{"paper_id":"376b1ce4-0b97-47cc-a484-5025d3d2e770","body_text":"A receptive uterine endometrium during the im-\nplantation window, a viable embryo and effective \ncompatible dialogue between them are indispensable \nfor accomplished embryo implantation. It is essential \nthat the surface of the embryo is mature, the hor-\nmone-protein content of uterine fluid is concordant, \nas required, and the right signals are raised. Implan-\ntation is a complex process involving the attachment \nand penetration of the blastocyst to the endometrium \nthrough adhesion molecules, secreted enzymes, and \nextracellular-intercellular matrix components, fol-\nlowing the placement of the embryo in the uterus.\n1-3 \nThe period that the uterine endometrium is re-\nceptive to the embryo is called the window of im-\nplantation. The luminal and glandular epithelium \nas well as endometrial stroma undergo significant \nchanges to reach the optimum state for implanta-\ntion. Apart from morphological changes, in recent \nstudies, several markers for endometrial receptivity \nwhich are expressed during the implantation win-\ndow and crucial for implantation have also been \nnoted.\n3-7 \nInsulin-like growth factor binding protein 1 \n(IGFBP-1) has a substantial effect in terms of im-\nplantation of the embryo. It is released from the ovar-\nian stroma and is involved in decidual differentiation \nof the stroma and proliferation/differentiation of the \nendometrium.\n8 Moreover, it has been proven that the \nJCOG. 2022;32(3):77-84\n77\nComparison of Endometrial Receptivity Markers Between \nWomen with Polycystic Ovary Syndrome, Endometrioma and \nUnexplained Subfertility: A Cross-Sectional Study\n \n     Emine DEMİRa,     Fulya OĞUZ TÜRKYILMAZa,     Mustafa ŞENGÜLa,     Sefa KELEKÇİa \naDeparment of Gynecology and Obstetrics, İzmir Katip Çelebi University, Atatürk Training and Research Hospital, İzmir, Türkiye \nABS TRACT Objective: Uterine receptivity and implantation are complex processes that require the coordinated expression of molecules by \nthe zygote and uterus. Some molecules have been identified at different stages of the luteal phase as receptivity markers that play roles in im-\nplantation. This cross-sectional prospective study aimed to compare the levels of insulin-like growth factor binding protein 1 (IGFBP 1), os-\nteopontin (OPN) and prostaglandin E2 (PGE2) in endometrial flushing liquid during the midluteal phase between patients diagnose d with \npolycystic ovary syndrome (PCOS), endometrioma and unexplained subfertility, and ovulatory women. Material and Methods:  The study \ngroups were formed by women with ovulatory PCOS (n=24), endometrioma (n=17) and unexplained subfertility (n=25). The control gr oup \nconsisted of fertile women (n=18). During the implantation window, endometrial flushing samples were taken and IGFBP1, OPN and PGE2 \nlevels were analyzed and compared among the groups. Results: There were no significant differences in the levels of IGFBP1, PGE2 and OPN \namong groups. PGE2 levels were 367.7±96.3 ng/mL and 239.2±106.9 ng/mL in women with PCOS and in healthy women, respectively. Th is \ndifference was statistically significant (p=0.002). The present results show that PGE2 might be an indicator of unfavorable end ometrial re-\nceptivity and might be responsible for the low pregnancy rates in patients with PCOS. Conclusion: We hypothesized that PGE2 downregu-\nlation may facilitate decidualization and improve the pregnancy rate in ovulatory PCOS. So, this can guide us about future trea tment in the \nmanagement of patients. \n \nKeywords: Endometrial receptivity; endometrioma; insulin-like growth factor binding protein 1; osteopontin; prostaglandin E2 \nDOI: 10.5336/jcog.2022-89394\nCorrespondence: Emine DEMİR \nDeparment of Gynecology and Obstetrics, İzmir Katip Çelebi University, Atatürk Training and Research Hospital, İzmir, Türkiye \nE-mail: er_em.dr@hotmail.com  \nPeer review under responsibility of Journal of Clinical Obstetrics & Gynecology.  \nRe ce i ved: 02 Mar 2022          Received in revised form: 10 May 2022         Ac cep ted: 26 Jun 2022          Available online: 05 Jul 2022  \n2619-9467 / Copyright © 2022 by Türkiye Klinikleri. This is an open \naccess article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nTurkiye Klinikleri Journal of Internal Medicine \nJournal of Clinical Obstetrics & Gynecology\nORIGINAL RESEARCH\n\n78\nincrease in IGFBP-1 expression in endometrial stro-\nmal cells throughout decidualization may increase \npregnancy rates in both spontaneous and assisted re-\nproductive techniques.\n9-11 \nOsteopontin (OPN) is located in the en-\ndometrium of fertile women with normal menstrual \ncycles, with maximum release throughout the im-\nplantation window.\n12,13 Hence, it has been claimed \nthat OPN is an effective marker of endometrial im-\nplantation and, together with its receptor αvβ3 inte-\ngrin, promotes embryonic adhesion to the uterine \nepithelium.\n13-18 Also, Wang, et al. showed that the \nOPN level was significantly suppressed in the group \nthat failed in vitro fertilization (IVF) cycles and so \nestablished that OPN plays a role in success of IVF \ntechniques.\n19 \nProstaglandins are lipid compounds that are also \ncontained in the endometrium, of which the impor-\ntance in female fertility has been emphasized in the \nevidence up to now. Among the prostaglandins, \nprostaglandin E2 (PGE2) is thought to have a signif-\nicant role especially for decidualization and implan-\ntation of pregnancy. The levels of PGE2 in \nendometrial fluid have been implicated as a marker \nfor endometrial receptivity.\n20 In addition, elevated \namounts of PGE2 were detected in polycystic ovarian \ncells compared to women with normal ovulation.\n21,22 \nThe purpose of the present study was to investi-\ngate the concentrations of IGFBP-1, OPN and PGE2 \nin endometrial flushing fluids of patients with ovula-\ntory polycystic ovarian syndrome (PCOS), en-\ndometrioma, unexplained subfertility and healthy \nfertile women. \n MATERIAL AND METHODS \nThis cross-sectional controlled study was carried out \nbetween January and June 2013 in Subfertility Unit of \nthe Department of Obstetrics and Gynecology, İzmir \nKatip Çelebi University, Atatürk Training and Re-\nsearch Hospital İzmir, Türkiye. The unit is a tertiary \ncenter that treats referral patients from the region. The \nstudy design was in accordance with the ethical stan-\ndards of the Helsinki Declaration and good clinical \npractice, and was approved by the Institutional Review \nBoard of İzmir Katip Çelebi University, School of \nMedicine, Atatürk Training and Research Hospital \n(date: 17.05.2012, no: 25). Detailed information was \nconveyed to all volunteers regarding the research and \nboth verbal and written informed consent were taken. \nA total of 112 patients ranging between the ages \n20 to 40 who referred to the subfertility outpatient \nclinic were included in the study. Voluntary patients \ndiagnosed with PCOS (n=38), endometrioma (n=19) \nand unexplained subfertility (n=27) constituted the \nstudy groups, while the control group consisted of \nfertile women (n=28). In these 4 groups, 14 patients \nwith PCOS, 2 patients with endometrioma, 2 patients \ndiagnosed with unexplained subfertility and 10 pa-\ntients in the control group who were detected as hav-\ning anovulation with blood progesterone levels on the \n21\nst day of menstruation were excluded from the \nstudy. The control group comprised of healthy \nwomen with no gynecologic disorder, not using an \nintrauterine device or hormonal contraception, or not \nreceiving any medication that may affect en-\ndometrium and who had the intellectual capacity to \ngive written informed consent and to understand the \ninformation concerning the study. Exclusion criteria \nfor the volunteers were having a pregnancy, smok-\ning, pelvic infection, a serum progesterone level of \n<3 ng/dL in the luteal phase or endometrial pathol-\nogy (submucosal myoma, endometrial polyp etc.) \nduring the endometrial fluid sampling or a patient’s \nreluctance to be included. \nA total of 24 patients who showed ovulatory \nphenotype and were diagnosed with PCOS accord-\ning to the ESHRE Rotterdam 2003 criteria; a total of \n17 patients who were diagnosed with endometrioma \nby clinical history, physical examination and \ntransvaginal ultrasonography (Medison Sono Ace X8 \nSeoul, South Korea); and a total of 25 patients diag-\nnosed with unexplained subfertility after undergoing \nbasic infertility evaluation which were performed ac-\ncording to American College of Obstetricians and \nGynecologists diagnostic criteria were included. The \ncontrol group consisted of a total of 18 healthy ovu-\nlatory, parous women who had no history of subfer-\ntility and who were using the barrier contraception \nmethod. \nEmine DEMİR et al. JCOG. 2022;32(3):77-84\n78\n\n797979\nIn the study and control groups, after confirma-\ntion of ovulation with the blood progesterone levels \non the 21\nst day of menstruation, 0.154 mol/L sodium \nchloride was administered via a thin cannula (2 mL \nper administration into the uterine cavity, a total of \n10 mL following fluid collection sampling performed \n5 times in total) resembling the saline infusion sonog-\nraphy administration technique, 1 mL of uterine as-\npirate was transferred to a standard micro test tube \n(Eppendorf, Hamburg, Germany), was frozen at -\n20°C and finally stored at -80°C until biochemical \nanalysis. After the endometrial fluid samples were ac-\ncumulated from study and control groups, IGFBP-1, \nOPN and PGE2 levels were analyzed by using East \nbiopharm branded (Hangzhou East biopharm Co., \nLtd./China) Elisa kits (PGE2 LOT: 20130924, OPN \nLOT: 20130924, IGFBP-1 LOT: 20130924, PGE2 \nCat. No: CK-E10702, OPN Cat. No: CK-E10857, \nIGFBP-1 Cat. No: CK-E10159) with the Biotec \nbranded Elisa device. The patients were warned about \nnot having sexual intercourse until the endometrial \nfluid is obtained in that menstrual cycle. Patients were \nkept under observation for half an hour after the en-\ndometrial fluid sampling. \nThe statistical analysis was performed using \nSPSS (version15.0, 2006; SPSS Inc., Chicago, IL, \nUSA) program. Shapiro-Wilks and Levene tests were \ncarried out to control the distribution of the data. Be-\ncause of the fundamental hypothesis of parametric \nstatistics was not met, use of non-parametric tests was \nconsidered appropriate instead of parametric \nMANOVA. Therefore, Kruskal-Wallis tests were \nconducted for 2 variables, 4 groups were tested in the \nsame hypothesis and paired comparisons were per-\nformed via Mann-Whitney U tests as follow-up tests \nbetween the groups in the event of statistically sig-\nnificant differences. Data analysis was considered \nsignificant when p values were less than 0.05. \n RESULTS  \nTwenty eight (25%) of 112 women included in the \nstudy were excluded from the study in both study and \ncontrol groups due to anovulation. This cross-sec-\ntional, controlled study consisted of 24 patients with \novulatory PCOS, 25 patients with unexplained sub-\nfertility, 17 patients with ovulatory endometrioma \nand 18 healthy fertile ovulatory women out of 84 vol-\nunteers.  \nThe demographic data and serum progesterone \nlevels of the patients were shown in \nTable 1. While \nthere was no statistically significant difference be-\ntween the endometrioma and control groups, there \nwas a statistically significant difference in terms of \nage only between unexplained subfertility and en-\ndometrioma groups in all other pairwise comparisons. \nThe mean body mass index (BMI) was highest in the \nPCOS group (28.67) and lowest in the endometrioma \ngroup (24.11), while it was similar in the unexplained \ninfertility (24.25) and control (25.16) groups. In ad-\ndition, there was no statistically significant difference \nin terms of BMI when the 3 groups were compared \nwith the control group and all 2-group comparisons. \nAll groups were similar in terms of demographically, \nexcept for gravidity and parity. Statistically signifi-\ncant differences were detected between fertile group \nand each one of study groups as expected. The mean \nserum progesterone level at mid-luteal phase was \nhighest in the unexplained subfertility group (10.38) \nand was similar in PCOS (9.98) and control groups \n(8.19), while it was statistically significantly lower in \nthe endometrioma group (5.95) when compared to \nthese other three groups. \nEmine DEMİR et al. JCOG. 2022;32(3):77-84\n79\nPCOS (n=24) US (n=25) End (n=17) Control (n=18) p-value*  \nAge (year) 29.87±5.61 29.05±4.81 33.05±6.68 33.55±5.90 0.013 \nBMI (kg/m\n2) 28.67±7.93 24.25±3.61 24.11±3.56 25.16±2.68 0.209 \nGravida (n) 0.95± 1.04 0.48±0.96 1.02±1.28 3.66±2.08 0.000 \nParite (n) 0.70±0.95 0.20±0.50 0.88±1.05 2.77±1.59 0.000 \nProgesteron (ng/mL) 9.98±4.61 10.38±5.51 5.95 ±3.32 8.19±3.92 0.006\n \nTABLE 1:  Evaluation of demographic and baseline data of the groups.\nData are presented as mean±standard deviation, *Kruskal Wallis test, BMI: Body Mass Index; PCOS: Polycystic ovary syndrome; US: Unexplained subfertility; End: Endometrioma.\n\nMean levels of IGFBP-1 (ng/mL) of endome-\ntrial flushing fluid were 396.5, 310.2, 391.1 and \n377.3 for the unexplained subfertility, PCOS, en-\ndometrioma and control groups, respectively (\nTable \n2). In addition, as seen in Table 3, there was no sta-\ntistically significant difference in all pairwise com-\nparisons when IGFBP-1 levels were compared \nbetween paired groups. Mean PGE2 (ng/mL) levels \nin the endometrial fluid were similar for endometri-\noma (259.16), unexplained subfertility (292.6) and \ncontrol groups (239.2). But, this marker was notably \nhigher in the PCOS (367.7) patients relative to the \nendometrioma (p<0.05) and control groups \n(p<0.001). On the contrary, mean OPN levels \n(ng/mL) in endometrioma (16.67), ovulatory PCOS \n(12.09), unexplained subfertility (13.03) and control \ngroups (10.04) were similar. No statistically signifi-\ncant difference was found in pairwise comparisons \nbetween all groups either. \n DISCUSSION \nThis prospective study was conducted to evaluate the \namounts of IGFBP-1, OPN and PGE2 in the uterine \nwashing fluids of patients with ovulatory PCOS, en-\ndometrioma, unexplained subfertility and fertile \nwomen during implantation window. According to \nthe findings of the present study, the levels of PGE2 \nwere greater in ovulatory PCOS patients compared \nto the control group. Midluteal PGE2 expression was \nalso found to be higher in patients with endometri-\noma and unexplained infertility group compared to \nthe control group, but the difference was not statisti-\ncally significant. It was determined that there was a \nsimilarity in IGFBP-1 and OPN values in both the pa-\ntient and control groups. \nThe dysregulated expression of uterine receptiv-\nity markers in women with PCOS has been addressed \nin most of the available evidence. In our study, mid-\nluteal PGE2 amount was greater in the ovulatory \nPCOS group than in the control group. Even though \novulatory dysfunction in PCOS appears to be the \nmain reason for subfertility, following the ovulation \ninduction, the weak link between ovulation and preg-\nnancy and low pregnancy rates despite providing \novulation are important indicators with regard to en-\ndometrial dysfunction. Recently, in PCOS as well as \nin other gynecological diseases which may influence \nfertility, endometrial receptivity studies concentrate \non endometrial receptivity markers. Meaningful ele-\nvation of PGE2 levels has been noted in polycystic \novaries and this was parallel to our finding.\n21,22 Fur-\nthermore, it has been pointed out that amount of \nPGE2 in the uterine endometrial fluid may be a po-\ntential endometrial receptivity marker.\n20 Data ob-\nEmine DEMİR et al. JCOG. 2022;32(3):77-84\n80\nPCOS (n=24) US (n=25) End (n=17) Control (n=18) p-value*  \nIGFBP-1, (ng/mL) 310.22±70.76 396.51±130.55 391.18±118.86 377.36±123.10 0.028 \nPGE2,(ng/mL) 367.75±96.37 292.68±123.42 259.16±117.80 239.25±106.97 0.003 \nOPN, (ng/mL) 12.09±7.72 13.03±9.61 16.67±6.27 10.04±4.74 0.029\n \nTABLE 2:  The distribution of IGFBP-1, PGE2 and OPN value according to the group.\nData are presented as mean±standard deviation; *Kruskal Wallis test; IGFBP-1: Insulin-like growth factor binding protein 1; PGE2: Prostoglandin E2; OPN: Osteopontin; PCOS: \nPolycystic ovary syndrome; US: Unexplained subfertility; End: Endometrioma.\nPCOS vs control US vs control End. vs control PCOS vs US PCOS vs end US vs end \nIGFBP-1 (ng/mL) 0.349 1.000 1.000 0.055 0.152 1.000 \nPGE2 (ng/mL) 0.002 0.769 1.000 0.133 0.017 1.000 \nOPN (ng/mL) 1.000 1.000 0.068 1.000 0.356 0.794\n \nTABLE 3:  The comparison of IGFBP-1, PGE2 and OPN values between the 2 groups. \n*Mann-Whitney U test; IGFBP-1: Insulin-like growth factor binding protein 1; PGE2: Prostoglandin E2; OPN: Osteopontin; PCOS: Polycystic ovary syndrome; US: Unexplained sub-\nfertility; End: Endometrioma. Polycystic ovary syndrome; US: Unexplained subfertility; End: Endometrioma.\n\ntained in the present study showed  similar findings. \nIncreased PGE2 in PCOS is coupled with suppressed \na propensity to apoptosis which plays a vital role with \na delicate cell balance between proliferation and dif-\nferentiation. It has been shown in both genital system \ncancers and the endometrial cells also.\n23,24 It is known \nthat cells overexpressing cyclooxygenase-2 have in-\nability to increase proliferation and the ability to \ndownregulate apoptotic processes. Besides the un-\nderlying of physiopathology that appears to be the re-\nsistance of endometrial cells to undergo programmed \ncell death, PGE2 may also contribute to endometrial \ndysfunction through its effects on cell proliferation, \nangiogenesis and immunosuppression by affecting \nthe estrogen levels at the receptor level. \nAlthough the distribution of IGFBP-1 in our \nPCOS patients with ovulatory phenotype was lower \nthan in the control group, the difference was statisti-\ncally insignificant. Low levels of IGFBP-1 have been \nfound in PCOS and obesity, but the results of studies \non this subject in the literature are contradictory. It \nhas been mentioned that decreased amount of \nIGFBP-1 in PCOS patients may be related to BMI \nrather than ovarian hyperandrogenism.\n25 Taking into \naccount that the BMI of the ovulatory PCOS group \nwas 28.6 kg/m\n2 in our study, it may clarify the low \nIGFBP-1 levels although it is not statistically signif-\nicant. In addition, considering the trend of the data in \nthe current study, the low expression of IGFBP-1 \nmay gain statistical significance by increasing the \nnumber of cases. OPN levels were reported to be sim-\nilar in patients with the ovulatory PCOS phenotype \ncompared to the controls; in a recent study.\n26 Impor-\ntant reduction of OPN levels was observed in infertile \nwomen with isolated PCO. But, ovulatory dysfunc-\ntion was the main factor for subfertility in this study. \nOf course, conflicting results affect the comparability \nof these data with our study. \nIn the current study, the amounts of 3 markers \nevaluated in the midluteal phase of patients with en-\ndometriosis were found to be similar to the normal \ncontrol group. Genetic factors are known to be asso-\nciated with the development and progression of en-\ndometriosis, but endometriosis-associated genes have \nnot been described. IGFBPs are thought to have \nmajor effects in cell apoptosis, proliferation and \npathophysiology of endometriosis. It has been stated \nthat IGFBP-1 is not associated with endometriosis, \nbut IGFBP-3 has a significant relationship with en-\ndometriosis.\n27 αvβ3 integrin and its extracellular ma-\ntrix ligand OPN are involved in the regulation of \nendometrial receptivity. While OPN expression was \nunaffected in patients with endometriosis, αvβ3 inte-\ngrin expression was shown to be decreased. On the \nother hand, OPN binding to the surface epithelium is \nso limited when αvβ3 expression is missing. This in-\nformation indicates that the endometrium of some \nwomen with endometriosis is dysfunctional and is re-\nsponsible for decreased fertilization.\n28 In the current \nstudy, making the diagnosis of the endometrioma \ngroup by history, physical examination and transvagi-\nnal sonography imaging may be the reason for par-\ntially inconsistent data. In addition, the relative \nincrease in OPN and IGFBP-1 levels and the relative \nlow expression of PGE2 may negatively affect em-\nbryo implantation in endometriosis by causing both \napoptosis inhibition and immune compromise. \nDiagnosis of unexplained subfertility made by \nexclusion in many guidelines, ovulation is diagnosed \nby excluding the male and tuboperitoneal factors. \nHowever, high prevalence of this diagnosis in all in-\nfertile couples and the perception that there is no \ntreatment terminologically lead to serious perceptual \nproblems. Nevertheless, many associated issues for \ninfertility may go unnoticed with basic infertility re-\nsearch. Endometrial dysfunction in unexplained sub-\nfertility has been ignored until recently. In this study, \nthe levels of all 3 markers in the midluteal phase in \nthe unexplained subfertility group were found to be \nsimilar to the control group. In the literature, studies \ninvestigating endometrial dysfunction during the im-\nplantation window in patients with unexplained in-\nfertility are very limited. OPN and its receptor αvβ3 \nintegrin, recently proposed as an important complex \nin embryo implantation, may be useful as endome-\ntrial receptivity markers in a variety of infertility \nstates.\n13 In the last 20 years, an extremely consider-\nable rise was observed in genomic studies and an un-\npredictable amount of data was collected. A total of \n1,453 gene pairs that have been identified are kept re-\nsponsible for implantation and nearly 200 of them \nEmine DEMİR et al. JCOG. 2022;32(3):77-84\n81\n\nhave quite important functions. Whereas, this is not \nsufficient to explain the mechanism of implantation \nof a single marker expressed by each gene, because \nimplantation has a complex physiopathology, and a \ndecrease in a protein that a gene expresses is com-\npensated by an increase in a protein that another gene \nexpresses.\n29 \nThe strengths of our study were that diseases \nscarcely included in the literature were selected, the \nnumber of subjects were sufficient, the biomarkers \nstudied were diverse and the subgroups were in-\ncluded in the analysis. But, the limitations of the pre-\nsent study were that the diagnosis of endometrioma \nwas made by imaging methods, the control group \nconsisted of random advanced age fertile women due \nto sequential collection, and fewer biomarkers were \nincluded in the study due to the limitation in gene ex-\npression. Another limitation of this study was the lack \nof the power analysis. Therefore; although PGE2 lev-\nels were higher in patients with endometrioma as well \nas unexplained subfertility compared to the normal \ncontrol group, the difference was not statistically sig-\nnificant. \n CONCLUSION \nConsequently, in the literature, endometriosis, un-\nexplained subfertility and PCOS may be associated \nto a decreased fertility cycle and impaired en-\ndometrium receptivity. According to our results, \nPGE2 may be an indicator of poor endometrial re-\nceptivity, which may be responsible for low preg-\nnancy rates in patients with ovulatory PCOS. A \nsingle marker is not satisfactory to explain the \nmechanism of implantation as well as many markers \nplay role in endometrial receptivity. For this reason, \nthere is a need for more comprehensive studies with \na large number of markers in more different female \ninfertility issues. \nAcknowledgments \nThe authors thank all the women whose participation made this \nstudy possible. \nSource of Finance \nDuring this study, no financial or spiritual support was received \nneither from any pharmaceutical company that has a direct con-\nnection with the research subject, nor from a company that pro-\nvides or produces medical instruments and materials which may \nnegatively affect the evaluation process of this study. \nConflict of Interest \nNo conflicts of interest between the authors and / or family mem-\nbers of the scientific and medical committee members or mem-\nbers of the potential conflicts of interest, counseling, expertise, \nworking conditions, share holding and similar situations in any \nfirm. \nAuthorship Contributions \nIdea/Concept: Emine Demir, Fulya Oğuz Türkyılmaz, Sefa Kelekçi; \nDesign: Emine Demir, Fulya Oğuz Türkyılmaz, Sefa Kelekçi; Con-\ntrol/Supervision: Emine Demir, Fulya Oğuz Türkyılmaz, Mustafa \nŞengül, Sefa Kelekçi; Data Collection and/or Processing: Emine \nDemir, Fulya Oğuz Türkyılmaz, Sefa Kelekçi; Analysis and/or In-\nterpretation:Emine Demir, Fulya Oğuz Türkyılmaz, Mustafa Şengül, \nSefa Kelekçi;  Literature Review: Emine Demir, Fulya O ğuz \nTürkyılmaz, Mustafa Şengül, Sefa Kelekçi; Writing the Article: \nEmine Demir, Fulya Oğuz Türkyılmaz, Mustafa Şengül, Sefa Kelekçi; \nCritical Review: Emine Demir, Fulya O ğuz Türky ılmaz, Sefa \nKelekçi; References and Fundings: İzmir Katip Çelebi University; \nMaterials: Emine Demir, Fulya Oğuz Türkyılmaz, Mustafa Şengül, \nSefa Kelekçi. \nEmine DEMİR et al. JCOG. 2022;32(3):77-84\n82\n\nEmine DEMİR et al. JCOG. 2022;32(3):77-84\n83\n1. Paria BC, Reese J, Das SK, Dey SK. Deciphering the cross-talk \nof implantation: advances and challenges. Science. \n2002;296(5576):2185-8. \n[Crossref]   [PubMed]   \n2. Lessey BA. Assessment of endometrial receptivity. Fertil Steril. \n2011;96(3):522-9. [Crossref]   [PubMed]   \n3. Aghajanova L, Hamilton AE, Giudice LC. Uterine receptivity to \nhuman embryonic implantation: histology, biomarkers, and tran-\nscriptomics. Semin Cell Dev Biol. 2008;19(2):204-11. \n[Crossref]   \n[PubMed]   [PMC]  \n4. Giacomini E, Scotti GM, Vanni VS, Lazarevic D, Makieva S, Priv-\nitera L, et al. Global transcriptomic changes occur in uterine fluid-\nderived extracellular vesicles during the endometrial window for \nembryo implantation. Hum Reprod. 2021;36(8):2249-74. \n[Cross-\nref]  [PubMed]   [PMC]  \n5. Kao LC, Tulac S, Lobo S, Imani B, Yang JP, Germeyer A, et al. \nGlobal gene profiling in human endometrium during the window of \nimplantation. Endocrinology. 2002;143(6):2119-38. \n[Crossref]   \n[PubMed]   \n6. Strowitzki T, Germeyer A, Popovici R, von Wolff M. The human \nendometrium as a fertility-determining factor. Hum Reprod Up-\ndate. 2006;12(5):617-30. \n[Crossref]   [PubMed]   \n7. Lee J, Oh J, Choi E, Park I, Han C, Kim DH, et al. Differentially ex-\npressed genes implicated in unexplained recurrent spontaneous \nabortion. Int J Biochem Cell Biol. 2007;39(12):2265-77. \n[Cross-\nref]  [PubMed]   \n8. Wang HS, Chard T. IGFs and IGF-binding proteins in the regula-\ntion of human ovarian and endometrial function. J Endocrinol. \n1999;161(1):1-13. \n[Crossref]   [PubMed]   \n9. Gibson DA, Simitsidellis I, Kelepouri O, Critchley HOD, Saunders \nPTK. Dehydroepiandrosterone enhances decidualization in \nwomen of advanced reproductive age. Fertil Steril. \n2018;109(4):728-34.e2. \n[Crossref]   [PubMed]   [PMC]  \n10. Tamura I, Jozaki K, Sato S, Shirafuta Y, Shinagawa M, Maekawa \nR, et al. The distal upstream region of insulin-like growth factor-\nbinding protein-1 enhances its expression in endometrial stromal \ncells during decidualization. J Biol Chem. 2018;293(14):5270-80. \n[Crossref]   [PubMed]   [PMC]  \n11. Santos ED, Moindjie H, Sérazin V, Arnould L, Rodriguez Y, Fathal-\nlah K, et al. Preimplantation factor modulates trophoblastic inva-\nsion throughout the decidualization of human endometrial stromal \ncells. Reprod Biol Endocrinol. 2021;19(1):96. \n[Crossref]   \n[PubMed]   [PMC]  \n12. Apparao KB, Murray MJ, Fritz MA, Meyer WR, Chambers AF, \nTruong PR, et al. Osteopontin and its receptor alphavbeta(3) in-\ntegrin are coexpressed in the human endometrium during the \nmenstrual cycle but regulated differentially. J Clin Endocrinol \nMetab. 2001;86(10):4991-5000. \n[Crossref]   [PubMed]   \n13. Lessey BA. Adhesion molecules and implantation. J Reprod Im-\nmunol. 2002;55(1-2):101-12. [Crossref]   [PubMed]   \n14. von Wolff M, Strowitzki T, Becker V, Zepf C, Tabibzadeh S,  \nThaler CJ. Endometrial osteopontin, a ligand of beta3-integrin,  \nis maximally expressed around the time of the \"implantation  \nwindow\". Fertil Steril. 2001;76(4):775-81. \n[Crossref]    \n[PubMed]   \n15. Johnson GA, Burghardt RC, Bazer FW, Spencer TE. Osteopon-\ntin: roles in implantation and placentation. Biol Reprod. \n2003;69(5):1458-71. \n[Crossref]   [PubMed]   \n16. Makker A, Singh MM. Endometrial receptivity: clinical assessment \nin relation to fertility, infertility, and antifertility. Med Res Rev. \n2006;26(6):699-746. \n[Crossref]   [PubMed]   \n17. Elnaggar A, Farag AH, Gaber ME, Hafeez MA, Ali MS, Atef AM. Al-\nphaVBeta3 Integrin expression within uterine endometrium in un-\nexplained infertility: a prospective cohort study. BMC Womens \nHealth. 2017;17(1):90. \n[Crossref]   [PubMed]   [PMC]  \n18. Casals G, Ordi J, Creus M, Fábregues F, Casamitjana R, Quinto \nL, et al. Osteopontin and alphavbeta3 integrin expression in the \nendometrium of infertile and fertile women. Reprod Biomed On-\nline. 2008;16(6):808-16. \n[Crossref]   [PubMed]   \n19. Wang XB, Qi QR, Wu KL, Xie QZ. Role of osteopontin in decidu-\nalization and pregnancy success. Reproduction. 2018;155(5):423-\n32. \n[Crossref]   [PubMed]   \n20. Vilella F, Ramirez L, Berlanga O, Martínez S, Alamá P, Meseguer \nM, et al. PGE2 and PGF2 α concentrations in human endometrial \nfluid as biomarkers for embryonic implantation. J Clin Endocrinol \nMetab. 2013;98(10):4123-32. \n[Crossref]   [PubMed]   \n21. Navarra P, Andreani CL, Lazzarin N, Pierro E, Mirtella A, Lanzone \nA, et al. Increased production and release of prostaglandin-E2 by \nhuman granulosa cells from polycystic ovaries. Prostaglandins. \n1996;52(3):187-97. \n[Crossref]   [PubMed]   \n22. Velez LM, Seldin M, Motta AB. Inflammation and reproductive \nfunction in women with polycystic ovary syndrome†. Biol Reprod. \n2021;104(6):1205-17. \n[Crossref]   [PubMed]   [PMC]  \n23. Ryu HS, Chang KH, Yang HW, Kim MS, Kwon HC, Oh KS. High \ncyclooxygenase-2 expression in stage IB cervical cancer with \nlymph node metastasis or parametrial invasion. Gynecol Oncol. \n2000;76(3):320-5. \n[Crossref]   [PubMed]   \n24. DuBois RN, Shao J, Tsujii M, Sheng H, Beauchamp RD. G1 delay \nin cells overexpressing prostaglandin endoperoxide synthase-2. \nCancer Res. 1996;56(4):733-7. \n[PubMed]   \n25. Kelly CJ, Stenton SR, Lashen H. Insulin-like growth  \nfactor binding protein-1 in PCOS: a systematic review and  \nmeta-analysis. Hum Reprod Update. 2011;17(1):4-16. \n[Crossref]   \n[PubMed]   \n26. DuQuesnay R, Wright C, Aziz AA, Stamp GW, Trew GH, Margara \nRA, et al. Infertile women with isolated polycystic ovaries are de-\nficient in endometrial expression of osteopontin but not alphav-\nbeta3 integrin during the implantation window. Fertil Steril. \n2009;91(2):489-99. \n[Crossref]   [PubMed]   \n REFERENCES\n\nEmine DEMİR et al. JCOG. 2022;32(3):77-84\n84\n27. Kim H, Ku SY, Kim SH, Choi YM, Kim JG. Association  \nbetween endometriosis and polymorphisms in insulin-like  \ngrowth factor binding protein genes in Korean women. Eur J  \nObstet Gynecol Reprod Biol. 2012;162(1):96-101. \n[Crossref]   \n[PubMed]   \n28. Lessey BA. Implantation defects in infertile women with en-\ndometriosis. Ann N Y Acad Sci. 2002;955:265-80; discussion 293-\n5, 396-406. [Crossref]   [PubMed]   \n29. Zhang D, Sun C, Ma C, Dai H, Zhang W. Data mining of spatial-\ntemporal expression of genes in the human endometrium during \nthe window of implantation. Reprod Sci. 2012;19(10):1085-98. \n[Crossref]   [PubMed]","source_license":"CC0","license_restricted":false}