{"paper_id":"1148e675-fc01-470f-97a3-fd91c05ce686","body_text":"Research Article\nVolume 9 Issue 1 -  March 2022\nDOI:  10.19080/GJORM.2022.09.555751\nGlob J Reprod Med\nCopyright © All rights are reserved by Semih Zeki Uludag\nEffect of Prolonged GnRH Agonist Therapy  \nPrior to Frozen Embryo Transfer on IVF-ET  \nOutcome in Patients with and without  \nEndometrioma Surgery\nArzu Yurci1 Nurettin Turktekin2 and Semih Zeki Uludag1* \n1Department of Obstetrics and Gynecology & IVF Center, Memorail Kayseri Hospital, Turkey \n2Private Clinic, Nisantası Istanbul, Turkey\nSubmission: February 17, 2022; Published: March 18, 2022\n*Corresponding author: Semih Zeki Uludag, Department of Obstetrics and Gynecology & IVF Center, Memorail Kayseri Hospital, 38010 Kayseri, \nTurkey\nGlob J Reprod Med 9(1): GJORM.MS.ID.555751 (2022)  001\nIntroduction\nThe hypothalamic Gonadotropin-Releasing Hormone (GnRH) \nis a decapeptide that plays an important role in the regulation of \nreproductive functions. In addition to pituitary expression GnRH/\nGnRH receptor (GnRHR) system was found to be expressed in \nextrapituitary regions such as endometrium and ovary [1,2]. \nGnRHR expressed in granulosa and luteal cells plays a role in \nfollicle development and growth [2]. At the endometrium GnRH/\nGnRHR has been reported to regulates interaction between \nthe embryo-endometrium in the early stage of implantation \n[3]. Antiproliferative activity of GnRH/GnRHR system has been  \n \nsuggested to be an effective direct molecular target for GnRH-\nanalog-based therapeutic approaches to treat endometriozis. \nContinuous administration of GnRH analogs (GnRHa) induces a \ndownregulation of GnRHR and suppresses the release of pituitary \ngonadotropins. In addition, GnRHa regulates the synthesis and \nrelease of peritoneal cytokines and endometrial integrin in \nendometriosis [4,5].\nThere is little evidence to support use of medical treatment \nin women with endometrioma who wish to improve fertility. In \nline with this, none of the hormonal drugs used in the medical \nAbstract \nObjective: It remains to be clarified whether prolonged Gonadotrophin-Releasing Hormone agonist (GnRHa) administration before frozen \nembryo transfer to patients with and without endometrioma resection improves reproductive outcome. This study was designed to investigate \nfreeze-all cycles with subsequent prolonged GnRHa administration in patients with and without endometrioma surgery.\nMethod: A total of 164 patients with complaints of infertility and diagnosed with endometrioma were included in this case controlled study. \nEndometrioma resection was performed in 65 out of 164 women and then Controlled Ovarian Stimulation (COS) was performed (Group 1). Fresh \nembryos were transferred to 40 of 65 patients who underwent endometrioma surgery. Embryos were vitrified in 25 patients and administered \nleuprolide acetate 3.75 mg for 3 months. The remaining 99 patients were referred directly to the COS without any surgery for endometrioma \n(Group 2). While fresh-ET was applied to 49 of 99 cases, embryos were frozen in the remaining 50 cases. Subsequently they were administered \nleuprolide acetate 3.75 mg for 3 months. Primary outcome was Clinical Pregnacy Rates (CPR), Ongoing Pregnancy Rates (OPR), and Live Birth \nRates (LBR).\nResults: No significant difference was found between the operated and non- operated groups in terms of CPR, OPR and LBR between patients \nwho received fresh-ET . While there was no significant difference in CPR and OPR in operated and non-operated groups who underwent frozen-ET , \nLBRs were found to be significantly higher in patients who were not operated (p<0.01). Making fresh-ET or frozen-ET in patients who underwent \nendometrioma surgery did not significantly affect CPR, OPR and LBR. Making frozen-ET in patients who did not undergo surgery significantly \nincreased both CPR (p <0.02) and OPR (p<0.03).\nConclusion: Prolonged use of GnRH agonist treatment before frozen-ET in patients without endometrioma surgery resulted in significantly \nhigher clinical and ongoing pregnancy rates than did patients with endometrioma surgery.\nKeywords: Endometrioma; Endometrioma surgery; GnRH agonist; Reproductive outcome\n\n\nHow to cite this article:  Arzu Y, Nurettin T, Semih Zeki U .  Effect of Prolonged GnRH Agonist Therapy Prior to Frozen Embryo Transfer on IVF-ET \nOutcome in Patients with and without Endometrioma Surgery. Glob J Reprod Med. 2022; 9(1): 555751. DOI:  10.19080/GJORM.2022.09.555751002\nGlobal Journal of Reproductive Medicine\ntreatment of endometriosis patients cause an increase in \nspontaneous pregnancy rates [4,6]. On the other hand, long-\nterm GnRHa suppression therapy has been reported to increase \nIVF-ET outcome during the time it is applied. Really, we have \nsufficient data to show that GnRHa application has both direct and \nindirect effects on folliculogenesis and endometrial receptivity in \ninfertile patients with endometriosis. For this reason, prolonged \nGnRHa administration has started to be widely used either before \ninitiation of controlled ovarian stimulation or before frozen-\nET in order to increase the implantation and pregnancy rates in \ncases with endometriosis. Most of the studies reported that long-\nterm GnRHa treatment performed before IVF-ET or frozen-ET in \npatients with stage III-IV endometriosis had a positive effect on \npregnancy rates. A recent study reported that pregnancy rates \nincreased in patients with endometriosis who received agonist \nsuppression after vitrification [7]. However, there are also studies \nreporting results that it does not provide any benefit. A recent \nstudy reported that long-term GnRHa suppression given before \nIVF-ET did not cause a significant change in reproductive outcome \ncompared to the untreated group [8].\nTo date, it remains to be clarified whether prolonged \ngonadotrophin-releasing hormone agonist administration \nbefore frozen embryo transfer to patients with and without \nendometrioma surgery improves reproductive outcome. When \nrewieving the literature there is no study comparing patients \nwho underwent endometrioma surgery with patients who did \nnot undergo surgery despite having endometrioma, giving GnRHa \ntreatment before frozen-ET . This retrospective cohort pilot study \nevaluates freeze-all cycles with subsequent prolonged GnRHa \nadministration in patients with and without endometrioma \nsurgery.\nMaterials and Methods\n164 patients who applied to the Department of Obstetrics \nand Gynecology & IVF Center, Memorail Kayseri Hospital between \n2016 and 2020 with complaints of infertility and were diagnosed \nwith endometrioma were included in the study. The diagnosis \nof ovarian endometrioma was made as a result of the detection \nof the following findings with USG (GE, Voluson 730 Pro.). The \nendometrioma was suspected when a diffuse, regular- margined \ncyst with a low level internal echo, indicating hemorrhagic cyst, \nwas present for at least 2 cycles, to exclude the nonendometriotic \nhemorrhagic cyst. Endometrioma patients were divided into two \ngroups according to whether surgical intervention was performed \nor not. Laparoscopic endometrioma resection was performed in \n65 of 164 cases and then controlled ovarian stimulation (COS) \nwas performed (Group 1). The remaining 99 patients were \nreferred directly to the COS without any surgical procedure for \nendometrioma (Group 2). Fresh embryos were transferred to \n40 of 65 patients who underwent endometrioma surgery. In the \nother 25 patients who underwent endometrioma surgery, all \nembryos were vitrified in Cryotops as described by previously [9]. \nSubsequently they were administered a long-lasting preparation \nof the GnRHa leuprolide acetate (Lucrin Depot®; Abbvie) 3.75 mg \nevery 28 days for 3 months. 99 patients with endometrioma who \ndid not undergo surgery in Group 2 were referred to COS. While \nfresh-ET was applied to 49 of 99 cases, embryos were frozen in the \nremaining 50 cases. Subsequently they were administered a long-\nlasting preparation of the GnRHa leuprolide acetate 3.75mg every \n28 days for 3 months. Primary outcome was clinical pregnacy \nrates (CPR), ongoing pregnancy rates (OPR), and live birth rates \n(LBR).\nAll participants underwent a routine laboratory and \nradiological examination to diagnose the underlying factors of \ninfertility. They had normal early follicular Follicle- Stimulating \nHormone (FSH), Luteinizing Hormone (LH), Estradiol (E2), \nThyroid-Stimulating Hormone (TSH), and Prolactine (PRL) levels, \nand normal midluteal progesterone levels indicating the presence \nof ovulation. To have information about over reserve Anti-Mullerian \nhormone (AMH) levels as well as antral follicle count determined \nat baseline transvaginal ultrasound examination performed in the \nearly follicular phase. Participants in each group were noted to \nhave a bilateral tubal patency, absence of intrauterine mass forming \npathology in uterine cavity documented at Hysterosalpingography \n(HSG). Two semen analysis was performed in the male partners \nof the each woman at least 3 weeks&#39; apart and upon 3 to \n7 days of abstinence. Because of these detailed examinations, \nthe only detectable cause of infertility was endometrioma in \nall participants. Participants found to have pathology in semen \nanalysis or HSG were not included in the study. Patients who \nhad received GnRH agonists, progestins or oral contraceptive \nfor treatment of symptomatic endometriosis within 6 months of \ninitiation of their IVF-ET treatment were excluded.\nStatistical analysis\nDescriptive statistics were presented as frequency, mean and \nstandart deviation. Shapiro Wilks test was used for evaluation of \nnormality of distribution. Pearson Chi- squared test was used in \nthe analysis of relationships between categorical variables. For the \ncomparison of continous variables, the Students t-test was used \nwith normal distribution. Statistical analyses were performed by \nusing the SPSS 21.0 packages program for Windows. p<.05 was \naccepted to show statistical significance.\nResults\nThe data including the demographic and IVF-ET results of the \ncases are shown in Table 1 & 2. No significant difference was found \nbetween the two groups in terms of age, duration of infertility \nand BMI. The number of total oocyte and MII oocyte counts \nwere found to be significantly higher in the non-surgical group \ncompared to the surgical group. While 65 of 164 endometrioma \npatients were operated, 99 patients did not undergo any surgical \nprocedure. While fresh-ET was applied to 40 of 65 patients who \nwere operated, 25 of them were frozen-Et. While fresh-ET was \napplied to 49 of 99 patients to be operated, frozen-ET was applied \nto 50 patients. No significant difference was found between the \n\nHow to cite this article:  Arzu Y, Nurettin T, Semih Zeki U .  Effect of Prolonged GnRH Agonist Therapy Prior to Frozen Embryo Transfer on IVF-ET \nOutcome in Patients with and without Endometrioma Surgery. Glob J Reprod Med. 2022; 9(1): 555751. DOI:  10.19080/GJORM.2022.09.555751003\nGlobal Journal of Reproductive Medicine\noperated and non- operated groups in terms of CPR, OPR and LBR \nbetween patients who received fresh-ET . On the other hand, while \nthere was no significant difference in CPR and OPR in operated \nand non-operated groups who underwent frozen-ET , live birth \nrates were found to be significantly higher in patients who \nwere not operated (p<0.01). When we evaluated the cases with \nsubgroup analysis, performing fresh-ET or frozen-ET in patients \nwho underwent endometrioma surgery did not significantly \naffect CPR, OPR and LBR (Table 1). On the other hand, performing \nfrozen-ET in patients who did not undergo surgery significantly \nincreased both CPR (p<0.02) and OPR (p<0.03). In terms of LBR, \na statistically insignificant increase trend was detected (p<0.056). \nIf we divide endometrioma patients into two groups as those who \nwent to surgery and those who did not, regardless of the use of \nGnRHa, pregnancy rates were found to be similar in both groups \nfollowing fresh-ET . If we do frozen-ET patients in these groups, \nCPR and OPR were found to be similar, while LBR was found to be \nsignificantly higher in the non-operated group.\nTable 1: Demographic and clinical characteristics of each group of participants.\nEndometrioma Patients without Surgery \n(n=99)\nEndometrioma Patients with Surgery \n(n=65) p\nAge (years) 31.70±4.94 32.65±4.83 0.226\nInfertility duration (years) 5.97±3.42 5.65±3.64 0.564\nBMI 26.00±3.49 25.42±2.63 0.253\nDay 2 E2 38.07±14.16 34.72±10.72 0.106\nDay 2 P4 0.40±0.22 0.32±0.16 0.328\nIVF attempt 1.89±1.17 2.20±1.49 0.137\nE2 on hCG day 1941.8±1279.3 1523.4±1195.7 0.037\nP4 on hCG day 0.32±0.14 0.34±0.15 0.869\nTotal oocyte 12.36±7.57 9.72±8.25 0.037\nMII oocyte 9.26±6.06 7.37±5.69 0.047\n2PN 7.23±5.15 5.71±4.07 0.046\nTable 2: Reproductive outcome of endometrioma patients taking prolonged course of GnRHa after freeze-all.\n N Clinical PR Ongoing PR Live BR\nFresh-ET\nOpere 40 17 14 11\nNon-opere 49 23 21 19\np 0.675 0.45 0.263\nFrozen-ET\nOpere 25 15 12 7\nNon-opere 50 35 32 29\np 0.386 0.185 0.014\nEndometrıoma Surgery\nFres 40 17 14 11\nFrozen 25 15 12 7\np 0.17 0.298 0.965\nNo-Surgery\nFresh 49 23 21 19\nFrozen 50 35 32 29\np 0.02 0.035 0.056\nDiscussion\nThis retrospective cohort pilot study evaluated the impact of \nfreeze-all cycles with subsequent prolonged GnRHa administration \nbefore embryo transfer on reproductive outcome in patients \nwith and without endometrioma resection. In this trial, we \nfound that administration of GnRHa therapy for 3 months before \nfrozen-ET in patients with a history of previous endometrioma \nsurgery resulted in significantly lower clinical and ongoing \npregnancy rates compared to endometrioma patients who had \nnot endometrioma surgery. With this study, it has been shown \nfor the first time that performing fresh or frozen ET for patients \nwith a history of endometrioma surgery does not significantly \naffect CPR, OPR and LBR. However, we do not know whether \nthe similar pregnancy rates in patients who underwent fresh or \nfrozen-ET after endometrioma surgery are a unique feature of \n\nHow to cite this article:  Arzu Y, Nurettin T, Semih Zeki U .  Effect of Prolonged GnRH Agonist Therapy Prior to Frozen Embryo Transfer on IVF-ET \nOutcome in Patients with and without Endometrioma Surgery. Glob J Reprod Med. 2022; 9(1): 555751. DOI:  10.19080/GJORM.2022.09.555751004\nGlobal Journal of Reproductive Medicine\nthe frozen cycle or a feature related to GnRHa suppression or the \ncombined effect of both. In this study, GnRHa suppression was \napplied to all patients undergoing thaw cycle. In fact, patients \nwho underwent thaw cycles should have been divided into two \ngroups and frozen-ET should be performed only in one group \nand GnRHa plus frozen-ET should have been performed in one \ngroup. In this way, we could say more clearly whether the main \neffect on pregnancy rates was due to agonist administration or \nfrozen-ET . However, as far as we know from the literature data, \nalthough it varies according to etiological factors and age, the \nreproductive outcome in frozen cycles is higher than fresh cycles. \nSimilarly, it has been reported that GnRHa treatment before IVF-\nET or before frozen-ET positively affects pregnancy rates. Surrey \net al. showed that prolonged GnRHa therapy prior to initiation of \nCOS in patients with endometriosis resulted in significantly higher \nongoing pregnancy rates [4]. In a meta-analysis written by Sallam \net al. it was reported that giving GnRHa treatment for 3-6 months \nbefore COS significantly increased both clinical pregnancy rates \nand live birth rates [10].\nIn our study, patients in surgery group who underwent \nendometrioma cystectomy received prolonged administration \nof GnRHa after vitrification of all embryos. Our expectation after \nthis treatment was a significant increase in pregnancy rates. The \nmain support behind this expectation was the studies of Celik et \nal. in which they reported a significant increase in endometrial \nreceptivity genes after endometrioma surgery [11]. However, \ndespite frozen-ET plus GnRHa treatment in patients with \nendometrioma surgery, the pregnancy rates were similar to those \ntreated with fresh-ET suggesting that vitrification and long-term \nsuppression are not beneficial in this patient group. When we \nevaluate our results and literature findings together performing \nfrozen-ET plus GnRHa treatment in patients who underwent IVF-\nET after endometrioma surgery does not provide any extra benefit \nin terms of reproductive outcome compared to fresh cycles.\nThe second most important result we obtained from this study \nis that combining freeze all-cyle with long-term GnRha treatment \nsignificantly increased both CPR and OPR in the patient without \nendometrioma surgery compared to fresh cycles. We can explain \nthe possible reasons for the significant increase in pregnancy \nrates after frozen-ET in the non-surgical group in two ways. The \nfirst reason may be due to the gains arising from the nature of \nfrozen cycles. With the help of frozen-ET , we can get rid of the \nnegative effect of estrogen increase due to COS on endometrial \nreceptivity. The second reason for the increase in pregnancy in \npatients without endometrioma surgery may be long-term GnRHa \ntreatment. There are many studies showing that administration \nof GnRHa treatment before IVF-ET or before frozen-ET leads to \nan increase in pregnancy rates [12]. However, there are studies \nshowing that long-term GnRHa treatment is useless. Pre-COS use \nof GnRHa has been replaced by pre-frozen-ET application due to \nthe possibility of decreasing the number of eggs to be collected. \nOur results are consistent with the publications reporting that \nlong-term suppressions performed before frozen-ET in patients \nwith endometriosis increase reproductive outcome. Surrey et al. \nreported that prolonged GnRHa therapy following vitrification of \nall embryos in patients with endometriosis led to high implantation \nand ongoing pregnancy rates [7]. However, there are no studies \ninvestigating the effect of agonist suppression in patients with and \nwithout endometrioma surgery.\nWhile applying GnRHa treatment before frozen-ET was \nuseless in patients who underwent endometrioma surgery, it \nshowed a positive effect on pregnancy rates in patients who did \nnot undergo surgery. We can explain this paradox-like difference \nas follows. Since pertioneal cytokine and natural killer cell activity \nwill be normalized in the group undergoing endometrioma \nresection, GnRHa administration may not provide extra benefit \nin these patients. Since the presence of endometriosis and/\nor endometrioma is required for the emergence of both the \ninflammation-blocking and cytokines regulating activities of \nGnRHa the use of this drug in a disease-free environment may \nprevent it from showing its normal effect [4,7,13]. On the other \nhand, in the patients without endometrioma surgery, the presence \nof endometrioma will trigger abnormal cytokine release and \ninflammation in the peritoneal microenvironment. Ferrero et al. \nshowed that GnRHa therapy reduces inflammatory proteins in \nperitoneal fluid proteome of women with endometriosis [13].\nAnother possible reason for the increased pregnancy rates may \nbe the increase in endometrial receptivity due to the administration \nof GnRHa. In line with this, Lessey et al. reported that endometrial \nintegrin β3 expression was normalized in patients with superficial \nendometriosis who received agonist therapy for 3 months or more \n[5]. As it is known, the production and release of integrins, one \nof the basic endometrial receptivity molecules, has decreased in \npatients with endometriosis. In the light of the above data, we can \nsummarize the reasons for the positive effects of long-term GnRHa \ntreatment before frozen-ET on pregnancy rates in non- operated \nendometrioma cases as follows. GnRHa treatment before frozen-\nET might increase the implantation rates by acting through the \nfollowing mechanisms; \n(i) regulates natural killer cell activity as well as cytokines \nsuch as interleukin-1 and tumor necrosis factor whose production \nand secretion are impaired in peritoneal fluids of patients with \nendometriosis, \n(ii) neutralizes the embryotoxic effects of peritoneal fluid, \n(iii) increases endometrial cell survival by decreasing \napoptosis in endometrial cells, \n(iv) enhances endometrial receptivity by increasing \nendometrial αvβ3 integrin expression, \n(v) down-regulates peritoneal fluids inflammatory proteins \n[4,5,7,10,13]. \n\nHow to cite this article:  Arzu Y, Nurettin T, Semih Zeki U .  Effect of Prolonged GnRH Agonist Therapy Prior to Frozen Embryo Transfer on IVF-ET \nOutcome in Patients with and without Endometrioma Surgery. Glob J Reprod Med. 2022; 9(1): 555751. DOI:  10.19080/GJORM.2022.09.555751005\nGlobal Journal of Reproductive Medicine\nHowever, these possible mechanism of actions of GnRHa \ntherapy need to be confirmed with more comprehensive studies.\nThe retrospective nature and the relative low number of cases \nare the main limitations of the study. Another limitation is that the \nabsence of the frozen-ET group that is not given GnRHa treatment \ndoes not allow us to explain whether the positive results are \nGnRHa treatment or freezing of embryos or a combined effect. \nThe strengths of our study include the fact that this is the first \npublication on the subject of use of prolonged GnRHa therapy in \nwomen with and without endometrioma surgery after vitrification \nof all embryos.\nConclusion\nPerforming endometrioma resection in the period before IVF \ndoes not provide any additional benefit to pregnancy rates. On the \nother hand, women with endometrioma who underwent IVF-ET \nwithout endometrioma surgery 3 months of GnRHa treatment \nbefore frozen-ET significantly increases CPR and OPR.\nReferences\n1. Raga F, Casan EM, Kruessel JS, Wen Y, Huang HY, et al. (1998) \nQuantitative gonadotropin-releasing hormone gene expression and \nimmunohistochemical localization in human endometrium throughout \nthe menstrual cycle. Biol Reprod 59(3): 661-669.\n2. Peng C, Fan NC, Ligier M, Vaananen J, Leung PC (1994) Expression \nand regulation of gonadotropin-releasing hormone (GnRH) and GnRH \nreceptor messenger ribonucleic acids in human granulosa-luteal cells. \nEndocrinology 135(5): 1740-1746.\n3. Wu HM, Huang HY, Lee CL, Soong YK, Leung PC, et al. (2015) \nGonadotropin-releasing hormone type II (GnRH-II) agonist regulates \nthe motility of human decidual endometrial stromal cells: Possible \neffect on embryo implantation and pregnancy. Biol Reprod 92(4): 98.\n4. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB (2002) Effect \nof prolonged gonadotropin-releasing hormone agonist therapy on \nthe outcome of in vitro fertilization-embryo transfer in patients with \nendometriosis. Fertil Steril 78(4): 699-704.\n5. Lessey B (2000) Medical management of endometriosis and infertility. \nFertil Steril 73(6): 1089-1096.\n6. Celik O, Acet M, Kucuk T , Haberal ET , Acet T , et al. (2017) Surgery for \nbenign gynecological disorders improve endometrium receptivity. \nReprod Sci 24(2): 174-192.\n7. Surrey ES, Katz-Jaffe M, Kondapalli LV, Gustofson RL, Schoolcraft WB \n(2017) GnRH agonist administration prior to embryo transfer in freeze-\nall cycles of patients with endometriosis or aberrant endometrial \nintegrin expression. Reprod Biomed Online 35(2): 145-151.\n8. Decleer W, Osmanagaoglu K, Verschueren L, Comhaire F, Devroey P \n(2016) RCT to evaluate the influence of adjuvant medical treatment \nof peritoneal endometriosis on the outcome of IVF. Hum Reprod 31: \n2017-2023.\n9. Kuwayama M (2007) Highly efficient vitrification for cryopreservation \nof human oocytes and embryos: the Cryotop method. Theriogenology \n67(1): 73-80.\n10. Sallam H, Garcia-Velasco J, Dias S, Arici A (2006) Long term pituitary \ndown-regulation before In Vitro  fertilization (IVF) for cultures from \npatients with endometriosis. Cochrane Database Syst Rev 2006(1): \nCD004635.\n11. Celik O, Unlu C, Otlu B, Celik N, Caliskan E (2015) Laparoscopic \nendometrioma resection increases peri-implantation endometrial \nHOXA-10 and HOXA-11 mRNA expression. Fertil Steril 104(2): 356-\n365.\n12. Jaafar SH, Sallam HN, Arici A, Garcia- Velasco JA, Abou-Setta AM, et al. \n(2019) Long-term GnRH agonist therapy before In Vitro  fertilization \n(IVF) for improving fertility outcomes in women with endometriosis. \nCochrane Database Syst Rev 2019(1): CD013240.\n13. Ferrero S, Gillott DJ, Remorgida V, Anserini P , Ragni N, et al. (2009) \nGnRH analogue remarkably down-regulates inflammatory proteins in \nperitoneal fluid proteome of women with endometriosis. J Reprod Med \n54(4): 223-231.\nYour next submission with Juniper Publishers    \n      will reach you the below assets\n• Quality Editorial service\n• Swift Peer Review\n• Reprints availability\n• E-prints Service\n• Manuscript Podcast for convenient understanding\n• Global attainment for your research\n• Manuscript accessibility in different formats \n         ( Pdf, E-pub, Full Text, Audio) \n• Unceasing customer service\n                        Track the below URL for one-step submission \n         https://juniperpublishers.com/online-submission.php\nThis work is licensed under Creative\nCommons Attribution 4.0 License\nDOI: 10.19080/GJORM.2022.09.5556751","source_license":"CC0","license_restricted":false}