertility treatment. Furthermore, the proteome of a group of patients suffering from repeated implantation failure was compared to that of the fertile group in order to transfer the basic science to clinical routine and application.

Eutopic endometrial immune profile of infertility-patients with and without endometriosis.

There is growing evidence that changes in the eutopic endometrial immune profile are a cause of endometriosis-associated infertility. Women affected by endometriosis experience a 2-fold increased risk of infertility compared to healthy controls. In our study we aimed to map out endometrial expressions of uterine natural killer cells, plasma cells, macrophages and the chemokine CXC-motif ligand 1 (CXCL1) as well as its main receptors CXC-motif receptor 2 (CXCR2) and Syndecan-1 in infertility-patients with endometriosis. 36 infertility patients were included of which 19 suffered from endometriosis and 17 served as a control cohort. All patients underwent endometrial scratching in the secretory phase and immunohistochemical staining which was evaluated by three independent observers. In endometriosis-patients, a higher concentration of macrophages coincided with an elevated number of uterine natural killer cells or plasma cells. Patients with endometriosis also showed a higher endothelial expression of VEGF-A. Furthermore, absence of stromal expression of SDC-1 was associated with an elevated level of uNK in general. Therefore, our study links endometriosis to an altered immune cell population in the eutopic endometrium, which might be a new approach to diagnosing endometriosis in infertility patients.

Are uterine natural killer and plasma cells in infertility patients associated with endometriosis, repeated implantation failure, or recurrent pregnancy loss?

PURPOSE: Infertility is a debilitating situation that millions of women around the world suffer from, but the causal relationship between infertility and endometriosis is still unclear. We hypothesize that the immune cell populations of uterine natural killer cells (uNK) and plasma cells (PC) which define chronic endometritis could differ in patients with or without endometriosis and therefore be the link to endometriosis-associated infertility. METHODS: Our retrospective study includes 173 patients that underwent an endometrial scratching in the secretory phase of the menstrual cycle and subsequently immunohistochemical examination for uNK cells and PC. Sixty-seven patients were diagnosed with endometriosis, 106 served as the control cohort. RESULTS: The risk for an elevated number of uNK cells in women with endometriosis is not increased as compared to the control group. Our findings suggest that patients with endometriosis are 1.3 times more likely to have chronic endometritis (CE) as compared to those without and that the treatment with doxycycline might increase pregnancy rates. Endometriosis and an increased number of uNK cells seem to be unrelated. CONCLUSIONS: In contrast to the lately published connection between endometriosis, infertility and increased uNK cells, we could not find any evidence that patients with endometriosis are more prone to elevated uterine uNK cells. Counting of PC in endometrial biopsies might be a new approach in the search of biomarkers for the nonsurgical diagnosis of endometriosis since our findings suggest a connection.

Expression of the vascular endothelial growth factor receptor neuropilin-1 at the human embryo-maternal interface.

OBJECTIVE: Angiogenesis is required for successful implantation of the invading blastocyst. Vascular endothelial growth factor (VEGF) is an important key player in angiogenesis and vascular remodeling during the implantation process. Besides its well-characterized receptors VEGFR1 and VEGFR2, neuropilin-1 (NRP-1) has been shown to play an additional role in the signaling process of angiogenesis in human endometrium during the menstrual cycle, as a co-receptor of VEGF. These findings led to the hypothesis that NRP-1 might play a role in the vascular remodeling process during embryo implantation and the establishment of a pregnancy. STUDY DESIGN: NRP-1 mRNA transcript and protein expression were investigated in human choriocarcinoma cell lines (JEG-3, Jar and BeWo) aiming to evaluate the expression of NRP-1 in vitro, as well as in human decidua of all three trimesters of pregnancy, by western blot analysis (three samples of each trimester of pregnancy). The localization of NRP-1 in human decidua of all three trimesters of pregnancy was analyzed by immunohistochemistry (five samples of each trimester of pregnancy). RESULTS: NRP-1 transcript and protein were expressed in all cell lines examined. Corresponding to the analysis of human tissue by western blot and the localization by immunohistochemistry, NRP-1 protein higher expressed in samples of early pregnancy in comparison to the end of pregnancy. NRP-1 was expressed in the decidua, villi and invading cytotrophoblast of all samples investigated. CONCLUSIONS: This is the first study clearly showing the expression of NRP-1 in human decidua and trophoblast, suggesting an important role for the VEGF co-receptor NRP-1 besides the established receptor VEGFR2 at the embryo-maternal interface during embryonic implantation and placentation.