Ultrasound examination and MRI make it possible to diagnose adenomyosis, a disease most typical for women of reproductive age. In most cases, it is not accompanied by specific complaints, complicating the diagnostic process. That is why ultrasound is an effective and affordable method that allows you to quickly and painlessly detect the problem.

A Denomyosis was first described by Carl von Rokitansky in 1860, after the invention of the microscope: he described the presence of endometrial glands in the wall of the uterus. But the terms “endometriosis” and “adenomyosis” themselves were proposed only in 1892 by Blair Bell. Later, in 1896, the Von Recklinghausen classification of endometriosis was proposed.

Adenomyosis is more common in women of reproductive age. It is found in approximately 30% of women from the total female population and in 70% of cases during pathological studies of preparations after hysterectomies. Diagnosis of this disease is possible through ultrasound or magnetic resonance imaging (MRI), in this article we will consider the characteristic ultrasound signs of adenomyosis.

DESIGNATION

Adenomyosis is the presence of ectopic inclusions of endometrial glands in the myometrial stroma. The presence of these inclusions leads to hypertrophy and hyperplasia of the myometrial stroma.

CLINICAL MANIFESTATIONS

Most patients do not express specific complaints. Symptoms associated with adenomyosis include dysmenorrhea, dyspareunia, chronic pelvic pain, and menometrorrhagia. Adenomyosis most often occurs as a diffuse form, spreading throughout the entire thickness of the myometrium (Fig. 1). A focal form known as adenomyoma also occurs (Figure 2).

Rice. 1. Adenomyosis is a diffuse form.

Rice. 2. Adenomyosis is a focal form.

Adenomyosis may be associated with other conditions such as uterine leiomyoma, endometrial polyp and endometriosis. Establishing a clinical diagnosis of endometriosis is difficult, since there are no characteristic symptoms for this disease. However, a diffusely enlarged (rounded) uterus during bimanual examination indicates adenomyosis.

DIAGNOSTICS

Confirmation of the diagnosis of adenomyosis is carried out by pathological examination of specimens after hysterectomy. The presence of endometrial glands in the myometrial stroma more than 2.5 mm from the basal layer of the endometrium confirms the diagnosis. Ultrasound and MRI can make a diagnosis. The latest meta-analysis of the diagnostic reliability of ultrasound examination showed that this method has a sensitivity of 82.5% (95% credible interval, 77.5-87.9) and a specificity of 84.6% (79.8-89.8) from the likelihood ratio to a positive result – 4.7 (3.1-7.0) and the likelihood ratio to a negative result – 0.26 (0.18-0.39). The sensitivity and specificity of MRI in diagnosing adenomyosis are similar to ultrasound data and are 77.5 and 92.5%. When performing transvaginal ultrasonography, the sensor directly touches the body of the uterus, providing clear visualization of the focus of adenomyosis. In the presence of fibroids, the possibility of ultrasound visualization of adenomyosis is reduced, and leiomyoma is generally associated with adenomyosis in 36-50% of cases.

Ultrasound signs

Ultrasound signs of adenomyosis during transvaginal sonography include the following:

1. Increase in the length of the uterine body - the rounded shape of the uterus, the length of which is generally more than 12 cm, not due to fibroids of the uterine body, is a characteristic feature (Fig. 3).

Rice. 3. The uterus is round in shape; an unclear border between the endometrium and the myometrium is also visualized.

2. Cysts with anechoic contents or lacunae in the myometrial stroma. Cysts with anechoic content within the myometrium come in different sizes and can fill the entire thickness of the myometrium (Fig. 4). Cystic changes outside the myometrium may represent small arcuate veins rather than foci of adenomyosis. To carry out differentiation, color Doppler mapping is used; the presence of blood flow in these lacunae excludes adenomyosis.

Rice. 4. Anegochene cystic lacunae behind the uterine wall (arrow) with a heterogeneous echo pattern.

3. Consolidation of the uterine walls may show asymmetry of the anterior and posterior walls, especially in the focal form of adenomyosis (Fig. 5).

Rice. 5. When measuring the thickness of the posterior wall of the uterus, we observe its thickening compared to the anterior wall (calipers), and a heterogeneous echo is visualized - the structure of the myometrium.

4. Subendometrial linear striations. Invasion of the endometrial glands into the subendometrial space results in a hyperplastic reaction, accounting for the linear striations outside the endometrial layer (Fig. 6).

Rice. 6. Linear striations (arrows) are outside the heterogeneous structure of the M-echo.

5. Heterogeneous structure of the myometrium. This is an insufficiently homogeneous structure of the myometrium with an obvious violation of the architectonics (Fig. 1 and 4). This finding is more typical of adenomyosis.

6. Fuzzy border of the endometrium and myometrium. Invasion of the myometrium by glands also results in an unclear endometrial-myometrial boundary. (Fig. 2 – 6).

7. Compaction of the transition zone. This is a zone of hypoechoic rim around the endometrial layer; its size more than 12 mm indicates the presence of adenomyosis.

The main criteria for diagnosing adenomyosis are: the presence of a rounded uterus, cystic cavities in the myometrial wall, linear striations in the endometrial zone. To carry out differential diagnosis with uterine leiomyoma, color Doppler scanning is used. When assessing the speed of blood flow in the uterine arteries, in 82% of cases of adenomyosis, the arteries inside or around the formation in the myometrium have a pulsation index of more than 1.17, and in 84% of cases with diagnosed uterine fibroids - less than 1.17.

CONCLUSIONS

Adenomyosis occurs predominantly in women of reproductive age. Most women do not have specific complaints. Symptoms characteristic of adenomyosis are: the presence of chronic pelvic pain and pathological uterine bleeding. Diagnosis of adenomyosis using ultrasound can be compared with the diagnostic capabilities of MRI. This is an effective, safe and inexpensive examination method.

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Over the past quarter century, there has been a steady increase in the incidence of genital endometriosis. Currently, endometriosis is gradually moving into third place in the structure of gynecological morbidity in Russia, since about 8-15% of women of reproductive age have this pathology. Genital endometriosis is the second most common disease in women of reproductive age, causing infertility, pain and various menstrual irregularities.

The problem of genital endometriosis is especially relevant for young women, since the disease is accompanied by significant disturbances in reproductive and menstrual functions, persistent pain, dysfunction of adjacent organs, as well as a deterioration in the general condition of patients and a decrease in their ability to work. The most common localization of genital endometriosis is damage to the uterus - adenomyosis, the share of which in the structure of this pathology ranges from 70 to 80%.

The purpose of our study was to improve treatment tactics in patients with adenomyosis with initial manifestations of the disease based on correction of the results of morpho-biochemical studies.

A comprehensive clinical, morpho-biochemical study was carried out in 90 patients with adenomyosis, including 50 patients (average age 42.6 ± 3.35 years) with a histologically verified diagnosis. The results of conservative treatment of 40 patients with adenomyosis (average age 38.7 ± 2.71 years) were analyzed.

To clarify the diagnosis, an instrumental examination was carried out: transabdominal and transvaginal ultrasound scanning using the Aloka-630 (Japan), Megas (Italy) devices and hysteroscopy using endoscopic equipment from Karl Storz (Germany). Sterile solutions of sodium chloride (0.9%) and glucose (5.0%) were used as a contrast medium. After the initial examination, separate diagnostic curettage of the cervical canal and the mucous membrane of the uterine cavity, followed by their histological examination, control hysteroscopy was performed.

The histological material was processed according to standard methods. Histochemical methods revealed the main substance of the connective tissue of the myometrium using Alcian blue according to the method of A. Krieger-Stoyalovskaya; the determination of neutral polysaccharides was carried out using the PHIK reaction, the DNA of cell nuclei - using the Feulgen method, the macromolecular stability of connective tissue tissue structures - using the method of K. Velikan.

Isolation of phosphoinositides (PINs) was carried out using an improved flow thin-layer chromatography method, which made it possible to determine the content of various PINs. The content of FIN in whole blood, monocytes, and lymphocytes was studied. The comparison group for determining the levels of FIN in the blood consisted of 50 healthy female donors (average age 39.3 ± 2.45 years).

An analysis of anamnestic and clinical data, the results of a comprehensive examination (hysteroscopy, ultrasound scanning) of 40 patients with adenomyosis (average age 38.7 ± 2.71 years) who received conservative therapy was carried out.

The most typical complaints of patients were identified: dysmenorrhea, which was noted by 34 (86.1%) women, menorrhagia - 17 (42.5%), pre- and postmenstrual bleeding from the genital tract - 14 (35.0%). In addition, 18 (45.0%) patients complained of pain in the lower abdomen; for pain in the pelvic area not associated with menstruation or sexual intercourse - 10 (25.0%) women; Dyspareunia was noted by 13 (32.5%) patients. In every fifth woman, dysmenorrhea was accompanied by headache and dizziness. Increased irritability, depressed mood, decreased performance and neurotic disorders were noted by 23 (57.5%) women. In the majority, the pain syndrome was accompanied by general weakness, feelings of anxiety, fear, excitability, emotional lability, distracted attention, memory loss, sleep disturbance and other psychoasthenic manifestations that bothered every second patient.

A gynecological examination revealed an increase in the size of the uterus, corresponding to 6-7 weeks of pregnancy, in 31 patients; in the remaining women, the uterus was enlarged until 8-9 weeks of pregnancy. Pathological formations in the area of ​​the uterine appendages were not found in any patient, both during two-hand and echographic examinations.

In order to clarify the clinical diagnosis, an examination was carried out using the most informative instrumental methods: ultrasound and hysteroscopy. The information content of ultrasound in detecting adenomyosis was 77.5 ± 6.69%, hysteroscopy - 87.5 ± 5.29%.

A morpho-biochemical study was carried out in 50 operated patients (average age 42.6 ± 3.35 years) with adenomyosis verified by morphological examination. It was established that the growth of heterotopic foci was accompanied by pronounced congestion of the myometrial microvasculature, lymphostasis, edema of the perivascular myometrial tissue, an increase in the number of tissue basophils around the foci of endometriosis, and a high content of alcian-positive glycosaminoglycans in the intercellular substance. These changes were most pronounced in degrees II-III of the lesion. Uneven compaction and liquefaction of the argyrophilic substance with loss of the fibrous structure around the glands located in the myometrium was detected. Disturbances in the structure of the main substance and fibrous structures of the connective tissue framework of the myometrium in the form of the development of baso- and picrinophilia, the progressive loss of intermolecular bonds, the accumulation of acidic non-sulfated glycosaminoglycans, and an increase in the number of tissue basophils are a consequence of the resulting tissue hypoxia. The morphological manifestation of the latter can be considered the congestion of the myometrial microvasculature present in the samples and the accompanying swelling of the perivasal spaces and pronounced lymphostasis. A pathological process that deeply infiltrates tissues leads to ischemia of nerves and their demyelination. The result of these processes is a change in the afferent input at the level of the spinal cord segment, the impulses entering the central nervous system permanently change, which leads to a change in the sensory quality of pain and the appearance of the most painful sensations. Reflex vascular spasm, developing in response to a painful stimulus, aggravating ischemic disorders, further enhances afferent impulses in the brain, contributing to the formation of “vicious circles” in sympathetic reflexes. In addition, functioning foci of endometriosis themselves turn into a powerful irritant of the higher centers of regulation of sexual function, which leads to further stimulation of the proliferative activity of cells. As a result, conditions are created for the progression of the pathological process, in which the main role belongs to the disruption of intracommunicative relationships in the blood-uterine tissue system. All this leads to the formation of a vicious circle, characterized by interconnected hormonal, immune, and cellular disorders, which are extremely difficult to completely eliminate with hormonal drugs alone. This is evidenced by the low effectiveness of therapy used in patients with this pathology.

Currently, much attention is paid to the study of arachidonic acid and its metabolites (prostaglandins and thromboxane A 2) in the processes of cell proliferation. It has been shown that prostaglandins may have an effect on the regulation of cell proliferation and/or differentiation, especially in the endometrium. The occurrence of pain in patients with adenomyosis may be due to overproduction of arachidonic acid derivatives - prostaglandins. The phenomenon of sensitization to algogenic products produced during inflammation, ischemia, and immunopathological processes is associated with prostaglandins. Prostaglandin F 2α (PGF 2α) and prostaglandin E 2 (PGE 2) accumulate in the endometrium during menstruation and cause symptoms of dysmenorrhea. PGF 2α and PGE 2 are synthesized from arachidonic acid through the so-called cyclooxygenase pathway. The main source of hyperproduction of prostaglandins are activated mononuclear cells. We conducted a study of the FIN content in phagocytic mononuclear cells from patients with adenomyosis, assessing their content by their presence in monocytes. The content of FIN in the blood reflects the specificity of changes in metabolic processes occurring in the body, since the participation of inositol-containing lipids in the transition of cells to uncontrolled growth and transformation has been proven. It was found that in monocytes from patients with adenomyosis, the amount of the main FIN, phosphatidylinositol (PI), was significantly reduced by 1.3 times compared to the values ​​in women in the control group. The data obtained indicate that in patients with adenomyosis, PI deficiency plays a very important role in proliferation processes, which means these disorders should be corrected in the treatment of this disease.

Currently, the most effective drugs for the treatment of adenomyosis are gonadotropin-releasing hormone agonists (zoladex, decapeptyl, diferelin, buserelin acetate, buserelin-depot, etc.). However, the high cost of the drugs does not allow them to be widely used in clinical practice. In this regard, patients with limited financial resources are prescribed progestogens whose active substance is norethisterone acetate - norkolut (Gedeon Richter, Hungary), primolut-nor (Schering, Germany).

We studied the results of traditional hormonal therapy and the method we developed for treating adenomyosis. The 1st group of patients included 20 women (average age 38.2 ± 2.88 years) who received only hormonal therapy (Norkolut - 10 mg per day from the 5th to the 25th days of the menstrual cycle for 6 months ). In the 2nd group of patients, which included 20 patients (average age 39.4 ± 2.97 years), complex treatment was carried out using the following drugs: norkolut (dosage regimen, as in patients of the 1st group) in combination with trental (1 tablet 3 times a day for 6 weeks), hofitol (Labor. Rosa-Phytopharma) (2-3 tablets 3 times a day before meals for 20 days) in combination with 10 sessions of low-energy laser therapy carried out by the device RIKTA (Russia) according to the methodology we developed (2004). A second course of laser therapy was carried out after 2 months. The therapeutic effectiveness of laser therapy is due to both the laser, infrared and magnetic effects of this device, and the specifics of the combined use of these types of energy. Hofitol is a herbal preparation with pronounced hepato-, nephroprotective and diuretic effects, and has an antioxidant effect. Treatment with this drug affects lipid metabolism and increases the production of coenzymes by hepatocytes. Due to the fact that hyperproduction of prostaglandins plays a certain role in the occurrence of pain in patients with adenomyosis, we included the non-steroidal anti-inflammatory drug Nurofen Plus (Boots Healthcare International) in the complex therapy.

Patients began taking trental and hophytol during the first cycle of treatment with a hormonal drug. Nurofen plus was prescribed 3-4 days before the onset of menstruation and during the first 3-5 days of menstruation (200-400 mg every 4 hours). The drug was taken taking into account individual tolerance. Low-energy laser therapy was carried out immediately after the end of menstruation, so that the course of treatment was not interrupted and fell within the framework of one menstrual cycle.

After 6 months, when analyzing the effectiveness of therapy, it was found that the treatment was better tolerated by patients from group 2. Thus, an improvement in general condition, well-being, and mood was noted by 5 (25.0%) patients from group 1 and 17 (85.0%) women from group 2. Such changes had a beneficial psycho-emotional effect and contributed to an increase in the performance of the patients. Sleep improved in 2 (10.0%) women from group 1 and in 10 (50.0%) women from group 2; 1 patient from group 1 and 8 women from group 2 became less irritable. When comparing the dynamics of changes in the clinical symptoms of the disease, the best therapeutic effect was observed in patients from group 2, compared with women receiving traditional hormonal treatment. Thus, dysmenorrhea decreased in 11 (64.7%) patients from group 1 and in 16 (94.1%) women from group 2, and it was completely relieved in 2 and 11 patients of the corresponding groups. Pain in the lower abdomen decreased in 4 out of 8 patients in group 1 and in 9 out of 10 women in group 2. It should be noted that patients from group 2 noted a decrease in the severity of pain and dysmenorrhea already in the next menstruation after laser therapy, carried out against the background of drug therapy. Dyspareunia decreased in 2 patients from group 1 and in 6 women from group 2. A decrease in the duration and intensity of menstrual blood loss was noted by 7 women from group 1 and 10 women from group 2. The lack of effect from the therapy, which led to surgery, was observed in 4 (20.0%) women from group 1 and 1 (5.0%) patient from group 2, who were diagnosed with a diffuse nodular form of adenomyosis .

Thus, comprehensive correction of disorders that occur in patients with adenomyosis helps to increase the effectiveness of treatment of this pathology. The inclusion of low-energy laser therapy in complex therapy for patients with adenomyosis, as well as drugs that improve microcirculation, a non-steroidal anti-inflammatory drug (nurofen plus) helps to increase the effectiveness of treatment and reduce the frequency of surgical interventions by 4 times compared to patients receiving traditional hormonal therapy.

Literature

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M. M. Damirov,Doctor of Medical Sciences, Professor
T. N. Poletova, Candidate of Medical Sciences
K. V. Babkov, Candidate of Medical Sciences
T. I. Kuzmina, Candidate of Medical Sciences, Associate Professor
L. G. Sozaeva, Candidate of Medical Sciences
Z. Z. Murtuzalieva

RMAPO, Moscow

As a manuscript

SOROKINA ANNA VLADIMIROVNA

PATHOGENESIS, PREDICTION AND POSTGENOMIC DIAGNOSIS OF ADENOMYOSIS

01/14/01 – Obstetrics and gynecology 03/14/03 – Pathological physiology

Moscow 2011

The work was carried out at the Department of Obstetrics and Gynecology with a perinatology course at the Russian Peoples' Friendship University.

Scientific consultants:

Honored Scientist of the Russian Federation, V.E. Radzinsky Doctor of Medical Sciences, Professor Corresponding Member of the Russian Academy of Medical Sciences, S.G. Morozov Doctor of Medical Sciences, Professor

Official opponents:

Professor of the Department of Family Medicine, State Educational Institution of Higher Professional Education, First Moscow State Medical University named after. THEM. Sechenov Ministry of Health and Social Development, Doctor of Medical Sciences K.G. Serebrennikova Professor, Department of Obstetrics and Gynecology, Pediatric Faculty, State Budgetary Educational Institution of Higher Professional Education, Russian National Research Medical University named after. N.I. Pirogova, Doctor of Medical Sciences L.M. Kapusheva head Department of Pathological Physiology, Faculty of Dentistry, Moscow State Medical and Dental University, Doctor of Medical Sciences, Professor A.G. Rusanova

Lead organization:

State Healthcare Institution "Moscow Regional Research Institute of Obstetrics and Gynecology"

The defense will take place on February 21, 2012 at 11.00 am at a meeting of the dissertation council D212.203.01 at the Peoples' Friendship University of Russia at the address: 117333, Moscow, st. Fotieva, 6.

The dissertation work can be found in the Scientific Library of the Peoples' Friendship University of Russia (117198, Moscow, MiklukhoMaklaya St., 6).

Scientific secretary of the dissertation council, Doctor of Medical Sciences, Professor I.M. Ordiyants General characteristics of the dissertation

Relevance problems. Despite the centuries-long history of studying various aspects of the problem of endometriosis, this disease remains one of the central medical and social problems. Endometriosis ranks third in the structure of gynecological morbidity and affects more than 50% of women of reproductive age, negatively affecting the psycho-emotional state, reducing performance and reproductive function (Adamyan L.V., Kulakov V.I., 2006).

Over the past decade, there has been an increase in the incidence of endometriosis, as well as a “rejuvenation” of the patient population.

However, it is difficult to judge with any accuracy the prevalence of this disease, since there are no clear statistical data (Damirov M.M., 2010).

The variety of localizations of endometriosis has led to a large number of theories of its origin. However, none of them can fully explain the emergence and proliferation of endometrioid heterotopias.

There is no doubt about the multifactorial nature of endometriosis. The basis of many of these diseases is a violation of the molecular mechanisms of both the synthesis and especially the transport of regulatory proteins, which was the basis for awarding the Nobel Prize in Physiology or Medicine to L. Hartwell and P. Nurse in 2001.

In recent years, genital internal endometriosis of the uterine body (adenomyosis) is usually considered as a special disease, which differs significantly from external endometriosis in pathogenesis, epidemiology and clinical picture (Sidorova I.S., Kogan E.A., 2008;

Bergeron C. et al., 2006).

The specific frequency of adenomyosis in the structure of genital endometriosis reaches 70-90%. Based on clinical manifestations, the diagnosis of “adenomyosis” can be made at best in 50% of cases, in 75% of cases the diagnosis is not established, in 35% overdiagnosis is observed (Gavrilova T.Yu., 2007). This is due to the fact that the etiology and pathogenetic mechanisms responsible for the development of adenomyosis have not yet been studied in detail and a histopathological conclusion after removal of the uterus is required for correct diagnosis.

Recently, the ultrasound diagnostic method (ultrasound) has been widely used to diagnose adenomyosis, but data on its informativeness are contradictory, since the visual characteristics of endometriotic lesions are based on indirect echographic signs (Rizk, 2010).

Hysteroscopy is more informative in diagnosing adenomyosis compared to ultrasound, but this method is invasive, requires hospitalization and also does not provide a reliable diagnosis in 100% of cases (Bradley, 2009). Widespread in the West, office hysteroscopy has not yet gained great popularity in our country due to the high cost of the equipment.

Therefore, it is necessary to develop and introduce into practice new and informative methods for the early diagnosis of adenomyosis.

In recent years, to search for new markers of various diseases in blood serum, postgenomic methods of analysis are increasingly used, among which proteomic technologies occupy a leading position (GehoD.H., 2006; Belluco S., 2007; Leiser A. et al., 2007; Ilyina E.N., Govorun V.M., 2009).

Mass spectrometry is a method of analyzing a substance by determining the mass-to-charge ratio and the relative amount of ions produced by ionization and fragmentation of the substance under study. For the development of this method, John Fenn and Koichi Tanaka were awarded the Nobel Prize in Chemistry in 2002.

Time-of-flight MALDI mass spectrometry has a number of advantages over other options. This method has greater productivity and sensitivity (Baumann S., 2005; De Noo M.E., 2005; Alexandrov T. et al., 2010).

The literature describes examples of the successful use of this method to identify differences between the blood serum of patients with cancer of the stomach, rectum, prostate, endometrium, ovary, hepatocellular carcinoma and the blood serum of healthy people (De Noo M.E., 2006; Engwegen J.Y., 2006;

Liotta L.A., 2006; Ziganshin R.Kh. et al., 2008). At the same time, the information content of MALDI mass spectrometry in adenomyosis has not yet been studied.

The results of many years of clinical research on the problem of endometriosis allowed V.E. Radzinsky et al. (2005) conclude that the natural course of the disease at the initial stage is completely unpredictable. Particularly noteworthy is the authors' data that a progressive course of adenomyosis is detected in 2/3 of patients within a year from the moment of diagnosis. However, it is impossible to predict in which patients the pathological process will progress.

According to recent data, the effectiveness of treatment for adenomyosis is determined by the degree of its activity, the establishment of which, especially at the preoperative stage, is very difficult (Hunanyan A.L., 2006;

To date, the role of many cytokines and growth factors in the pathogenesis of endometriosis can be considered proven (Khan K.N. et al., 2005; Lee S. et al., 2007; Kim J.G. et al., 2008). At the same time, only a very small number of studies dealt with adenomyosis (Sidorova I.S., Unanyan A.L., 2006; Burlev V.A., 2006; Bergeron C., 2006; Yesayan N.G., 2007; Gavrilova T.Yu., 2007).

In recent years, the idea of ​​the role of the innate (nonspecific) immune system has changed. It was found that this system is activated not only in response to the introduction of infectious pathogens, but also during various endogenous destructive processes.

(Klyushnik T.P., 2007; Lehnardt S., 2010).

The activity of leukocyte elastase (LE) and 1-proteinase inhibitor (1-PI) in blood serum reflects the degree of activation of the innate immune system, as well as the state of the antiproteolytic (compensatory) potential.

As an illustration of the above, we can cite the work of L.V. Adamyan. et al. (2005), which demonstrated the dependence of the concentration of LE in the blood and peritoneal fluid on the extent of adenomyosis, which was determined morphologically, but the relationship with the clinical picture and the severity of adenomyosis was not studied.

Thus, a comprehensive determination of the above indicators of immunity makes it possible to identify the presence of a pathological destructive process in the body and clarify its severity, as well as the severity of the compensatory potential.

To summarize, it should be noted that, despite the large number of studies devoted to various aspects of adenomyosis, the etiology and pathogenesis of the disease have not yet been clarified, there are no clear diagnostic criteria and reliable non-invasive diagnostic methods, methods for determining the prognosis of adenomyosis. In this regard, it is of great interest to develop issues of the pathogenesis of the development of adenomyosis, modern criteria for diagnosing and predicting the course of this disease.

Purpose of the study To develop and implement a set of post-genomic research methods to improve the accuracy of diagnosis and prediction of the course of adenomyosis based on expanding knowledge about the molecular biological aspects of its pathogenesis.

Research objectives 1. Assess the information content of existing traditional methods for diagnosing adenomyosis.

2. Identify potential peptide markers of adenomyosis in blood serum and justify the possibility of their use for diagnosing this disease.

3. To compare potential peptide markers in blood serum in patients with various benign and malignant gynecological diseases as part of the differential diagnosis of adenomyosis.

4. Determine the role of growth factors and a number of cytokines in the occurrence and development of adenomyosis, as well as the relationship between their concentration in the blood serum and the degree of activity of adenomyosis.

5. Analyze the activity of Th1- and Th2-cells, which make up the bulk of the CD4+ population, in adenomyosis.

6. Determine the role of some components of nonspecific immunity (leukocyte elastase and 1-proteinase inhibitor) in the pathogenesis of adenomyosis, as well as the relationship between their concentration in the blood serum and the degree of activity of adenomyosis.

7. Assess the possibility of using cytokines, growth factors, and indicators of the nonspecific immune system in predicting and diagnosing adenomyosis, as well as determining the activity of its course.

8. Develop and justify an algorithm for examining women at risk of adenomyosis to determine the prognosis and/or early diagnosis of the disease.

Scientific novelty The understanding of the pathogenesis of adenomyosis and its features has been expanded, and clinical signs have been shown for different activity of the disease.

A comparative assessment of visual diagnostic methods (ultrasound, hysteroscopy) of adenomyosis is given.

For the first time, using proteomic profiling of blood serum using MALDI mass spectrometry, diagnostic markers of adenomyosis were determined, the possibility of differential diagnosis between adenomyosis and other gynecological diseases (uterine fibroids, endometrial hyperplasia, etc.) was proven. In new and expanded ideas about the pathogenesis of adenomyosis, the role of T- helper types 1 and 2, which make up the bulk of the CD4+ population and determine the type of immune response. It has been shown that Th1 cells that synthesize IF, TNF and IL-2 are not directly involved in the development of adenomyosis, while Th2 cells that synthesize IL-6 and IL-10 play a significant role in immune reactions in adenomyosis.

In addition, the role of pro- and anti-inflammatory cytokines, as well as growth factors in the pathogenesis of adenomyosis has been established. For the first time, a relationship has been identified between the level of these indicators in the blood serum and the degree of activity of the course of adenomyosis, which is important in predicting the disease, as well as choosing tactics for managing patients.

Based on a comprehensive study of innate immunity indicators in blood serum, their place in the diagnosis of the disease was determined and possible ways of correction were outlined. The significance of the degree of impairment of the proteolysis system in predicting the disease was determined.

Practical significance An algorithm for examination, prognosis, early diagnosis and management tactics for patients with adenomyosis has been developed, which makes it possible to reliably establish a diagnosis without the use of invasive diagnostic methods, as well as assess the degree of disease activity and determine further management tactics for patients.

The high value of a comprehensive examination of patients with adenomyosis (analysis of complaints, anamnesis, hormonal and immunological determinants) and modern innovative diagnostic methods, such as MALDI mass spectrometry, the study of cytokines, growth factors and innate immunity indicators, which allows determining the extent of the process and the prognosis of the disease, has been established. , choose the right treatment method.

The use of the proposed diagnostic algorithm is advisable not only from a clinical point of view, but also from an economic point of view, because allows you to reduce the costs of a medical institution due to faster and more reliable diagnostics. The blood serum used in this diagnostic method is a clinical sample that is convenient to obtain, store and transport from any remote area.

Provisions for defense 1. Traditional methods for diagnosing adenomyosis - clinical, ultrasound, hysteroscopy and their combinations do not achieve high sensitivity and specificity and, therefore, are not sufficient to verify the diagnosis, determine the degree of activity of the process and select the optimal tactics.

2. Changes in blood serum that occur during adenomyosis, determined by proteomic profiling using MALDI mass spectrometry, are informative in the differential diagnosis of adenomyosis and other benign and malignant gynecological diseases.

3. In the development of adenomyosis, an important role is played by disturbances in the system of cytokines (interleukins - 6 and 10), growth factors (vascular endothelial growth factor, epidermal growth factor), components of innate immunity (leukocyte elastase and 1-proteinase inhibitor). The reactions of Th1 cells are not associated with the pathogenesis of adenomyosis, while the activity of Th2 cells is of fundamental importance for the development of effective immunity in adenomyosis.

4. An increase in the content of cytokines, growth factors and leukocyte elastase in the blood serum correlates with the degree of adenomyosis activity; Based on the concentration values ​​of 1-proteinase inhibitor, one can draw conclusions about the degree of compensatory potential and determine the prognosis of the disease.

Approbation of dissertation material Materials and main provisions of the dissertation were reported and discussed at International Congresses: VI Regional Scientific Forum “Mother and Child” (Ekaterinburg, 2010), XI All-Russian Scientific Forum “Mother and Child” (Moscow, 2010), V Congress of the International Association of Reproductive Medicine Medicine (Moscow, 2010), XIII World Congress “Issues of Obstetrics, Gynecology and Infertility” (Germany, Berlin, 2010), XI World Congress on Endometriosis (France, Montpellier, 2011), All-Russian Conference with international participation on gynecological endocrinology and menopause ( Moscow, 2011).

The dissertation was discussed at a joint scientific conference of the staff of the Department of Obstetrics and Gynecology with the course of perinatology of the Faculty of Medicine of the Russian Peoples' Friendship University and practical doctors of the City Clinical Hospital No. 29 of Moscow on September 15, 2011.

Implementation of the results of the work The developed system for diagnosing adenomyosis and the results of the work are used in the materials of seminars, lectures, and in practical classes to improve the qualifications of obstetrician-gynecologists of the Federal State Budgetary Educational Institution of Higher Professional Education RUDN University.

Structure and scope of the dissertation The dissertation is presented on 181 pages of typewritten text and consists of an introduction, 5 chapters, conclusions, practical recommendations and a bibliography. The bibliography includes 334 literature sources (150 domestic and 184 foreign). The work is illustrated with 17 tables and 21 figures.

The control group consisted of 50 patients of reproductive and premenopausal age without adenomyosis, who underwent hysterectomy followed by pathological examination of the uterine body for genital prolapse.

To increase the specificity of the study, patients with adenomyosis in combination with uterine fibroids and endometrial hyperplasia were excluded from the study. These diseases are often combined, therefore, in order to identify the true aspects of the pathogenesis of adenomyosis, as well as for the purpose of differential diagnosis of benign diseases of the uterine body, it was decided to study patients with adenomyosis without concomitant gynecological pathology.

The study was conducted on materials from the gynecological departments of City Clinical Hospital No. 64, City Clinical Hospital No. 29, City Clinical Hospital No. 12, National Medical Clinical Hospital named after. N.I. Pirogov Roszdrav, outpatient department of the Federal State Institution Research Institute of Physics and Chemistry of the Federal Medical and Biological Agency of Russia, Russian Cancer Research Center named after. N.N.

Blokhin RAMS of Russia.

In the main group, adenomyosis was diagnosed clinically using additional examination methods. Diagnosis of the degree of spread was carried out on the basis of vaginal examination data (dynamics of size, shape, consistency of the uterus during the cycle), hysteroscopic, ultrasound criteria and pathomorphological examination data.

36 (30%) of 120 patients with adenomyosis underwent radical surgical treatment - removal of the uterus. In this group of patients, blood serum was taken again on average 6 months after surgical treatment and further studies were carried out.

When conducting proteomic profiling of blood sera, we used the accumulated collection of blood sera and a database of patients with uterine fibroids (n=60), endometrial hyperplastic processes (n=50), uterine cancer (n=50) and ovarian cancer (n=60) , stored in the proteomics laboratory of the Institute of Bioorganic Chemistry named after.

M.M.Shemyakin and Yu.A.Ovchinnikov RAS.

In connection with the identified differences and features in the clinical course and molecular biological processes, in our work we used the terms “active” and “inactive” adenomyosis, reflecting the degree of clinical and morphological activity of the endometrioid process (Sidorova I.S., Unanyan A.L. , 2006).

Depending on the severity of the main clinical manifestations characteristic of adenomyosis, all studied patients with adenomyosis (n=120) were conditionally divided into 2 clinical groups: group I consisted of 76 patients with clinically “active” adenomyosis; Group II – 44 patients with clinically “inactive” adenomyosis. Group III consisted of 50 patients without adenomyosis (control).

To determine the forms of clinical activity, the most common clinical manifestations of adenomyosis were assessed - pain syndrome and hyperpolymenorrhea.

The degree of pain was assessed using the method proposed by MacLaverty C.M., Shaw P.W. (1995) system for determining the severity of pain and dysmenorrhea, according to which the intensity of pain was determined in points: 1-3 points - mild pain; 4-6 – moderate pain; 7-9 – strong.

It is well known that the presence of adenomyosis is often accompanied by uterine bleeding, often causing anemia in patients. In this regard, hyper- and polymenorrhea were distinguished without anemia and with anemia. Based on the severity, anemia was classified into mild (Hb 90-110g/l), moderate (Hb 70-90g/l) and severe (Hb - below 70g/l).

Patients with moderate and severe pain and patients with hyperpolymenorrhea in combination with moderate and severe anemia were classified into group I of patients with clinically active manifestations of the disease. Patients with mild pain, absence of anemia or hyperpolymenorrhea in combination with mild anemia were assigned to group II of patients with a clinically inactive course of adenomyosis.

In accordance with the set goals and objectives, a patient examination program was developed, providing for a comprehensive examination of the health status, including traditional and special innovative examination methods (Fig. 1).

The analysis of case histories was carried out using a statistical map developed by us. An individual card was compiled for each patient, which contained more than 200 parameters. The study of anamnestic data was based on clarifying family predisposition to gynecological and other diseases.

Close attention was paid to diseases suffered at different periods of life (childhood infections, somatic, gynecological diseases), their course, and outcome. Surgical interventions were recorded with specification of the time of their implementation.

TRADITIONAL METHODS SPECIAL METHODS OF DIAGNOSTICS Proteomic profiling of blood serum with Complaints, anamnesis data, using MALDI mass gynecological examination spectrometry Determination of cytokines and growth factors in serum Ultrasound of the pelvic organs of blood using an enzyme immunoassay Determination of innate immunity indicators in Hysteroscopy of blood serum using the spectrophotometric method Pathomorphological study STATISTICAL PROCESSING Fig. 1. Research methods.

A special place was given to the study of the specific functions of the female body. The analysis of menstrual function included, in addition to establishing the age of menarche, the study of its nature, regularity and duration of the menstrual cycle. Sexual life: at what age did it start, what kind of marriage? Reproductive function was assessed by the number of pregnancies, course, outcome for the mother and fetus. Attention was paid to the analysis of the number and characteristics of the course of labor, the frequency of complications, and the use of surgical interventions.

The course of the present disease was studied based on the time of its discovery, the dynamics of development, previous treatment and its effectiveness, and the state of function of adjacent organs.

During the clinical examination, a general examination was carried out, an assessment of the physique and constitutional features, the condition of the mammary glands, cardiovascular, respiratory, urinary, digestive, and endocrine systems.

Gynecological status was determined based on examination of the external genitalia, examination of the vagina and cervix using speculum, bimanual vaginal examination, and, if indicated, rectovaginal examination.

Laboratory research methods were used as routine (clinical blood test, general urine test, determination of blood group and Rh, analysis of biochemical parameters and hemostasiogram reflecting liver and kidney function, blood glucose, Wasserman test, test for HIV infection and HBS- antigen, electrocardiography, radiography of the chest organs, bacterioscopic examination of vaginal discharge), and modern highly informative visualization methods - ultrasound transabdominal and transvaginal scanning of the pelvic organs using Echoview 80 L Di and Aloka SSD - 636 and 650 devices, hysteroscopy using rigid hysteroscopes Hamou I (30°) and Hopkins II (30°) (Karl Storz GmbH & C0., Germany) with an outer diameter of 5 mm.

For this work, blood serum was required, obtained according to a standard method, which was poured into 6 Eppendorf tubes of 1 ml each and stored at -20C for a maximum of 1 month until transported in a refrigerator to the laboratory, where storage continued at -70C.

Proteomic profiling of blood serum was carried out by researchers from the proteomics laboratory of the Institute of Bioorganic Chemistry named after.

M.M. Shemyakin and Yu.A. Ovchinnikov of the Russian Academy of Sciences (head – Prof. V.M. Govorun).

To fractionate blood serum samples, we used profiling kits containing magnetic microparticles with a functionalized surface MB-HIC 8, MB-HIC 18, MB-WCX and MB-IMAC Cu produced by Bruker Daltonics (Germany). A description of these profiling kits, as well as their recommended fractionation protocols, can be found on the company's website - www.bdal.de.

Blood serum fractionation was carried out using a specialized ClinProt robot (Bruker Daltonics, Germany), according to the protocol recommended by the manufacturer of magnetic microparticles, with minor modifications. Mass spectra were obtained using an Ultraflex time-of-flight mass spectrometer (Bruker Daltonics, Germany).

After profiling the blood sera using the resulting mass spectral arrays, the combination of peaks that best distinguished the spectra of the pathology samples from the control was determined.

Mass spectrometric data were analyzed using a Genetic Algorithm (GA) and a Controlled Neural Network (CNN), as well as the computer program ClinProTools 2.1 (Bruker Daltonics, Germany) (Hammer B. et al., 2005).

Determination of growth factors and other cytokines in blood serum using enzyme-linked immunosorbent assay was carried out at the Department of Clinical and Experimental Immunology of City Clinical Hospital No. 29 named after.

N.E. Bauman, Moscow (head – corresponding member of the Russian Academy of Medical Sciences, Prof. S.G. Morozov).

In this work, the concentration of cytokines was determined - IL-6, IL-10, IL-8, IL-1, IL-2, TNF, IF using diagnostic test systems of JSC Vector-Best (Russia). Growth factors - EGF, VEGF - were determined using BioSource International test systems.

The determination of innate immunity parameters was carried out in the laboratory of clinical biochemistry of the Scientific Center for Mental Health of the Russian Academy of Medical Sciences (headed by Prof. T.P. Klyushnik).

To determine the activity of LE present in the blood serum in combination with 1-PI, a spectrophotometric method was used using a set of reagents for quantitative determination of the activity of leukocyte elastase in blood serum (ELASTASE) (Biofarm-test LLC, Moscow) and a set of reagents for quantitative determination of the activity of 1-proteinase inhibitor in human serum (ALFA-1-PI) (Biopharm-test LLC, Moscow) in accordance with the Instructions for use of these kits.

Statistical analysis of the data was carried out jointly with an employee of the Department of Medical Cybernetics and Informatics of the State Budgetary Educational Institution of Higher Professional Education RNRMU named after.

N.I.Pirogov Ministry of Health and Social Development of Russia Leading Researcher Olimpeva S.P. using a personal computer program developed at the department, which allows for comparison of groups of data organized by the user using the Student's t-test (T-criterion) and a statistical non-parametric criterion - Fisher's exact method, which does not depend on the nature of the distribution of the indicator.

After comparing the groups for each feature separately, the information content of the complete feature space is assessed to distinguish all user-specified groups. To obtain such an assessment, a sliding examination of the correctness of the automatic assignment of each individual to one of the compared groups is carried out using a sequential Baysen recognition procedure.

EXCEL 2003 and STATISTICA 6.0.

Research results and their discussion In this study, based on an analysis of the results of examination and treatment of 120 patients with adenomyosis and 50 patients without adenomyosis, data on the pathogenesis, features of the clinical course and diagnosis of this disease are summarized.

In our observations, the age of patients with adenomyosis varied widely - 26-50 years, averaging 39.5 ± 5.7 years: in the group of patients with “active” adenomyosis, the average age was 40.8 ± 5.2 years, in the group patients with “inactive” adenomyosis – 38.2±4.7 years, without significant differences between groups, which confirms the data that in recent years adenomyosis is more common at a younger age (Safe G.M. et al, 2011; Zhou R. et al, 2011).

According to a number of authors, the age at menarche is not decisive for adenomyosis (Gavrilova T.Yu., 2007). In our study, the age of menarche was 11.7±1.4 years (no significant relationship was found between the age of menarche and the activity of adenomyosis), which does not differ significantly from population data (12.2±1.54 years). Not all researchers agree with this point of view, considering late onset of menarche a risk factor for the development of adenomyosis. At the same time, according to A.I. Ishchenko and E.A. Kudrina (2008), rather early menarche with a shortened cycle, long and heavy menstruation and, consequently, greater exposure of the uterine cavity and pelvis to retrograde menstrual blood is a factor risk of endometriosis of any location.

In our study, menstrual irregularities were observed in 92.5% of patients. Thus, dysmenorrhea (100%), hyperpolymenorrhea (73.7%) and spotting perimenstrual bleeding (93.4%) were significantly more often recorded in the group of patients with “active” adenomyosis (p

Hypermenorrhea was observed with almost the same frequency in both groups (26.3% and 22.7%). These data indicate the inferiority of the mechanisms regulating the menstrual cycle, primarily the hypothalamic-pituitary-ovarian system.

Our opinion coincides with the data of a number of authors that the volume and duration of menstruation may be a predisposing factor for the implantation of endometrioid cells, however, factors such as hereditary predisposition and disorders of general and local immunity have priority in the development of adenomyosis (Adamyan L.V., Kulakov V.I., 2006; Di W. et al., 2007; Zhao Z.Z. et al. The high degree of burden of reproductive history in patients with adenomyosis deserves attention, especially in the group with “active” adenomyosis (p

In the patients we examined, there was a high frequency of chronic salpingoophoritis and endometritis in the anamnesis - 51.6%; In the population, the average frequency of these diseases is 37.2%.

The findings support the view that intrauterine interventions are risk factors for the development of adenomyosis. A number of authors believe that favorable conditions for invasion and growth of endometrial cells in the myometrium are created by neurodystrophic changes in the histobiological barrier zone, resulting from dimolytic and desmoplastic processes in the mucous membrane, connective and muscle tissue, often resulting from inflammation (Lucidi R.S. et al. , 2005; Bergeron C. et al., 2006;

Ishchenko A.I., Kudrina I.A., 2008).

The incidence of infertility in patients with endometriosis ranges from 25 to 60%.

Endometriosis ranks second among the causes of infertility after inflammatory diseases of the pelvic organs (Klemmt P.A. et al., 2006;

Adamyan L.V., Kogan E.A., 2010; Selkov S.A., Yarmolinskaya M.I., 2011;

Boguslavskaya D.V., Lebovic D.I., 2011). According to our data, infertility was detected in 47.5% of patients with adenomyosis and significantly more often with “active” adenomyosis (p

When studying the family history, it was found that 45% of the patients had a family history of diseases of the genital organs, fibrocystic mastopathy (30.8%), tumors of extragenital localization (18.3%), endocrinopathies - thyroid diseases, diabetes mellitus, obesity ( 28.3%).

A study of the premorbid background with special attention to morbidity in childhood, past and current concomitant diseases revealed that the health index of the examined patients with adenomyosis was significantly low.

When studying anamnesis data, it was found that patients with adenomyosis suffered a number of infectious diseases in childhood - 89 (74.2%) cases versus 14 (28%) in the control group (p

Chronic somatic diseases are also of great importance in the genesis of adenomyosis. As follows from the analysis of clinical anamnestic data, patients with adenomyosis have a significant incidence of chronic diseases. Thus, metabolic and endocrine disorders in patients with adenomyosis were most common - in 23.3% of cases, in second place were diseases of the gastrointestinal tract - 20%; further – chronic respiratory diseases (17.5%), cardiovascular diseases (12.5%), pathology of the urinary system was observed in the anamnesis in 9.2% of patients.

22.5% of patients had allergic reactions to medications and various household factors, which may indirectly indicate disturbances in immune homeostasis.

Some patients had several of the above diseases. Depending on the degree of activity of adenomyosis, the number of patients with identified extragenital pathology increased, amounting to 34.1% with “inactive” adenomyosis and 51.3% with “active” adenomyosis.

Analysis of our own results of the clinical course of adenomyosis in patients did not confirm significant differences in age, time of menarche, number of births and heredity depending on the degree of activity of adenomyosis (p>0.05).

Significant differences in the two groups of patients with “active” and “inactive” adenomyosis were characterized by a burdened gynecological and somatic anamnesis, which was manifested by a lower health index of patients with “active” adenomyosis.

Thus, inflammatory processes in the genital organs and surgical interventions on the uterus are of great importance in the pathogenesis of adenomyosis. This is confirmed by studies showing that pregnancy often has an inhibitory effect on endometriotic lesions, and abortions and complicated childbirth worsen the course of adenomyosis (Purandare C.N., 2006; Melin A. et al., 2007).

In addition, a high infectious index and concomitant extragenital diseases are also characteristic features of adenomyosis. It is possible that these diseases do not directly affect the development of adenomyosis, but a decrease in the body’s resistance to environmental factors is a background to the formation of persistent metabolic disorders and a weakening of the immune system. These changes are not specific, since according to a number of authors, similar features of morbidity and infectious index are found in patients with uterine fibroids, endometrial hyperplasia, etc. (Brinton D.A. et al., 2005; Guriev T.D., 2005; Graesslin O. et al., 2006).

The proposed modern concept of the pathogenesis of hormone-dependent diseases of the reproductive system of women considers such processes from the point of view of local and general morphofunctional and endocrine disorders and the appearance of a “vicious circle” in the hypothalamic-pituitary-ovarian system against the background of immunodeficiency (Adamyan L.V., Kulakov V.I., 2006 ; Ishchenko A.I., Kudrina I.A., 2008).

Analysis of the duration of the disease with adenomyosis, depending on the moment of initial clinical manifestations before the first hospitalization, revealed that with “active” adenomyosis, the duration of this period in more than 50% of patients was 1-3 years, and with “inactive” adenomyosis - 4-8 years, that is, “active” adenomyosis is characterized by a shorter duration of the disease from the moment of the first symptoms to hospitalization and, accordingly, rapid progression of the process.

Our results, based on a comparison of the clinical picture of adenomyosis with the data of a pathomorphological study, are consistent with the data of other authors and confirm that pathognomonic manifestations of adenomyosis are characteristic of stages 2-4 of the diffuse form, as well as the nodular form. Diffuse adenomyosis stage 1 is not characterized by the presence of typical clinical manifestations (dysmenorrhea, hyperpolymenorrhea, etc.), however, it can be combined with infertility I or II and, possibly, be its cause (Gavrilova T.Yu., 2007; Batt R.E., 2011; Exacoustos C., 2011).

According to a number of authors, the clinical diagnosis of “adenomyosis” coincides with the histological one only in 25-65% of cases; There is both over- and underdiagnosis of adenomyosis, which determines erroneous management tactics and prognosis (Ballard K.D., 2008; Benagiano G., Carrara S., 2009; Damirov M.M., 2010).

As a result of the analysis of preliminary diagnoses at the prehospital stage in patients with adenomyosis, their significant heterogeneity was revealed. Thus, out of 120 patients, in 49% this diagnosis was made correctly, in 18% adenomyosis was mistaken for uterine fibroids, in 11% for endometrial hyperplasia and polyps, in 7% for dysfunctional uterine bleeding; in 3% - for ovarian cystadenoma. 9% of patients were examined and treated for a long time by a neurologist, gastroenterologist, or general practitioner with suspected disc herniation, osteochondrosis, colitis, adhesions, etc.

Thus, based on clinical and anamnestic data and the results of a gynecological examination, adenomyosis was suspected in patients, of which it was confirmed in 56 cases. The rate of false positive results was 41%. At the same time, out of 120 patients with confirmed adenomyosis, this pathology was included in the clinical diagnosis in 62.

Thus, the rate of false negative results was 48%.

The sensitivity of the method is 51.7%, specificity is 59%.

Recently, ultrasound has taken a leading place in the primary diagnosis of adenomyosis. To diagnose adenomyosis, in all 120 patients, along with bimanual and rectovaginal examination, ultrasound of the pelvic organs and hysteroscopy were performed.

Ultrasound examination was performed on all patients admitted to the hospital. Characteristic ultrasound signs of diffuse adenomyosis were: unevenness of the border of the basal layer of the endometrium (in 70%);

the predominance of the thickness of the posterior wall of the uterus over the anterior one by 15% or more (in 65%); the presence of heterogeneous echogenicity of the myometrium (61%); the presence of cystic dilated cavities in the myometrium containing fine suspension (in 45%).

In nodular adenomyosis, the ultrasound picture was characterized by the presence in the myometrium of endometrial echodensity foci of a round, oval or lumpy shape without a pronounced capsule, which in 68% of cases was regarded as uterine fibroids.

The round shape of the uterus, an increase in its anteroposterior size and the appearance in the myometrium on the eve of menstruation of abnormal cystic cavities with an average diameter of 3-5 mm do not always indicate the presence of adenomyosis.

According to our data, the specificity of ultrasound in the diagnosis of adenomyosis was 68.2%, sensitivity – 70%. The main reason for false-negative results was hyperplastic processes of the endometrium, uterine fibroids, which practically does not differ from the results of other authors (Strizhakov A.N., Davydov A.I., 2006; Bazot M. et al., 2006; Atri M. et al. , 2007; Wolfman D. J., 2011).

The accuracy of diagnosing adenomyosis using transvaginal ultrasound, according to M.M. Damirov et al. (2010), Reuter K.L. (2011) does not exceed 62-86%.

Another research method most often used to diagnose adenomyosis is hysteroscopy. During diagnostic hysteroscopy, signs of adenomyosis were found in (75%) patients, namely: endometrioid tracts in the form of “eyes” of a dark bluish color or open, bleeding tracts (in 65%); uneven relief of the walls of the uterine cavity in the form of longitudinal or transverse ridges, disintegrated muscle fibers (in 75%); bulging of the walls of the uterine cavity of various sizes without clear contours with endometrioid ducts (in 35%).

The lack of information content of hysteroscopy is associated with a combination of adenomyosis and endometrial hyperplasia, the presence of nodular adenomyosis, and also with the fact that some of the manipulations are performed against the background of uterine bleeding.

Hysteroscopy after curettage of the walls of the uterine cavity is not informative due to the development of edema and imbibition of the basal layer of the endometrium with blood (Reuter K.L., 2011; Valentini A.L., 2011).

According to our data, the specificity of hysteroscopy in the diagnosis of adenomyosis was 81.2%, sensitivity – 75%, which also practically does not differ from the results of other authors (Mechcatie E., 2008; Indman P.D., 2010; Resad P.P. et al., 2010).

Despite the fairly high accuracy of hysteroscopy in diagnosing adenomyosis, this method is invasive, requiring hospitalization, general anesthesia and is a surgical intervention, which can be accompanied by both surgical (uterine perforation, embolism) and anesthetic complications, and also contribute to the progression of adenomyosis (Baggish M.S. et al., 2007; Van Kruchten P.M. et al., 2010;

The above limits the use of hysteroscopy for diagnosing adenomyosis and makes it urgent to search for new non-invasive methods that are not inferior in accuracy to hysteroscopy.

Thus, according to our data, based on clinical and instrumental research methods, 21% of patients have an underdiagnosis of adenomyosis, while at the same time, in those cases where adenomyosis was suspected, there was an overdiagnosis of this pathology (15% of diagnostic errors).

In this regard, the search for reliable markers of adenomyosis remains an urgent problem.

Recently, both abroad and in our country, efforts have been made to create minimally invasive screening methods for diagnosing adenomyosis and determining the degree of its activity.

To search for new markers of various diseases in blood serum, postgenomic analysis methods are increasingly used, among which proteomic technologies occupy a leading position (Liu H. et al., 2008; Leiser A. et al., 2007).

Based on mass spectrometric profiling (1 blood sera from patients with adenomyosis and 50 healthy women in the control group) after their fractionation on magnetic microparticles with a weak cation exchange surface (MB-WCX), classification models were built using two mathematical algorithms (GA and ONS).

With the parameters used for processing the mass spectra, 96 peaks were reproducibly detected. After studying the contribution of individual peak areas to classification models, 3 peaks were identified as the most significant for diagnosis, because their combination in classification models gives high values ​​of specificity and sensitivity:

specificity – 100%, sensitivity – 95.8%.

Rice. 2. Final analysis of mass spectrometric profiles of blood serum samples from the “adenomyosis” and “control” groups.

As can be seen in Fig. 2, the constructed classification model included 3 mass spectrometric peaks, selected by a computer program as the most significant, with m/z values: 1589; 2671; 4333, which differ significantly in the “adenomyosis” and “control” groups.

When analyzing the blood serum of 36 patients with adenomyosis from group I after surgical treatment (removal of the uterus) after an average of 6 months, no such peaks were found and, in accordance with the classification models created, these patients were assigned to the control group, which confirms the specificity of these peaks specifically for adenomyosis .

In addition to comparing mass spectrometric profiles of patients with adenomyosis and healthy women from the control group, data from patients with the following diagnoses were compared: uterine fibroids (n=60), endometrial hyperplasia (n=50), ovarian cancer stages I-IV (n=60 ), uterine cancer (n=50).

The results of profiling patients with endometrial hyperplasia turned out to be unsatisfactory, showing sensitivity and specificity values ​​of less than 50%, which cannot be used in diagnosis.

When checking the specificity of the constructed model in relation to mass spectrometric profiles of blood serum samples from patients with uterine fibroids, uterine cancer and ovarian cancer, the following values ​​were obtained:

93.8%, 90.5%, 100%, respectively (Table 1).

Table Specificity values ​​of the “adenomyosis” model in relation to mass spectrometric profiles of blood serum samples from patients with other gynecological diseases.

Diseases Specificity of the “adenomyosis” model, % Uterine fibroids (n=60) 93, Uterine cancer (n=50) 90, Ovarian cancer (n=60) 1HPE (n=50)

There is no clear answer to the question of the relationship between the changes in peptide-protein patterns recorded in blood serum and the pathological process being studied in the body. It is assumed that these changes may reflect real fluctuations in the concentrations of proteins and peptides directly associated with the disease, but on the other hand, the possibility of their occurrence cannot be excluded, for example, as a result of pathology-induced deviations in the processes of blood coagulation ex vivo when serum is obtained from it ( Polanski M. et al., 2006; Liotta L.A. et al., 2006;

From our point of view, the diagnostic value of the found signatures does not depend on the nature of their occurrence, provided that their appearance in the blood serum of patients is strictly reproducible. It was previously shown that the procedure for obtaining serum, namely the duration of the time delay before the separation of the serum from the formed clot during blood coagulation does not affect its mass spectrometric profile (Ziganshin R.Kh. et al., 2008).

However, this diagnostic method only allows one to differentiate one disease from another; It is not possible to determine the degree of activity using mass spectrometry. At the same time, according to a number of authors, the effectiveness of conservative treatment of adenomyosis depends on the degree of its activity, the determination of which at the preoperative stage is very difficult (Izawa M. et al., 2006; Surrey E.S. et al., 2007; Radzinsky V.E. ., Khamoshina M.B., 2009; Adamyan L.V., Sonova M.M., 2009).

Current methods for determining the functional activity of adenomyosis are mainly based on the severity of one or another clinical symptomatology, or on the effectiveness of treatment, which is largely subjective and does not allow identifying the early stages of the disease (Tomina O.V., 2011).

The diagnostic significance of assessing the level of cytokine concentration lies in stating the very fact of its increase or decrease in a given patient with a specific disease, and to assess the severity and prognosis of the course of the disease, it is advisable to determine the concentration of both pro-inflammatory (IL-1, IL-2, IL-6, IL- 8, TNF, IF) and anti-inflammatory (IL-10) cytokines over time. It can be assumed that a change in the ratio of pro- and anti-inflammatory cytokines creates favorable conditions for invasion and subsequent growth of viable endometrial fragments.

Considering the literature data that in various pathological conditions there is activation of cytokines, growth factors and the proteolysis system, in our study we paid great attention to this issue (Girling G.E. et al., 2005; Ulukus E.S. et al., 2005;

Yang J.N. et al., 2006; Inagaki M. et al., 2007; Gentilini D. et al., 2008).

In the study of cytokines, growth factors and the proteolysis system, we identified features of the distribution of their values ​​in patients with adenomyosis, and also assessed the dependence of the type of distribution on the degree of activity of adenomyosis, which made it possible to predict the course of the disease.

Our study found that with clinically active adenomyosis, the production of pro-inflammatory cytokines (IL-6), anti-inflammatory cytokines (IL-10), growth factors EGF, VEGF, i.e. the processes of proliferation and neoangiogenesis are activated.

An enzyme-linked immunosorbent assay of cytokines (IL-6, IL-10, IL-8, IL-1, IL-2, TNF, IF) and growth factors (EGF, VEGF) revealed the relationship between the degree of adenomyosis activity and the concentration of IL-6 , IL-10, EGF, VEGF in blood serum.

At the same time, there was no significant increase in the concentrations of IL-8, IL-1, IL-2, TNF, and IF in patients with adenomyosis and in the control group.

Yang J.N. et al., 2006; Bangura A.V., 2006). At the same time, conflicting data were obtained when studying the cytokine profile in patients with endometrial hyperplasia (Zhdanov A.V., Sukhikh G.T., 2003; Kisilev V.I., Lyashchenko A.A., 2005).

It is possible that it is the combination of several pathological processes (including benign diseases of the uterus - fibroids, endometrial hyperplasia, adenomyosis) with the predominance of one of them, based on competitive interactions, that can cause one or another reaction of the immune system. According to L.V. Adamyan et al. (2007) the most significant disturbances in the content of IL-8, TNF, IF were recorded with a combination of uterine fibroids and endometrial hyperplasia.

In the literature available to us, no data were found on the cytokine profile in patients with isolated adenomyosis, in the absence of other benign diseases of the uterus. All studies concerning adenomyosis were carried out in patients with a combination of this pathology and uterine fibroids, endometrial hyperplastic processes, etc.

Perhaps this explains our results - the absence of changes in the concentrations of IL-8, IL-1, IL-2, TNF, IF in the blood serum in patients with isolated adenomyosis.

The obtained results of the study of certain aspects of the pathogenesis of isolated adenomyosis seem important for expanding the understanding of the pathogenesis of this disease and its features.

It has been established that there are two populations of CD4+ Tx cells that differ in the set of cytokines they synthesize, and which of the two main types of immune response will be realized depends on this profile.

In humans, Th1 cells typically produce IF, TNF, IL-2 and participate in cell-mediated inflammatory reactions. In contrast to Th1 cells, Th2 cells synthesize IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13 and enhance the formation of antibodies, especially IgE. As a result, they stimulate hyperproduction of antibodies and allergic reactions.

Our results from studying the cytokine profile in patients with adenomyosis allow us to conclude that Th1 cells producing IF, TNF and IL-2 are not directly involved in the pathogenesis of adenomyosis, while Th2 cells synthesizing IL-6 and IL -10 play a significant role in the development of immune reactions in adenomyosis. Most likely, they play a major protective role in the body against this pathology.

According to the results of our study, the average concentrations in the blood serum of cytokines - IL-6 and IL-10, as well as growth factors - EGF, VEGF in both groups of patients with “active” and “inactive” adenomyosis turned out to be significantly higher (p

The average values ​​of IL-6, IL-10, EGF, VEGF in patients with “active” adenomyosis were significantly higher compared to patients with “inactive” adenomyosis (p

When analyzing the content of IL-6, IL-10, VEGF and EGF in the blood serum of 36 patients with adenomyosis 6 months after removal of the uterus, in (80.6%) patients these indicators did not exceed the normative values, which indicates the role of these cytokines in the pathogenesis of adenomyosis.

Based on the results of the distributions of immunological parameters, threshold values ​​for each of them were determined. The statistical analysis made it possible to reliably distinguish between two groups with “active” and “inactive” adenomyosis.

Immunological indicators above threshold concentrations predominate in patients with “active” adenomyosis, and below threshold concentrations are significantly more common in patients with “inactive” adenomyosis, which is statistically significant (p

The proportion of patients with a serum level of IL-6 greater than 300 pkg/ml was 80% in the group with “active” adenomyosis, and with a level less than 3 pkg/ml - 87.1% in the group with “inactive” adenomyosis.

Table Average values ​​of the studied parameters in groups of patients with “active” adenomyosis (group I), with “inactive” adenomyosis (group II) and in the control group (group III), pg/ml.

Groups IL-6 IL-10 VEGF EGF patients group I (n=76) 376.2 ± 11.43 331.6 ± 10.23 417.4 ± 21.46 225.2 ± 5, group II 228.4 ± 7.22 181.3 ± 7.71 240.3 ± 8.94 175.1 ± 4, (n=44) 35.08 ± 2.34 40.39 ± 2, group III 69.72 ±3.01 66.54 ± 3,(n=50) Significance 1-2.3 *** 2-3 *** differences (p) Notes: *** indicate the significance level p

The proportion of patients with a serum level of IL-10 greater than 250 pkg/ml was 82.5% in the group with “active” adenomyosis, and with a level less than 2 pkg/ml - 84.8% in the group with “inactive” adenomyosis.

The proportion of patients with a VEGF level in the blood serum of more than 300 pg/ml was 84.4% in the group with “active” adenomyosis, and with a level of less than 300 pg/ml - 80.8% in the group with “inactive” adenomyosis.

The proportion of patients with a serum EGF level greater than 200 pkg/ml was 81.0% in the group with “active” adenomyosis, and with a level less than 2 pkg/ml - 84.3% in the group with “inactive” adenomyosis.

The results obtained indicate that the selected ranges of immunological parameters are highly informative and can be considered as risk factors for the “activity” of adenomyosis.

It should be noted that the sensitivity of the immunological indicators being studied is already quite high for each of the parameters and is in the range of 80%-84.4% (specificity is in the range of 80.8%-87.1%), however, a complex of such indicators may be more informative than each of the indicators separately.

Taking into account the words of one of the founders of the domestic doctrine of endometriosis - Professor V.P. Baskakov - “only patients with clinically active adenomyosis need to be treated, and the use of hormonal drugs in patients with mild clinical activity and in the initial stages of the disease can, on the contrary, contribute to progression adenomyosis", determining the degree of activity is considered an important step in choosing tactics for managing patients with adenomyosis.

The diagnostic rule developed in this study, using growth factors and other cytokines, has a high diagnostic accuracy of 86%.

Thus, analysis of the information content of the studied indicators, determined in groups of patients with “active” and “inactive” forms of adenomyosis, indicates that the values ​​of IL-6, IL-10, EGF, VEGF exceeding the threshold values ​​(300 pkg/ml, 250 pkg/ml, 300 pkg/ml and 2 pkg/ml, respectively) can be used as risk factors for the progression of adenomyosis. These results confirm the feasibility of measuring the concentrations of IL-6, IL-10, EGF, VEGF in the blood plasma and the use of the resulting diagnostic approach for a more reliable diagnosis of the clinical activity of adenomyosis, which will justify the need for therapy at the present time.

The results obtained can become an important differential diagnostic criterion for assessing the extent of prevalence and activity of adenomyosis. According to a number of authors, the use of antiangiogenic drugs currently used in cancer patients will make it possible to most effectively influence the pathological process in adenomyosis. This direction can be very promising in the creation of a new generation of drugs that block angiogenesis and are free from a large number of side effects that exist today (Burlev V.A. et al., 2006).

Activation of innate immunity occurs when TOLL-like receptors (monocytes, macrophages, microglia) interact with their ligands. In most cases, these ligands are pathogens, but some TOLL receptors (subtypes 2, 4) interact with endogenous ligands during various destruction in organs and tissues (Klyushnik T.P., 2010).

Therefore, there is reason to believe that with adenomyosis, nonspecific immunity is also activated through TOLL receptors in response to destruction in the myometrium (Hirata T., 2005).

One of the proteolytic enzymes secreted by neutrophils during the development of a nonspecific immune response is LE. Once in the extracellular space, LE breaks down the ground substance, elastin and collagen fibers of the vascular basement membranes, acting in some cases as a powerful destructive factor. By destroying the extracellular matrix and elastase of the vascular endothelium, LE can promote the migration and transformation of various cells, activation of angiogenesis and metastasis.

High specific activity of LE was found in all patients with adenomyosis, while in patients with “active” adenomyosis the level of LE exceeded the normative values ​​and was significantly higher than in patients with “inactive” adenomyosis: 329.4 ± 5.71 nmol/(minml) and 251 .2±5.nmol/(minml) (p

In the control group, LE activity did not exceed the norm and averaged 178.1±2.59 nmol/(minml) – Fig. 3.

In the absence of pathology, LE activity does not exceed the normal limit.

This may serve as confirmation of the absence of certain pathological conditions associated with inflammatory or destructive reactions, including adenomyosis.

Normally, the activity of LE is 150-200 nmol/(minml) - in accordance with the instructions for this set of reagents. An activity range of 201-250 nmol/(minml) is interpreted as a mild increase, and a range of 251-300 nmol/(minml) as a moderate increase. An increase in LE activity above 300 nmol/(minml) is considered to be a pronounced sign of pathology.

In patients with a slight increase in LE activity, it is possible to assume the presence in the blood (in low concentrations) of factors that cause activation of neutrophils. Such weak activation of nonspecific immunity indicates the presence of inflammatory and/or destructive reactions. This is typical for patients at the initial stage of adenomyosis, which occurs without pronounced clinical symptoms.

With a moderate increase in LE activity, there is a more significant activation of nonspecific immunity, which confirms the presence of a process associated with local inflammatory reactions. The localization of this process can be established with a more thorough clinical examination of the patient and additional biochemical tests.

A weak to moderate increase in LE (from 202.3 to 296.2 nmol/(minml) is characteristic of “inactive” adenomyosis.

43322110 1 2 3 active adenomyosis inactive adenomyosis control Fig. 3. LE content in the blood serum of patients with adenomyosis With a pronounced increase in LE activity, there is a significant activation of nonspecific immunity, which is a reflection of an actively ongoing pathological process associated with destructive inflammatory reactions. A high level of LE activity may indicate that adenomyosis is accompanied by an inflammatory process, the intensity of which correlates with the extent and depth of the lesion, and, as a consequence, with the severity of clinical symptoms.

This increase in LE activity most often accompanies a severe destructive process in the myometrium caused by adenomyosis in patients with “active” adenomyosis.

The conducted studies confirmed the activation of the proteolysis and angiogenesis system in adenomyosis, which coincides with the opinion of T.Yu. Gavrilova (2007), who pointed out the possibility of inducing angiogenesis due to the release of proteases, especially LE, growth factors and cytokines.

In patients with various non-infectious diseases, other signs of activation of nonspecific immunity have also been identified, such as changes in the activity of 1-proteinase inhibitor (1-PI) synthesized in the liver and an increase in the concentration of proinflammatory cytokines in the blood serum. The normal activity of 1-PI is 28-IU/ml.

nmol/(min * ml) Leukocyte elastase activity. An increase in 1-PI activity parallel to LE, aimed at limiting destructive reactions, characterizes the preservation of the antiproteolytic potential; reduced 1-PI activity compared to the control is an unfavorable prognostic factor in terms of further progression of the destructive process.

The activity of LE and 1-PI in blood serum reflects the degree of activation of certain innate immune reactions, as well as the state of the antiproteolytic (compensatory potential).

In the work Adamyan L.V. et al. (2005) demonstrated the dependence of the concentration of LE in the blood and peritoneal fluid on the extent of adenomyosis, which was determined morphologically, but the relationship with the clinical picture and the severity of adenomyosis was not studied.

When studying the functional activity of 1-PI, wide variability of this indicator was noted in the range from 16 to 63 IU/ml.

It was shown that in cases where an increase in LE activity was not accompanied by an adequate compensatory increase in 1-PI activity (30.75±2.48 IU/ml), the pathological process was significantly more active. On the other hand, when 1-PI values ​​are higher than normative (more than 32 IU/ml) against the background of increased PE, there is a reserve of anti-proteolytic potential that blocks the physiological effects carried out by elastase and other proteases - in these patients the course of adenomyosis was less aggressive and the 1-PI values were 44.29±1.81 IU/ml (p

When analyzing the content of LE and 1-PI in the blood serum of 36 patients with adenomyosis 6 months after removal of the uterus, in 31 (86.1%) patients these indicators did not exceed standard values, which indicates the relationship between adenomyosis and disorders in the innate immune system .

Based on the results of the distributions of these indicators, threshold values ​​for 1-PI were determined so that both ranges (less than or greater than the threshold value) turned out to reliably distinguish between two groups with “active” and “inactive” adenomyosis.

The studied indicators above threshold concentrations prevail in patients in the group with “inactive” adenomyosis, and below threshold concentrations are significantly more common in the group with “active” adenomyosis: the proportion of patients with a 1-PI level of more than 35 IU/ml was in the group with “inactive” adenomyosis 89.3%, and with a 1-PI level less than 35 IU/ml - was 87.1% in the group with “active” adenomyosis (p

The diagnostic accuracy of determining the 1-PI threshold value is 89%.

0 1 2 3 active adenomyosis inactive adenomyosis control Fig. 4. Content of 1-PI in the blood serum of patients with adenomyosis The results obtained indicate that the selected range of 1-PI is highly informative and can be considered as a risk factor for the activity of adenomyosis, which determines the prognosis of the disease.

According to our data, all patients with adenomyosis had a significantly increased level of LE in the blood serum compared to the control group.

In parallel with this, in the group of patients with “active” adenomyosis there is a significant lack of reserve antiproteolytic potential, which manifests itself in a more pronounced clinical picture of the disease and a severe course.

Thus, a comprehensive determination of the above indicators of nonspecific immunity allows us to assess the activity of the pathological destructive process in the myometrium (adenomyosis), clarify the severity of the disease, as well as the severity of the compensatory potential. This can facilitate the timely prescription of adequate therapy, as well as the assessment of its effectiveness.

This study opens the way for possibly more effective pathogenetic treatment of adenomyosis using exogenous protease inhibitors, as well as hepatoprotectors to increase the synthesis of 1-PI.

Activity of 1PI, IU / ml Today, the drug “Eglin-S”, isolated from Hirudo medicinalis, exists abroad, which reduces the concentration of LE in the blood and is successfully used in the treatment of chronic inflammatory diseases of the lungs, joints, etc. (Desalites A., 2006 ). The centuries-old tradition of treatment with leeches is now receiving scientific confirmation of its effectiveness in the treatment of many acute and chronic diseases, including adenomyosis. The studied mechanisms of the pathogenesis of adenomyosis explain the effectiveness of hirudotherapy in the treatment of this disease.

In conclusion, it should be noted that patients with adenomyosis require special treatment at each stage of examination and treatment. The algorithm for non-invasive examination of patients with suspected adenomyosis developed in this study makes it possible to carry out early diagnosis of the disease with high accuracy, determine the degree of activity of the course of adenomyosis and timely select adequate treatment methods, which will improve the prognosis of the disease and the quality of life of patients (Fig. 5).

Complaints Medical history Gynecological examination Ultrasound of the pelvic organs Special diagnostic methods Profiling of blood serum using stage I: MALDI mass spectrometry Practical. Myoma Adenomyosis Body cancer Cancer healthy uterus uterus ovaries stage II: Definition Determination of cytokines: IL-6,10 growth factors:

(pkg/ml) VEGF, EGF (pkg/ml) > 300 IL-6 250 IL-10 300 VEGF 200 EGF 200 nmol/(min x ml) + “Active” 35 “Inactive” adenomyosis adenomyosis Unfavorable Favorable prognosis prognosis Fig. 5. Algorithm for examining patients with adenomyosis CONCLUSIONS 1. The information content of the applied methods for diagnosing adenomyosis remains insufficient: clinical diagnosis - sensitivity 51.7%, specificity 59%; Ultrasound – sensitivity 70%, specificity 68.2%; hysteroscopy - sensitivity 75%, specificity 81.2%, and only their combination increases the reliability of the study to 79.2% sensitivity and 85% specificity;

These methods do not provide the possibility of prediction, reliable verification of the process and its activity.

2. Existing post-genomic diagnostic methods, based on proteomic profiling of blood serum using MALDI mass spectrometry, can increase the accuracy of diagnosing adenomyosis to 95.8% sensitivity and 100% specificity.

3. Proteomic profiling of blood serum using MALDI mass spectrometry allows for differential diagnosis of adenomyosis with other benign and malignant gynecological diseases: specificity for uterine fibroids - 93.8%, uterine cancer - 90.5%, ovarian cancer - 100%.

4. An increase in the content of cytokines - interleukin-6 and interleukin10 in the blood serum of patients with adenomyosis indicates activation of the production of pro- and anti-inflammatory cytokines at the systemic level and positively correlates with the degree of disease activity. The threshold values ​​for interleukin are 300 pg/ml, for interleukin-10 – 250 pg/ml: exceeding these concentrations is a sign of active adenomyosis. The diagnostic accuracy is 86%.

5. Increased concentrations of growth factors - vascular endothelial and epidermal in the blood serum of patients with adenomyosis indicate activation of neovascularization and proliferation processes at the systemic level, and also positively correlate with the severity of adenomyosis.

The threshold values ​​for vascular endothelial growth factor are 300 pkg/ml, for epidermal growth factor – 2 pkg/ml: exceeding these concentrations is a manifestation of the activity of adenomyosis. The diagnostic accuracy is 86%.

6. Type 1 T-helper cells are not directly involved in the pathogenesis of adenomyosis, while type 2 T-helper cells that synthesize interleukin-6 and interleukin-10 determine effective immunity in adenomyosis. The use of these differences is possible for the differential diagnosis of pathological processes.

7. Proteolytic enzyme - leukocyte elastase and proteinase inhibitor are important diagnostic and prognostic markers for adenomyosis. The level of proteinase inhibitor 1 in the blood serum characterizes the severity of the compensatory (antiproteolytic) potential and determines the prognosis of the disease. The threshold concentration for a 1-proteinase inhibitor is 35 IU/ml:

values ​​above the threshold determine a favorable prognosis, below - an unfavorable prognosis for the course of adenomyosis. The diagnostic accuracy of the method is 89%.

8. The algorithm for examining women with suspected adenomyosis, based on proteomic profiling of blood serum using MALDI mass spectrometry, as well as determining the threshold values ​​of immunological parameters in blood serum, allows diagnosing (with 100% specificity and 95.8% sensitivity), determining the degree activity of the process (with an accuracy of 86%), predict (with an accuracy of 89%) and evaluate the effectiveness of treatment of adenomyosis.

PRACTICAL RECOMMENDATIONS 1. Diagnosis of adenomyosis, based on proteomic profiling of blood serum using MALDI mass spectrometry, allows you to most accurately establish the diagnosis of adenomyosis with 100% specificity and 95.8% sensitivity, as well as differentiate it from other benign and malignant organ diseases pelvis (uterine fibroids, uterine cancer, ovarian cancer).

2. When examining patients with adenomyosis in order to objectively assess the activity of the disease, and therefore determine management tactics, it is advisable to conduct an immunological study with the determination of cytokines (interleukins-6, 10), growth factors (vascular endothelial, epidermal), the innate immune system (leukocyte elastase, 1-proteinase inhibitor).

3. Determination of indicators of the innate immune system - leukocyte elastase and 1-proteinase inhibitor using the spectrophotometric method in dynamics is proposed to be used for prediction, early diagnosis of adenomyosis and selection of patient management tactics.

4. The use of the proposed diagnostic algorithm is advisable not only from a clinical point of view, but also from an economic point of view, because allows you to reduce the costs of a medical institution due to faster and more reliable diagnostics.

Blood serum, in which peptide markers are determined, can be stored and transported from any remote area.

List of works published on the topic of the dissertation 1. Sorokina A.V., Orazmuradova L.D., Paendi F.A. Genetic determinants of adenomyosis from the perspective of evidence-based medicine // Bulletin of RUDN, Series Medicine Obstetrics and Gynecology. – 2009. - No. 5. – pp. 197-207.

2. Radzinsky V.E., Sorokina A.V., Morozov S.G., Zhilina N.V.

Cytokines in the blood serum of patients with adenomyosis // Bulletin of RUDN University, Series Medicine, Obstetrics and Gynecology. – 2010. - No. 5. – P. 129134.

3. Sorokina A.V., Totchiev G.F., Toktar L.R. Modern approaches to the diagnosis of adenomyosis // Bulletin of RUDN University, Series Medicine, Obstetrics and Gynecology. – 2010. - No. 5. – pp. 181-191.

4. Radzinsky V.E., Sorokina A.V., Zhilina N.V., Morozov S.G.

Immunological determinants of adenomyosis from the position of evidence-based medicine // Bulletin of RUDN, Series Medicine Obstetrics and Gynecology. – 2010. - No. 6. – pp. 138-145.

5. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Arapidi G.P.

Potential proteomic markers of adenomyosis in blood serum // Doctor. – 2010. - No. 1. – pp. 61–64.

6. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Arapidi G.P.

Potential biomarkers of adenomyosis: state of the problem and possible prospects // Doctor. – 2010. - No. 8. – pp. 76–79.

7. Morozov S.G., Sorokina A.V., Zhilina N.V. The role of growth factors and cytokines in the pathogenesis of adenomyosis // Obstetrics and Gynecology. – 2010. - No. 2. – pp. 15-17.

8. Sorokina A.V., Radzinsky V.E., Morozov S.G., Zhilina N.V. Growth factors in the blood serum of patients with adenomyosis // Doctor. Ru, Part 1, Gynecology. – 2010. - No. 7 (58). – P.7-9.

9. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Arapidi G.P.

Proteomic markers of adenomyosis // Materials of the IV Regional Scientific Forum “Mother and Child” June 28-30, 2010, Ekaterinburg, p.273.

10. Sorokina A.V., Radzinsky V.E., Morozov S.G. The role of growth factors and cytokines in the diagnosis of adenomyosis // Materials of the XI All-Russian Scientific Forum “Mother and Child”, 09.28-10.1.2010, Moscow, Russia, pp.515-516.

11. Sorokina A.V., Radzinsky V.E., Ziganshin R.H., Arapidi G.P. The new approach to early diagnosis of adenomyosis // Abstract of the 5th Congress of the World Association of Reproductive Medicine, 1013.10.2010, Moscow, Russia, P.96-97.

12. Sorokina A.V., Radzinsky V.E., Ziganshin R.H., Arapidi G.P.

Peptidomic analysis of blood serum from patients with adenomyosis // Abstracts of the 13th World Congress on Controversies in Obstetrics, Gynecology and Infertility, 4-7.11.2010, Berlin, Germany, poster.

13. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Arapidi G.P.

Algorithm for diagnosing adenomyosis using non-invasive research methods // Bulletin of the National Medical and Surgical Center named after. N.I. Pirogova. – 2011. - No. 1, volume 6. – P.124-128.

14. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Arapidi G.P.

A new approach to the diagnosis of adenomyosis using proteomic profiling of blood serum // Doctor. Ru, Part 1, Gynecology. – 2011. - No. 9 (68). – P.5-8.

15. Sorokina A.V., Radzinsky V.E., Sokhova Z.M., Korsikova T.A., Ziganshin R.Kh., Arapidi G.P., Govorun V.M. Potential proteomic markers of benign diseases of the uterus in blood serum // Obstetrics and Gynecology. – 2011. - No. 3. – P.4752.

16. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Mustafina E.A., Barinov V.V., Arapidi G.P. Mass spectrometry - a new approach in the diagnosis of adenomyosis and uterine cancer // Tumors of the female reproductive system. – 2011. - No. 2. – P.65-72.

17. Sorokina A., Radzinsky V., Khamoshina M., Totchiev G., Ziganshin R., Arapidi G., Morozov S. The modern view to diagnostic of adenomyosis // Abstracts of the 11th World Congress on Endometriosis, 4-7.09 .2011, Montpellier, France, poster.

18. Sorokina A.V., Radzinsky V.E., Morozov S.G. The role of the innate immune system in the pathogenesis of adenomyosis // Materials of the All-Russian conference with international participation on gynecological endocrinology and menopause “Hormonal-associated diseases of the reproductive system: from new scientific concepts to management tactics”, 8-11.11.2011, Moscow, Russia, P.42.

19. Sorokina A.V., Radzinsky V.E., Morozov S.G. Changes in indicators of nonspecific immunity in adenomyosis // Pathological physiology. – 2011. - No. 4. – P. 8-12.

20. Sorokina A.V., Radzinsky V.E., Morozov S.G., Olimpieva S.P., Kilikovsky V.V. Criteria for assessing the activity of adenomyosis // Molecular medicine. – 2011. - No. 6. – pp. 12-17.

21. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Arapidi G.P.

Search for peptide markers of gynecological diseases in blood serum using MALDI mass spectrometry // Bulletin of RUDN, Series Medicine, Obstetrics and Gynecology. – 2011.

- No. 6. – pp. 25-29.

22. Sorokina A.V., Radzinsky V.E., Ziganshin R.Kh., Arapidi G.P.

Adenomyosis is a disease of mystery and speculation. Prospects for post-genomic research // Doctor Ru, Part 2, Endocrinology - 2011. - No. 9 (68). – pp. 18-22.

23. Andreeva E.N., Khamoshina M.B., Sorokina A.V., Plaksina N.D.

Endometriosis: new horizons of hormone-modulating therapy // Doctor Ru, Part 2, Endocrinology. – 2011. - No. 9(68). – P. 9-13.

24. Radzinsky V.E., Sorokina A.V., Gus A.I., Semyatov S.M., Butareva L.B. Textbook “Endometriosis” // Publishing house of the Russian Peoples' Friendship University, 2011. – 62 p.

Pathogenesis, prognosis and post-genomic diagnosis of adenomyosis SOROKINA ANNA VLADIMIROVNA (Russia) The work proposes to use a non-invasive two-step approach to the early diagnosis of adenomyosis. 120 patients diagnosed with adenomyosis of varying severity were examined, 50 practically healthy patients formed the control group. At the first stage, proteomic profiling of blood serum was carried out using MALDI mass spectrometry, which made it possible to differentiate patients with adenomyosis and the control group with sensitivity and specificity approaching 100%. This diagnostic method makes it possible to differentiate adenomyosis from other benign and malignant gynecological diseases - uterine fibroids, uterine cancer and ovarian cancer.

At the second stage, a study of cytokines (IL-6, IL-10) and growth factors (EGF, VEGF) in blood serum was carried out using an enzyme-linked immunosorbent assay, which made it possible to identify active forms of adenomyosis and thereby determine the prognosis of the disease.

Using spectrophotometric analysis, the state of the nonspecific immune system - leukocyte elastase (LE) and 1-proteinase inhibitor (1-PI) was studied, which made it possible to identify significant activation of the innate immune system in all patients with adenomyosis.

It has been shown that the higher the LE content in the blood serum, the more active adenomyosis occurs. Based on the concentration of 1-PI in the blood serum, which determines the degree of activity of adenomyosis, it is possible to determine the prognosis of the disease.

Informative ranges of values ​​for the listed immunological parameters were identified and, on their basis, a diagnostic algorithm was created to assess the degree of activity of adenomyosis.

The data obtained are important for determining the prognosis of the disease and clarifying the tactics of patient management.

Pathogenesis, prediction and postgenomic diagnostics of adenomyosis SOROKINA ANNA VLADIMIROVNA (Russia) The using of non-invasive methods are offered to early diagnostics of adenomyosis.

Comparative MALDI mass spectrometry profiling of blood serum samples from patients with verified adenomyosis (n=120) as well as from a control group of healthy women (n=50) has been carried out. Mass spectrometry profiles demonstrated sensitivity and specificity close to 100% for the detection of adenomyosis. Besides that, this method can lead to differentiation of adenomyosis and other gynecological diseases - leiomyoma, endometrial cancer and ovarian cancer.

On the second stage we discovered the production of cytokines (IL-6, IL-10) and growth factors (EGF, VEGF) by an enzyme-linked immunosorbent assay from women with adenomyosis. We observed that levels of IL-6, IL-10, EGF, VEGF are correlated with the severity of the disease and prognosis. Informative levels of immune markers were found and diagnostic algorithm for detecting the degree of adenomyosis activities was made.

The investigation of leukocytic elastase (LE) and 1-proteinase inhibitor (1-PI) from patients with different stage adenomyosis and in control group was found activation of innate immunity system in all the patients with adenomyosis. The degree of LE activity is a prevalence rate of adenomyosis. The degree of 1-PI activity is correlated with antiproteolytic potential that blocks the effects shown by LE. It can lead the prognosis of disease and timely treatment.

On the basis of detected pathogenic features of adenomyosis a differential attitude was worked out for the formation of the risk groups of adenomyosis progression.

Principles of early diagnosis of adenomyosis were formulated.

2

1 State Budgetary Educational Institution of Higher Professional Education "St. Petersburg State Pediatric Medical University" of the Ministry of Health of the Russian Federation

2 Federal State Budgetary Institution “Federal Medical Research Center named after V. A. Almazov” of the Ministry of Health of the Russian Federation

We studied the prevalence of gene variants of metalloproteinase-1 (MMP-1) (1G/2G) and plasminogen activator inhibitor-1 (PAI-1) (4G/5G) in patients with various clinical variants of adenomyosis to identify the significance of genetic factors in the pathogenesis of adenomyosis . The prevalence of matrix metalloproteinase-1 (MMP-1) (1G/2G) and plasminogen activator inhibitor-1 (PAI-1) (4G/5G) gene variants was assessed in 150 patients with adenomyosis. The population control group consisted of 200 residents of St. Petersburg and the Leningrad region. The results of the study showed that the presence in patients of a homozygous (2G/2G) or heterozygous (1G/2G) state of the MMP-1 gene and the combination of the 2G MMP-1 and 5GPAI-1 alleles is characteristic of the proliferating form of adenomyosis and disease progression. A molecular genetic study of changes in gene activity in patients with adenomyosis revealed a significant role of certain gene polymorphic variants of the matrix metalloproteinase gene (MMP-1) and the plasminogen activator inhibitor type 1 gene (PAI-1) in the development of various clinical forms of the disease, which showed significance in the pathogenesis adenomyosis mechanisms regulating the processes of remodeling of the extracellular matrix.

extracellular matrix.

plasminogen activator inhibitor type 1(pai-1)

Adenomyosis

matrix metalloproteinase-1 (mmp-1)

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10. Curry T.E.Jr., Osteen K.G. The matrix metalloproteinase system:

changes, regulation, and impact throughout the ovarian and uterine reproductive cycle // Endocr Rev. – 2003. – Vol. 24. – P. 428–465.

Adenomyosis is one of the most common diseases, occupying third place in the structure of gynecological pathology after inflammatory diseases and uterine fibroids. According to a number of authors, its frequency ranges from 12 to 50%. The concept of clinical manifestations, management tactics, patho- and morphogenesis of adenomyosis have been discussed in detail in the literature for decades. , however, many aspects of this problem remain poorly understood. There is practically no information about the molecular biological features of the processes of neoangiogenesis and the expression of growth factors, reflecting stromal remodeling in adenomyosis. At this stage of medical development, given the important role of matrix metalloproteinases (MMPs) in the remodeling of tissues and organs, their regulation in the reproductive organs of women is of interest. More than 20 types of MMPs are known, which carry out various stages of degradation of collagen, elastin and other extracellular matrix proteins. Among them, a special role is played by interstitial collagenase (matrix metalloproteinase-1, MMP-1), which carries out the primary degradation of collagen molecules, after which their further breakdown occurs under the influence of other MMPs, in particular, stromelysin-1 (MMP-3). Factors of the hemocoagulation system, which, as a rule, are specialized proteases that activate factors in the blood coagulation and fibrinolysis cascade, also play a significant role in the remodeling of uterine tissue. Due to this the purpose of this study was to study the prevalence of gene variants of metalloproteinase-1 (MMP-1) (1G/2G) and plasminogen activator inhibitor-1 (PAI-1) (4G/5G) in patients with various clinical variants of adenomyosis to identify the significance of genetic factors in the pathogenesis of adenomyosis .

Materials and methods. The present study included 150 patients with internal endometriosis of the uterine body. The criterion for inclusion of patients in the study was: the presence of diffuse adenomyosis in women of reproductive and perimenopausal age (based on a thorough analysis of clinical, anamnestic and instrumental diagnostic data: echographic, Doppler, hysteroscopic examination with puncture biopsy of the myometrium). The age of the patients ranged from 32 to 48 years (41±2.5 years). The duration of clinical manifestations of the disease ranged from several months to 10 years. The main symptoms of the disease were heavy and prolonged menstruation in 34 (22.7%) patients, scanty dark brown discharge before and (or) after menstruation in 97 (64.7%) women, painful menstruation in 58 (38.7%) women. examined. 73 (48.7%) patients had pelvic pain of varying intensity and 33 (22%) women had dyspareunia. Primary infertility occurred in 14 (9.3%) women, and secondary infertility in 19 (12.7%). It is known that adenomyosis is often accompanied by uterine bleeding, leading to anemia in patients. Based on the data obtained, the hemoglobin level in the range of 125-110 g/l was observed in 116 (77.3%) patients with internal endometriosis of the uterine body. A hemoglobin level of 109-100 g/l was noted by 34 (22.7%) patients with adenomyosis. When determining the size of the uterus, the following results were obtained: in 58 (38.7%) patients, the uterus corresponded to dimensions of 5-6 n.b., in 61 (40.7%) patients - 7-8 n.b., in 31 (20 .6%) women - 9-12 n.b. The average size of the uterus was 7.8 + 1.2 n.b. 49 patients underwent hysterectomy; the issue of removal of appendages was decided individually. The main indications for hysterectomy in the examined patients with adenomyosis were: uterine bleeding in 34 patients (69.4%); severe pelvic pain in 15 patients (30.6%); posthemorrhagic anemia in 34 patients (69.4%); no effect from GnRH therapy in 37 (75.5%).

Ultrasound examination of the pelvic organs was performed using an ultrasound diagnostic device SonolineG40, Siemens, using a transvaginal sensor (frequency 6.7 MHz). Ultrasound examination determined the size of the uterus, the thickness and structure of the myometrium, endometrium, and the size of the ovaries. After biometry of the uterus and ovaries, color Doppler mapping was performed, followed by assessment of blood flow velocity curves in the uterine arteries. A 100 Hz filter was used to eliminate low-frequency signals produced by vessel wall movements. The total power of Doppler radiation did not exceed 100 mW/cm2. Ultrasound examination of the pelvic organs and Doppler sonography were performed on days 20-23 of the menstrual cycle. For qualitative analysis of spectral curves of blood flow velocities, IR - resistance index was assessed. Surgical hysteroresectoscopy (Olimpys) with myometrial biopsy was performed in patients with a monopolar resectoscope loop. Areas of the myometrium in the area of ​​visualized glandular ducts were captured (in their absence, at several arbitrary points on different walls of the uterine cavity).

Morphological studies were performed in all 49 operated patients. Sections of surgical material were stained with hematoxylin-eosin and picrofuchsin to identify connective tissue. Viewing of micropreparations was carried out on a MIKMED-2 microscope; videograms were obtained using an automatic image analyzer VIDIO-TEST-2.0. When determining the functionally active and inactive types of endometrioid heterotopias, we used the morphological classification proposed by I.I. Kutsenko, which allows us to distinguish the following forms of the disease: proliferating, stable (fibrous), regressive (dystrophic).

An assessment of the prevalence of gene variants of matrix metalloproteinase-1 (MMP-1) (1G/2G) and plasminogen activator inhibitor-1 (PAI-1) (4G/5G) was carried out in 150 patients with adenomyosis. The population control group consisted of 200 residents of St. Petersburg and the Leningrad region. Genomic DNA was isolated from blood leukocytes of patients and donors using the DNA-Sorb kit (Litekh, Moscow). The type of promoter polymorphism of the MMP-1 (1G/2G), PAI-1 (4G/5G) genes was determined using allele-specific DNA polymerase chain reaction (DNA PCR). PCR products after electrophoresis were assessed in an agarose gel stained with ethidium bromide.

Statistical processing of the obtained results was carried out using commonly used methods of parametric and nonparametric statistics. Methods of descriptive statistics included assessment of the arithmetic mean (M), the mean error of the mean (m) - for characteristics with a continuous distribution; as well as the frequency of occurrence of features with discrete values. To assess intergroup differences in the values ​​of features with a continuous distribution, Student's t-test was used. Analysis of the relationship between characteristics was carried out using the Pearson r test (where r = 0.3-0.5 - moderate, r = 0.5-0.7 - significant and r = 0.7-0.9 - strongly expressed relationship ). Statistical processing of the material was carried out on a computer using a standard software package for applied statistical analysis (Statistica for Windows v. 6.0). The critical level of significance of the null statistical hypothesis (about the absence of significant differences or factor influences) was taken equal to 0.05.

Research results and discussion

Analysis of the distribution of the studied gene variants showed a high frequency of occurrence of alternative alleles of the MMP-1, PAI-1 genes in the examined patients with adenomyosis. Results were obtained indicating a high frequency of occurrence of the 1G/1G MMP-1 genotype in a group of 25 women (16.7%) who were in perimenopause and who, according to anamnesis, had an inactive course of the disease (small, stable size of the uterus, low incidence of menorrhagia). The main symptoms were scanty dark brown discharge before and/or after menstruation and algodismenorrhea. The size of the uterus in this group of patients corresponded to sizes 5-6 n.b. When analyzing Doppler characteristics of blood flow, IR in the uterine arteries averaged IR = 0.83 ± 0.01. In addition, it was found that in patients with a stable course of the disease there was an increased occurrence of the 1G/1G genotype of the MMP-1 gene, then the progress of adenomyosis was associated with a reduced frequency of this allele (p = 0.02). Molecular genetic research has established the role of hyperactive gene variants of matrix metalloproteinase-1 in the progression of adenomyosis. The presence of a homozygous (2G/2G) or heterozygous (1G/2G) state of the MMP-1 gene in 92 (61.3%) patients is associated with disease progression. The main symptoms in patients from this clinical group were heavy and prolonged menstruation and pain. The size of the uterus in 31 patients in this group of patients corresponded to sizes 9-12 n.b., in 61 patients - 7-8 n.b. When analyzing Doppler characteristics of blood flow, the IR in the uterine arteries averaged IR = 0.70 ± 0.02. When studying the frequency of occurrence of various genotypes of the PAI-1 gene in patients with different clinical courses of adenomyosis, a significant association was found between the presence of the 5G allele of the PAI-1 gene and the proliferating form of the disease (p = 0.04). When analyzing the MMP-1/PAI-1 haplotypes in the examined patients with adenomyosis, it was found that the combination of the 2G MMP-1 and 5GPAI-1 alleles correlated with the progression of the disease and was significantly more common in patients with the proliferating form of adenomyosis (p = 0.05) compared with 33 (22%) patients who had a stable or fibrous tumor. In patients who had a stable or fibrous form of the tumor, the main symptoms were: scanty dark brown discharge before and (or) after menstruation, algomenorrhea and dyspareunia. The size of the uterus in all patients in this group corresponded to sizes 5-6 n.b. When analyzing Doppler characteristics of blood flow, the IR in the uterine arteries averaged IR = 0.79 ± 0.02.

Among 49 operated patients, the 1G/1G MMP-1 genotype was present in 8 (16.3%) women who were in perimenopause, who, according to morphology, had a regressing (dystrophic) type of tumor and 10 (20.4%) patients who had a stable or fibrous form tumors that were in the reproductive period. In 31 (63.3%) operated patients with a proliferating form of adenomyosis, homozygous (2G/2G) or heterozygous (1G/2G) states of the MMP-1 gene and a combination of the 2G MMP-1 and 5GPAI-1 alleles were identified. On macroscopic examination, the uterus was round or tuberous in shape, enlarged mainly due to thickening of the posterior (61.2%) and anterior walls, due to the presence of adenomyosis. The consistency of the maca was unevenly dense in most cases. On a section in the myometrium, foci of adenomyosis looked like areas of compacted cellular structure, without a capsule and clear boundaries, representing infiltrates and cystic formations. In a number of cases, in the thickness of the myometrium there were small (0.3-0.8 cm) cavities with hemorrhagic contents. Foci of adenomyosis were represented by glandular structures of various sizes and the stroma of the surrounding gland, which was cytogenic in nature and consisted of numerous fibroblast-like cells with varying contents of collagen fibers. Characteristic was the presence of many thin-walled vessels. As a rule, the stromal component predominated over the glandular component. The predominance of the stromal component was mainly noted in the group of 31 (63.3%) patients with a clinically active manifestation, in whom the proliferating form of adenomyosis was morphologically verified. Around the foci of adenomyosis, characteristic changes in the myometrium were found: hypertrophy of myocytes, formation of perivascular growth zones, similar to those observed in fibroids. Functionally active endometrioid heterotopias were often located near heterotopias in which the epithelium had no signs of functional activity, which is consistent with the data of A.L. Unanyan. .

A molecular genetic study of changes in gene activity in patients with adenomyosis revealed a significant role of certain gene polymorphic variants of the matrix metalloproteinase gene (MMP-1) and the plasminogen activator inhibitor type 1 gene (PAI-1) in the development of various clinical forms of the disease, which showed significance in the pathogenesis adenomyosis mechanisms regulating the processes of remodeling of the extracellular matrix. The extracellular matrix, which is a supramolecular complex that forms the extracellular environment, influences the differentiation, proliferation, organization and attachment of cells. It includes interstitial collagen, proteoglycans, fibronectin, laminin and other large molecular compounds. During tumor growth in the myometrium, changes in the expression of a number of extracellular matrix genes occur, which leads to increased accumulation of collagen and mucopolysaccharides. The ultrastructure of collagen fibrils in adenomyosis tissue has an atypical structure, orientation and differs from normal myometrial tissue. Matrix metalloproteinases are involved in the processes of collagen remodeling in tumor tissues, carrying out various stages of degradation of collagen, elastin and other extracellular matrix proteins. Polymorphism of regulatory regions of physiologically significant genes significantly changes the transcriptional activity of genes, the production of mRNA and specific proteins, which leads to increased gene activity. Our study established the role of hyperactive gene variants of matrix metalloproteinase-1 in the development of clinically active forms of adenomyosis. The presence in patients of a homozygous (2G/2G) or heterozygous (1G/2G) state of the MMP-1 gene is associated with an increased tendency to tumor dissemination and, consequently, to the development of disease progression. On the contrary, carriage of the low-active 1G allele (genotype 1G/1G) plays a protective role in the development of clinically active forms of adenomyosis. When carrying the 2G allele, patients experience more active production of the MMP-1 proenzyme, this leads to activation of collagenolysis and increases the likelihood of endometrial cell invasion into adjacent areas with their subsequent ectopic growth. In addition, the processes of neoangiogenesis, which play an important role in the pathogenesis of adenomyosis and uterine fibroids, progress with increased activity of matrix metalloproteinases. By participating in the processes of matrix degradation during tissue growth, they thereby form spaces for the germination of new capillaries in the intercellular matrix, providing nutrition to new growths. Hemocoagulation factors, which are specialized proteases that activate factors in the blood coagulation and fibrinolysis cascade, also play a significant role in the remodeling of myometrial tissue. The results of our study of the polymorphism of the plasminogen activator inhibitor type 1 (PAI-1) gene showed the importance of the presence of the 5G allele, characterized by moderate transcription and, consequently, a low level of PAI-1 induction, in the development of clinically significant forms of adenomyosis. In addition, a correlation was found between disease progression and the presence of the 2GMMP-1/5GPAI-1 allele association in patients. The role of these polymorphic variants in the pathogenesis of clinically significant forms of the disease is associated with changes in fibrinolysis processes. The presence of the 5G allele of the PAI-1 gene is characterized by low protein expression and, thus, the production of plasmin is inhibited to a lesser extent, which leads to increased formation of active matrix metalloproteinase-1 from its precursor.

Conclusions

Thus, a molecular genetic study of changes in gene activity in patients with adenomyosis revealed a significant role of certain gene polymorphic variants of the matrix metalloproteinase gene (MMP-1) and the plasminogen activator inhibitor type 1 (PAI-1) gene in the development of various clinical forms of the disease, which showed the importance in the pathogenesis of adenomyosis of the mechanisms regulating the processes of remodeling of the extracellular matrix. The presence in patients of a homozygous (2G/2G) or heterozygous (1G/2G) state of the MMP-1 gene and the combination of the 2G MMP-1 and 5GPAI-1 alleles is characteristic of the proliferating form of adenomyosis and the progression of the disease. Determination of polymorphic gene variants of MMP-1 and PAI-1 can be used to predict the course of the disease.

Bibliographic link

Arutyunyan A.F., Gaidukov S.N., Kustarov V.N. SIGNIFICANCE OF GENETIC FACTORS IN THE PATHOGENESIS OF ADENOMYOSIS // Modern problems of science and education. – 2016. – No. 3.;
URL: http://site/ru/article/view?id=24830 (access date: 11/04/2019).

We bring to your attention magazines published by the publishing house "Academy of Natural Sciences"

INTRODUCTION

CHAPTER 1 LITERATURE REVIEW

1.1 Epidemiology of endometriosis

1.2 Theories of the development of adenomyosis

1.3 The role of estrogen metabolites in the mechanisms of occurrence of hormone-dependent human tumors and endometriosis

1.4 Genetic aspects of adenomyosis

1.4.1 Polymorphism of estrogen metabolism genes in women

with adenomyosis

1.4.2 Expression of genes for steroid receptors ERa and ER/I, PgR, AE

and SUR 19 for adenomyosis

1.5 Clinical and anamnestic features of patients with adenomyosis

CHAPTER 2 MATERIAL AND METHODS OF CLINICAL STUDY

2.1 Study design

2.2 Brief description of the research object

2.3 Methods and scope of clinical, instrumental and laboratory studies

2.3.1 Clinical examination methods

2.3.2 Instrumental research methods

2.3.3 Laboratory research methods

2.3.4 Statistical data processing

CHAPTER 3 FREQUENCY OF ADENOMYOSIS, CLINICAL AND ANAMNESTIC FEATURES OF PATIENTS WITH ADENOMYOSIS

3.1 Frequency of adenomyosis in gynecological patients

3.2 Clinical and anamnestic features of patients with adenomyosis

CHAPTER 4 MOLECULAR GENETIC FEATURES OF PATIENTS WITH ADENOMYOSIS

4.1 Analysis of allelic variants of the cytochrome P450 genes: CYP 1A1, CYP 1A2, CYP 19, LbT 1A1 in women with adenomyosis

4.2 Expression of genes for steroid receptors ERA, ER.fi, PgR, AE and CYP 19 (aromatase) in endometriosis

CHAPTER 5 RISK FACTORS AND COMPLEX SYSTEM FOR PREDICTING THE DEVELOPMENT OF ADENOMYOSIS

5.1 Risk factors for adenomyosis

5.2 Computer program for predicting adenomyosis

5.3 Comparative assessment of the information content of risk factors, computer programs and molecular genetic markers in forecasting

development of adenomyosis

LIST OF ABBREVIATIONS

REFERENCES

Recommended list of dissertations

• Endometrial cancer: molecular genetic and hormonal-metabolic features, prognosis in a antenatal clinic 2008, Candidate of Medical Sciences Ilenko, Elena Vladimirovna

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Introduction of the dissertation (part of the abstract) on the topic “Adenomyosis: prognosis, clinical, anamnestic and molecular genetic features”

INTRODUCTION

Relevance. Endometriosis continues to be one of the pressing problems of modern gynecology. More than a century ago, the first reports of endometriosis appeared, but some aspects of the etiology, pathogenesis, clinical, morphofunctional, immunological, biochemical, and genetic variants of this disease continue to attract scientific researchers. Many issues have been studied, but the relevance of this problem does not decrease.

According to world statistics, genital endometriosis is diagnosed in 7 - 50% of women of childbearing age.

The most common localization of genital endometriosis is damage to the uterus - adenomyosis, the specific frequency of which reaches 70-80%. In 55 - 85% of patients, internal endometriosis is combined with uterine fibroids, about half suffer from infertility. The rapid development of medical technologies in recent decades has made it possible to increase the accuracy of diagnosis of endometriosis, but it remains insufficient, especially in cases of I-II degree of prevalence of the disease.

Endometriosis is an estrogen-dependent, chronic disease characterized by the location of the endometrium outside its normal localization, with signs of inflammation, and the presence of the phenomenon of peripheral and central sensitization. Endometriosis has many of the hallmarks of a benign neoplastic process and the potential for malignant transformation.

More than ten theories of its origin have been proposed, but none of them can explain all the mystery of the forms and manifestations of this disease. All this makes it difficult to develop preventive measures and

early diagnosis, effective methods of treatment and prevention of severe complications of endometriosis.

According to modern concepts, endometriosis is an independent nosological unit (endometrioid disease) - a chronic condition with different localization of endometriotic foci, characterized by autonomous and invasive growth, changes in the molecular biological properties of cells of both ectopic and eutopic endometrium. In modern literature, there are discussions about the legality of using this terminology in relation to endometriosis.

Heterotopies of internal genital endometriosis are considered as derivatives of the basal layer of the endometrium, and not as a functioning one, as in the translocation theory of “true endometriosis”. Recently, data have begun to appear on the commonality of endometriosis and adenomyosis, their origin, the similarity of mechanisms that support the existence of heterotopias and their ability to progress.

In the pathogenesis of endometriosis, the genetic concept of origin is increasingly being studied, which is based on the presence of familial forms of the disease, frequent combination with malformations of the urogenital tract and other organs, as well as features of the course of endometriosis (early onset, severe course, relapses, resistance to treatment) in hereditary forms of the disease. Verification of specific genetic markers will allow us to identify genetic predisposition to this disease, carry out early diagnosis and prevention at the preclinical stage of the disease. All this makes it promising to study the molecular biological features of eutopic and ectopic endometrium: expression of estrogen and progesterone receptors, markers of proliferation, apoptosis, adhesion, angiogenesis, cell invasion.

Degree of development of the research topic

Candidate genes for the development of endometriosis have been studied: genes of the cytokinase system and inflammatory response: CCR2, CCR5, CTLA4, IFNG, IL4, IL6 and many others; detoxification: AhR, AhRR, ARNT, CYP17A1, CYP19A1, CYP1A1, CYP1B1, GSTM1, etc., apoptosis and angiogenesis; CDKN1H, HLA-A, HLA-B, HLA-C2, etc.

Cytochrome P450 genes: CYP1A1 (A2455G (Ile462Val)), CYP2E1 (C9896G), CYP19 (TTTA) and del (TST) - in endometriosis were studied only in a few studies [Shved N.Yu., 2006, Montgomery et al, 2008], There are no studies that evaluate the prognostic significance of these polymorphisms.

Currently, a large number of studies have been carried out to determine risk factors for proliferative processes, but there are no informative computer programs adapted to practical healthcare for predicting these diseases among a population of women of different age groups; The prognostic capabilities of genetic and hormonal research methods have not been sufficiently studied.

Thus, the study of the characteristics of estrogen metabolism and their genetic determinants, a comparative assessment of the information content of various methods for predicting internal genital adenomyosis in women of different age groups will allow a more differentiated approach to the formation of risk groups for appropriate prevention.

The purpose of the study is to develop a comprehensive system for predicting the development of adenomyosis based on the assessment of clinical and anamnestic data and the determination of molecular genetic markers.

Research objectives:

1. To determine the frequency of adenomyosis in gynecological patients who have undergone hysterectomy, to analyze the clinical and anamnestic features of women with adenomyosis.

2. Assess the frequencies of alleles of variants of genes encoding enzymes of estrogen metabolism: CYP1A1, CYP1A2, CYP19, SULT1A1 in patients with adenomyosis and women without proliferative diseases of the uterus.

3. Assess the level of expression of the genes for estrogen, progesterone and androgen receptors: ERa, ERft, PgR, AR and CYP19 in the tissues of the ectopic and eutopic endometrium in women with adenomyosis and in patients without proliferative diseases of the uterus.

4. Establish risk factors for the development of adenomyosis, develop and implement a computer program for predicting adenomyosis, based on the analysis of clinical and anamnestic data.

5. Assess the information content of a computer program and molecular genetic markers in predicting adenomyosis.

Scientific novelty

The frequency of morphologically verified adenomyosis in gynecological patients was established, which was 33.4%. It was revealed that adenomyosis is recorded in isolation only in 17.9%. The most common combination is with uterine leiomyoma and endometrial hyperplastic processes - in 40.4%, with uterine leiomyoma - in 31.4%, simple endometrial hyperplasia without atypia - in 10.4%.

The understanding of the pathogenesis of adenomyosis has been expanded. It was revealed that patients with histologically verified adenomyosis have certain features of polymorphism of estrogen metabolism. Women with adenomyosis are characterized by the presence of a mutant allele C of the CYP1A1 gene and genotypes T/C and C/C, allele A of the CYP1A2 gene, genotypes A/A, C/A and C/C, allele T of the CYP19 gene and genotypes C/T and T /T and, on the contrary, a decrease in the frequency of occurrence of the mutant allele and the heterozygous and mutant homozygous genotype of the CYP1A2 gene. It was also noted that among patients

with adenomyosis, the proportion of homozygotes T/T of the CYP1A1 gene is lower than in the comparison group, the frequency of occurrence of genotypes A/A of the CYP1A2 gene is statistically lower relative to the comparison group.

It was shown for the first time that patients with adenomyosis are characterized by an increase in the expression of the EPR gene by 1.5-4.5 times, a decrease in the expression of ERAa by 1.4-13.3 times and PgR by 2.2-7.7 times in the ectopic endometrial tissue relative to eutopic endometrial tissue in women without proliferative diseases.

Practical significance

The main clinical and anamnestic features of patients with adenomyosis were determined. It has been established that women suffering from adenomyosis complain of heavy (94.8%) and painful (48.5%) menstruation on average from 38.5 ± 0.7 years, the time interval from the onset of symptoms of the disease to seeing a doctor is 5.3±0.4 years, while treatment for adenomyosis is prescribed to only 10% of women, and surgical treatment is carried out 7.2±0.3 years after treatment and 12.5 years after the appearance of the first symptoms of the disease. Anamnestic features of patients with adenomyosis are a high frequency of extragenital diseases: obesity (66%) and hypertension (58.5%), as well as gynecological diseases: uterine fibroids (35.6%) and endometrial hyperplasia (48.3%); high frequency of abortion by induced abortion (72.5%) and a family history of cancer of the reproductive system (4.9%).

Risk factors for the development of adenomyosis have been established: obesity, a family history of malignant diseases of the reproductive system in the female line, the presence of menstruation, the use of intrauterine contraception, a history of abortion and curettage of the uterine cavity; their prognostic significance was determined.

It was revealed that the clinical and anamnestic indicator with the greatest sensitivity in predicting adenomyosis is the presence of a history of diagnostic curettage of the uterine cavity (90.7%), and the greatest specificity is the presence of an induced abortion (92.2%).

A comprehensive system for predicting the development of adenomyosis has been developed, including a computer program based on the assessment of clinical and anamnestic data and the assessment of molecular genetic markers. The computer program “Forecasting the development of adenomyosis” was developed using the logistic regression method and allows predicting the development of the disease with a probability of 99%. The sensitivity of the program is 85.8%, specificity is 89.9%. The information content of molecular genetic research methods has been established. It has been shown that a comprehensive determination of genetic markers of estrogen metabolism: SUR1A1, StA2, SUR 19, BSHTY! - has a sensitivity of 86.7% and a specificity of 90.6% and can be used to predict the development of adenomyosis in adolescents and young women in order to form groups at increased risk for developing the disease for preventive measures.

Implementation of results in practice

Based on the study, methodological recommendations “Adenomyosis: molecular genetic features, risk factors and prognosis” were developed; approved by the Department of Health of the Kemerovo Region (implementation act dated March 11, 2013), introduced into the practice of medical institutions (implementation act dated March 12, 2013) and the educational process of the departments of obstetrics and gynecology No. 1 and 2 of the State Budgetary Educational Institution of Higher Professional Education of the Kemerovo State Medical Academy of the Ministry of Health of Russia (implementation act dated March 12, 2013).

Provisions for defense:

1. The incidence of adenomyosis in gynecological patients undergoing hysterectomy is 33.4%. The main clinical symptoms of the disease are heavy and painful menstruation. Patients with adenomyosis have certain anamnestic features: a high frequency of extragenital and gynecological diseases, abortions, intrauterine contraception, and a family history of cancer of the reproductive system. Patients with adenomyosis are characterized by late diagnosis of the disease, conservative treatment is prescribed to only 10% of women, the duration of the disease from the appearance of the first complaints to surgery averages 12.5 ± 0.4 years.

2. The molecular genetic characteristics of patients with adenomyosis is the presence of a mutant allele C of the SURA 1 gene (OR=3.69; P<0,001) генотипа Т/С (0111=3,43; Р<0,001) и С/С (ОШ=36,8; Р<0,001), мутантного аллеля А гена СУР1А2 (0ш=0,41; Р<0,001) генотипов А/А (0111=0,12; Р<0,001) и С/А (0ш=0,34; Р<0,001), мутантного аллеля Т гена СУР19 (ОШ = 4,14; Р<0,001) и генотипов С/Т (ОШ=4,14; Р<0,001) и Т/Т (ОШ= 15,31; Р<0,001); а также повышение экспрессии гена ЕВ.р в 1,5-4,5 раза, снижение экспрессии ЕЯа в 1,4-13,3 раза и PgR в 2,2-7,7 раза в тканях эндометриоидных гетеротопий относительно эндометрия женщин группы сравнения.

3. The developed complex system for predicting adenomyosis includes a computer program based on the assessment of 6 clinical and anamnestic risk factors (obesity, family history of malignant diseases of the reproductive system, the presence of menstruation, intrauterine contraception, abortion and curettage of the uterine cavity) and the determination of molecular genetic markers. The computer program is highly informative, has

sensitivity 85.8%, specificity - 89.9%. A comprehensive assessment of polymorphisms of the CYP1A1, CYP1A2, CYP19 and SULT1A1 genes in predicting the development of adenomyosis has a sensitivity of 86.7% and a specificity of 90.6%.

Approbation of dissertation material. The main provisions of the work were presented at the XI International Congress on Endometriosis (Montpellier, France, 2011), XII All-Russian Scientific Forum “Mother and Child” (Moscow, Russia, 2011), Kemerovo Regional Day of Obstetrician-Gynecologist Specialist (Kemerovo, 2011), XVI International scientific and practical conference “From assumption - to establishing the truth” (Russia, Kemerovo, 2012), XV World Congress on Human Reproduction (Italy, Venice, 2013), XVII International scientific and practical conference “Conceptual approaches to solving reproductive problems” ( Russia, Kemerovo, 2013), discussed at the interdepartmental meeting of the departments of obstetrics and gynecology No. 1, No. 2 of the State Budgetary Educational Institution of Higher Professional Education of the Kemerovo State Medical Academy of the Ministry of Health.

Scope and structure of the dissertation

The dissertation is presented on 145 sheets of typewritten text and consists of 5 chapters, discussions, conclusions, practical recommendations, and a list of references. The work is illustrated with 39 drawings and 22 tables. The bibliographic list consists of 238 sources (101 domestic and 137 foreign).

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Conclusion of the dissertation on the topic “Obstetrics and Gynecology”, Zotova, Olga Aleksandrovna

1. The frequency of adenomyosis among patients undergoing hysterectomy is 33.4%; adenomyosis occurs alone in 17.9% of cases, in combination with uterine fibroids - in 31.4%, endometrial hyperplasia - in 10.4%. These patients are characterized by heavy (94.8%) and painful (48.5%) menstruation on average from 38.5 ± 0.7 years, only 10% of women receive treatment for adenomyosis, and the time interval from the onset of symptoms of the disease to surgical Treatment averages 12 years. Anamnestic features of patients with adenomyosis are a high frequency of obesity (66%), hypertension (58.5%), history of medical abortion (72.5%), use of an IUD (45.8%), family history of cancer of the reproductive system (4.9%).

2. Patients with adenomyosis have a higher frequency of occurrence of the mutant allele C of the CYP1A1 gene (30%) (OR = 3.69; P<0,001) генотипа Т/С (42,4 %) (ОШ = 3,43; Р<0,001) и С/С (8,8 %) (ОШ = 36,8; Р<0,001), мутантного аллеля А гена CYP1A2 (51,2%) (ОШ = 0,41; Р<0,001) генотипов А/А (27,1 %) (ОШ=ОД2; Р<0,001) и С/А (0ш=0,34; Р <0,001), мутантного аллеля Г гена CYP19 (20%) (ОШ = 4,14; Р<0,001) и генотипов С/Т (31,8%) (0111=4,14; Р<0,001) и Т/Т (ОШ= 15,31; Р<0,001); более низкую частоту гомозигот Т/Т гена CYP1A1 (48,8 %), генотипов А/А (27,1%) гена CYP1A2 и С/А (ОШ=0,34; Р<0,001) относительно группы сравнения.

3. Patients with adenomyosis are characterized by an increase in the expression of the ERß gene by 1.5 - 4.5 times, a decrease in the expression of ERa by 1.4 - 13.3 times and PgR by 2.2 - 7.7 times in endometrioid heterotopias relative to endometrial tissue in women from the comparison group.

4. Factors, the totality of which determines the possibility of developing adenomyosis, are a history of curettage of the uterine cavity (0111=106.7), obesity (OR=11.0), a history of abortion (OR=7.8), use of intrauterine contraception (OR=6.1), family history of malignant diseases of the reproductive system (OR=3.9), presence of menstruation (OR=2.2). The indicator with the greatest sensitivity in predicting adenomyosis is a history of diagnostic curettage of the uterine cavity (90.7%), and the highest specificity is induced abortion (92.2%).

5. The computer program “Predicting Adenomyosis”, developed using the logistic regression method, makes it possible to predict the development of adenomyosis in 99% of cases. The sensitivity of the program in an independent sample is 85.8%, specificity is 93.3%. Isolated assessment of polymorphisms of individual genes CYP1A1, CYP1A2, CYP19, SUT1A1 has a sensitivity of 68.6-79.8% and low specificity - 6.9-23.4%. A comprehensive assessment of polymorphisms of these genes has a high sensitivity of 86.7% and specificity of 90.6% in predicting adenomyosis.

1. If the patient has complaints of heavy and/or prolonged menstruation, adenomyosis should be included in the differential diagnosis.

2. To prevent adenomyosis, controllable risk factors should be avoided: intrauterine interventions (surgical abortions and curettage of the uterine cavity), as well as the use of intrauterine contraception.

3. To carry out preventive measures and a differentiated approach to the formation of a risk group for the development of adenomyosis, it is advisable to use the developed computer program “Prediction of internal genital endometriosis (adenomyosis)” in women over 33 years of age.

4. Comprehensive assessment of allelic variants of the genes CYP1A1 (allele C and genotype T/C, C/C), CYP1A2 (allele A, genotypes A/A, C/A, C/C), CYP19 (allele T, genotypes C/T and T/T), SULT1A1 (allele A, genotypes A/G and A/A) in adolescents and young women at risk may be useful for predicting the development of adenomyosis for preventive measures.

List of references for dissertation research Candidate of Medical Sciences Zotova, Olga Aleksandrovna, 2013

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