{"paper_id":"d0be2abb-1bbc-41a7-804e-5253063a5d8f","body_text":"ANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nApoptotic Pathways and Anti-Müllerian Hormone \naffects the Ovarian Tissue Damage during \nEndometrioma Cystectomy \n \nTanzil al Hair 1*, Wachyu Hadisaputra 2, Soegiharto Soebijanto 2, Primariadewi Rustamadji 2 \n \n \nAbstract \nBackground: Endometriomas are cysts caused by \nendometriosis that can impair ovarian function and \nfertility. Anti-Müllerian hormone (AMH) is an important \nmarker for ovarian reserve. This study aimed to determine \nthe optimal timing of operative management fo r \nendometrioma by evaluating the impact of cyst size on \novarian tissue damage and hormone levels. Methods: The \nstudy included 32 endometrioma patients who underwent \nlaparoscopic cystectomy between February 2018 and \nDecember 2019 at Women and Children’s YPK  Hospital, \nJakarta. Patient characteristics were recorded, including \nage, parity, BMI, and cyst diameter. Serum AMH levels \nwere measured using ELISA before and one month after \ncystectomy. Immunohistochemical examination assessed \napoptotic factor gene expre ssion on the inner surface \nepithelium of endometriomas. Results: AMH levels \ndeclined post-cystectomy in both endometriomas ≤4 cm \nand >4 cm, with significant differences in the latter group. \nAdditionally, there was increased Bax expression in >4 cm \nendometriomas. Correlation tests revealed a strong \npositive relationship between TNFR1 and Caspase-3 in  \n  \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nboth groups. Multivariate analysis suggested a connection \nbetween apoptotic factor gene expression and reduced \nAMH levels. Conclusion: TNF -α appears to initiate \napoptosis in endometriomas through the intrinsic \npathway. It is advisable to perform endometrioma surgery \nwhen the diameter is ≤4 cm and before the age of 30 to \nachieve optimal outcomes. \nKeywords: AMH, apoptosis, caspase -3, caspase -8, caspase -9, gene \nexpression, endometrioma, intrinsic pathway, P53, Bcl -2/Bax ratio, \ncytokine TNF-α. \n \n \nIntroduction \nEndometriosis, a medical disorder characterized by the growth of \nendometrial tissue outside the uterus, causes an endometrioma, an \novarian cyst. Endometriomas, also known as brown cysts, are cysts \nin the ovaries that contain menstrual blood or endometrial tissue \n(Benagiano et al. 2016). Endometriosis, a disorder characterized by \nthe growth of endometrial tissue outside the uterus, is the primary \ncause of endometriomas. The World Health Organization (WHO) \naims to advocate for and support the adoption of effective strategies \nand measures to tackle endometriosis worldwide, with a specific \nemphasis on low - and middle-income nations. WHO (2023), will \nwork together with a range of partners, such as educational \ninstitutions, non -state organizations, and other research -focused \ngroups, to identify effective approaches for preventing, diagnosing, \ntreating,   and   providing   care   for   endometriosis.  Roughly  10% \n  \n \n \n \n \n \n \n \n \n \nSignificance | Early laparoscopic cystectomy for endometriomas, \nespecially before 4 cm diameter, preserves ovarian function, preventing \nsignificant AMH decline and reducing long-term fertility risks. \n*Correspondence.  Tanzil al Hair, Department Obstetrics and \nGynecology, Faculty of Medicine Universitas \nIndonesia, Indonesia. \nE-mail: tanzilalhair11@gmail.com \n \n \n \n \nEditor Mohamed Khadeer Ahamed Basheer, And accepted by the Editorial \nBoard May 20, 2024 (received for review Mar 31, 2024) \n \n \nAuthor Affiliation.  \n1 Department Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, \nIndonesia \n2 Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia \n \nPlease cite this article.  \nTanzil al Hair et al.  (2024). Apoptotic Pathways and Anti-Müllerian Hormone affects the \nOvarian Tissue Damage during Endometrioma Cystectomy , Journal of Angiother apy, \n8(5), 1-18, 9690 \n   \n2207-8843/© 2024 ANGIOTHERAPY, a publication of Eman Research, USA. \nThis is an open access article under the CC BY-NC-ND license. \n(http.//creativecommons.org/licenses/by-nc-nd/4.0/). \n(https./publishing.emanresearch.org). \n \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nEndometriosis and endometriomas, prevalent disorders globally, \naffect approximately 10% of women in their reproductive years \n(Cardoso 2020).  cystectomy is a frequently used surgical technique \nin gynecology (Brilhante et al. 2017). The consequences of ovarian \ntissue damage resulting from endometrioma cystectomy might be \nsubstantial, particularly for women desiring to conceive (Vercellini \net al. 2014). Endometriosis, as described by Ballard et al. (2008), is a \nprevalent condition where endometrial glands grow outside the \nuterus, leading to potential health concerns and a detrimental \nimpact on the patient's lifestyle. The primary symptoms linked to \nthis uterine -infiltrating ailment include intense pain, which can \nsignificantly affect specific patients, as well as the inability to \nconceive (Abrao, Muzii, and Marana 2013) . Dysmenorrhea, \ndyspareunia, low back pain, tenesmus, painful bowel movements, \npelvic pain that persists, and urinary dysfunction are among the \ncommon complaints (Andres 2014). \nEndometriomas are ovarian cysts caused by endometriosis. These \ncysts account for roughly 17 –44% of all cases of endometriosis. \nEndometriomas induce pain and infertility by inflicting harm on \nthe adjacent ovarian tissue (Brosens et al. 2013; Fassbender et al. \n2015). Drug administration alone is ineffective in treating \nendometrioma; hence, cystectomy surgery is necessary. However, \nthe use of cystectomy surgery is still a topic of debate (Garcia -\nVelasco and Somigliana 2009; Kitajima et al. 2014; Margarida 2017). \nCystectomy can result in the extraction of viable ovarian tissue, as \nwell as a reduction in ovarian reserve (Barnhart, Dunsmoor-Su, and \nCoutifaris 2002; Raffi, Shaw, and Amer 2012; Yeung et al. 2011). In \norder to assess the decline in ovarian reserve, the levels of anti -\nmullerian hormone (AMH) are evaluated (Brosens et al. 2014; \nGardner 2011; Keyhan et al. 2015; Obstet et al. 2016). The diameter \nof an endometrioma increases, leading to a drop in the value of anti-\nMüllerian hormone (AMH). The AMH value will also decrease if \nthe endometrioma remains untreated surgically (Carnahan et al. \n2013; Chen et al. 2014) . Postponing surgery exacerbates ovarian \nharm (Chen et al. 2014; Gordts et al. 2015; Rosen et al. 2012) . 71–\n83% of recurring cases detect endometriosis advancement during a \nsecond laparoscopy (Fassbender et al. 2015; Keyhan et al. 2015) . \nBrosens et al. (2014), Kitajima et al. (2011), Obstet et al. (2016), it is \nnecessary to remove tumor tissue in order to safeguard ovarian \nreserve. This should be done early, before the tumor reaches a size \nof 4 cm. Endometriosis causes the initiation of inflammatory \nresponses in the abdominal cavity, which negatively impa ct the \nquality and quantity of oocytes. These effects are further intensified \nby the presence of endometriomas. Endometriomas serve as an \nindicator of the extent of endometriosis disease (Briley et al. 2016; \nMatsuzaki 2010). According to Gupta et al. (2008) , endometriosis \npatches in the peritoneal area affect 99% of instances with an \nestablished endometrioma, impairing the patient's ability to \nbecome pregnant. It has been mentioned by various researchers \n(Brosens et al. 2004; Foti et al. 2018; Koninckx et al. 2021)  in their \nstudies.  \nThe peritoneal fluid of patients with endometriosis has a higher \nconcentration of macrophages. 22 A measure of inflammation, \ntumor necrosis factor alpha (TNF-α), is produced by macrophages. \nPatients with endometrioma exhibit a significant presence of TNF-\nα in their blood, peritoneum, and endometrioma fluid, along with \nother harmful chemicals. Toxic substances cause harm to the \nsurrounding healthy tissue of the ovary, resulting in fibrosis. This, \nin turn, leads to a decrease in the density of follicles (Isono et al. \n2019; Somigliana et al. 2012; Sugita et al. 2013) . It is important to \nunderstand the function of TNF -α in regulating the damage to \nhealthy ovarian tissue surrounding endometrioma. An \ninvestigation was conducted to examine the TNF -α receptors \npresent on the surface of endometrioma epithelial cells. We can  \nassess epithelial damage, which acts as a natural protective barrier, \nby examining the expression of specific genes involved in apoptosis. \nWe can determine apoptosis, a form of programmed cell death, by \ncomparing the levels of Bax expression, a pro -apoptotic factor, to \nthe expression of Bcl-2, an anti-apoptotic factor, and by measuring \ncaspase-3 activity, which executes cell death (Obstet et al. 2016; \nSugita et al. 2013) . In endometrioma patients, it is possible to \nprevent harm to ovarian tissue by removing the cyst and its \nprotective capsule from the ovarian tissue as soon as possible with \na cystectomy (Canis et al. 2001; Celik et al. 2012) . This procedure \ncan lead to the excision of healthy tissue surrounding the \nendometrioma, resulting in the depletion of follicles (Raffi et al. \n2012). Granulosa cells in ovarian follicles synthesize Anti-Müllerian \nhormone (AMH). A reduction in AMH levels might serve as an \nindicator of the remaining egg supply in the ovaries, also known as \nthe ovarian reserve (Iwase et al. 2010; Somigliana et al. 2012; Sugita \net al. 2013) . The European Society of Human Reproduction and \nEmbryology, or ESHRE, suggests doing laparoscopic cystectomy \nfor endometriomas in cysts that are equal to or larger than 3 cm. \nIdentifying an endometrioma already damages the adjacent healthy \ntissue, and delaying the cystectomy will worsen the condition of the \nsurrounding healthy tissue (Matsuzaki 2010) . Nevertheless, the \nintensity of discomfort does not correlate with the extent of ovarian \ninjury (Porpora et al. 1999; Shi et al. 2011) . As a result, cystectomy \nis recommended for endometrioma patients who do not experience \npain. The impact of early cystectomy on ovarian reserve before the \nendometrioma reaches a size of 3 or 4 cm is currently uncertain in \nterms of its benefits or drawbacks. Furthermore, it remains unclear \nhow much the endometrioma has affected the healthy tissue \nsurrounding it before its diameter grows to 3 or 4 cm, particularly \nin terms of ovarian tissue apoptotic factor expression (Bast 2011; \nMiller, Samec, and Alexander -Bryant 2021; Vercellini et al. 2018) . \nWe must decide when to perform a cystectomy. \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nThe objective of this study is to establish the best time for a \ncystectomy while maintaining ovarian reserve by analyzing the \ndamage to ovarian tissue in endometriomas with dimensions of < 4 \ncm and > 4 cm. The research aims to provide evidence for the \nbenefits of early surgical intervention by comparing AMH values \nand the expression of apoptotic genes (p53, Bcl -2, Bax, caspase -8, \ncaspase-9, caspase -3, and TNF -α receptor) before and after \ncystectomy. Because the results may improve ovarian reserve \nprotection in endometrioma-affected women, lowering the chance \nof infertility, they will have important socioeconomic ramifications. \nTheoretical implications include a more profound understanding \nof the relationship between the growth of endometriomas and the \nharm inflicted on ovarian tissue, facilitated by apoptotic pathways. \nThe study also seeks to innovate by identifying biomarkers that \nmight predict the optimal timing for cystectomy, which could \npotentially result in more personalized and efficient treatment \napproaches for individuals with endometrioma. \n \nMaterial and methods \nResearch Sample \nThis quasi- experimental study was conducted to evaluate the \nimpact of laparoscopic cystectomy on serum Anti -Müllerian \nHormone (AMH) levels in patients with endometrioma. The study \nwas performed at RSIA YPK Jakarta and RSIA Bunda Jakarta from \nFebruary 2018 to December 2019. A total of 44 patients were \ninitially recruited, but only 32 subjects met the inclusion criteria \nand completed the study. Inclusion criteria were women aged 18 to \n45 years with endometriomas ≤7 cm in diameter and ≤2 cysts, \nregular menstrual cycles, no hormonal treatment or contraceptive \nuse for three months prior, and no pregnancy or history of \nrecurrent miscarriages. Exclusion criteria included patients with \nmalignancies, previous ovarian surgeries, smoking within six \nmonths, or endocrine disorders. AMH levels were measured before \nand one month after surgery. Non -probability consecutive \nsampling was employed to select participants. The sample size was \ncalculated using a standard formula with α=5%, β=20%, standard \ndeviation of AMH (s=0.25),  and a clinically significant difference \n(Δ=15%), resulting in a minimum of 16 subjects per group, with a \nfinal sample size of 32 accounting for a 10% dropout rate. This \nmethodological approach ensures the reliability and validity of the \nfindings regarding  the effect of cystectomy on ovarian reserve as \nindicated by AMH levels. \n \nResearch Variables and Operational Definition \nThe independent variable in this study is the size of the \nendometrioma, while the dependent variables include AMH levels, \nand the expression of p53, Bcl-2, Bax, caspase-3, caspase-8, caspase-\n9, and TNFR -1. The operational definitions for these variables are \nas follows: Endometrioma size is measured via two -dimensional \nultrasound by a specialist, with the result recorded in centimeters \n(Nominal). The expressions of p53, Bcl -2, Bax, caspase-3, caspase-\n8, caspase -9, and TNFR -1 are assessed through \nimmunohistochemistry (IHC) by comparing the epithelial cell \nresponses to negative controls, indicating cellular damage, survival, \napoptosis initiation, and TNF -α induced apoptosis, respectively \n(Ordinal). AMH levels, before and one month after surgery, are \nmeasured using ELISA to evaluate ovarian reserve (Ordinal). The \ndifference in AMH levels pre-  and post-operation is calculate d to \nobserve changes in ovarian reserve (Ordinal). The AMH \nnormogram is referenced from the Yasmin Clinic 2011 data to \ndetermine normal blood levels based on age (Ordinal). These \nprecise measurements and definitions ensure accurate evaluation of \nthe study's outcomes related to endometrioma impact and surgical \neffects on ovarian function. \n \nObservation Research Methods \nThe preparation phase included drafting the research proposal and \nobtaining ethical approval and permissions for the study at RSIA \nBunda and RSIA YPK Mandiri Jakarta. The study involved \nexperienced and trained healthcare professionals, including doctors \nand nurses, who managed patients with endometrioma and \nperformed laparoscopic cystectomy procedures. The researcher, \nwith the help of these professionals, observed and recorded relevant \npatient data. Laboratory staff were responsible for blood sample \ncollection and immunohistochemistry (IHC) analysis, while a \npathology expert assisted in reading and documenting the IHC \nresults. The laboratory staff also prepared materials to measure the \nexpression of p53, Bcl -2, Bax, caspase -3, caspase-8, caspase-9, and \nTNFR-1, and conducted AMH testing. \nSubjects were consecutively selected based on inclusion and \nexclusion criteria. Blood samples were drawn from the antecubital \nvein to measure preoperative AMH levels. Endometrioma capsule \ntissue samples were obtained via stripping during cystectomy and \nimmediately transported fresh to the Anatomical Pathology \nLaboratory for paraffin block preparation and histopathological \nexamination. IHC staining was performed, and the expression of \np53, Bcl-2, Bax, caspase -3, caspase -8, caspase-9, and TNFR -1 was \nevaluated by three doctors: a general practitioner (research \nassistant), the primary researcher, and an anatomical pathology \nexpert. The staining was assessed using an Olympus CX 21 light \nmicroscope, and results were documented with a Nikon Eclipse E \n200 and Indomicro camera. Each variable's immunoexpression was \nquantified using the histoscore (H-score) formula; \nH-score=∑(i×Pi) (1) \nWhere 𝑖𝑖i is the staining intensity score and 𝑃𝑃𝑖𝑖Pi is the percentage of \ncells with positive staining. The epithelial cells were examined at \nthree fields of view at 400x magnification. Staining intensity was \ncategorized as weak (1), moderate (2), or strong (3), and \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \npercentages of positive cells were scored as 1 (< 20%), 2 (20 –50%), \n3 (50– 80%), or 4 (> 80%). IHC expression was considered weak if \nthe H-score was < 6 and strong if the H-score was > 6, based on the \nreceiver operating characteristic (ROC) curve. One month  post-\nsurgery, another blood sample was taken from the antecubital vein \nto measure postoperative AMH levels, which are expected to \nincrease after six months. The initial blood sample was collected just \nbefore entering the operating room. \nData Management and Analytics \nThe collected data were processed comprehensively. Data entry was \nperformed using SPSS version 20, including sample characteristics \nand the expression levels of p53, Bcl -2, Bax, caspase -3, caspase-8, \ncaspase-9, TNFR-1, and AMH values before and after surgery. Each \ndata point was coded according to the endometrioma size groups \n(≤ 4 cm and > 4 cm) and entered into tables categorized \naccordingly. Rows represented the expression levels and AMH \nvalues, while columns denoted the endometrioma size groups. \nUnivariate analysis was conducted to describe the characteristics of \nthe variables in frequency distribution form. For numerical data, \nmean and standard deviation were used for normally distributed \ndata, while median and range were applied for non -normally \ndistributed data. The Kolmogorov -Smirnov test was used to assess \nthe normality of numerical data distribution. Bivariate analysis \nexamined the relationships between the expression levels of p53, \nBcl-2, Bax, caspase -3, caspase -8, caspase -9, TNFR -1, and \nendometrioma size. It also explored the relationship between the \nchange in AMH values before and after surgery and endometrioma \nsize, as well as changes in preoperative AMH values against age -\nadjusted AMH normograms. Independent t -tests were used for \nnormally distributed data and Mann -Whitney tests for non -\nnormally distributed data. Bivariate analysis also assessed the \nrelationship between preoperative and postoperative AMH values \nwithin each endometrioma size group, using paired t -tests for \nnormally distributed data and Wilcoxon-signed rank tests for non-\nnormally distributed data. Correlation tests determined the \nrelationships between the expression levels of p53, Bcl -2, Bax, \ncaspase-3, caspase-8, caspase-9, TNFR-1, and AMH values before \nand after surgery. Multivariate analysis was performed to ascertain \nthe direction and strength of the relationships between the \nexpression levels of p53, Bcl-2, Bax, caspase-3, caspase-8, caspase-9, \nTNFR-1, and postoperative AMH values. Linear regression was \napplied to significant variables (p < 0.2) assuming normal, linear, \nand homogeneous data distributions. A significance level of α = 0.05 \nwas used, with p-values < 0.05 considered statistically significant. \nThe study was conducted after receiving ethical approval from the \nEthics Committee of the Faculty of Medicine, University of \nIndonesia. Blood samples were taken from patients before and after \nsurgery, and tissue samples were obtained during the removal of the \nendometrioma capsule and a ccompanying healthy tissue. All \nsamples and blood materials were recorded and numbered \nsystematically. All procedures were carried out with the knowledge \nand consent of the patients or their families, documented in the \nmedical records. \n \nResults \nTable 1. shows that in the paired t test there is no significant \ndifference in the decrease in AMH values in endometriomas with a \ndiameter of ≤ 4 cm. In endometriomas with a diameter of > 4 cm, \nanalysis with a paired t test found a significant difference indicating \nthat AMH values were associated with surgery. \nComparison of Delta AMH in the Endometrioma Group \nIn Table 2. It can be seen that the difference in the decrease in AMH \n(delta AMH) before cystectomy with normogram values in groups \n≤ 4 cm and > 4 cm (delta AMH 2) unpaired t test does not show \nsignificant differences. In both endometrioma groups, there wa s \nalso no significant difference in the decrease in AMH before and \nafter cystectomy (delta AMH 1). \nComparison of Delta AMH in Age Groups \nTo determine the difference in AMH difference before and after \nsurgery (delta AMH 1) in endometriomas ≤ 4 cm based on age, an \nunpaired t test was conducted and the results showed no significant \ndifference. The difference between preoperative AMH and normal \nvalues in endometriomas ≤ 4 cm (delta AMH 2) was also not \nsignificantly different in both age groups (Table 3.). \nIn Table 4. Statistical tests were conducted on the endometrioma > \n4 cm group in the age group (< 30 years and ≥ 30 years) on the \ndifference between AMH before and after surgery (delta AMH 1), \nas well as the difference between AMH before surgery and normal  \nvalues (delta AMH2). \nStatistical test Table 4., there was no significant difference in the \ndecrease in AMH endometrioma > 4 cm (delta AMH 1) in both age \ngroups. However, delta AMH 2 of the endometrioma > 4 cm group \nfound a significant difference (p 0.028) in the age group. \nComparison of TNF-α Receptor p53, Bcl -2 and Bax Expression \nIn Table 5, with IHK examination, there was an increase in TNFR -\n1 expression and an increase in diameter > 4 cm, but not significant. \nStatistical tests performed on both endometrioma diameter groups \ndid not find significant differences in the expression of p53 and Bcl-\n2. A significant increase in Bax expression (p 0.010) in the \nendometrioma > 4 cm group. Increased Bax expression illustrates \nheavier tissue damage in ovarian tissue with endometrioma \ndiameter > 4 cm.  \nIn Table 6., immunohistochemical examination showed an increase \nin the expression of Caspase -8, Caspase -9, Caspase -3. Statistical \ntests performed on both endometrioma diameter groups found no \nsignificant differences in overall gene expression.  \nCorrelation of Apoptosis Factor Gene Expression and \nEndometrioma Diameter \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nIn Table 7, the correlation test of Caspase-3 and Caspase-9 found a \nstrong positive relationship (r 0.780 and r 0.653) and significant (p \n= 0.005 and p = 0.001, respectively) in both endometrioma groups \n(≤ 4 cm and > 4 cm), illustrating apoptosis takes pla ce through the \ninstrinsic pathway and apoptosis is strongly associated with both \nendometrioma groups. Moderate positive association of Caspase -9 \nand p53 (r 0.594) and significant (p = 0.054) in endometriomas ≤ 4 \ncm. Moderate positive association of Bax and  p53 (0.508) was not \nsignificant (p = 0.111) in endometrioma ≤ 4 cm.  \nIn Table 7, the TNFR-1 and Caspase-3 correlation test found a very \nstrong positive relationship (r 0.859) significant (p = 0.001) in \nendometrioma diameter ≤ 4 cm and moderate positive (r 0.425) \nsignificant (p = 0.055) in endometrioma diameter > 4 cm. The \nTNFR-1 and Caspase -9 correlation test found a strong positive \nrelationship (r 0.747) significant (p = 0.008) in the endometrioma ≤ \n4 cm group and a moderate positive correlation (r 0.495) significant \n(p = 0.023) in the endometrioma diameter > 4 cm. Increase d \nexpression of TNFR -1 and p53, positively related moderate (r \n0.595) significant (p = 0.053) in endometrioma ≤ 4 cm and weakly \npositively related not significant (r 0.375 and p = 0.094) in \nendometrioma > 4 cm. \nComparison of AMH, Apoptosis Factor Gene Expression and \nEndometrioma Diameter  \nIn Table 8., a comparison was made of AMH before and after \ncystectomy in both endometrioma groups. In AMH before \ncystectomy, there was no significant decrease in AMH in both \nendometrioma groups (≤ 4 cm and > 4 cm) although AMH was \nfound to be lower in the endometrioma group > 4 cm. In Table 4.9, \nthere was an increase in the expression of apoptotic factor genes in \nendometriomas > 4 cm except p53. A significant differenc e was \nfound in the expression of Bax (p = 0.010). \nComparison of AMH, Apoptosis Factor Gene Expression and Age \nGroups \nIn Table 9, AMH before and after cystectomy was higher in the age \ngroup < 30 years compared to age ≥ 30 years but no significant \ndifference was found. Comparison of apoptotic factor gene \nexpression in both age groups (≥ 30 years and < 30 years) found no \nsignificant difference. Bax was fou nd to be higher in the < 30 year \nold group but not significant. \nExpression of Bax, Caspase-9 and Diameter Increase \nIn this study, it was found that the increase in diameter was followed \nby an increase in gene expression, especially Bax. Other parameters \nin the 3 cm cyst and 4-5 cm diameter cyst groups were also followed \nby an increase in gene expression except in the 6 cm diameter group \nwhere there was a downward trend. \nThere was an increasing trend in Bax expression values with \nincreasing cyst diameter, but not in the expression of other genes in \nthe study. In other gene expressions, the increase occurred up to \ndiameter 4-5 and decreased at diameter 6. \nPercentage of Positive Values of Apoptosis Factor Gene Expression \nIn Figure 3, it appears that in this study all factors examined showed \npositive values or positive. \nCPI reactions with the lowest exposure presented by Caspase -8 at \n25% and the highest was Bax 97%. \nFigure 3. Percentage of Positive Values of Apoptosis Factor \nExpression \nIn Table 10, the number of cysts and age were found to be weakly \nnegative and not significant, as well as postoperative, there was a \nweak negative relationship not significant in more than one cyst and \nage after surgery. \nTable 10., Correlation between the number of cysts and age \nIn Figure 4A, there is a decrease in AMH values from normal values \nwith increasing age of endometrioma patients who have more than \none cyst and AMH values lower than normal before surgery. \nRelationship between AMH-post Surgery and Age \nIn Figure 4B., this study found a decrease in AMH as the number of \ncysts increase; \nIn Figure 4C. it is found that the age of patients with endometrioma \nand more than one cyst will have a lower decrease in AMH value \nafter surgery. The decrease in AMH value in cysts that are more \nthan one is much lower. \nIn Table 11, the correlation test found a positive association of \ndecreased AMH values before surgery with apoptotic factor gene \nexpression. Increased p53 expression was positively associated very \nstrongly (r 0.895) and significantly (p < 0.001) with delta AMH-2 in \nthe endometrioma ≤ 4 cm group. Increased expression of TNFR -1 \nhad a moderate positive relationship and was not significant with \ndelta AMH-2 in the endometrioma ≤ 4 cm group. A moderate and \nsignificant positive relationship was found for Bax expre ssion, in \nthe endometrioma > 4 cm group. \nIn multivariate analysis Table 12. it was found that the expression \nof apoptotic factors was significantly positively and strongly \nassociated with a decrease in baseline AMH levels (before surgery) \nin the endometrioma ≤ 4 cm group (R2 = 0.918) and signific antly \npositively and strongly associated with the > 4 cm group. \nRelationship between Apoptosis Factor and Delta AMH -1 Gene \nExpression \nIn Table 13, the correlation test of AMH difference after before \nsurgery in the endometrioma group > 4 cm, TNFR-1 expression was \nfound to have a strong negative relationship (r -0.687) significant (p \n= 0.001) and a moderate negative relationship ( -0.506) significant \n(p = 0.019) Bax expression.  \nIn Table 13. the endometrioma ≤ 4 cm group, TNFR -1 expression \nhad a moderate negative relationship and was not significant. A \nstrong negative relationship (r- 0.654) significant (p = 0.029) was \nfound in Caspase-9 expression, Caspase-3 expression (r -0.705 p = \n0.010) and p53 (r - 0.738 p = 0.010). The expression of these \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \napoptotic factors illustrated a strong association with decreased \nAMH after surgery, except for Bcl-2. \nIn Table 14, there was a very strong relationship (R2 0.957) of \napoptosis factor gene expression to AMH values after surgery in the \nendometrioma ≤ 4 cm group. There was a moderate positive \nassociation (R2 0.405) in the endometrioma > 4 cm group in the \ndecrease of AMH after surgery. \nIn this study, the gene expression of apoptotic factors was examined \nby means of IHK to see the role of pro- inflammatory TNF -𝛼𝛼 \ninducing cell apoptosis in ovarian tissue damage. TNFR -1 \nexpression was found to be 47% strong intensity, Caspase -8 strong \nintensity 25%, p53 expression strong intensity 66% and Bax \nexpression strong intensity increased 97%. This increase in Bax \nexpression was found in both groups of endometriomas ≤ 4 cm and \n> 4 cm. \nBcl-2 expression (Figure 5A ) was found in 48% of strong positive \nreactions and 97% % of cases were found in strong intensity Bax \nexpression (Figure 5B ). The normal ratio of cells in defending \nthemselves from exposure is high anti -apoptotic (Bcl -2) and low \npro apoptotic (Bax). Increased expression of Bax followed by high \nexpression of Caspase -9 (85%) (Figure 5C ) proves mitochondrial \ndamage which shows a strong positive reaction and high expression \nof Caspase -3 (Figure 5D) (56%) as the executor of cell death \nindicates apoptosis occurs. \nFigure 5. Blue arrows indicate positive CPI values, black arrows \nindicate negative CPI values.  \n \nDiscussion \nLaparoscopic Cystectomy for Endometrioma \nThis study divided the diameter of endometriomas into two groups, \nnamely ≤ 4 cm and > 4 cm. This grouping refers to the HIFERI \npolicy on the management of endometriosis pain with \nendometriomas. Currently, surgery is performed on large \ndiameters. In accordance with Chen et al. (2014) Henes and Engler \n(2018) because AMH values decrease after 5 cm and 7 cm \nendometrioma diameter. In contrast to them, this study showed \nthat the AMH value of endometriomas ≤ 4 cm had decreased before \nsurgery. This proves that exposure to toxic substances damages \nhealthy tissue since small diameters before reaching 4 cm (Rumph \net al. 2020) . In accordance with Feng, Gao, and Peng (2019), \nKitajima et al. (2014), Matsuzaki (2010) , reported high 8 -\nhydroxydeoxyguanosine as an indicator of DNA damage due to \noxidative stress and the formation of fibrosis in the tissue around \nendometriomas as an indication of chronic inflammatory \nprocesses. It is necessary to perform small diameter surgery to avoid \nextensive fibrosis formation... \nIn endometriomas ≤ 4 cm and > 4 cm, AMH values had decreased \nbefore surgery and worsened significantly after surgery in \nendometriomas > 4 cm. However, it was not significant in ≤ 4 cm. \nEndometriomas decrease ovarian reserve and the risk increases \nwith increasing diameter. AMH values falling from normal \npreoperatively are in line with (Davies et al. 2019; Uncu et al. 2013). \nDelaying surgery is avoided because surgery of small \nendometriomas (≤ 4 cm) does not significantly reduce AMH values. \nAlso to prevent worsening of ovarian reserve due to time, as well as \nwhen cystectomy of endometriomas > 4 cm. \nIn this study, AMH values after and before surgery for \nendometriomas ≤ 4 cm did not differ significantly. In line with \nBrosens et al. (2014) , early preventive measures are needed to \nmaintain fertility. Endometrioma surgery ≤ 4 cm is recommended, \nbecause small endometriomas without surgery have reduced AMH \nvalues. According to Dr. Kasapoglu131, the rate of AMH decline \nwas greater in endometriom as (26.4%) than in normal ovaries \n(7.4%). The rate of decline based on age in normal ovaries was 0.2 \nng/mL/year130. In line with Gordts (2017), loss of ovarian reserve \nin endometriomas < 4 cm coincides with fibrosis in the ovarian \ncortex. Therefore, early detection and removal of endometrioma \ntoxic substances is necessary to minimize the risk of ovarian tissue \ndamage with endometrioma surgery before it is > 4 cm in diameter. \nEndometrioma Diameter and Age \nWhen compared to unilateral endometriomas, large, bilateral \nendometriomas considerably lower AMH values. AMH readings \nwere much lower in this study due to the age of the individuals and \nseveral endometriomas. Bilateral AMH readings were lower than \nunilateral AMH values both before and one month after surgery. \nAccording to research by Busacca and Vignali (2009), Hwu et al. \n(2011), Kitajima et al. (2011) , the postoperative AMH value drop \nwill depend on the cyst's width and bilaterality. Prior to surgery, the \nbasal AMH value was low, which is a factor that exacerbates the fall \nin AMH value and should be taken seriously. In order to prevent \nharm early on an d prevent the basal AMH value from worsening \nthe postoperative AMH value, surgery should be performed before \nthe diameter reaches 4 cm. 62% of the participants in this study had \nAMH readings that were below normal and that dramatically \ndropped following su rgery for endometriomas larger than 4 cm. \nThis shows the possibility of a significant drop in AMH values in \nthe event that surgery is postponed. Large diameter surgery carries \na higher risk of increased ovarian reserve depletion and decreased \nbasal AMH lev els. According to Chiu et al. (2022) , there is a \nsignificant correlation between large endometriomas and the high \nincidence of recurrence following surgery. Surgery at small \ndiameters is recommended because to the potential for greater loss \nof healthy tissue in larger diameters and the significance of the basal \nAMH value prior to surgery (Alammari, Lightfoot, and Hur 2017).  \nIn this study, 77% of the participants were older than 30, and 40% \nof the subjects had AMH values less than 1.4 ng/mL.  If the embryo \ntransfer is done at a young age, Iwase et al. (2010), Shi et al. (2011)  \nstates that these low AMH values are strongly linked to the failure   \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nTable 1. AMH Values Before and After Cystectomy in Endometriomas ≤ 4 cm and \nEndometrioma   Sebelum Sesudah p \n≤ 4 cm 2,393 (± 1,619) 1,752 (± 1,955) 0,083 \n> 4 cm 1,656 (± 0,945) 1,276 (± 0,911) 0,023 \n \nTable 2. Association of Delta AMH 1 and Delta AMH 2 with Endometrioma ≤ 4 cm versus > 4 cm \nDelta AMH ≤ 4 cm (n = 11)  > 4 cm (n = 21) p \nDelta AMH 1 -1,029 (± 0,710) -0,599 (±0,854) 0,164 \nDelta AMH 2 -0,971 (±1,951) -0,985 (±1,484) 0,982 \n \nTable 3. Delta AMH in Endometrioma ≤ 4 cm by Age Group \nDelta AMH ≥ 30 tahun \n (n = 7) \n< 30 Tahun \n(n = 4) \np \nDelta AMH 1 -0,878 (± 0,618) -1,292 (± 0,878) 0,380 \nDelta AMH 2 -0,512 (± 1,642) -1,772 (± 2,438) 0,328 \n \nTable 4. Delta AMH in Endometrioma > 4 cm by Age Group \nDelta AMH ≥ 30 tahun  (n = 13) < 30 Tahun (n = 8) p \nDelta AMH 1 -0,512 (± 0,761) -0,738 (± 1,027) 0,570 \nDelta AMH 2 -0,441 (± 0,950) -1,868 (± 1,817) 0,028 \n \nTable 5. Apoptosis Factor Gene Expression in Endometriomas < 4 cm and ≥ 4 cm \nEkspresi Gen ≤ 4 cm (n = 11)  > 4 cm (n = 21) p \nTNFR-1, Rerata (SB) 5,414 (± 3,350) 5,855 (± 3,387) 0,728 \nEkspresi p53, Rerata (SB) 6,831 (± 3,304) 6,127 (± 2,270) 0,483 \nBcl-2, Rerata (SB) 5,107 (± 2,328) 5,981 (± 3,691) 0,420 \nBax , Rerata (SB) 11,340 (± 4,125) 14,981 (± 3,222) 0,010 \n \nTable 6. Expression of Caspase-8, Caspase-9, Caspase-3 in Endometriomas ≤ 4 cm and > 4 cm \nEkspresi Gen ≤ 4 cm (n = 11)  > 4 cm (n = 21) p \nCaspase-3, Rerata (SB) 5,841 (± 4,096) 7,367 (± 4,675) 0,369 \nCaspase-8, Rerata (SB) 3,969 (± 2,269) 4,436 (± 4,624) 0,756 \nCaspase-9, Rerata (SB) 8,353 (± 3,948) 11,245 (± 4,109) 0,065 \n \nTable 7. Correlation of Apoptosis Factor Gene Expression on Endometrioma Diameter \nGene Expression ≤ 4 cm (n = 11) > 4 cm (n = 21) \nr p r p \nCaspase-3 – Caspase-9 \nCaspase 3 – Bax \nCaspase 9 – Bax \n0,780 \n0,607 \n0,630 \n0,005 \n0,048 \n0,038 \n0,653 \n0,380 \n0,443 \n0,001 \n0,089 \n0,045  \nCaspase-9 – p53 0,594 0,054  0,078 0,736 \nTNFR-1 – Caspase-3 0,859 0,001 0,425 0,055 \nTNFR-1 – Caspase-8 0,467 0,147 0,231 0,313 \nTNFR-1 – Caspase-9 0,747 0,008 0,495 0,023 \nTNFR-1 – p53 \nTNFR-1 – Bax \np53       – Bax \nBcl-2     – Bax \nCaspase 8– Bax \n0,595 \n0,586 \n0,508 \n0,487 \n0,160 \n0,053 \n0,056 \n0,111 \n0,137 \n0,638 \n0,375 \n0,456 \n0,172 \n0,407 \n0,116 \n0,094 \n0,038 \n0,455 \n0,067 \n0,617 \n \nTable 8. AMH and Apoptosis Factor Gene Expression in Endometrioma Diameter ≤ 4 cm and > 4 cm \nAMH dan Ekspresi Gen  ≤ 4 cm (n = 11)  > 4 cm (n = 21) p \nAMH  \nSebelum \n \n2,392 (± 1,619) \n \n1,656 (± 0,945) \n \n0,113 \nSesudah 1,753 (± 1,955) 1,276 (± 0,911) 0,352 \nExpression  \nExpression p53, Rerata (SB) \n \n6,831 (± 3,304) \n \n6,127 (± 2,270) \n \n0,483 \nBcl-2, Rerata (SB) 5,107 (± 2,328) 5,981 (± 3,691) 0,420 \nBax, Average (SB) 11,340 (± 4,125) 14,981 (± 3,222) 0,010 \nCaspase-3, Rerata (SB) 5,841 (± 4,096) 7,367 (± 4,675) 0,369 \nCaspase-8, Rerata (SB) 3,969 (± 2,269) 4,436 (± 4,624) 0,756 \nCaspase-9, Rerata (SB) 8,353 (± 3,948) 11,245 (± 4,109) 0,065 \nTNFR-1, Rerata (SB) 5,414 (± 3,350) 5,855 (± 3,387) 0,728 \n \n \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nTable 9. AMH and Apoptosis Factor Gene Expression by Age Group ≥ 30 Years and < 30 Years \nAMH dan Ekspresi Gen ≥ 30 tahun  \n(n = 20) \n< 30 Tahun \n (n = 12) \np \nAMH  \nBefore \n \n1,747 (± 1,180) \n \n2,180 (± 1,353) \n \n0,349 \nAfter 1,350 (± 1,515) 1,590 (± 1,063) 0,635 \nExpression \nEkspresi p53, Rerata (SB) \n \n6,596 (± 2,403) \n \n5,991 (± 3,065) \n \n0,539 \nBCL-2, Rerata (SB) 6,340 (± 3,194) 4,581 (± 3,248) 0,144 \nBax , Rerata (SB) 13,489 (± 4,207) 14,130 (± 3,494) 0,661 \nCaspase-3, Rerata (SB) 7,00 (± 3,870) 6,575 (± 5,526) 0,798 \nCaspase-8, Rerata (SB) 4,806 (± 4,772) 3,392 (± 1,731) 0,333 \nCaspase-9, Rerata (SB) 10,256 (± 4,146) 10,243 (± 4,546) 0,993 \nTNFR-1, Rerata (SB) 6,045 (±3,260) 5,133 (± 3,501) 0,461 \n \nTable 10. Correlation between the number of cysts and age \n      Kista r p \nUnilateral (pre) -0,052 0,832 \nBilateral (pre) \nUnilateral (post) \nBilateral (post) \n-0,319 \n-0,104 \n-0,286 \n0,289 \n0,672 \n0,343 \n \nTable 11. Association of Apoptosis Factor Gene Expression with Delta AMH-2 Based on Endometrioma \nGene Expression ≤ 4 cm (n = 11) > 4 cm (n = 21) \nr p r p \nTNFR-1 – Delta AMH-2 0,569 0,068 0,437 0,048 \n p53 – Delta AMH-2 0,895 < 0,001 0,181 0,432 \nBax – Delta AMH-2 0,455 0,160 0,533 0,013 \nCaspase-3– Delta AMH-2 0,539 0,087 0,198 0,389 \nCaspase-8– Delta AMH-2 -0,279 0,406 0,159 0,490 \nCaspase-9– Delta AMH-2 0,532 0,092 0,170 0,461 \nBCL-2 – Delta AMH-2 0,648 0,031 0,005 0,984 \n \nTable 12. Correlation of Apoptosis Factor Gene Expression to AMH-1 Based on Endometrioma Size \nGene Expression ≤ 4 cm (R 2 = 0,918) > 4 cm (R2 = 0,648) \nKoefisien p Koefisien p \nTNFR --1 1,390 0,035 -0,620 0,016 \n p53  -0,989 0,024 0,182 0,386 \nBax  0,371 0,127 -0,280 0,191 \nCaspase-3 -1,069 0,033 0,156 0,544 \nCaspase-8 -0,581 0,094 -0,090 0,629 \nCaspase-9 -403 0,180 -0,234 0,368 \nBCL-2  - - 0,197 0,416 \n \nTable 13. Association of Apoptosis Factor Gene Expression with Delta AMH-1 by Endometrioma Size \nEkspresi  ≤ 4 cm (n = 11) > 4 cm (n = 21) \nr p r p \nTNFR-1 - Delta AMH -0,472 0,143 -0,687 0,001 \n p53 - Delta AMH -0,738 0,010 -0,014 0,953 \nBax - Delta AMH -0,313 0,349 -0,506 0,019 \nCaspase-3 - Delta AMH -0,705 0,010 -0,239 0,296 \nCaspase-8 - Delta AMH 0,099 0,773 -0,146 0,528 \nCaspase-9 - Delta AMH -0,654 0,029 -0,484 0,026 \nBCL-2 - Delta AMH -0,227 0,502 -0,027 0,906 \n \n \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nTable 14. Multivariate Analysis of Apoptosis Factor Gene Expression on AMH-2 in the Endometrioma Group \nEkspresi  ≤ 4 cm (R 2 = 0,957) > 4 cm (R2 = 0,405) \nKoefisien p Koefisien p \nTNFR-1  0,491 0,286 - - \n p53  0,594 < 0,001 - - \nBax  -0,114 0,555 0,295 0,184 \nCaspase-3 -0,318 0,340 0,521 0,031 \nCaspase-8 -0,319 0,249 - - \nCaspase-9 0,055 0,808 - - \nBCL-2  0,387 0,074 -0,301 0,165 \n \n \n \n \n \nFigure 1. Theoretical Framework of Ovarian Reserve Damage in Endometrioma \n \n \n \n          \n \nFigure 2. Bax Expression and Endometrioma Diameter Increase. \n \n \n \nFigure 3. Percentage of Positive Values of Apoptosis Factor Expression. \n0.00\n50.00\n100.00\nTNFR Cas 8 BCL2 BAX Cas 9 Cas 3 P 53\n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n                                  A       B \n \n  C \n \n  A         B \n   \n            C          D \n     \n \n \nFigure 4 (A) Relationship between Age and Pre-operative AMH.  (B) \nRelationship between Post-operative AMH and Number of Cysts. (C) \nRelationship between Age and Post-operative AMH Value. \n \nFigure 5 (A) Expression of Bcl-2; Cytoplasm of Moderately \nPositive Epithelium by Immunohistochemistry.  (B) Bax \nExpression; Strong Positive Epithelial Cytoplasm by \nImmunohistochemistry. (C) Caspase-9 Expression; Cytoplasm \nof Strongly Positive Epithelial Cells by Immunohistochemical \nReaction. (D) Caspase-3 Expression; Strong Positive Epithelial \nCell Cytoplasm by Immunohistochemical Reaction \n \nFigure 6. Proposed Mechanism of Ovarian \nTissue Damage by TNF-α \n \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nof the embryo transfer process. An estimated 17 –44% of \nendometriosis patients also have endometriomas, and 20 –40% of \nthem will use assisted reproductive technologies. AMH readings \nwill decline with age, and Briley et al. (2016), Seifer, Baker, and \nLeader (2011), state that age is a significant factor in aggravating the \nloss of ovarian reserve. It is critical to identify endometriomas as \nsoon as possible to preserve ovarian reserve. 25% of the individuals \nhad an AMH value of less than 1 ng/mL when they were brought to \nthe hospital; this indicated a poor prognosis for a successful \ninduction of ovulation and a lowered likelihood of becoming \npregnant. The group with the highest severity was composed of 6% \nof patients who arrived at the hospital with an AMH result bel ow \n0.5 µg/mL, which is the cutoff point for early menopause. The \nproportion of patients with low fertility rose following cystectomy. \nIn that order, 31% (< 0.5 ng/mL), 44% (< 1 ng/mL), and 56% (< 1.4 \nng/mL) were found. This is in line with the findings of Celik et al. \n(2012), who have indicated that patients with basal or preoperative \nAMH concentrations will have worse reproductive outcomes. \nTherefore, surgery should be done while AMH readings are still \ngood in order to prevent more serious harm (Lew 2019; Sugita et al. \n2013; Zikargae 2018). \nThe 30-year restriction used in this study is based on Isono et al. \n(2019), who stated that severe endometriosis was managed before \nthe age of 30 in order to conceive. Atkins' research indicates that \nprimordial follicles are also strongly impacted by age.49 AMH \nreadings become basal values prior to surgery as people age, \naccording to Briley et al. (2016), Seifer, Baker, and Leader (2011). \nAge is therefore a factor in this investigation. The deterioration of \nhealthy ovarian tissue is related to age. Age -related increases in \novarian tissue damage are marked by elevated Bax expression at 30 \nyears of age and greater attempts by the body to re pair the damage \nby markedly raising Bcl -2 at 30 years of age. This study also \nindicated that age has an impact on AMH values. Before surgery, \nthere was a statistically significant difference in the low AMH values \nbetween the age 30 and endometrioma > 4 cm groups. According \nto Isono et al. (2019), it is advised that attempts be made to achieve \nconception before the age of thirty. The findings of this study \nsuggest that endometrioma surgery should be performed before to \nthe age of thirty years and before the endometrioma diameter \nreaches four centimeters (Gordts et al. 2015). \nApoptosis Factor and AMH Gene Expression \nThe study observed a correlation between the growth of \nendometrioma and the upregulation of genes associated with \napoptosis. This was demonstrated by the increased expression of \nTNF-α receptors, Caspase-8, Bcl-2, Bax, Caspase-9, and Caspase-3, \nwhich are kn own to play a role in cell death. Apoptosis of the \nendometrioma epithelium is enhanced, leading to the removal of \nnatural barriers and causing more harm to the ovarian reserves, \nparticularly the primordial follicles. According to Gupta's findings, \nit has been observed that granulosa cells, which are responsible for \nproducing AMH, undergo apoptosis. The study observed a rise in \napoptosis, which was subsequently accompanied by a decrease in \nAMH levels from their initial normal values before to surgery. \nThere was no significant difference in the expression of apoptotic \nfactor genes between the two endometrioma groups, one with a size \nof 4 cm or less and the other with a size greater than 4 cm. This \ndemonstrates that the exposure to hazardous compounds occurs \nover a range of dimensions, starting from small (2.5 cm) and \nextending to larger (6 cm) sizes.  This study demonstrates that the \nexistence of endometrioma has caused early harm to healthy tissue \nand is linked to preoperative exposure to toxic substances. Thi s \nstudy additionally demonstrated that pro -inflammatory cytokines \ncontribute to the destruction of ovarian tissue.  \nThe expression of caspase increased as the diameter of the \nendometrioma increased. The enlargement of endometrioma \ndiameter to more than 4 cm is indicative of heightened Caspase -9 \nexpression, which signifies mitochondrial impairment. This \nprocess commences  with an upregulation of Bax expression, \nleading to the creation of apoptosomes that trigger the conversion \nof procaspase-9 into active Caspase -9. Elevated levels of Caspase -9 \ninduce the activation of Caspase -3, leading to the initiation of \nprogrammed cell  death. This diagram depicts the progressive \ndeterioration of ovarian tissue as the size of the endometrioma \nincreases. According to Sanchez et al. (2014), Gene expression alters \nthe physical barrier separating cyst fluid from healthy ovarian \ntissue, allowing reactive oxygen species (ROS) to induce fibrosis by \ncrossing the cyst wall. This study found that TNF -α stimulated the \nexpression of genes associated with programmed cell death and was \nassociated with harm to nearby healthy tissue. Brosens et al. (2004), \nChiu et al. (2022) , provided evidence that smooth muscle \nmetaplasia, fibrosis of the cortical layer, and the extent of the \nendometrioma are associated with a decrease in AMH levels. \nCystectomy is necessary to halt the enlargement of the cyst's \ndiameter and minimize exposure to harmful substances. \nActivation of TNF -α receptors by pro -inflammatory cytokines, \nwhich in turn initiated the process of programmed cell death in the \nepithelial cells of both endometrioma groups (≤ 4 cm and > 4 cm). \nThis aligns with the findings of Vetvicka,11 who demonstrated  the \ninvolvement of pro -inflammatory cytokines in triggering the \napoptotic cascade. The IHK's response to TNFR -1 is feeble, which \naligns with the findings of Salmeri's research.The number is 68. An \nescalation in the severity of endometriosis leads to a red uction in \nthe level of TNF -α binding with its receptor (TNFR -1). \nEndometriosis is a persistent inflammatory condition. During the \nchronic inflammatory process, the M1 phenotype transitions into \nthe M2 phenotype. M2 is a type of immune cell called a macrophage \nthat plays a role in tissue regeneration and the development of \nfibrosis. As a result, the presence of TNF -α, a pro -inflammatory \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nmolecule, is reduced. Hence, it is imperative to halt the \ninflammatory process that triggers damage to ovarian tissue and the \ndevelopment of permanent fibrosis once the diagnosis is \nestablished.  \nGene expression is the process by which organisms modify gene \ntranscription in order to respond to environmental factors such as \nhormones, heavy metals, and toxins. This work demonstrates that \ncells undergo a process of adaptation in response to the risk o f \nmortality, characterized by an upregulation of Bcl -2 expression, \nalbeit with low intensity. Similarly, studies carried out by \n(Dufournet et al. 2006; Korkmaz et al. 2013; Pejovic et al. 2020) . \nrevealed a low level of Bcl-2 expression in 25% of the analyzed cases. \nThe Bcl-2/Bax ratio serves as an indicator of the cell's capacity to \nwithstand exposure to harmful chemicals. The endometrioma \nepithelium exhibited a significant increase in Bax expre ssion in \ncomparison to Bcl -2 expression. Elevated levels of pro -apoptotic \nexpression are indicative of the intensity of toxicant exposure, \nleading to cellular demise. Eliminating exposure to hazardous \nsubstances is a viable strategy to enhance the flexibil ity of the \nnatural barrier in the ovaries. \nThe cell membrane contains TNF-α receptors, which are referred to \nas death receptors (DRs) or death signals. The correlation analysis \nbetween TNFR -1 expression and apoptosis occurrence revealed a \nrobust positive association, indicating that the pro -inflammatory \ncytokine TNF-α initiates the apoptotic pathway in the epithelium of \nendometriomas. Apoptosis occurs via the intrinsic mechanism, \nnamely including upregulation of Bax, Caspase -9, and Caspase -3. \n(Illustration of the proposed mechanism can be found in F igure 6) \nThis contrasts with the findings of Haupt et al. (2003), Obstet et al. \n(2016), Salmeri et al. (2015), propose that the active TNF-α receptor \ninduces apoptosis via the extrinsic pathway. Specifically, the active \ndeath receptor activates Caspase -8 and Caspase -3. Contrarily, this \nwork aligns with Bredesen's findings that TNF-α effectively attaches \nto death receptors and triggers apoptosis both directly via caspases \nand indirectly through mitochondria.  \nThe study found a drop in the balancing ratio of Bcl -2/Bax. The \nlevels of pro -apoptotic Bax were higher in both endometrioma \ngroups (≤ 4 cm and > 4 cm) and showed a significant difference. \nElevated Bax expression leads to mitochondrial impairment, which \nserves as a vital energy source for cells.Prolonged exposure to \nharmful substances will result in cellular apoptosis and irreversible \ncellular harm. 121 Activation of death receptors triggers the \nproduction of Bax and p53, which are involved in preserving th e \nintegrity of the genome (the guardian of the genome).One hundred \neighteen If cell damage cannot be healed, the presence of activated \nBax alters the proportion of Bcl-2 to Bax (Depalo et al. 2009; Haupt \net al. 2003).  The investigation revealed a notable increase (66%) in \np53 expression, indicating the presence of significant damage. \nConsistent with (Fauvet et al. 2005; Haupt et al. 2003) .  Dufournet \net al. (2006) Fauvet et al. (2005), observed that the expression of p53 \nwas elevated in borderline cysts, specifically endometriomas and \novarian cancers, compared to benign ovarian cysts. Ensuring the \ncessation of contact with harmful substances is of utmost \nimportance after endometrioma is  diagnosed. According to \nLincenstein, mitochondrial damage is both permanent and \nprogressively worsens from a mild to severe state.One hundred \nseventeen The study demonstrates a significant upregulation of Bax \nand p53, which are indicators of apoptosis, i ndicating the severity \nof exposure. The upregulation of p53 in this study is consistent with \nthe findings of (Chen et al. 2014; Fauvet et al. 2005) . In contrast to \nNezhat's research, which found negative p53 staining in 30 cases of \novarian endometriosis cysts, this study observed positive Bcl -2 \nexpression that aligns with its own findings. Higher levels of p53 \nexpression serve as a sign of advancing cases that necessitate \nimmediate intervention, hence it is advisable to refrain from \npostponing endometrioma surgery. All instances showed a high \nlevel of Bax expression (97%), suggesting a reduced Bcl-2/Bax ratio. \nCell death occurs as a result of mitochon drial dysfunction caused \nby damage to the mitochondrial membrane (Bateman, Blanco, and \nSheffi 2017; Heca et al. 2018) . Apoptosis is observed by the \nupregulation of Caspase-3, which acts as the executor of cell death. \nThis diverges from (Depalo et al. (2009), Giacomini et al. (2017) , \nstates that endometrial lesions sustain their survival by evading \napoptosis or enhancing the Bcl -2/Bax ratio. Nevertheless, this \ndistinction aligns with the viewpoint of Nisolle and Donnez (2019), \nwho argues that endometrioma, as a cyst caused by endometriosis \nin the ovary, is a distinct entity from endometriosis lesions in the \nperitoneal cavity and deep infiltrating endometriosis located in the \nrectum. Therefore, medicine alone is not a successful treatment for \nendometrioma, and surgery is the preferred initial option. \nApoptotic factor gene expression (Bax, Caspase -9, Caspase-3) was \ngreater in endometriomas larger than 4 cm compared to those that \nwere 4 cm or less. There was a notable disparity in the expression of \nBax, with a p -value of 0.01. The levels of Caspase -9 and Caspase-3 \nwere elevated in endometriomas larger than 4 cm, however the \ndifference was not statistically significant. A correlation test was \nconducted to examine the expression of apoptotic factor genes in \nthe endometrioma group with a size more than 4 cm.  The results \nshowed a significant and strong positive association between \nCaspase-3 and Caspase -9. The expression of TNFR -1 showed a \nmodest and statistically significant positive connection with \nCaspase-9 (r = 0.495) and Caspase-3 (r = 0.425).  This demonstrates \nhow the intrinsic pathway's apoptotic process is triggered by \nproinflammatory cytokines (TNF -α) in both endometrioma \ngroups. This study demonstrates that gene expression reveals \nserious damage when the diameter exceeds 4 cm. Therefore, to \nprevent the widespread deterioration of the ovarian natural barrier, \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nit is advisable to undergo surgery prior to the ovarian diameter \nreaching 4 cm. \nThis study observed a rise in the mortality of the epithelial cells in \nthe endomyoma wall. According to Muzii et al. (2007)  out of 40% \nof the cyst surface lacks epithelium. The absence of a natural barrier \nfacilitates the susceptibility of surrounding healthy tissue to damage \nfrom exposure to poisonous substances released by endometrioma. \nThe injury is identified by a reductio n in the AMH value prior to \nthe surgical procedure. These findings align with the research \nconducted by (Garcia -Velasco and Somigliana 2009; Giacomini et \nal. 2017) . They indicate that endometriomas decrease the anti -\nMüllerian hormone (AMH) levels in both blood and follicular fluid. \nEndometriomas have a detrimental impact on the surrounding \ntissue as a result of disruptions in iron metabolism and the \noccurrence of oxidative stress. Kitajima et al. (2011), in their study, \nobserved a higher occurrence of primary follicle degeneration in the \novarian cortex of endometriomas, along with increased caspase -3 \nexpression and reduced diameter of primordial follicles, as \ncompared to ovaries without cysts. This study  examines how the \nabsence of the normal protective barrier in the ovaries affects the \nharm caused to the surrounding healthy tissue by the \nendometrioma. Consequently, it is imperative to perform surgery \npromptly upon diagnosing endometrioma in order to pre vent the \nspread of harmful compounds from the endometrioma and prevent \nmore harm. \nConsistent with the findings of Khan et al. (2013), Kitajima et al. \n(2014), Matsuzaki (2010), our study demonstrates that the absence \nof endometrioma epithelium raises the risk of further harm to the \novarian reserve from additional hazardous substances associated \nwith endometrioma. Measures must be implemented to safeguard \nthe quantity and qualit y of oocytes, particularly the primordial \nfollicles, as well as the ovarian reserve. Consistent with the findings \nof Coccia et al. (2014), Nisolle and Donnez (2019), the mesothelium \nthat covers the ovary might fold inward, causing the primordial \nfollicles to be displaced towards the rear of the cyst. The study found \nthat the lack of epithelium allowed hazardous chemicals to directly \naccess the primordial follicles. T he reduction in the quantity of \nprimordial follicles will impact the AMH level. Prior to surgery, it \nis crucial to assess the basal anti -Müllerian hormone (AMH) levels \nin order to prevent any potential ovarian dysfunction. Early surgical \nintervention is necessary in order to safeguard fertility and prevent \nharm to the adjacent healthy tissue surrounding the endometrioma. \nThis study revealed that the expression of apoptotic factor genes \ninfluences the ability of free radicals to traverse the natural barrier. \nThe upregulation of TNF -α receptors marks the initiation of the \napoptotic pathway, leading to ovarian tissue damage and decreased \nAMH levels prior to surgery in both groups with endometrioma. \nAccording to Sanchez's research, the AMH value decreases as a sign \nof ovarian reserve loss caused by fibrosis surrounding the \nendometrioma. ROS, or reactive oxygen species, penetrates the cyst \nwall and contributes to the development of ovarian fibrosis, \nresulting in a decrease in follicular density. Miller et al. (2021), it has \nbeen observed that reactive oxygen species (ROS) can permeate past \nthe cyst membrane barrier and cause harm to the surrounding \nhealthy tissue around the endometrioma. It is crucial to inhibit the \nactivation of death receptors by pro- inflammatory c ytokines to \nprevent extensive damage to the ovaries (Akhtar Muhammad 2021; \nFoti et al. 2018). \nAccording to a correlation test, there was a substantial positive link \nbetween TNFR -1 expression and increased expression of Bax, \ncaspase-9, and caspase -3 with moderate, strong, and very strong \nresults in both endometrioma groups (≤ 4 cm and > 4 cm). This \ndemonstrates th at apoptosis takes place via the intrinsic \nmechanism. The activity of the intrinsic pathway was enhanced by \nupregulation of Bax, leading to increased production of caspase -9 \nand caspase -3, which exhibited a highly significant positive \ncorrelation. Both set s of endometriomas had a significant \ncorrelation between the expression of apoptotic factor genes, \nranging from mild to strong. Unlike Vetvicka's study, TNF -α \ntriggers apoptosis through the extrinsic mechanism by activating \nreceptors. This work demonstrate s that exposure to the pro-\ninflammatory cytokine TNF-α activates the TNFR-1 receptor in the \nepithelium of endometrioma, leading to apoptosis via the intrinsic \npathway. The presence of natural barriers to apoptosis will regulate \nthe toxic compounds in endom etriomas, particularly the pro-\ninflammatory cytokine TNF -α, which stimulates the development \nof fibrosis and decreases follicular density. (Illustration of the \nproposed mechanism can be found in Figure 6. \nEarly Detection and Treatment of Endometrioma is Important \nA significant positive connection was seen between AMH levels and \nthe expression of apoptotic factor genes in both types of \nendometriomas, those with a size of 4 cm or less and those larger \nthan 4 cm. A multivariate correlation test was conducted to \nexamine the relationship between the expression of apoptotic factor \ngenes and the decrease in AMH values before surgery. The results \nrevealed a highly significant positive connection (R2 0.918). A \nrobust and statistically significant inverse correlation was seen  in \nthe expression of TNFR-1 in the group with endometriomas larger \nthan 4 cm. According to Obstet et al. (2016) , TNF -α is a pro-\ninflammatory cytokine that interacts to its receptor TNFR- 1, \nleading to the initiation of apoptosis. The detrimental effects of the \nendometrioma facilitate the passage of other hazardous substances \nbeyond the natural barrier, leading to de struction of the \nsurrounding healthy tissue. This leads to the development of \nfibrosis and a decrease in follicular density, resulting in lower AMH \nreadings prior to surgery. Therefore, it is crucial and paramount to \nprevent any additional harm (Baker et al. 2018; Lew 2019; \nSomigliana et al. 2012). \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nThis study demonstrates a decline in anti -Müllerian hormone \n(AMH) levels prior to surgery. In the correlation test conducted on \nendometrioma measuring 4 cm or less, there was a robust and \nstatistically significant positive association between p53 expressio n \nand a decrease in AMH value prior to surgery. Similarly, there is a \nfavorable correlation between the expression of Bcl -2 and a \nsubstantial and statistically significant reduction in AMH levels \nprior to surgery in endometriomas that are 4 cm or less. Thi s \nsuggests that there is an ongoing attempt to compensate cells in \norder to adjust to the encountered exposure. In contrast to larger \ndiameters (> 4 cm), there is no correlation between Bcl-2 expression \nand the decrease in AMH readings prior to surgery (Parameswaran \nand Patial 2010) . Endometrioma larger than 4 cm is linked to a \nnotable reduction in AMH levels, which is correlated with a \nsubstantial and meaningful rise in TNFR -1 and Bax expression. \nThis suggests that the presence of harmful compounds that \nstimulate TNF -α receptors lea ds to damage in ovarian tissue, \nparticularly when the diameter exceeds 4 cm. \nThis study observed a significant upregulation of Bax expression, \nwhich exhibited a positive correlation with the cyst diameter. \nGreater levels of Bax and caspase -9 expression were observed in \nendometriomas larger than 4 cm, indicating more extensive \ndamage. The expression of Bax showed a statistically significant \ndifference (p = 0.01) between both groups of endometrioma. This \ndemonstrates that as the diameter of an endometrioma increases, \nthere is a corresponding increase in damage to the ovarian tissue, as \nobserved through changes in gene expression. This study \ndemonstrates that the damage to endometriomas begins with the \nlowest diameter (2.5 cm) and progresses to the largest diameter (6.5 \ncm). This damage is associated with the pro-inflammatory cytokine \nTNF-α and is influenced (Molvig 1988; Parsa et al. 2018; Sipak -\nSzmigiel et al. 2017) . Therefore, it is crucial to discover \nendometriomas early. \nFailure to promptly address the presence of endometrioma from the \noutset will exacerbate the likelihood of diminishing the patient's \novarian reserve. This study revealed a significant difference in the \nlowering of the AMH value following cystectomy in the group with \nendometrioma larger than 4 cm. It is crucial to prevent ovarian \nfunction failure, particularly during reproductive years, as it would \nprevent the possibility of using assisted reproductive technologies \nin cases where the AMH value is extremely low. This study revealed \nthat 31% of the total participants experienced a decline in their \nAMH readings below 0.5 ng/mL after cystectomy. This decrease \nserves as a threshold, indicating that patients with endometrioma \nmay be at risk of early menopause. \nThe main finding of this study is that surgery for endometriomas \nmeasuring < 4 cm does not have a significant impact on anti -\nMüllerian hormone (AMH) levels, but surgery for endometriomas \nmeasuring > 4 cm considerably reduces AMH levels. The size of \novarian cysts directly correlates with the extent of damage to \novarian tissue, as evidenced by the upregulation of genes associated \nwith programmed cell death. Bax expression, in particular, \ncontinues to rise as cyst width increases. The expression \nupregulation begins with the activation of TNF receptor -α, which \nsubsequently triggers the intrinsic pathway, le ading to an increase \nin the expression of Bax and caspase-9. This ultimately results in the \ndeath of epithelial cells. The presence of caspase -3 indicates \napoptosis in the epithelium of endometrioma, resulting in the loss \nof the ovary's natural protective barrier. This process also affects the \nexposure of the ovary to harmful substances, which can cause \ndamage to the healthy tissue. The presence of tissue damage in the \ntiny-diameter cyst, measuring 2.5 cm, and the decline in AMH \nvalues prior to surgery are apparent. The drop in anti -Müllerian \nhormone (AMH) levels was a result of injury to the ovarian tissue. \nInvestigators found a positive correlation between this decrease and \nthe expression of genes related to programmed cell death \n(apoptosis). Endometrioma decreases fertility, and the presence of \ncyst fluid jeopardizes the progression of ovarian tissue damage. To \nsave the ovarian reserve, it is advisable to extract the fluid from \nendometrioma cysts before they reach a diameter of 4 cm, \nparticularly in patients who are 30 years of age or younger. \nAccording to this study, 50% of endometriomas have surface \nepithelium that has undergone apoptosis due to the pro -\ninflammatory cytokine TNF-α. However, given the high expression \nof p53 (66%), 97% of endometriomas have Bax, and 56% of them \nhave caspase-3, it is impossible to rule out the possibility that other \nendometrioma-causing toxins are also responsible for seriously \nharming epithelial cell mitochondria. ROS, generated by the Fenton \nreaction, can permeate the cyst wall in endometrioma fluid \n(Scutiero et al. 2017). \n \nConclusion \nBased on the findings, laparoscopic cystectomy for endometriomas \nsmaller than 4 cm does not significantly reduce AMH levels, \nwhereas for endometriomas larger than 4 cm, there is a significant \ndecline in AMH. The increase in endometrioma diameter is \nassociated with elevated Bax expression, indicating ovarian tissue \ndamage. Laparoscopic cystectomy of endometriomas larger than 4 \ncm in women over 30 years significantly decreases AMH and poses \na risk of ovarian failure, with 31% of cases experiencing early \nmenopause. The expression of apoptosis-related genes shows a very \nstrong positive correlation with AMH reduction in endometriomas \nsmaller than 4 cm and a strong correlation in larger \nendometriomas. These results suggest that imme diate surgical \nintervention for endometriomas is crucial, particularly before the \ndiameter reaches 4 cm, to preserve ovarian function and prevent \nlong-term reproductive complications. \n \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nAuthor contributions \nT.A.H. was the primary researcher and was responsible for the \nstudy design, data collection, data analysis, and manuscript \npreparation. Dr. W. H., Dr. S. S., and Dr. P. R. provided supervision, \ncritical revisions, and guidance throughout the research process. All \nauthors contributed to the interpretation of the data and approved \nthe final manuscript. \n \nAcknowledgment  \nThe authors sincerely thanked the staff and medical team at \nWomen and Children’s YPK Hospital Jakarta for their invaluable \nsupport during this study. Special thanks went to Dr. W. \nHadisaputra, Dr. S. Soebijanto, and Dr. P. Rustamadji for their \nguidance and expertise. The y also appreciated the Department of \nObstetrics and Gynecology, Faculty of Medicine, Universitas \nIndonesia, for providing essential resources. Lastly, the authors \nthanked the patients for their cooperation and trust. \n \nCompeting financial interests  \nThe authors have no conflict of interest. \n \nReferences \nAbrao, Mauricio S., Ludovico Muzii, and Riccardo Marana. 2013. “International Journal \nof Gynecology and Obstetrics Anatomical Causes of Female Infertility and \nTheir Management.” International Journal of Gynecology and Obstetrics \n123:S18 – 24. doi: 10.1016/j. ijgo.2013.09.008.  \nAkhtar Muhammad, Kong Yusheng. 2021. Performance , and Profitability.  \nAlammari, Roa, Michelle Lightfoot, and Hye -Chun Hur. 2017. “Impact of Cystectomy on \nOvarian Reserve: Review of the Literature.” Journal of Minimally Invasive \nGynecology 24(2):247 – 57. doi: https://doi.org/10.1016/j.jmig.2016.12.010.  \nAndres, Marina de Paula. 2014. “Endometriosis Is an Important Cause of Pelvic Pain in \nAdolescence.” 60(6):560 – 64. \nBaker, Valerie L., Clarisa Gracia, Michael J. Glassner, Vicki L. Schnell, Kevin Doody, \nCharles C. Coddington, Sanghyuk S. Shin, Lorna A. Marshall, Michael M. \nAlper, Arlene J. Morales, Mary Ellen Pavone, Millie A. Behera, Edward A. \nZbella, Bruce S. Shapiro,  Joely A. Straseski, and Dennis L. Broyles. 2018. \n“Multicenter Evaluation of the Access AMH Antimüllerian Hormone Assay for \nthe Prediction of Antral Follicle Count and Poor Ovarian Response to \nControlled Ovarian Stimulation.” Fertility and Sterility 110(3) :506-513.e3. \ndoi: https://doi.org/10.1016/j.fertnstert.2018.03.031.  \nBallard, K. D., H. E. Seaman, C. S. De Vries, and J. T. Wright. 2008. “Can Symptomatology \nHelp in the Diagnosis of Endometriosis? Findings from a National Case -\nControl Study - Part 1.” BJOG: An International Journal of Obstetrics and \nGynaecology 115(11):13 82– 91. doi: 10.1111/j.1471 -0528.2008.01878.x.  \nBarnhart, Kurt, Rebecca Dunsmoor -Su, and Christos Coutifaris. 2002. “Effect of \nEndometriosis on in Vitro Fertilization.” Fertility and Sterility 77(6):1148 – 55. \ndoi: https://doi.org/10.1016/S0015 -0282(02)03112 -6. \nBast, R. C. 2011. “Molecular Approaches to Personalizing Management of Ovarian \nCancer.” Annals of Oncology 22:viii5 – 15. doi: \nhttps://doi.org/10.1093/annonc/mdr516.  \nBateman, Alexis H., Edgar E. Blanco, and Yossi Sheffi. 2017. “Disclosing and Reporting \nEnvironmental Sustainability of Supply Chains.” Springer Series in Supply \nChain Management 4:119 – 44. doi: 10.1007/978 -3-319-29791-0_6. \nBenagiano, Giuseppe, Felice Petraglia, Stephan Gordts, and Ivo Brosens. 2016. “A New \nApproach to the Management of Ovarian Endometrioma to Prevent Tissue \nDamage and Recurrence.” Reproductive BioMedicine Online 32(6):556 – 62. \ndoi: 10.1016/j.rbmo.2016.03.001.  \nBriley, Shawn M., Susmita Jasti, Jennifer M. McCracken, Jessica E. Hornick, Barbara \nFegley, Michele T. Pritchard, and Francesca E. Duncan. 2016. \n“Reproductive Age -Associated Fibrosis in the Stroma of the Mammalian \nOvary.” Reproduction (Cambridge, England) 152(3):245 – 60. doi: \n10.1530/REP -16-0129. \nBrilhante, Aline Veras Morais, Kathiane Lustosa Augusto, Manuela Cavalcante Portela, \nLuiz Carlos Gabriele Sucupira, Luiz Adriano Freitas Oliveira, Ana Juariana \nMagalhães Veríssimo Pouchaim, Lívia Rocha Mesquita Nóbrega, Thaís \nFontes de Magalhães, and Leona rdo Robson Pinheiro Sobreira. 2017. \n“Endometriosis and Ovarian Cancer: An Integrative Review (Endometriosis \nand  Ovarian Cancer).” Asian Pacific Journal of Cancer Prevention  : APJCP \n18(1):11 – 16. doi: 10.22034/APJCP.2017.18.1.11.  \nBrosens, I., P. Puttemans, Sy Gordts, R. Campo, S Gordts, and G. Benagiano. 2013. “Early \nStage Management of Ovarian Endometrioma to Prevent Infertility.” FVV In \nOBGyn 5(4):309 – 14. \nBrosens, Ivo, Stephan Gordts, Patrick Puttemans, and Giuseppe Benagiano. 2014. \n“Pathophysiology Proposed as the Basis for Modern Management of the \nOvarian Endometrioma.” Reproductive BioMedicine Online 28(2):232 – 38. \ndoi: 10.1016/j.rbmo.2013.09.024.  \nBrosens, Ivo, Patrick Puttemans, Rudi Campo, Stephan Gordts, and Karen Kinkel. 2004. \n“Diagnosis of Endometriosis: Pelvic Endoscopy and Imaging Techniques.” \nBest Practice & Research Clinical Obstetrics & Gynaecology 18(2):285 – 303. \ndoi: https://doi.org/10.10 16/j.bpobgyn.2004.03.002.  \nBusacca, Mauro, and Michele Vignali. 2009. “Endometrioma Excision and Ovarian \nReserve: A Dangerous Relation.” Journal of Minimally Invasive Gynecology \n16(2):142 – 48. doi: https://doi.org/10.1016/j.jmig.2008.12.013.  \nCanis, M., J. L. Pouly, S. Tamburro, G. Mage, A. Wattiez, and M. A. Bruhat. 2001. “Ovarian \nResponse during IVF –  Embryo Transfer Cycles after Laparoscopic Ovarian \nCystectomy for Endometriotic Cysts of > 3 Cm in Diameter.” 16(12):2583 –\n86. \nCardoso, Jéssica Vilarinho. 2020. “Epidemiological Profile of Women with Endometriosis  : \nA Retrospective Descriptive Study. ” Revista Brasileira de Sa úde Materno \nInfantil 20(4):1057 – 67. \nCarnahan, Molly, Jennifer Fedor, Ashok Agarwal, and Sajal Gupta. 2013. “Ovarian \nEndometrioma: Guidelines for Selection of Cases for Surgical Treatment or \nExpectant Management.” Expert Review of Obstetrics and Gynecology \n8(1):29 – 55. doi: 10.1586/eog.12.75.  \nCelik, Hale Goksever, Erbil Dogan, Emre Okyay, Cagnur Ulukus, Bahadir Saatli, Sezer \nUysal, and Meral Koyuncuoglu. 2012. “Effect of Laparoscopic Excision of \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nEndometriomas on Ovarian Reserve: Serial Changes in the Serum \nAntimüllerian Hormone Levels.” Fertility and Sterility 97(6):1472 – 78. doi: \nhttps://doi.org/10.1016/j.fertnstert.2012.03.027.  \nChen, Yuqing, Huihui Pei, Yajie Chang, Minghui Chen, Haihe Wang, Hongzhe Xie, and \nShuzhong Yao. 2014. “The Impact of Endometrioma and Laparoscopic \nCystectomy on Ovarian Reserve and the Exploration of Related Factors \nAssessed by Serum Anti -Mullerian Hormone  : A Prospective Cohort Study. ” \n1– 8. doi: 10.1186/s13048 -014-0108-0. \nChiu, Chui -Ching, Teh -Fu Hsu, Ling -Yu Jiang, I. San Chan, Ying -Chu Shih, Yen -Hou \nChang, Peng -Hui Wang, and Yi -Jen Chen. 2022. “Maintenance Therapy for \nPreventing Endometrioma Recurrence after Endometriosis Resection \nSurgery –  A Systematic Review and Networ k Meta -Analysis.” Journal of \nMinimally Invasive Gynecology 29(5):602 – 12. doi: \nhttps://doi.org/10.1016/j.jmig.2021.11.024.  \nCoccia, Maria Elisabetta, Francesca Rizzello, Stefano Barone, Sara Pinelli, Erika Rapalini, \nCristiana Parri, Domenico Caracciolo, Savvas Papageorgiou, Gianpaolo \nCima, and Loredana Gandini. 2014. “Is There a Critical Endometrioma Size \nAssociated with Reduce d Ovarian  Responsiveness in Assisted Reproduction \nTechniques?” Reproductive Biomedicine Online 29(2):259 – 66. doi: \n10.1016/j.rbmo.2014.04.019.  \nDavies, Melanie J., Caroline A. Kristunas, Abualbishr Alshreef, Simon Dixon, Helen \nEborall, Agnieszka Glab, Lisa Huddlestone, Nicky Hudson, Kamlesh Khunti, \nGraham Martin, Alison Northern, Mike Patterson, Rebecca Pritchard, Sally \nSchreder, Bernie Stribling,  Jessica Turner, and Laura J. Gray. 2019. “The \nImpact of an Intervention to Increase Uptake to Structured Self -Management \nEducation for People with Type 2 Diabetes Mellitus in Primary Care (the \nEmbedding Package), Compared to Usual Care, on Glycaemic Contr ol: Study \nProtocol for a Mixed Methods Stu.” BMC Family Practice 20(1):152. doi: \n10.1186/s12875 -019-1038-0. \nDepalo, Raffaella, Aldo Cavallini, Filomenamila Lorusso, Emma Bassi, Ilaria Totaro, and \nAndrea Marzullo. 2009. “Article Apoptosis in Normal Ovaries of Women with \nand without Endometriosis.” Reproductive BioMedicine Online 19(6):808 –\n15. doi: 10.1016/j.rbmo. 2009.09.024.  \nDufournet, Charlotte, Catherine Uzan, Raffaèle Fauvet, Annie Cortez, Jean -Pierre Siffroi, \nand Emile Daraï. 2006. “Expression of Apoptosis -Related Proteins in \nPeritoneal, Ovarian and Colorectal Endometriosis.” Journal of Reproductive \nImmunology 70(1):151 – 62. doi: https://doi.org/10.1016/j.jri.2005.11.003.  \nFassbender, Amelie, Richard O. Burney, Dorien F. O, Thomas D’Hooghe, and Linda \nGiudice. 2015. “Update on Biomarkers for the Detection of Endometriosis -\nProtein and Contraction.” BioMed Research International 2015.  \nFauvet, Raffaèle, Charlotte Dufournet, Christophe Poncelet, Catherine Uzan, Danièle \nHugol, and Emile Daraï. 2005. “Expression of Pro -Apoptotic (P53, P21, Bax, \nBak and Fas) and Anti -Apoptotic (Bcl -2 and Bcl -x) Proteins in Serous versus \nMucinous Borderline O varian Tumours.” Journal of Surgical Oncology \n92(4):337 – 43. doi: https://doi.org/10.1002/jso.20424.  \nFeng, Guohua, Jiti Gao, and Bin Peng. 2019. “An Integrated Panel Data Approach to \nModelling Economic Growth.”  \nFoti, Pietro Valerio, Renato Farina, Stefano Palmucci, Ilenia Anna, Agata Vizzini, Norma \nLibertini, Maria Coronella, Saveria Spadola, Rosario Caltabiano, Marco Iraci, \nAntonio Basile, Pietro Milone, Antonio Cianci, and Giovanni Carlo Ettorre. \n2018. “Endometriosis  : Clinical Features , MR Imaging Findings and \nPathologic Correlation. ” 149– 72. \nGarcia -Velasco, Juan A., and Edgardo Somigliana. 2009. “Management of \nEndometriomas in Women Requiring IVF: To Touch or Not to Touch.” Human \nReproduction (Oxford, England) 24(3):496 – 501. doi: \n10.1093/humrep/den398.  \nGardner, David K. 2011. Human Assisted Reproductive Technology.  \nGiacomini, Elisa, Ana M. Sanchez, Veronica Sarais, Soha Al Beitawi, Massimo Candiani, \nand Paola Viganò. 2017. “Characteristics of Follicular Fluid in Ovaries with \nEndometriomas.” European Journal of Obstetrics, Gynecology, and \nReproductive Biology 209:34 – 38. doi: 10.1016/j.ejogrb.2016.01.032.  \nGordts, Stephan, Philippe Koninckx, and Ivo Brosens. 2017. “Pathogenesis of Deep \nEndometriosis.” Fertility and Sterility 108(6):872 -885.e1. doi: \nhttps://doi.org/10.1016/j.fertnstert.2017.08.036.  \nGordts, Stephan, Patrick Puttemans, Sylvie Gordts, and Ivo Brosens. 2015. “Ovarian \nEndometrioma in the Adolescent: A Plea for Early -Stage Diagnosis and Full \nSurgical Treatment.” Gynecological Surgery 12(1):21 – 30. doi: \n10.1007/s10397 -014-0877-x. \nGupta, Sajal, Jeffrey M. Goldberg, Nabil Aziz, Eric Goldberg, Natalie Krajcir, and Ashok \nAgarwal. 2008. “Pathogenic Mechanisms in Endometriosis -Associated \nInfertility.” Fertility and Sterility 90(2):247 – 57. doi: \nhttps://doi.org/10.1016/j.fertnstert.2008.02 .093.  \nHaupt, Susan, Michael Berger, Zehavit Goldberg, and Ygal Haupt. 2003. “Apoptosis –  the \nP53 Network.” doi: 10.1242/jcs.00739.  \nHeca, Cancer Cell Line, Meryem İ. Karagül, Derya Yetkin, Gülsen Bayrak, and Didem \nÇelikcan. 2018. “P53 , Bcl2 and Bax Expression and Apoptosis in Perifosine \nand Vitamin D -Treated Endometrial.” 25:3 – 7. doi: \n10.3390/proceedings2251564.  \nHenes, Melanie, and Engler. 2018. “Ovarian Cyst Removal Influences Ovarian Reserve \nDependent on Histology, Size and Type of Operation.” Women’s Health \n14:1745506518778992. doi: 10.1177/1745506518778992.  \nHwu, Yuh -ming, Frank Shao -ying Wu, Sheng -hsiang Li, Fang -ju Sun, Ming -huei Lin, and \nRobert Kuo -kuang Lee. 2011. “The Impact of Endometrioma and \nLaparoscopic Cystectomy on Serum Anti -Müllerian Hormone Levels.” \nReproductive Biology and Endocrinology 9(1):80.  doi: 10.1186/1477 -7827-\n9-80. \nIsono, Wataru, Osamu Wada -Hiraike, Nana Akino, Hiromi Terao, Miyuki Harada, Tetsuya \nHirata, Yasushi Hirota, Kaori Koga, Tomoyuki Fujii, and Yutaka Osuga. 2019. \n“The Efficacy of Non -Assisted Reproductive Technology Treatment Might Be \nLimited in Infertile Pa tients with Advanced Endometriosis in Their 30s.” \nJournal of Obstetrics and Gynaecology Research 45(2):368 – 75. doi: \n10.1111/jog.13826.  \nIwase, Akira, Wakana Hirokawa, Maki Goto, Sachiko Takikawa, Yoshinari Nagatomo, \nTatsuo Nakahara, Shuichi Manabe, and Fumitaka Kikkawa. 2010. “Serum \nAnti-Müllerian Hormone Level Is a Useful Marker for Evaluating the Impact of \nLaparoscopic Cystectomy on Ovar ian Reserve.” Fertility and Sterility \n94(7):2846 – 49. doi: https://doi.org/10.1016/j.fertnstert.2010.06.010.  \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \nKeyhan, Sanaz, Claude Hughes, Thomas Price, and Suheil Muasher. 2015. “An Update \non Surgical versus Expectant Management of Ovarian Endometriomas in \nInfertile Women.” 2015. doi: 10.1155/2015/204792.  \nKhan, Khaleque Newaz, Michio Kitajima, Akira Fujishita, Koichi Hiraki, Ayumi Matsumoto, \nMasahiro Nakashima, and Hideaki Masuzaki. 2013. “Pelvic Pain in Women \nwith Ovarian Endometrioma Is Mostly Associated with Coexisting Peritoneal \nLesions.” Human Reproduc tion 28(1):109 – 18. doi: \n10.1093/humrep/des364.  \nKitajima, Michio, Sylvie Defrère, Marie -Madeleine Dolmans, Sebastien Colette, Jean \nSquifflet, Anne Van Langendonckt, and Jacques Donnez. 2011. \n“Endometriomas as a Possible Cause of Reduced Ovarian Reserve in Women \nwith Endometriosis.” Fertility and Sterili ty 96(3):685 – 91. doi: \nhttps://doi.org/10.1016/j.fertnstert.2011.06.064.  \nKitajima, Michio, D. Ph, Marie -madeleine Dolmans, D. Ph, Olivier Donnez, and D. Ph. \n2014. “Enhanced Follicular Recruitment and Atresia in Cortex Derived from \nOvaries with Endometriomas.” Fertility and Sterility 101(4):1031 – 37. doi: \n10.1016/j.fertnstert.201 3.12.049.  \nKoninckx, Philippe R., Rodrigo Fernandes, Anastasia Ussia, Larissa Schindler, Arnaud \nWattiez, Shaima Al -Suwaidi, Bedayah Amro, Basma Al -Maamari, Zeinab \nHakim, and Muna Tahlak. 2021. “Pathogenesis Based Diagnosis and \nTreatment of Endometriosis.” Frontiers i n Endocrinology 12(November):1 –\n13. doi: 10.3389/fendo.2021.745548.  \nKorkmaz, D., E. Bastu, O. Dural, C. Yasa, E. Yavuz, and F. Buyru. 2013. “Apoptosis \nthrough Regulation of Bcl -2, Bax and Mcl -1 Expressions in Endometriotic \nCyst Lesions and the Endometrium of Women with Moderate to Severe \nEndometriosis.” Journal of Obstetri cs and Gynaecology 33(7):725 – 28. doi: \n10.3109/01443615.2013.824416.  \nLew, Raelia. 2019. “Natural History of Ovarian Function Including Assessment of Ovarian \nReserve and Premature Ovarian Failure.” Best Practice and Research: \nClinical Obstetrics and Gynaecology 55:2 – 13. doi: \n10.1016/j.bpobgyn.2018.05.005.  \nMargarida. 2017. “Endometrioma Em Contexto de Infertilidade.” Angewandte Chemie \nInternational Edition, 6(11), 951 – 952. 5 – 24. \nMatsuzaki, Sachiko. 2010. “Oxidative Stress Status in Normal Ovarian Cortex Surrounding \nOvarian Endometriosis.” Fertility and Sterility 93(7):2431 – 32. doi: \n10.1016/j.fertnstert.2009.08.068.  \nMiller, Emily M., Timothy M. Samec, and Angela A. Alexander -Bryant. 2021. \n“Nanoparticle Delivery Systems to Combat Drug Resistance in Ovarian \nCancer.” Nanomedicine: Nanotechnology, Biology and Medicine \n31:102309. doi: https://doi.org/10.1016/j.nano.2020.10 2309. \nMolvig. 1988. “Endotoxin -Stimulated Human Monocyte Secretion of Interleukin 1, \nTumour Necrosis Factor Alpha, and Prostaglandin E2 Shows Stable \nInterindividual Differences.” Scandinavian Journal of Immunology \n27(6):705 – 16. doi: https://doi.org/10.1111/j.136 5-3083.1988.tb02404.x.  \nMuzii, Ludovico, Antonella Bianchi, Filippo Bellati, Emanuela Cristi, Milena Pernice, \nMarzio A. Zullo, Roberto Angioli, and Pierluigi Benedetti Panici. 2007. \n“Histologic Analysis of Endometriomas: What the Surgeon Needs to Know.” \nFertility and Sterility 87 (2):362 – 66. doi: 10.1016/j.fertnstert.2006.06.055.  \nNisolle, Michelle, and Jacques Donnez. 2019. “Reprint of: Peritoneal Endometriosis, \nOvarian Endometriosis, and Adenomyotic Nodules of the Rectovaginal \nSeptum Are Three Different Entities.” Fertility and Sterility 112(4):e125 – 36. \ndoi: 10.1016/j.fertnstert.2 019.08.081.  \nObstet, Arch Gynecol, Francesca Maria Salmeri, Vaclav Vetvicka, and Antonio Simone. \n2016. “Regulation of Apoptotic Pathways during Endometriosis  : From the \nMolecular Basis to the Future Perspectives. ” doi: 10.1007/s00404 -016-\n4195-6. \nParameswaran, Narayanan, and Sonika Patial. 2010. “Tumor Necrosis Factor -α Signaling \nin Macrophages. ” Critical Reviews in Eukaryotic Gene Expression 20(2):87 –\n103. doi: 10.1615/critreveukargeneexpr.v20.i2.10.  \nParsa, Sepideh, Ian Roper, Michael Muller -Camen, and Eva Szigetvari. 2018. “Have \nLabour Practices and Human Rights Disclosures Enhanced Corporate \nAccountability? The Case of the GRI Framework.” Accounting Forum \n42(1):47 – 64. doi: 10.1016/j.accfor.2018.01.00 1. \nPejovic, Tanja, Sarah Thisted, Michael White, and Farr R. Nezhat. 2020. “Endometriosis \nand Endometriosis -Associated Ovarian Cancer (EAOC) BT  - Hormonal \nPathology of the Uterus.” Pp. 73 – 87 in, edited by L. Deligdisch -Schor and A. \nMareş Miceli. Cham: Spring er International Publishing.  \nPorpora, M. G., P. R. Koninckx, J. Piazze, M. Natili, S. Colagrande, and E. V Cosmi. 1999. \n“Correlation between Endometriosis and Pelvic Pain.” The Journal of the \nAmerican Association of Gynecologic Laparoscopists 6(4):429 – 34. doi: \nhttps://doi.org/10.1016/ S1074 -3804(99)80006 -1. \nRaffi, F., R. W. Shaw, and S. A. Amer. 2012. “National Survey of the Current Management \nof Endometriomas in Women Undergoing Assisted Reproductive Treatment.” \nHuman Reproduction 27(9):2712 – 19. doi: 10.1093/humrep/des195.  \nRosen, Mitchell P., Erica Johnstone, Charles E. McCulloch, Sonya M. Schuh -Huerta, \nBarbara Sternfeld, Renee A. Reijo -Pera, and Marcelle I. Cedars. 2012. “A \nCharacterization of the Relationship of Ovarian Reserve Markers with Age.” \nFertility and Sterility 97 (1):238 – 43. doi: \nhttps://doi.org/10.1016/j.fertnstert.2011.10.031.  \nRumph, Jelonia T., Victoria R. Stephens, Anthony E. Archibong, Kevin G. Osteen, and \nKaylon L. Bruner -Tran. 2020. “Environmental Endocrine Disruptors and \nEndometriosis.” Advances in Anatomy, Embryology, and Cell Biology \n232:57 – 78. doi: 10.1007/978 -3-030-51856-1_4. \nSalmeri, Francesca M., Vincenza Sofo, Antonio S. Lagana, Onofrio Triolo, Emanuele \nSturlese, Giovanni Retto, Alfonsa Pizzo, Angela D. Ascola, and Salvatore \nCampo. 2015. “Behavior of Tumor Necrosis Factor - α and Tumor Necrosis \nFactor Receptor 1 / Tumor Necrosis Factor Receptor 2 System in \nMononuclear Cells Recovered From Peritoneal Fluid of Women With \nEndometriosis at Different Stages. ” Reproductive Sciences 22(2):165 – 72. \ndoi: 10.1177/1933719114536472.  \nSanchez, A. M., P. Viganò, E. Somigliana, P. Panina -Bordignon, P. Vercellini, and M. \nCandiani. 2014. “The Distinguishing Cellular and Molecular Features of the \nEndometriotic Ovarian Cyst: From Pathophysiology to the Potential \nEndometrioma -Mediated Damage t o the Ovary.” Human Reproduction \nUpdate 20(2):217 – 30. doi: 10.1093/humupd/dmt053.  \nScutiero, Gennaro, Piergiorgio Iannone, Giulia Bernardi, Gloria Bonaccorsi, Savino \nSpadaro, Carlo Alberto Volta, Pantaleo Greco, and Luigi Nappi. 2017. \n\nANGIOTHERAPY                                     RESEARCH \n \nhttps://doi.org/10.25163/angiotherapy.859690                                                                                                1–18 | ANGIOTHERAPY | Published online May 20, 2024 \n \n“Oxidative Stress and Endometriosis: A Systematic Review of the Literature” \nedited by V. M. Victor. Oxidative Medicine and Cellular Longevity \n2017:7265238. doi: 10.1155/2017/7265238.  \nSeifer, David B., Valerie L. Baker, and Benjamin Leader. 2011. “Age -Specific Serum Anti -\nMüllerian Hormone Values for 17,120 Women Presenting to Fertility Centers \nwithin the United States.” Fertility and Sterility 95(2):747 – 50. doi: \nhttps://doi.org/10.1016/ j.fertnstert.2010.10.011.  \nShi, Jinghua, Jinhua Leng, Quancai Cui, and Jinghe Lang. 2011. “Follicle Loss after \nLaparoscopic Treatment of Ovarian Endometriotic Cysts.” International \nJournal of Gynecology & Obstetrics 115(3):277 – 81. doi: \nhttps://doi.org/10.1016/j.ijgo.2011.07.026.  \nSipak-Szmigiel, Olimpia, Piotr Włodarski, Elżbieta Ronin -Walknowska, Andrzej \nNiedzielski, Beata Karakiewicz, Sylwia Słuczanowska -Głąbowska, Maria \nLaszczyńska, and Witold Malinowski. 2017. “Serum and Peritoneal Fluid \nConcentrations of Soluble Human Leukocyt e Antigen, Tumor Necrosis Factor \nAlpha and Interleukin 10 in Patients with Selected Ovarian Pathologies.” \nJournal of Ovarian Research 10(1):1 – 14. doi: 10.1186/s13048 -017-0320-\n9. \nSomigliana, Edgardo, Nicola Berlanda, Laura Benaglia, Paola Viganò, Paolo Vercellini, \nand Luigi Fedele. 2012. “Surgical Excision of Endometriomas and Ovarian \nReserve: A Systematic Review on Serum Antimüllerian Hormone Level \nModifications.” Fertility and St erility 98(6):1531 – 38. doi: \nhttps://doi.org/10.1016/j.fertnstert.2012.08.009.  \nSugita, Atsuko, Akira Iwase, Maki Goto, Tatsuo Nakahara, Tomoko Nakamura, Mika \nKondo, Satoko Osuka, Masahiko Mori, Ai Saito, and Fumitaka Kikkawa. 2013. \n“One-Year Follow -up of Serum Antimüllerian Hormone Levels in Patients with \nCystectomy: Are Different Se quential Changes Due to Different Mechanisms \nCausing Damage to the Ovarian Reserve?” Fertility and Sterility 100(2):516 -\n522.e3. doi: https://doi.org/10.1016/j.fertnstert.2013.03.032.  \nUncu, Gurkan, Isil Kasapoglu, Kemal Ozerkan, Ayse Seyhan, Arzu Oral Yilmaztepe, and \nBaris Ata. 2013. “Prospective Assessment of the Impact of Endometriomas \nand Their Removal on Ovarian Reserve and Determinants of the Rate of \nDecline in Ovarian Reserve†.” H uman Reproduction 28(8):2140 – 45. doi: \n10.1093/humrep/det123.  \nVercellini, Paolo, Paola Viganò, Laura Buggio, Sofia Makieva, Giovanna Scarfone, Fulvia \nMilena Cribiù, Fabio Parazzini, and Edgardo Somigliana. 2018. \n“Perimenopausal Management of Ovarian Endometriosis and Associated \nCancer Risk: When Is Medical or Surgica l Treatment Indicated?” Best \nPractice & Research Clinical Obstetrics & Gynaecology 51:151 – 68. doi: \nhttps://doi.org/10.1016/j.bpobgyn.2018.01.017.  \nVercellini, Paolo, Paola Viganò, Edgardo Somigliana, and Luigi Fedele. 2014. \n“Endometriosis  : Pathogenesis and Treatment. ” 10(May). doi: \n10.1038/nrendo.2013.255.  \nWHO. 2023. “Endometriosis.” WHO. Retrieved (https://www.who.int/news -room/fact -\nsheets/detail/endometriosis).  \nYeung, Patrick, Ken Sinervo, Wendy Winer, and Robert B. Albee. 2011. “Complete \nLaparoscopic Excision of Endometriosis in Teenagers: Is Postoperative \nHormonal Suppression Necessary?” Fertility and Sterility 95(6):1909 -\n1912.e1. doi: https://doi.org/10.1016/j .fertnstert.2011.02.037.  \nZikargae, Mekonnen Hailemariam. 2018. “Analysis of Environmental Communication and \nIts Implication for Sustainable Development in Ethiopia.” Science of the Total \nEnvironment 634:1593 – 1600. doi: 10.1016/j.scitotenv.2018.04.050.","source_license":"CC0","license_restricted":false}