Antioxidant defense system correction in treatment of payients with infertility and peritoneal endometriosis
Evaluation of the effectiveness of therapeutic plasmapheresis (TP) in the complex treatment of patients with peritoneal endometriosis, infertility and point mutations in the NAT2 gene. The effectiveness of the treatment: laparoscopy and the course of TP.
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Antioxidant defense system correction in treatment of payients with infertility and peritoneal endometriosis
Dubinskaya E.D.1, Lapteva N.V.2, Dmitrieva N.V.3, Lukianova I.S.4, Dutov A.A.5
1Рrofessor, MD, Obstetrics, Gynecology and Reproductive Medicine department, People's Friendship University of Russia, 2 Assistant, Obstetrics, Gynecology and Reproductive Medicine department, People's Friendship University of Russia, 3 MD, Obstetrics, Gynecology and Reproductive Medicine department, People's Friendship University of Russia, 4 Postgraduate student, institute of medicine, Ogarev Mordovia State University, 5Assistent, Obstetrics, Gynecology and Reproductive Medicine department, People's Friendship University of Russia
therapeutic plasmapheresis infertility laparoscopy
Коррекция системы детоксикации в лечении пациенток с бесплодием и перитонеальным эндометриозом
Дубинская Е.Д.1 Доктор медицинских наук, профессор кафедры акушерства, гинекологии и репродуктивной медицины ФПК МР РУДН,
Лаптева Н.В.2 Ассистент, кафедра акушерства, гинекологии и репродуктивной медицины ФПК МР РУДН,
Дмитриева Н.В.3 Кандидат медицинских наук, кафедра акушерства, гинекологии и репродуктивной медицины ФПК МР РУДН,
Лукьянова Я.С.4Аспирант, кафедра акушерства и гинекологии медицинского института национального исследовательского Мордовского государственного университета им. Н.П. Огарева,
Дутов А.А.5Ассистент, кафедра акушерства, гинекологии и репродуктивной медицины ФПК МР РУДН
Известно, что 30-40% женщин с наружным генитальным эндометриозом страдают бесплодием. У половины больных эндометриозом выявляются точечные мутация в NAT2 - гене, который играет важную роль в ацетилировании ароматических и гетероциклических аминов, в накоплении эндотоксинов, активации процессов свободнорадикального окисления, нарушением микроциркуляции. Эти факторы предполагают использование методов гемафереза, которые имеют детоксикационный, реокорригирующий, иммунокорригирующий эффекты. Целью настоящего исследования явилась оценка эффективности терапевтического плазмафереза в комплексном лечении пациенток с перитонеальной формой эндометриоза, бесплодием и точечными мутациями в гене NAT2.
Полученные данные свидетельствуют об эффективности предложенной комплексной методики лечения (лапароскопия и последующий курс терапевтического плазмафереза) пациенток с бесплодием и перитонеальным эндометриозом, имеющими точечные мутации в гене NAT2. Использование плазмафереза патогенетически обосновано у пациенток исследуемой группы.
Ключевые слова: бесплодие, перитонеальный эндометриоз, точечные мутации в гене NAT2,эндотоксикоз, оксидативный стресс, микроциркуляция, терапевтический плазмаферез, беременность.
It is known that 30-40% of patients with peritoneal endometriosis suffer from infertility. Half of the patients with endometriosis are identified point mutation in NAT2 - gene, which plays an important role in the acetylation of aromatic and heterocyclic amines, in the accumulation of endotoxins, activation of free radical oxidation, impaired microcirculation. These factors involve the use of methods of gemapheresis which have detoxification, the blood rheology corrective and immune corrective effects.
The purpose of this study was to evaluate the efficacy of therapeutic plasma exchange in treatment of patients with peritoneal form of endometriosis, infertility and point mutations in the gene NAT2.
The findings suggest that the efficiency of the proposed comprehensive treatment techniques (laparoscopy and subsequent course of therapeutic plasmapheresis) of patients with peritoneal endometriosis and infertility and with point mutations in the gene NAT2. The use of plasmapheresis is pathogenetically justified in patients of the studied group.
Keywords: infertility, peritoneal endometriosis, point mutations in the gene NAT2, endotoxicosis, oxidative stress, therapeutic plasmapheresis, pregnancy.
Infertility is an important medical and social problem. One of the most frequent causes of reproductive function disorder (30-40%) is endometriosis. Half of the patients with endometriosis are identified to have point mutation in NAT2 gene. NAT2 gene product arylamine- N-acetyltransferase-2 is known to play an important role in the acetylation of aromatic and heterocyclic amines. That is why the disorder of its function, caused by encoding gene polymorphism, leads to accumulation of endotoxins, which, by their turn, strengthens process of free-radical oxidation in a cell. The importance of oxidative stress in case of endometriosis also has been proved on the basis of studying of specific markers that comes with endotoxicosis, activation of lipid peroxidation, impaired microcirculation. These factors involve the usage of gemapheresis methods which have detoxification, the blood rheology corrective and immune corrective effects. For decades, the efferent methods of treatment are used in complex therapy of almost 70 nosological forms of diseases, including pediatrics. [3,5,11,1,17,18,9,16]
Plasmapheresis in complex therapy of placental insufficiency after myom- and hysterectomy, as well as in treatment of women with a climacteric syndrome, chronic inflammatory diseases of pelvic organs and in the preparation for the procedure of in vitro fertilization of patients with infertility inflammatory genesis, is proved to be efficient. [1,2,4,8,10,12,13,14,5,6]
However, up to the present moment, the issue of the pathogenetically substantiated use of plasmapheresis in treatment of patients with infertility and peritoneal form of endometriosis is not yet fully studied.
Taking into account the evident detoxification effect of plasmapheresis, not only due to the mechanical removal of microbes and their toxins, inflammation mediators, metabolism products, damaged and necrotic-changed cell components, but also due to the stimulation of organs and body systems, which are responsible for binding, inactivation and elimination of endo- and exotoxins, along with the reduction of free-radical reactions of lipid peroxidation, it can be assumed that its use will have a beneficial effect on condition of the detoxification body system, including the antioxidant protection and, therefore, will improve the treatment results of patients with infertility and peritoneal form of endometriosis.
The purpose of the research is to evaluate the effect of plasmapheresis on the processes of natural detoxication and antioxidant protection of the organism in patients with infertility and peritoneal form of endometriosis depending on number of point mutations in NAT2 gene.
Materials and methods:
The study included 140 patients with infertility, peritoneal form of endometriosis, verified by the laparoscopy, and point mutations in the gene NAT2. All patients were performed coagulation foci of endometriosis during laparoscopy, salpingoovariolisis, fimbrioplasty (on therapeutic grounds). Then all patients were divided into 2 groups: the main group included 93 (66.4%) women, who underwent a course of plasmapheresis (2nd stage of complex treatment) in the next cycle after laparoscopy; the comparison group included 47 (33.6%) patients who did not experience efferent methods of treatment. Considering the current recommendations of the European Society of Human Reproduction on the ineffectiveness of hormone replacement therapy and biologically active dietary supplements with regard to increasing fertility after surgery for endometriosis, it was decided not to prescribe any drugs. The course of therapeutic plasmapheresis (PA) for patients of the main group was held in the first phase of the menstrual cycle starting on 5th or 6th day and included 3 sessions of PA with an interval of 2-4 days. The procedure was carried out in the PCS2 device made by “Haemonetics» (USA). The assembly of line system was carried out under aseptic conditions, immediately before the procedure. SDA-A solution (acidic dextrose) supplied automatically in a ratio of 1/12 to the blood was used as anticoagulant. Before starting the procedure the patient was intravenously administered with heparin in an amount of 25 units for kg / body weight. The therapeutic plasmapheresis was carried out with the blood flow to the device at speed of 25-40 ml per minute, depending on the catheter capacity and the vein ability. The spin speed of PCS2 centrifuge is 7500 rpm, plasma was removed at speed of 15-30 ml per min depending on speed of blood flow supply.
Simultaneously with the blood sampling and removal of plasma, it was produced the plasma replacement by crystalloid (saline 0.9%) and colloidal (hydroxyethylated starch solutions of 6% or 10% with the molecular weight of 130/04 or 200/04) solutions at a ratio of 1:1.5 by volume of exfusion in the device automatic mode. In case of low albumin (less than 60 g / l) 10% albumin solution (100 ml) was included in the plasma replacement procedure.
To calculate the volumes of circulating plasma and blood and quantity of plasma to remove, mathematical calculation program, based on certain anthropometric patient data and some physiological constants, was used. The circulating blood volume (CBV) was counted considering body weight, height, constitutional type based on Moore method.
CBV = М x Bq,
where М is body weight in kg;
Bq is the blood quantity in ml per kg of body weight (depends on body build of a woman and is from 55 to 70 ml / kg).
Then the hematocrit, that is triple hemoglobin level, was calculated (h%).
Ht = Hn x 3
where Ht is hematocrit in %; Hn is hemoglobin contents in h %.
Then on the base of calculated CBV and hematocrit, CPV (circulating plasma volume) was counted:
CPV = CBV x (100% - Ht)
Using estimated CPV the planning percentage of plasma to remove (P) was calculated, adding to it 5% for additionally administrated anticoagulant solution into the affluent line, the most part of which is removed with plasma, and got the planning removing plasma quantity (RPQ):
Criteria for inclusion:
1. Patients with infertility, peritoneal form of endometriosis, verified by the laparoscopy;
2. Age: 20-39;
3. Normal ovarian reserve (FSH indicators are less than 8 IU/l, Anti-Mullerian Hormone is more than 2 uh/ml and quantity of antral follicles is more than 10 in each ovary on the 2nd -3rd day of the cycle);
4. Presence of 3 or more point mutations in the gene NAT2
Criteria for exclusion:
1. Patients with uterine myoma, benign ovarian tumors, hydrosalpinx, malformations of female genitalia;
2. Presence of a somatic pathology associated with the presence of point mutations in the gene NAT2(psoriasis, neurodegenerative diseases, lung and bladder disease)
3. Patients with endocrine factor of infertility.
· General clinical examination
Making anamnesis the special attention was paid to menstrual and reproductive functions of patients, outcome of previous pregnancies and their complications. There were estimated frequency of infectious diseases in childhood, the nature of inflammation, there were got data accompanying extragenital pathology and experienced surgeries, trauma, hereditary diseases.
· Genetic study
Presence of NAT2 gene polymorphism was studied at the laboratory on the base of N. F. Gamaleya Research Institute of Epidemiology and Microbiology of Ministry of Healthcare and Social Development of the Russian Federation. All patients gave informed consent for the use of the blood for the research.
The material for this study was DNA samples separated from peripheral blood leukocytes of the patients. As a preservative 1 ml of 0.5M EDTA pH 8.0 was used.
· Quantitative assessment of the level of endogenous intoxication (endotoxic index (EI), the molecules of average weight (AWM)) and quantitative assessment of the level of oxidative stress (malonaldehyde (МА), superoxide dismutase (SOD), total antioxidant activity (TAA)) before and after plasmapheresis.
· Statistical data manipulation
To analyze the results statistical computer programs SPSS (version 10.0.7) and Statistica (Version 6.0) for Windows were used. Differences between groups were considered to be reliable at р<0.05
Results of the research and discussion:
The evaluation of results obtained from the research revealed that the original average value of the concentration of middle-mass molecules (MM) in patients with three and more point mutations was higher than in patients with 1-2 mutations in NAT2 gene (р>0,05).
After the course of plasmapheresis a significant reduction of concentration of middle-mass molecules was observed in the treatment group in relation to the experimental group results (р<0,05).
The analysis of endotoxic index indicators established that originally the value of EI254 and EI280 in patients with a smaller number of point mutations was 5,11±1,1 and 4,34±0,39, which is by 4,12% and 5,5% more than those in patients with three and more mutations.
In the course of treatment the increase of EI (р<0,05) was observed in the treatment group in relation to the experimental group results.
For the evaluation of oxidative stress the comparative study of the concentration of malonaldehyde, superoxide dismutase and the total antioxidant status in blood of patients was used.
The results obtained revealed that the concentration of malonaldehyde is reliably higher in the group with a greater number of mutations than in the group of patients with 1-2 point mutations (р<0,05). While the amount of superoxide dismutase and the total antioxidant status are by 12% and 18% less respectively.
In the group of patients where plasmapheresis was used the tendency of decrease of the amount of malonaldehyde was observed (р<0,05). Increase of the level of superoxide dismutase and total antioxidant status amounted to 23,4% and 14,8% respectively (р<0,01).
The further observation was carried out during 2-24 months in order to evaluate the effect of the use of plasmapheresis on long-term results of the infertility treatment in patients with the peritoneal form of endometriosis and point mutations in NAT2 gene.
The analysis conducted has shown that the group of patients who had not used the efferent methods of treatment have a lower chance of getting pregnant: 12 (27,9%) patients - natural pregnancy, 9 (20,9%) - in vitro fertilization. In the treatment group number of women who became pregnant was 46 (47,4%) and 35 (36,1%) respectively.
Thus, the results of the studies showed the effectiveness of plasmapheresis as a method for stabilizing the oxidative status of the system and its positive role, from clinical view, for patients with infertility and peritoneal endometriosis. After the complex treatment in this group of patients it was exposed significant increase in the number of intrauterine pregnancies occurrence (both independent and in the course of assisted reproduction programs), as well as decrease of missed abortion number.
By all appearances, this effect is relatively short-termed and allows to create some “reproductive window” of fertility improvement in the group of women with point mutations in NAT2 gene and impaired detoxification system (a group of poor prognosis in relation to the uterine pregnancy occurrence), which explains the best results during 3 months after treatment.
The developed method of the differentiated approach to care of patients with infertility and peritoneal endometriosis considering particularities of NAT2 gene polymorphism allows improving significantly remote results of treatment (uterine pregnancy occurrence and its prolongation).
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