The current demographic balance in Europe is at risk due to the dropped fertility rate, pushing us to revise our understanding about factors influencing the demographic situation. The wish to become parents can be considered as one of the core principles of humanity. However, substantial numbers of families ready to become parents are sadly unable to get children. This condition is medically referred to as infertility and describes the situation where pregnancy is prevented due to various medical causes. It is remarkable that the prevalence of infertility is high in different societies, ranging up to 10% of couples. The incidence of infertile patients is also increasing due to the general trend to delay the marriage age and pregnancy. Taken these circumstances, infertility has been recognized as the major medical factor contributing to the worsening demographic situation and falling fertility rates in Europe. _x000D_ _x000D_Infertility can be caused by diverse medical conditions of female and male origin. In more than half of the cases it is caused by female factors, with Fallopian tube defects, endocrinological diseases, endometriosis, and advanced maternal age being the most prevalent. Despite meticulous medical examination, the reason for infertility reCOs unexplained in 10% of the patients. In these cases it can be attributed to the endometrial dysfunction disturbing the embryo’s attachment to the uterine lining and further development. Endometriosis, characterized by unusual occurrence of endometrium-like tissue outside of the uterine cavity is also often a risk factor for female infertility._x000D__x000D_Infertility treatment using assisted reproduction technologies (ART) is becoming more popular in Europe with up to 5% of children born thanks to medical help. Despite many technological improvements the overall pregnancy rate after infertility treatment using the most commonly practiced in vitro fertilization (IVF) and embryo transfer reCOs only 30% per single cycle. One of the reasons for failed IVF is our inability to judge correctly the quality of the endometrium providing us to predict the chance for pregnancy. Secondly, the diagnostics of endometrial quality (receptivity) and endometriosis still rely on invasive interventions, with endometrial biopsy and diagnostic laparoscopy belonging to the golden standard of the clinical routine. _x000D_ _x000D_The NOTED project (NOn-invasive Tests for Endometrial Dysfunction – Novel Clinical Perspectives for Infertility and Endometriosis Diagnostics) addresses the top priorities in reproductive medicine – diagnostics and treatment of female infertility. The goal of the project is to develop novel non-invasive tests for reproductive medicine – tests for endometrial receptivity and endometriosis available for end users (clinics and laboratories) all over the world. Endometrial receptivity test enables to assess endometrial quality from patients’ blood or endometrial fluid samples by measuring the panel of transcriptomic or proteomic markers, respectively. The second test will offer an alternative way to endometriosis diagnostics by analyzing the disease transcriptomic biomarkers from blood samples. As the result of non-invasive testing the number of expensive and medically complicated invasive procedures in reproductive medicine will decrease. In our plans, the identification of clinically relevant biomarkers will be accomplished by exploiting cutting-edge genomics (RNA-sequencing) and proteomics (mass-spectrometry) technologies. _x000D__x000D_To reach the objectives, the international NOTED consortium, combining the competences required for a successful project, is set up. The Pship includes five (5) commercial and academic institutions from three (3) European countries. BioEximi from Estonia, a start-up RTD performing SME working in the field of reproductive medicine is the coordinator of the NOTED project. iGenomix is a large company from Spain belonging to the group of academic and commercial institutions of Fundación IVI. IVI infertility clinics and iGenomix’s medical genetic laboratory are internationally renowned reproductive health care providers having 20 infertility clinics in 8 countries all over the world – Europe, Asia and South-America. Lifesequencing is a fast-growing innovating Spanish technology (RTD) SME specialized in genomic research. Competence Centre on Reproductive Medicine and Biology from Estonia is an RTD SME advancing technologies for reproductive medicine. Uppsala University from Sweden represents the academic research institution having clinical and life-science competences in reproductive medicine. _x000D__x000D_The market entry and commercialization of the developed clinical tests will be accomplished COly through iGenomix’ and IVI Clinics’ existing representation in world markets.

Acronym NOTED (Reference Number: 6478)
Duration 01/12/2011 - 31/05/2015
Project Topic Infertility is a serious medical concern at individual, family and social levels, preventing the parenthood in 10% of couples. The NOTED European consortium develops novel non-invasive tests to diagnose female infertility caused by endometrial dysfunction and endometriosis.
Project Results
(after finalisation)
The aim of the NOTED project was to identify the molecular biomarkers for female fertility and endometriosis diagnostics. At the end of the project we obtained:_x000D_WP1: A.) List of transcriptome biomarkers for endometrial receptivity; B.) A novel molecular tool – E-SSPL (Endometrial - Strand Sequencing by Proximity Ligation) for targeted analysis (sequencing) of transcriptomic markers, including the mRNA markers for endometrial receptivity and C.) The novel single-cell transcriptome analysis pipeline for analyzing the whole-transcriptome of single-cells from any native (solid) tissue, including the single-cells of endometrial origin. _x000D_WP2: A.) Invention, referred as ‘GlobinLock’ a kit and a method to reduce globin contamination from blood-extracted RNAs for full transcriptome analysis. _x000D_WP3: A.) List of proteomic biomarkers from endometrial fluid that could reveal, 24 hours before the in vitro fertilization (IVF) embryo transfer, the endometrial receptivity of the patients._x000D_WP5: A.) Three miRNA biomarkers and a molecular diagnostic qPCR-test for reliable and accurate discrimination of endometriotic tissue from lesion-like tissue structures and B.) Three miRNA biomarkers and a molecular diagnostic qPCR-test for non-invasive endometriosis diagnostics from blood-plasma samples.
Network Eurostars
Call Eurostars Cut-Off 6

Project partner

Number Name Role Country
5 BioEximi OÜ (Ltd.) Coordinator Estonia
5 Iviomics S.L. Partner Spain
5 Lifesequencing S.L. Partner Spain
5 Uppsala University Partner Sweden
5 Competence Centre on Reproductive Medicine and Biology (Ltd.) Partner Estonia