{"paper_id":"b7bd0dc3-13b8-4e34-a483-033aea11ad31","body_text":"PERIÓDICO TCHÊ QUÍMICA \n  ARTIGO ORIGINAL\n \nPeriódico Tchê Química\n.\n  ISSN 2179-0302. (202\n0); vol.17 (n°35)\n \nDownloaded from www.periodico.tchequimica.com \n \n \n813\n \n \n \n \nINFLUÊNCIA DA PRODUÇÃO\n DE CITOCINAS, METABO\nLITOS DE ÓXIDO DE \nNITROGÊNIO E TROCA DE LÍPIDOS \nNA FORMAÇÃO DE EST\nÁGIOS EXTERNOS \nDE \nENDOMETRIOSE GENITAL NOS P\nACIENTES EM IDADE REPRODUTIVA \n \nINFLUENCE OF CYTOKINES PRODUCTION\n, NITROGEN OXIDE METABOLITES A\nND \nLIPIDS EXCHANGE ON THE FOR\nMATION OF EXTERNAL GENITAL \nENDOMETRIOSIS STAGES IN PAT\nIENTS OF REPRODUCTIVE AGE \n \nВЛИЯНИЕ ПРОДУКЦИИ ЦИТОКИНОВ, М\nЕТАБОЛИТОВ ОКСИДА АЗОТА   \nИ ОБМЕНА ЛИПИДОВ НА ФОРМИР\nОВАНИЕ СТАДИЙ  НАРУЖНОГО \nГЕНИТАЛЬНОГО ЭНДОМЕТРИОЗА У П\nАЦИЕНТОК РЕПРОДУКТИВНОГО \nВОЗРАСТА \n \nERMOLOVA, Natalya Victorovna*¹\n; PETROV, Yuriy Alekseevich¹; \n LEVKOVICH, Marina Arkadevna¹; KOL\nESNIKOVA, Ludmila Valerievna¹\n;  \nDRUKKER, Nina Aleksandrovna¹;\n \n \nRostov State Medical Univer\nsity, Russian Federation \n \n* Correspondence author \n \ne-mail: rniiap.ermolova@gmail.com \n \nReceived 10 April 2020; received i\nn revised form 26 May 2020; a\nccepted 20 June 2020\n \n \nRESUMO \n \nA relevância do estudo se deve à prevalência e aumento da incid\nência de endometriose, \nprincipalmente em pacientes jovens, sua influência na função re\nprodutiva e a falta de diagnóstico não \ninvasivo confiável da doença e seus estágios. Não existem opini\nões unificadas sobre a etiologia e \npatogênese multifatorial desta doença. Este artigo tem como obj\netivo revelar os mecanismos de formação \nde estágios de endometriose com base no estudo do efeito da pro\ndução de citocinas, metabólitos de óxido \nnítrico e metabolismo lipídico. A principal abordagem para estu\ndar esse problema é investigar os níveis \nsistêmico (soro sanguíneo) e local (líquido peritoneal), sua co\nmparação. Isso permite uma consideração \nabrangente da patogênese da doença e a determinação do valor do\ns fatores biologicamente ativos \nmencionados, dependendo dos estági\nos da doença. O artigo aprese\nnta novos dados sobre o conteúdo de \nlipoproteínas de alta e baixa den\nsidade, colesterol, fator de c\nrescimento transformador β1 e fator de necrose \ntumoral α, conteúdo de metabólitos de óxido nítrico e sua inter\npretação clínica é dada de acordo com os \nestágios da doença. Os materiais do artigo são de valor prático\n para pesquisadores de endometriose e \npraticantes de ginecologistas e obstetras. \n \nPalavras-chave\n: \nendometriose genital externa, lipoproteínas,\n óxido nítrico, fator de crescimento \ntransformador beta 1, fator de necrose tumoral alfa\n. \n \nABSTRACT\n \n \n \nThe relevance of the study is due to the prevalence and increas\ne in the incidence of endometriosis, \nespecially in young patients, its\n influence on reproductive fun\nction, and the lack of reliable non-invasive \ndiagnosis of the disease and its stages. There are no unified v\niews on the etiology\n and multifactorial \npathogenesis of this disease. This article is aimed at revealin\ng the mechanisms of the formation of \nendometriosis stages basing on the \nstudy of the effect of cytok\nines production, nitric oxide metabolites and \nlipid metabolism. The main approach to study this problem is bo\nth to investigate systemic (blood serum) and \nlocal (peritoneal fluid) levels, their comparison. This allows \ncomprehensive consideration of the pathogenesis \nof the disease and determination \nof the value of the mentioned \nbiologically active factors depending on the \nstages of the disease. The artic\nle presents new data on the con\ntent of high- and low-density lipoproteins, \ncholesterol, transforming growth factor β1 and tumor necrosis f\nactor α, the content of nitric oxide metabolites \nDOI\n:\n \n10\n.\n52571\n/\nPTQ\n.\nv\n17\n.\nn\n35\n.\n2020\n.\n69\n_\nERMOLOVA\n_\npgs\n_\n813\n_\n824\n.\npdf\n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  814 \nand their clinical interpretation is given according to the stages of the disease. The materials of the article are \nof practical value for researchers of endometriosis and practicing obstetrician-gynecologists.. \n \nKeywords: external genital endometriosis, lipoproteins, nitric oxide, transforming growth factor beta 1, tumor \nnecrosis factor alpha.  \n \nАННОТАЦИЯ \nАктуальность исследования обуслов лена распространенностью и рос том заболеваемости \nэндометриозом, особенно у пациенток молодого возраста, влиянием его на репродуктивную функцию, \nотсутствием  надежной неинвазивной диагностики  заболевания и его стадий. Нет единых взглядов на \nэ т и о л о г и ю  и  м н о г о ф а к т о р н ы й  п а т о г е н е з  э т о г о  з а б о л е в а н и я .    В  с в яз и  с  э т и м ,  д а н н а я  с т а т ь я   \nнаправлена на раскрытие механизмов формирования стадий эндометр иоза на основании изучения \nвлияния продукции цитокинов, мет аболитов оксида азота и обмена липидов. Ведущим подходом к \nисследованию данной проблемы является исследование как системно го (сыворотка крови), так и \nместного (перитонеальная жидкост ь) уровней, их сопоставление. Э то  позволяет комплексно \nрассмотреть  патогенез з аболевания и определ ить значение обозна ченных биологически активных  \nфакторов в зависимости от стадий заболевания. В статье представ л е н ы  н о в ы е  д а н н ы е  п о  \nсодержанию липоротеинов высокой и низкой плотности, холестерину , трансформирующего фактора \nроста β1 и фактора некроза опухоле й α, содержанию метаболитов о ксида азота и дана их \nклиническая интерпретация в соответствии со стадиями заболевани я. Материалы статьи \nпредставляют практическую ценно сть для исследователей эндометри оза и практикующих врачей \nакушеров-гинекологов.   . \nКлючевые слова: наружный генитальный эндометриоз, липопротеины, оксид азота, \nтрансформирующий фактор роста бета 1, фактор некроза опухоли альфа. \n \n \n \n1. INTRODUCTION  \n  \nEndometriosis is a chronic, recurring, \ngenetically determined, inflammatory disease. Its \nmain clinical manifestations are persistent pain \nand infertility. According to morphological and \nfunctional properties It is a benign growth outside \nthe uterine cavity tissue similar to the \nendometrium (Adamyan et al., 2016). \nAbout 2-10% of women of the \nreproductive age in the population suffer from this \ndisease (Adamyan et al ., 2016; Falcone and \nLebovic, 2011) and up to 50% of women \nscreened for infertility (Vercellini et al., 2011). Still \nthere are no non-invasive markers of external \ngenital endometriosis (EGE). Scientists discuss \nthe problem of the systematic progression of this \ndisease but no solution is found. \nProcesses occurring in the peritoneal \ncavity pay an important role in the development \nof external genital endometriosis in patients of the \nreproductive age. The amount of peritoneal fluid \n(PF) is known to be increased in women with \nendometriosis comparing with healthy women \nwithout endometriosis (Sonova et al ., 2010). PF \nin these patients is characterized by a high \ncontent of activated macrophages (Berbic et al., \n2009) producing cytokines: TNF-α (Sonova et al., \n2011), TGF-β1 (Ermolova , 2009) stimulating \nangiogenesis (Wang et al. , 2009) and also \ncontains a large amount of lipoproteins, \nespecially of low density, which generate oxidized \nlipid components as part of a macrophage \ninflammatory medium (Anderson Sanches Melo \net al., 2010) \nThe TGF-β1, found in high concentrations \nin the PF of patients with EGE (Charles et al. , \n2010), has anti-inflammatory properties and is \nable to inhibit TNF-α, IL-1β and other cytokines \nsynthesis, inhibit endothelial cell proliferation. \nInformation on the TNF-α role in the cell is \nrather contradictory, and often it produces \nopposite effects on the same cell types (Laschke, \n2011). TNF-α activates lipolysis and inhibits \nlipogenesis. \nThe development of so-called local \naseptic inflammation and immunocompetent cell \ndysfunction is generally considered as a fact \nestablished both in an experimental model of \nendometriosis in mice and in the abdominal \ncavity of patients with endometriosis (Schmidt et \nal., 2015). In endometriosis macrophages are not \nable to perform their all functions, and an \nestrogen-dependent chronic inflammation is \ntriggered (Takebayashi et al., 2014). Imbalance in \nthe formation of free radicals makes the basis of \nthe inflammatory process in endometriosis \n(Darling, 2013). \n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  815 \nNitric oxide plays the role of a universal \nregulator of many biological functions having both \nprotective and damaging character. Thus, being \nan important regulator of vascular tone, providing \nimmune responses, neuronal transmission and \nantioxidant protection, nitric oxide can under \ncertain conditions also act as a free radical, which \nhas a pronounced destructive effect (Babushkina, \n2009; . Bryan et al., 2009). Nitric oxide is formed \nin cells from L-arginine under the action of NO-\nsynthase enzyme (Vanin, 2008). There is a \nsecond way of converting L-arginine, by means of \narginase, it is hydrolyzed to ornithine and urea, \nfollowed by the formation of proline (Babushkina, \n2009), which in turn is a source of tissue \nhardening, and, it is well known, moderate and \nsevere degree of EGE in 100% of cases is \naccompanied by the development of the adhesive \nprocess (Luciano and Adhesion, 2008). In this \ncase, the problem is not only in the clinical \nmanifestations of the adhesive process (pelvic \npain, infertility) (Chernukha, 2011), but also in the \nhigh recurrence rate after mechanical \nadhesiolysis during laparoscopy. Arginase and \nNO-synthase compete with each other for a \ncommon substrate - L-arginine. Arginase, an \nenzyme in the urea synthesis cycle, has a higher \nactivity and exceeds that of NO-synthase (Vanin, \n2008). \nN. Santanam et al . (2002), found the \npresence of an acidic environment in the PF of \nwomen with endometriosis. PF lipoproteins in \npatients with endometriosis have a greater ability \nto oxidation compared with blood plasma \nlipoproteins. \nMany scientists search for new non-\ninvasive markers of endometriosis, and \nbiochemical and immunohistochemical indicators \nalready developed are unfortunately not specific \n(Vodolazkaia, 2012; Gajbhiye et al. , 2012). \nAdditional studies are necessary to determine the \neffectiveness of the early diagnosis of \ndyslipidemia in order to prevent endometriosis in \npatients of reproductive age. Of particular interest \nis the participation of cytokines, metabolites of \nnitric oxide and lipoproteins in the formation of \nthe stages of the disease, which will allow to \npersonalize the treatment tactics of these \npatients. \nThe purpose of the study was to \ndetermine clinical significance of lipid and \ncytokine markers status, nitric oxide metabolites \nin the formation of disease stages in patients of \nreproductive age with external genital \nendometriosis. \n2. MATERIALS AND METHODS \nThe study, approved by the Local Ethics \nCommittee of the Research Institute of Obstetrics \nand Pediatrics at Rostov State Medical \nUniversity, included 96 patients, 74 were patients \nwith EGE and 22 women without endometriosis \n(control group) who underwent examination and \ntreatment at the gynecology department of the \nResearch Institute of Rostov State Medical \nUniversity. \nAll patients were divided into 3 clinical \ngroups: group I consisted of 28 patients with I-II \nstages of EGE according to r-AFS classification \n(1985), group II - 46 patients with stages III-IV of \nthe disease. The III control group consisted of 22 \npatients without endometriosis. \nTo achieve the above purpose, the \nfollowing methods were used: clinical (medical \nhistory, examination), laboratory, ultrasound, \nendoscopic (laparoscopy, hysteroscopy, \ncolposcopy), histological examination of biopsy \nspecimens obtained during laparoscopy.  \nThe following criteria were used to include \nthe patients into the study: Criteria for the \ninclusion of patients in the study: 1. The patient \nunderwent endoscopic surgery (laparo- and \nhysteroscopy), confirming EGE with subsequent \nmorphological verification of the diagnosis, in \npatients without EGE to exclude tubal-peritoneal \ninfertility factor, sterilization. 2. Reproductive age \nof patients. 3. Complaints of infertility and/or pain. \n4. Body mass index 18.5 - 25 kg/m². \nThe criteria for the exclusion from the \nstudy were the puberty and perimenopausal age \nof the patients, obesity or metabolic syndrome. \nThe patients were included into the study \nafter obtaining informed consent and were \nrecorded according to the standards of the Ethics \nCommittee of the Russian Federation (protocol \nNo. 46 dated 04/17/2014). Blood, peritoneal fluid \nof patients obtained by laparoscopy was used in \nthe study. \nAnalysis of clinical data showed that in all \npatients menstrual cycle was preserved, its mean \nduration in group I (EGE stage I-II) was 28.04 ± \n1.2 days, in group II (EGE stage III-IV) - 28.7 ± \n1.4 days, in group III (control) - 26.1 ± 1.3 days. \nEarly menarche (up to 11 years old) was more \ncommon in patients with EGE from group II \n(60.9%) and group I (52.7%), i.e. in patients with \nEGE, early menarche was found, unlike patients \nin the control group. The mean age menstruation \nbeginning was in group I 10.2 ± 0.11 years, in \ngroup II - 11.8 ± 0.19 years, in group III - 13.4 ± \n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  816 \n0.1 years. Algomenorrhea occurred in 50% of \npatients with EGE with menarche, in 85.1% of \npatients with I-II stage of EGE and only in 21.7% \nof patients with III-IV stage of EGE. \n34.9% of patients with EGE complained of \nprogressively increasing pelvic pains, before and \nduring menstruation 54%, dyspareunia 22%, \nspotting blood excretions before or during \nmenstruation 28%. It should be noted that with \nminimal forms of the disease, pelvic pain was \nfound only in 4% patients, while in severe forms \n(stage III-IV of EGE) this symptom was present in \nmore than half (55.2%) of patients which is \nsignificantly higher (p <0.05) when conducting \nintergroup comparisons. Psychoemotional \ndisorders were in 38% in patients with EGE. \nProgression of the disease leads to increased \nfrequency of symptoms. The severity and \nintensity of complaints prevailed in the group of \npatients with III - IV stage of EGE. \n40.8% with EGE had primary infertility. In \npatients with EGE I-II stages it was registered in \n68% of cases, which was 1.2 times higher than in \nthe group with EGE III-IV stages, 39.5%. \nSecondary infertility was in 21.2% with EGE: in \nthe first group of patients it was in 28% of \npatients and in the second group – in 23.6% of \npatients.  \n79.7% of the patients with stage I-II EGE \n(group I) had in their anamnesis sexually \ntransmitted infections (STIs), and inflammatory \ndiseases of the pelvic organs (PID) in 57.4% of \npatients, while in group II patients with EGE of \nthe III-IV stage of STIs were found in 78.3%, and \nPID - in 60.9% of women. \nAnalysis of the duration of the disease \nfrom the onset of clinical manifestations to the 1st \nhospitalization revealed that this period ranged \nfrom 3 months to 6 years. \nIn 53.9% of patients ultrasound \nexamination showed endometrioid cysts from 4 to \n10 cm in size with a fine suspension of both \nunilateral (4%) and bilateral (95%). Only in 18% \nof patients with EGE typical endometrioid \ninfiltrates from 2.5 to 3 cm were identified in the \narea of the uterine isthmus. \nColposcopy revealed background \ndiseases of the cervix in 60.1% of patients with \nEGE stage I-II, in 76.6% of patients with EGE \nstage III-IV, while cervical dysplasia was found in \n16.9% of in group I patients and in 21.7% group II \npatients. In the control group of patients, \nbackground cervical pathology was found in 30%, \nand cervical dysplasia in 10% of women. \nIn all cases surgical treatment was \nperformed by laparoscopic access in the organ-\nsaving volume. The main tasks of laparoscopic \ntreatment were: maximum removal of all \nendometrioid foci; elimination of the adhesive \nprocess; restoration of the normal anatomy of the \ninternal genital organs. Endometriosis prevalence \nwas determined by laparoscopy using the \nrecommendations of the revised classification \ndeveloped by the American Society for Fertility (r-\nAFS) (1985). In our study, laparoscopy revealed \na high percentage of endometrioid ovarian cysts \n(53.97%), which may indicate the untimely \ndiagnosis of EGE. Superficial foci of \nendometriosis in the ovaries were detected in \n42.8% of cases. Sacro-uterine ligaments (77.7%) \nand the rectum-uterine space (69.8%) lesions \nwere most common, while in the vesicoureteral \nspace foci of endometriosis were detected only in \n31.7% of cases. On the wide uterus ligament \nendometriotic lesions were detected less often - \n4.7% of cases. \nIn patients of the first group with EGE \nstage I-II, adhesions of the I degree were found in \n12.8% of patients, of the II degree – in 10.8%, of \nthe III degree – in 2.7%, and of the IV degree – In \n2%. In women of the second group, with EGE \nstage III - IV, adhesions were found in 12%, \n16.3%, 17.4%, 16.3% of cases, respectively. \nIn stage I-II, ovarian lesions were \nregistered in 31% of cases, endometrioid cysts in \n4%. Only peritoneum lesion was in 66.2%, \ncombined forms - (peritoneum and ovaries) – in \n48.7%. In EGE stages III - IV ovarian lesions in \nthe form of endometrioid cysts were revealed in \n94.6% of cases. Damage to the peritoneum was \nin 40.2% of cases. Combined forms (peritoneum \nand ovaries) were in 78% of patients. \nHysteroscopy revealed endometrial \nhyperplastic process in the form of simple \nhyperplasia without atypical signs was detected \nin 27% of group I patients and in 35.3% of group \nII patients, while in the control group this \npathology was found only in 5% of women. \nEGE was histologically confirmed in all \npatients of clinical groups I and II. Endometriosis \nverification was carried out according the degree \nof the process prevalance and the \nmorphofunctional characteristics of heterotopic \nfoci. The morphological diagnosis was based on \nthe microscopic detection of ectopic endometrioid \nepithelium in combination with elements of the \nendometrioid stroma. Macrophages containing \nhemosiderin were also found in it. Endometrioid \nheterotopy was microscopically presented by an \n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  817 \naccumulation of cellular formations, tubular, \nbranching or cystically dilated. Internally the \nglands were lined with a cylindrical epithelium, \nsometimes even with cilia. In heterotopic foci, \nthere were two types their existence – \nprogression and regression. Proliferation of \nglandular epithelium of varying severity, secretory \nchanges, decidualization of the cytogenic stroma \nwere most common and typical for the \nprogressing EGE foci. Regressing OGE foci \nwithout signs of functional activity were \ncharacterized by the presence of cystic gland \ntransformation, epithelial atrophy, fibroplastic \nrestructuring and angiomatosis of the cytogenic \nstroma in 19.6%  of all patients, in EGE I-II \nstages – in 13.5% of patients, III- IY stages - in \n24.5% of women. Histological examination of the \nsurgical material revealed endometrial glands in \nendometrioid heterotopia in 71.7% of cases, \n49.6% of patients had it in the proliferation phase, \n50.4% of patients – in the secretion phase, and \n18.3% in the middle secretion phase – 18.3%, in \nlate - 81.7%. Since laparoscopy was performed in \nthe first phase of the menstrual cycle, the data \nobtained indicate that in half of cases there was \nno correlation of the state of endometrioid \nheterotopy to the uterine cycle. \nAngiomatosis was more pronounced \n(24.5% of cases) in patients with EGE stage III-\nIV. Moreover, in the stroma surrounding the \ngland, a mild lymphoid and plasmocytic infiltration \nwas in 11.7% of cases of a focal character. As a \npercentage, there were no differences in EGE \nstages. Thus, at stage I-II they made 13.4% and \nin EGE stage III-IV - 12.5%. Stromal sclerosis \nwas found in 55.7% of EGE patients. Moreover, \ndiffuse sclerosis, which develops at the end of \ninflammation, or chronic insufficiency of blood \nsupply, was in 50% of cases, while focal sclerosis \noccurred in 25% of patients. In OGE stage I-II it \nwas revealed in 43.9% of patients, in stage III-IV \n– in 65.2% of patients. Hyalinosis was found in \n33.4% of patients, and it was more pronounced \nwith OGE stage III-IV – 42.9% of patients, versus \n21.6% of patients with stage I-II of the disease. \nInflammation in the stroma of endometrioid \nheterotopia in was found in 34.9% of cases in the \ngeneral group, in OGE stages I-II – in 43.2% of \npatients, in stages III-IV – in 28.3% of patients. It \nshould be noted that inflammatory changes in \nendometrioid heterotopies are more pronounced \nin EGE stage I-II, while sclerosis and tissue \nhyalinosis as outcomes of this process prevail in \npatients with EGE stage III-IV. \nSerum lipoproteins and EGE were \ndetermined using Randox kits (Germany) on \nSapphire-400 biochemistry analyzer (Japan). The \nendogenous level of nitric oxide in the form of a \nnitrite anion (NO-) was determined using Griss \nreagent. Nitroxide synthase (NOS) activity was \nassessed by the increased nitric oxide production \nfrom L-arginine in the presence of NADPH. \nGrowth factors, cytokines, were determined by \nenzyme-linked immunosorbent assay using “R£D \nSystems” kits (USA). Statistical data processing \nwas carried out using the Statistica licensed \nsoftware package (version 5.1, made by Stat \nSoft). The sample size in the work completely \ncorresponds to the range of obtaining a \nconfidence interval of probability, 0.95, and \naccuracy of calculation of statistical parameters, \n0.05. Results are presented as median and \ninterquartile interval. The significance of \ndifferences between the compared parameters \nwas determined by the Mann-Whitney criterion \nfor nonparametric distributions. The results were \nconsidered to be statistically significant at p \n<0.05. In correlation analysis of the data, the \nPearson criterion was used in the case of a \nnormal distribution of variables and otherwise the \nSpearman criterion, and the significance level \nwas 0.05. \n \n3. RESULTS AND DISCUSSION \nThe results obtained in patients with \nstages I-II of EGE are presented in Table 1. It \nshows that the content of TGF-β1 in the blood \nserum in these was 1.4 times higher compared to \nthe control group of women (p <0.004). \nThe study of lipoproteins revealed \nsignificant changes in the content of HDL in the \nblood serum, characterized by their increase of \n1.1 times (p <0,013) (Table  1). Nitric oxide (NOx) \nmetabolites content in the blood serum of \npatients with I-II stages of EGE was 6.9 times \nhigher than in the control group (p <0.041), while \nNO synthase activity was not change significantly \nand remained at physiological level. \n  At stage III-IV of EGE, the content of \nTNF-α in the blood serum of patients was 1.9 \ntimes higher compared with the data of women in \nthe control group (p <0.014). \nSignificant changes in the content of the \nstudied lipid fractions concerned only HDL both in \nminimal and severe forms of EGE (p <0.013 and \np <0.06, respectively). The content of NOx in the \nblood serum of patients with III-IV stages of EGE \n(Table 1) was 13.4 times higher than in the \ncontrol group (p <0.001). \n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  818 \nThe study of the lipid spectrum in the PF \nin patients with stages I-II of EGE showed the \nincrease of free cholesterol 1.43 times content, \nHDL - 1.73 times and HDL - 1.6 times (p <0.008, \np <0.004, p <0.003, respectively) (Table 2). \nThe content of TNF-α in the PF in patients \nwith stages III-IV of EGE was 1.5 times less \ncompared with the control group of women (p \n<0.050) (Table 2), while the level of TGF-β1 in \nthese patients was 1.7 times higher than the \ncontrol (p <0.001). \nThe content of NOx in the PF of patients \nwith III-IV stages of EGE was 3.3 times higher \nthan in patients in the control group (p <0.039) \n(Table 2). The activity of NO synthase exceeded \nphysiological parameters by almost 1.5 times (p \n<0.001). \nThere is no doubt that for the most \nsuccessful solution of the EGE problem it is \nnecessary to use modern methodological \napproaches, in particular, a comprehensive study \nof the molecular basis of the disease \ndevelopment and the relationship of metabolic \ndisorders at the local and systemic levels. \nFormation of the disease stages is of special \ninterest since it makes the basis for the further \nmanagement of patients. The proliferation factors \nof endometrioid heterotopia (cytokines and \ngrowth factors) and metabolic (lipid) parameters \nthat affect the activity of enzymes involved in the \nprocesses of angiogenesis were studied. \nBiologically active polypeptides - growth \nfactors that stimulate or inhibit angiogenesis, and \nalso regulate cellular mitogenic effects play an \nimportant role in the regulation of intracellular \nmetabolism. This refers to TGFβ1 (Burlev,2012; \nErmolova, 2008; Ermolova, 2009). TGFβ1 inhibits \nproliferation and induces differentiation of most \ntypes of cells that have been studied already. As \nfor TGFβ1 metabolic features, it inhibits NO \nsynthase activity and activates arginase \n(Babushkina, 2009). Significance of the systemic \nlevel of regulation of metabolic processes that \ncontrol cell growth (TGF-β1) in the study \nindicates the presence of compensatory reactions \nin patients with I-II EGE stages. \nIt was shown in the experiments that \nincubation of recruited macrophages with \ncholesterol causes a significant increase in TGF-\nβ1 (Schwartz, 2009). Cholesterol can directly \ninduce the synthesis and secretion of TGF-β1 in \nmonocytes - macrophages. \nVariations in the lipid content of cell \nmembranes can also significantly change the \nactivity of proteins that are their components \n(Keelet, 2012). In the presence of inflammatory \nprocesses in the body, cholesterol and \nphospholipids content changes. Cell membranes, \nmainly the middle phospholipid layer, with \nintensively occurring processes, serve as a \nscreen to reflect the aggressive effects of the \ncascade of toxic products. As a result of the \nchanges caused, the structure, membrane \nfunctions, balance between radical oxidative \nprocesses and the functional antioxidant defense \nsystem are disturbed. A large number of low-\ndensity lipoproteins (LDL) generate very low-\ndensity lipoproteins (VLDL) (oxidized \ncomponents), which enhance the growth of \nheterotopia by activating endometrial cell growth \nfactors (Verit, 2013; Melo, 2010). \nHDL increase causes paraoxonase-1 \n(PON-1) increase in the content, which is a part \nof lipoprotein complex, and, consequently, its \nactivity. Study of the paraoxonase gene \npolymorphism (Kolesnikova et al., 2012) confirms \nthis proposition, which showed the absence of its \ndifferences compared with the parameters in \npatients of the control group. HDL modification in \nwomen with EGE I-II stages at the systemic level \nis compensatory in nature, aimed at preventing \nthe formation of more \"significant\" endometrioid \nheterotopia in the peritoneal cavity. \nIncrease in nitric oxide production is due \nto the activation of the nitrite reductase pathway \nfor its synthesis. NO metabolites hyperproduction \ncontributes to the progression of endometrioid \nheterotopia due to vasodilation of the existing \nvessels and the formation of new ones by \nstimulating migration and proliferation of \nendothelial cells (Sonova et al ., 2010). Nitric \noxide is also known as a powerful anti-apoptotic \ncompound, high generation of which plays an \nimportant role in the synthesis and deposition of \ncollagen, which contributes to the formation of \nadhesions (Adamyan et al., 2016; Guidice, 2010). \nAn almost 2-fold increased TNF-α level \nenhances the induction of phospholipase A2 \n(FLA2), which is involved in the triggering of the \narachidonic acid cascade, resulting in the \nsynthesis of prostaglandins that cause pain \nsyndrome. According to our study, 68.9% of \npatients with EGE suffered periodic pains before \nor during menstruation, 8.1% had dyspareunia. \n66.0% of patients had dysmenorrhea with \nmenarche, which was significantly higher than in \nthe control group (13.6%). TNF-α acts on \nproliferating cells by enhancing apoptosis. These \npatients had an inflammatory process, since \nTNF-α synthesis is observed in stimulated cells, \n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  819 \nsuggesting that its high level is the result of \ninfection, which was found in 78.3% (pelvic \ninflammatory diseases) and in 14.4% (sexually \ntransmitted infections) of patients. \nLDL in patients with stages III-IV of the \ndisease at the system level corresponded to \ncontrol values. This is provided by an increased \nHDL content, which includes the enzyme \nparaoxonase, which protects against LDL \noxidation. This enzyme promotes the breakdown \nand elimination of oxidized cholesterol. High \nlevels of HDL cholesterol (hLDPV) in patients \nwith external genital endometriosis at all stages \nof the disease suppresses inflammation. This \nsituation follows from the previously identified \ninflammatory process in the pancreas, confirmed \nby the increased content of proinflammatory \ncytokines (TNF-α and IL-1β) in it (Ermolova, \n2008). However, it was found that in the \ninflammatory process, HDLPs change their \nfunction to pro-inflammatory due to a decrease in \nthe concentration of the main HDL apolipoprotein \n- ApoA. It provides reverse transport of \ncholesterol to the liver and increases the activity \nof paraoxonase. If the detected high level of HDL \nin the pancreas increases the anticoagulant \nproperties of red blood cells - on the one hand, \nand on the other hand, it manifests pro-\ninflammatory properties on the background of the \ninflammatory process, which enhances \ninflammation, then a complex metabolic situation \nis revealed when it is difficult to determine which \nHDL function predominates. \nIn the pancreas of women with I-II stages \nof EGE, the increased LDL level (p <0.003) was \nfound comparing to the control data, which may \nbe the result of compensatory reactions aimed at \nincreasing the activity of PLA2, LDL structural \nunit.  \nA correlation analysis of the actual \nmaterial was carried out in the experiment. \nSignificant negative correlation between the \ncontent of free cholesterol and metabolites of \nnitric oxide (r = -0.8) in the blood serum and \nbetween free cholesterol and the activity of NO \nsynthase (r = -0.85) is of special interest. The \nrevealed regularity shows that at the systemic \nlevel there is a dependence of nitric oxide \nproduction and NO-synthase activity on the lipid \nspectrum, and in particular, on the level of free \ncholesterol in women with EGE I-II stages. \nChanges in TNF-α production suggest \nthat there is a reduced function of this cytokine as \nan angiogenesis factor (Guidice, 2010) and cell \nproliferation in the pancreas. TNF-α regulatory \ncapabilities in the pancreas are determined by its \nability to induce apoptosis and produce \nantibacterial protective effect. In this case they \nare sharply reduced. \nChange of metabolic processes at the \nsystemic level can play a significant role in their \ndisruption at the local level. First, TGF-β1 high \nlevel as a factor that reduces proliferation is \ncontrolled by the central cerebral structures. \nHowever, modification of the molecular \nrelationships of lipid metabolism (HDL) with \nangiogenic compounds in endothelial cells \nincreases NO generation, causing an increase in \nheterotopies blood supply. It should be pointed \nout that a high level of TGF-β1 inhibits NO-\nsynthase, reducing one of the reactions of NO \nformation, i.e. the development of compensatory \nprocesses occurs at the systemic level. \nThus, the metabolic features of the \nformation of I-II stages of EGE in patients at the \nsystemic level (blood serum) are significantly \nincreased levels of TGF-β1, HDL and nitric oxide \nmetabolites. Besides, significant changes in the \ncontent of lipid metabolism products were found \nin the pancreas (local level). They were \ncharacterized by a significant increase in \ncholesterol, HDL and LDL, which contribute to the \nformation of oxidative stress in the abdominal \ncavity. \nIn EGE stages III – IV a high level of TGF-\nβ1 is a factor in the development of fibrosis, \nwhich underlies the adhesive process. According \nto the data obtained by of N.V. Ermolova (2008), \na high level of this growth factor is due to the \ninflammatory process both at the systemic and \nlocal levels. \nNonsteroidal products of the mevalonate \nlipid exchange pathway perform prenylation of \nsmall G-proteins (Rho, Rac), which ensure their \nintegration into membranes and manifestation of \nfunctional activity. Modification of molecular \nbonds of lipid metabolism in endothelial cells \nincreases NO generation, causing an increase in \nblood supply to endometrioid formations. \nIn this study, in women with EGE stages \nIII-IV, different lipid fractions were differentiated in \nconnection with the existing metabolic \nrelationship of the mevalonate lipid exchange \npathway and the generation of the main \nvasodilator, nitric oxide. In EGE stages III-IV, an \nincrease in HDL content at the systemic level \nobviously plays a significant role in the state of \nlipid metabolism at the local level. \n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  820 \n The increased blood supply to \nendometrioid heterotopia is due to the high \ncontent of nitric oxide metabolites in the pancreas \nof patients with EGE stages III-IV stages. This \ncompound is a powerful vascular growth factor, \nvasodilator, and apoptosis inhibitor (Guidice, \n2010). NOx excess is acco mpanied by oxidative \nstress and acts as a mutagenic, carcinogenic, \nand antiapoptotic factor (Sonova et al. , 2010; \nAdamyan et al.  ,2016). High NOx generation in \nthe pancreas, is due to the NO-synthase \npathway, as evidenced by the high activity of this \nenzyme. There are few reports on the increased \nNO-synthase expression in endometrioid \nheterotopies, which can be explained by the \npresence of a functionally defective enzyme form \nor the secondary nature of this process \n(Kinugasa, 2011; Cayci, 2011; Rogers et al. , \n2013). \nThe revealed very high NO generation in \nthe peritoneal fluid can play an important role in \nthe development of hypoxia. Recently, it has \nbeen proved that in the case of excessive NO \nproduction, its interaction with superoxidion (O\n2-) \nis observed with the formation of peroxynitrite \n(ONOO-), a powerful oxidizing agent that \nmodifies hemoglobin and changes its affinity for \noxygen (Zinchuk, 2006). The latter leads to a \ndecrease in the oxygen-binding properties of \nblood, and, consequently, to hypoxia, which leads \nto cellular metabolism disorders during \nendometriosis foci formation of (Taylor et al.  \n2002; Lee et al., 2009).  \nCorrelation analysis of the studied \nparameters in the blood serum of patients with \nEGE stages III-IV showed a close positive \nrelationship between the HDL level and TNF-α \ncontent of (r = 0.60). In this case, a negative \ncorrelation between NO-synthase activity and the \nTGF-β1 level (r = -0.33) was found. A significant \nnegative relationship was in the peritoneal fluid \nbetween HDL and NO (r = -0.75). \nThere is no doubt that the accompanying \ninflammatory process, immunological \ndysregulation, apoptosis inhibition, angiogenesis \nactivation, and oxidative stress in the abdominal \ncavity are pathogenetic factors contributing to the \nsurvival and growth of endometrioid heterotopies \n(Adamyan, 2016). \nPatients from our clinical sample mainly \ncomplained of infertility and / or pain, so we tried \nto find an explanation of their origin within the \nlimits of our studies. We found prevalence of \nprimary infertility regardless of the EGE stage. \nHowever, in percentage terms, both primary and \nsecondary infertility prevailed in patients with \nEGE stage I-II stage (57.1% and 32.1%, \nrespectively). Apparently, both ovarian factors \nand the adhesion process in the abdominal \ncavity, characterized in our conditions by the \ninvolvement of the peritoneum of the sub-ovarian \nfossa and cul-de-sac, which may interfere with \nfertilization. The decrease in the ovarian reserve \nwas due to the existing formation of endometrioid \novarian cysts from 3 to 10 cm, marked high TGF-\nβ1content, influencing arginase and, \nsubsequently, enhancing the synthesis of proline, \nthe main substrate of the connective tissue. On \nthe other hand, it is not possible ignore in this \nconnection (with TGFβ1) the importance of high \nnitric oxide generation due to nitrite reductase \nsynthesis in the absence of NO-synthase activity \nchanges, which also contributed to the formation \nof adhesions. In this metabolic situation, \nsignificantly high HDL levels both in blood serum \nand peritoneal fluid should be taken into \nconsideration, since they contribute to high \ngeneration of nitric oxide metabolites and the \nformation of oxidative stress. \nThe pain syndrome in our patients was \nprobably due to the significant production of \nprostaglandins, which, on the one hand, were \nstimulated by high TNF-α content, which \nactivates phospholipase A2 (a structural unit of \nLDL). On the other hand, the high generation of \nnitric oxide metabolites, changing the metabolism \nof arachidonic acid, acts on cycloosigenase and \nthereby stimulates the formation of \nprostaglandins. \n The revealed changes in the relationship \nof the lipid spectrum, growth factors, and \nangiogenic compounds are the theoretical basis \nfor additional therapeutic measures aimed at \nnormalizing metabolic processes in OGE. \n \n4. CONCLUSION \nIn patients with EGE stages I-II a high \ncontent of TGF-β1, HDL and nitric oxide \nmetabolites was found in the blood serum \n(systemic level). Modification of metabolic \nprocesses at the systemic level plays a significant \nrole in disrupting them locally (peritoneal cavity). \nA change in the molecular interactions of lipid \nmetabolism (HDL) and angiogenic compounds in \nendothelial cells increases nitric oxide generation, \nwhich enhances blood supply to heterotopies. \nCompensatory processes develop at the \nsystem level, in the form of a nitrite reductase \npathway for the synthesis of nitric oxide, since a \n\nPeriódico Tchê Química.  ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  821 \nhigh level of TGF-β1 inhibits NO-synthase. \nAdaptive reactions in the peritoneal cavity, \ncontributing to a decrease in proliferation and \ninflammation, are caused by an increase in free \ncholesterol, LDL and HDL. \nIn patients with EGE stages III-IV there is \nrelationship between HDL and TNF-α at the \nsystemic level, which has anti-inflammatory \nproperties. In the pancreas of patients of this \ngroup the parameters of TGF-β1, nitric oxide \nmetabolites and NO-synthase are significantly \nincreased, which indicates NO-synthase pathway \nfor the synthesis of nitric oxide. \nThe change in the relationship of the lipid \nspectrum, nitric oxide metabolites and cytokines \nis the theoretical basis for additional therapeutic \nmeasures aimed at normalizing metabolic \nprocesses in EGE. \n \n5. REFERENCES \n1. Adamyan, L. V.; Kulakov, V. I.; Andreeva, \nE.N. Endometriosis Clinical \nrecommendations. 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ISSN 2179-0302. (2020); vol.17 (n°35) \nDownloaded from www.periodico.tchequimica.com \n  823 \n37. Wang, G.; Tokushige, N.; Markham, R.; \nFraser, I.S. Rich innervations of deep \ninfiltrating endometriosis. Hum Reprod  \n2009; 24:827-34. \n \n \n \n \n \nTable  1. Parameters Indicators of cell metabolism regulators in patients with EGE \n(blood serum). \nParameter EGE st age Control Р \nI-II EGE stage \nTGF-β1 (pg/ml) \n12936.0 \n[7650.0-\n28050.0] \n9332.0 \n[4736.0-\n21100.0] \n0.004 \nHDL (mmol/l) \n1.25 \n[0.77-2.20] \n1.10 \n[0.56-1.80] \n0.013 \nNOх (mmol/l) \n16.50 \n[0.80-61.50] \n2.39 \n[0.10-62.50] \n0.041 \nIII-IV EGE stage \nTNF-α  \n(pg/ml) \n15.56 \n[4.70-64.00] \n8.04 \n[0.40-23.60] \n0.014 \nTGF (mmol/l) \n1.25 \n[0.91-2.30] \n1.10 \n[0.56-1.80] \n0.006 \nNOх (mmol/l) \n32.00 \n[0.48-56.00] \n2.39 \n[0.10-62.50] \n0.001 \nNote: Results are presented as median and interquartile interval. \np - significance of differences compared with the control group. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nPeriódico\n \nTchê\n \nQuímica\n.\n  \nISSN\n \n2179\n-\n0302\n.\n \n(\n202\n0\n);\n \nvol\n.\n17\n \n(\nn\n°\n35\n)\n \nDownloaded\n \nfrom\n \nwww\n.\nperiodico\n.\ntchequimica\n.\ncom\n \n \n \n824\n \nTable  2. Parameters of cell metabolism regulators in patients with EGE (peritoneal \nfluid) \nParameter \nEGE st\nage \nControl \nР \nI-II EGE stageЭ \nCholesterol \n(mmol/l) \n2.0 \n[1.07 –3.09] \n1.39 \n[1.21 – 1.81] \n0.008 \nHDL (mmol/l) \n0.78 \n[0.34-1.17] \n0.45 \n[0.33-0.59] \n0.004 \nLDL (mmol/l) \n0.77 \n[0.0-1.21] \n0.48 \n[0.01-0.70] \n0.003 \nIII-IV EGE stage \nTNF-α \n (pg/ml) \n8.30 \n[0.02-29.86] \n12.59 \n[4.0-31.20] \n0.050 \n           TGF-1β \n           (pg/ml) \n2480.0 \n[1513.60-\n5720.0] \n1425.40 \n[1011.0-\n2200.40] \n0.001 \nNOх (mcmol/l) \n24,00 \n[7.52-65.00] \n7.25 \n[0.14-64.50] \n0.039 \nNO-synthase \n(mcmol/l) \n35.00 \n[28.60-67.40] \n23.00 \n[0.79-57.60] \n0.001 \nNote: results are presented as median and interquartile interva\nl. \np - significance of differences compared with the control group\n. \n \n \nThe\nPeriódico\nTchê\nQuímica\n(\nISSN\n:\n1806\n-\n0374\n;\n2179\n-\n0302\n)\nis\nan\nopen\n-\naccess\njournal\nsince\n2004\n.\nJournal\nDOI\n:\n10\n.\n52571\n/\nPTQ\n.\nhttp\n://\nwww\n.\ntchequimica\n.\ncom\n.\nThis\ntext\nwas\nintroduced\nin\nthis\nfile\nin\n2021\nfor\ncompliance\nreasons\n.\n©\nThe\nAuthor\n(\ns\n)\nOPEN\nACCESS\n.\nThis\narticle\nis\nlicensed\nunder\na\nCreative\nCommons\nAttribution\n4\n.\n0\n(\nCC\nBY\n4\n.\n0\n)\nInternational\nLicense\n,\nwhich\npermits\nuse\n,\nsharing\n,\nadaptation\n,\ndistribution\n,\nand\nreproduction\nin\nany\nmedium\nor\nformat\n,\nas\nlong\nas\nyou\ngive\nappropriate\ncredit\nto\nthe\noriginal\nauthor\n(\ns\n)\nand\nthe\nsource\n,\nprovide\na\nlink\nto\nthe\nCreative\nCommons\nlicense\n,\nand\nindicate\nif\nchanges\nwere\nmade\n.\nThe\nimages\nor\nother\nthird\n-\nparty\nmaterial\nin\nthis\narticle\nare\nincluded\nin\nthe\narticle\n’\ns\nCreative\nCommons\nlicense\nunless\nindicated\notherwise\nin\na\ncredit\nline\nto\nthe\nmaterial\n.\nIf\nmaterial\nis\nnot\nincluded\nin\nthe\narticle\n’\ns\nCreative\nCommons\nlicense\nand\nyour\nintended\nuse\nis\nnot\npermitted\nby\nstatutory\nregulation\nor\nexceeds\nthe\npermitted\nuse\n,\nyou\nwill\nneed\nto\nobtain\npermission\ndirectly\nfrom\nthe\ncopyright\nholder\n.\nTo\nview\na\ncopy\nof\nthis\nlicense\n,\nvisit\nhttp\n://\ncreativecommons\n.\norg\n/\nlicenses\n/\nby\n/\n4\n.\n0\n/.","source_license":"CC0","license_restricted":false}