GynecologyGynecology2079-56962079-5831Consilium Medicum3396510.26442/20795696.2020.1.200028Research ArticleExpression of MSX1, HOXA11 and TP53I3 in the endometrium associated with the onset of pregnancy after repeated failed IVF attempts in patients with tubo-peritoneal factor infertilityKnyazevaEkaterina A.<p>Postgraduate Student</p>dr.knyazeva.ea@gmail.comhttps://orcid.org/0000-0002-1472-2018KuznetsovaMaria V.<p>Cand. Sci. (Biol.)</p>mkarja@mail.ruhttps://orcid.org/0000-0003-3790-0427BurmenskayaOlga V.<p>D. Sci. (Biol.)</p>o_bourmenskaya@oparina4.ruDonnikovAndrey E.<p>Cand. Sci. (Med.)</p>a_donnikov@oparina4.ruhttps://orcid.org/0000-0003-3504-2406KalininaElena A.<p>D. Sci. (Med.)</p>e_kalinina@oparina4.ruhttps://orcid.org/0000-0002-8922-2878Kulakov Research Center for Obstetrics, Gynecology and Perinatology0105202022123280105202001052020Copyright © 2020, Consilium Medicum2020<p><strong>Relevance. </strong>The success of the in vitro fertilisation (IVF) program, among other factors, depends on the readiness of the endometrium to accept the embryo. It is believed that this is possible during the so-called implantation window, the timing of which can be shifted under the influence of various factors. Evaluation of endometrial receptivity and the implantation window based on analysis of endometrial gene expression before embryo transfer is a promising approach for predicting the likelihood of pregnancy in IVF programs.</p>
<p><strong>Aim. </strong>To construct a classifier based on the expression of endometrial genes for predicting the outcome of an IVF program in patients with tubal-peritoneal infertility factor and repeated failed IVF attempts in history.</p>
<p><strong>Materials and methods.</strong> Before the IVF program, a genome-wide transcriptome profiling of endometrial samples of 15 women with tubal-perioneal infertility factor and repeated unsuccessful IVF attempts in history was carried out using Affymetrix arrays. Potential genes capable of classifying IVF program outcomes were selected, after which the expression of these genes was analyzed by qPCR-RT in the endometrium of 47 women to construct IVF outcome classifiers based on the expression of pairs or triples of genes.</p>
<p><strong>Results. </strong>A classifier based on the expression of the triple of genes <em>MSX1</em> (<em>HOX7</em>), <em>HOXA11</em>, and <em>TP53I3</em> made it possible to determine the onset of pregnancy in an IVF program with a sensitivity of 73% and a specificity of 71% with an area under the ROC-curve (AUC) of 0.738 (95% confidence interval 0.5770.898). Earlier, a relationship was found between the expression of these genes and receptivity of the endometrium, which suggests that these genes play a role in the onset of the implantation window.</p>
<p><strong>Conclusions. </strong>The use of a classifier based on the genes <em>MSX1</em> (<em>HOX7</em>), <em>HOXA11</em>, and <em>TP53I3</em> can determine the readiness of the endometrium to accept an embryo and create an individual prognosis of the outcome of an IVF program in women with tubal-peritoneal infertility factor and repeated failed IVF attempts in history.</p>in vitro fertilisationinfertilityendometrial receptivityimplantation windowDNA methylationHOX genesHOXA11MSX1TP53I3экстракорпоральное оплодотворениебесплодиерецептивность эндометрия«окно имплантации»метилирование ДНКНОХ-геныНОХА11MSX1TP53I3[Хабаров С.В., Хадарцева К.А. Возрастные аспекты в неудачах программ вспомогательных репродуктивных технологий. Вестн. новых медицинских технологий. 2018; 12 (2): 74–9. [Khabarov S.V., Khadartseva K.A. Vozrastnye aspekty v neudachakh programm vspomogatel’nykh reproduktivnykh tekhnologii. Vestn. novykh meditsinskikh tekhnologii. 2018; 12 (2): 74–9 (in Russian).]][Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions 11 Medical and Health Sciences 1114 Paediatrics and Reproductive Medicine. Reprod Biol Endocrinol 2018; 16 (1): 1–18.][Teh WT, McBain J, Rogers P. What is the contribution of embryo-endometrial asynchrony to implantation failure? J Assist Reprod Genet 2016; 33 (11): 1419–30.][Hertig AT, Rock J, Adams EC. A description of 34 human ova within the first 17 days of development. Am J Anat 1956; 98 (3): 435–93.][Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril 2017; 108 (1): 15–8.][Ruiz-Alonso M, Blesa D, Díaz-Gimeno P et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 2013; 100 (3): 818–24.][Mahajan N. Endometrial receptivity array: Clinical application. J Hum Reprod Sci 2015; 8 (3): 121–9.][Kibanov MV, Makhmudova GM, Gokhberg YA. In search for an ideal marker of endometrial receptivity: from histology to comprehensive molecular genetics-based approaches. Alm Clin Med 2019; 47 (1): 12–25.][Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril 2011; 95 (1): 50–60.e15.][Craciunas L, Gallos I, Chu J et al. Conventional and modern markers of endometrial receptivity: A systematic review and meta-analysis. Hum Reprod Update 2019; 25 (2): 202–23.][Nikulin SV, Knyazev EN, Poloznikov AA et al. Expression of SLC30A10 and SLC23A3 Transporter mRNAs in Caco-2 Cells Correlates with an Increase in the Area of the Apical Membrane. Mol Biol 2018; 52 (4): 577–82.][Burmenskaya OV, Bozhenko VK, Smolnikova VY et al. Transcription profile analysis of the endometrium revealed molecular markers of the personalized “window of implantation” during in vitro fertilization. Gynecol Endocrinol 2017; 33 (Suppl. 1): 22–7.][Bolnick AD, Bolnick JM, Kilburn BA et al. Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility. Hum Reprod 2016; 31 (9): 2042–50.][Salilew-Wondim D, Hölker M, Rings F et al. Bovine pretransfer endometrium and embryo transcriptome fingerprints as predictors of pregnancy success after embryo transfer. Physiol Genomics 2010; 42 (2): 201–18.][Qin L, Wang R, Li S et al. Differentially Gene Expression Profile Related to Inflammation in Endometrial Cells Induce by Lipopolysaccharide. J Reprod Contracept 2009; 20 (1): 27–34.][Knyazeva EA, Alieva KU, Kalinina EA. Ovarian pregnancy after an IVF program in a patient with reduced endometrial receptivity. Akusherstvo Ginekol (Russian Fed.) 2018; 8: 180–4.][Knyazeva EA, Kalinina EA, Bystritsky AA et al. Role of HOX genes associated with infertility in female reproductive system diseases. Akusherstvo Ginekol (Russian Fed.) 2017; 11: 16–22.][Bourdiec A, Ahmad S-F, Lachhab A et al. Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells. Reprod Biomed Online 2016; 32 (1): 85–95.][Du H, Taylor HS. The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility. Cold Spring Harb. Perspect Med 2016; 6 (1): a023002.][Nazarenko TA, Kalinina EA, Knyazeva EA et al. The role of abnormal hypermethylation of the HOXA10 and HOXA11 promoters in implantation failures in IVF programs. Gynecol Endocrinol 2019; 35 (Suppl. 1): 31–4.]