EFFECTS OF ENDOMETRIOSIS ON QUALITY OF LIFE (Benefit of combined hystero-laparoscopic surgery on quality of life and fertility performance in endometriosis)

in pregnancy, while 144 (83.2%) did. • CO2 Laser Evaporation Technique: In the 54 cases where the CO2 laser evaporation technique was used, 13 (24.1%) did not lead to pregnancy, and 41 (75.9%) did. • Electrocoagulation Excision of Deep Infiltrating Endometriosis Lesions (EEDL) & Adhesiolysis: Of the 29 cases involving EEDL and adhesiolysis, 6 (20.7%) did not result in pregnancy, while 23 (79.3%) did. • Electrocoagulation Excision of Superficial Peritoneal (EEPL) & Deep Infiltrating Lesion & Endometrioma Stripping & Adhesiolysis: In this category, 13 out of 95 cases (13.7%) did not result in pregnancy, whereas 82 cases (86.3%) did. • Cauterization of Bilateral Ovarian Endometriosis & EEPL & EEDL & Adhesiolysis: Of the 12 cases in this category, 2 (16.7%) did not lead to pregnancy, and 10 (83.3%) did. 33 • Endometrioma Stripping & Adhesiolysis & Cauterization of Ovary Endometriosis: In this group, 10 out of 42 cases (23.8%) did not result in pregnancy, while 32 (76.2%) did. • EEPL & Adhesiolysis: Out of 7 cases, 2 (28.6%) did not result in pregnancy, and 5 (71.4%) did. • EEPL & EEDL & Adhesiolysis: In this category, 12 out of 43 cases (27.9%) did not lead to pregnancy, while 31 (72.1%) did. The data suggest variability in pregnancy outcomes following different laparoscopic surgical procedures for endometriosis. The highest percentage of pregnancies was observed in cases where laser was not used (83.2%), and the lowest in cases involving electrocoagulation excision of superficial peritoneal & deep infiltrating lesion & endometrioma stripping & adhesiolysis (86.3%). Post-surgical fertility performance among women 25 – 35-years-old with infertility – related endometriosis Preoperative ART Postoperative ART treatment No pregnancy Pregnancy Total N(Row%) N(Row%) N No No 15(16.3%) 77(83.7%) 92 Yes 6(13.6%) 38(86.4%) 44 Total 21(15.4%) 115(84.6%) 136 Yes No 14(25.9%) 40(74.1%) 54 Yes 7(8.8%) 73(91.2%) 80 Total 21(15.7%) 113 (84.3%) 134 Total 42(15.6%) 228(84.4%) 270 Post-surgical fertility performance among women 36 – 46-years-old with infertility – related endometriosis Preoperative ART treatment Postoperative ART treatment No pregnancy Pregnancy Total N(Row%) N(Row%) N No No 11(42.3%) 15(57.7%) 26 Yes 3(16.7%) 15(83.3%) 18 Total 14(31.8%) 30(68.2%) 44 Yes No 14(26.4%) 39(73.6%) 53 Yes 15(17.0%) 73(83.0%) 88 Total 29(20.6%) 112(79.4%) 141 Total 43 (23.2%) 142 (76.8%) 185 Table 5. Postoperative fertility outcomes in patients with endometriosis-related infertility. The study investigated the post -surgical fertility performance among women aged 25 to 35 years with infertility -related endometriosis. The focus was on the impact of preoperative and postoperative Assisted Reproductive Technology (ART) on fertility 34 outcomes. The sample consisted of 270 cases, divided based on their utilization of ART before and after surgery and their subsequent pregnancy outcomes. • Preoperative ART Not Used: Among the women who did not use preoperative ART, 92 did not undergo postoperative ART, with 15 (16.3%) of these cases not resulting in pregnancy and 77 (83.7%) resulting in pregnancy. In contrast, 44 women used postoperative ART, with 6 (13.6%) not achieving pregnancy and 38 (86.4%) achieving pregnancy. Overall, in the group not using preoperative ART, 21 (15.4%) did not achieve pregnancy, while 115 (84.6%) did. • Preoperative ART Used: In the group that used preoperative ART, 54 did not undergo postoperative ART, with 14 (25.9%) not resulting in pregnancy and 40 (74.1%) resulting in pregnancy. Among those who used both preoperative and postoperative ART, 7 (8.8%) did not achieve pregnancy, while 73 (91.2%) did. Overall, in the group using preoperative ART, 21 (15.7%) did not achieve pregnancy, while 113 (84.3%) did. • Total: Combining both groups, the total number of cases not resulting in pregnancy was 42 (15.6%), while those achieving pregnancy were 228 (84.4%). The findings indicate that most women aged 25 to 35 years with infertility -related endometriosis achieved pregnancy post -surgery, regardless of the use of ART either before or after surgery. Notably, the highest pregnancy rate (91.2%) was observed among women who utilized both preoperative and postoperative ART, suggesting a potential benefit of continuous ART intervention in this subgroup. The study further examined the post-surgical fertility performance among women aged 36 to 46 years with infertility-related endometriosis. Similar to the younger cohort, this group was analyzed based on their use of preoperative and postoperative Assisted Reproductive Technology (ART) and their subsequent pregnancy outcomes. The sample included 185 cases. • Preoperative ART Not Used: Among women who did not use preoperative ART, 26 did not undergo postoperative ART, with 11 (42.3%) of these cases not resulting in pregnancy and 15 (57.7%) resulting in pregnancy. In contrast, 18 women used postoperative ART, with 3 (16.7%) not achieving pregnancy and 15 (83.3%) achieving pregnancy. Overall, in the group not using preoperative ART, 14 (31.8%) did not achieve pregnancy, while 30 (68.2%) did. • Preoperative ART Used: In the group that used preoperative ART, 53 did not undergo postoperative ART, with 14 (26.4%) not resulting in pregnancy and 39 (73.6%) 35 resulting in pregnancy. Among those who used both preoperative and postoperative ART, 15 (17.0%) did not achieve pregnancy, while 73 (83.0%) did. Overall, in the group using preoperative ART, 29 (20.6%) did not achieve pregnancy, while 112 (79.4%) did. • Total: Combining both groups, the total number of cases not resulting in pregnancy was 43 (23.2%), while those achieving pregnancy were 142 (76.8%). The results indicate that in the older age group of women with infertility -related endometriosis (36 to 46 years), a significant proportion achieved pregnancy post - surgery, with a notable impact observed from the use of ART. The highest pregnancy rate (83.0%) was observed among women who utilized both preoperative and postoperative ART, suggesting the effectiveness of ART in enhancing fertility outcomes in this age group. Age groups Pregnancy No pregnancy 25-30 (n=91) 81% 19% 31-35 (n=179) 86% 14% 36-40 (n=159) 78% 22% 41-46 (n=26) 69% 31% Figure 8. Effect of laparoscopic surgery on fertility performance by age in Study II. The study examined the relationship between age and pregnancy outcomes in a sample of women with endometriosis. The participants were categorized into four age groups: 25-30 (n=91), 31 -35 (n=179), 36 -40 (n=159), and 41 -46 (n=26). The frequency of pregnancy and no pregnancy outcomes was reported for each age group. 36 • Age Group 25-30: Out of 91 women, 81% achieved pregnancy, while 19% did not. • Age Group 31 -35: In this group of 179 women, a slightly higher pregnancy rate was observed, with 86% achieving pregnancy and 14% not achieving pregnancy. • Age Group 36 -40: Among the 159 women in this age group, the pregnancy rate was 78%, with 22% not achieving pregnancy. • Age Group 41 -46: The oldest age group, consisting of 26 women, had the lowest pregnancy rate, with 69% achieving pregnancy and 31% not achieving pregnancy. The Chi-square test was conducted to determine if there was a statistically significant difference in pregnancy rates across the different age groups. The Chi -square value was calculated to be 6.282, with a p-value of 0.099. The analysis suggests a trend where the likelihood of achieving pregnancy decreases with increasing age among women with endometriosis. The highest pregnancy rate was observed in the 31-35 age group, and the lowest in the 41-46 age group. However, the Chi -square test indicated that these differences across age groups were not statistically significant (χ² = 6.2816, p = 0.0987). This implies that while there appears to be a trend of decreasing pregnancy rates with age, the differences observed in this sample are not strong enough to rule out the possibility that they occurred by chance. Figure 9. Effect of laparoscopic surgery on fertility performance by stage of endometriosis in Study II. The study investigated the relationship between the stage of endometriosis and pregnancy outcomes. Participants were categorized into four groups based on the stage of endometriosis: Stage 1 (n=61), Stage 2 (n=132), Stage 3 (n=162), and Stage 4 37 (n=100). The frequency of pregnancy and no pregnancy outcomes was reported for each stage. • Stage 1 Endometriosis: Out of 61 women with Stage 1 endometriosis, 80% achieved pregnancy, while 20% did not. • Stage 2 Endometriosis: In this group of 132 women, 76% achieved pregnancy, and 24% did not achieve pregnancy. • Stage 3 Endometriosis: Among the 162 women in this stage, a higher pregnancy rate was observed, with 86% achieving pregnancy and 14% not achieving pregnancy. • Stage 4 Endometriosis: In the most advanced stage, Stage 4, consisting of 100 women, 81% achieved pregnancy, and 19% did not. The analysis suggests a variation in pregnancy rates across different stages of endometriosis, with the highest pregnancy rate observed in Stage 3 (86%) and the lowest in Stage 2 (76%). However, the Chi -square test indicated that these differences across stages were not statistically significant (χ² = 5.5081, p = 0.1382). This implies that while there appears to be a variation in pregnancy rates across different stages of endometriosis, the differences observed in this sample are not strong enough to rule out the possibility that they occurred by chance. 8.2.4. Discussion Infertility affects women around the world, and the socio -cultural stigma that surrounds it varies and can often result in family breakdown [228 -230]. Many studies have shown an association between endometriosis and infertility. The combined hysteroscopic–laparoscopic surgical treatment of endometriosis -related infertility improves fertility performance; therefore, it is considered one of the best options currently available, irrespective of the few shortcomings associated with the procedure. Furthermore, w ell-timed ART has also been proven to enhance the reproductive performance of affected women [231 -233]. Our results demonstrated the significant benefits of hysterolaparoscopic management of endometriosis -related infertility. Our goal for the applied surgical technique was to eradicate all active endometriotic lesions. In our study, the pregnancy rate improved considerably after surgery, reaching 81.3%, with a live birth rate of 94.2%. We also observed that the stage of endometriosis did not significantly i nfluence fertility performance. We propose that fertility performance is more dependent on surgical expertise and patient age rather than on the stage of endometriosis. Consistent with our results, a review conducted by Jacobson et al. concluded that the laparoscopic treatment of minimal and 38 mild endometriosis improved pregnancy and live birth rates [230, 233]. Fuchs et al. recorded a high pregnancy rate (65%) within an 8.5 -month postoperative follow -up period, of which 86.9% of pregnancies resulted in deliveries [232 -234]. For minimal and mild endometriosis -related infertility, clinicians commonly share the opinion that laparoscopic surgery may increase the likelihood of future pregnancy and live birth [10, 18, 235]. Another study reported a pregnancy rate of 81.6% and a live birth rate of 43.7% in stage I and II endometriosis, respectively, and a 56.7% pregnancy rate and 40.3% live birth rate was recorded in patients with stage III and IV endometriosis, respectively, after ICSI [228, 236]. However, with a relatively smaller study population, Słabuszewska -Jóźwiak et al. reported that 20.75% of patients became pregnant spontaneously and concluded their pregnancy with live birth, without ART in the first 6 months of follow-up [34]. Nardo et al. reported a cumulative pregnancy rate of 23.2% after laparoscopic treatment with the Helica Thermal Coagulator for minimal and mild endometriosis [236]. Both study outcomes were similar to ours, as we reported an overall spontaneous pregnancy rate of 28.8% during the follow -up period. However, our study had a broader patient population by including all stages of endometriosis [235, 237-239]. A systematic review highlighted the beneficial effect of laparoscopic surgery for the treatment of subfertility related to minimal and mild endometriosis [231, 240 -242]. Several studies concluded that the overall pregnancy outcomes improved after laparoscopic surgical intervention regarding endometriosis - related infertility, regardless of the stage of endometriosis [91, 231, 232, 244]. Many authors reported that the ASRM’s classification of endometriosis was a useful tool in predicting IVF success and fertility performance [240]. Furthermore, the ESHRE suggests that lesions classified as moderately severe to severe have a better chance with IVF as the first line of treatment [9, 34, 241]. However, in our study, there was no statistically significant difference in fertility outcome regarding different stages of endometriosis, with expectant management or with IVF, even without any anatomical deficiencies. Explanation of the relatively improved fertility performance observed in this study may be provided by the application of combined hysteroscopic -laparoscopic surgery. Surgical expertise is another crucial factor, in addition to others, such as study population, environment, and the efficiency of IVF centers. Hysteroscopy is an efficient tool in the evaluation and correction of intrauterine and intra -tubal abnormalities. The direct imagining of the tubal os, chromopertubation, and peritubal 39 adhesiolysis via laparoscopy enhances the likelihood of pregnancy as compared with painful hysterosalpingography (HSG) or hysterosalpingo -contrast-sonography (HYCOSY) [34, 235,245]. Similarly to other centers, we routinely apply various surgical approaches ranging from electro -cauterization of visible endometriotic implants, excision or stripping of ovarian endometriomas, and laser coagulation, adhesiolysis, and adenomyomectomy [34, 234, 246, 247]. The hysterolaparoscopic surgical procedure plays an integral role as it enables the surgeon to treat or correct anatomical abnormalities found in the uterine cavity, including uterine fibroid, Asherman syndrome and synechia, polyps, uterine septum, isthmocele (scar defect or niche), ovarian cysts, or chronic PID; these conditions were present in our study in 17.8%, 0.8%, 5.4%, 6.6%, 1.0%, 0.8%, and 1.8% of cases, respectively. Similar findings were reported by Sreekanth [246]. In our study, approximately 52.2% of patients had tubal patency restoration via Peritubal adhesiolysis, 3.5% had unilateral tubal patency, 4.6% had a total tubal blockage, and only 39.7% had normal tubal function. Godinjak et al. reported bilateral tubal occlusion in 18 patients (5%) and unilateral tubal occlusion in 30 patients (8.33%) [247]. Our data were also comparable to those of Alborzi et al. who reported 66 spontaneous pregnancies (33.1%) and 5 pregnancies (25%) through intrauterine insemination [227, 248 -250]. However, we must highlight that there are limitations of such studies because of patient desire, patient withdrawal of consent during the study, heterogeneity of study subjects, and loss to follow -up. Other limitations were the retrospective nature of the study, population size, and potential pitfalls in data collection. Nevertheless, we believe that improved fertility outcome after a combined hysterolaparoscopic approach in infertile patients is beyond doubt. 8.3. Study III: Effectiveness of combined hysterolaparoscopy on quality of life of endometriosis patients 8.3.1. Background Worldwide, endometriosis is reported to affect up to 10% of women of reproductive age [21, 96]. Symptoms associated with endometriosis vary and are dependent on localization, stage of the disease, individual pain threshold, and individual goals and needs [3, 9, 21]. Endometriotic tissues outside the uterine cavity behave like eutopic endometrium and are cyclically influenced by sex hormones [251 -253]. Endometriosis causes chronic inflammatory reactions that can result in scar tissue formation, 40 adhesion, and eventual displacement or distortion of lower pelvic reproductive organs [96, 254]. Usually, the disease is accompanied by increased peritoneal fluid concentrations of biochemical substances, such as prostaglandins, proteases, and inflammatory cytokines, including IL -1, IL6, and TNFα [159, 254 -256]. Angiogenic cytokines, such as IL-8 and VEGF, are secreted from the distorted reproductive organs and adhesion [159, 254, 256]; this milieu favors the presence of specific symptoms. Sometimes, endometriosis is associated with mood swings and depression, which can occasionally lead to self -destructive lifestyles. Frequently reported symptoms are chronic pelvic pain, waist pain, dysmenorrhea, and dyspareunia; more severe symptoms include dysuria and gastrointestinal dysfunction, such as bloating and dyschezia [252 -254]. Subsequently, changes in the anatomical and biochemical environment can adversely affect pelvic organ function, leading to infertility [159, 255-257]. The purpose of our investigation was to evaluate whether hysterolaparoscopy in patients with impaired QoL caused by endometriosis could lead to significant improvements. 8.3.2. Materials and methods We conducted a single -center analysis on the impact of laparoscopic surgery on the QoL of patients with endometriosis at Róbert Private Hospital, Budapest. The study had two arms: the first arm was a retrospective cohort analysis from 1 st. January 2010 to 31 st. December 2016; and the second arm was based on a prospective cohort investigation between 1 st. January 2017 and 31 st. December 2018 using the Endometriosis Health Profile 30 (EHP -30) questionnaire, visual analogue scale (VAS), and Numeric Rating Scal e (NRS-11) instruments. Both data for retrospective studies and prospective study questionnaires were retrieved or collected personally. In both arms, the cohorts consisted of patients of reproductive age who complained of endometriosis-related symptoms and underwent laparoscopy. In the first arm, a random sample comprising 777 patients with histologically confirmed endometriosis was recruited. In the second arm, 87 patients with histologically confirmed endometriosis and relevant symptoms were recruited. A ccess to the hospital database was approved by the hospital ethics committee (RRC -RMK) 001 -3/2017. Exclusion criteria were PCOS; PID; current use of drugs that could affect cognition and mood; and primary medical conditions, such as neurologic, psychiatric, gastrointestinal, 41 urologic, and orthopedic diseases. In the first arm, we applied a standard questionnaire 3, 6, and 12 months after surgery to collect information from women on the following groups of variables: age, type of pain -related symptoms (i.e., dysmenorrhea, dyspareunia, chronic pelvic pain, or urinary symptoms), general history, history of previous gynecological surgery, mode of diagnosis, type of surgery, stage of endometriosis, surgical outcome, infertility, pregnancy outcome, and other relevant ultrasound findings, such as the presence of polyps, septum, and adhesion. In the second arm, the EHP-36 questionnaire was applied to measure demographics, physical and mental health, emotional problems, and general perception of health and QoL. Moreover, the VAS and the NRS -11 were employed to measure painful distress associated with endometriosis. We commenced with “0” representing no pain and “10” representing the least bearable pain. None of the patients received preoperative adjuvant therapy. Questionnaires were completed before and after surgical interventions. Post-surgical follow-up was performed in the first 6 months, 12 months, and 24 months after surgery via postal questionnaire using email and by direct telephone conversation. Other complementary information was used to test for a possible association of symptoms with lifestyle, nutrition, and genetic predisposition. The questionnaire was pretested with the aid of voluntary hospital staff and the average time needed to complete the questionnaire was noted. A decision for surgical management was made based on the symptoms and signs suggestive of endometriosis, past medical history, ultrasound findings, and results of other investigative procedures, including clinical examination, MRI, CT, and serum markers (Figure 10). 42 Figure 10. Mode of discovery of endometriosis in women in Study III/a. Laparoscopic surgeries were performed by experienced surgeons, ensuring that identical surgical approaches were used in both arms of the study. Following the operations, a standard operative report was completed to provide relevant nonoperative information. The severity of endometriosis was staged according to the American Fertility Society revised definition [258, 259]. In all patients, endometriotic lesions were laparoscopically removed by excision, electrocauterization, vaporization, or excision by laser, and were sent for histological examination. Only patients with histologically confirmed endometriosis were eligible to continue the study. Postoperative follow-up lasted for 1 –2 years (until 31 st. December 2018). Participants who became pregnant during the study period were followed up until term or the end of pregnancy. Those with complaints other than infertility, such as chronic pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia, were followed up for 12 months. During each visit, patients underwent general gynecological and ultrasound evaluations for symptom or disease recurrence. Data obtained from patients were statistically analyzed using SPSS software version 24 and the Stata program v.11. Correlations between age, stage and laparoscopic surgical management were assessed using the chi -square test and Fisher exact test for categorical data. We investigated continuous variables using the independent-sample t- test, non -parametric Mann –Whitney U test, or the two -sample t -test, where appropriate. Multiple logistic and linear regression analyses were performed to investigate associations between variables and outcomes, adjusting for potential confounders independently associated with exposure and sequel of interest in univariate analysis. We used the multiple binary logistic regression model to determine statistical relationships, using age as a control. For comparison of the emotional characteristics of study individuals before and after surgery according to the timing of the follow -up (6, 12, and 24 months), we used the Mauchly variance homogeneity test and MANOVA. A p -value <0.05 was considered nominally significant. Results are expressed as mean ± standard deviation, frequency, percentage, or cumulative percentage. 8.3.3. Results In the first arm of the study, all patients were Caucasian, and the mean age of the patients was 34.3 ± 5.1 years (18–53 years). The mean age at menarche was 13.1 ± 1.4 43 years, the mean duration of menstruation was 5.9 ± 2.1 days, the average age at the onset of endometriosis-related symptoms was 29.1 ± 4.3 years, and the duration from onset of symptoms to the diagnosis of endometriosis was 5.1 ± 2.9 years (Table 6). The distribution of different stages of endometriosis was stage I in 15% (113/777) of patients, stage II in 31% (243/777) of patients, stage III in 34% (264/777) of patients, and stage IV in 20% (157/777) of patients (Table 6). The most frequently encountered complaints were dyspareunia 80% (621/777) and dysmenorrhea 74% (574/777). Among the 534 patients (69%) who initially complained about infertility, 49 did not wish to conceive after surgery (Figure 11). The coexistence of symptoms appeared to be significant for the following variables: dysmenorrhea and obstipation, dysmenorrhea, and obtuse pain, crushing pain and obtuse pain, and sharp pain and obtuse pain (Table 7, Figure 11 and 12). Table 6. General characteristics of patients with endometriosis in Study III/a. Age Frequency Percentage (%) Cumulative (%) Age of Patients 18-25 27 3.47% 3.5% 26-31 155 19.9% 29.5% 32-37 349 44.9% 74.4% 38-43 172 22.1% 96.5% 44-53 27 3.4% 100% Age at menarche 8-11 76 9.8% 9.8% 12-15 664 85.5% 95.3% 16-20 37 4.7% 100% Duration of menstruation 2-7 629 81.0% 81% 8-15 148 19.0% 100% Age at the onset of symptoms 15-20 16 2.1% 2.1% 21-25 136 17.0% 19.1% 26-30 345 44.4% 63.5% 31-35 228 29.3% 92.5% 36-40 47 6.1% 98.5% 41-43 7 0.9% 100% Duration of symptoms before diagnosis 0-5 450 57.9% 57.9% 6-11 286 36.8% 94.7% 12-18 41 5.3% 100% Stages of endometriosis (rASRM) classification) Stage 1 113 14.5% 14.5% Stage 2 243 31.3% 45.8% Stage 3 264 34.0% 79.8% Stage 4 157 20.2% 100.0% Total 777 100.0% 100.0% 44 Figure 11. Distribution of endometriosis-related symptoms in Study III/a. Figure 12. The prevalence and overlap of pain-related symptoms in women with endometriosis, 45 as diagnosed surgically in Study III/a. 1 2 3 4 5 6 7 8 9 10 1 Dysmenorrhe a 2 Dyschezia 0.223* 3 Dyspareunia 0.287* 0.275* 4 Dysuria 0.156* 0.470* 0.202* 5 Bloody defecation 0.146* 0.581* 0.208* 0.491* 6 Blooting (abd. swelling) 0.431* 0.366* 0.300* 0.248* 0.268* 7 Obstipation (intestinal obstruction) 0.070 0.215* 0.107* 0.205* 0.361* 0.095* 8 Diarrhea 0.318* 0.469* 0.250* 0.318* 0.383* 0.570* 0.146* 9 Crushing pain 0.572* 0.271* 0.243* 0.204* 0.223* 0.467* 0.100* 0.423* 10 Obtuse pain 0.040 0.226* 0.119* 0.260* 0.246* 0.124* 0.064* 0.194* -0.039 11 Sharp pain 0.279* 0.233* 0.455* 0.185* 0.185* 0.292* 0.052 0.324* 0.242 * -0.005 Table 7. Relationship between type of pain and symptoms in patients with endometriosis in Study III/a [*P<0.001. In the case of dysmenorrhea, the most probable type of pain was crushing pain. In the case of dyschezia, there was no typical pain, as all three types occurred. In the case of dyspareunia, the most probable type of pain was sharp pain. In the case of dysuria, there was no typical pain, as all three occurred.] Among different anatomical locations, the recto -vaginal septum and the left ovary were the most affected sites, with involvement of 59% (458/777) and 45% (349/777), respectively (Figure 13). 46 Figure 13. Frequent localization of endometriosis in Study III/a. Unexpectedly, the incidence of previous gynecological surgery was high at 44.4% (345/777), which may present an opportunity for further evaluation or study (Figure 14). Figure 14: The incidence of other previous gynecological surgery prior to onset of endometriosis symptoms in women in Study III/a [More than half of the patients (55.6%) had no surgical history, 44.4% had different gynecological surgery, and 1 in 9 patients (10.9%) had curettage for missed abortion and curettage for metrorrhagia (10.8%). Frequency of cesarean section (6.9%), artificial abortion (6.8%), and HSG/hysteroscopy (6.7%) was low. Frequency of myomectomy and conization were negligible.] More complex symptomatology was observed with right ovary involvement, while deep infiltration found either underneath the peritoneum or within the recto -vaginal septum appeared second (Table 8). There was a significant improvement in QoL at 3, 6, and 12 months after surgery, and most of the patients reported significant to complete cessation of symptoms (Table 9 and Figure 15). The rate of successful live births was 94.2% (327/347) and the rate of pregnancy loss was 5.8%. Overall, there was gradual improvement in the QoL of the women. There 47 was a significant relationship between improvement rate and the time of visit; patients reported increasing improvement over time. The moderate improvement rate alone decreased, but this also strengthened the degree of progress, as the other two improvement factors (“significant” and “complete”) were “at the expense of” the change. Significant to complete improvement in QoL was observed, recorded as 57 – 59% on the first follow-up visit and 74–85% on the final visit (after 1st. the year), and all woman reported a significant level of improvement (p=0.0005) (Table 9, Figure 15 and 17). Patients reported improvement in QoL as follows: 41/421 moderate, 196/421 significant, and 184/421 as complete at 12 months of follow -up, at the first 3 months (250/455), 6 months (341/455), and at 12 months 432/reported this positive change. Only 23/455 were non-respondents concerning fertility performance and QoL. Table 8 in Study III/a presents the relationship between the type of pain experienced and the localization of endometriosis in the study participants. The types of pain assessed include dysmenorrhea (painful menstruation), dyschezia (pain during defecation), dyspareunia (pain during sexual intercourse), bloating (abdominal swelling), obstipation (intestinal obstruction), diarrhea, dysuria (painful urination), and bloody defecation. The localization of endometriosis considered are the right ovary, left ovary, superficial peritoneal involvement, deep involvement of the ovary with multiple unilateral or bilateral endometriosis, deep peritoneal endometriosis with bladder peritoneum involvement, deep recto -vaginal septum endometriosis with intestinal peritoneal involvement, and deep recto -vaginal septum (RVS -B-R) without bowel involvement. • Right Ovary: Participants with endometriosis in the right ovary reported experiencing all types of pain assessed in the study. • Left Ovary: Endometriosis in the left ovary was associated with dysmenorrhea, bloating, and dysuria. • Superficial Peritoneal Involvement: No specific types of pain were reported for superficial peritoneal involvement. • Deep Involvement of the Ovary with Multiple Unilateral or Bilateral Endometriosis: Participants with this type of endometriosis reported experiencing all types of pain assessed. • Deep Peritoneal Endometriosis with Bladder Peritoneum Involvement: This condition was associated with all types of pain assessed in the study. 48 • Deep Recto -vaginal Septum Endometriosis with Intestinal Peritoneal Involvement: Participants with this type of endometriosis also reported experiencing all types of pain assessed. • Deep Recto-vaginal Septum (RVS -B-R) Without Bowel Involvement: This condition was associated with dyschezia, dyspareunia, bloating, obstipation, diarrhea, dysuria, and bloody defecation. Localization Dysmen orrhea Dys- Chezia Dys- pareuni a Bloating (abdominal swelling) Obstipation (intestinal obstruction) Diar - rhea Dy- suria Bloody defecation Right ovary X X X X X X X Left ovary X X X Superficial peritoneal involvement Deep involvement of the ovary with multiple unilateral or bilateral endometriosis X X X X X X X X Deep peritoneal endometriosis with bladder peritoneum involvement X X X X X X X X Deep recto-vaginal septum endometriosis with intestinal peritoneal involvement X X X X X X X X Deep recto vaginal septum; RVS-B-R without bowel involvement X X X X X X X Table 8. Relationship between type of pain and localization of endometriosis in study III/a. The findings from Study III/a, indicate a significant relationship between the localization of endometriosis and the type of pain experienced by participants. Notably, deep involvement of endometriosis, whether in the ovaries, peritoneum, or recto-vaginal septum, was associated with a broader range of pain symptoms, including dysmenorrhea, dyspareunia, bloating, obstipation, diarrhea, dysuria, and bloody defecation. In contrast, superficial peritoneal involvement did not report specific pain types in this study. These results highlight the diverse and often severe symptomatology associated with different localization of endometriosis. The presence of pain in multiple locations and of various types underscores the complexity of diagnosing and managing endometriosis. It also emphasizes the need for a comprehensive and individualized approach to treatment, considering the specific localization and symptom patterns in each case. 49 Time (months) Moderate Significant Complete Total 1st 3 months No 7 52 53 112 46.70% 74.30% 88.30% 77.20% Yes 8 18 7 33 53.30% 25.70% 11.70% 22.80% Total 15 70 60 145 100.00 % 100.00% 100.00 % 100.00% 1st 6 months No 4 52 55 111 40.00% 75.40% 84.60% 77.10% Yes 6 17 10 33 60.00% 24.60% 15.40% 22.90% Total 10 69 65 144 100.00 % 100.00% 100.00 % 100.00% 1st. 12 months No 5 44 51 100 31.30% 77.20% 86.40% 75.80% Yes 11 13 8 32 68.80% 22.80% 13.60% 24.20% Total 16 57 59 132 100.00 % 100.00% 100.00 % 100.00% Table 9. Comparison of the improvement in symptoms after surgery across the different stages of follow-up in patients with endometriosis in Study III/a. At the first 3 -month follow-up, the Chi -square test revealed a statistically significant association between the level of symptom improvement and the follow -up period, χ² (2) = 12.524, p = 0.002. This indicates that the differences in symptom improvement levels among patients are not due to chance. At the 6 -month follow-up, the Chi-square test again, showed a statistically significant association, χ² (2) = 9.988, p = 0.007. This suggests that the variation in symptom improvement observed among patients at this stage is statistically significant and unlikely to be due to random variation. At the 12 - month follow-up, the Chi -square test results were χ² (2) = 20.988, with a p -value of less than 0.001. This indicates a very strong statistical significance, suggesting that the differences in symptom improvement levels among patients at one -year post-surgery are highly unlikely to be due to chance. Across all three follow -up periods (3, 6, and 12 months), the Chi -square tests consistently indicate statistically significant differences in symptom improvement among patients with endometriosis who underwent surgery. These results suggest that the level of improvement in symptoms varies significantly among patients over time, underscoring the importance of individualized postoperative care and monitoring. 50 Symptoms First month visit Sixth month visit First year visit Dysmenorrhea <0.001 <0.001 <0.001 Dyschezia <0.001 <0.001 <0.001 Dyspareunia <0.001 <0.001 <0.001 Blooting (abdominal swelling) <0.001 <0.001 <0.001 Obstipation (intestinal obstruction) 0.585 0.700 0.701 Diarrhea <0.001 <0.001 <0.001 Dysuria <0.001 <0.001 <0.001 Bloody defecation <0.001 <0.001 <0.001 Crushing pain <0.001 <0.001 <0.001 Obtuse pain 0.006 <0.001 <0.001 Sharp pain <0.001 <0.001 <0.001 Table 10. Improvement of individual endometriosis-related symptoms and quality of life 12 months after surgery in Study III/a. 95% confidence interval Visit Improvement Chi- square df Sig. Odds ratio Lower Upper 1 month Little improvement less than 50% 1.253 1 0.263 0.000 0.000 0.000 Moderate improvement of symptoms 50- 60% 30.418 1 <0.001 0.052 0.012 0.220 Significant improvement of symptoms 70- 80% 0.823 1 0.364 1.152 0.012 0.220 Complete improvement os symptoms 90- 100% 2.125 1 0.145 1.254 0.925 1.702 6 months Moderate improvement of symptoms 50- 60% 29.912 1 <0.001 0.000 0.000 0.000 Significant improvement of symptoms 70-80% 2.3519 1 0.126 1.272 0.935 1.731 Complete improvement of symptoms 90-100% 0.224 1 0.636 1.076 0.758 1.445 1 year Moderate improvement of symptoms 50- 60% 32.478 1 <0.001 0.000 0.000 0.000 Significant improvement of symptoms 70-80% 3519 1 0.061 1.371 0.986 1.908 Complete improvement of symptoms 90-100% 0.077 1 0.782 1.047 0.758 1.445 Beyond 1 year Moderate improvement of symptoms 50- 60% 13.988 1 <0.001 0.000 0.000 0.000 Significant improvement of symptoms 70- 80% 86.37 1 <0.001 6.850 4411 10.637 Complete improvement of symptoms 90-100% 65.441 1 <0.001 3.837 2.749 5.356 Table 11. Post-surgery well-being and quality of life of endometriosis patients in Study III/a. 51 Figure 15. The post-surgical outcome regarding general well-being during the follow-up period beyond 12 months in Study III/a. The study employed the Wilcoxon Signed -Rank Test to compare the improvement in symptoms of patients with endometriosis at various follow-up intervals post-surgery: 1 month, 6 months, 1 year, and beyond 1 year. The improvement was categorized as: no changes of symptoms (0 -20% improvement), little improvement (less than 50%), moderate improvement (50 -60%), significant improvement (70-80%), and complete improvement (90-100%). At the 1 -month follow -up, 49% of patients reported complete improvement (90 - 100%), and 46% reported significant improvement (70-80%). By the 6 -month follow- up, the percentage of patients reporting complete improvement increased slightly to 54%, while those reporting significant improvement decreased to 42%. At the 1 -year mark, the percentages remained stable for complete improvement (54%) but decreased for significant improvement (35%). Beyond 1 year, the proportion of patients reporting complete improvement decreased to 42%, and significant improvement further decreased to 26%. The Wilcoxon Signed -Rank Test results indicated statistically significant differences between the follow-up periods: • 6 Months vs. 1 Month: There was a statistically significant difference in the improvement of symptoms between the 1-month and 6-month follow-ups, with a greater improvement observed at 6 months. (Z = 6.714, Asymptotic Significance (2-tailed) < 0.001.) • 1 Year vs. 6 Months: 52 The improvement in symptoms was significantly different between the 6-month and 1- year follow-ups, indicating continued improvement over time. (Z = 3.81, Asymptotic Significance (2-tailed) < 0.001.) • 1 Year vs. 1 Month: A statistically significant difference was observed in symptom improvement between the 1-month and 1-year follow-ups, suggesting substantial improvement over the first - year post-surgery. (Z = 7.362, Asymptotic Significance (2-tailed) < 0.001.) The findings indicate a significant improvement in symptoms of endometriosis in the first year following surgery, with the most notable improvements observed between the 1-month and 6-month follow-ups. The level of improvement appears to stabilize or slightly decrease beyond one -year post -surgery. These results underscore the effectiveness of the surgical intervention in the short term and highlight the need for ongoing monitoring and management of symptoms in the long term. Figure 16. Relationship between well-being and infertility following surgery in Study. III/a. 53 (There was a significant correlation between the rate of improvement and pregnancy after 1 month (Cramer’s V = 0.218; 2 (3) = 31.847; p <0.001) and 6 months after surgery (Cramer’s V = 0.213; 2 (2) = 30.302; p <0.001), 1 year after the intervention (Cramer’s V = 0.232; 2 (2) = 33.510; p <0.001), and on a visit later than 1 year (Cramer’s V = 0.303; 2 (2) = 43.513; p <0.001). Figure 17. Effect of surgery on the quality of life during follow-up in Study III/a The study assessed the well -being of respondents with various complaints associated with endometriosis, measured at three different time points post -treatment: after 1 month, 6 months, and 1 year. Well-being was quantified on a scale from 0% (worst) to 100% (best). The complaints evaluated included hematochezia, dyschezia, dysuria, obstipation, diarrhea, crushing pain, bloating, sharp pain, dysmenorrhea, dyspareunia, and obtuse pain. • Hematochezia: Well -being scores improved marginally from 80% after 1 month to 81% after 6 months, and to 82% after 1 year. • Dyschezia: Scores for dyschezia showed a slight improvement from 80% after 1 month to 82% after both 6 months and 1 year. 54 • Dysuria: Well-being scores increased from 81% after 1 month to 82% after 6 months, and further to 83% after 1 year. • Obstipation: Scores improved from 81% after 1 month to 83% after 6 months, and to 84% after 1 year. • Diarrhea: There was an improvement in well -being from 82% after 1 month to 83% after 6 months, and to 84% after 1 year. • Crushing Pain: Scores increased from 82% after 1 month to 84% after both 6 months and 1 year. • Bloating: Well-being scores improved from 82% after 1 month to 84% after 6 months, and to 85% after 1 year. • Sharp Pain: Scores for sharp pain showed an improvement from 82% after 1 month to 84% after both 6 months and 1 year. • Dysmenorrhea: Well-being scores increased from 83% after 1 month to 84% after 6 months, and to 85% after 1 year. • Dyspareunia: Scores improved from 83% after 1 month to 84% after 6 months, and to 85% after 1 year. • Obtuse Pain: Well -being scores for obtuse pain showed an improvement from 83% after 1 month to 85% after both 6 months and 1 year. The findings indicate a gradual improvement in the well -being of respondents across all complaints over the course of one year following treatment. The most notable improvements were observed in symptoms such as bloating, dysmenorrhea, dyspareunia, and obtuse pain, where well -being scores increased by 3 percentage points over the year. While the improvements in well -being for each symptom were modest, the consistent upward trend across all complaints is encouraging. These results suggest that the treatment provided had a positive impact on the well - being of patients with various endometriosis -related complaints. The gradual nature of improvement underscores the importance of ongoing management and support for individuals with endometriosis. It also highlights the chronic and often fluctuating course of endometriosis symptoms, necessitating long -term strategies for symptom management and patient support. In the second arm of the study, all patients were Caucasian. A higher level of education and higher income category was reported in 81.6% of the enrolled patients. 55 The mean age at diagnosis was 34.2 ± 5.97 years (22 –48 years). The mean duration of infertility was 3.8 ± 2.1 years. The mean duration between symptom onset and diagnosis was 9.7 ± 0.35 years. The most reported complaints or symptoms were infertility in 70.1%, dysmenorrhea in 82.8%, dyspareunia in 60.9%, bloating in 93.1%, and urinary discomfort in 49.4% (Table 12). During surgery, the involvement of the left ovary as a single affected organ was more frequently observed (42.5%), while recto-vaginal septum involvement or superficial peritoneal implants were found in 55.2% and 66.7%, respectively. The third stage of endometriosis was the most frequently observed (48.3%). NRS-11 scale data analyses revealed a mean preoperative pain score of 6 –10 (moderate to severe pain) in 85/87 patients (94.8%). Postoperative pain perception improved to an average 0 –2 score (none or slight periodic discomfort) in 71/87 patients (81.6%). Before surgery, the average VAS score was 8 –10 (moderate to severe pain) in 82/87 patients (94.3%). Postoperative VAS score declined to 0.47–0.89 (minimal to no pain) in 81/87 patients (93.1%) (Figure 19). The completion rate was 100%, except for three cases of pregnancy. Post surgically, all patients reported significant changes and improvements in QoL (Table 13, Figure 18). When considering different types of complaints associated with endometriosis in the study, we found that the most frequent complaint was pricking pain/discomfort, while the least frequent was rectal bleeding (Table 13). When considering QoL indicators, we found a marked improvement in all indices (Table 14, Figure 20). All the Mauchly variance homogeneity tests proved heteroscedasticity. Regarding MANOVA testing for the differences among the changes in emotions over time, all tests showed significant decreases in all depressing problems and emotions after surgery (Table 13, Figure 18). 56 General Characteristics of women with endometriosis in this study (n=87) Mean Age at menarche (years) 13.2 ± 1.293 (9–17) Mean Age at diagnosis of endometriosis (years) 34.2 ± 5.97 (20–48) Mean Age at the onset of symptoms relating to endometriosis (years 24.5 ± 5.71 (15–37) Duration of infertility (years) 3.8 ± 2.1 Duration of symptoms before diagnosis (years) 9.7 ± 0.35 Characteristics Types Number (n) Percentage (%) Localization of endometriosis Superficial/Deep left ovary involvement 37 42.6 Deep right ovary involvement 14 16.2 Bilateral ovary involvement 27 31 Superficial (RVS)/Deep rectovaginal septum involvement 62 71.3 Superficial bladder involvement 48 55.2 Deep bladder involvement 10 11.5 Intestinal involvement 13 14.9 Superficial peritoneal involvement 58 66.7 Adenomyosis 10 11.5 Other surgical procedures Adhesiolysis 61 70.1 Bladder resection 8 9.2 Dixon operation 2 2.3 Relapse of endometriosis 5 5.7 Stages of endometriosis 1 3 4.9 2 12 19.7 3 29 47.5 4 17 27.9 Other complication Endometrioid carcinoma 1 1.6 Fertility Preoperative infertility issue 61 70.1 Mode of pregnancy Spontaneous pregnancy 23 37.7 IVF-ET 9 14.1 Outcome of pregnancy Spontaneous delivery 17 53.1 Cesarean section 7 21.9 Missed abortion 4 12.5 Lost to follow up 3 9.4 Preoperative pain score (NRS–11) Moderate to severe pain 85 94.8 Postoperative pain score (NRS–11) Mild to no pain 71 81.6 Preoperative VAS score Moderate to severe pain 82 94.3 Postoperative VAS score Minimal to no pain 81 93.1 Additional factors Family history of endometriosis ** 15 High red meat/fish ** *** Smoking (≥5 cigarettes/day) 17 19.5 Alcohol consumption (beer/wine regularly) 8 9.2 Alcohol consumption (gin/whisky regularly) 14 16.1 Coffee consumption (>1 cup/daily) 29 33.5 Menstrual history Bleeding disorder (metrorrhagia) 57 66 Cycle dysfunction (spotting) 43 49 Miscellaneous issues Use of sanitary napkins (solely to more regularly) 63 72 Table 12. General characteristics of women with endometriosis in Study III/b. 57 Emotion Test Value F Hypothes is df Error df Sig. Exhausting emotionally Wilks' Lambda 0.129 189.285 3 84 <0.001 Sickening emotionally Wilks' Lambda 0.275 73.854 3 84 <0.001 Unbearable emotionally Wilks' Lambda 0.117 211.495 3 84 <0.001 Miserable emotionally Wilks' Lambda 0.136 176.23 3 83 <0.001 Torturing emotionally Wilks' Lambda 0.115 215.733 3 84 <0.001 Depressing emotionally Wilks' Lambda 0.123 198.814 3 84 <0.001 Affect your work negatively Wilks' Lambda 0.165 141.547 3 84 <0.001 Affect your learning negatively Wilks' Lambda 0.188 121.096 3 84 <0.001 Table 13. Comparison of emotional assessment of individuals before and after surgery according to the timing of follow-up (6, 12, and 24 months) in Study III/b. Women’ s emotional, socioeconomic and physical state assessment before surgery Assessment Very bad (0-20%) 7- 16 score Bad (20-50%) 5-7 score Satisfactory (60- 70%) 3-5 score Good (80-100%) 0- 3 score Characteristics n % n % n % n % Quality of life 47 54.0% 31 35.6% 8 9.2% 1 1.1% General wellbeing 48 55.2% 33 37.9% 6 6.9% NA NA Sexual problems (dyspareuma) 34 39.1% 22 25.3% 19 21.8% 12 13.8% Urinary-problems 5 5.7% 25 28.7% 12 13.8% 45 51.7% All painful complaints associated with endometriosis 53 60.9% 34 39.1% NA NA NA NA Dyschezia 8 9.2% 30 34.5% 19 21.8% 30 34.5% Characteristics No improvement /relapse/ (0-20%) 7- 10 score Little improvement (20-50%) 5-7 score Moderate improyement (60- 70%) 3-5 score Significant/Comple te improyement (80-100%) 0-3 score n % n % n % n % Quality of life 5 5.7% 1 1.1% 2 2.3% 79 90.8% General wellbeing 1 1.1% 4 4.5% 19 21.8% 63 72.4% Sexual problems (dyspareuma) 2 2.2% 6 6.8% 4 4.6% 75 86.2% Urman-problems NA NA 1 1.1% 6 6.9% 80 92.0% All painful complaints associated with endometriosis 2 2.2% 5 5.7% 9 10.3% 71 81.6% Dyschezia NA NA 2 2.2% 8 9.1% 77 88.5% Table 14. Improvement in quality of life and general well-being after surgery in women with endometriosis in Study III/b. 58 Figure 18. Psychological-emotional assessment of individuals before and after surgery according to different follow-up intervals (April to June 2 and 24 months) in Study III/b. Multivariate Tests Value F Hypothesis df Error df Sig. Pillai’s Trace 0.933 391.797b 3 84 <0.001 Wilks’ Lambda 0.067 391.797b 3 84 <0.001 Hotelling’s Trace 13.993 391.797b 3 84 <0.001 Roy’s Largest Root 13.993 391.797b 3 84 <0.001 Figure 19. Comparison of NRS-11 and VAS scores before and after surgery according to the timing of follow-up (6, 12, and 24 months) in Study III/b. [Because the Mauchly variance homogeneity test proved heteroscedasticity (chi- squared (5) =113.835, p<0.001), we also used MANOVA for testing the differences among the pain rating changes over time. The MANOVA tests proved a significant decrease in all pain after surgery] 59 Figure 20. EHP-36 scores before and after surgery at different follow-up intervals (6, 12, and 24 months) in Study III/b. Tests Value F Hypothesis df Error df Sig. Pillai's Trace 0.526 31.02 3 84 <0.001 Wilks' Lambda 0.474 31.02 3 84 <0.001 Hotelling's Multivariate Trace 1.108 31.02 3 84 <0.001 Roy's Largest Root 1.108 31.02 3 84 <0.001 Figure 21. EHP -36 scores before and after surgery at different follow -up intervals (6, 12, and 24 months) in Study III/b. 60 8.3.4. Discussion Our study focused on the potential positive effects of hysterolaparoscopy on the QoL of patients suffering from endometriosis. The economic burden that endometriosis imposes on individuals and society is significant [97]. In 2012, an endometriosis survey in the UK revealed that approximately 1.6 million women were affected, with an estimated financial burden of £10.6 billion [86, 260, 261]. In Australia, approximately 550,000 women have endometriosis, costing £2.75 billion [119, 262, 263]. In the United States, approximately 7.6 million women are affected, with financial implications of approximately £52.1 billion per year due to loss of work and healthcare costs [260, 261]. The accurate prevalence and subsequent economic burden of the disease Hungary remains unknown, although a multicenter study estimated an affected population of approximately 184,000 women, with an estimated cost of €1.6 billion per year [86, 262, 263]. In the first arm of our study, the average age of the patients and the duration of diagnosis were similar to those reported in other studies [24, 86]. Interestingly, the left side of the lower pelvis seemed to be involved more frequently, likely owing to the intra-abdominal fluid circulation pattern, which is in a clockwise direction and stops at the pouch of Douglas [40, 264 -266]. This circulation may increase the possibility of implantation of endometriotic cells in an asymmetric pattern [267]. In concordance with other studies, our results demonstrated a possible direct association of endometriosis with dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility [24, 192, 268]. Endometriosis can significantly lower QoL for women. In our study, almost 95% of women had substantial or complete resolution of symptoms at 1 month postoperatively. This result is higher than those of similar studies reporting on QoL and sexual performance after laparoscopic surgical treatment for endometriosis [235, 269-271]. Furthermore, combined hysterolaparoscopy had positive effects on QoL, regardless of the stage of the disease. Our results were in line with those of Mabrouk et al. [176]. Other studies focusing on endpoints, such as dysmenorrhea, dyspareunia, pelvic pain, dyschezia, and dysuria, have also highlighted the beneficial effect of endoscopic surgery on symptom relief [37, 271]. Further improvement in women's well-being and QoL is achievable with the help of combined hysterolaparoscopy [240, 259]. The second arm of our study demonstrated the usefulness of EHP -36, VAS, and NRS- 11 questionnaires in evaluating the QoL of patients with endometriosis. Interestingly, in this arm, the mean age of onset of initial symptoms was 24.5 ± 5.71 years, similar to 61 other studies that demonstrated the first symptom onset between 20 and 29 years of age [273, 274]. In the first arm of the study, we found the mean age for first symptoms to be 29.1 years. This finding does not contradict the literature, and this value overlaps with the standard deviation of our first arm data (29.1 ± 4.3 years). We believe that there is a shift in general awareness of endometriosis in society, and within decades we will likely experience significantly earlier detection rates, partly due to earlier personal detection of alarming signs and symptoms and due to better public education and awareness. Furthermore, in the second arm of our study, the average age of diagnosis was 34.2 ± 5.97 years (20 –48 years). This value is in line with our findings in the first arm of the study. The question might be raised, as to why there might be a longer duration between onset of first symptoms and definitive diagnosis in the second arm. Because of the difference between the study samples of the two arms, we were not yet able to draw firm conclusions. This field requires further studies involving a larger number of participants. The negative effect of endometriosis on physical well - being significantly improved after surgery, as demonstrated by VAS and NRS pain score analyses (8.0 ± 2.11 score before surgery vs. 0.47 ± 1.25 score after surgery). It is an improvement that is in line with the results of a study conducted by Alborzi et al. in 2017, where the initial score of 8.23 ± 2.03 decreased to 4.46 ± 2.47 in 93% of patients [250]. The positive effect of surgery on socio -emotional well-being that was detected by the modified EHP -36 questionnaire was like the results of earlier studies [127, 275, 276]. In summary, the EHP -36 instrument, in addition to the VAS and NRS -11, is a useful tool in the evaluation of the QoL of patients experiencing the misery of endometriosis, especially in a comparative setting applied pre- and postoperatively. 9. SUMMARY OF RESULTS Our study comprised two major parts. In the first part, three retrospective studies involved collection of patients’ information from the hospital database. Study I recorded 28 women with post -cesarean section isthmocele who underwent combined hysteroscopic and laparoscopic repair. Return of fertility after surgery was 82.4% (n=14/17). Endometriosis was found in 16 patients (57.1%), which is high in patients in this group who had no previous history of endometriosis prior to the cesarean section. Overall, patient satisfaction was 92.9% (26/28) in terms of improved QoL. In Study II, records were collected of 455 patients with endometriosis -related infertility who were managed with combined radical laparoscopy surgery and ART between 62 2010 and 2018. Fertility return was 81.3% (370/455), with 94.2% (327/347) live births and 5.8% (20/347) pregnancy loss. Pregnancy occurred spontaneously in 39.5% (146/370) of patients, in 3.8% (14/370) of women after AIH, and in 56.8% (210/370) after IVF-ET, with patients aged ≤35 years having a higher chance of conception post - surgery (84% vs. 77%, respectively [p=0.039]). Comparatively, this effect was 91.3% vs. 74.1% (p=0.007; OR=3.7; 95% CI=1.4 –9.8) among the ≤35- and >35-year-old age groups, respectively. There was no significant difference in reproductive performance in difference stages of endometriosis. Study III was based on the records of 777 patients with endometriosis who underwent combined radical hysteroscopy –laparoscopy surgery, incorporated with occasional ART treatment for those with infertility issues. The postoperative QoL improved significantly, with 46–49% having moderate to significant improvement, and 35 –54% achieving complete resolution of symptoms (p<0.0005). This improvement was achieved in the areas corresponding to the most common complaints: dyspareunia (80%), dysmenorrhea (74%), and infertility (69%). The fourth study was a prospective study of 87 women with endometriosis who were requested to complete a modified EHP -36 questionnaire pre - and post -surgery to assess their perspective on endometriosis in terms of their QoL, General WB, and fertility. Women underwent combined radical hysteroscopy –laparoscopy surgery based on their conditions and disorders, such as infertility, in which case operative or diagnostic hysteroscopy was always included. There was a significant improvement in the QoL in this group (p<0.001). The VAS for pain score decreased from 8 ± 2.11 (86.0%), moderate to severe pain, preoperatively, and to 0.47 ± 1.24 (93.1%) negligible to no pain, postoperatively (p <0.001). Of those women with infertility, 58.45% (32/61) became pregnant. Analysis showed a loss to follow -up, with 77.4% (24/31) live births. Postoperative general well -being was rated “very good” or “good” in 94.2% (82/87) of participants. There was a significant improvement observed in sexual life, with 86.2% (75/87) of women rating it as “good” or “very good” (p<0.001). 10. ANSWERS TO OUR HYPOTHESES 1. Our results demonstrate a link between history of cesarean section and an increased likelihood of development of endometriosis, supporting our first hypothesis. 63 2. Our results demonstrate that combined hysteroscopic and laparoscopic endometriosis surgery significantly improved fertility outcomes in patients with endometriosis, supporting our second hypothesis. 3. Our data showed that combined hysterolaparoscopy significantly improved the QoL of endometriosis patients. Furthermore, our results proved that the validated EHP -36 instrument, along with the VAS and the NRS-11, were useful tools in the evaluation of the QoL of endometriosis patients, supporting our third hypothesis. 11. GENERAL DISCUSSION Endometriosis remains a plague in the lives of many women worldwide. The negative effects of the disease range from direct daily health challenges to socio -cultural, socioeconomic, and QoL impairment. Our study provided positive evidence that early meticulous radical laparoscopy surgery significantly improves QoL. The combination of hysteroscopy and assisted ART was found to improve overall fertility performance. We demonstrated a positive impact on the QoL with laparoscopy surgical excision of endometriotic lesions, as was reported in previous studies [10, 15, 17, 217]. Our first study demonstrated a controversial view relating to the role of prior surgery on the uterus and the possible association with the onset of the disease in support of the implantation hypothesis [36, 54, 55]. Our study demonstrated incredibly high frequency of the disease in this group of patients, with 57.14% (16/28) cases supporting our hypotheses (p˂0.05). Doubts were raised about the possibility of prior cesarean section (scar defect) being one of the contributing factors to the onset of endometriotic lesions. The mechanism is unknown; however, it could be triggered by direct implantation or by diffusion due to prolonged stagnation of menstrual fluid trapped in the scarred pouch -like structure. Other possibilities, like the inability of the defensive mechanism to remove endometrial tissues disseminated during cesarean section, require consideration. The postoperative outcomes were satisfactory, with 80% for infertility, 95.65% for LAP, 100% for vaginal discharge, 94.44% for dysmenorrhea, and 100% for PMBD; these results are more favorable or similar to studies by Changdong Li et al. and Cuilan Li et al. [278, 279]. Our second study demonstrated post -surgical fertility performance with or without ART. The current prevalence of endometriosis is approximately 1 –2 per 10 women [56, 75, 140]. Our study demonstrated that early expert minimal surgical treatment of endometriosis-related infertility and timely introduction of ART is currently the most feasible option, and supports our hypotheses [233, 234]. The result showed that the 64 pregnancy rate improved dramatically after surgery (370/455, 81.3%), with a live birth rate of 88.1% (326/370). Our study also demonstrated that the stage of endometriosis did not significantly influence fertility performance, while age had a significant influence on fertility. This observation is similar to reviews conducted by Jacobson et al. and others [233, 236, 238 -240]. The positive outcomes may have resulted from the individualized combined hysterolaparoscopic surgical approach. The inclusion of hysteroscopy was necessary because uterine abnormalities and other tubal abnormalities contribute to approximately 30 –35% of female infertility issues [155, 237]. All based on patient desire, the recurrence ratio was low. The expectant management option was initially applied before the recommendation of ART was considered [237]. Patients with primary infertility made up 55.2% (278/504), while secondary infertility made up 30.9% (156/504). The results from this study showed that meticulous and timely surgical management of endometriosis improves fertility performance irrespective of the age, stage, or duration of infertility. Endometriosis can cause constant debilitating pain, broken homes, loss of jobs, economic burden, and infertility [44]. Many studies have reported financial burdens: about £10.6 billion in healthcare costs in the UK (2012), about £2.75 billion in Australia, and $52.1 billion per year in the USA [241, 280]. A study conducted by Bokor et al. estimated €1.6 billion per year, accumulated from out -of-pocket (OoP) and national health insurance policies [62,70]. Our study showed direct association of endometriosis with dysmenorrhea, chronic pelvic pain (CPP), dyspareunia, and other sexual aberrations, which may affect fertility [114, 217, 243]. Our study demonstrated that hysterolaparoscopic surgery significantly positively influenced fertility, as 81.3% of patients in all stages of endometriosis became pregnant, with a successful live birth rate of 94.2%; these findings are like a study by Kuivasaari et al. [236]. Our study also showed that QoL improved significantly, as close to 95% of women had substantial or complete resolution of symptoms at 1 month postoperatively; these findings are similar to a study conducted by Ferrero et al. and Denny E et al. [97, 98]. We observed a progressive improvement in all indices of the patient’s needs as time elapsed, even more favorable than in the previous studies [106, 224, 226]. The most common sites were deep infiltrating recto-vaginal septum endometriosis, left ovarian fossa and endometrioma, and right ovarium fossa. Our study demonstrated the 65 correlation between the localization of the endometriosis and the degree and type of presenting pain-associated symptoms. Our last study demonstrated the usefulness of the EHP-36, VAS, and another questionnaire in evaluating the QoL and General WB in patients with endometriosis before and after radical laparoscopic surgery. Our findings were similar to other studies in this regard [258, 259]. The study exposed some of the unbearable suffering that women with endometriosis encounter daily (e.g., self-reported depression and anxiety). Post -surgical follow-up outcomes demonstrated significant improvements in all areas (all p <0.001) (Table 13–15, Figure 18–21). The average pain score gradually decreased from 8.0 ± 2.11 points before surgery to 0.47 ± 1.25 points after surgery, higher than that reported in a study conducted by Alborzi et al. [263-265]. Our study demonstrated significant improvement in reducing or eliminating those agonizing physical, emotional, and socioeconomic deprivation caused by endometriosis; close to 93.1% of patients reported improvement in their QoL. Other studies have not reported outcomes superior to those of our study [263, 266]. Fertility outcomes also improved, as 52.5% of patients became pregnant; 61% had presented with infertility issues. This observation represents an improvement as compared with other similar studies [110, 271]. Our study did not demonstrate any significant association between cigarette smoking or alcohol consumption and endometriosis, in concordance with studies conducted by Bravi et al. in 2014 and Thylan in 1995 [273, 274]. We could not confirm any associated eating habits and/or types of food, or a direct link between other medical conditions and endometriosis. However, more women reported drinking because of the impact of endometriosis on their lives, and we observed a slight correlation of 15% with family (genetic) history of endometriosis [126]. Other observation included a link between endometriosis and the use of sanitary napkins (pads) (63/87; 72%) and tampon use, findings that were similar to a study conducted by Kamalifard et al. [276]. 12. CONCLUSION Based on the results from our studies, only large and comprehensive studies can confirm the assertion that tissue dissemination –by direct or diffusion process as a

of some surgical procedures –could induce the development of endometriosis. Excessive or improperly performed obstetric and gynecological surgical interventions (i.e., abortions, HSG, and other gynecological interventions) could also cause tissue dissemination. Our study contributed to the literature by providing new perspectives 66 and approaches to managing obstetric and gynecological cases, including information on the potential etiological aspects of the implantation theory of endometriosis. The studies also ascertained that combined hysterolaparoscopy treatment was an efficient and reliable procedure; it enhanced women’s well -being and QoL and significantly improved reproductive performance. The study also demonstrates a correlation between the site of endometriosis and association with pain -related and other symptoms. The integration of a modified EHP -36 questionnaire could provide service providers with a broader scope for accessing women in outpatient clinics, with an early suspicion of endometriosis as the background disease behind the patient’s symptoms, thereby reducing the frequency of delayed diagnosis. In conclusion, our study highlighted that radical combined hysteroscopy –laparoscopy or laparoscopic surgery significantly improved fertility performance and, moreover, improved the QoL and general well -being of patients. Our study also showed that the procedure was safe in the hands of an expert endoscopy surgeon. The postoperative outcomes highlighted the significant improvements achieved in relieving some of the socioeconomic burden of individuals or society in general as a result of endometriosis. 13. PUBLICATIONS RELATED TO THE THESIS: 1. Ekine AA, István F, & Árpád R, & István T, & Boldizsár N. Endoscopic surgical treatment of isthmocele and its probable link with endometriosis. A 3 -years retrospective review of combined laparoscopic and hysteroscopic surgery. Indian J Obstet Gynecol Res. 2018; 5:458–464. 10.18231/2394-2754.2018.0105.(IF:1.34) 2. Ekine AA, Fülöp I, Tekse I, Rúcz Á, Jeges S, Koppán Á, Koppán M. The Surgical Benefit of Hysterolaparoscopy in Endometriosis -Related Infertility: A Single Center Retrospective Study with a Minimum 2 -Year Follow-Up. J Clin Med. 2020. február 13.; 9(2):507. doi: 10,3390/jcm9020507. PMID: 32069800; PMCID: PMC7073634. (IF: 3.9) 3. Ekine AA, Fülöp I, Tekse I, Kovács Z, Siklós P, Koppán Á, Koppán M. Effectiveness of Combined Hysterolaparoscopy on the Quality of Patients with Endometriosis: A Retrospective Review in Hungary. J Women's Health Dev. 2020; 3:032–055. (IF: 1.1) 4. Ekine AA , Fülöp I, Racz A, Koppan A, Siklós P, Koppan M. The benefits of Radical Laparoscopic Surgery and a Modified Endometriosis Health Profile–36 (EHP– 67 36) on Quality of life. Journal of Women's Health and Development 3 (2020):379 - 397. (IF: 1.1) 14. AUTHOR’S PUBLICATIONS NOT RELATED TO THE THESIS 1 Ekine AA, Israel J, Tubotonye H, Levi WO. Factors influencing the prevalence of Preeclampsia-eclampsia in booked and unbooked patients: 3 years retrospective study in NDUTH, Okolobiri. . World J Med Medical Sci. Jan 2015;3(1):1 –14. ISSN: 2330—1341 [Online] 2 Ekine A.A, Isioma AJ, Levi WO. Influence of Culturally based Abdominal Massage and Antenatal Care Uptake among Pregnant Women in a Tertiary Hospital in Southern Nigeria. J Adv Med Med Res. 2016;18(6):1 –9. https://doi.org/10.9734/BJMMR/2016/27109 3 Lawani L, & Iyoke C, & Onoh R, & Nkwo P, & Ayuba II, & Ekwedigwe K, Ekine AA . Obstetric benefits of health insurance: A comparative analysis of obstetric indices and outcome of enrollees and non -enrollees in southeast Nigeria. J Obstet Gynaecol. 2016;36. 10.1080/01443615.2016.1174830. 4 Ekine AA , Lawani L, Iyoke C, Jeremiah I, Ayuba II. Review of the Clinical Presentation of Uterine Fibroid and the Effect of Therapeutic Intervention on Fertility. Am J Clin Med Res. 2015; 3:9–13. 10.12691/ajcmr-3-1-2. 5 Abasi I, Jeremiah I, Ekine AA. Risk Factors and Pregnancy Outcome of Placental Abruption at the Niger Delta University Teaching Hospital, Okolobiri, South - South Nigeria. Br J Med Med Res. 2015; 5:1000 –1006. 10.9734/BJMMR/2015/12842. 6 Ayuba II, Obilahi A, Ekine A.A. The Safety of Induction of Labour in the Niger Delta Region. J Med Sci. 2012; 2:173–178. 7 Fülöp I, Ekine A A, Tekse I, Rucz Á, Siklos P. Isthmocele: Successful Surgical Management of an Under -Recognized Iatrogenic Cause of Secondary Infertility; 2017 8 Ekine AA, West LO, Gani O. Awareness of Female Health Workers and Non - Health Workers on Cervical Cancer and Cervical Cancer Screening: South – South, Nigeria. Int J Med Sci Clin Invent. 2015;2. 9 Ekine AA , Udoye PE, West OL. Determinants and Factors influencing the prevalence of uterine rupture in a tertiary rural hospital in the Niger Delta: A 5 - year retrospective study in NDUTH, Okolobiri. Pharma Innov. 2015;4(2):97–101. 68 10 Ekine AA , West OL, Adhuze JI. Patients Attitude towards Antenatal care and Factors Determining its Uptake in Rural Communities in the Niger Delta, Nigeria. J Pharm Biomed Sci. 2015;05(04):344–350. Available at www.jpbms.info 11 Ekine AA, Abasi I. Socio-Cultural and Economic Influence in the Incidence of Obstructed Labor: 5 Years Review in NDUTH ISSN 2278 – 0211 (Online),2015 12 Ayuba II, Oyeyemi AS, Ekine AA. Knowledge, attitude, and practice of female genital mutilation among doctors and nurses in Yenagoa, Niger -Delta of Nigeria. Int J Med Biomed Res. 2013;2(1):40–47. 13 Ekine AA , Ikeanyi A E, Abasi I, Ayuba II. Risk factors, challenges, and management of post -partum haemorrhage in Nduth, Okolobiri, Nigeria: A 5 -year experience. Aejpmr. 2014;1(1):168–182. 14 Ikeanyi AE, Israel J, Ekine AA . Teenage Pregnancy and Obstetric Outcome: A Comparative Study in Urban Nigeria (2020). 15 Ikeanyi AE, Israel J, Ekine AA . An Appraisal of Awareness and Practice of Modern Contraception among Prenatal Clinic Attendees in Southern, Nigeria (2020). 16 Ekine AA, Rúcz Á, Veres V, Csáthy L, Tsehai N, Kovács Z. Maternal Distress due to Spontaneous Antepartum Rupture of Unscarred Uterus with a Live Fetus in the Abdominal Cavity at 31 Weeks: A Case Report and Literature Review, (2021) 17 Ekine AA , Udoye EP, et al. Spontaneous Bilateral Ruptured and Unruptured Tubal Ectopic Pregnancies: A Case Report and Literature Review from Niger Delta, Nigeria. Int J Med Res Health Sci. 2014;3(4):1028–1033 18 Ekine AA, Ibrahim IA, Unachukwu CE, Jeremiah I, West O, Akanate ID. Acute abdomen as a result of unsuspected spontaneous heterotopic pregnancy with tubal rupture: a case report and review of the literature. Int J Curr Res. 2019;11(03):2028–2031. 19 Kovács, Z.; Ekine A.A , E.; Hegyi, G.; Szőke, H. The Effect of Aviva Exercise Intervention on Pain Level and Body Awareness in Women with Primary Dysmenorrhea. Medicina 2024, 60, 184. https://doi.org/10.3390/medicina60010184 (IF: 2.6) 69 15. ACKNOWLEDGEMENTS I thank the directors and the management staff of Róbert Private Hospital for granting me the opportunity and enabling me to use the hospital materials for my research. I wholeheartedly thank my supervisors Prof. Miklos Koppán and Dr. Ágnes Koppán for their professional and moral support during this period. I also thank my colleagues, Dr. István Fülöp, Dr. Pál Siklós, and Dr. Árpád R ucz for their professional and personal support. I would also like to express my thanks to all the other staff of the hospital, the Department of Obstetrics and Gynecology, the administrative staff, and nurses of the assisted reproductive units and Proprietors of the Róbert Private Hospital, who have also been supportive and encouraging. The lecturers and other doctoral students have proven to be wonderful listeners and the opportunities we had to share our concerns and triumphs with one another certainly helped the long years feel less lonely. I also give thanks to a good friend who completed most of the statistical editing of the document. I give special thanks to the women who participated in the studies and committed their time to talk about their life experiences with endometriosis and postsurgical outcomes, and for their selfless and fantastic approach. Perhaps more than that, however, they gave something of themselves as they discussed with me about intimate, sad, frustrating, and distressing times. It was also wonderful to hear of some of their very special moments of joy. I am extremely grateful for their participation and their interest in this study. Finally, I would like to thank my family and special friends for supporting my efforts in various ways and having given unstinting support and encouragement along the journey. Thank you. 70 16. REFERENCES 1. Ballweg ML. Impact of endometriosis on women’s health: comparative historical data show that the earlier the onset, the more severe the disease. Best Pract Res Clin Obstet Gynaecol. 2004 Apr 1; 18(2):201–18. 2. Gao X, Yeh YC, Outley J, Simon J, Botteman M, Spalding J. Health -related quality of life burden of women with endometriosis: a literature review. Curr Med Res Opin. 2006 Sep 1; 22(9):1787–1797. 3. El-Maraghy, M. The impact of endometriosis symptoms on health-related quality of life and work productivity in Egypt. Austin J Obstet Gynecol. 4. 10.26420/austinjobstetgynecol.2017.1078. 4. Giudice LC, Kao LC. Endometriosis. 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Acta Obstetricia et Gynecologica Scandinavica. 2012; 91:692–698. 91 17. ANNEX No. 1 Annex 1: Checklist for Postsurgical retrospective study II-III A: General information At what age symptoms appeared: … Menarche… years old, Last menstruation… Cycle regular: yes / no Cycle length: days. Duration of menstruation: Pregnancy number… Abortion number… / Date….… Number / date / method of birth ……………………………………………………………. B. Present complaints: DysMenorrhea: DysChesia: DysPareunia: Obstipation: Puffiness: Diarrhea: Pencil-like stools: HaematoChezia: DysUria: a Present complaints / onset (pain) ( 1 year, 3 years, 5 years, 10 years) When did the pain begin in your life? b Location and types of pain: Convulsive, dull, Sharp, (lower abdomen and waist, abdomen and back, other pain, does it radiate to the rectum or bladder?) c History of abdominal surgery (day and date) d Other diseases… Infertility complaints. a Duration: (> 1 year, 3 years, 5 years, 10 years) b Reason: (Female / male, both, unknown?) c Have you had this IVF / AIH before? (yes / no), effectiveness... d Postoperative IVF / AIH? (yes / no), successful / unsuccessful e Other conditions (hyperprolactinaemia, myoma, galactorrhea, insulin resist, hypo-hyperthyroidism, polypus endomy, uterine anomaly (septum), ovarian cyst, PID, Synechia or Asherman syndrome, other lesions, etc.) 92 C: Status (endometriosis): a Endometrioma (left or right or both sides) Single-compartment or multicompartment b peritoneal (as a surgical finding) c adenomyosis d deeply infiltrating, if so, where… Endometrium Stadium: 1) I.std., 2) II.std., 3) III.std., 4). IV.std. D: Establishing a diagnosis of endometriosis a Routine ultrasound examination b Laparoscopy c During laparotomy d Anamnestic? E: Surgical interventions: a CHT: tuba permeability after peritubary adhesion or spontaneous b sychneciolyis hysteroscopica (yes / no) c Septum eradication (yes / no) d Salpingectomy e cystectomy (right / left) f EEPL, EEDL, AEOL, Laser (excision of endometriosis Douglasi et peritonealis, ablation of endometriosis ovarii laparoscopy) g adhaesiolysis intraabdominalis F: Events after the intervention: a Has pregnancy occurred (yes / no) b How to conceive (spontaneous / AIH / IVF-ET) c The course of pregnancy (childbirth / abortion) ... d Time between surgery and pregnancy (months) e After pregnancy, did the patient leave for another institution? (Yes No) f Patient did not return to the institution after surgery (LTFU = lost to follow-up) g Are you planning to become pregnant after having an endometriosis surgery? (Yes No) h Is the patient receiving medication after surgery (Visanne, GnRH analogue, other?) Yes / No i i.Has your complaints decreased during the postoperative examination (yes / no) 1Hh, 6Mont, 1 year from now j Has there been a relapse ( 1 year,> 3 years,> 5 years) k Nature of your complaints (lower abdominal pain, dysmenorrhea, dyspareunia, other pain, rectal, bladder bleeding or other complaints) l Sites of endometriosis: Sites and stages I. II. III. IV. Ovary Deep infiltrating/ retrovaginal septum involvement Peritoneal involvement 93 Adenomyosis Bladder, intestine, and other localizations No. 2 Annex 2 – Modified EHP- 36 (Modified Endometriosis Health Profile-36) Questionnaire: QUESTIONNAIRE "A" Log number… 2017

Complaints caused by endometriosis, including constant abdominal and abdominal pain, menstrual complaints, and discomfort related to marriage, have been a relative setback in the doctors work for decades. Infertility as a condition or disease has existed since the beginning of humanity. With the development of medicine, new possibilities have opened up, such as IVF-ET, AIH, conservative drug treatments, and newer surgical techniques (laparoscopy), with the help of which significant results is achievable. We try to find out unique facts, the recognition of which, and with proper attention, we can get better results in solving such problems in the future. We ask for your help while providing information on any questions we handle discreetly and anonymously. A. General information B. Your age: First month bleeding...… How old did you start… Did your complaint occur with your first regular menstrual bleeding? Yes No If yes? Menstruation characteristics Yes No Other options Do your periods last more than 5 days? Do your periods last more than 5 days? Is your menstrual cycle generally shorter than 26 days? Is your menstrual cycle generally longer than 31 days? Do you ever experience irregular bleeding during your cycle (i.e. mid- cycle spotting)? Do you ever miss periods or have long breaks between periods? Does stress make your menstrual cycle length more irregular? Is your period dark in colour with a heavy flow and includes many small clots? Do you use sanitory pad? Do you use sanitory napkins? Do you experience a downward, dragging sensation in your abdominal region Do experience strong pelvic cramping with sharp pains and/or nausea during your period? Do you frequently experience sharp, stabbing period pain that feels worse when you apply pressure and/or warmth to it, but feels better if you lie or sit still? Do you frequently experience diarrhoea or loose stools at the onset of your period? Do you frequently faint or vomit at the onset of your period? Do all of your symptoms improve if you are relaxed and not under stress? Are you trying to conceive or have experienced difficulty conceiving? Have you undergone IVF treatment after the on set of symptoms 94 Have you lost weight recently or are you underweight? Do you feel exhausted, pale and fatigued after your period? Do you frequently experience lower back pain following your period? Do you experience breast tenderness and/or swelling before your period? Do you have Lower abdominal burning pain? Do you experience premenstrual mood swings e.g. frustration, anger,irritability? Do you feel flat, depressed and/or weepy before your periods? Do you feel cold, tired and/or become pale before your period? Do you experience fluid retention and/or abdominal bloating before your period? Are you prone to premenstrual migraines or tension headaches? Do you experience changes in your stool e.g. diarrhoea, constipation or other digestive changes?dysmenorrhea Dyspareunia Have you been medically diagnosed with endometriosis? Have you been medically diagnosed with uterine fibroids? Have you been medically diagnosed with ovarian cysts? Have you been medically diagnosed with pelvic adhesions or masses? Have you been medically diagnosed with polycystic ovarian syndrome (PCOS)? Pain relief is achived only after medication Pain reliefs spontaneously After you had an abortion? After you had spontaneous deliver? After you had cesarean section operation(s)? After any abdominal surgery? After severe pelvic inflammatory diseases Few years after the first menstruation After serious stress and grieve situation Endometriosis related symptoms Characteristics Yes No Stabbing Pressing Tender Crushing Pricking Gastrointestinal discomfort Rectal bleeding Urinary problems Painful defecation Emotional and other related implications (Scale: measuring from 1-10 pending on severity) Igen Nem 1 2 3 4 5 6 7 8 9 Exhausting Sickening Unbearable Miserable Torturing 95 Depressing Affect your work negatively Affect your learning negatively Strength of pain in endometriosis The Numeric Rating Scale (NRS–11) is an 11–point scale for patient self-reporting of pain Pain rating Pain level 0 No pain 1-3 Mild Pain (nagging, annoying, interfering little with ADLs 4-6 Moderate Pain (interferes significantly with ADLs) 7-10 Severe Pain (disabling; unable to perform ADLs) Other information: (Before symptoms) 1.What foods do you prefer (Sugar, fatty, spicy, pasta, baked goods, dairy, meat, fish, fruit, vegetables, eggs, Etc.) their may be more than one answer. 2.Do you often consume pleasure drugs (Cigarettes, alcohol, coffee, narcotics or illicit drugs, other). How often? On a daily / multiple daily / weekly / monthly basis? 3.Have you taken any medications (contraceptives, thyroid disease, hormones, epilepsy, sedatives, hypertension, diabetes, gastrointestinal disorders, urinary tract diseases, Etc.) How often? On a daily / multiple daily / weekly / monthly basis? 4.Did you have an endometriosis problem in your family (yes / no), and how is it related. Have you been treated for endometriosis before (yes / no) by what method (medicine, surgery, both) The questionnaire helps us gather information to detect their complaints, especially about their pain and infertility. The results comparing the responses obtained, may provide information on the epidemiology, symptoms, and location of endometriosis. Questionnaire „B” Characteristics of pain and other symptoms of Endometriosis Characteristics-Dysmenorrhea Yes No Other options Very painful menstruation Lower abdominal pain Pain depends on the time in the monthly cycle Paralysing, handicapping pain that affects mobility, difficulty walking Pain that is unbearable, overwhelming, violent, intense Continuous pain with peaks or attacks of more intense pain Pain on one side, pain stronger on one side Ovarian pain 96 The pain lasts longer than menstrual pain, and continues after the bleeding has stopped The pain increases in intensity over time Pain starts a few days before menstruation begins Pain throughout the monthly cycle, present all the time Pain spreads towards the back Pain before, during and after menstruation Stabbing pain Prickly pain, like being pricked or having an injection Lower abdominal burning pain The pain prevents sleep or wake up at night Pain interferes with work or daily life Pain spreads to the legs and hips Different types of pain at the same time, several different pain symptoms Dyspareunia Deep internal pain felt during sexual intercourse Pain in certain positions during sexual intercourse Distracting pain that prevents or interrupts sexual intercourse Burning feeling during or after sexual intercourse Bowels Symptoms Pain when passing a stool, painful bowel movements Bloating, bloated abdomen Diarrhoea during menstruation Spasms, cramp, pain in the bowel before having a bowel movement Constipation during menstruation Nausea, vomiting Anal pain Diarrhoea alternating with constipation Bloody stools painful urinary tract symptoms Feeling the need to urinate often, only small quantities at a time Pain with urge to urinate, pain when holding back Painful pressure on the bladder Pain or burning when urinating Difficult to start urination Bloody urine Other pathological manifestations 97 Becoming increasingly tired, extreme exhaustion Dizziness, fainting Sciatica during menstruation Pain spreads toward breast or shoulder, right chest pain Depression Pneumothorax Inability to concieve Candidates are screened with a questionnaire to obtain information about their pain and infertility problems in comparism to the epidemological, symptomological and localizational diversity of the disease? 98 18. ABBREVIATION ART: Artificial reproductive technique ASRM: American Society of Reproductive Medicine BSOE: Bilateral superficial ovarian endometriosis BDOE: Bilateral ovarian endometrioma CA-125: Cancer antigen 25 CA-19-9: Cancer antigen 19-9 CD16: Cluster of differentiation molecule 16 CHLS: Combined hysterolaparoscopic surgery CPP: Chronic pelvic pain CT: Computed tomography CVD: Chronic vaginal discharge CDKN2BAS: Cyclin-dependent kinase inhibitor 2B anti sense 3-D: Three-dimensional EEDL: Electrocoagulation excision of deep endometriosis lesion EEPL: Electrocoagulation excision peritoneal endometriosis lesion ERK: Extracellular signal-related kinase ESHRE: European Society for Human Reproduction and Embryology EURO QoL (EQ- 5D): Euro-form Quality of Life GnSAF: Gonadotropin surge-attenuating factor General WB: General well-being GWAS: Genome-wide association studies HSG: Hysterosalpingography HYCOSY: Hysterosalpingo-contrast sonography ICAM-1: Inter cellular adhesion molecule 1 IL-1β: Interleukin 1β IBS: Irritable bowel syndrome IL-6: Interleukin 6 IVF/ICSI: in vitro fertilization and intracytoplasmic sperm injection IVF-ET: in vitro fertilization-embryo transfer L LAP: Lower abdominal pain LH: Luteinizing hormone LUS: Lower uterine segment MAP: Mitogen-activated protein kinase MFR: Monthly fecundity rate mEHP-36: Modified Endometriosis Health Profile (EHP-36) MRI: Magnetic resonance imaging NKp46: Natural killer cell receptor NKs: Natural killer cells NRS-11: Numeric rating scale NSAIDs: Non-steroidal anti-inflammatory drugs OCPs: Organochlorine pesticides 99 OoP: Out-of-pocket payment PCOS: Polycystic ovarian syndrome PFD: Pelvic floor dysfunction PID: Pelvic inflammatory disease PCBs: Polychlorinated biphenyls Hormonal-IUCD: Hormonal intrauterine contraceptive device PMBD: Postmenstrual bleeding disorder QoL: Quality of life rAFS: Revised American Fertility Society ROS: Reactive oxygen species RVS: Rectovaginal septum TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin TGF-β: Transforming growth factor β TNFR2: Tumor necrosis factor receptor 2 uNKs: Uterine natural killer cells VAS: Visual analogue scale VEGF: Vascular endothelial growth factor