{"paper_id":"6420411b-1439-4ccf-a147-6231e1a8dbef","body_text":"247\nORIGINAL SCIENTIFIC PAPER    ORIGINALNI NAUČNI RAD    ORIGINAL SCIENTIFIC PAPER\nCorresponding author: Marija Šorak,\nDepartment of Gyneacology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia, soraks@sbb.rs\nUDK: 618.177-076 / Ser J Exp Clin Res 2018; 19 (3): 247-253\nDOI: 10.1515/SJECR20170001\nABSTRACT\nGlycodelin (or placental protein 14) is a glycoprotein located \nin the glandular and thin epithelium of the endometrium. It is \nconsidered an important factor in the implantation process, and \nits traces can be found in elevated concentrations in the uterine \nfl ushing\n obtained at the time of implantation, while in the prolif-\nerative phase of the cycle, its levels are low. A certain concentra-\ntion has been found to inhibit the binding of spermatozoids to the \nzona pellucida of the oocites therefore, it eff ects conception. It has \na role in angiogenesis and is in high concentrations in the tissues of \nboth benign and malignant gynaecological tumours.\nTh e aim of this study is to analyse and display the gly-\ncodelin level changes before and after hysteroscopic polyp-\nectomy in infertile patients in the uterine fl  ushing fl uid and \nserum. Th is survey covers 80 infertile patients, who were \ndivided into two groups. Th e fi  rst group, the experimental \ngroup, consisted of 50 infertile patients with endometrial \npolyps, and a control group of 30 infertile patients without \nendometrial polyps was also included.\nTh e results primarily indicate the existence of changes in \nglycodelin levels preoperatively in the fl  ushing and venous \nblood in infertile patients with endometrial polyps compared \nwith the levels after surgery. In the control group of patients, \nno signifi cant change in the glycodelin levels was detected in \nthe fl ushing and venous blood. When comparing these two \ngroups, statistically signifi cant diff erences in the glycodelin \nlevels in the fl ushing and venous blood were noted. We con-\nclude that the presence of endometrial polyps in the cavum \nuteri aff ects the increase in the glycodelin concentration in \nthe fl ushing fl uid and in the plasma. Increased glycodelin \nconcentrations complicate fertilization and implantation.\nKeywords: cytokine, glycodelin, endometrial polyp, \nfl ushing and serum.\nANALYSIS OF GLYCODELIN LEVELS BEFORE AND AFTER\nHYSTEROSCOPIC POLYPECTOMY IN INFERTILE PATIENTS\nMarija Sorak1*and Ana Devic2*\n1Department of Gynecology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia\n2Clinical Hospital Center Zemun, Hospital for Gynecology and Obstretics, Serbia\n*Authors Marija Sorak and Ana Devic contributed equally to this study\nANALIZA NIVOA GLIKODELINA PRE I POSLE HISTEROSKOPSKE\nPOLIPEKTOMIJE KOD INFERTILNIH PACIJENTKINJA\nMarija Šorak1*i Ana Dević2*\n1Katedra za ginekologiju, Fakultet medicinskih nauka, Univerzitet u Kragujevcu, Kragujevac, Srbija\n2Kliničko bolnički centar Zemun, Bolnica za ginekologiju i akušerstvo, Srbija\n*Autori Marija Šorak i Ana Dević su podjednako učestvovali u izradi ove studije\nReceived / Primljen: 13. 12. 2016. Accepted / Prihvaćen: 17. 01. 2017.\nSAŽ ETAK\nGlikodelin (ili placentni protein 14) je glikoprotein koji \nse nalazi u glandularnom i površinskom epitelu endome-\ntrijuma. Smatra se da je jedan od bitnih faktora u proce-\nsu implantacije i nalazi se u povišenim koncentracijama \nu ispirku uterusa dobijenom u vreme implantacije, dok \nsu u proliferativnoj fazi ciklusa njegove vrednosti niske. U \nodređenoj koncentraciji nađeno je da inhibira vezivanje \nspermatozoida za zonu pelucidu ovuuma, tako da utiče \ni na koncepciju. Ima ulogu u angiogenezi, te se nalazi u \npovišenim koncentracijama u tkivu i benignih i malignih \nginekoloških tumora.\nCilj ovog rada je analiza i prikaz promena nivoa gliko-\ndelina, pre i posle histeroskopske polipektomije kod infertil-\nnih pacijentkinja, u ispirku uterusa i serumu. Istraživanje \nobuhvata 80 infertilnih pacijentkinja, koje su podeljene u dve \ngrupe. Prvu grupu, eksperimentalnu, čini 50 infertilnih paci-\njentkinja sa polipom endometrijuma, a kontrolnu grupu 30 \ninfertilnih pacijentkinja bez polipa endometrijuma. \nDobijeni rezultati prvenstveno ukazuju na postojanje \npromena nivoa g likodelina preop erativno, i u ispirku i u \nvenskoj krvi, kod infertilnih pacijentkinja sa endometrijal-\nnim polipom u odnosu na nivoe nakon operativnog zahvata. \nU kontrolnoj grupi pacijentkinja nema značajnih promena \nnivoa glikodelina u ispirku i venskoj krvi. Poređenjem ove \ndve grupe prisutne su statistički  značajne razlike u nivoima \nglikodelina i u ispirku i u venskoj krvi. Možemo zaključiti da \nprisustvo endometrijalnog polipa u kavumu uterusa utiče \nna porast koncentracije g likodelina, i u ispi rku i u plazmi. \nPovećana koncentracija glikodelina otežava i oplodnju i im-\nplantaciju. \nKljučne reči:  citokin, glikodelin , endometrijalni polip, \nispirak i serum. \n\n\n248\nINTRODUCTION\nInfertility is a problem that affects approximately 80 \nmillion couples worldwide. It is believed that approximate-\nly 15% of the general population is affected by this prob-\nlem. Endometrial polyps occur when the endometrium is \nhypertrophic, due to oestrogen stimulation (1). A diagno-\nsis is based on sonographic, hysteroscopic or hysterosono-\ngraphic findings, when a polyp is spotted in the cavum \nuteri (2).\nCytokines are a large family of protein molecules that \nfunction as a mediator and regulator of cellular communi-\ncations, in both physiological and pathological conditions \n(3). Different cells produce a variety of cytokines, which \nact on the chemotaxis, activation, proliferation and dif-\nferentiation of other cells. Cells that secrete the highest \namounts of cytokines are leukocytes. Glycodelin (or pla-\ncental protein 14) is a cytokine and is a 28kDa glycoprotein \nthat contains 180 amino acids (4). Glycodelin is encoded \nby a single gene that is located in the chromosomal region \n9q34; it is derived from the endometrium. It consists of a \nsingle (GaINAcβ1-4GlcNAc) oligosaccharide series and \nis located in the glandular and surface epithelium of the \nendometrium. Glycodelin is the primary product during \nthe secretion phase of endometrial cells. Maximum lev-\nels are produced in the secretory endometrium and early \npregnancy decidual. It is produced in the lumen of the en-\ndometrial glands and can be detected in circulation. The \nhighest concentration of glycodelin is produced during \nthe secretory phase of the endometrial cycle, while at the \nearly proliferative phase, its concentration is low. There are \nstrong indicators that, in conjunction with other cytokines, \nglycodelin represents an important factor that facilitates \nimplantation (5). It is found in elevated concentrations in \nthe uterine flushing obtained at the time of implantation. \nDuring conception, glycodelin levels remain elevated. Gly-\ncodelin has an immunosuppressive effect and probably has \na protective role in the preservation of embryos from natural \nkiller (NK) cell destruction. Additionally, it has been found \nthat in certain concentrations, glycodelin inhibits the bind-\ning of sperm to the zona pellucida of the oocites therefore, it \neffects conception. Recently, it has been shown that it plays \na role in angiogenesis and is elevated in the tissues of both \nbenign and malignant gynaecological tumours (6). \nMATERIAL AND METHODS\nThe survey was conducted as a study of 80 infertile pa-\ntients. The two groups of female patients were compared. \nThe first group of patients, the experimental group, con-\nsisted of 50 infertile patients diagnosed with endometrial \npolyps. The second group was a control group of 30 in-\nfertile patients without endometrial polyps. The research \nwas carried out at the Gynaecology and Obstetrics Clinic \n“National Front” in Belgrade, from May 2012 to November \n2013, and in the Center for Molecular Medicine and Test-\ning of Stem Cells, Faculty of Medical Sciences, in Kragu-\njevac.\nThis study was conducted on patients with childbear-\ning potential (aged 20-43 years) who were diagnosed with \nendometrial polyps as a cause of infertility. The polyp diag-\nnoses were determined by transvaginal ultrasound exami-\nnations during the first phase of the cycle, by hysterosono-\ngraphic examinations, or during an actual hysteroscopy \nin patients with suspected endometrial polyps, based on \nanamnesis. In addition to the group who participated in \nthe study, there was a control group of patients of the same \nage who were treated for infertility did not have endome-\ntrial polyps. The patients were evaluated for one month \nafter the intervention in terms of peripheral venous blood \nsampling, cytokine level determinations, and control ultra-\nsound examinations. \nDiagnostic and operative hysteroscopies were per-\nformed under general anaesthesia in the operating room \nwith appropriate equipment and instruments. The preop-\nerative preparation included a complete diagnosis and the \nnecessary routine analyses including cervical and vaginal \nsmears, chlamydia, mycoplasma and ureaplasma evalua-\ntions, Pap test, ultrasound, blood typing, blood count and \nbiochemical analysis with an anaesthetic examination and \nsurgical treatment approval. Surgical procedures were per-\nformed in infertile patients to mid-proliferative phase im-\nmediately after menstrual bleeding.\nHysteroscopic examination and intervention-polyp-\nectomy are done during the first phase of the menstrual \ncycle (9). During hysteroscopy, the uterine cavity is viewed \nat a 30-degree angle, which allows for visualization of both \nmouths of the fallopian tube, fundus, anterior and poste-\nrior wall of the uterus as well as the lateral sides of the uter-\nine cavity (10). At the height of the internal uterine mouth \nwith the hysteroscope, a panoramic image of the uterine \ncavity is displayed, and the presence of any pathological \nfindings, such as endometrial polyps (which are often ob-\nserved), submucosal fibroids, septa, and adhesions, can be \neasily visualized. Polyps are removed with hysteroscopic \ngraspers and hysteroscopic scissors\n followed by electroco-\nagulation of their base (11).\nTo determine the glycodelin (PP14) concentration in \nthe uterus flushing during hysteroscopic polypectomy, the \noperation sequence was as follows: 10 ml injection of sa-\nline into the cavum uteri and immediate aspiration with-\nout contamination. Then, the flushing was centrifuged at \n2500 rpm for 10 minutes. The supernatant was collected \nand stored at -20° C. The glycodelin concentration was de-\ntermined with the ELISA method at the Center for Mo-\nlecular Medicine and Testing of Stem Cells, at the Faculty \nof Medical Sciences in Kragujevac (15).\nTo determine the glycodelin (PP14) serum concen-\ntration, approximately 5 ml of peripheral venous blood \nwas taken from patients in both groups, before hystero-\nscopic surgery and one month after surgery. The sample \nprocessing methodology is as follows: the blood was col-\nlected in a \nvacutainer  with heparin and centrifuged for \n\n249\n10 minutes at 2500 rpm. The supernatant was collected \nand stored at -20 ° C. Detection and determination of the \nglycodelin concentration was then determined with the \nELISA method (16).\nThe study inclusion criteria were women with endo-\nmetrial polyps who were verified as 20-43 years of age \nand treated for primary or secondary infertility as well as \ninfertile women without endometrial polyps of the same \nage (16).\nCriteria for exclusion from the study for both groups \nof respondents were the existence of submucosal fibroids, \nendometriosis, endometrial cancer, uterine anomalies, \nand patients who had surgery on their uterus and tubes, as \nwell as patients with a previous failed ovulation following \nstimulation.\n \nStatistical data analysis was based on use of the t-test. \nAs the sample distribution in this study (with a minimum \ngroup of 30 patients) was mildly leptokurtic and skewed, \nfor this study, t-tests were successfully implemented, and \neven for similar mean values of the sample, the t-test pro-\nvided more accurate results than the Wilconxon Mann-\nWhitney test (17).\nRESULTS\nWe analysed the glycodelin levels in the uterus flush-\ning and venous blood from both test and control group pa-\ntients (8). The levels of this cytokine were examined before \nand one month after hysteroscopic polypectomy.\nStatistical analysis of the patient groups was based on \ntesting the null hypothesis with t-tests of group differences \naccording to the mean value and variance (7). The groups \nwere significantly different if p <0.05.\nFigure 1 shows the glycodelin values in the uterine flush-\ning from patients with endometrial polyps compared with \nthe control group during surgery. It can easily be seen that \nthe glycodelin levels in the uterine flushing were signifi-\ncantly decreased in the control group subjects compared \nwith the experimental group. Using the t-test and analysis \nof the obtained results, it can be concluded that there was a \nstatistically significant difference (t=1.992; p=0.0144).\nAnalysis of the venous blood glycodelin levels in the en-\ndometrial polyp patients is shown in Figure 2. Notably, the \nvenous blood glycodelin levels that were collected a month \nafter hysteroscopic polypectomy were significantly lower. \nBy applying the t-test, it can be concluded that the groups \ndiffer statistically (t=2.01; p=0.00017).\nThe venous blood glycodelin values in the endometrial \npolyp and control group patients before hysteroscopic pol-\nypectomy are shown in Figure 3. Applying a t-test leads to \nthe conclusion that the groups differ statistically and that \nthe glycodelin levels were significantly higher in the endo-\nmetrial polyp patients (t=1.996; p=0.0036).\nFigure 4 provides the venous blood glycodelin values \nin the control group before and one month after hysteros-\ncopy. By applying the t-test, it can be concluded that the \ngroups did not differ statistically, i.e., the glycodelin levels \ndid not significantly differ in the control group before and \nafter hysteroscopy (t=2.048; p=0.851).\nThe venous blood glycodelin values in patients one \nmonth after hysteroscopic polypectomy and in the control \ngroup one month after hysteroscopy are shown in Figure \n5. These levels were found to not be significantly different \nusing the t-test (t=2.004; p=0.838).\nDISCUSSION\nThe glycodelin concentrations in the flushing and se-\nrum were significantly higher in patients with endometrial \npolyps in comparison with the control group. A month af-\nFigure 1. Glycodelin average values in the uterine fl ushing from patients with endometrial polyps compared with control \ngroup patients during hysteroscopy. Th ese are the t-test parameters, the critical average values for accepting the null \nhypothesis.\n\n\n250\nFigure 2. Venous blood glycodelin average values in patients with endometrial polyps before hysteroscopic polypectomy \nand one month after surgery.\nglycodelin (pg/mol) \n    Before   After \nHysteroscopic polypectomy \nFigure 3. Venous blood glycodelin average values in the endometrial polyp and control group patients before hystero-\nscopic polypectomy.\nglycodelin (pg/mol) \nЕxperimental group      Control group \nBefore hysteroscopic polypectomy \nter hysteroscopic polypectomy, the serum glycodelin levels \nwere reduced in the experimental group and reached values \nvery similar to the those of the control group. These results \nwere confirmed in most studies that examined glycodelin \nlevels in the uterine flushing and plasma of infertile patients.\nEndometrial polyps are common in infertile patients \nwho are preparing for in vitro fertilization, and their pres-\nence does not affect pregnancy rates, but there is a higher \nrisk of pregnancy loss in these patients (18, 19). Polyps \nare endometrial tissue growths covered with epithelium. \nThey have glands, stroma and blood vessels that contrib-\nute to increased glycodelin secretion in the cavum uteri \n(12, 13). The common assumption is that glycodelin may \n“leak” from blood vessels near polyps and dissolve in sa-\nline, which is used during hysteroscopy uterine flushing \n(14, 20). Glycodelin levels in uterus flushing fluid are then \ndetermined using ELISA measurements, and in most sur-\nveys, it was confirmed that the values were significantly \nhigher in uterine flushing with endometrial polyp or sub-\nmucosal fibroids compared with the control group (21).\n\n251\nFigure 5. Venous blood glycodelin average values in the endometrial polyp and control group patients one month after \nsurgery.\n  Еxperimental group   Control group \n After hysteroscopic polypectomy \nFigure 4. Th e venous blood glycodelin average values in the control group patients before hysteroscopy and one month \nafter surgery.\nglycodelin (pg/mol) \n    Before   After \nHysteroscopic polypectomy \n\n252\nGlycodelin contributes to polyp growth by encouraging \nneovascularization and thus allowing a better flow of the \nnutrients necessary for polyp growth. It can be detected \nin the circulation; therefore, in various studies, its concen-\ntration in plasma was often determined. In most of these \nstudies, elevated glycodelin levels in the plasma of patients \nwith endometrial polyps was observed compared with \ncontrol group patients (22).\nIt has been proven that glycodelin inhibits sperm and \noocyte binding as well as NK cell activity (23). Glycodelin \nvalues are very low in the period 6 days before and 5 days \nafter ovulation (periovulatory period). Thus, low glycode-\nlin levels allow for fertilization. Then, 6 days after ovula-\ntion, glycodelin secretion increases significantly and be-\ncomes a key to the formation of a receptive endometrium \nand suppresses NK cell activity. The results of this study \nindicate that the glycodelin levels measured during the \nmiddle and late proliferative phase of the menstrual cycle \nwere elevated when they should have been at their lowest \nvalues, or even absent; however, they significantly affected \nfertilization and altered endometrial receptivity in patients \nwith endometrial polyps (20).\nChanges in glycodelin concentrations are registered in \nthe endometrium, or uterine flushing and are correlated \nwith the values obtained in the serum of the experimental \ngroup patients. We conclude that changes in the glycodelin \nvalues can be tracked by just specifying the venous blood \nin patients in whom a hysteroscopic polypectomy was per-\nformed and can thus monitor the success of the operational \nprocedures and limit possible polyp recurrences by avoid-\ning administering complicated uterus flushings, which \nrequire preoperative preparation and general anaesthesia \nduring a hysteroscopy. \nCONCLUSION\nTwo groups of infertile patients were analysed, one \nwith endometrial polyps and a second control group that \ndid not have polyps. The glycodelin values in the uterus \nflushing fluid and in the venous blood before surgery \nwere significantly higher in the patients with endome-\ntrial polyps. The uterus flushing fluid and venous blood \nglycodelin values in the polyp group were significantly \ndecreased one month after surgery. The glycodelin levels \nin the serum of the control group patients who were de-\ntected preoperatively remained similar, even one month \nafter surgery. Additionally, there was no significant dif-\nference in the glycodelin levels one month after surgery in \na group of patients where the polyps were removed com-\npared with the control group patients.\nThe results of this study clearly indicate that the gly-\ncodelin levels in infertile patients with endometrial polyps \nwere elevated; therefore, we can safely conclude that gly-\ncodelin is a cytokine that has a crucial impact on endome-\ntrial miles and can significantly disturb homeostasis at the \nmolecular level, thus affecting fertility.\nАcknowledgement\nThis work was supported by the Faculty of Medical Sci-\nences, University of Kragujevac, Serbia (Grants JP 11/14 \n(13-2015) “Cytokine levels before and after hysteroscopic \npolypectomy in infertile patients).\nREFERENCES\n 1. 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