{"paper_id":"9b9c04ea-7814-430e-89a1-d9819a7c4848","body_text":"Submit Manuscript | http://medcraveonline.com\nIntroduction\nEndometriosis is a common disease that affects 6 to 10% of woman \nof childbearing age. It is characterized by growth of endometrial \ntissue outside the uterine cavity. The deep infiltrating endometriosis \nis a progressive and hormone-dependent disease with estrogen \ndependence and progesterone resistance. The main symptoms are \ndysmenorrhea, chronic pelvic pain, dyspareunia and infertility. 1 The \nendometriosis is subdivided according to the type and location of \nthe lesions into peritoneal endometriosis, deep endometriosis and \nendometrioma.2\nMany factors are believed to cause this condition. The leading \ntheory is retrograde menstruation in which the menstrual blood \nflows into the abdominal cavity. The viable cells in this flow can \nimplant, cultivate, and penetrate the peritoneal cavity. The retrograde \nmenstruation is a phenomenon that is somewhat normally seen in a \nlarge fraction of females of reproductive age.3\nThe embryo implantation is the most important event in achieving \npregnancy. In endometriosis, this process is affected. \nThis study investigated the impact of endometriosis on embryo \nimplantation in Saudi patients undergoing in vitro fertilization \nprocedures, find ways to improve its diagnosis and to recommend \nguidelines to reduce its effects on the patients.\nThe infertility is failure to achieve a clinical pregnancy after \n12 months or more of regular unprotected sexual intercourse. Its \nincidence is increasing worldwide, and endometriosis is one of the \ncommon causes of infertility. The incidence of endometriosis in the \nWorld is about 8 to 12%. 4 Previously published reports found that \nendometriosis is a cause of infertility. 5,6 The endometriosis infertility \nis due to endocrine abnormalities, fibrosis, adhesions, immune and \ninflammatory disorders. The females suffering from endometriosis \nusually have poor growth of ovarian follicles, thus produce low \nnumber of oocytes despite high dose of follicle stimulating hormone, \nand achieve low pregnancy rate. 7,8 Many studies have focused on \nfactors affecting the success rate in in-vitro fertilization procedure, \nhowever, there is need to explore the success rate after in-vitro \nfertilization procedure in females suffering from endometriosis, \nespecially in Kingdom of Saudi Arabia.11 \nTherefore, the aim of this study is to review the current knowledge \nregarding endometriosis, and efficiency of embryo implantation \nin IVF procedures. Some studies explored embryo implantation in \nIVF cycles in endometriosis. 12–14 Zhong et. al., studies 330 patients \nundergoing IVF or ICSI. They concluded that endometriosis causes \na harmful impact on the outcomes of IVF and ICSI and the better \ncontrol and management of endometriosis improved live birth rate.14\n Sanchez et. al. reported similar fertilization and quality of \nembryos but a reduced pregnancy rate in women previously operated \nfor moderate/severe endometriosis as compared with non-affected \nwomen.15 In a study to determine the prevalence of endometriosis \nin women who had gynecologic laparoscopy at a university hospital \nin Jeddah, Saudi Arabia between January 2008 and December 2013, \nRouzi et al. reported 11.1 % incidence of endometriosis.11\nThe mechanism that leads to failure of reproduction in women \nsuffering from endometriosis is still not clear. One of the options is \nthat the endometrial tissue generates progesterone, oestradiol and \ncytokines that create inflammatory condition and enhance apoptosis \nin granulosa cells harming fertility. Additionally, endometriosis \ncauses adhesions in the reproductive system resulting in mechanical \ninterferences for ovulation and fertilization. It has been reported that \n30–50% of women diagnosed with endometriosis are infertile.16\nObstet Gynecol Int J. 2022;13(4):267‒271. 267\n©2022 Alfhead et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which \npermits unrestricted use, distribution, and build upon your work non-commercially.\nThe impact of endometriosis on embryo \nimplantation in IVF procedures\nVolume 13 Issue 4 - 2022\nNoura K Alfhead,1 Khaleel Al Yahya,1 \nSameera Shaheen,1 Murid Javed2\n1College of Medicine, King Saud University, Riyadh, 11523, Saudi \nArabia\n2Anova Fertility and Reproductive Health, T oronto, M2N 6S6, \nCanada\nCorrespondence: Murid Javed, Anova Fertility and \nReproductive Health, T oronto, M2N 6S6, Canada, T el +1-416-\n731-9885, Email \nReceived: August 07, 2022 | Published: August 29, 2022\nAbstract\nEmbryo implantation is the most important event in the achievement of conception. In the \npresence of any endometrial disease, this process can be hampered. The endometriosis is \nlinked to causing infertility. It is a chronic uterine disease that is dependent on estrogens \nand is associated with reduced fecundity. The objective of this study was to investigate \nthe impact of endometriosis on embryo implantation in patients undergoing IVF. This is \na case-control study, with case to control ratio of 5:1. The study included 50 patients with \nendometriosis and 10 patients without endometriosis served as control. The endometriosis \nwas diagnosed by symptoms, pelvic and transvaginal ultrasound examinations. The serum \nestrogen levels, fertilization rate and implantation rate were determined. Since the presence \nof a haemorrhagic cyst was suspected at the ultrasonographic finding of masses parallel to \nthe ovaries, measurement of the CA 125 marker was carried out for differential diagnosis. \nThe data were recorded in Excel sheets and analysed using statistical functions of Excel. \nThe significance level was set at 0.05%. Most of the patients in endometriosis group \n(68%) had elevated CA125 Levels and 56 % had high E 2 level. In the control, only one \npatient had high E2 level. In the endometriosis group, 31.67% had positive pregnancy test, \nwhile 90% patients without endometriosis had positive pregnancy test. These differences \nwere statistically significant. These data reveal that the patients with endometriosis had \nsignificantly higher levels of E2 and CA125 marker in blood and had significantly lower \nimplantation rates as compared to those in the control group. \nKeywords: Endometriosis, implantation, IVF, pregnancy, pelvic examination, vaginal \nultrasound\nObstetrics & Gynecology International Journal\nResearch Article\n Open Access\n\n\nThe impact of endometriosis on embryo implantation in IVF procedures\n268\nCopyright:\n©2022 Alfhead et al.\nCitation: Alfhead NK, Al Yahya K, Shaheen S, et al. The impact of endometriosis on embryo implantation in IVF procedures. Obstet Gynecol Int J. \n2022;13(4):267‒271. DOI: 10.15406/ogij.2022.13.00660\nEndometriosis and endometrial polyps are also the key contributors \nto the reduction of female fertility, however, with the introduction of \nIVF technology, a lot of infertile couples with polyps or endometriosis \ncan conceive and enjoy childbirth. Although, a dubious situation is \nstill hanging whether these assisted reproductive technologies can \nresolve all infertility-associated concerns of \nAdditionally, patients with endometriosis mostly have genetic \nabnormalities associated with apoptosis, adhesion, wound, and \nhealing reaction.17 It also produces aberrations in the processes where \nmorphological and functional alterations within the endometrium \ntake place to make the decidual lining for the implantation of the \nblastocyst, a process known as decidualization. All of this largely \nleads to the failure of the implantation of embryos.18\nIn fact, the condition of endometriosis reduces a female’s fertility \nby influencing the quality of egg and embryo. A low rate of fertilization \nin endometriosis and more atypical eggs (oocytes) in comparison to \npatients with no endometriosis in the control group. They linked this \nto the abnormality of steroids in endometriosis patients.19 \nEstrogen, progesterone, and sex related steroids are largely \nsynthesised in the ovaries and they control the development \nof endometrial tissue, essentially by activating and preventing \nproliferation of cell. Estrogen also has vital function in the discharge \nof gonadotropin and in the formation of follicles. 20 There are four \ndifferent varieties of estrogen, namely estrone (E1), oestradiol (E2), \nestriol (E3), and estetrol (E4). E2 has a major function in the female \nreproductive tract.21\nThe estrogen hormone is responsible for the growth and regulation \nof the menstrual cycle and female reproductive system. In addition, \nestrogen plays a vital role in various other biological systems such \nas immune systems, vascular system, skeletal, and neuroendocrine \nsystem. For this reason, estrogen is implicated in problems like \ninfertility. \nEstrogen plays a critical role in the apparent alterations of the \nuterus that are taking place during early pregnancy. Uterus undergoes \nfunctional and structural changes to become receptive to the invading \nblastocyst. Estrogen is also responsible for the control of the \nimplantation.22 This hormone is also used during the transfer of embryos \nto assist the implantation. Different types of routes of administration \nand doses of estrogen are used along with progesterone. Receptive \nendometrium is an important factor for deciding the successful \nembryo implantation and receptivity to implantation can be achieved \nwith the use of estrogen and progesterone given exogenously.23\nLikewise, studies have also suggested that estrogen and \nprogesterone take part in an important function of preparing \nendometrium to become receptive to embryo. 24 They also stated that \nwell-timed and appropriate initiation of endometrial receptivity is a \nkey process for offering triumphant embryo implantation. A study \nby Young also concluded that estrogen is essential for endometrial \nreceptivity to embryo implantation. This phase exists for a short period \nof time and can be accomplished only following adequate exposure.25 \nKlonos et.al., was also of the same opinion that both estrogen and \nprogesterone help in achieving success in IVF process owing to their \neffects that lead to a succession of autocrine and paracrine signals. \nThey are needed for processing of adhesion molecules for successful \npenetration and adherence of blastocytes to the endometrium.22 \nFurthermore, estrogen levels on the endometrium are also \nfirmly regulated and in case of low level of estrogen, receptivity of \nthe uterus persists and when levels go high, it is effects in role of \nendometrium. Thus, estrogen holds a fundamental and critical role in \nthe establishment of receptivity of the endometrium and it can be said \nthat success of IVF procedure depends on it.25\nEndometriosis is sometimes the result of high levels of estrogen \nand is believed to enhance the growth of endometrial tissues in the \nbody. Similarly, endometrial polyps are also sensitive to estrogen. \nMaterials and methods\nThe study was conducted in collaboration with an IVF laboratory \nat a private medical center in Riyadh, Saudi Arabia. This was a case-\ncontrol study, with case to control ratio of 5:1 i.e., for 50 patients with \nendometriosis, 10 patients without endometriosis served as control. \nThe endometriosis was diagnosed by symptoms, and pelvic and \ntransvaginal ultrasounds. The oocytes from all patients were fertilized \nby intracytoplasmic sperm injection and embryo transfers were \ncarried out on day-5. The study parameters included measurement \nof serum estrogen and CA 125 marker levels, fertilization rate, \npregnancy rate, implantation rate, and pelvic ultrasound observations. \nThe measurement of CA 125 marker helped in differentiation of \nhaemorrhagic cyst and the endometriosis masses. For detection of \npregnancy, serum beta human chorionic gonadotropin (b-hCG) levels \nwere determined using Abbott Architect. All data were recorded in \nExcel sheet for statistical analysis. The significance level was set at \n0.05% for all statistical tests.\nResults\nIn patients without endometriosis, the average longitudinal \nmeasurement of the uterus was 7.5cm with a range of 5cm to 8.5cm \nand the average transverse measurement was 5.0cm with a range of \n4.5cm-6.4cm (Figure 1).26 In the presence of endometriosis, this size \nincreased depending on the size and site of the endometrioma. The \nFigure 2 shows dilation of the uterine cavity due to the presence of \nendometrioma. In this patient, the transverse measurement increased \nto 6.5cm (Figures 3a & 3b).\nFigure 1 An ultrasound image of the uterus showing normal size.  The \nhorizontal line shows longitudinal measurement (7.5 cm), and the vertical line \nshows transverse measurement (5 cm).\nFigure 2 An ultrasound image of the uterus showing dilation of the uterine \ncavity due to the presence of an endometrioma.\n\n\nThe impact of endometriosis on embryo implantation in IVF procedures\n269\nCopyright:\n©2022 Alfhead et al.\nCitation: Alfhead NK, Al Yahya K, Shaheen S, et al. The impact of endometriosis on embryo implantation in IVF procedures. Obstet Gynecol Int J. \n2022;13(4):267‒271. DOI: 10.15406/ogij.2022.13.00660\nFigure 3a An ultrasound image of the uterus showing left endometrioma. The \ndots indicate size of masses present.\nFigure 3b An ultrasound image of the uterus showing right endometrioma. \nThe dots indicate size of masses present.\nIn all patients participating in this study, it was found that almost \nhalf 48.3% (n= 29) had high estrogen levels, 36.7% (n=22) had normal \nlevels and 15% (n= 9) had low estrogen levels (Figure 4).\nFigure 4 Estrogen levels in all patients participating in this study regardless \nof endometriosis. In this study, high estrogen levels were observed in 48.33 %, \nnormal in 36.67 % and low in 15%).\nIn the endometriosis group, 28 patients had high estrogen levels \nand only 14 had normal levels, while the patients in the control group \nwithout endometriosis, only one patient had high estrogen level, and 8 \nhad normal estrogen level (Figure 5).\nIn the endometriosis group, it was found that more than two \nthirds 68.37% (n=41) had a negative pregnancy test result, and \n31.67% (n=19) had positive pregnancy results (Figure 6). Whereas \nin the control group, the biochemical pregnancy rate was 90%. These \ndifferences were significant.\nFigure 5 A comparison of estrogen levels in study and control groups.\nFigure 6 Showing pregnancy rate in patient suffering from endometriosis. A \nhigh percentage (68.33%) of patients in endometriosis group did not achieve \npregnancy.\nThe blood level of CA125 marker was measured to differentiate \nbetween endometriosis and haemorrhagic cyst. Most of the patients \nwith endometrioma had high levels of CA125 marker in the blood. \nThe average CA125 value was 127.26±269U/ml, with a range of 37-\n1444U/ml whereas the normal value is 35 U/ml.\nDiscussion\nThe results of this study indicate that patients suffering from \nendometriosis has significantly lower pregnancy rate after in vitro \nfertilization and embryo transfer stressing the need to seek medical \ntreatment for endometriosis. 27 In endometriosis cases, the lower \npregnancy is mainly due to endocrine abnormalities, fibrosis, \nimmune and inflammatory disorders. Since the pregnancy rate in \nIVF procedure is negatively correlated with endometriosis severity, 28 \ntherefore, a strategy to improve pregnancy rate in endometriosis cases \nis to defer the embryo transfer until the endometriosis is treated to \nimprove the endometrial receptivity. Significant improvements in \nembryo vitrification had made it possible and many clinics have \nadopted the “freeze all” approach. It has now become an attractive \napproach to increase pregnancy rate in patients with endometriosis.29 \nThe endometriosis causes pain and reduces reproductive potential, \ntherefore, its treatment becomes essential. A common treatment is to \nuse hormonal contraceptives or levonorgestrel-releasing intrauterine \nsystem. In severe cases, laparoscopic surgery is recommended to \nremove the endometriosis tissue. If the ovaries are involved, and \nhave to be surgically incised or removed, oocyte cryopreservation to \npreserve fertility is recommended.30 \n\n\nThe impact of endometriosis on embryo implantation in IVF procedures\n270\nCopyright:\n©2022 Alfhead et al.\nCitation: Alfhead NK, Al Yahya K, Shaheen S, et al. The impact of endometriosis on embryo implantation in IVF procedures. Obstet Gynecol Int J. \n2022;13(4):267‒271. DOI: 10.15406/ogij.2022.13.00660\nDuring the diagnostic procedure some patients presented an \nultrasonographic pattern that resembled a mass that was parallel to \nthe ovaries. In such cases, CA125 marker levels were determined \nto rule out the presence of a haemorrhagic cyst. Normal values of \nCA125 marker are between 0 and 35U/ml. According to the current \nliterature, endometriosis is a disease that triggers the production and \nrelease of this marker, so the patients with endometriosis exhibit high \nvalues of CA125 marker. The patients with CA125 marker values less \nthan 35U/ml were considered to have a haemorrhagic cyst rather than \nendometriosis. The average value of CA125 marker in this study was \n127U/ml which is higher than the value found in normal woman. \nThe estrogen levels in patients suffering from endometriosis were \nsignificantly higher than those in the control group. The endometriosis \nis estrogen-dependent disease. Its etiology includes interactions of \ngenetic, immunological, hormonal and environmental factors. That \nis why no single theory can explain all aspects of endometriosis. 31 \nThe previous reports indicated that molecular and cellular features of \nendometriosis differ from those of endometrium. 32,33 The aromatase \nand 17β-HSD type 1 mRNA levels are extremely low in normal \nhuman endometrium, however, in endometriosis, the enzymes \nproducing estrogen are more active. This is due to a suppression of \ntypes 2 and 4 17β-HSD, and an increased expression of aromatase \nand type 1 17β-HSD in ectopic endometrium which results in higher \nlevels of estrogen in endometriosis 34 facilitating the implantation of \nendometrial fragments.\nConclusion\nThe results of this study indicated that the patients suffering from \nendometriosis exhibited higher estrogen and CA 125 marker values \nand had significantly lower implantation rate as compared to those \nin the control group. A larger study is warranted to confirm these \nfindings.\nAcknowledgments\nNone.\nFunding \nNone.\nConflicts of interest \nAuthor declares there is no conflict of interest exists.\nReferences\n1. Gosset A, Susini M, Vidal F, et al. Quality of life of patients with bilateral \noophorectomy before the age of 45 for the treatment of endometriosis. \nMaturitas. 2022;162:52–57.\n2. Members of the Endometriosis Guideline Core Group, Becker CM, \nBokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis. \nHuman reproduction open. 2022;2022(2):hoac009.\n3. Tsamantioti ES, Mahdy H. Continuing education activity. 2022. \n4. Vander Borght M, Wyns C. Fertility and infertility: Definition and \nepidemiology. Clin Biochem. 2018;62:2–10.\n5. Lin S, Xie X, Guo Y , et al. Clinical characteristics and pregnancy \noutcomes of infertile patients with endometriosis and endometrial \npolyps: A retrospective cohort study. Taiwan J Obstet Gynecol . \n2020;59(6):916–921. \n6. 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