{"paper_id":"4ff6481b-5005-49e5-b067-523e9c747871","body_text":"22\nMold J Health Sci. 2024;11(3):22-26\nRESEARCH ARTICLE\nDeep endometriosis – impact on infertility, endometriosis \nfertility index, and reproductive prognosis (comparative study)\nNadejda Codreanu*, Elena Ivanova\nDepartment of Obstetrics and Gynecology, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova\nABSTRACT\nUDC: 618.145-007.415:618.177\nhttps://doi.org/10.52645/MJHS.2024.3.03\nCite this article: Codreanu N, Ivanova E. Deep endometriosis – impact on infertility, endometriosis fertility index, and reproductive prognosis \n(comparative study). Mold J Health Sci. 2024;11(3):22-26. https://doi.org/10.52645/MJHS.2024.3.03.\nIntroduction. Deep infiltrating endometriosis (DIE) is the most severe form of endometriosis, contributes to pelvic pain \nsyndrome, extragenital symptoms, fertility problems, and diminished reproductive prognosis for affected individuals. It \nis recommended to use the Endometriosis Fertility Index (EFI) to assess reproductive prognosis and conduct clinical re -\nsearch to compare reproductive prognosis in different forms of endometriosis.\nObjective. Comparison of the impact of the DIE and others forms of endometriosis on EFI, patients’ fertility and on repro-\nductive prognosis to understand the management approach.\nMaterials and methods. A cohort study included 190 reproductive-age women, divided according to the #Enzian clas -\nsification: the main group - 85 patients with DIE, the control group - 105 women with other forms of endometriosis. The \nEFI was utilized for reproductive prognosis. Pain was evaluated with Visual Analog Scale (VAS). Statistical analyses were \nperformed using SPSS, with calculation of the Mann-Whitney U and Pearson’s chi-square test (χ²).\nResults. In main group, the frequency of infertility was 83.5% compared to the control group’s 71.4% (p > 0.05). The EFI in \nmain group was 7.18±0.25 points vs the control group’s 7.13±0.28 points (p = 0.852). Patients in the main group suffered \nfrom intense pelvic pain (>7 points by the VAS, p < 0.01), including severe dyspareunia (7.85±0.33 points vs 2.18±0.46 \npoints in control group, p < 0.01). \nConclusions. Our results suggest that infertility in women with DIE may be more often associated with sexual abstinence \ndue to significant dyspareunia rather than organic impairments. Thus, EFI in patients with DIE does not reflect all aspects \nof infertility and has reservations, and consideration of both physical symptoms and sexual health is crucial in managing \nDIE to optimize fertility outcomes. These findings open the way to the feasibility of surgical treatment of DIE to improve \nsexual quality of life, which will reduce the need for IVF and increase the chances of spontaneous pregnancy in patients, \nbut this conclusion requires further investigation in randomized clinical trials.\nKeywords: endometriosis, deep endometriosis, EFI, reproductive prognosis.\nManuscript received: 14.06.2024\nAccepted for publication: 03.09.2024\nPublished: 20.09.2024\n*Corresponding author: Nadejda Codreanu, PhD, Associate professor,\nDepartment of Obstetrics and Gynecology, \nNicolae Testemițanu State University of Medicine and Pharmacy, \nChisinau, Republic of Moldova\n165, Stefan cel Mare și Sfânt blvd., MD-2004\ne-mail: nadejda.codreanu@usmf.md\nAuthors’ ORCID IDs\nNadejda Codreanu – https://orcid.org/0009-0008-8740-0379\nElena Ivanova – https://orcid.org/0000-0001-8460-9849\nKey messages\nWhat is not yet known on the issue addressed in the submitted \nmanuscript\nThe connection between deep endometriosis and infertility, \nthe impact of deep endometriosis on the EFI index and the \nreproductive prognosis of patients – these outstanding questions \nremain debatable.\nThe research hypothesis\nDeep endometriosis is a form of endometriosis that significantly \naffects a woman’s fertility, reducing the EFI index and dramatically \nworsening the patient’s reproductive prognosis.\n\n23\nMold J Health Sci. 2024;11(3):22-26Deep endometriosis and reproductive prognosis\nThe novelty added by the manuscript to the already published scientific literature\nThe study allowed to clarify the features of the influence of deep endometriosis on infertility, the fertility index, and the \nreproductive prognosis of patients, and to compare these results with data from patients suffering from other forms of \nendometriosis.\nIntroduction \nThe deep infiltrative endometriosis (DIE) is acknowl -\nedged as the most severe manifestation of pelvic endome -\ntriosis, comprising a quarter of its various phenotypes [1-3]. \nDIE is characterized by fibromuscular infiltration of organs \nand anatomical structures with subperitoneal invasion of \nendometrial tissues, regardless of the depth of infiltration, \nand it presents as a systemic, chronic inflammatory disease \ncyclically dependent on menstruation, with chronic pelvic \npain being its common manifestation [1, 4-6]. \nThe occurrence of DIE is on the rise. Despite ongoing re-\nsearch efforts worldwide, understanding its pathogenesis, \nclinical features, diagnostic methods, and treatment op -\ntions remains a focus of intensive investigation. Impacting \napproximately 2% of females in their reproductive years, \nDIE contributes to pelvic pain syndrome, extragenital symp-\ntoms, fertility problems, and diminished reproductive prog-\nnosis for affected individuals [1, 5].\nAt the global consensus in 2021, the following classifica-\ntions for clinical use in endometriosis were recommended: \nrASRM (revised American Society for Reproductive Medi -\ncine), the EFI scale (Endometriosis Fertility Index), and the \n#Enzian classification. These classifications not only allow \nfor staging the pathological process but also for evaluating \nthe reproductive prognosis of the patients [7, 8]. Of partic -\nular interest for our study are the #Enzian classification, \nwhich completely describes all possible forms of DIE, and \nthe EFI, which provides a precise reproductive prognosis \nand allows for specific recommendations regarding fertility \nmanagement for patients in the postoperative period [9-11].\nAs per the literature, clinical manifestations of DIE en -\ncompass the 4 “D” symptoms: dysmenorrhea, dyspareunia, \ndysuria, and dyschezia, frequently accompanied by infer -\ntility [12]. The primary cause of infertility associated with \nendometriosis (DIE) is the distortion of normal pelvic or -\ngan anatomy. Additionally, endometriosis impairs fertility \nthrough other mechanisms: inflammation and scarring of \nsurrounding tissues lead to dysfunction of the ovaries and \nuterus, affecting the quality of oocytes and their ability to be \nfertilized. High levels of inflammatory cytokines and media-\ntors negatively impact embryo implantation [13]. \nScientific literature indicates that DIE, being the most \naggressive and clinically prominent phenotype of endome -\ntriosis, notably diminishes the QoL for patients [14, 15]. \nThis deterioration arises not only due to severe pain and \nextragenital symptoms but also because of the infertility. \nThese factors collectively exacerbate the challenges faced \nby affected women, further diminishing their QoL [3]. \nAfter analyzing the scientific literature dedicated to the \nissue of DIE, it was decided to implement a study, the aim \nof which was to compare the impact of the DIE and others \nforms of endometriosis on EFI, patients’ fertility and on re -\nproductive prognosis to understand the management ap -\nproach.\nMaterial and methods\nA cohort clinical study was carried out over a span of \n2 years at the Gheorghe Paladi Municipal Clinical Hospital \nin Chisinau. Approval for the study was obtained from the \nResearch Ethics Committee of Nicolae Testemiţanu  State \nUniversity of Medicine and Pharmacy (minutes No. 38, from \n21.05.2021). The research involved women of reproductive \nage diagnosed with “Endometriosis,” confirmed through in-\ntraoperative findings or indications from ultrasound/MRI \nscans according to the #Enzian classification from 2019, \nadhering to predefined inclusion and exclusion criteria. Ex-\nclusion criteria encompassed patients below the legal age, \nthose who were virgins, retired individuals, cases of endo -\nmetriosis with malignancy, severe extragenital pathologies \n(such as hypertension, cardiovascular, or liver disorders), \nprecancerous or cancerous conditions (including cervical, \nendometrial, or ovarian), and patients who declined partici-\npation in the clinical investigation. Each participant provid-\ned informed consent prior to enrollment.\nConsequently, the cohort comprised 190 women divided \ninto two distinct groups according to the #Enzian classifi -\ncation: the study group comprised 85 patients diagnosed \nwith DIE (compartments A, B, C, F), while the control group \nconsisted of 105 women diagnosed with endometriosis of \nthe ovaries, tubes, and superficial peritoneal endometriosis \n(corresponding to compartments O, T , P in the #Enzian clas-\nsification 2019).\nTo quantify the impact of endometriosis on patient fertil-\nity, the EFI was employed. Pain severity was assessed using \nthe Visual Analog Scale (VAS). Data analysis was conducted \nusing an Excel spreadsheet, and statistical analyses were \nperformed using the SPSS software. The Mann-Whitney U \ntest was employed to compare quantitative variables be -\ntween groups, while the Pearson’s Chi-square test (χ²) was \nutilized for comparing qualitative variables among groups.\nResults\nThe cohort of women was divided into two groups ac -\ncording to the #Enzian classification. So, in the main group \nof 85 patients, the lesions were distributed as follows in \n#Enzian compartments: A - 55.3%; B - 8.2%; C - 1.2%; FA \n- 17.6%; FB - 17.6%; FI - 9.4%; FO - 12.9%; P - 34.1%; O - \n\n24\nMold J Health Sci. 2024;11(3):22-26Codreanu Nadejda et al.\n70.6%; T - 51.8%. In the control group of 105 patients, the \nlocalization of endometriosis was distributed as follows in \ncompartments by the #Enzian: P - 15.2%; O - 90.5%; T - \n50.5%.\nReproductive anamnesis data. An important objective \nof the study was to determine the frequency of infertility \namong groups of patients, as well as to calculate the score of \nthe EFI index for patients’ reproductive prognosis. \nThus, among patients with DIE, the frequency of infer -\ntility was 83.5% (71 patients out of 85). Detailed fertili -\nty calculations revealed that primary infertility in main \nstudy group is 48.2±5.7%; 95% CI (36.5 – 59.3%), while \n35.3±5.4% of women were diagnosed with secondary infer-\ntility. Additionally, 14.1±3.8% of women in this group did \nnot suffer from infertility, and 2.4±1.6% utilized contracep-\ntive methods (withdrawal method, condoms, Figure 1). \nAmong the patients in the control group, the percent -\nage of infertility was 71.4% (75 women out of 105). Fer -\ntility calculation in this group revealed that 37.1±4.7% of \nwomen experienced primary infertility, while 34.3±4.8% of \nwomen reported secondary infertility. However, within this \nstudy group, 21.0±4.0% did not suffer from infertility, and \n7.6±2.7% utilized contraception (withdrawal method, con -\ndoms, Figure 1). \nFig. 1 Frequency of infertility in study groups\nFig. 2 Comparison of reproductive losses in research groups.\nStatistical comparison of the infertility parameter did \nnot reveal a statistically significant difference between the \nstudy groups (χ2 = 5.088a, df = 3, p = 0.165).\nReproductive losses. In addition, comparison between \npatients in the study groups did not reveal any differences \nin terms of reproductive losses (U = 4463.000, p = 0.839). In \nthe main group, the frequency of reproductive losses was 13 \ncases out of 85 - 15.3%, while in the control group it was 11 \nout of 105 - 10.5% (Figure 2). \nCalculations of EFI. For the final fertility prognosis cal -\nculation in the study groups, the EFI index was computed \n(Figure 3). The median EFI among women with DIE was \n7.00 points (mean value - 7.18±0.25 points; 95% CI [6.68 – \n7.68 points]). Simultaneously, the median EFI in the control \ngroup was also 7.00 points (mean value 7.13±0.29 points; \n95% CI [6.55 – 7.71 points]). \nComparison of these data did not reveal a statistically \nsignificant difference in this parameter between the study \ngroups (U = 3712.000, p = 0.852), despite the fact that the \nmain group included patients with complete obliteration of \nthe Douglas pouch, whose EFI tends towards 0 points.\nPain levels. The distribution of pain levels on the VAS \namong women of main group in comparison to the con -\ntrol group of patients is reflected in the Table 1. It is worth \nnoting that patients with DIE are characterized by severe \n\n25\nMold J Health Sci. 2024;11(3):22-26Deep endometriosis and reproductive prognosis\ndyspareunia (7.85±0.33 points (95% CI; 7.18 – 8.53 points) \nvs 2.18±0.46 points (95% CI; 1.23 – 3.13 points) in control \ngroup, p < 0.01), which is the cause of sexual abstinence \nand, accordingly, infertility.\nTable 1. Comparison of pain levels according to the VAS\nPain symptom Main Group Control Group P\nCPP 7.90±0.21 2.41±0.45 p < 0.01\nDm 9.02±0.17 5.31±0.52 p < 0.01\nDp 7.85±0.33 2.18±0.47 p < 0.01\nDu 1.46±0.47 0 p < 0.01\nDh 3.83±0.56 0 p < 0.01\nNote: VAS - visual analog scale ; CPP - chronic pelvic pain, Dm - \ndysmenorrhea, Dp - dyspareunia, Dy - dysuria, Dx – dyschezia\nDiscussion \nThe study found that although bilateral endometriomas \n(“kissing ovaries”) were included in the DIE group, the total \nEFI score was greater than 7, similar to the control group. \nIf “kissing ovaries” , where EFI approaches 0 and pregnan -\ncy can only be achieved with ART , are excluded from DIE, \nother forms of DIE (88%), where the ovaries are not affect-\ned, show higher EFI values than the control group. Howev -\ner, infertility I and II frequencies are similar. This suggests \nthat infertility in women with DIE may not be solely due to \nthe organic changes reflected by EFI but also due to sexu -\nal disharmony associated with severe dyspareunia, sexual \nabstinence, or long-term use of pain-relieving medications, \nwhich may delay pregnancy but not always inhibit the pro -\ngression of endometriosis.\nTherefore, using EFI in the DIE group has limitations, \npotentially delaying ART use and wasting time in achieving \nspontaneous pregnancy. On the other hand, for women with \nDIE excluding “kissing ovaries” , prolonged periods without \npregnancy desire may benefit from multidisciplinary sur -\ngical treatment, reducing pain syndrome and dyspareunia, \nachieving spontaneous pregnancy in the future.\nThe benefits of surgical treatment for DIE were high -\nlighted in a study by the Endometriosis School in Bordeaux \n(Horace Roman), showing increased rates of spontaneous \npregnancies. Recent studies on the failure of progestin \ntreatment due to the lack of progesterone receptors in DIE \nlesions, and our data, support surgical treatment in patients \nnot opting for immediate pregnancy, especially in distant \ncompartment DIE forms after #Enzian that do not directly \ninvolve the genitals.\nTherefore, our study demonstrates the limitations of \nusing EFI scores alone, excluding “kissing ovaries” , to eval-\nuate reproductive prognosis in DIE patients. Besides EFI, as-\nsessing sexual life quality is crucial to support spontaneous \npregnancy in women with DIE. Relying solely on EFI for re-\nproductive prognosis in DIE patients could result in wasted \ntime and unfavorable reproductive outcomes, as it fails to \nconsider dyspareunia and high EFI scores that may delay \nthe timely use of IVF or other ART methods.\nConclusions \nOur results suggest that infertility in women with DIE \nmay be more often associated with sexual abstinence due \nto significant dyspareunia rather than organic impairments. \nThus, EFI in patients with DIE does not reflect all aspects of \ninfertility and has reservations, and consideration of both \nphysical symptoms and sexual health is crucial in managing \nDIE to optimize fertility outcomes. These findings open the \nway to the feasibility of surgical treatment of DIE to improve \nsexual quality of life, which will reduce the need for IVF and \nincrease the chances of spontaneous pregnancy in patients, \nbut this conclusion requires further investigation in ran -\ndomized clinical trials.\nCompeting interests \nNone declared.\nAuthors’ contributions\nNC proposed the study’s area, conceived the study de -\nsign, controlled main points of its realization, reviewed the \nwork critically, and approved the final version of the man -\nuscript. EI participated in the study design, contacted and \nincluded subjects in research, analyzed and calculated in -\nformation from questionnaires, performed the statistical \nanalysis of collected data, drafted the manuscript, reviewed \nthe work critically.\nAcknowledgements and funding\nWe express our gratitude to academician Gheorghe Pal -\nadi, who advised us to pursue research in the gynecological \nfield and supported the realization of this study. The study \nhad no external funding.\nPatient consent \nObtained.\nFig. 3 Comparison of the EFI in the research groups.\n\n\n26\nMold J Health Sci. 2024;11(3):22-26Codreanu Nadejda et al.\nEthics approval\nThe study protocol was approved by the Research Ethics \nCommittee of Nicolae Testemiţanu State University of Medi-\ncine and Pharmacy (minutes No. 38, from 21.05.2021).\nReferences\n1. Saridogan E, Becker CM, Feki A, Grimbizis GF, Hummelshoj \nL, Keckstein J, et al. 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