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- W2040397732 abstract "The editorial by Dr. Robert Norman in this issue of Fertility and Sterility (1Norman R.J. Biomarkers of endometrial receptivity through a minimally invasive approach.Fertil Steril. 2013; 100: 654-655Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar) succinctly summarizes the various approaches currently used to identify biomarkers of endometrial receptivity toward development of a viable predictive/assessment test for clinical application. As Dr. Norman points out, multiple approaches have been applied to identify candidate biomarkers, including proteomic and lipidomic assessments of uterine aspirate fluid and gene expression profiling of endometrial biopsies. In his editorial, Dr. Norman introduces our paper in which we demonstrate the feasibility of performing genome-wide gene expression profiling on uterine aspirations (2Chan C. Virtanen C. Winegarden N.A. Colgan T.J. Brown T.J. Greenblatt E.M. Discovery of biomarkers of endometrial receptivity through a minimally-invasive approach: a validation study with implications for assisted reproduction.Fertil Steril. 2013; 100: 810-817Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Using unsupervised hierarchic clustering, we demonstrate that the phase of sampling (LH+2 vs. LH+7) affects gene expression more than individual differences in gene expression between patients. We identified and verified robust differences in expression of 245 genes due to phase of sampling and determined that expression of 53 of these genes efficiently separated our two groups and those of a publically available dataset of gene expression signatures obtained from endometrial biopsy samples. Because LH+2 coincides with a prereceptive phase and LH+7 with a receptive phase in fertile women, the differentially expressed genes identified in our study encode for candidate biomarkers of endometrial receptivity. The 53-gene list overlaps significantly with those indicated in other studies, including the 238-gene list comstituting the endometrial receptivity assay used by Diaz-Gimeno et al. (3Diaz-Gimeno P. Ruiz-Alonso M. Blesa D. Bosch N. Martinez-Conejero J.A. Alama P. et al.The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity.Fertil Steril. 2013; 99: 508-517Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar) in their algorithm for predicting the receptive period from endometrial biopsy samples. We are excited by the potential of our approach because uterine aspiration is less traumatic to the endometrium than biopsy. Unlike endometrial biopsy, uterine aspiration is compatible with evaluation within an active IVF or natural cycle in which a patient is attempting pregnancy (4Boomsma C.M. Kavelaars A. Eijkemans M.J. Amarouchi K. Teklenburg G. Gutknecht D. et al.Cytokine profiling in endometrial secretions: a noninvasive window on endometrial receptivity.Reprod Biomed Online. 2009; 18: 85-94Abstract Full Text PDF PubMed Scopus (98) Google Scholar, 5van der Gaast M.H. Beier-Hellwig K. Fauser B.C. Beier H.M. Macklon N.S. Endometrial secretion aspiration prior to embryo transfer does not reduce implantation rates.Reprod Biomed Online. 2003; 7: 105-109Abstract Full Text PDF PubMed Scopus (96) Google Scholar), enabling us and other researchers to directly associate altered gene expression with implantation success. This approach will facilitate our future identification of those candidate biomarkers for further development of point-of-care assays for clinical use. Although our 53-gene cassette includes several interesting candidate biomarkers, including those encoding secreted products, we do not propose these as a clinical test. Rather, we propose that our approach enables further testing and reduction of this signature to identify those genes that are most predictive. We agree with Dr. Norman that protein-based assays would be preferable to transcript measurements for clinical assays; however, gene expression data are necessary to direct proteomic discovery assays to improve these approaches. Dr. Norman points out that we did not fully characterize the cell types present in the uterine aspirations and that changes in cell types would affect gene expression signatures. However, this criticism applies equally to proteomic approaches and to gene expression studies of endometrial biopsies and misses the point. Alterations in infiltrating immune cells undoubtedly contribute to the gene expression profiles, just as they contribute to differences in proteins present in the aspirated fluid and likely affect receptivity of the endogenous intrauterine environment. Our discovery approach mirrors the situation one would encounter in a clinical testing situation, with multiple cell types contributing to the proteome or transcriptome. Dr. Norman also raises an issue of blood contamination and an inability to obtain uterine fluid from patients. We did not encounter either of these issues. Before adopting the technique, we tested various catheters in patients undergoing surgery. We selected the catheter used in our study because it was cost-effective, reliably acquired fluid and cells, and did not inflict pain, and only very few red blood cells were noted on histology as reviewed by a pathologist. Finally, Dr. Norman seems to suggest that we are proposing our 53-gene signature as a clinical test for endometrial assessment. It is important to stress that this is not our claim in the paper. Rather, we recommend adoption of our less invasive sampling approach, which would allow the further validation of gene expression changes associated with the clinically receptive period. We point out that this approach can be used to directly associate biomarker expression with implantation success, and that those findings can guide proteomic discovery and assay development. Such studies are presently underway in our laboratory. Discovery of biomarkers of endometrial receptivity through a minimally invasive approach: a validation study with implications for assisted reproductionFertility and SterilityVol. 100Issue 3PreviewTo determine whether a minimally invasive approach to sampling endometrial cells that can be applied during an active conception cycle can generate robust biomarker candidates for endometrial receptivity by genomewide gene expression profiling. Full-Text PDF Open Access" @default.
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- W2040397732 title "Response to editorial entitled “Biomarkers of endometrial receptivity through a minimally invasive approach”" @default.
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