{"paper_id":"a9750233-4b0a-4245-8011-39a1ac66af45","body_text":"University of Pécs, Faculty of Health Sciences \nDoctoral School of Health Sciences \nHead of the Doctoral School of Health Sciences: \nProf. Dr. István Kiss MD, DSc \n \n \nEFFECTS OF ENDOMETRIOSIS ON QUALITY OF LIFE \n(Benefit of combined hystero-laparoscopic surgery on quality of life and \nfertility performance in endometriosis) \n \nDoctoral (PhD) thesis \n \n \n \nDR. EKINE ATOMBOSOBA ADOKIYE \n \nProgram Leader: Prof. Dr. József Bódis \nSupervisor: Prof. Dr. Miklós Koppán \nCo-Supervisor: Dr. Ágnes Koppán \n \nPÉCS, 2024 \nTE/11077-1/2025\n\nCONTENTS \n1. INTRODUCTION ............................................................................................................................... 1 \n1.1. Theories on the pathogenesis of endometriosis .................................................................................. 4 \n1.1.1. Retrograde menstruation (transplantation) ....................................................................................... 4 \n1.1.2. Altered cellular immunity. ............................................................................................................... 5 \n1.1.3. Coelomic metaplasia (transformation theory) .................................................................................. 6 \n1.1.4. Steroid metabolism dysfunction and progesterone regulation ......................................................... 7 \n1.1.5 Genetic background .......................................................................................................................... 8 \n1.1.6. Oxidative stress ................................................................................................................................ 9 \n1.1.7. Environmental factors ...................................................................................................................... 9 \n2. SYMPTOMATOLOGY OF ENDOMETRIOSIS ........................................................................... 10 \n3. GENERAL IMPACT OF ENDOMETRIOSIS ............................................................................... 11 \n3.1. Impact on fertility ............................................................................................................................. 12 \n3.1.1. Chronic inflammation .................................................................................................................... 12 \n3.1.2. Tuboperitoneal distortion ............................................................................................................... 12 \n3.1.3. Hormonal changes on implantation ............................................................................................... 12 \n3.1.4. Decrease in ovarian reserve. .......................................................................................................... 13 \n3.2. Pain-related symptoms (reduced or absent sexual activity) .............................................................. 14 \n3.3. Impact on socioeconomic life ........................................................................................................... 15 \n3.4. Impact on quality of life and well-being ........................................................................................... 15 \n4. DIAGNOSIS ....................................................................................................................................... 17 \n4.1. Endoscopy findings ........................................................................................................................... 17 \n4.2. Histological confirmation ................................................................................................................. 18 \n5. CONSERVATIVE MANAGEMENT .............................................................................................. 19 \n5.1. Medical therapy ................................................................................................................................ 20 \n5.1.1. Hormones ....................................................................................................................................... 20 \n5.1.2. Other drugs (NSAIDs) ................................................................................................................... 20 \n5.2. Physiotherapy ................................................................................................................................... 20 \n5.3. Acupuncture Therapy ....................................................................................................................... 21 \n5.4. Psychotherapy ................................................................................................................................... 21 \n5.5. Prevention ......................................................................................................................................... 21 \n6. SURGICAL PROCEDURES ............................................................................................................ 21 \n6.1. Treatment of ovarian endometriosis associated with pain and infertility. ......................................... 22 \n6.2. Other surgical options ....................................................................................................................... 23 \n7. HYPOTHESES .................................................................................................................................. 23 \n8. RESEARCH STUDIES ..................................................................................................................... 24 \n8.1. Study I: Isthmocele and its probable link with endometriosis. ......................................................... 24 \n8.1.1. Background .................................................................................................................................... 24 \n8.1.2. Materials and methods ................................................................................................................... 24 \n8.1.3. Results............................................................................................................................................ 25 \n8.1.4. Discussion ...................................................................................................................................... 27 \n8.2. Study II: Benefits of hysterolaparoscopy in endometriosis-related infertility .................................. 28 \n8.2.1. Background .................................................................................................................................... 28 \n8.2.2. Materials and methods ................................................................................................................... 28 \n8.2.3. Results............................................................................................................................................ 29 \n8.2.4. Discussion ...................................................................................................................................... 37 \n8.3. Study III: Effectiveness of combined hysterolaparoscopy on quality of life of endometriosis patients\n ................................................................................................................................................................. 39 \n8.3.1. Background .................................................................................................................................... 39 \n8.3.2. Materials and methods ................................................................................................................... 40 \n8.3.3. Results............................................................................................................................................ 42 \n8.3.4. Discussion ...................................................................................................................................... 60 \n9. SUMMARY OF RESULTS .............................................................................................................. 61 \n10. ANSWERS TO OUR HYPOTHESES ........................................................................................... 62 \n11. GENERAL DISCUSSION .............................................................................................................. 63 \n12. CONCLUSION ................................................................................................................................ 65 \n13. PUBLICATIONS RELATED TO THE THESIS: ........................................................................ 66 \n14. AUTHOR’S PUBLICATIONS NOT RELATED TO THE THESIS  .......................................... 67 \n15. ACKNOWLEDGEMENTS ............................................................................................................ 69 \n16. REFERENCES................................................................................................................................. 70 \n17. ANNEX ............................................................................................................................................. 91 \n18. ABBREVIATION ............................................................................................................................ 98 \n \n\n1 \n1. INTRODUCTION \nEndometriosis is a common, progressive, chronic disease with detrimental effects on \naffected women. It is a mostly benign but potentially debilitating gynecological \ndisorder with rare malignant transformation [1]. Endometriosis is estimated to affect \n10–15% of the female population of reproductive age [2, 3]. It is an estrogen -\ndependent disorder characterized by the growth of endometrium -like tissue outside the \nuterine cavity. Organs distant from the pelvis can be involved, such as the lungs and \nskin [4,5,6]. These displaced or relocated ectopic endometriotic lesions are \npredominately located in the pelvic cavity and can involve the ovaries, rectovaginal \nseptum, peritoneal surfaces, uterine bladder, bowels, ligaments, pelvic sidewall \nstructures, and the Fallopian tubes. \n \n \nFigure 1: Possible sites of endometriosis (Dr. Lane et al. Adelaide Obstetrics & Fertility).  \n \nThe quality of life (QoL) of women with symptomatic endometriosis is markedly \nreduced by subfertility or infertility, chronic pelvic pain, dysmenorrhea (painful \nperiods), and dyspareunia (pain during sexual intercourse) [7, 8]. Endometriosis is \nestimated to affect 20 –50% of the female population with fertility issues (subfertility \n\n2 \nor infertility) [9, 10] and 40 –60% of women with dysmenorrhea [11]. The complexity \nof its pathogenesis has made endometriosis difficult to identify using universally \nstandard biomarkers; several attempts have been made with little or no success [12]. \nThe major challenge of the disease is the delay in diagnosis, which frequently requires \ninvasive procedures, such as laparoscopy, and —less frequently —diagnostic \nlaparotomy [13, 14]. The severity of the disease reflects the resultant extent of pelvic \nadhesions and distortion of the pelvic anatomy, which can both lead to subfertility and \ninfertility [4]. Endometriosis is categorized into stages by scoring systems developed \nby the American Fertility Society in 1979. The American Society for Reproductive \nMedicine (ASRM) classification of endometriosis is referred to by many authors as a \nuseful tool for predicting in vitro fertilization (IVF) success and fertility performance \n[15]. Furthermore, the European Society for Human Reproduction and Embryology \n(ESHRE) suggests that patients with lesions classified as “moderately severe” or \n“severe” have a higher likelihood of success with IVF as the first line of treatment [16, \n17, 18]. Several treatment modalities have been developed over the decades: \nsymptomatic treatment of pain with nonsteroidal anti -inflammatory drugs (NSAIDs), \nother painkillers, oral contraceptive pills, progestogen -releasing intrauterine \ncontraceptive devices (hormonal IUCDs), and agonists of gonadotropin -releasing \nhormone (GnRH). The complexity of the pathogenesis of endometriosis and the lack \nof clear -cut target molecules makes the development of therapeutics difficult. \nCurrently, the only successful treatment modality for severe endometriosis consists of \nsurgical removal of visible lesions with or without adjuvant medical therapy. \nRecurrence is relatively frequent depending on the surgical expertise and is estimated \nto range from 4.2 –75% within 2 years; therefore, the need for repeated surgery is \ncommon [19, 20]. \n \nThis dissertation aims to investigate the effectiveness of laparoscopic surgery on \nimproving QoL, GeneralWB, and fertility performance in patients with endometriosis. \nFurthermore, its objectives are to test some of the hypotheses regarding the \npathogenesis of endometriosis, such as the implantation theory (retrograde \nmenstruation), the dietetic effect, and genetic disposition. \nEndometriosis was first described in 1860 as “adenomyoma” by Karl Freiherr von \nRokitansky, an Austrian pathologist. The first formal description of the disease was \nmade by Dr. John Sampson in his paper describing 13 cases in which the presence of \n\n3 \nendometrial tissue was noticed during abdominal surgery [1, 21]. Earlier, in 1690, \nDaniel Shroen recorded several detailed descriptions of the disease [21]. There are \nreports with medical implications of the disease dating back approximately 4,000 \nyears. Some women presenting with symptoms similar to those of endometriosis were \nconsidered to be demon-possessed, witches, or mad; these women were regarded with \ncontempt by society, rejected, and sometimes murdered. 2,500 years ago, Hippocratic \ndoctors also documented a similar medical condition, which was merely referred to as \n“chronic pain”. Thomas Sydenham and others referred to women presenting with these \nsymptoms as “hysterics” [1, 14, 21]. The attitudes of male medical professionals in the \nearly days, the insufficient technology at the time, and the complexity of \nendometriosis resulted in the delayed discovery of the disease. Therefore, the affected \nwomen were in a state of agony for most of their lives, which may support the \ndevelopment of some of the behaviors termed as “possessed” [4, 21]. \nAccurate and reliable figures for endometriosis prevalence are unascertained. The \nstatistics regarding the disease are controversial; they may vary from country to \ncountry, and they largely depend on the quality of healthcare, which is not uniform \nacross countries. Centered on the few reliable data, the prevalence of endometriosis \ncan be assumed to be around 3.5–10.8%. The following figures have been estimated in \ndifferent countries: 6 –10% in the USA, 7% in Canada, 10% in the UK, 10% in \nHungary, and 3.7% in Australia [14, 22 -24]. The age group with the highest \nprevalence is women aged 40 –44 years in Italy (18.6%), as reported by Morassutto et \nal. [14, 25-27]. \n \nApproximately 176 million women worldwide have endometriosis [28]. The disease is \nalso discovered in asymptomatic women undergoing tubal ligation, and figures range \nfrom 3% to 43% [29, 30]. \n \nEndometriosis is principally a disease of reproductive -aged women; it is also found in \npost-menopausal women receiving hormone replacement therapy and in adolescents \n[31-33]. Endometriosis has no ethnic, racial, cultural, social class, or geographical \npredilection as it is present in every environment. Studies have shown that a high \nprevalence of endometriosis was observed in women with infertility and chronic \npelvic pain (20–90%) [34-36]. \n \n\n4 \n1.1. Theories on the pathogenesis of endometriosis \nEndometriosis is among the most common diseases with no unifying theory regarding \nits etiology.  Endometriosis has remained mystifyingly elusive, with multiple \nhypotheses each contributing to characterize the disease as multifactorial in etiology \nand pathogenetically complex. The number of theories proposed to explain the \npathogenesis of endometriosis has increased over the decades. \n \n1.1.1. Retrograde menstruation (transplantation) \nThe retrograde menstruation theory is widely accepted; it is the oldest theory regarding \nthe formation of ectopic endometrium in endometriosis. The theory was first proposed \nby Sampson in the mid-1920s (1927) [37]. \nThe retrograde menstruation theory explains that, during menstruation, some \nendometrial tissue flows backward through the Fallopian tubes into the peritoneal \ncavity, implanting on the peritoneal surface (lining of the abdominal cavity). This \ntissue later invades the surrounding tissues, causing inflammatory reactions and \nleading to painful symptoms and deformity [38]. \nAlthough retrograde menstruation is presumed to occur in 70 –90% of women [39], \nKoninckx reported that the larger volume of retrograde menstrual fluid in the pelvises \nof patients with endometriosis as compared with healthy women could increase their \nrisk of endometriotic lesion implantation [40]. \nOther studies have reported the presence of peritoneal endometrial cells in women \nduring the early follicular phase and menstruation [41, 42]. Although this has been the \nleading theory for many decades, it is evident that the incidence and prevalence of \nendometriosis is lower than the frequency of retrograde menstruation, which suggests \netiological multiplicity of the disease, with not only one factor being involved but a \nseries of disorders in other systems (e.g., immunological, molecular, or genetic \ndefects) [43]. Sampson’s theory was further reinforced by the observation that many \nconditions could result in obstruction of menstrual flow. Such obstructing genital \nanomalies include imperforate hymen, non -communicating rudimentary uterine horns, \nvaginal agenesis, and iatrogenic cervical stenosis —all of which increase retrograde \nmenstruation and the risk of endometriosis [44]. A higher incidence of endometriosis \nis observed in women with more frequent and longer menstrual periods than in those \nwith a normal cy cle and duration [45]. In retrograde menstruation, the survival of \nendometrial cells in a hypoxic microenvironment may require involvement of pro -\nangiogenic factors. Hypoxia promotes the expression of downstream genes involved in \n\n5 \nimplantation and the persistence of ectopic endometrium; the failure of the immune \nsystem to clear implants from the peritoneal surface also plays a role in disease \nprogression (Giudice & Kao, 2004) [4]. \n \n1.1.2. Altered cellular immunity. \nSeveral theories have been postulated over the decades to verify the role of \nimplantation and defective clearance of endometrial cells from the pelvic floor in \nfacilitating the development of endometriosis. It is an acknowledged occurrence that \nretrograde menstruation is relatively common, with most women (75 –90%) \nexperiencing some degree of retrograde menstruation [46]; however, not every woman \nwith retrograde menstruation develops endometriosis. It has been suggested that \nendometriosis is the consequence of an inappropriate immune defense response, \nreduced immunologic clearance of viable endometrial cells (reduced natural killer cell \n[NK] and macrophage activity [47]), or that the pelvic and peritoneal inflammation is \na consequence of the disease [48, 49]. The immunological pathogenesis of \nendometriosis has two dimensions: (i) reduced NK and macrophage activity; and (ii) \nimmune tolerance of ectopic endometrial and stromal cells, leading to complete \nsystem failure essential in the development of endometriosis. \n \nThere is significant evidence to suggest that endometriosis is associated with a state of \nlatent or subclinical inflammation, characterized by increased peritoneal fluid volume, \nwhite blood cell concentration, and levels of inflammatory cytokine, growth factors, \nand angiogenesis-promoting substances [50, 51]. However, in cell-mediated immunity, \nthe core function of the NKs is to eliminate cells of an origin other than the \nintraperitoneal cells (e.g., infected cells, ectopic endometrial cells, tumor cells). Local \nand systemic variations in NK function and decreased NK -mediated cytotoxicity have \nbeen reported in women with endometriosis [52]. All these factors contribute to the \nelimination of endometrial cells in the pelvis. However, some studies have reported \nthat NKs have an altered phenotype in women with endometriosis, with increased \nexpression of the cytotoxic cell surface receptor CD16 and NK receptor NKp46, a \nphenomenon that might play a role in endometriosis-associated infertility [53]. \n \nEisenberg et al. [54] reported an increase in the numbers and activation of peritoneal \nmacrophages, pro -inflammatory chemoattractant cytokines for monocytes, \nmacrophages, and granulocytes in women with endometriosis [55]. Moreover, \n\n6 \ninterleukin 1 (IL -1) was reported by Taylor [56] as having angiogenetic potential \nthrough vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) activation. \nSeveral processes and factors are involved in enhancing the establishment of \nendometriotic lesions that can escape immune surveillance, such as intercellular \nadhesion molecule 1 (ICAM -1), which conciliates immune cell -to-cell synergy, and \nthe Fas–Fas ligand system, which mediates the cell death of activated immune cells in \na pro -inflammatory environment, such as the peritoneal fluid of women with \nendometriosis [56]. \n \n1.1.3. Coelomic metaplasia (transformation theory) \nThe transformation of coelomic epithelium to endometrial tissue has been proposed as \nthe mechanism for the genesis of endometriosis, i.e., endometriosis originates from \nabnormally differentiated extrauterine cells. This theory, heralded by Gruenwald et al. \n[57], postulates that endometriosis is derived from metaplasia of specialized cells \npresent in the mesothelial lining of the visceral and abdominal peritoneum. In support \nof this theory, Dinulescu et al. [58] conducted a study involving genetic induction of \novarian endometriosis in mice and reported that ovarian endometriotic lesions may \narise directly from the ovarian surface epithelium through a metaplastic differentiation \nprocess induced by activation of an oncogenic K -Ras allele. Vercellini et al. [59] \nsuggested that the theory of coelomic metaplasia could be supported for ovarian \nendometriosis development, as the coelomic epithelium lining the peritoneum and \novary undergoes metaplastic transformation. Regarding endometriosis on the surface, \nthe survival of the endometrial implants could be explained by altered endometrial \ngene transcription and increased endometrial invasion induced by the early \nendometriotic lesion (Nair et al.), and by the failure of the immune system to clear \nimplants from the peritoneal surface [4, 60]. Scholars believe that, for this \ntransformation to be successful, some hormonal or immunological factors could be \nresponsible for the stimulation of a normal peritoneal cell to form endometrium -like \ntissues [46, 61]. Furthermore, the coelomic metaplasia theory could explain the \nincidence of endometriosis in prepubertal girls; in this age group, endometrial growth -\nstimulating estrogen is absent, and this condition could be differentiated from the \ndisease found in women of reproductive age [62]. \n \nRecent molecular genetic findings on endometriosis and the normal endometrium have \nsuggested a modified model in which circulating epithelial progenitor or stem cells \n\n7 \nintended to regenerate uterine endometrium after menstruation may become overactive \nand trapped outside the uterus [63]. These trapped epithelium -committed progenitor \ncells form nascent glands through clonal expansion and recruit polyclonal stromal \ncells, leading to the establishment of deep infiltrating endometriosis [46, 63]. Once \ndeveloped, the ectopic tissue is subject to immune surveillance, resulting in chronic \ninflammation. However, the inflammatory response orchestrated by nuclear factor -κB \n(NF-κB) signaling is exacerbated by aberrations in the estrogen receptor β and \nprogesterone receptor pathways, which are also affected by local inflammation, \nresulting in a dysregulated inflammatory –hormonal loop [64]. Glandular epithelium \nwithin endometriotic tissue harbors cancer-associated mutations that are often detected \nin endometriosis-related ovarian cancers. Recent advances have illuminated the origin \nand pathogenesis of endometriosis and have provided new avenues for research that \npromise to improve the early diagnosis and management of endometriosis [62]. \n \n1.1.4. Steroid metabolism dysfunction and progesterone regulation \nHistorically, endometriosis was considered to be regulated or modulated by estrogen. \nStudies have shown that progesterone dysfunction or incompetence is also involved in \nthe pathogenesis of endometriosis [65]. Steroid hormones play a significant role in the \nmanifestation of endometriosis, as the disease is commonly present during the \nreproductive age; however, there are some exceptions, and younger and even older \nwomen are affected [60, 65]. A study conducted by Kao et al. in 2003 reported the \nderegulation of many target genes vital to implantation in women with endometriosis, \nand many of the genes correlated with progesterone receptors and metabolism [63]. \nFurthermore, both eutopic endometrium and ectopic lesions are regulated by ovarian \nhormones. The ectopic lesions also exhibit increased responsiveness to estrogen, \nwhich may enhance the development of endometriosis [66]. \n \nThe activated progesterone receptor plays a vital role in regulating tissue remodeling \nin the uterus that is necessary for menstruation or pregnancy. However, dysfunction of \nthese progesterone regulatory processes —aggravated by the chronic inflammatory \nstate caused by endometriosis —results in a condition known as “progesterone \nresistance” [20, 60]. Progesterone resistance could involve the progesterone receptor \n(PR) isoforms PR -A and PR -B, in addition to downstream molecules, such as \ntransforming growth fac tor (TGF), retinoic acid, c -myc, or the co -activators of the \n\n8 \nreceptor itself [20]. Remarkable reduction in PR -A and PR -B levels have been \nobserved in endometriotic tissue [5]. \n \n1.1.5 Genetic background \nStudies have shown that some factors responsible for the onset of endometriosis are \nheritable [5, 67]. A sevenfold risk of developing the disease has been reported in \nwomen with an affected mother or sister [68]. Reports have shown an increased \nincidence of endometriosis among monozygotic twins, and correlation has also been \nobserved in the stage of the disease [69, 70]. \n \nMany studies have suggested that genetic polymorphisms are among the factors \ninvolved in the development of endometriosis. Endometriosis is inherited by a \npolygenic model, as evidenced by the identification of a Mendelian inheritance \npattern, which indicates a form of multifactorial inheritance. Inheritance is likely to \ninvolve multiple specific loci and chromosomal regions, which some studies have \nreported to be associated with the corresponding endometriosis phenotype [70, 71]. \n \nInherited and acquired factors could facilitate the attachment of ectopic endometrial \ncells to the peritoneal epithelium and the evasion of these lesions from immune \nclearance [46]. Burney et al. reported in 2013 that genes assumed to be involved in \ncytokine-related inflammation, steroid and hormone receptors, and matrix degradation \nmay be differentially expressed in women with endometriosis [72]. Recently, genome -\nwide association studies (GWAS) have revealed several genes that are possibly \ninvolved in the pathogenesis of endometriosis. European and Japanese GWAS have \nshown a significant association between the LD block on chromosome 1 near the \ncyclin-dependent kinase inhibitor 2B antisense RNA (CDKN2BAS) and the wingless -\ntype MMTV integration site family 4 (WNT4) gene [73]. \n \nThe epigenetic research model has recently gained wide acceptance. It is characterized \nby a reversible condition, influenced by age and lifestyle factors, which underlies a \nwide range of pathologies. The most frequent and well -documented epigenetic \nmechanism is DNA methylation, followed by histone modification and regulation of \nchromatin modification. This research model demonstrates that a single endometriotic \nlesion is monoclonal and —based on gene expression profiling studies —a large \nnumber of genes are dysregulated in endometriosis [74, 75]. \n\n9 \nThe first documentation of epigenetic alterations in endometriosis was the HOXA10 \ngene, which showed hypermethylation in the endometria of women with \nendometriosis (Wu et al., 2005) [76]. However, evidence supports the estimate that \nendometriosis is approximately 51% heritable; the identification of a specific gene \nconsistently associated with endometriosis is complex, with predictive potential in \nidentifying high-risk women [77, 78]. \n \n1.1.6. Oxidative stress \nThe oxidative stress theory describes excessive presence or overload of iron released \nfrom the pathway that is caused by the destruction of erythrocytes that contain the \niron-binding protein hemoglobin, or a deficiency in peritoneal iron metabolism. This \niron is associated with the local destruction of the peritoneal mesothelium, leading to \nthe adhesion of ectopic endometrial cells [79]. Furthermore, an association with \nincreased oxidation of lipoproteins is observed, where reactive oxygen species (ROS) \ncause lipid peroxidation that leads to DNA damage in endometrial cells [80]. A study \nshowed that oxidative activity and ROS were higher than average in patients with \nendometriosis. The excess chemical changes observed in oxidative stress and in the \npresence of ROS could cause tissue damage and induce rapid cellular division [79], \nthereby recruiting lymphocytes and activated macrophages that produce cytokines that \ninduce the oxidation of enzymes and promote endothelial growth [81]. Accumulation \nof ROS may contribute to the propagation and maintenance of endometriosis and its \nassociated symptoms [80]. Finally, several cellular pathways have been identified by \nwhich oxidative stress and ROS can induce endometriotic lesion proliferation, such as \nthe mitogen -activated protein kinase (MAPK) and the extracellular signal -related \nkinase (ERK) pathways. The activation of these pathways leads to increased levels of \nc-Fos and c -Jun, which are proto -oncogenes that are associated with high -grade \nlesions [79]. \n \n1.1.7. Environmental factors \nStudies have shown that some environmental toxins, such as dioxin, behave similarly \nto estrogen by interacting with the estrogen receptor and are involved in the etiology \nof endometriosis [82]. However, the mechanism by which dioxin and similar \nsubstances 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls \n(PCBs) affect endometrial physiology remains unclear as it is difficult to assess \nexposure to these chemicals in the intrauterine period, in childhood, and in adulthood. \n\n10 \nThe limitations for reproducing their effect and the possible consequences remain \nunclear [66]. In support of this theory, a study published in 2013 reported a high \nconcentration of organochlorine pesticides (OCPs) in the blood of 248 women with \nendometriosis [82]. The study revealed a possible link between high concentrations of \ntwo OCPs —β-hexachlorocyclohexane (β -HCH) and dechlorane (Mirex) —and an \nincreased risk of endometriosis; ovarian endometriosis was found to have a stronger \nassociation with the β-HCH [83-85]. \n \n2. SYMPTOMATOLOGY OF ENDOMETRIOSIS \nThe symptomatology of endometriosis is unclear and complex. There is no single \nsymptom or complaint with a sensitivity and specificity close to 100%. Several studies \nhave reported diverse symptoms [7, 126 -128]. Pelvic pain is a common complaint \namong women with endometriosis. Singularly, it is proven insufficient as an indicator \nof endometriosis by many authors as it can be associated with other gynecological \n(and non -gynecological) conditions [129 -132]. Other medical conditions, such as \npelvic inflammatory disease (PID), ovarian cysts, and irritable bowel syndrome (IBS), \ncan mimic the symptoms of endometriosis [133 -135]. When these pain -related \nsymptoms persist, are progressive (i.e., worsen over time), or coexist with other \nrelated symptoms, the likelihood of association with endometriosis increases [7, 135 -\n137]. \nThe development of painful symptoms varies with time; typically, initial menstrual \npain (dysmenorrhea) may progress to non -menstrual pelvic pain, which is dominant \namong women diagnosed with endometriosis. Symptoms associated with \nendometriosis are usually intertwined, as they are mostly uncommon. The other, less \ncommon symptoms of endometriosis include severe menstrual cramps unresponsive to \nNSAIDs, long -term lower back and pelvic pain, periods lasting longer than 7 days, \nheavy menstrual bleeding, intermenstrual bleeding, bowel, and urinary problems \nincluding pain, diarrhea, constipation and bloating, bloody stools or urine, nausea, \nvomiting, and fatigue [19]. A possible implication and complication of endometriosis \nis infertility, affecting 30–50% of those with the condition [19, 138]. \n\n11 \n \nFigure 2. Non -specific and specific symptoms associated with endometriosis (Agarwal. Clinical \ndiagnosis of endometriosis. Am J Obstet Gynecol (2019) [7]). \n \nThe evaluation of symptoms, complaints, and their severity indicates the likelihood of \nendometriosis in a patient. However, caution is required before dismissing NSAID -\nresponsive pain as simple dysmenorrhea; early symptoms of endometriosis may be \nresponsive to these agents. \n \n3. GENERAL IMPACT OF ENDOMETRIOSIS \nEndometriosis affects a substantial percentage of the female population, mainly in \ntheir prime, and its impact is considered to be high. Some of the pitfalls of the \nmanagement of this disease are a lack of proper understanding, lack of awareness, and \nthe multifaceted presentation to health professionals [86, 87]. Among other pitfalls are \nthe general inadequate social health education policies put in place by health personnel \nand authorities that lead to delayed diagnosis. Significant strides have been made, but \nthey are still taking too long [86, 88]; however, there is increasing knowledge and \nunderstanding of the disease [86, 87]. The main challenges of the disease include \nsubfertility, infertility, and its debilitating symptoms, which include persistent chronic \nlower pelvic pain and other forms of pain —dependent or independent on \nmenstruation—with adverse psychological outcomes that affect work productivity and \nlearning. Sexuality and sexual life are seriously affected in most patients. Overall, \npatients experience a significantly reduced QoL [89]. \n \n\n12 \nThe impact of endometriosis involves three intertwined aspects that negatively \ninfluence the QoL of women with endometriosis: infertility (reduced reproductive \ncapacity), socio-economic impact, and QoL. \n \n3.1. Impact on fertility \nAlthough there has not been any absolute proven mechanism on how exactly it occurs, \nan association between endometriosis and subfertility is widely acknowledged based \non epidemiological, retrospective, and cross -sectional studies on women and non -\nhuman primate research [86, 89]. According to studies conducted by Giudice [90], \nendometriosis negatively affects fertility. The average monthly fecundity rate (MFR) \nin women is 15–20% (MFR 0.150.2), while women with untreated endometriosis have \nan estimated MFR of <0.05 (2–10%) [91]. Other authors have an estimated prevalence \nof between 2% and 10% in women in the general population and a staggering 20 –50% \nin the female population with fertility issues [92, 93]. \n \n3.1.1. Chronic inflammation \nEndometrial tissue localization outside the uterine cavity might cause a chronic \ninflammatory state that generates a favorable environment for adhesion development, \nas reported by Seli et al. and Moradi et al. [94-97]. \n \n3.1.2. Tuboperitoneal distortion \nPeritubal adhesions are common in patients with endometriosis, mainly when the \novaries are involved. These adhesions can affect the tubo -ovarian, tuboperitoneal, or \nDouglas pouch peritoneal walls, adhering the tubes to neighboring organs or pelvic \nsidewall, and may appear slight, moderate, or dense when visualized intraoperatively. \nDamaged tubal function caused by adhesions not only inhibits sperm mobility toward \nthe ampullary region, but also impairs oocyte collection by the fimbriae. Moreover, \nseverely damaged tubes can increase the incidence of ectopic pregnancy. Studies have \nshown a detrimental effect of tubal adhesions on fertility [96, 98]. \n \n3.1.3. Hormonal changes on implantation \nStudies have shown that there is a higher concentration of steroid hormones in the \nperitoneal fluid after ovulation in normal women than in women with luteinized \nunruptured follicle (LUF) syndrome. LUF syndrome is most frequently observed in \nwomen with endometriosis. Furthermore, studies have shown an association between \nendometriosis and LUF syndrome, accompanied by a low-grade inflammatory reaction \n\n13 \nwithin the peritoneal space, as indicated by a relatively large number of macrophages \nand their by-products [96, 99, 100]. \nThere is a suboptimal luteinizing hormone (LH) level surge with concomitant \nimpaired ovulation in patients with endometriosis that is triggered by gonadotropin -\nsurge attenuating factor (GnSAF) [101]. \nAnother observation is the presence of progesterone resistance, causing decreased \nfertilizing capacity [100, 101]. \n \n3.1.4. Decrease in ovarian reserve. \nOvarian reserve depletion remains the main problem in endometriosis. Ovarian reserve \nis determined either by measuring anti -Mullerian hormone (AMH) pre - and post -\nsurgery or by measuring the number of follicles or ovary size via ultrasound. Ovarian \nreserve depletion might originate primarily from ovarian endometriosis itself or from \nsubsequent ovarian surgery. \nEndometriomas can affect ovarian reserve by impairing circulation in the ovarian \ncortex due to compression, leading to follicle loss; the inflammatory environment \nwithin the cyst walls may also leading to follicular damage [102]. The destruction of \novarian tissue could be partial or complete, with or without a viable oocyte on the \naffected ovary. The left ovary is reported to be more frequently involved. \nEndometriosis can also affect the ovarian capsule, enhancing the formation of \nadhesions with the surrounding tissue. Furthermore, the chronic inflammatory process \nmay induce the development of LUF syndrome, which could reduce ovulation. In \naddition to the decrease in reserve oocytes, embryo quality can also be affected, which \ncan lead to decreased pregnancy rates in spontaneous gestation and IVF or \nintracytoplasmic sperm injection (ICSI) cycles. Some studies have also shown that \npatients with endometriosis have a reduced number of preovulatory follicles, follicular \ngrowth, dominant follicle size, and follicular estradiol concentration in their ovaries \n[103-105]. \n \nThe other cause of ovarian reserve depletion is a direct result of the surgical \ndestruction of ovarian tissue [104]. Endometriomas can be removed by stripping, \nablation, combined techniques, or complete removal of the affected ovary [105, 106]. \nEach of the surgical procedures may invariably cause loss of ovarian tissues, including \nviable follicles. Studies reported that baseline anti -Mullerian hormone (AMH) values \nwere significantly lower in individuals with endometrioma than in a control group \n\n14 \n[107, 108]. Furthermore, bilateral endometriomas had a significantly greater rate of \ndecline, and the rate of AMH  decline was positively correlated with baseline \npreoperative AMH values and the size of the removed endometrioma [107, 108]. \nMoreover, Urman et al. stated that AMH was a better indicator for postoperative \nassessment of ovarian reserve, while Esinler et al. believed that endometriomas ≤3 cm \nin diameter did not have a deleterious effect on ovarian reserve in ICSI cycles [109, \n110]. \n \n3.2. Pain-related symptoms (reduced or absent sexual activity) \nInfertility creates complex psychological dysfunction in women’s lives. In many \ncultures, infertile women are forced out of their marriages, resulting broken homes; it \ninstigates antisocial behaviors and depression. Adequate and harmonic sexual activity \nis among the prerequisites for good fertility outcomes. With the advent of artificial \nreproductive techniques (ART), some of these obstacles have been alleviated [111]. \nSexual function is a vital aspect of health, general well -being, and QoL. Sexual \nactivities are influenced by both medical conditions and healthcare interventions, \nespecially when gynecological disorders—such as endometriosis—are involved [112]. \nDyspareunia is among the main factors that affect sexual functioning, and the \nprevalence of this symptom is reported to be between 50% and 75% in women who \nsuffer from endometriosis. Sexual functioning is a central and complex phenomenon, \ndriven by social, psychological, and biochemical factors. Consequently, the pain \nassociated with endometriosis might further affect sexual function and the quality of a \nsexual relationship [113]. \n \nDyspareunia can alter a woman’s perspective on life enough to avoid engaging in \nsexual intercourse; in severe situations, a loss of self -esteem or destruction of \nrelationships with partners can lead to a complete cessation of sexual activities, which \ncould hamper fertility [113]. Endometriosis negatively affects different domains of \nsexual function and health. It is among the most highlighted impacts on well-being and \nQoL in a marital setup. Studies have shown that women with deep infiltrating \nendometriosis of the uterosacral ligament and vagina complain of a higher incidence \nof dyspareunia [114, 115]. The impact of deep dyspareunia on sexual dysfunction is \nsignificant [115, 116]. \n \n \n\n15 \n3.3. Impact on socioeconomic life \nEndometriosis is a complex medical condition with a multifaceted presentation. The \npain-associated symptoms of endometriosis can be so frustrating and exhausting that \nthey can compel sufferers to self -isolate; it limits involvement in certain physical and \nsocial activities. Weekends and work -free days are about indulging in a person’s \nfavorite activities, such as visiting restaurants, bowling, parties, beach barbecues, and \noutings with friends and family members. Social life can be impaired significantly due \nto the exhaustion from inadequate rest due to pain, and a flare-up can force the sufferer \nto remain in bed at home; therefore, relationships are affected, resulting in social \ndecline over time [117]. The cost of medications and hospital treatment results in \nfinancial constraints, limiting spending for other social activities [118]. The cost of the \nburden of illness is enormous, with most costs generated by reductions in productivity, \nloss of working hours, and medical expenses. Although it is difficult to ascertain the \nexact financial implications for individuals and society, a study conducted by Simoens \net al. in 2012 estimated the average cost of endometriosis of about €9,579 per \nwoman/year; in the breakdown, an average of €6,298 was a loss in productivity, and \nan average €3,113 was spent directly on healthcare [117]. In another study conducted \nby Armour et al. in 2019, they estimated an economic burden to the system in \nAustralia of $6.50 billion annually [119]. These financial burdens are due to loss of \nproductivity, absenteeism, and health costs, and affect spending in other areas of life, \nsuch as entertainment, sports, and social activities.  \n \n3.4. Impact on quality of life and well-being \nThe psychological, social, and clinical impacts of endometriosis are significant, and \nthe effect of pain on the general well -being and QoL of patients is multidimensional \n[97, 120]. Painful symptoms of endometriosis have a direct impact on sufferers’ \nphysical activity, their ability to play roles and work, social activities, sexual \nrelationships, mental and psychological health, and energy [121]. In addition to the \npain associated with direct impacts, other factors, such as infertility, affect mental \nhealth and personalities [88, 122-126]. The strong psychological and emotional impact \nof endometriosis also has adverse effects on an individual’s self -image and can lead to \na loss of feeling physically strong, impaired fertility, and can even lead to broken \nhomes. Moreover, the depressive mental state encountered in people with \nendometriosis aggravates a feeling of guilt and distress in the workplace caused by the \npain and infertility. Studies on the QoL of women affected by endometriosis have \n\n16 \nsuggested that QoL and General WB are significantly altered in many aspects —such \nas infertility, severe dysmenorrhea, and dyspareunia —which not only influences \nfertility performance but also compromises work capacity, with lost days at work and \npossible surgery-related complications and costs [88, 124, 125]. \nCurrently, the exact quantifiable financial burden of endometriosis cannot be \naccurately noted due to many independent factors influencing healthcare globally: \ncultural, educational, and developmental differences, the priority of health -sector \nfinancing, and attitude towards healthcare. A study conducted by Simeons et al. in \n2012 estimated the overall annual cost of endometriosis in several European countries: \n€14.2 billion in the UK, €17.8 billion in Germany, and €2.3 billion in Hungary [86]. \nOverall, the cost burden for the United States of America is estimated to be €70.9 \nbillion annually. A study conducted by Armours et al. in 2019 reported an estimated \ncost of about $6.50 billion in Australia, of which the majority (75 –84%) of costs were \ndue solely to lost days at work [119, 122, 126]. \nThe health and socioeconomic challenges affecting women with endometriosis are \npartly due to diagnostic delay, which ranges between 5 and 10 years in symptomatic \nwomen [88, 115]. Reasons for delaying diagnosis include cultural habits regarding \nhealthcare-seeking behaviors, normalization or trivialization of painful symptoms, \nintermittent suppression of symptoms by contraceptives, or misdiagnosis due to lack \nof knowledge from healthcare providers [126]. Recent studies have shown that \nendometriosis affected work in 51% of the investigated women, and 50% of the \nwomen reported that it had a profound impact on their relationships [127]. \nNumerous studies estimate that most of the sufferers encounter symptoms associated \nwith endometriosis either in combination or as a single symptom, such as \ndysmenorrhea (65 –75%), dyspareunia (50 –70%), lower abdominal pain (60 –85%), \nand infertility (50–65%) [88, 90, 115, 121]. \nTo strengthen some of the facts attributed to endometriosis, Simoens et al. conducted a \nprospective multicenter study in 10 countries in 2012 that assessed the costs and QoL \nfactors related to endometriosis. Pain and discomfort were reported by 56% of the \nstudy participants, anxiety, or depression by 36%, and 29% of the participants reported \ndifficulty with usual activities [121]. \nWorldwide, an estimated 176 million women at aged 15 to 49 years suffer persistently \nfrom endometriosis [128]. Therefore, endometriosis carries a reasonable \nsocioeconomic burden [129]. \n\n17 \n4. DIAGNOSIS \nThe currently available diagnostic procedures are limited to those that have been used \nfor decades, such as patient medical history, clinical physical examination, \nradiological examinations (e.g., vaginal, rectal, and abdominal ultrasound, magnetic \nresonance imaging [MRI]). A definite diagnosis is currently made only by laparoscopy \nand appropriate biopsy followed by histopathology examination. \n \n4.1. Endoscopy findings \nExtrapelvic manifestations of endometriosis are infrequent (0.7 –2.5%). Some of these \nextrapelvic implants are detectable with the naked eye on the skin, urinary tract, \ngastrointestinal tract, or vulva; some are discovered during other medical \ninvestigations [139, 140-142]. \nPelvic and intra -abdominal endometriosis is usually revealed during laparoscopy by \ndirect imagining of suspicious lesions. This method is accepted as the gold standard \nfor diagnosis. A few cases are diagnosed through laparotomy or hysteroscopy; the \nlatter procedure is used to investigate for intrauterine endometriosis [143-145]. \nDuring hysteroscopy in young women, meticulous attention is needed to rule out \nendometriosis implants (black -blue-dark brown spots in the cavity [Figure 3]). More \nimportantly, during laparoscopy or laparotomy, pelvic and abdominal areas are \ninvestigated for the presence of endometriosis [42, 146-148]. \n \n \nFigure 3. A hysteroscopic picture of endometriosis, as seen in the cavity.  \n \nEndoscopic surgery provides an opportunity to document the disease by type, location, \nand extent of all lesions and adhesions [149, 150]. Pelvic and intra -abdominal \nendometriotic lesions differ from stage to stage and by their presenting sites. \n\n18 \nSuperficial ovarian endometriosis and ovarian endometriotic cysts are frequently \nlocated on the lateral aspect of the ovary and are associated with retraction, \npigmentation, and adhesion to the pelvic sidewall. Ovarian endometriotic cysts \n(endometriomas) usually contain a thick and viscous, dark brown fluid (chocolate -\nlike). Endometrioma fluid contains hemosiderin derived from previous intra -ovarian \nhemorrhage; such fluid can also be present in other conditions, such as hemorrhagic \ncorpus luteum cysts or neoplastic cysts. Other presentations, as seen in Figure 4, \ninclude involvement of the superficial peritoneum. The lesions appear in several forms \nand coloration, with features such as the typical “powder -burn” or “gunshot” lesions \non the serosa surfaces of the peritoneum, or black, dark brown, or bluish nodules or \nsmall cysts containing old hemorrhage surrounded by a variable degree of fibrosis [26, \n151]. Other uncharacteristic features can be observed, including red implants \n(petechial, vesicular, polypoid, hemorrhagic, red flame -like), serous or clear vesicles, \nand sometimes white plaques or scarring, yellow -brown discoloration of the \nperitoneum, and tubo-ovarian adhesion. \n \n \nFigure 4. Common presentations of endometriosis, with subtle lesions, serous and clear vesicles, and \ndeep infiltrating endometriosis of the recto-vaginal septum and rectum. (By Ekine A.A., 2020, Róbert \nPrivate Hospital) \n \n4.2. Histological confirmation \nThe diagnosis of endometriosis is based upon surgical findings and imagining \nfollowed by histological confirmation of the extracted tissues. Studies have shown that \nhistological findings do not always correlate with surgical findings; however, Moen et \n\n19 \nal. reported that approximately 51% of patients who underwent surgery received \nhistological confirmation [155]. In another study by Mettler et al., biopsies confirmed \nthe presence of endometriosis in 84.1% of patients [156]; 100% of “red” lesions, 92% \nof “black” lesions, and 31% of “white” lesions were confirmed as endometriosis. The \nmost accurate diagnosis was made in lesions on the parietal peritoneum of the pelvis \n(100%); however, only 66.7% of cases were confirmed in the ovarian fossa and 60.1% \nof cases at the uterosacral ligaments and posterior surface of the broad ligament. \nConfirmation rates from lesions on the ovarian surface, bowel serosa, and \nvesicouterine fold were 48%, 40%, and 13%, respectively [20]. Confirmation rates in \nadditional studies varied from 42% to 99%. A possible reason for discrepancies \nbetween surgical and histological findings might be the presence of fibrosis, as shown \nin Figure 5 [157, 158]. \n \n \nFigure 5. Histological findings of normal endometrial tissue and endometriosis. Source: Francisco J. \nValdez-Morales (2014).[Glandular epithelium (GE), normal stroma (S) (A and C). Eutopic \nendometrium with endometriosis (B and D). Arrows show typical GE proliferative (A and B) and \nsecretory (C and D) phases in the control and endometriotic endometrium, respectively. Scale bar 1⁄4 \n100 mm. Biopsy samples were stained with hematoxylin-eosin] \n \n5. CONSERVATIVE MANAGEMENT \nManagement options in endometriosis must be tailored according to the multifaceted \nclinical presentations and their effect on QoL. The condition might persist despite \nsufficient surgical or medical treatment. The complexity of symptoms requires proper \ncounseling and, in some cases, multidisciplinary management [62]. \n \nThe objective purpose of endometriosis treatment is to alleviate symptoms, restore, \npreserve, or improve fertility, and to ensure normal organ function. Endometriosis is a \n\n20 \ndisease with a high recurrence rate, and the recurrence of endometriosis depends on \ntreatment modules and expertise. Studies have reported recurrence rates ranging from \n4.5% to 50% within 2 years of surgery [19, 78, 159-164]. \n \n5.1. Medical therapy \n5.1.1. Hormones \nPathophysiological evidence shows that endometriosis is stimulated by hormones \nproduced in the ovaries, and hormonal suppression of ovarian function is an effective \ntreatment. Hormonal management is not suitable for women who wish to become \npregnant. Hormonal treatments in endometriosis are oral progestins, combined \ncontraceptive pills or patches, progestin containing intrauterine devices, GnRH \nanalogues, androgenic substances, and aromatase inhibitors that prevent ovulation \n[165]. GnRH analogues are potent inhibitors of the hypothalamus -hypophyseal-\ngonadal axis and can markedly influence endometriosis symptoms; however, their side \neffects can be severe [166]. Side effects of progestins include spotting, weight gain, \nreduced sexual desire, breast tenderness, and headaches [167 -170]. Effective \nandrogenic compounds, like Danazol, are capable of decreasing pain; however, they \nhave many severe side effects [170]. The use of an oral contraceptive regimen is \nuseful in reducing symptoms and may delay progression of endometriosis [166]. \n \n5.1.2. Other drugs (NSAIDs) \nThe pain -related symptoms associated with endometriosis demand frequent use of \npainkillers; the most common drugs are NSAIDs. These drugs account for \napproximately 10% of the total financial burden of endometriosis [171-174]. However, \nthe constant use of these drugs is not without potential complications; long -standing \nuse can adversely affect the gastrointestinal tract, renal function, and other systems \n[175]. \n \n5.2. Physiotherapy \nThe role of physiotherapy in the treatment of endometriosis focuses on the following \nmodalities: pelvic floor strengthening; internal and external trigger point management, \nmanual myofascial therapy, stretching and flexibility exercises, spinal mobilization, \nand nerve glides [165, 201, 202]. \nOther studies have established regular physical activities and physiotherapy as having \na favorable impact on women’s QoL [128, 165, 203, 204]. The decision to treat \npatients diagnosed with endometriosis is based on the presentation of musculoskeletal \n\n21 \nand non-musculoskeletal symptoms [4, 5, 58, 205]. Regular physical exercise appears \nto have a protective effect against diseases that involve inflammatory processes as it \ninduces an increase in the systemic levels of cytokines with anti -inflammatory and \nantioxidant properties and reduces estrogen levels [165, 204, 206]. \n \n5.3. Acupuncture Therapy \nA study conducted by Yang Xu et al. reported that acupuncture reduced pain and \nserum CA -125 levels, regardless of the control intervention used [165, 207]. Other \nstudies also reported positive effects of acupuncture use in endometriosis [128, 165, \n208, 209]. Acupuncture is primarily an adjuvant therapy because it focuses on \nsymptom management rather than a permanent treatment for the disease. \n \n5.4. Psychotherapy \nEndometriosis is associated with debilitating symptoms, such as dyspareunia, \ndysmenorrhea, dysuria, and infertility. These symptoms reduce a woman’s self -esteem \nand general well -being. Many women require psychotherapy due to the physical, \npsychological, and economic burden of the disease. Studies have reported the positive \nimpact of psychotherapy in the management of endometriosis [165, 210-212]. \n \n5.5. Prevention \nThe complexity of the pathogenesis and multifaceted presentation of the disease has \nmade it almost impossible to formulate an adequate preventive strategy. There is \ninsufficient evidence to support measures such as physical activity or exercise, diet, \nand the use of contraceptive pills at an early age as being preventive [4, 30, 204, 213]; \nhowever, more investigations are needed to validate the effectiveness of these \npreventive measures. \n \n6. SURGICAL PROCEDURES \nMany studies have shown that surgical removal of endometrial implants and \nendometriomas of the ovaries appears to relieve pain in mild or severe endometriosis \n[176, 177]. Other research suggested that removing endometrial implants during \nlaparoscopy can improve fertility outcomes [178, 179]. Little research has been \nconducted to confirm which of the surgical approaches is most effective in treating \nendometriosis. Several studies have reported a possible impact on QoL after \nlaparoscopy [19, 180]. \n\n22 \nGenerally, surgical removal of endometriotic lesions relieves symptoms and restores a \nnormal anatomical state. Surgical treatment can involve laparotomy or laparoscopy as \nboth procedures are efficient. Laparoscopy is the superior treatment option and is \nassociated with shorter hospital stays, less post -surgical pain, and a shorter recovery \ntime [181, 182]. \nAll stages of endometriosis are usually effectively treated via excision and/or ablation. \nCystectomy for endometrioma is a preferred treatment option to reduce pain or restore \nfertility. Cystectomy also provides a sample for histological confirmation of the \ndisease [182, 183]. \n \n6.1. Treatment of ovarian endometriosis associated with pain and infertility. \nDifferent surgical techniques have been used in the management of ovarian \nendometrioma: fenestration, drainage, fenestration and ablation, and cystectomy. The \nhistorically preferred surgical procedure is cystectomy. This involves opening the \novarian cortex, ascertaining the cyst wall, and stripping it from the healthy ovarian \ntissue. Some patients exhibit no physical symptoms despite the presence of an \nendometrioma and may instead benefit from conservative therapy. Surgical treatment \nis usually encouraged as the treatment for pelvic pain, dyspareunia, and to improve \nsexual function and potentially improve the likelihood of spontaneous conception \n[184, 185]. \n \n \nFigure 6. Images of different laparoscopic surgical procedures performed at Róbert Private Hospital \n(Ekine A.A.). \n \nSome reviews report a clear improvement in spontaneous and assisted fertility after \ncystectomy as compared with fenestration or electrocautery; however, the benefits \nassociated with IVF outcomes are less evident. Other noticeable benefits are reduced \n\n23 \nrecurrence and increased ovarian response to gonadotropin use during ART [186]. \nStudies have also demonstrated a benefit for spontaneous conceptions [180, 187-189]. \n \n6.2. Other surgical options \nThe cardinal symptom of endometriosis is pain. Pain is the main indication for surgical \ntreatment after various primary conservative treatments. Surgical management of \nendometriosis comprises three essential techniques: removal or destruction (excision) \nof endometriotic lesions, interruption of nerve pathways, and lysis of adhesion. The \napplication of these techniques has evolved from open laparotomy to minimally \ninvasive laparoscopic or robotic surgery. The recovery time and morbidity are much \nlower following laparoscopy; however, other benefits and efficacy have not been \nestablished between the two surgical procedures [181, 200]. \n \nSevere, deep infiltrating endometriosis (DIE) is the presence of endometriosis at 5 mm \nor greater depth from the peritoneal surface and can involve the uterosacral ligaments, \nvagina, bowel, bladder, ureters, or other organs [190, 200]. Many studies have \nsuggested that an increase in the intensity of symptoms is correlated with the severity \nof the disease [191, 192, 200]. Several surgical techniques have been employed in the \nmanagement of DIE: shaving off the endometriotic nodule, disc excision, and \nsegmental bowel resection with end -to-end anastomosis. Every surgical treatment \nappears to significantly reduce pain, with higher complication rates associated with \nbowel resection [193, 194, 200]. However, fertility outcomes following surgery for \nDIE are less clear and there is no robust evidence to suggest a significant benefit [195, \n200]. Other surgical options are available when women have completed their family \nplanning or if other forms of conservative management fail, such as total or subtotal \nhysterectomy with bilateral salpingo -oophorectomy. [196 -198, 200]. Surgical \ntreatment of DIE reduces pain and improves QoL [196, 197, 200]. \n \n7. HYPOTHESES \n1. We suppose that there might be a possible link between patient history of cesarean \nsection and an increased likelihood of the development of endometriosis. \n2. We suppose that combined hysteroscopic and laparoscopic endometriosis surgery \nsignificantly improves fertility outcomes in patients with endometriosis. \n3. We suppose that combined hysterolaparoscopy may significantly improve the QoL \nof endometriosis patients. We believe that the validated EHP -36 instrument, along \n\n24 \nwith the VAS and the NRS -11, are useful tools in the evaluation of the QoL of \nendometriosis patients. \n \n8. RESEARCH STUDIES \n8.1. Study I: Isthmocele and its probable link with endometriosis. \n8.1.1. Background \nIsthmocele is an iatrogenic gynecological disorder characterized by thinning of the \nuterine wall and bulging at the site of uterotomy performed during prior cesarean \nsection. It is frequently associated with abnormal uterine bleeding, suprapubic pain, \nand chronic vaginal discharge. Isthmocele can cause secondary infertility, although the \nmechanism is still poorly understood. There is a paucity of literature regarding the \npossible link between isthmocele and the development of endometriosis or \nadenomyosis [214, 215]. \n \n8.1.2. Materials and methods \nThe study was conducted at the Endoscopic Surgical Unit, Department of Obstetrics \nand Gynecology, Róbert Private Hospital, Budapest, Hungary. The study protocol was \napproved by the ethical committee of Róbert Private Hospital (RRC -RMK) 001 -\n3/2017. Using the hospital database, we conducted a retrospective analysis of data \nfrom 34 patients with post -cesarean isthmocele. After initial screening, 28 patients \nagreed to surgical management, and all underwent combined hysteroscopic and \nlaparoscopic repair, except for one patient who opted for only hysteroscopy repair. \nPatients were followed up between 3 rd. January 2013 and 30 th. June 2016. Inclusion \ncriteria were: (a) a history of cesarean section, (b) the presence of a V - or U-shaped \narea of an echoic space (with or without fluid) of at least 2 mm at the site of the \ncesarean section scar, (c) thinning of the myometrial wall of the anterior portion of the \nuterus, (d) vascular hyperplasia and blood clots in the vicinity of the defect, (e) lack of \nrelated symptoms or definite diagnosis of endometriosis before the cesarean section in \nthe history, and (f) lack of previous diagnosis of any form of infertility. Exclusion \ncriteria were: (a) congenital abdominal wall dysplasia, (b) isthmocele resulting from \nother postoperative abdominal incisional hernia, (c) previous myomectomy, and (d) \nrefusal of consent. \n \nLaparoscopic and hysteroscopic surgical procedures were performed in the post -\nmenstrual cycle phase under general anesthesia. Patients were placed in the \nTrendelenburg (head down) position. Hysteroscopic evaluation of the endometrial \n\n25 \ncavity was performed to exclude or treat other pathologies in the uterine cavity, and to \nidentify the presence of isthmocele, which appeared partially white, thus allowing the \nconfirmation of the pathology in addition to its location, size, and relationship with the \nbladder (Figure 7). Hysteroscopy was followed by careful laparoscopic inspection of \nthe abdominal cavity to evaluate the presence of other pathologies, including \nendometriosis, uterine fibroids, or intra -abdominal adhesion (Figure 7). If such \npathologies were found, endometriotic lesions were excised and sent for \nhistopathological examination to confirm the diagnosis. A monopolar hook was used \nto open the isthmocele. Then, in toto  resection was made, the uterine wound was \ntrimmed, and 2 -0 absorbable suture was placed to perform the full -thickness repair. \nThe resected specimen was sent for a histopathological examination. The \nvesicouterine peritoneal fold was repaired. Histology reports were evaluated. For \nstatistical analysis, we used a multiple binary logistic regression model (using age as a \ncontrol). A p -value <0.05 was considered statistically significant. Statistical analysis \nwas performed using SPSS version 24 (IBM Corp, Armonk, NY, USA). \n \n8.1.3. Results \nThe mean age of the patients was 36.9 ± 4.5 years, with a range of 23 –42 years. Of the \n28 patients, 20 (71.4%) had undergone a single previous cesarean section, while  8 \npatients (28.6%) had undergone ≥2 cesarean sections (Table 1). A total of 25 patients \n(89.3%) had different forms of bleeding disorders, 18 patients (64.3%) experienced \nchronic menstrual pain, 13 patients (46.4%) had recurrent vaginitis, 23 patients \n(82.1%) had chronic supra -pubic or lower abdominal pain, and 17 patients (60.7%) \nwere diagnosed with secondary infertility (Table 1). Lysis of pelvic adhesions were \nperformed in 15 patients (53.6%), and we performed endometrial polyp resection in 4 \npatients (14.3%). A total of 2 patients (7.1%) had myoma and underwent \nmyomectomy. Endometriosis of different sites was found in 16 patients (57.1%) \n(Table 2a-b, Figure 7). The stages of endometriosis ranged between stage I and III, as \nclassified by the ASRM. There was a significant reduction of symptoms and \nimprovement of the patients’ general health from the first month after isthmocele \nsurgery as compared with prior to surgery (Table 2a -b). Of 17 patients, 14 (82.4%) \nunderwent cesarean section within 24 months of surgery. \n \n \n \n\n26 \nSymptoms and Characteristics (N=28) Number Percent \nAge 36±4.1(range 29-42) years - - \nAll symptoms associated with isthmocele 5 64.3% \nDysmenorrhea 18 67.3% \nSupra-pubic pain (LAP-lower abdominal pain) 19 60.7% \nDuration of infertility in years (between ±2years - ±8 years) 17 89.3% \nPMBD (post menstruation bleeding disorder) Length of bleeding in days \n(between ±9 - ±17 days \n25 46.4% \nCVD (Chronic Vaginal discharge) 13 60.7% \nHistory of 1 cesarean section delivery 17 39.3% \nHistory of > 2 cesarean section delivery 11 71.4% \nCesarean section incision closure (single layer) 20 57.1% \nSize of isthmocele (<6-15x>6xl5mm) 16 25.0% \nSize of isthmocele (<15-20x>15×20mm) 7 17.9% \nSize of isthmocele (>20×25mm) 5 17.9% \nEndo-myometrium thickness (<3mm) 16 57.1% \nEndo-myometrium thickness (>3mm) 12 42.9% \nTable 1. General characteristics of patients undergoing surgery for isthmocele.  \n \nIntra-Operative characteristics Number Percent \nAverage duration of surgery   \nAverage blood loss   \nEndometriosis 16 57.0% \nUterine fibroid 2 7.1% \nEndometrial polyp 4 14.3% \nIntra-abdominal adhesion 15 53.6% \nPreoperative clinical outcome Frequency Percent \nLost to follow up after 3 months post operation 7 25.0% \nPregnancy 14/17 82.4% \nFertility related characteristics Frequency Percent \nPregnant – ART 7/14 50.0% \nPregnant^ Spontaneous 7/14 50.0% \nTotal number of pregnancies within 24 months post-surgery 14/17 82.4% \nTotal number of non-pregnant patients after 24 months, including those with lost to \nfollow up with infertility issues \n3/17 17.6% \nTotal infertility patients before isthmocele surgery 17/17 100.0% \n \nSymptoms Relief of symptoms by months Total \n1st \nmonth \n3rd month 6th month 12th month 24th month  \nDysmenorrhea 16 \n(88.9%) \n17 \n(94.4%) \n18 \n(100%) \n- - 18 \n(100%) \nPost- menstrual bleeding \ndisorder (PMBD) Duration \nof menstruation reduces to \n3.6 days ±1.069 days \n23 \n(92.0%) \n24 \n(96.0%) \n25 \n(100%) \n- - 25 \n(100%) \nSupra-pubic lower \nabdominal pain (LAP) \n16 \n(84.2%) * \n18 \n(94.7%) \n18 (94.7%) 19 (100%) - 19 \n(100%) \nChronic Vaginal Discharge \n(CVD) \n10 \n (76.9%) \n** \n13 (100.0%) - - - 13 \n(100.%) \nInfertility - - 5/17 \n(29.4%) \n8/17 \n(47. 1%) \n1/17 \n(5.9 %) \n14/17 \n(82.4%) \nTable 2a-b. Postoperative outcomes of patients who underwent surgery for isthmocele. \n \n\n27 \n \nFigure 7. Images of different surgical stages of hysterolaparoscopic repair of isthmocele at Róbert   \nHospital (Ekine A.A.). \n1: hysteroscopy image showing the area of the scar; 2: closure of scar tissue; 3: adhesion/attachment of \nscar tissue to bladder peritoneum; 4a/b: scar tissue preparation; 5: areas affected by endometriosis; 6: \nuterine wound during surgical procedures. \n \n8.1.4. Discussion \nComplications of cesarean section may arise due to poor alignment, single -layer \nuterine closure technique, poor wound healing, dysplastic endometrial capillary \ndilatation, and inflammatory tissue infiltration, increasing the risk of the expansion of \nthe uterine incision [216, 217]. While the frequency of fibroid was not statistically \nsignificant, the frequency of intra -abdominal adhesion was statistically significant at \n53.6% (15/28). This finding could be explained as a probable postoperative \ncomplication of abdominal surgery (Figure 6). However, unlike intra -abdominal \nadhesion, endometriosis is not expected to be a possible late complication of \nabdominal surgery such as cesarean section [217]. However, we observed a relatively \nhigh incidence of endometriosis during combined hysterolaparoscopic management of \nisthmocele of 57.1% (16/28). This is likely not an accidental phenomenon and should \nraise questions about the correlation and possible link between cesarean section or \nisthmocele and the onset of endomet riosis [216, 217]. This observation could support \nthe well -known transplantation theory. One possible explanation is that transport of \nendometriotic cells occurs via lymphogenous or hematogenous pathways [216 -219]. \nOther options include direct extension of adenomyotic nodules through the thin uterine \nwall or by direct iatrogenic dissemination of endometrial cells following poor \nalignment of tissues during closure or by curettage during cesarean section [220, 221]. \n\n28 \nFurthermore, dissemination of endometrial cells through the isthmocele due to \nprolonged stagnation of menstrual fluid may be a possible cause. Although the exact \nmechanism is not yet understood, our finding strongly supports the implantation \ntheory of endometriosis (Figure 7). \n \n8.2. Study II: Benefits of hysterolaparoscopy in endometriosis-related infertility \n8.2.1. Background \nIt is well known that women in their prime childbearing age (between 25 and 40 years) \nare the most likely to be affected by endometriosis [222]. The possible association \nbetween the disease and infertility is becoming more apparent. The fecundity rate is \nabout 0.15 –0.20 per month among average couples, whereas women with \nendometriosis have a reported range of 0.02 –0.1 per month [223]. Endometriosis \naffects millions of women worldwide, although the actual prevalence is unknown \n[222, 224]. Some authors estimate the prevalence of isthmocele to be between 2% and \n10% for women in the general population and a staggering 20 –50% of the female \npopulation with infertility [9, 10, 14]. Infertility causes loss of self -esteem in women, \nwhile endometriosis-associated infertility constitutes a significant burden on the QoL \nof women, their families, and the healthcare system [88, 225]. Studies have combined \nhysteroscopy and laparoscopy in patients with endometriosis -related infertility with \nvarying degrees of success [10, 222, 226, 227]. This study aimed to determine the \npost-surgical performance of patients regarding fertility, with or without other \nendometriosis-related symptoms. \n \n8.2.2. Materials and methods \nA retrospective, single-center study was conducted at the Endoscopic and IVF Unit of \nthe Róbert Private Hospital, Budapest, from 1st. June 2010 to 30th. June 2018, based on \nthe hospital database. Ethical approval was obtained from the hospital ethical \ncommittee (RRC -RMK) 001 -3/2017. The study sample comprised 533 infertile \nwomen who had received prior infertility treatments —either artificial insemination \n(AI) or IVF—on at least one occasion. A decision for surgical management was made \nbased on the symptoms and signs suggestive of endometriosis, previous medical \nhistory, ultrasonography findings, and results from other diagnostic procedures, \nincluding MRI, computed tomography (CT), and serum markers. Patients diagnosed \nwith different stages of endometriosis were enrolled in the study. Exclusion criteria \nwere Pelvic inflammatory disease (PID), polycystic ovary syndrome (PCOS), \n\n29 \nadhesion from previous surgical interventions, and infection. All patients underwent \ncombined hysterolaparoscopic surgical treatment between 1 st. January 2010 and 31 st. \nDecember 2016. Endometriosis stage was evaluated according to the revised \nAmerican Fertility Society (rAFS) scoring system. The size, penetration depth, and \nlocation of the lesions were precisely recorded to ensure proper staging. During \nsurgery, all visible endometriotic lesions were removed. Post -surgical follow-up lasted \nfor a maximum of 2 years. Finally, 455 patients were eligible to complete the study. \nImmediately after surgery, patients without apparent post -surgical anatomical \nabnormalities were advised to conceive naturally, while those with proven complete \ntubal obliteration or those who failed to become pregnant 12 months after surgery \nwere offered IVF. Patients were followed up for a maximum of 24 months; during this \nperiod, we collected relevant clinical data using personal and electronic \ncommunication forms. The determined study variables included age, parity, type of \ninfertility, duration of infertility, stage of endometriosis, mode of conception, \npregnancy outcome, and other presenting symptoms (dysmenorrhea, dyspareunia, \nchronic pelvic pain, and urinary symptoms). Ultrasonography findings, such as the \npresence of endometrioma, adenomyosis, tenderness, adnexal masses, and mobility of \nthe uterus, were also recorded. Statistical analysis included the chi -square test for \ncategorical data and the two -sample t -test for continuous variables using SPSS \nsoftware version 24. A multiple binary logistic regression model was used to ascertain \nthe relationship between pregnancy occurrence  and the investigated variables by \ncontrolling for age (≤35 and >35 years). Data were expressed either as mean ± \nstandard deviation, or frequency, percentage, or cumulative percentage. Meanwhile, \nthe associations between age, stage of the disease, mode of conception, laparoscopic \nsurgical management, and fertility performance were assessed. We adopted a multiple \nbinary logistic regression model to determine the statistical relationship (using age as a \ncontrol). A p-value <0.05 was considered statistically significant. \n \n8.2.3. Results \nThe average age range of the subjects was 25 –46 years, with a mean of 34.3 ± 4.1 \nyears. The overall cumulative pregnancy rate was 81.3% (370/455). The live birth rate \nwas 94.2% (Figure 8 and 9, Table 3 –5). There were no statistical differences between \nage, cycle length, duration of menstruation, and stage of endometriosis of the women \nbecoming pregnant or remaining infertile after surgery (Chi -square-test 6.28; df=3; \np=0.099) (Figure 8 and 9, Table 3). A marked difference was observed in successful \n\n30 \nconception rate after surgery, with 85 remaining non -pregnant and 370 becoming \npregnant (p=0.001) (Table 4). Moreover, there was a significant difference in type of \nconception (spontaneous vs. ART) following surgery between age groups ≤35 years or \n>35 years (74.1% [40/54] vs. 91.3% [73/80]; p=0.007; OR=3.7; 95% CI=1.4 –9.8) \n(Table 5). There was no statistical difference between pregnancy rates among those \nwho underwent or did not undergo pre -surgery ART in both studied age groups (≤35 \nyears vs. >35 years) (Tables 4 and 5). However, patients who underwent post -surgery \nART had a significantly higher chance of becoming pregnant (OR=2.2; 95% CI =1.2 –\n3.6) (Tables 3 and 4). Among those who received preoperative ART in the >35 -years \nage group, there was no statistically significant difference in the type of conception \n(spontaneous vs. ART) following surgery (83.0% [73/88] vs. 73.6% [39/53]; p=0.111). \nThere was no significant difference between the effect of various types of surgical \nprocedures on postoperative fertility performance (Table 4). \n \nCharacteristics Category Total (n=455) Number of \npregnancies \n(n=85) \nPregnancy (n=370) Chi2 \ntest \nN (Col. %) N (Row%) N (Row\n%) \np \nAge (years) 25-30 91 20.0% 17 18.7% 74 81.3% 0.099 \n31-35 179 39.3% 25 14.0% 154 86.0% \n36-40 159 35.0% 35 22.0% 124 78.0% \n41-46 26 5.7% 8 30.8% 18 69.2% \nLength of \nmenstrual cycle \n(days) \n≤24 93 20.4% 18 19.4% 75 80.6% 0.409 \n25-35 338 74.3% 65 19.2% 273 80.8% \n36+ 24 5.3% 2 8.3% 22 91.7% \nLength of \nmenstrual (days) \n<4 125 27.5% 18 14.4% 107 85.6% 0.318 \n5-6 219 48.1% 46 21.0% 173 79.0% \n7+ 111 24.4% 21 18.9% 90 81.1% \nStages of \nendometriosis \n1 61 13.4% 12 19.7% 49 80.3% 0.138 \n2 132 29.0% 32 24.2% 100 75.8% \n3 162 35.6% 22 13.6% 140 86.4% \n4 100 22.0% 19 19.0% 81 81.0% \nTable 3. General characteristics of endometriosis in patients with infertility.  \n \nThe study examined the relationship between various demographic and clinical \ncharacteristics and the history of pregnancy in a sample of 455 women diagnosed with \nendometriosis. The characteristics analyzed included age, length of menstrual cycle, \nduration of menstruation, and stage of endometriosis. The sample was divided into two \ngroups: those who had experienced pregnancy (n = 370) and those who had not (n = \n85). \n \n \n\n31 \n• Age: \nThe age of participants ranged from 25 to 46 years. The distribution across age groups \nwas as follows: 25 -30 years (20.0%), 31 -35 years (39.3%), 36 -40 years (35.0%), and \n41-46 years (5.7%). \nThe proportion of women who had experienced pregnancy was highest in the 31 -35 \nage group (86.0%) and lowest in the 25 -30 age group (81.3%). However, the Chi -\nsquare test revealed no statistically significant association between age and pregnancy \nhistory (χ² (3) = 0.5799, p =0.99). \n• Length of Menstrual Cycle: \nThe length of the menstrual cycle was categorized into ≤24 days (20.4%), 25 -35 days \n(74.3%), and 36+ days (5.3%). \nThe highest proportion of women who had been pregnant was in the 36+ days \ncategory (91.7%), but the Chi -square test indicated no significant association between \nthe length of the menstrual cycle and pregnancy history (χ² (2) = 1.5188, p =0.409). \n• Length of Menstruation: \nThe duration of menstruation was categorized into <4 days (27.5%), 5-6 days (48.1%), \nand 7+ days (24.4%). \nThe highest proportion of women who had been pregnant was in the <4 days category \n(85.6%). However, the Chi -square test showed no significant association between the \nduration of menstruation and pregnancy history (χ² (2) = 0.7655, p =0.318). \nStage of Endometriosis: \n \nThe stages of endometriosis were classified as Stage 1 (13.4%), Stage 2 (29.0%), \nStage 3 (35.6%), and Stage 4 (22.0%). \nThe highest proportion of women who had been pregnant was in Stage 3 (86.4%). The \nChi-square test, however, indicated no significant association between the stage of \nendometriosis and pregnancy history (χ² (3) = 0.7474, p = 0.138). \n \nThe analysis revealed that there were no statistically significant associations between \nthe history of pregnancy and the demographic and clinical characteristics studied, \nincluding age, length of menstrual cycle, duration of menstruation, and stage of \nendometriosis. \n \n \n \n\n32 \nType of laparoscopic surgical procedures No pregnancy Pregnancy Total \n  N (Row%) N (Row%)   \nLaser not used 29 16.8% 144 83.2% 173 \nCo2 laser evaporation technique used 13 24.1% 41 75.9% 54 \nElectrocoagulation excision of deep infiltrating \nendometriosis lesions & adhesiolysis \n6 20.7% 23 79.3% 29 \nElectrocoagulation excision of superficial peritoneal & \ndeep infiltrating lesion & endometrioma stripping& \nadhesiolysis \n13 13.7% 82 86.3% 95 \nCauterization of bilateral ovarian endometriosis & \nElectrocoagulation excision of superficial peritoneal & deep \ninfiltrating lesion & adhesiolysis \n2 16.7% 10 83.3% 12 \nEndometrioma stripping & adhesiolysis & cauterization of \novary endometriosis \n10 23.8% 32 76.2% 42 \nElectrocoagulation excision of superficial peritoneal lesion \n& adhesiolysis \n2 28.6% 5 71.4% 7 \nElectrocoagulation excision of superficial peritoneal lesion \n& deep infiltrating lesion & adhesiolysis \n12 27.9% 31 72.1% 43 \nTable 4. Types of laparoscopic surgical procedures performed on patients with endometriosis -related \ninfertility. \n \nThe study examined the relationship between the type of laparoscopic surgical \nprocedure performed for endometriosis and subsequent pregnancy outcomes. The \nprocedures were categorized into various types based on the surgical techniques and \nextent of lesion treatment. The sample included a total of 455 cases, with the \ndistribution of pregnancy outcomes (pregnancy vs. no pregnancy) reported for each \nprocedure type. \n• Laser Not Used: Out of 173 cases where laser was not used, 29 (16.8%) did not \nresult in pregnancy, while 144 (83.2%) did. \n• CO2 Laser Evaporation Technique: In the 54 cases where the CO2 laser \nevaporation technique was used, 13 (24.1%) did not lead to pregnancy, and 41 \n(75.9%) did. \n• Electrocoagulation Excision of Deep Infiltrating Endometriosis Lesions \n(EEDL) & Adhesiolysis: Of the 29 cases involving EEDL and adhesiolysis, 6 (20.7%) \ndid not result in pregnancy, while 23 (79.3%) did. \n• Electrocoagulation Excision of Superficial Peritoneal (EEPL) & Deep \nInfiltrating Lesion & Endometrioma Stripping & Adhesiolysis: In this category, 13 \nout of 95 cases (13.7%) did not result in pregnancy, whereas 82 cases (86.3%) did. \n• Cauterization of Bilateral Ovarian Endometriosis & EEPL & EEDL & \nAdhesiolysis: Of the 12 cases in this category, 2 (16.7%) did not lead to pregnancy, \nand 10 (83.3%) did. \n\n33 \n• Endometrioma Stripping & Adhesiolysis & Cauterization of Ovary \nEndometriosis: In this group, 10 out of 42 cases (23.8%) did not result in pregnancy, \nwhile 32 (76.2%) did. \n• EEPL & Adhesiolysis: Out of 7 cases, 2 (28.6%) did not result in pregnancy, \nand 5 (71.4%) did. \n• EEPL & EEDL & Adhesiolysis: In this category, 12 out of 43 cases (27.9%) \ndid not lead to pregnancy, while 31 (72.1%) did. \n \nThe data suggest variability in pregnancy outcomes following different laparoscopic \nsurgical procedures for endometriosis. The highest percentage of pregnancies was \nobserved in cases where laser was not used (83.2%), and the lowest in cases involving \nelectrocoagulation excision of superficial peritoneal & deep infiltrating lesion & \nendometrioma stripping & adhesiolysis (86.3%). \n \nPost-surgical fertility performance among women 25 – 35-years-old with infertility – related \nendometriosis \nPreoperative ART Postoperative \nART treatment \nNo pregnancy Pregnancy Total \nN(Row%) N(Row%) N \nNo No 15(16.3%) 77(83.7%) 92 \n  Yes 6(13.6%) 38(86.4%) 44 \n  Total 21(15.4%) 115(84.6%) 136 \nYes No 14(25.9%) 40(74.1%) 54 \n  Yes 7(8.8%) 73(91.2%) 80 \n  Total 21(15.7%) 113 (84.3%) 134 \nTotal   42(15.6%) 228(84.4%) 270 \nPost-surgical fertility performance among women 36 – 46-years-old with infertility – related endometriosis \nPreoperative ART \ntreatment \nPostoperative \nART treatment \nNo pregnancy Pregnancy Total \nN(Row%) N(Row%) N \nNo No 11(42.3%) 15(57.7%) 26 \n  Yes 3(16.7%) 15(83.3%) 18 \n  Total 14(31.8%) 30(68.2%) 44 \nYes No 14(26.4%) 39(73.6%) 53 \n  Yes 15(17.0%) 73(83.0%) 88 \n  Total 29(20.6%) 112(79.4%) 141 \nTotal   43 (23.2%) 142 (76.8%) 185 \nTable 5. Postoperative fertility outcomes in patients with endometriosis-related infertility. \n \nThe study investigated the post -surgical fertility performance among women aged 25 \nto 35 years with infertility -related endometriosis. The focus was on the impact of \npreoperative and postoperative Assisted Reproductive Technology (ART) on fertility \n\n34 \noutcomes. The sample consisted of 270 cases, divided based on their utilization of \nART before and after surgery and their subsequent pregnancy outcomes. \n• Preoperative ART Not Used: Among the women who did not use preoperative ART, \n92 did not undergo postoperative ART, with 15 (16.3%) of these cases not resulting \nin pregnancy and 77 (83.7%) resulting in pregnancy. In contrast, 44 women used \npostoperative ART, with 6 (13.6%) not achieving pregnancy and 38 (86.4%) \nachieving pregnancy. Overall, in the group not using preoperative ART, 21 (15.4%) \ndid not achieve pregnancy, while 115 (84.6%) did. \n• Preoperative ART Used: In the group that used preoperative ART, 54 did not undergo \npostoperative ART, with 14 (25.9%) not resulting in pregnancy and 40 (74.1%) \nresulting in pregnancy. Among those who used both preoperative and postoperative \nART, 7 (8.8%) did not achieve pregnancy, while 73 (91.2%) did. Overall, in the \ngroup using preoperative ART, 21 (15.7%) did not achieve pregnancy, while 113 \n(84.3%) did. \n• Total: Combining both groups, the total number of cases not resulting in pregnancy \nwas 42 (15.6%), while those achieving pregnancy were 228 (84.4%). \nThe findings indicate that most women aged 25 to 35 years with infertility -related \nendometriosis achieved pregnancy post -surgery, regardless of the use of ART either \nbefore or after surgery. Notably, the highest pregnancy rate (91.2%) was observed \namong women who utilized both preoperative and postoperative ART, suggesting a \npotential benefit of continuous ART intervention in this subgroup. \nThe study further examined the post-surgical fertility performance among women aged \n36 to 46 years with infertility-related endometriosis. Similar to the younger cohort, this \ngroup was analyzed based on their use of preoperative and postoperative Assisted \nReproductive Technology (ART) and their subsequent pregnancy outcomes. The \nsample included 185 cases. \n• Preoperative ART Not Used: Among women who did not use preoperative ART, 26 \ndid not undergo postoperative ART, with 11 (42.3%) of these cases not resulting in \npregnancy and 15 (57.7%) resulting in pregnancy. In contrast, 18 women used \npostoperative ART, with 3 (16.7%) not achieving pregnancy and 15 (83.3%) \nachieving pregnancy. Overall, in the group not using preoperative ART, 14 (31.8%) \ndid not achieve pregnancy, while 30 (68.2%) did. \n• Preoperative ART Used: In the group that used preoperative ART, 53 did not undergo \npostoperative ART, with 14 (26.4%) not resulting in pregnancy and 39 (73.6%) \n\n35 \nresulting in pregnancy. Among those who used both preoperative and postoperative \nART, 15 (17.0%) did not achieve pregnancy, while 73 (83.0%) did. Overall, in the \ngroup using preoperative ART, 29 (20.6%) did not achieve pregnancy, while 112 \n(79.4%) did. \n• Total: Combining both groups, the total number of cases not resulting in pregnancy \nwas 43 (23.2%), while those achieving pregnancy were 142 (76.8%). \nThe results indicate that in the older age group of women with infertility -related \nendometriosis (36 to 46 years), a significant proportion achieved pregnancy post -\nsurgery, with a notable impact observed from the use of ART. The highest pregnancy \nrate (83.0%) was observed among women who utilized both preoperative and \npostoperative ART, suggesting the effectiveness of ART in enhancing fertility \noutcomes in this age group. \n \nAge groups Pregnancy No pregnancy \n25-30 (n=91) 81% 19% \n31-35 (n=179) 86% 14% \n36-40 (n=159) 78% 22% \n41-46 (n=26) 69% 31% \n \n \nFigure 8. Effect of laparoscopic surgery on fertility performance by age in Study II.  \nThe study examined the relationship between age and pregnancy outcomes in a sample \nof women with endometriosis. The participants were categorized into four age groups: \n25-30 (n=91), 31 -35 (n=179), 36 -40 (n=159), and 41 -46 (n=26). The frequency of \npregnancy and no pregnancy outcomes was reported for each age group. \n\n36 \n• Age Group 25-30: Out of 91 women, 81% achieved pregnancy, while 19% did not. \n• Age Group 31 -35: In this group of 179 women, a slightly higher pregnancy rate \nwas observed, with 86% achieving pregnancy and 14% not achieving pregnancy. \n• Age Group 36 -40: Among the 159 women in this age group, the pregnancy rate \nwas 78%, with 22% not achieving pregnancy. \n• Age Group 41 -46: The oldest age group, consisting of 26 women, had the lowest \npregnancy rate, with 69% achieving pregnancy and 31% not achieving pregnancy. \nThe Chi-square test was conducted to determine if there was a statistically significant \ndifference in pregnancy rates across the different age groups. The Chi -square value \nwas calculated to be 6.282, with a p-value of 0.099. \n \nThe analysis suggests a trend where the likelihood of achieving pregnancy decreases \nwith increasing age among women with endometriosis. The highest pregnancy rate \nwas observed in the 31-35 age group, and the lowest in the 41-46 age group. However, \nthe Chi -square test indicated that these differences across age groups were not \nstatistically significant (χ² = 6.2816, p = 0.0987). This implies that while there appears \nto be a trend of decreasing pregnancy rates with age, the differences observed in this \nsample are not strong enough to rule out the possibility that they occurred by chance. \n \n \nFigure 9. Effect of laparoscopic surgery on fertility performance by stage of endometriosis in Study II.  \nThe study investigated the relationship between the stage of endometriosis and \npregnancy outcomes. Participants were categorized into four groups based on the stage \nof endometriosis: Stage 1 (n=61), Stage 2 (n=132), Stage 3 (n=162), and Stage 4 \n\n37 \n(n=100). The frequency of pregnancy and no pregnancy outcomes was reported for \neach stage. \n• Stage 1 Endometriosis: Out of 61 women with Stage 1 endometriosis, 80% achieved \npregnancy, while 20% did not. \n• Stage 2 Endometriosis: In this group of 132 women, 76% achieved pregnancy, and \n24% did not achieve pregnancy. \n• Stage 3 Endometriosis: Among the 162 women in this stage, a higher pregnancy rate \nwas observed, with 86% achieving pregnancy and 14% not achieving pregnancy. \n• Stage 4 Endometriosis: In the most advanced stage, Stage 4, consisting of 100 women, \n81% achieved pregnancy, and 19% did not. \nThe analysis suggests a variation in pregnancy rates across different stages of \nendometriosis, with the highest pregnancy rate observed in Stage 3 (86%) and the \nlowest in Stage 2 (76%). However, the Chi -square test indicated that these differences \nacross stages were not statistically significant (χ² = 5.5081, p = 0.1382). This implies \nthat while there appears to be a variation in pregnancy rates across different stages of \nendometriosis, the differences observed in this sample are not strong enough to rule \nout the possibility that they occurred by chance. \n \n8.2.4. Discussion \nInfertility affects women around the world, and the socio -cultural stigma that \nsurrounds it varies and can often result in family breakdown [228 -230]. Many studies \nhave shown an association between endometriosis and infertility. The combined \nhysteroscopic–laparoscopic surgical treatment of endometriosis -related infertility \nimproves fertility performance; therefore, it is considered one of the best options \ncurrently available, irrespective of the few shortcomings associated with the \nprocedure. Furthermore, w ell-timed ART has also been proven to enhance the \nreproductive performance of affected women [231 -233]. Our results demonstrated the \nsignificant benefits of hysterolaparoscopic management of endometriosis -related \ninfertility. Our goal for the applied surgical technique was to eradicate all active \nendometriotic lesions. In our study, the pregnancy rate improved considerably after \nsurgery, reaching 81.3%, with a live birth rate of 94.2%. We also observed that the \nstage of endometriosis did not significantly i nfluence fertility performance. We \npropose that fertility performance is more dependent on surgical expertise and patient \nage rather than on the stage of endometriosis. Consistent with our results, a review \nconducted by Jacobson et al. concluded that the laparoscopic treatment of minimal and \n\n38 \nmild endometriosis improved pregnancy and live birth rates [230, 233]. Fuchs et al. \nrecorded a high pregnancy rate (65%) within an 8.5 -month postoperative follow -up \nperiod, of which 86.9% of pregnancies resulted in deliveries [232 -234]. For minimal \nand mild endometriosis -related infertility, clinicians commonly share the opinion that \nlaparoscopic surgery may increase the likelihood of future pregnancy and live birth \n[10, 18, 235]. Another study reported a pregnancy rate of 81.6% and a live birth rate of \n43.7% in stage I and II endometriosis, respectively, and a 56.7% pregnancy rate and \n40.3% live birth rate was recorded in patients with stage III and IV endometriosis, \nrespectively, after ICSI [228, 236]. However, with a relatively smaller study \npopulation, Słabuszewska -Jóźwiak et al. reported that 20.75% of patients became \npregnant spontaneously and concluded their pregnancy with live birth, without ART in \nthe first 6 months of follow-up [34]. Nardo et al. reported a cumulative pregnancy rate \nof 23.2% after laparoscopic treatment with the Helica Thermal Coagulator for minimal \nand mild endometriosis [236]. Both study outcomes were similar to ours, as we \nreported an overall spontaneous pregnancy rate of 28.8% during the follow -up period. \nHowever, our study had a broader patient population by including all stages of \nendometriosis [235, 237-239]. A systematic review highlighted the beneficial effect of \nlaparoscopic surgery for the treatment of subfertility related to minimal and mild \nendometriosis [231, 240 -242]. Several studies concluded that the overall pregnancy \noutcomes improved after laparoscopic surgical intervention regarding endometriosis -\nrelated infertility, regardless of the stage of endometriosis [91, 231, 232, 244]. Many \nauthors reported that the ASRM’s classification of endometriosis was a useful tool in \npredicting IVF success and fertility performance [240]. Furthermore, the ESHRE \nsuggests that lesions classified as moderately severe to severe have a better chance \nwith IVF as the first line of treatment [9, 34, 241]. However, in our study, there was no \nstatistically significant difference in fertility outcome regarding different stages of \nendometriosis, with expectant management or with IVF, even without any anatomical \ndeficiencies. \nExplanation of the relatively improved fertility performance observed in this study \nmay be provided by the application of combined hysteroscopic -laparoscopic surgery. \nSurgical expertise is another crucial factor, in addition to others, such as study \npopulation, environment, and the efficiency of IVF centers. Hysteroscopy is an \nefficient tool in the evaluation and correction of intrauterine and intra -tubal \nabnormalities. The direct imagining of the tubal os, chromopertubation, and peritubal \n\n39 \nadhesiolysis via laparoscopy enhances the likelihood of pregnancy as compared with \npainful hysterosalpingography (HSG) or hysterosalpingo -contrast-sonography \n(HYCOSY) [34, 235,245]. Similarly to other centers, we routinely apply various \nsurgical approaches ranging from electro -cauterization of visible endometriotic \nimplants, excision or stripping of ovarian endometriomas, and laser coagulation, \nadhesiolysis, and adenomyomectomy [34, 234, 246, 247]. The hysterolaparoscopic \nsurgical procedure plays an integral role as it enables the surgeon to treat or correct \nanatomical abnormalities found in the uterine cavity, including uterine fibroid, \nAsherman syndrome and synechia, polyps, uterine septum, isthmocele (scar defect or \nniche), ovarian cysts, or chronic PID; these conditions were present in our study in \n17.8%, 0.8%, 5.4%, 6.6%, 1.0%, 0.8%, and 1.8% of cases, respectively. Similar \nfindings were reported by Sreekanth [246]. In our study, approximately 52.2% of \npatients had tubal patency restoration via Peritubal adhesiolysis, 3.5% had unilateral \ntubal patency, 4.6% had a total tubal blockage, and only 39.7% had normal tubal \nfunction. Godinjak et al. reported bilateral tubal occlusion in 18 patients (5%) and \nunilateral tubal occlusion in 30 patients (8.33%) [247]. Our data were also comparable \nto those of Alborzi et al. who reported 66 spontaneous pregnancies (33.1%) and 5 \npregnancies (25%) through intrauterine insemination [227, 248 -250]. However, we \nmust highlight that there are limitations of such studies because of patient desire, \npatient withdrawal of consent during the study, heterogeneity of study subjects, and \nloss to follow -up. Other limitations were the retrospective nature of the study, \npopulation size, and potential pitfalls in data collection. Nevertheless, we believe that \nimproved fertility outcome after a combined hysterolaparoscopic approach in infertile \npatients is beyond doubt. \n \n8.3. Study III: Effectiveness of combined hysterolaparoscopy on quality of life of \nendometriosis patients \n \n8.3.1. Background \nWorldwide, endometriosis is reported to affect up to 10% of women of reproductive \nage [21, 96]. Symptoms associated with endometriosis vary and are dependent on \nlocalization, stage of the disease, individual pain threshold, and individual goals and \nneeds [3, 9, 21]. Endometriotic tissues outside the uterine cavity behave like eutopic \nendometrium and are cyclically influenced by sex hormones [251 -253]. Endometriosis \ncauses chronic inflammatory reactions that can result in scar tissue formation, \n\n40 \nadhesion, and eventual displacement or distortion of lower pelvic reproductive organs \n[96, 254]. Usually, the disease is accompanied by increased peritoneal fluid \nconcentrations of biochemical substances, such as prostaglandins, proteases, and \ninflammatory cytokines, including IL -1, IL6, and TNFα [159, 254 -256]. Angiogenic \ncytokines, such as IL-8 and VEGF, are secreted from the distorted reproductive organs \nand adhesion [159, 254, 256]; this milieu favors the presence of specific symptoms. \nSometimes, endometriosis is associated with mood swings and depression, which can \noccasionally lead to self -destructive lifestyles. Frequently reported symptoms are \nchronic pelvic pain, waist pain, dysmenorrhea, and dyspareunia; more severe \nsymptoms include dysuria and gastrointestinal dysfunction, such as bloating and \ndyschezia [252 -254]. Subsequently, changes in the anatomical and biochemical \nenvironment can adversely affect pelvic organ function, leading to infertility [159, \n255-257]. \n \nThe purpose of our investigation was to evaluate whether hysterolaparoscopy in \npatients with impaired QoL caused by endometriosis could lead to significant \nimprovements. \n \n8.3.2. Materials and methods \nWe conducted a single -center analysis on the impact of laparoscopic surgery on the \nQoL of patients with endometriosis at Róbert Private Hospital, Budapest. The study \nhad two arms: the first arm was a retrospective cohort analysis from 1 st. January 2010 \nto 31 st. December 2016; and the second arm was based on a prospective cohort \ninvestigation between 1 st. January 2017 and 31 st. December 2018 using the \nEndometriosis Health Profile 30 (EHP -30) questionnaire, visual analogue scale \n(VAS), and Numeric Rating Scal e (NRS-11) instruments. Both data for retrospective \nstudies and prospective study questionnaires were retrieved or collected personally. In \nboth arms, the cohorts consisted of patients of reproductive age who complained of \nendometriosis-related symptoms and underwent laparoscopy. In the first arm, a \nrandom sample comprising 777 patients with histologically confirmed endometriosis \nwas recruited. In the second arm, 87 patients with histologically confirmed \nendometriosis and relevant symptoms were recruited. A ccess to the hospital database \nwas approved by the hospital ethics committee (RRC -RMK) 001 -3/2017. Exclusion \ncriteria were PCOS; PID; current use of drugs that could affect cognition and mood; \nand primary medical conditions, such as neurologic, psychiatric, gastrointestinal, \n\n41 \nurologic, and orthopedic diseases. In the first arm, we applied a standard questionnaire \n3, 6, and 12 months after surgery to collect information from women on the following \ngroups of variables: age, type of pain -related symptoms (i.e., dysmenorrhea, \ndyspareunia, chronic pelvic pain, or urinary symptoms), general history, history of \nprevious gynecological surgery, mode of diagnosis, type of surgery, stage of \nendometriosis, surgical outcome, infertility, pregnancy outcome, and other relevant \nultrasound findings, such as the presence of polyps, septum, and adhesion. In the \nsecond arm, the EHP-36 questionnaire was applied to measure demographics, physical \nand mental health, emotional problems, and general perception of health and QoL.  \n \nMoreover, the VAS and the NRS -11 were employed to measure painful distress \nassociated with endometriosis. We commenced with “0” representing no pain and \n“10” representing the least bearable pain. None of the patients received preoperative \nadjuvant therapy. Questionnaires were completed before and after surgical \ninterventions. Post-surgical follow-up was performed in the first 6 months, 12 months, \nand 24 months after surgery via postal questionnaire using email and by direct \ntelephone conversation. Other complementary information was used to test for a \npossible association of symptoms with lifestyle, nutrition, and genetic predisposition. \nThe questionnaire was pretested with the aid of voluntary hospital staff and the \naverage time needed to complete the questionnaire was noted. A decision for surgical \nmanagement was made based on the symptoms and signs suggestive of endometriosis, \npast medical history, ultrasound findings, and results of other investigative procedures, \nincluding clinical examination, MRI, CT, and serum markers (Figure 10). \n \n\n42 \nFigure 10. Mode of discovery of endometriosis in women in Study III/a. \nLaparoscopic surgeries were performed by experienced surgeons, ensuring that \nidentical surgical approaches were used in both arms of the study. Following the \noperations, a standard operative report was completed to provide relevant \nnonoperative information. The severity of endometriosis was staged according to the \nAmerican Fertility Society revised definition [258, 259]. In all patients, endometriotic \nlesions were laparoscopically removed by excision, electrocauterization, vaporization, \nor excision by laser, and were sent for histological examination. Only patients with \nhistologically confirmed endometriosis were eligible to continue the study. \nPostoperative follow-up lasted for 1 –2 years (until 31 st. December 2018). Participants \nwho became pregnant during the study period were followed up until term or the end \nof pregnancy. Those with complaints other than infertility, such as chronic pelvic pain, \ndysmenorrhea, dyspareunia, dysuria, and dyschezia, were followed up for 12 months. \nDuring each visit, patients underwent general gynecological and ultrasound \nevaluations for symptom or disease recurrence. \n \nData obtained from patients were statistically analyzed using SPSS software version \n24 and the Stata program v.11. Correlations between age, stage and laparoscopic \nsurgical management were assessed using the chi -square test and Fisher exact test for \ncategorical data. We investigated continuous variables using the independent-sample t-\ntest, non -parametric Mann –Whitney U test, or the two -sample t -test, where \nappropriate. Multiple logistic and linear regression analyses were performed to \ninvestigate associations between variables and outcomes, adjusting for potential \nconfounders independently associated with exposure and sequel of interest in \nunivariate analysis. We used the multiple binary logistic regression model to \ndetermine statistical relationships, using age as a control. For comparison of the \nemotional characteristics of study individuals before and after surgery according to the \ntiming of the follow -up (6, 12, and 24 months), we used the Mauchly variance \nhomogeneity test and MANOVA. A p -value <0.05 was considered nominally \nsignificant. Results are expressed as mean ± standard deviation, frequency, percentage, \nor cumulative percentage. \n \n8.3.3. Results \nIn the first arm of the study,  all patients were Caucasian, and the mean age of the \npatients was 34.3 ± 5.1 years (18–53 years). The mean age at menarche was 13.1 ± 1.4 \n\n43 \nyears, the mean duration of menstruation was 5.9 ± 2.1 days, the average age at the \nonset of endometriosis-related symptoms was 29.1 ± 4.3 years, and the duration from \nonset of symptoms to the diagnosis of endometriosis was 5.1 ± 2.9 years (Table 6).  \nThe distribution of different stages of endometriosis was stage I in 15% (113/777) of \npatients, stage II in 31% (243/777) of patients, stage III in 34% (264/777) of patients, \nand stage IV in 20% (157/777) of patients (Table 6). The most frequently encountered \ncomplaints were dyspareunia 80% (621/777) and dysmenorrhea 74% (574/777). \nAmong the 534 patients (69%) who initially complained about infertility, 49 did not \nwish to conceive after surgery (Figure 11). \n \nThe coexistence of symptoms appeared to be significant for the following variables: \ndysmenorrhea and obstipation, dysmenorrhea, and obtuse pain, crushing pain and \nobtuse pain, and sharp pain and obtuse pain (Table 7, Figure 11 and 12). \n \nTable 6. General characteristics of patients with endometriosis in Study III/a. \nAge  Frequency Percentage (%) Cumulative \n(%) \nAge of Patients 18-25 27 3.47% 3.5% \n26-31 155 19.9% 29.5% \n32-37 349 44.9% 74.4% \n38-43 172 22.1% 96.5% \n44-53 27 3.4% 100% \nAge at menarche 8-11 76 9.8% 9.8% \n12-15 664 85.5% 95.3% \n16-20 37 4.7% 100% \nDuration of menstruation 2-7 629 81.0% 81% \n8-15 148 19.0% 100% \nAge at the onset of symptoms 15-20 16 2.1% 2.1% \n21-25 136 17.0% 19.1% \n26-30 345 44.4% 63.5% \n31-35 228 29.3% 92.5% \n36-40 47 6.1% 98.5% \n41-43 7 0.9% 100% \nDuration of symptoms before diagnosis 0-5 450 57.9% 57.9% \n6-11 286 36.8% 94.7% \n12-18 41 5.3% 100% \nStages of endometriosis (rASRM) \nclassification) \nStage 1 113 14.5% 14.5% \nStage 2 243 31.3% 45.8% \nStage 3 264 34.0% 79.8% \nStage 4 157 20.2% 100.0% \nTotal  777 100.0% 100.0% \n\n44 \n \n \n \nFigure 11. Distribution of endometriosis-related symptoms in Study III/a. \n \n \n \nFigure 12. The prevalence and overlap of pain-related symptoms in women with endometriosis, \n\n45 \nas diagnosed surgically in Study III/a. \n    1 2 3 4 5 6 7 8 9 10 \n1 Dysmenorrhe\na \n          \n2 Dyschezia 0.223*          \n3 Dyspareunia 0.287* 0.275*         \n4 Dysuria 0.156* 0.470* 0.202*        \n5 Bloody \ndefecation \n0.146* 0.581* 0.208* 0.491*       \n6 Blooting \n(abd. \nswelling) \n0.431* 0.366* 0.300* 0.248* 0.268*      \n7 Obstipation \n(intestinal \nobstruction) \n0.070 0.215* 0.107* 0.205* 0.361* 0.095*     \n8 Diarrhea 0.318* 0.469* 0.250* 0.318* 0.383* 0.570* 0.146*    \n9 Crushing pain 0.572* 0.271* 0.243* 0.204* 0.223* 0.467* 0.100* 0.423*   \n10 Obtuse pain 0.040 0.226* 0.119* 0.260* 0.246* 0.124* 0.064* 0.194* -0.039  \n11 Sharp pain 0.279* 0.233* 0.455* 0.185* 0.185* 0.292* 0.052 0.324* 0.242\n* \n-0.005 \nTable 7. Relationship between type of pain and symptoms in patients with endometriosis in Study III/a \n \n[*P<0.001. In the case of dysmenorrhea, the most probable type of pain was crushing \npain. In the case of dyschezia, there was no typical pain, as all three types occurred. In \nthe case of dyspareunia, the most probable type of pain was sharp pain. In the case of \ndysuria, there was no typical pain, as all three occurred.] \nAmong different anatomical locations, the recto -vaginal septum and the left ovary \nwere the most affected sites, with involvement of 59% (458/777) and 45% (349/777), \nrespectively (Figure 13). \n \n \n\n46 \nFigure 13. Frequent localization of endometriosis in Study III/a. \nUnexpectedly, the incidence of previous gynecological surgery was high at 44.4% \n(345/777), which may present an opportunity for further evaluation or study (Figure \n14). \n \n \nFigure 14:  The incidence of other previous gynecological surgery prior to onset of endometriosis \nsymptoms in women in Study III/a \n \n[More than half of the patients (55.6%) had no surgical history, 44.4% had different \ngynecological surgery, and 1 in 9 patients (10.9%) had curettage for missed abortion \nand curettage for metrorrhagia (10.8%). Frequency of cesarean section (6.9%), \nartificial abortion (6.8%), and HSG/hysteroscopy (6.7%) was low. Frequency of \nmyomectomy and conization were negligible.] \n \nMore complex symptomatology was observed with right ovary involvement, while \ndeep infiltration found either underneath the peritoneum or within the recto -vaginal \nseptum appeared second (Table 8). There was a significant improvement in QoL at 3, \n6, and 12 months after surgery, and most of the patients reported significant to \ncomplete cessation of symptoms (Table 9 and Figure 15). \nThe rate of successful live births was 94.2% (327/347) and the rate of pregnancy loss \nwas 5.8%. Overall, there was gradual improvement in the QoL of the women. There \n\n47 \nwas a significant relationship between improvement rate and the time of visit; patients \nreported increasing improvement over time. The moderate improvement rate alone \ndecreased, but this also strengthened the degree of progress,  as the other two \nimprovement factors (“significant” and “complete”) were “at the expense of” the \nchange. Significant to complete improvement in QoL was observed, recorded as 57 –\n59% on the first follow-up visit and 74–85% on the final visit (after 1st. the year), and \nall woman reported a significant level of improvement (p=0.0005) (Table 9, Figure 15 \nand 17). Patients reported improvement in QoL as follows: 41/421 moderate, 196/421 \nsignificant, and 184/421 as complete at 12 months of follow -up, at the first 3 months \n(250/455), 6 months (341/455), and at 12 months 432/reported this positive change. \nOnly 23/455 were non-respondents concerning fertility performance and QoL. \nTable 8 in Study III/a presents the relationship between the type of pain experienced \nand the localization of endometriosis in the study participants. The types of pain \nassessed include dysmenorrhea (painful menstruation), dyschezia (pain during \ndefecation), dyspareunia (pain during sexual intercourse), bloating (abdominal \nswelling), obstipation (intestinal obstruction), diarrhea, dysuria (painful urination), and \nbloody defecation. The localization of endometriosis considered are the right ovary, \nleft ovary, superficial peritoneal involvement, deep involvement of the ovary with \nmultiple unilateral or bilateral endometriosis, deep peritoneal endometriosis with \nbladder peritoneum involvement, deep recto -vaginal septum endometriosis with \nintestinal peritoneal involvement, and deep recto -vaginal septum (RVS -B-R) without \nbowel involvement. \n• Right Ovary: Participants with endometriosis in the right ovary reported experiencing \nall types of pain assessed in the study. \n• Left Ovary: Endometriosis in the left ovary was associated with dysmenorrhea, \nbloating, and dysuria. \n• Superficial Peritoneal Involvement: No specific types of pain were reported for \nsuperficial peritoneal involvement. \n• Deep Involvement of the Ovary with Multiple Unilateral or Bilateral Endometriosis: \nParticipants with this type of endometriosis reported experiencing all types of pain \nassessed. \n• Deep Peritoneal Endometriosis with Bladder Peritoneum Involvement: This condition \nwas associated with all types of pain assessed in the study. \n\n48 \n• Deep Recto -vaginal Septum Endometriosis with Intestinal Peritoneal Involvement: \nParticipants with this type of endometriosis also reported experiencing all types of \npain assessed. \n• Deep Recto-vaginal Septum (RVS -B-R) Without Bowel Involvement: This condition \nwas associated with dyschezia, dyspareunia, bloating, obstipation, diarrhea, dysuria, \nand bloody defecation. \n \nLocalization Dysmen\norrhea \nDys-\nChezia \nDys-\npareuni\na \nBloating \n(abdominal \nswelling) \nObstipation \n(intestinal \nobstruction) \nDiar\n-\nrhea \nDy-\nsuria \nBloody \ndefecation \nRight ovary X X  X X X X X \nLeft ovary X   X  X   \nSuperficial peritoneal \ninvolvement \n        \nDeep involvement of \nthe ovary with \nmultiple unilateral or \nbilateral \nendometriosis \nX X X X X X X X \nDeep peritoneal \nendometriosis with \nbladder peritoneum \ninvolvement \nX X X X X X X X \nDeep recto-vaginal \nseptum endometriosis \nwith intestinal \nperitoneal \ninvolvement \nX X X X X X X X \nDeep recto vaginal \nseptum; RVS-B-R \nwithout bowel \ninvolvement \n X X X X X X X \nTable 8. Relationship between type of pain and localization of endometriosis in study III/a.  \n \nThe findings from Study III/a, indicate a significant relationship between the \nlocalization of endometriosis and the type of pain experienced by participants. \nNotably, deep involvement of endometriosis, whether in the ovaries, peritoneum, or \nrecto-vaginal septum, was associated with a broader range of pain symptoms, \nincluding dysmenorrhea, dyspareunia, bloating, obstipation, diarrhea, dysuria, and \nbloody defecation. In contrast, superficial peritoneal involvement did not report \nspecific pain types in this study. \nThese results highlight the diverse and often severe symptomatology associated with \ndifferent localization of endometriosis. The presence of pain in multiple locations and \nof various types underscores the complexity of diagnosing and managing \nendometriosis. It also emphasizes the need for a comprehensive and individualized \napproach to treatment, considering the specific localization and symptom patterns in \neach case. \n\n49 \nTime (months) Moderate Significant Complete Total \n1st 3 months         \nNo 7 52 53 112 \n  46.70% 74.30% 88.30% 77.20% \nYes 8 18 7 33 \n  53.30% 25.70% 11.70% 22.80% \nTotal 15 70 60 145 \n  100.00 % 100.00% 100.00 % 100.00% \n1st 6 months         \nNo 4 52 55 111 \n  40.00% 75.40% 84.60% 77.10% \nYes 6 17 10 33 \n  60.00% 24.60% 15.40% 22.90% \nTotal 10 69 65 144 \n  100.00 % 100.00% 100.00 % 100.00% \n1st. 12 months         \nNo 5 44 51 100 \n  31.30% 77.20% 86.40% 75.80% \nYes 11 13 8 32 \n  68.80% 22.80% 13.60% 24.20% \nTotal 16 57 59 132 \n  100.00 % 100.00% 100.00 % 100.00% \nTable 9. Comparison of the improvement in symptoms after surgery across the different stages of \nfollow-up in patients with endometriosis in Study III/a. \n \nAt the first 3 -month follow-up, the Chi -square test revealed a statistically significant \nassociation between the level of symptom improvement and the follow -up period, χ² \n(2) = 12.524, p = 0.002. This indicates that the differences in symptom improvement \nlevels among patients are not due to chance. At the 6 -month follow-up, the Chi-square \ntest again, showed a statistically significant association, χ² (2) = 9.988, p = 0.007. This \nsuggests that the variation in symptom improvement observed among patients at this \nstage is statistically significant and unlikely to be due to random variation. At the 12 -\nmonth follow-up, the Chi -square test results were χ² (2) = 20.988, with a p -value of \nless than 0.001. This indicates a very strong statistical significance, suggesting that the \ndifferences in symptom improvement levels among patients at one -year post-surgery \nare highly unlikely to be due to chance. \nAcross all three follow -up periods (3, 6, and 12 months), the Chi -square tests \nconsistently indicate statistically significant differences in symptom improvement \namong patients with endometriosis who underwent surgery. These results suggest that \nthe level of improvement in symptoms varies significantly among patients over time, \nunderscoring the importance of individualized postoperative care and monitoring. \n \n\n50 \nSymptoms First \nmonth visit \nSixth \nmonth visit \nFirst year visit \nDysmenorrhea <0.001 <0.001 <0.001 \nDyschezia <0.001 <0.001 <0.001 \nDyspareunia <0.001 <0.001 <0.001 \nBlooting (abdominal swelling) <0.001 <0.001 <0.001 \nObstipation (intestinal obstruction) 0.585 0.700 0.701 \nDiarrhea <0.001 <0.001 <0.001 \nDysuria <0.001 <0.001 <0.001 \nBloody defecation <0.001 <0.001 <0.001 \nCrushing pain <0.001 <0.001 <0.001 \nObtuse pain 0.006 <0.001 <0.001 \nSharp pain <0.001 <0.001 <0.001 \nTable 10. Improvement of individual endometriosis-related symptoms and quality of life 12 months \nafter surgery in Study III/a.  \n \n 95% confidence interval \nVisit Improvement Chi-\nsquare \ndf Sig. Odds \nratio \nLower Upper \n1 month Little improvement less than \n50% \n1.253 1 0.263 0.000 0.000 0.000 \nModerate improvement of \nsymptoms 50- 60% \n30.418 1 <0.001 0.052 0.012 0.220 \nSignificant improvement of \nsymptoms 70- 80% \n0.823 1 0.364 1.152 0.012 0.220 \nComplete improvement os \nsymptoms 90- 100% \n2.125 1 0.145 1.254 0.925 1.702 \n6 months Moderate improvement of \nsymptoms 50- 60% \n29.912 1 <0.001 0.000 0.000 0.000 \nSignificant improvement of \nsymptoms 70-80% \n2.3519 1 0.126 1.272 0.935 1.731 \nComplete improvement of \nsymptoms 90-100% \n0.224 1 0.636 1.076 0.758 1.445 \n1 year Moderate improvement of \nsymptoms 50- 60% \n32.478 1 <0.001 0.000 0.000 0.000 \nSignificant improvement of \nsymptoms 70-80% \n3519 1 0.061 1.371 0.986 1.908 \nComplete improvement of \nsymptoms 90-100% \n0.077 1 0.782 1.047 0.758 1.445 \nBeyond 1 \nyear \nModerate improvement of \nsymptoms 50- 60% \n13.988 1 <0.001 0.000 0.000 0.000 \nSignificant improvement of \nsymptoms 70- 80% \n86.37 1 <0.001 6.850 4411 10.637 \nComplete improvement of \nsymptoms 90-100% \n65.441 1 <0.001 3.837 2.749 5.356 \nTable 11. Post-surgery well-being and quality of life of endometriosis patients in Study III/a. \n \n\n51 \n \nFigure 15. The post-surgical outcome regarding general well-being during the follow-up period beyond \n12 months in Study III/a. \n \nThe study employed the Wilcoxon Signed -Rank Test to compare the improvement in \nsymptoms of patients with endometriosis at various follow-up intervals post-surgery: 1 \nmonth, 6 months, 1 year, and beyond 1 year. The improvement was categorized as: no \nchanges of symptoms (0 -20% improvement), little improvement (less than 50%), \nmoderate improvement (50 -60%), significant improvement  (70-80%), and complete \nimprovement (90-100%). \nAt the 1 -month follow -up, 49% of patients reported complete improvement (90 -\n100%), and 46% reported significant improvement (70-80%). By the 6 -month follow-\nup, the percentage of patients reporting complete improvement increased slightly to \n54%, while those reporting significant improvement decreased to 42%. At the 1 -year \nmark, the percentages remained stable for complete improvement (54%) but decreased \nfor significant improvement  (35%). Beyond 1 year, the proportion of patients \nreporting complete improvement decreased to 42%, and significant improvement  \nfurther decreased to 26%. \nThe Wilcoxon Signed -Rank Test results indicated statistically significant differences \nbetween the follow-up periods: \n• 6 Months vs. 1 Month: \nThere was a statistically significant difference in the improvement of symptoms \nbetween the 1-month and 6-month follow-ups, with a greater improvement observed at \n6 months. (Z = 6.714, Asymptotic Significance (2-tailed) < 0.001.) \n• 1 Year vs. 6 Months: \n\n52 \nThe improvement in symptoms was significantly different between the 6-month and 1-\nyear follow-ups, indicating continued improvement over time. (Z = 3.81, Asymptotic \nSignificance (2-tailed) < 0.001.) \n• 1 Year vs. 1 Month: \nA statistically significant difference was observed in symptom improvement between \nthe 1-month and 1-year follow-ups, suggesting substantial improvement over the first -\nyear post-surgery. (Z = 7.362, Asymptotic Significance (2-tailed) < 0.001.) \nThe findings indicate a significant improvement in symptoms of endometriosis in the \nfirst year following surgery, with the most notable improvements observed between \nthe 1-month and 6-month follow-ups. The level of improvement appears to stabilize or \nslightly decrease beyond one -year post -surgery. These results underscore the \neffectiveness of the surgical intervention in the short term and highlight the need for \nongoing monitoring and management of symptoms in the long term. \n \n \nFigure 16. Relationship between well-being and infertility following surgery in Study. \nIII/a. \n\n53 \n(There was a significant correlation between the rate of improvement and pregnancy \nafter 1 month (Cramer’s V = 0.218; 2 (3) = 31.847; p <0.001) and 6 months after \nsurgery (Cramer’s V = 0.213; 2 (2) = 30.302; p <0.001), 1 year after the intervention \n(Cramer’s V = 0.232; 2 (2) = 33.510; p <0.001), and on a visit later than 1 year \n(Cramer’s V = 0.303; 2 (2) = 43.513; p <0.001). \n \nFigure 17. Effect of surgery on the quality of life during follow-up in Study III/a \n \nThe study assessed the well -being of respondents with various complaints associated \nwith endometriosis, measured at three different time points post -treatment: after 1 \nmonth, 6 months, and 1 year. Well-being was quantified on a scale from 0% (worst) to \n100% (best). The complaints evaluated included hematochezia, dyschezia, dysuria, \nobstipation, diarrhea, crushing pain, bloating, sharp pain, dysmenorrhea, dyspareunia, \nand obtuse pain. \n \n• Hematochezia: Well -being scores improved marginally from 80% after 1 \nmonth to 81% after 6 months, and to 82% after 1 year. \n• Dyschezia: Scores for dyschezia showed a slight improvement from 80% after \n1 month to 82% after both 6 months and 1 year. \n\n54 \n• Dysuria: Well-being scores increased from 81% after 1 month to 82% after 6 \nmonths, and further to 83% after 1 year. \n• Obstipation: Scores improved from 81% after 1 month to 83% after 6 months, \nand to 84% after 1 year. \n• Diarrhea: There was an improvement in well -being from 82% after 1 month to \n83% after 6 months, and to 84% after 1 year. \n• Crushing Pain: Scores increased from 82% after 1 month to 84% after both 6 \nmonths and 1 year. \n• Bloating: Well-being scores improved from 82% after 1 month to 84% after 6 \nmonths, and to 85% after 1 year. \n• Sharp Pain: Scores for sharp pain showed an improvement from 82% after 1 \nmonth to 84% after both 6 months and 1 year. \n• Dysmenorrhea: Well-being scores increased from 83% after 1 month to 84% \nafter 6 months, and to 85% after 1 year. \n• Dyspareunia: Scores improved from 83% after 1 month to 84% after 6 months, \nand to 85% after 1 year. \n• Obtuse Pain: Well -being scores for obtuse pain showed an improvement from \n83% after 1 month to 85% after both 6 months and 1 year. \n \nThe findings indicate a gradual improvement in the well -being of respondents across \nall complaints over the course of one year following treatment. The most notable \nimprovements were observed in symptoms such as bloating, dysmenorrhea, \ndyspareunia, and obtuse pain, where well -being scores increased by 3 percentage \npoints over the year. While the improvements in well -being for each symptom were \nmodest, the consistent upward trend across all complaints is encouraging. \n \nThese results suggest that the treatment provided had a positive impact on the well -\nbeing of patients with various endometriosis -related complaints. The gradual nature of \nimprovement underscores the importance of ongoing management and support for \nindividuals with endometriosis.  It also highlights the chronic and often fluctuating \ncourse of endometriosis symptoms, necessitating long -term strategies for symptom \nmanagement and patient support. \n \nIn the second arm of the study,  all patients were Caucasian. A higher level of \neducation and higher income category was reported in 81.6% of the enrolled patients. \n\n55 \nThe mean age at diagnosis was 34.2 ± 5.97 years (22 –48 years). The mean duration of \ninfertility was 3.8 ± 2.1 years. The mean duration between symptom onset and \ndiagnosis was 9.7 ± 0.35 years. The most reported  complaints or symptoms were \ninfertility in 70.1%, dysmenorrhea in 82.8%, dyspareunia in 60.9%, bloating in 93.1%, \nand urinary discomfort in 49.4% (Table 12). During surgery, the involvement of the \nleft ovary as a single affected organ was more frequently observed (42.5%), while \nrecto-vaginal septum involvement or superficial peritoneal implants were found in \n55.2% and 66.7%, respectively. The third stage of endometriosis was the most \nfrequently observed (48.3%). \n \nNRS-11 scale data analyses revealed a mean preoperative pain score of 6 –10 \n(moderate to severe pain) in 85/87 patients (94.8%). Postoperative pain perception \nimproved to an average 0 –2 score (none or slight periodic discomfort) in 71/87 \npatients (81.6%). Before surgery, the average VAS score was 8 –10 (moderate to \nsevere pain) in 82/87 patients (94.3%). Postoperative VAS score declined to 0.47–0.89 \n(minimal to no pain) in 81/87 patients (93.1%) (Figure 19). The completion rate was \n100%, except for three cases of pregnancy. Post surgically, all patients reported \nsignificant changes and improvements in QoL (Table 13, Figure 18). \n \nWhen considering different types of complaints associated with endometriosis in the \nstudy, we found that the most frequent complaint was pricking pain/discomfort, while \nthe least frequent was rectal bleeding (Table 13). When considering QoL indicators, \nwe found a marked improvement in all indices (Table 14, Figure 20). \n \nAll the Mauchly variance homogeneity tests proved heteroscedasticity. Regarding \nMANOVA testing for the differences among the changes in emotions over time, all \ntests showed significant decreases in all depressing problems and emotions after \nsurgery (Table 13, Figure 18). \n \n \n \n \n \n \n \n\n56 \nGeneral Characteristics of women with endometriosis in this study (n=87) \nMean Age at menarche (years) 13.2 ± 1.293 (9–17) \nMean Age at diagnosis of endometriosis (years) 34.2 ± 5.97 (20–48) \nMean Age at the onset of symptoms relating to endometriosis (years 24.5 ± 5.71 (15–37) \nDuration of infertility (years) 3.8 ± 2.1   \nDuration of symptoms before diagnosis (years) 9.7 ± 0.35 \nCharacteristics Types Number (n) Percentage \n(%) \nLocalization of \nendometriosis \nSuperficial/Deep left ovary involvement 37 42.6 \nDeep right ovary involvement 14 16.2 \nBilateral ovary involvement 27 31 \nSuperficial (RVS)/Deep rectovaginal septum \ninvolvement \n62 71.3 \nSuperficial bladder involvement 48 55.2 \nDeep bladder involvement 10 11.5 \nIntestinal involvement 13 14.9 \nSuperficial peritoneal involvement 58 66.7 \nAdenomyosis 10 11.5 \nOther surgical \nprocedures \nAdhesiolysis 61 70.1 \nBladder resection 8 9.2 \nDixon operation 2 2.3 \nRelapse of endometriosis 5 5.7 \nStages of \nendometriosis \n1 3 4.9 \n2 12 19.7 \n3 29 47.5 \n4 17 27.9 \nOther complication Endometrioid carcinoma 1 1.6 \nFertility Preoperative infertility issue 61 70.1 \nMode of pregnancy Spontaneous pregnancy 23 37.7 \n IVF-ET 9 14.1 \nOutcome of \npregnancy \nSpontaneous delivery 17 53.1 \nCesarean section 7 21.9 \nMissed abortion 4 12.5 \nLost to follow up 3 9.4 \nPreoperative pain \nscore (NRS–11) \nModerate to severe pain 85 94.8 \nPostoperative pain \nscore (NRS–11) \nMild to no pain 71 81.6 \nPreoperative VAS \nscore \nModerate to severe pain 82 94.3 \nPostoperative VAS \nscore \nMinimal to no pain 81 93.1 \nAdditional factors Family history of endometriosis ** 15 \nHigh red meat/fish ** *** \nSmoking (≥5 cigarettes/day) 17 19.5 \nAlcohol consumption (beer/wine regularly) 8 9.2 \nAlcohol consumption (gin/whisky regularly) 14 16.1 \nCoffee consumption (>1 cup/daily) 29 33.5 \nMenstrual history Bleeding disorder (metrorrhagia) 57 66 \n Cycle dysfunction (spotting) 43 49 \nMiscellaneous \nissues \nUse of sanitary napkins (solely to more regularly) 63 72 \nTable 12. General characteristics of women with endometriosis in Study III/b.  \n \n \n\n57 \nEmotion Test Value F Hypothes\nis df \nError df Sig. \nExhausting emotionally Wilks' Lambda 0.129 189.285 3 84 <0.001 \nSickening emotionally Wilks' Lambda 0.275 73.854 3 84 <0.001 \nUnbearable emotionally Wilks' Lambda 0.117 211.495 3 84 <0.001 \nMiserable emotionally Wilks' Lambda 0.136 176.23 3 83 <0.001 \nTorturing emotionally Wilks' Lambda 0.115 215.733 3 84 <0.001 \nDepressing emotionally Wilks' Lambda 0.123 198.814 3 84 <0.001 \nAffect your work negatively Wilks' Lambda 0.165 141.547 3 84 <0.001 \nAffect your learning \nnegatively \nWilks' Lambda 0.188 121.096 3 84 <0.001 \nTable 13. Comparison of emotional assessment of individuals before and after surgery according to the \ntiming of follow-up (6, 12, and 24 months) in Study III/b. \n \n \nWomen’ s emotional, socioeconomic and physical state assessment before surgery \nAssessment Very bad (0-20%) 7-\n16 score \nBad (20-50%) 5-7 \nscore \nSatisfactory (60-\n70%) 3-5 score \nGood (80-100%) 0-\n3 score \nCharacteristics n % n % n % n % \nQuality of life 47 54.0% 31 35.6% 8 9.2% 1 1.1% \nGeneral wellbeing 48 55.2% 33 37.9% 6 6.9% NA NA \nSexual problems \n(dyspareuma) \n34 39.1% 22 25.3% 19 21.8% 12 13.8% \nUrinary-problems 5 5.7% 25 28.7% 12 13.8% 45 51.7% \nAll painful \ncomplaints \nassociated with \nendometriosis \n53 60.9% 34 39.1% NA NA NA NA \nDyschezia 8 9.2% 30 34.5% 19 21.8% 30 34.5% \n         \nCharacteristics No improvement \n/relapse/ (0-20%) 7-\n10 score \nLittle improvement \n(20-50%) 5-7 score \nModerate \nimproyement (60-\n70%) 3-5 score \nSignificant/Comple\nte improyement \n(80-100%) 0-3 \nscore \n  n % n % n % n % \nQuality of life 5 5.7% 1 1.1% 2 2.3% 79 90.8% \nGeneral wellbeing 1 1.1% 4 4.5% 19 21.8% 63 72.4% \nSexual problems \n(dyspareuma) \n2 2.2% 6 6.8% 4 4.6% 75 86.2% \nUrman-problems NA NA 1 1.1% 6 6.9% 80 92.0% \nAll painful \ncomplaints \nassociated with \nendometriosis \n2 2.2% 5 5.7% 9 10.3% 71 81.6% \nDyschezia NA NA 2 2.2% 8 9.1% 77 88.5% \nTable 14. Improvement in quality of life and general well-being after surgery in women with \nendometriosis in Study III/b. \n \n \n \n\n58 \nFigure 18. Psychological-emotional assessment of individuals before and after surgery according to \ndifferent follow-up intervals (April to June 2 and 24 months) in Study III/b. \n \n \n \nMultivariate Tests Value F Hypothesis df Error df Sig. \nPillai’s Trace 0.933 391.797b 3 84 <0.001 \nWilks’ Lambda 0.067 391.797b 3 84 <0.001 \nHotelling’s Trace 13.993 391.797b 3 84 <0.001 \nRoy’s Largest Root 13.993 391.797b 3 84 <0.001 \nFigure 19. Comparison of NRS-11 and VAS scores before and after surgery according to the timing of \nfollow-up (6, 12, and 24 months) in Study III/b. \n[Because the Mauchly variance homogeneity test proved heteroscedasticity (chi-\nsquared (5) =113.835, p<0.001), we also used MANOVA for testing the differences \namong the pain rating changes over time. The MANOVA tests proved a significant \ndecrease in all pain after surgery] \n\n59 \n \n \nFigure 20. EHP-36 scores before and after surgery at different follow-up intervals (6, 12, and 24 \nmonths) in Study III/b. \n \n \n \nTests Value F Hypothesis df Error df Sig. \nPillai's Trace 0.526 31.02 3 84 <0.001 \nWilks' Lambda 0.474 31.02 3 84 <0.001 \nHotelling's Multivariate \nTrace 1.108 31.02 3 84 <0.001 \nRoy's Largest Root 1.108 31.02 3 84 <0.001 \nFigure 21. EHP -36 scores before and after surgery at different follow -up intervals (6, 12, and 24 \nmonths) in Study III/b. \n \n\n60 \n8.3.4. Discussion \nOur study focused on the potential positive effects of hysterolaparoscopy on the QoL \nof patients suffering from endometriosis. The economic burden that endometriosis \nimposes on individuals and society is significant [97]. In 2012, an endometriosis \nsurvey in the UK revealed that approximately 1.6 million women were affected, with \nan estimated financial burden of £10.6 billion [86, 260, 261]. In Australia, \napproximately 550,000 women have endometriosis, costing £2.75 billion [119, 262, \n263]. In the United States, approximately 7.6 million women are affected, with \nfinancial implications of approximately £52.1 billion per year due to loss of work and \nhealthcare costs [260, 261]. The accurate prevalence and subsequent economic burden \nof the disease Hungary remains unknown, although a multicenter study estimated an \naffected population of approximately 184,000 women, with an estimated cost of €1.6 \nbillion per year [86, 262, 263]. \nIn the first arm of our study, the average age of the patients and the duration of \ndiagnosis were similar to those reported in other studies [24, 86]. Interestingly, the left \nside of the lower pelvis seemed to be involved more frequently, likely owing to the \nintra-abdominal fluid circulation pattern, which is in a clockwise direction and stops at \nthe pouch of Douglas [40, 264 -266]. This circulation may increase the possibility of \nimplantation of endometriotic cells in an asymmetric pattern [267]. In concordance \nwith other studies, our results demonstrated a possible direct association of \nendometriosis with dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility \n[24, 192, 268]. Endometriosis can significantly lower QoL for women. In our study, \nalmost 95% of women had substantial or complete resolution of symptoms at 1 month \npostoperatively. This result is higher than those of similar studies reporting on QoL \nand sexual performance after laparoscopic surgical treatment for endometriosis [235, \n269-271]. Furthermore, combined hysterolaparoscopy had positive effects on QoL, \nregardless of the stage of the disease. Our results were in line with those of Mabrouk \net al. [176]. Other studies focusing on endpoints, such as dysmenorrhea, dyspareunia, \npelvic pain, dyschezia, and dysuria, have also highlighted the beneficial effect of \nendoscopic surgery on symptom relief [37, 271]. Further improvement in women's \nwell-being and QoL is achievable with the help of combined hysterolaparoscopy [240, \n259]. \nThe second arm of our study demonstrated the usefulness of EHP -36, VAS, and NRS-\n11 questionnaires in evaluating the QoL of patients with endometriosis. Interestingly, \nin this arm, the mean age of onset of initial symptoms was 24.5 ± 5.71 years, similar to \n\n61 \nother studies that demonstrated the first symptom onset between 20 and 29 years of \nage [273, 274]. In the first arm of the study, we found the mean age for first symptoms \nto be 29.1 years. This finding does not contradict the literature, and this value overlaps \nwith the standard deviation of our first arm data (29.1 ± 4.3 years). We believe that \nthere is a shift in general awareness of endometriosis in society, and within decades \nwe will likely experience significantly earlier detection rates, partly due to earlier \npersonal detection of alarming signs and symptoms and due to better public education \nand awareness. Furthermore, in the second arm of our study, the average age of \ndiagnosis was 34.2 ± 5.97 years (20 –48 years). This value is in line with our findings \nin the first arm of the study. The question might be raised, as to why there might be a \nlonger duration between onset of first symptoms and definitive diagnosis in the second \narm. Because of the difference between the study samples of the two arms, we were \nnot yet able to draw firm conclusions. This field requires further studies involving a \nlarger number of participants. The negative effect of endometriosis on physical well -\nbeing significantly improved after surgery, as demonstrated by VAS and NRS pain \nscore analyses (8.0 ± 2.11 score before surgery vs. 0.47 ± 1.25 score after surgery). It \nis an improvement that is in line with the results of a study conducted by Alborzi et al. \nin 2017, where the initial score of 8.23 ± 2.03 decreased to 4.46 ± 2.47 in 93% of \npatients [250]. The positive effect of surgery on socio -emotional well-being that was \ndetected by the modified EHP -36 questionnaire was like the results of earlier studies \n[127, 275, 276]. \nIn summary, the EHP -36 instrument, in addition to the VAS and NRS -11, is a useful \ntool in the evaluation of the QoL of patients experiencing the misery of endometriosis, \nespecially in a comparative setting applied pre- and postoperatively. \n \n9. SUMMARY OF RESULTS \nOur study comprised two major parts. In the first part, three retrospective studies \ninvolved collection of patients’ information from the hospital database. Study I \nrecorded 28 women with post -cesarean section isthmocele who underwent combined \nhysteroscopic and laparoscopic repair. Return of fertility after surgery was 82.4% \n(n=14/17). Endometriosis was found in 16 patients (57.1%), which is high in patients \nin this group who had no previous history of endometriosis prior to the cesarean \nsection. Overall, patient satisfaction was 92.9% (26/28) in terms of improved QoL. In \nStudy II, records were collected of 455 patients with endometriosis -related infertility \nwho were managed with combined radical laparoscopy surgery and ART between \n\n62 \n2010 and 2018. Fertility return was 81.3% (370/455), with 94.2% (327/347) live births \nand 5.8% (20/347) pregnancy loss. Pregnancy occurred spontaneously in 39.5% \n(146/370) of patients, in 3.8% (14/370) of women after AIH, and in 56.8% (210/370) \nafter IVF-ET, with patients aged ≤35 years having a higher chance of conception post -\nsurgery (84% vs. 77%, respectively [p=0.039]). Comparatively, this effect was 91.3% \nvs. 74.1% (p=0.007; OR=3.7; 95% CI=1.4 –9.8) among the ≤35- and >35-year-old age \ngroups, respectively. There was no significant difference in reproductive performance \nin difference stages of endometriosis. \n \nStudy III was based on the records of 777 patients with endometriosis who underwent \ncombined radical hysteroscopy –laparoscopy surgery, incorporated with occasional \nART treatment for those with infertility issues. The postoperative QoL improved \nsignificantly, with 46–49% having moderate to significant improvement, and 35 –54% \nachieving complete resolution of symptoms (p<0.0005). This improvement was \nachieved in the areas corresponding to the most common complaints: dyspareunia \n(80%), dysmenorrhea (74%), and infertility (69%). \n \nThe fourth study was a prospective study of 87 women with endometriosis who were \nrequested to complete a modified EHP -36 questionnaire pre - and post -surgery to \nassess their perspective on endometriosis in terms of their QoL, General WB, and \nfertility. Women underwent combined radical hysteroscopy –laparoscopy surgery \nbased on their conditions and disorders, such as infertility, in which case operative or \ndiagnostic hysteroscopy was always included. There was a significant improvement in \nthe QoL in this group (p<0.001). The VAS for pain score decreased from 8 ± 2.11 \n(86.0%), moderate to severe pain, preoperatively, and to 0.47 ± 1.24 (93.1%) \nnegligible to no pain, postoperatively (p <0.001). Of those women with infertility, \n58.45% (32/61) became pregnant. Analysis showed a loss to follow -up, with 77.4% \n(24/31) live births. Postoperative general well -being was rated “very good” or “good” \nin 94.2% (82/87) of participants. There was a significant improvement observed in \nsexual life, with 86.2% (75/87) of women rating it as “good” or “very good” \n(p<0.001). \n \n10. ANSWERS TO OUR HYPOTHESES \n1. Our results demonstrate a link between history of cesarean section and an increased \nlikelihood of development of endometriosis, supporting our first hypothesis. \n\n63 \n2. Our results demonstrate that combined hysteroscopic and laparoscopic \nendometriosis surgery significantly improved fertility outcomes in patients with \nendometriosis, supporting our second hypothesis. \n3. Our data showed that combined hysterolaparoscopy significantly improved the QoL \nof endometriosis patients. Furthermore, our results proved that the validated EHP -36 \ninstrument, along with the VAS and the NRS-11, were useful tools in the evaluation of \nthe QoL of endometriosis patients, supporting our third hypothesis. \n \n11. GENERAL DISCUSSION \nEndometriosis remains a plague in the lives of many women worldwide. The negative \neffects of the disease range from direct daily health challenges to socio -cultural, \nsocioeconomic, and QoL impairment. Our study provided positive evidence that early \nmeticulous radical laparoscopy surgery significantly improves QoL. The combination \nof hysteroscopy and assisted ART was found to improve overall fertility performance. \nWe demonstrated a positive impact on the QoL with laparoscopy surgical excision of \nendometriotic lesions, as was reported in previous studies [10, 15, 17, 217]. Our first \nstudy demonstrated a controversial view relating to the role of prior surgery on the \nuterus and the possible association with the onset of the disease in support of the \nimplantation hypothesis [36, 54, 55]. Our study demonstrated incredibly high \nfrequency of the disease in this group of patients, with 57.14% (16/28) cases \nsupporting our hypotheses (p˂0.05). Doubts were raised about the possibility of prior \ncesarean section (scar defect) being one of the contributing factors to the onset of \nendometriotic lesions. The mechanism is unknown; however, it could be triggered by \ndirect implantation or by diffusion due to prolonged stagnation of menstrual fluid \ntrapped in the scarred pouch -like structure. Other possibilities, like the inability of the \ndefensive mechanism to remove endometrial tissues disseminated during cesarean \nsection, require consideration. The postoperative outcomes were satisfactory, with \n80% for infertility, 95.65% for LAP, 100% for vaginal discharge, 94.44% for \ndysmenorrhea, and 100% for PMBD; these results are more favorable or similar to \nstudies by Changdong Li et al. and Cuilan Li et al. [278, 279]. \nOur second study demonstrated post -surgical fertility performance with or without \nART. The current prevalence of endometriosis is approximately 1 –2 per 10 women \n[56, 75, 140]. Our study demonstrated that early expert minimal surgical treatment of \nendometriosis-related infertility and timely introduction of ART is currently the most \nfeasible option, and supports our hypotheses [233, 234]. The result showed that the \n\n64 \npregnancy rate improved dramatically after surgery (370/455, 81.3%), with a live birth \nrate of 88.1% (326/370). Our study also demonstrated that the stage of endometriosis \ndid not significantly influence fertility performance, while age had a significant \ninfluence on fertility. This observation is similar to reviews conducted by Jacobson et \nal. and others [233, 236, 238 -240]. The positive outcomes may have resulted from the \nindividualized combined hysterolaparoscopic surgical approach. The inclusion of \nhysteroscopy was necessary because uterine abnormalities and other tubal \nabnormalities contribute to approximately 30 –35% of female infertility issues [155, \n237]. All based on patient desire, the recurrence ratio was low. The expectant \nmanagement option was initially applied before the recommendation of ART was \nconsidered [237]. Patients with primary infertility made up 55.2% (278/504), while \nsecondary infertility made up 30.9% (156/504). The results from this study showed \nthat meticulous and timely surgical management of endometriosis improves fertility \nperformance irrespective of the age, stage, or duration of infertility. \n \nEndometriosis can cause constant debilitating pain, broken homes, loss of jobs, \neconomic burden, and infertility [44]. Many studies have reported financial burdens:  \nabout £10.6 billion in healthcare costs in the UK (2012), about £2.75 billion in \nAustralia, and $52.1 billion per year in the USA [241, 280]. A study conducted by \nBokor et al. estimated €1.6 billion per year, accumulated from out -of-pocket (OoP) \nand national health insurance policies [62,70]. Our study showed direct association of \nendometriosis with dysmenorrhea, chronic pelvic pain (CPP), dyspareunia, and other \nsexual aberrations, which may affect fertility [114, 217, 243]. Our study demonstrated \nthat hysterolaparoscopic surgery significantly positively influenced fertility, as 81.3% \nof patients in all stages of endometriosis became pregnant, with a successful live birth \nrate of 94.2%; these findings are like a study by Kuivasaari et al. [236]. Our study also \nshowed that QoL improved significantly, as close to 95% of women had substantial or \ncomplete resolution of symptoms at 1 month postoperatively; these findings are \nsimilar to a study conducted by Ferrero et al. and Denny E et al. [97, 98]. We observed \na progressive improvement in all indices of the patient’s needs as time elapsed, even \nmore favorable than in the previous studies [106, 224, 226]. \n \nThe most common sites were deep infiltrating recto-vaginal septum endometriosis, left \novarian fossa and endometrioma, and right ovarium fossa. Our study demonstrated the \n\n65 \ncorrelation between the localization of the endometriosis and the degree and type of \npresenting pain-associated symptoms. Our last study demonstrated the usefulness of \nthe EHP-36, VAS, and another questionnaire in evaluating the QoL and General WB \nin patients with endometriosis before and after radical laparoscopic surgery. Our \nfindings were similar to other studies in this regard [258, 259]. The study exposed \nsome of the unbearable suffering that women with endometriosis encounter daily (e.g., \nself-reported depression and anxiety). Post -surgical follow-up outcomes demonstrated \nsignificant improvements in all areas (all p <0.001) (Table 13–15, Figure 18–21). \n \nThe average pain score gradually decreased from 8.0 ± 2.11 points before surgery to \n0.47 ± 1.25 points after surgery, higher than that reported in a study conducted by \nAlborzi et al. [263-265]. Our study demonstrated significant improvement in reducing \nor eliminating those agonizing physical, emotional, and socioeconomic deprivation \ncaused by endometriosis; close to 93.1% of patients reported improvement in their \nQoL. Other studies have not reported outcomes superior to those of our study [263, \n266]. Fertility outcomes also improved, as 52.5% of patients became pregnant; 61% \nhad presented with infertility issues. This observation represents an improvement as \ncompared with other similar studies [110, 271]. Our study did not demonstrate any \nsignificant association between cigarette smoking or alcohol consumption and \nendometriosis, in concordance with studies conducted by Bravi et al. in 2014 and \nThylan in 1995 [273, 274]. We could not confirm any associated eating habits and/or \ntypes of food, or a direct link between other medical conditions and endometriosis. \nHowever, more women reported drinking because of the impact of endometriosis on \ntheir lives, and we observed a slight correlation of 15% with family (genetic) history \nof endometriosis [126]. Other observation included a link between endometriosis and \nthe use of sanitary napkins (pads) (63/87; 72%) and tampon use, findings that were \nsimilar to a study conducted by Kamalifard et al. [276]. \n \n12. CONCLUSION \nBased on the results from our studies, only large and comprehensive studies can \nconfirm the assertion that tissue dissemination –by direct or diffusion process as a \nresult of some surgical procedures –could induce the development of endometriosis. \nExcessive or improperly performed obstetric and gynecological surgical interventions \n(i.e., abortions, HSG, and other gynecological interventions) could also cause tissue \ndissemination. Our study contributed to the literature by providing new perspectives \n\n66 \nand approaches to managing obstetric and gynecological cases, including information \non the potential etiological aspects of the implantation theory of endometriosis. The \nstudies also ascertained that combined hysterolaparoscopy treatment was an efficient \nand reliable procedure; it enhanced women’s well -being and QoL and significantly \nimproved reproductive performance. The study also demonstrates a correlation \nbetween the site of endometriosis and association with pain -related and other \nsymptoms. \n \nThe integration of a modified EHP -36 questionnaire could provide service providers \nwith a broader scope for accessing women in outpatient clinics, with an early \nsuspicion of endometriosis as the background disease behind the patient’s symptoms, \nthereby reducing the frequency of delayed diagnosis.  \nIn conclusion, our study highlighted that radical combined hysteroscopy –laparoscopy \nor laparoscopic surgery significantly improved fertility performance and, moreover, \nimproved the QoL and general well -being of patients. Our study also showed that the \nprocedure was safe in the hands of an expert endoscopy surgeon. The postoperative \noutcomes highlighted the significant improvements achieved in relieving some of the \nsocioeconomic burden of individuals or society in general as a result of endometriosis. \n \n13. PUBLICATIONS RELATED TO THE THESIS: \n1. Ekine AA, István F, & Árpád R, & István T, & Boldizsár N. Endoscopic surgical \ntreatment of isthmocele and its probable link with endometriosis. A 3 -years \nretrospective review of combined laparoscopic and hysteroscopic surgery. Indian J \nObstet Gynecol Res. 2018; 5:458–464. 10.18231/2394-2754.2018.0105.(IF:1.34) \n2. Ekine AA, Fülöp I, Tekse I, Rúcz Á, Jeges S, Koppán Á, Koppán M. The Surgical \nBenefit of Hysterolaparoscopy in Endometriosis -Related Infertility: A Single Center \nRetrospective Study with a Minimum 2 -Year Follow-Up. J Clin Med. 2020. február \n13.; 9(2):507. doi: 10,3390/jcm9020507. PMID: 32069800; PMCID: PMC7073634. \n(IF: 3.9) \n3. Ekine AA,  Fülöp I, Tekse I, Kovács Z, Siklós P, Koppán Á, Koppán M. \nEffectiveness of Combined Hysterolaparoscopy on the Quality of Patients with \nEndometriosis: A Retrospective Review in Hungary. J Women's Health Dev. 2020; \n3:032–055. (IF: 1.1) \n4. Ekine AA , Fülöp I, Racz A, Koppan A, Siklós P, Koppan M. The benefits of \nRadical Laparoscopic Surgery and a Modified Endometriosis Health Profile–36 (EHP–\n\n67 \n36) on Quality of life.  Journal of Women's Health and Development 3 (2020):379 -\n397. (IF: 1.1) \n \n14. AUTHOR’S PUBLICATIONS NOT RELATED TO THE THESIS \n1 Ekine AA, Israel J, Tubotonye H, Levi WO. Factors influencing the prevalence of \nPreeclampsia-eclampsia in booked and unbooked patients: 3 years retrospective \nstudy in NDUTH, Okolobiri. . World J Med Medical Sci. Jan 2015;3(1):1 –14. \nISSN: 2330—1341 [Online] \n2 Ekine A.A,  Isioma AJ, Levi WO. Influence of Culturally based Abdominal \nMassage and Antenatal Care Uptake among Pregnant Women in a Tertiary \nHospital in Southern Nigeria. J Adv Med Med Res. 2016;18(6):1 –9. \nhttps://doi.org/10.9734/BJMMR/2016/27109 \n3 Lawani L, & Iyoke C, & Onoh R, & Nkwo P, & Ayuba II, & Ekwedigwe K, \nEkine AA . Obstetric benefits of health insurance: A comparative analysis of \nobstetric indices and outcome of enrollees and non -enrollees in southeast Nigeria. \nJ Obstet Gynaecol. 2016;36. 10.1080/01443615.2016.1174830. \n4 Ekine AA , Lawani L, Iyoke C, Jeremiah I, Ayuba II. Review of the Clinical \nPresentation of Uterine Fibroid and the Effect of Therapeutic Intervention on \nFertility. Am J Clin Med Res. 2015; 3:9–13. 10.12691/ajcmr-3-1-2. \n5 Abasi I, Jeremiah I, Ekine AA. Risk Factors and Pregnancy Outcome of Placental \nAbruption at the Niger Delta University Teaching Hospital, Okolobiri, South -\nSouth Nigeria. Br J Med Med Res. 2015; 5:1000 –1006. \n10.9734/BJMMR/2015/12842. \n6 Ayuba II, Obilahi A, Ekine A.A. The Safety of Induction of Labour in the Niger \nDelta Region. J Med Sci. 2012; 2:173–178. \n7  Fülöp I, Ekine A A,  Tekse I, Rucz Á, Siklos P. Isthmocele: Successful Surgical \nManagement of an Under -Recognized Iatrogenic Cause of Secondary Infertility; \n2017 \n8 Ekine AA,  West LO, Gani O. Awareness of Female Health Workers and Non -\nHealth Workers on Cervical Cancer and Cervical Cancer Screening: South – \nSouth, Nigeria. Int J Med Sci Clin Invent. 2015;2. \n9 Ekine AA , Udoye PE, West OL. Determinants and Factors influencing the \nprevalence of uterine rupture in a tertiary rural hospital in the Niger Delta: A 5 -\nyear retrospective study in NDUTH, Okolobiri. Pharma Innov. 2015;4(2):97–101. \n\n68 \n10 Ekine AA , West OL, Adhuze JI. Patients Attitude towards Antenatal care and \nFactors Determining its Uptake in Rural Communities in the Niger Delta, Nigeria. \nJ Pharm Biomed Sci. 2015;05(04):344–350. Available at www.jpbms.info \n11  Ekine AA, Abasi I. Socio-Cultural and Economic Influence in the Incidence of \nObstructed Labor: 5 Years Review in NDUTH ISSN 2278 – 0211 (Online),2015 \n12  Ayuba II, Oyeyemi AS, Ekine AA. Knowledge, attitude, and practice of female \ngenital mutilation among doctors and nurses in Yenagoa, Niger -Delta of Nigeria. \nInt J Med Biomed Res. 2013;2(1):40–47. \n13  Ekine AA , Ikeanyi A E, Abasi I, Ayuba II. Risk factors, challenges, and \nmanagement of post -partum haemorrhage in Nduth, Okolobiri, Nigeria: A 5 -year \nexperience. Aejpmr. 2014;1(1):168–182. \n14 Ikeanyi AE, Israel J, Ekine AA . Teenage Pregnancy and Obstetric Outcome: A \nComparative Study in Urban Nigeria (2020). \n15 Ikeanyi AE, Israel J, Ekine AA . An Appraisal of Awareness and Practice of \nModern Contraception among Prenatal Clinic Attendees in Southern, Nigeria \n(2020). \n16 Ekine AA, Rúcz Á, Veres V, Csáthy L, Tsehai N, Kovács Z. Maternal Distress \ndue to Spontaneous Antepartum Rupture of Unscarred Uterus with a Live Fetus in \nthe Abdominal Cavity at 31 Weeks: A Case Report and Literature Review, (2021) \n17 Ekine AA , Udoye EP, et al. Spontaneous Bilateral Ruptured and Unruptured \nTubal Ectopic Pregnancies: A Case Report and Literature Review from Niger \nDelta, Nigeria. Int J Med Res Health Sci. 2014;3(4):1028–1033 \n18 Ekine AA, Ibrahim IA, Unachukwu CE, Jeremiah I, West O, Akanate ID. Acute \nabdomen as a result of unsuspected spontaneous heterotopic pregnancy with tubal \nrupture: a case report and review of the literature. Int J Curr Res. \n2019;11(03):2028–2031. \n19 Kovács, Z.; Ekine A.A , E.; Hegyi, G.; Szőke, H. The Effect of Aviva Exercise \nIntervention on Pain Level and Body Awareness in Women with Primary \nDysmenorrhea. Medicina 2024, 60, 184. \nhttps://doi.org/10.3390/medicina60010184 (IF: 2.6) \n\n69 \n15. ACKNOWLEDGEMENTS \nI thank the directors and the management staff of Róbert Private Hospital for granting \nme the opportunity and enabling me to use the hospital materials for my research. I \nwholeheartedly thank my supervisors Prof. Miklos Koppán and Dr. Ágnes Koppán for \ntheir professional and moral support during this period. I also thank my colleagues, Dr. \nIstván Fülöp, Dr. Pál Siklós, and Dr. Árpád R ucz for their professional and personal \nsupport. I would also like to express my thanks to all the other staff of the hospital, the \nDepartment of Obstetrics and Gynecology, the administrative staff, and nurses of the \nassisted reproductive units and Proprietors of the Róbert Private Hospital, who have \nalso been supportive and encouraging. The lecturers and other doctoral students have \nproven to be wonderful listeners and the opportunities we had to share our concerns \nand triumphs with one another certainly helped the long years feel less lonely. I also \ngive thanks to a good friend who completed most of the statistical editing of the \ndocument. I give special thanks to the women who participated in the studies and \ncommitted their time to talk about their life experiences with endometriosis and \npostsurgical outcomes, and for their selfless and fantastic approach. Perhaps more than \nthat, however, they gave something of themselves as they discussed with me about \nintimate, sad, frustrating, and distressing times. It was also wonderful to hear of some \nof their very special moments of joy. I am extremely grateful for their participation \nand their interest in this study. Finally, I would like to thank my family and special \nfriends for supporting my efforts in various ways and having given unstinting support \nand encouragement along the journey. \n \nThank you. \n\n70 \n16. REFERENCES \n1. Ballweg ML. 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Reprodução & Climatério. 2013; 31:48–\n54. \n276.  Setälä M, Härkki P, Matomäki J, Mäkinen J, KössiJ. Sexual functioning, quality of \nlife and pelvic pain 12 months after endometriosis surgery including vaginal resection. \nActa Obstetricia et Gynecologica Scandinavica. 2012; 91:692–698. \n\n91 \n17. ANNEX \nNo. 1 Annex 1:  Checklist for Postsurgical retrospective study II-III \nA: General information \nAt what age symptoms appeared: … \nMenarche… years old, Last menstruation… \nCycle regular: yes / no \nCycle length: days. \nDuration of menstruation: \nPregnancy number… Abortion number… / Date….… \nNumber / date / method of birth \n……………………………………………………………. \nB. Present complaints: \nDysMenorrhea: \nDysChesia: \nDysPareunia: \nObstipation: \nPuffiness: \nDiarrhea: \nPencil-like stools: \nHaematoChezia: \nDysUria: \na Present complaints / onset (pain) (<1 year,> 1 year, <3,> 3 years, <5 years,> 5 \nyears, <10 years,> 10 years) When did the pain begin in your life? \nb Location and types of pain: Convulsive, dull, Sharp, (lower abdomen and \nwaist, abdomen and back, other pain, does it radiate to the rectum or bladder?) \nc  History of abdominal surgery (day and date) \nd Other diseases… \nInfertility complaints. \na Duration: (> 1 year, <3 years,> 3 years, <5 years,> 5 years, <10 years,> 10 \nyears) \nb Reason: (Female / male, both, unknown?) \nc Have you had this IVF / AIH before? (yes / no), effectiveness... \nd Postoperative IVF / AIH? (yes / no), successful / unsuccessful \ne Other conditions (hyperprolactinaemia, myoma, galactorrhea, insulin resist, \nhypo-hyperthyroidism, polypus endomy, uterine anomaly (septum), ovarian \ncyst, PID, Synechia or Asherman syndrome, other lesions, etc.) \n\n92 \nC: Status (endometriosis): \na Endometrioma (left or right or both sides) Single-compartment or \nmulticompartment \nb peritoneal (as a surgical finding) \nc adenomyosis \nd deeply infiltrating, if so, where… \nEndometrium Stadium: 1) I.std., 2) II.std., 3) III.std., 4). IV.std. \nD: Establishing a diagnosis of endometriosis \na Routine ultrasound examination \nb Laparoscopy \nc During laparotomy \nd Anamnestic? \nE: Surgical interventions: \na CHT: tuba permeability after peritubary adhesion or spontaneous \nb sychneciolyis hysteroscopica (yes / no) \nc Septum eradication (yes / no) \nd Salpingectomy \ne cystectomy (right / left) \nf EEPL, EEDL, AEOL, Laser (excision of endometriosis Douglasi et \nperitonealis, ablation of endometriosis ovarii laparoscopy) \ng adhaesiolysis intraabdominalis \nF: Events after the intervention: \na Has pregnancy occurred (yes / no) \nb How to conceive (spontaneous / AIH / IVF-ET) \nc The course of pregnancy (childbirth / abortion) ... \nd Time between surgery and pregnancy (months) \ne After pregnancy, did the patient leave for another institution? (Yes No) \nf Patient did not return to the institution after surgery (LTFU = lost to follow-up) \ng Are you planning to become pregnant after having an endometriosis surgery? \n(Yes No) \nh Is the patient receiving medication after surgery (Visanne, GnRH analogue, \nother?) Yes / No \ni i.Has your complaints decreased during the postoperative examination (yes / \nno) 1Hh, 6Mont, 1 year from now \nj Has there been a relapse (<1 year,> 1 year,> 3 years,> 5 years) \nk Nature of your complaints (lower abdominal pain, dysmenorrhea, dyspareunia, \nother pain, rectal, bladder bleeding or other complaints) \nl Sites of endometriosis: \n \nSites and stages I. II. III. IV. \nOvary     \nDeep infiltrating/ retrovaginal septum involvement     \nPeritoneal involvement     \n\n93 \nAdenomyosis     \nBladder, intestine, and other localizations     \n \nNo. 2 Annex 2 – Modified EHP- 36 (Modified Endometriosis Health Profile-36) \nQuestionnaire: \nQUESTIONNAIRE \"A\" \nLog number… 2017 \nIntroduction: Complaints caused by endometriosis, including constant abdominal and \nabdominal pain, menstrual complaints, and discomfort related to marriage, have been a \nrelative setback in the doctors work for decades. Infertility as a condition or disease \nhas existed since the beginning of humanity. With the development of medicine, new \npossibilities have opened up, such as IVF-ET, AIH, conservative drug treatments, and \nnewer surgical techniques (laparoscopy), with the help of which significant results is \nachievable. We try to find out unique facts, the recognition of which, and with proper \nattention, we can get better results in solving such problems in the future. We ask for \nyour help while providing information on any questions we handle discreetly and \nanonymously. \nA. General information \nB. Your age: \nFirst month bleeding...… \nHow old did you start… \nDid your complaint occur with your first regular menstrual bleeding? Yes No \nIf yes? \nMenstruation characteristics Yes No Other \noptions \nDo your periods last more than 5 days?    \nDo your periods last more than 5 days?    \nIs your menstrual cycle generally shorter than 26 days?    \nIs your menstrual cycle generally longer than 31 days?    \nDo you ever experience irregular bleeding during your cycle (i.e. mid-\ncycle spotting)? \n   \nDo you ever miss periods or have long breaks between periods?    \nDoes stress make your menstrual cycle length more irregular?    \nIs your period dark in colour with a heavy flow and includes many \nsmall clots? \n   \nDo you use sanitory pad?    \nDo you use sanitory napkins?    \n Do you experience a downward, dragging sensation in your \nabdominal region \n   \nDo experience strong pelvic cramping with sharp pains and/or nausea \nduring your period? \n   \nDo you frequently experience sharp, stabbing period pain that feels \nworse when you apply pressure and/or warmth to it, but feels better if \nyou lie or sit still? \n   \nDo you frequently experience diarrhoea or loose stools at the onset of \nyour period? \n   \nDo you frequently faint or vomit at the onset of your period?    \nDo all of your symptoms improve if you are relaxed and not under \nstress? \n   \nAre you trying to conceive or have experienced difficulty conceiving?    \nHave you undergone IVF treatment after the on set of symptoms    \n\n94 \nHave you lost weight recently or are you underweight?    \nDo you feel exhausted, pale and fatigued after your period?    \nDo you frequently experience lower back pain following your period?    \nDo you experience breast tenderness and/or swelling before your \nperiod? \n   \nDo you have Lower abdominal burning pain?    \n Do you experience premenstrual mood swings e.g. frustration, \nanger,irritability? \n   \nDo you feel flat, depressed and/or weepy before your periods?    \nDo you feel cold, tired and/or become pale before your period?    \nDo you experience fluid retention and/or abdominal bloating before \nyour period? \n   \nAre you prone to premenstrual migraines or tension headaches?    \nDo you experience changes in your stool e.g. diarrhoea, constipation \nor other digestive changes?dysmenorrhea \n   \nDyspareunia    \nHave you been medically diagnosed with endometriosis?    \n Have you been medically diagnosed with uterine fibroids?    \nHave you been medically diagnosed with ovarian cysts?    \nHave you been medically diagnosed with pelvic adhesions or masses?     \nHave you been medically diagnosed with polycystic ovarian \nsyndrome (PCOS)? \n   \nPain relief is achived only after medication    \nPain reliefs spontaneously    \n \nAfter you had an abortion?    \nAfter you had spontaneous deliver?    \nAfter you had cesarean section operation(s)?    \nAfter any abdominal surgery?    \nAfter severe pelvic inflammatory diseases    \nFew years after the first menstruation    \nAfter serious stress and grieve situation    \n \nEndometriosis related symptoms \nCharacteristics Yes No \nStabbing   \nPressing   \nTender   \nCrushing   \nPricking   \nGastrointestinal discomfort   \nRectal bleeding   \nUrinary problems   \nPainful defecation   \n \nEmotional and other related implications (Scale: measuring from 1-10 pending on severity) \n Igen Nem 1 2 3 4 5 6 7 8 9 \nExhausting            \nSickening            \nUnbearable            \nMiserable            \nTorturing            \n\n95 \nDepressing            \nAffect your work negatively            \nAffect your learning negatively            \n \nStrength of pain in endometriosis \nThe Numeric Rating Scale (NRS–11) is an 11–point scale for patient self-reporting of \npain \nPain rating Pain level \n0 No pain \n1-3 Mild Pain (nagging, annoying, interfering little with \nADLs \n4-6 Moderate Pain (interferes significantly with ADLs) \n7-10 Severe Pain (disabling; unable to perform ADLs) \n \nOther information: (Before symptoms) \n1.What foods do you prefer (Sugar, fatty, spicy, pasta, baked goods, dairy, meat, fish, \nfruit, vegetables, eggs, Etc.) their may be more than one answer. \n2.Do you often consume pleasure drugs (Cigarettes, alcohol, coffee, narcotics or illicit \ndrugs, other). How often? On a daily / multiple daily / weekly / monthly basis? \n3.Have you taken any medications (contraceptives, thyroid disease, hormones, \nepilepsy, sedatives, hypertension, diabetes, gastrointestinal disorders, urinary tract \ndiseases, Etc.) How often? On a daily / multiple daily / weekly / monthly basis? \n4.Did you have an endometriosis problem in your family (yes / no), and how is it \nrelated. Have you been treated for endometriosis before (yes / no) by what method \n(medicine, surgery, both) \nThe questionnaire helps us gather information to detect their complaints, especially \nabout their pain and infertility. The results comparing the responses obtained, may \nprovide information on the epidemiology, symptoms, and location of endometriosis. \n                                      \n Questionnaire „B” \nCharacteristics of pain and other symptoms of Endometriosis \nCharacteristics-Dysmenorrhea Yes No Other options \nVery painful menstruation    \nLower abdominal pain    \nPain depends on the time in the monthly cycle    \nParalysing, handicapping pain that affects mobility, \ndifficulty walking \n   \nPain that is unbearable, overwhelming, violent, \nintense \n   \nContinuous pain with peaks or attacks of more \nintense pain \n   \nPain on one side, pain stronger on one side    \nOvarian pain    \n\n96 \nThe pain lasts longer than menstrual pain, and \ncontinues after the bleeding has stopped \n   \nThe pain increases in intensity over time    \nPain starts a few days before menstruation begins    \nPain throughout the monthly cycle, present all the \ntime \n   \nPain spreads towards the back    \nPain before, during and after menstruation    \nStabbing pain    \nPrickly pain, like being pricked or having an \ninjection \n   \nLower abdominal burning pain    \nThe pain prevents sleep or wake up at night    \nPain interferes with work or daily life    \nPain spreads to the legs and hips    \nDifferent types of pain at the same time, several \ndifferent pain symptoms \n   \nDyspareunia    \nDeep internal pain felt during sexual intercourse    \nPain in certain positions during sexual intercourse    \nDistracting pain that prevents or interrupts sexual \nintercourse \n   \nBurning feeling during or after sexual intercourse    \nBowels Symptoms    \nPain when passing a stool, painful bowel \nmovements \n   \nBloating, bloated abdomen    \nDiarrhoea during menstruation    \nSpasms, cramp, pain in the bowel before having a \nbowel movement \n   \nConstipation during menstruation    \nNausea, vomiting    \nAnal pain    \nDiarrhoea alternating with constipation    \nBloody stools    \npainful urinary tract symptoms    \nFeeling the need to urinate often, only small \nquantities at a time \n   \nPain with urge to urinate, pain when holding back    \nPainful pressure on the bladder    \nPain or burning when urinating    \nDifficult to start urination    \nBloody urine    \nOther pathological manifestations    \n\n97 \nBecoming increasingly tired, extreme exhaustion    \nDizziness, fainting    \nSciatica during menstruation    \nPain spreads toward breast or shoulder, right chest \npain \n   \nDepression    \nPneumothorax    \nInability to concieve    \n \nCandidates are screened with a questionnaire to obtain information about their pain \nand infertility problems in comparism to the epidemological, symptomological and \nlocalizational diversity of the disease? \n\n98 \n \n18. ABBREVIATION \n \nART: Artificial reproductive technique \nASRM: American Society of Reproductive Medicine \nBSOE: Bilateral superficial ovarian endometriosis \nBDOE: Bilateral ovarian endometrioma \nCA-125: Cancer antigen 25 \nCA-19-9: Cancer antigen 19-9 \nCD16: Cluster of differentiation molecule 16 \nCHLS: Combined hysterolaparoscopic surgery \nCPP: Chronic pelvic pain \nCT: Computed tomography \nCVD: Chronic vaginal discharge \nCDKN2BAS: Cyclin-dependent kinase inhibitor 2B anti sense \n3-D: Three-dimensional \nEEDL: Electrocoagulation excision of deep endometriosis lesion \nEEPL: Electrocoagulation excision peritoneal endometriosis lesion \nERK: Extracellular signal-related kinase \nESHRE: European Society for Human Reproduction and Embryology \nEURO QoL (EQ-\n5D): Euro-form Quality of Life \nGnSAF: Gonadotropin surge-attenuating factor \nGeneral WB: General well-being \nGWAS: Genome-wide association studies \nHSG: Hysterosalpingography \nHYCOSY: Hysterosalpingo-contrast sonography \nICAM-1: Inter cellular adhesion molecule 1 \nIL-1β: Interleukin 1β \nIBS: Irritable bowel syndrome  \nIL-6: Interleukin 6 \nIVF/ICSI: in vitro fertilization and intracytoplasmic sperm injection \nIVF-ET: in vitro fertilization-embryo transfer \nL  LAP: Lower abdominal pain \nLH: Luteinizing hormone \nLUS: Lower uterine segment \nMAP: Mitogen-activated protein kinase \nMFR: Monthly fecundity rate \nmEHP-36: Modified Endometriosis Health Profile (EHP-36) \nMRI: Magnetic resonance imaging \nNKp46: Natural killer cell receptor \nNKs: Natural killer cells \nNRS-11: Numeric rating scale \nNSAIDs: Non-steroidal anti-inflammatory drugs \nOCPs: Organochlorine pesticides \n\n99 \nOoP: Out-of-pocket payment \nPCOS: Polycystic ovarian syndrome \nPFD: Pelvic floor dysfunction \nPID: Pelvic inflammatory disease \nPCBs: Polychlorinated biphenyls \nHormonal-IUCD: Hormonal intrauterine contraceptive device \nPMBD: Postmenstrual bleeding disorder   \nQoL: Quality of life \nrAFS: Revised American Fertility Society \nROS: Reactive oxygen species \nRVS: Rectovaginal septum \nTCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin \nTGF-β: Transforming growth factor β \nTNFR2: Tumor necrosis factor receptor 2 \nuNKs: Uterine natural killer cells \nVAS: Visual analogue scale \nVEGF: Vascular endothelial growth factor","source_license":"CC0","license_restricted":false}